发明内容 DISCLOSURE

本发明涉及式I.的化合物、它们的N-氧化物和农业上适用的盐 The present invention relates to compounds of formula I., their N- oxides and agriculturally suitable salts

其中 Among them

A和B独立地为O或S; A and B are independently O or S;

R1为H、C1-C6烷基、C2-C6烷氧羰基或C2-C6烷基羰基； R1 is H, C1-C6 alkyl, C2-C6 alkoxycarbonyl or C2-C6 alkylcarbonyl group;

R2为H或C1-C6烷基； R2 is H or C1-C6 alkyl;

R3为H; C1-C6烷基、C2-C6链烯基、C2-C6炔基或C3-Cs环烷基，它们各自任选地被一个或多个选自以下的取代基取代：卤素、CN、NO2,羟基、C1-C4烷基、C1-C4烷氧基、C1-C4卤烷氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、C2-C6烷氧羰基、C2-C6烷基羰基、C3-C6三烷基甲硅烷基、苯基、苯氧基、5元杂芳环和6元杂芳环；苯基、苯氧基、5元杂芳环和6元杂芳环各自任选地被I至3个独立地选自以下的取代基取代：C1-C4烷基、C2-C4链烯基、C2-C4炔基、C3-C6环烷基、C1-C4S烷基、C2-C4卤链烯基、C2-C4卤炔基、C3-C6卤环焼基、卤素、CN、NO2, C1-C4炼氧基、C1-C4卤烷氧基、 R3 is H; C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-Cs cycloalkyl, each optionally substituted with one or more substituents selected from the following substituents: halogen, CN, NO2, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl , C2-C6 alkoxycarbonyl, C2-C6 alkylcarbonyl group, C3-C6 trialkylsilyl, phenyl, phenoxy and 5-membered heteroaromatic ring, and 6-membered heteroaromatic ring; a phenyl group, a phenoxy group 5-membered heteroaromatic ring and a 6-membered heteroaromatic ring optionally substituted with I to 3 independently selected substituents: C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C1-C4S alkyl, C2-C4 halo alkenyl, C2-C4 haloalkynyl group, C3-C6 cycloalkyl firing halogen group, halogen, CN, NO2, C1-C4 alkoxy refining, C1 -C4 haloalkoxy,

9基、C2-C8 二烷基氨基、C3-C6环烷基氨基、C4-C8(焼基X环烷基)氨基、C2-C4烷基羰基、C2-C6烷氧羰基、C2-C6烷基氨基羰基、C3-C8 二烷基氨基羰基和C3-C6三烷基甲硅烷基；C1-C4烷氧基；C1-C4烷基氨基；C2-C8 二烷基氨基；C3-C6环炼基氨基；C2-C6烷氧羰基或C2-C6踪基羰基； 9 group, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C4-C8 (firing group X cycloalkyl) amino, C2-C4 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkyl aminocarbonyl group, C3-C8 dialkylaminocarbonyl group, and C3-C6 trialkylsilyl group; C1-C4 alkoxy; C1-C4 alkylamino; C2-C8 dialkylamino; C3-C6 cycloalkyl refining amino; C2-C6 alkoxycarbonyl or C2-C6-ylcarbonyl track;

R4为H、C1-C6烷基、C2-C6链稀基、C2-C6炔基、（：3-(：6环烷基、C1-C6卤烷基、CN、卤素、C1-C4烷氧基、C1-C4卤烷氧基或NO2; R4 is H, C1-C6 alkyl, C2-C6 dilute chain group, C2-C6 alkynyl, (: 3 - (: 6 cycloalkyl, C1-C6 haloalkyl, CN, halogen, C1-C4 alkoxy group, C1-C4 haloalkoxy or NO2;

R5为H、C1-C6烷基、C1-C6卤烷基、CrC4烧氧基烷基、CrC4羟基烷基、C(O)R' CO2R1' C(O)NR10R11,卤素、C1-C4烷氧基、CrC4卤烷氧基、NRWRU、N(R11)C(O)R1' N(R11)CO2Rw 或S(O)nR12; R6为H、C1-C6烷基、C1-C6卤烷基、卤素、CN、C1-C4烷氧基或C1-C4 1¾炼氧基； R5 is H, C1-C6 alkyl, C1-C6 haloalkyl, CrC4 burning alkoxyalkyl, CrC4 hydroxyalkyl, C (O) R 'CO2R1' C (O) NR10R11, halogen, C1-C4 alkoxy group, CrC4 haloalkoxy, NRWRU, N (R11) C (O) R1 'N (R11) CO2Rw or S (O) nR12; R6 is H, C1-C6 alkyl, C1-C6 haloalkyl, halo , CN, C1-C4 alkoxy or C1-C4 1¾ refining group;

R7S C1-C6烧基、C2-C6链烯基、C2-C6炔基、C3-C6环烷基、C1-C6卤烷基、C2-C6 _链烯基、C2-C6齒炔基或C3-C6齒环烷基；或 R7S C1-C6 burn group, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 _ alkenyl, C2-C6 alkynyl or C3 teeth Tooth -C6 cycloalkyl; or

R7为苯基环、苄基环、5或6元杂芳环、萘基环体系或芳香性8、9或10元稠合杂双环体系，每个环或环体系任选地被I至3个独立地选自R9的取代基取代； R7 is a phenyl ring, benzyl ring, a 5- or 6-membered heteroaromatic ring, naphthyl ring system or an aromatic 8, 9 or 10-membered fused heterobicyclic system, each ring or ring system optionally substituted by I to 3 R9 independently selected substituents;

R8为H、C1-C6烷基、C1-C6卤烷基、卤素、C1-C4烷氧基或C1-C4卤烷氧基； R8 is H, C1-C6 alkyl, C1-C6 haloalkyl, halo, C1-C4 alkoxy or C1-C4 haloalkoxy;

每个R9独立地为C1-C4烷基、C2-C4链烯基、C2-C4炔基、C3-C6环烷基、C1-C4 ή烷基、C2-C4商链烯基、C2-C4卤炔基、C3-C6卤环烷基、卤素、CN、NO2, C1-C4烷氧基、C1-C4卤烷氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酷基、C1-C4烷基氨基、C2-C8 二烷基氨基、C3-C6环烷基氨基、C4-C8(烷基)(环烷基)氨基、C2-C4烷基羰基、C2-C6烷氧羰基、C2-C6烷基氨基羰基、C3-C8 二烷基氨基羰基或CrC6二焼基甲桂院基；Rn为H或C1-C4烷基； Each R9 is independently C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C1-C4 ή alkyl, C2-C4 alkenyl Suppliers, C2-C4 halo alkynyl, C3-C6 halo cycloalkyl, halo, CN, NO2, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1 Cool -C4 alkyl sulfo group, C1-C4 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C4-C8 (alkyl) (cycloalkyl) amino, C2-C4 alkyl carbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl group or a methyl group CrC6 two firing Guiyuan Ji; Rn is H or C1-C4 alkyl;

R12为CrC4烷基或C1-C4 S烷基；且n为O、I或2。 R12 is CrC4 alkyl or C1-C4 S-alkyl; and n is O, I, or 2.

本发明提供保护繁殖体或从其生长的植物免受无脊椎害虫侵害的方法。 The present invention provides for the protection of propagules or plant grown from an invertebrate pests method thereof. 该方法包括使该繁殖体或该繁殖体的场所与生物有效量的式I的化合物、其N-氧化物或其农业上适用的盐接触。 Which comprises reacting a compound of formula I and biological properties of the propagules or the propagules effective amount of salt thereof applicable on their N- oxide or agriculture.

本发明还提供一种繁殖体，其包含生物有效量的式I的化合物、其N-氧化物或其农业上适用的盐。 The present invention also provides a propagule, a biologically effective amount of a compound of formula I, which comprises, salts of N- oxides thereof, or agriculture.

本发明进一步提供一种繁殖体，其与生物有效量的式I的化合物、 其N-氧化物或其农业上适用的盐接触。 The present invention further provides a propagules with a biologically effective amount of a compound of formula I, salt thereof applicable on their N- oxide or agriculture.

本发明还进一步提供用于涂覆繁殖体的无脊椎害虫防治组合物，其包含生物有效量的式I的化合物、其N-氧化物或其农业上适用的盐，以及成膜剂或粘合剂。 The present invention still further provides an invertebrate pest control composition for coating a propagule, the biologically effective amount of a compound of formula I, which comprises, N- oxide thereof or an agriculturally suitable salt thereof, and a film former or adhesive agent.

具体实施方案 Specific embodiments

在本发明的说明书和权利要求书中'所提到的术语“繁殖体”指种子或可再生的植物部分。 In the description and claims of the present invention requires' term referred to "propagule" means a seed or plant part may be reproduced. 术语“可再生的植物部分”指除种子外的植物部分，当将该植物部分置于园艺或农业生长介质中时，整个植物可以生长或再生，所述生长介质如湿润的土壤、泥煤苔、沙子、蛭石、珍珠岩、矿毛绝缘纤维、玻璃丝、椰子壳纤维、椤纤维等，或者甚至是完全液态的介质如水。 The term "renewable plant parts" means parts of the plant except the seeds, when gardening or agriculture growth medium when the plant part is placed, the entire plant can grow or regenerate, such as the growing medium moist soil, peat moss , sand, vermiculite, perlite, mineral wool insulation fiber, glass fiber, coir, fern fiber, or even completely liquid medium such as water. 可再生的植物部分通常包括地下芽植物品种如马铃薯、甘薯、山药、洋葱、大丽花、郁金香、水仙等的根茎、块茎、鳞茎和球茎》可再生的植物部分包括被分开(例如切割)以保持它们长成新植物的能力的植物部分。 Renewable plant parts generally include underground bud plant species such as potato, sweet potato, yam, onion, dahlias, tulips, daffodils and other roots, tubers, bulbs and corms "plant parts, including renewable separated (such as cutting) to keep them Plants grow into some of the new plant capacity. 因此可再生的植物部分包括根茎、块茎、鳞莲和球茎的活的分割部分，它们保留有分生组织，如芽眼。 Therefore, renewable plant parts including live divided portion rhizomes, tubers and bulbs lotus scales, they retain partakers Health Organization, such as the buds. 可再生的植物部分还可以包括其它植物部分，如切割或分离的茎和 Regenerable plant parts can also include other plant parts such as cut or separated stems and

11叮，四乙驭;tCf土 渺/Λ'匕1丨一竺徂初06W。 11 bite, tetraethyl Yu; tCf soil vague / Λ 'a dagger 1 Shu Zhu CU beginning 06W. 仕半及明的说明书和权利要求书中所提及的，除非另外指明的术语“种子”包括未发芽的种子和外种皮(种子包被)仍部分包裹着显露的幼芽和根的发芽的种子。 Shi Ming half the book and the specification and claims mentioned, unless otherwise specified term "seed" includes not germinating seeds and testa (seed coat) still partially wrapped around exposed roots and shoots sprout seed.

在上面的陈述中，术语“烷基”，单独使用或在组合词，如“烷硫基”或“卤烷基”中使用，包括直链或支链院基，如甲基、乙基、正丙基、异丙基或不同的丁基、戊基或己基异构体。 In the above statement, the term "alkyl", alone or in a combination of words such as "alkylthio" or "haloalkyl", including straight-chain or branched hospital groups such as methyl, ethyl, n-propyl, isopropyl or the different butyl, pentyl or hexyl isomers. “链烯基”包括直链或支链烯，如I-丙稀基、2-丙烯基和不同的丁烯基、戊烯基和己烯基异构体。 "Alkenyl" includes straight-chain or branched alkenyl, e.g. I- propenyl, 2-propenyl and the different butenyl, pentenyl and hexenyl isomers. “链稀基〃也包括多烯，如i，2-丙二烯基和2,4-己二烯基。“炔基”包括直链或支链炔，如I-丙炔基、2-丙炔基和不同的丁炔基、戊炔基和己炔基异构体。“炔基”也可以包括含有多个三键的基团，如2,5-己二炔基。“烷氧基”包括，例如甲氧基、乙氧基、正丙氧基、异丙氧基和不同的丁氧基、戊氧基和己氧基异构体》“炼氧基烷基”指烷基上有烷氧基取代。“烷氧基烷基”的实例包括CH3OCH2、CH3OCH2CH2' CH3CH2OCH2、CH3CH2CH2CH2OCH2 和CH3CH2OCH2CH2。“烷硫基”包括支链和直链烷硫基，如甲硫基、乙硫基和不同的丙硫基、丁硫基、戊硫基和己硫基异构体。“环烷基”包括，例如，环丙基、环丁基、环戊基和环己基。 "Dilute chain polyene group 〃 including, e.g. i, 2- allenyl group and 2,4-hexadiene." Alkynyl "includes straight-chain or branched alkynyl, such as propynyl I-, 2- propynyl and the different butynyl, pentynyl and hexynyl isomers. "alkynyl" may also include groups containing more triple bonds, such as 2,5-hexadiynyl. "alkoxy "includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy and the different butoxy, pentoxy and hexyloxy isomers." "refining alkoxyalkyl" refers to an alkyl group has alkoxy. Examples of the "alkoxyalkyl" include CH3OCH2, CH3OCH2CH2 'CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2. "alkylthio" includes both branched and straight-chain alkyl group, such as methylthio, ethylthio, and the different The propylthio, butylthio, pentylthio and hexylthio isomers. "cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

术语“杂环”或“杂环体系”指环或环体系，其中至少一个环原子不是碳，并含有1-4个独立地选自氮、氧和硫的杂原子，条件是每个杂环含有不多于4个氮原子，不多于2个氧和不多于2个硫原子。 The term "heterocycle" or "heterocyclic system" ring or ring system, wherein at least one ring atom is not carbon, and containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur atoms, provided that each heterocyclic ring contains more than four nitrogen atoms, not more than 2 oxygen and no more than two sulfur atoms. 杂环可以通过取代任何存在的碳或氮上的氢而与所述的碳或氮相连。 Heterocyclic ring may be connected to the carbon or nitrogen substituted by hydrogen the presence of any carbon or nitrogen. 术语“芳环体系”指完全不饱和的碳环和杂环，其中该多环体系的至少一个环是芳香性的(这里芳香性指该环体系满足Htickel规则)。 The term "aromatic ring system" refers to a fully unsaturated carbon ring and heterocyclic ring system wherein the plurality of at least one ring is aromatic (where aromatic ring system means that meet Htickel rules). 术语“杂芳环”指完全芳香性的环，其中至少一个环原子不是碳，并含有 The term "heteroaromatic ring" refers to a fully aromatic ring, wherein at least one ring atom is not carbon and comprises

1-4个独立地选自氮、氧和硫的杂原子/条件是每个杂环含有不多于4个氮，不多于2个氧和不多于2个硫(这里芳香性指满足Huckel规 1-4 independently selected from nitrogen, oxygen and sulfur atoms / condition that each heterocyclic ring contains no more than four nitrogen, no more than 2 oxygen and no more than two sulfur (here refers to an aromatic meet Huckel Regulation

12夕、.J JO νΛ* AlitAci-1TZv | \( |_l_. | V IJ IL^ H -I HV ^E-Vi HU VI/ I MV *^/、-^$、· IH 12 evening, .J JO νΛ * AlitAci-1TZv | \ (| _l_ | V IJ IL ^ H -I HV ^ E-Vi HU VI / I MV * ^ /, - ^ $, · IH

连。 Even. 术语“芳香性杂环体系”包括完全芳香性的杂环和其中多环体系的至少一个环是芳香性的杂环(这里芳香性指满足Hiickel规则)。 The term "aromatic heterocyclic system" includes fully aromatic heterocyclic ring system and many of them at least one ring is aromatic heterocyclic (aromatic herein refers to meet Hiickel rules). 术语“稠合杂双环体系”包括由两个稠合的环组成的环体系，其中至少一个环原子不是碳，并且如上所定义，可以是芳香性的或非芳香性的。 The term "fused heterobicyclic system" includes two fused rings of the ring system, wherein at least one ring atom is not carbon, and as defined above, may be non-aromatic aromatic.

术语“卤素”，单独使用或在组合词，如“卤烷基”中使用，包括氟、氯、溴或碘。 The term "halogen", alone or in compound words such as "haloalkyl", including fluorine, chlorine, bromine or iodine. 而且，当用于如“卤烷基”的组合词时，所述的烷基可以被卤原子部分或完全取代，所述卤原子可以相同或不同。 Furthermore, when used as "haloalkyl" when the word combination, said alkyl may be partially or fully substituted with halogen atoms, the halogen atoms may be the same or different. “卤烷基”的实例包括F3C、ClCH2, CF3CH2和CF3CC12。 Examples of "haloalkyl" include F3C, ClCH2, CF3CH2 and CF3CC12. 术语“卤链烯基”、“卤炔基”和“卤烷氧基”等的定义与术语“卤烷基”类似。 The term "halo alkenyl", "alkynyl halo" and "haloalkoxy" and defined with the term "haloalkyl" is similar. “卤链烯基”的实例包括(Cl2)C=CHCH2和Cf3CH2CH=CHCH2。 Examples of the "halo alkenyl" include (Cl2) C = CHCH2 and Cf3CH2CH = CHCH2. “卤炔基”的实例包括HOCCHC1、CF3C=C、CCl3C=C和FCH2ChCCH2。 Examples of the "halo alkynyl" include HOCCHC1, CF3C = C, CCl3C = C and FCH2ChCCH2. “卤烷氧基”的实例包括CF3CK CCl3CH2O , HCF2CH2CH2O 和CF3CH2Ch Examples of "haloalkoxy" include CF3CK CCl3CH2O, HCF2CH2CH2O and CF3CH2Ch

在取代基中的碳原子总数以“QC/'前缀表示，其中i和j是1-8的数字。例如，C1-C4烧基磺酰基表示甲磺酰基至丁磺酰基；C2院氧基烷基表示CH3OCH2; C3烷氧基烧基表示，例如，CH3CH(OCH3)、CH3OCH2CH2或CH3CH2OCH2;而C4烷氧烷基表示总共含有4个碳原子的焼氧基取代的烷基的不同异构体，实例包括CH3CH2CH2OCH2和CH3CH2OCH2CH3。在上述陈述中，当式I的化合物含有杂环时，所有的取代基都通过取代任何存在的碳或氮上的氢而通过所述的碳或氮连接于该环上。 The total number of carbon atoms in the substituents in "QC / 'prefix where i and j are numbers 1-8 e.g., C1-C4 burn-ylsulfonyl represents mesyl through butylsulfonyl;. C2 alkoxy group homes group represents CH3OCH2; C3 alkoxy group represented burning, for example, CH3CH (OCH3), CH3OCH2CH2 or CH3CH2OCH2; and C4 alkoxyalkyl group containing a total firing group represents 4 carbon atoms, substituted alkyl of different isomers, Examples include CH3CH2CH2OCH2 and CH3CH2OCH2CH3. In the above statement, when the compound of formula I contains a heterocyclic ring, all substituents are substituted by any presence of hydrogen on carbon or nitrogen through the carbon or nitrogen on the ring connected to .

当基团具有可为氢的取代基时，例如R3，则当该取代基为氢时>认为这相当于所述基团是未取代的。 When the group has a substituent can be hydrogen, for example R3, then when the substituent is hydrogen> think this is equivalent to said group being unsubstituted.

式I的化合物可以作为一种或多种立体异构体存在。 The compounds of formula I can be used as one or more stereoisomers. 各种立体异构体包括对映体、非对映体、阻转异构体和几何异构体。 Various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. 本领域技术人员将理解，当一种立体异构体相对于其它立体异构体为富集时或当 Those skilled in the art will appreciate that when one stereoisomer relative to the other stereoisomer is enriched or when

13另外，本领域技术人员知道如何分离、富集和/或选择性制备所述的立体异构体。 13 In addition, those skilled in the art would know how to separate, enrich, and / or stereoisomers selectively prepare said. -因此，—本发明的化合物可以作为立体异构体的混合物、单个立体异构体存在，或者作为旋光活性的形式存在》 - Thus, - compounds of the invention can be used as a mixture of stereoisomers, individual stereoisomers, or as an optically active form of presence "

式I的化合物的盐包括与无机或有机酸，如氢溴酸、盐酸、硝酸、磷酸、硫酸、醋酸、丁酸、富马酸、乳酸、马来酸、丙二酸、草酸、丙酸、水杨酸、酒石酸、4-甲苯磺酸或戊酸成的酸加成盐。 The salts of the compounds of formula I with inorganic or organic acids include, e.g. hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, acetic acid, butyric acid, fumaric acid, lactic acid, maleic acid, malonic acid, oxalic acid, propionic acid, salicylic acid, tartaric acid, 4-toluene sulfonic acid or acid into an acid addition salt thereof.

出于成本、化学合成或应用的容易和/或生物活性原因，本发明的方法、繁殖体和组合物优选涉及以下优选的化合物： For easy and / or biological activity cost reasons, chemical synthesis or application, the method of the present invention, propagules and compositions preferably involve the following preferred compounds:

优选I.式I的化合物，其中A和B都为O; R7为苯基环或选自下组的5或6元杂芳环 I. Preferred compounds of formula I wherein A and B are both O; R7 is selected from the group phenyl ring or a 5- or 6-membered heterocyclic aromatic ring

每个环任选地被I至3个独立地选自R9的取代基取代； Each ring is optionally substituted with I to 3 independently selected from R9; and

Q 为O、S、NH 或NR9;且 Q is O, S, NH or NR9; and

W、X、Y和Z独立地为N、CH或CR9,条件是在J-3和M中，W、X、Y或Z至少之一是N。 W, X, Y and Z are independently N, CH or CR9, provided that in J-3 and M, W, X, Y or Z is at least one N.

优选2.优选I的化合物，其中R1、R2和R8都为H; Preferably 2. Preferred compounds I, wherein R1, R2 and R8 are both H;

R3为任选地被卤素、CN、OCH3或S(O)pCH3取代的C1-C4烷基； R4连接于2位;' R3 is optionally substituted with halogen, CN, OCH3 or S (O) pCH3 substituted C1-C4 alkyl; R4 is connected to 2; '

R4 为CH3、CF3. OCF3, ochf2、CN 或卤素； R4 is CH3, CF3 OCF3, ochf2, CN or halogen.;

R5为H、CH3或卤素； R5 is H, CH3 or halogen;

R6为CH3、CF3或卤素； R6 is CH3, CF3 or halogen;

R7为苯基或2-吡啶基，它们各自任选地被取代；并且r yv I 巩ώο R7 is phenyl or 2-pyridyl, each of which is optionally substituted; and r yv I Gong ώο

优选3.优选2的化合物，其中R3为C1-C4烷基而R6为CF;。 Preferably 3. Preferably the compound 2, wherein R3 is C1-C4 alkyl and R6 is CF ;.

优选4.优选2的化合物，其中R3为C1-C4焼基而R6为Cl或Br。 The preferred compound is preferably 2, wherein R3 is C1-C4 firing group and R6 is Cl or Br.

如上所指出，R7(尤其)为苯基、苄基、5或6元杂芳环、萘基环体系或芳香性8、9或10元稠合杂双环体系，每个环或环体系任选地被I至3个独立地选自R9的取代基取代。 As noted above, R7 (in particular) is phenyl, benzyl, a 5- or 6-membered heteroaromatic ring, naphthyl ring system or an aromatic 8, 9 or 10-membered fused heterobicyclic system, each ring or ring system optionally I to 3 being independently selected from R9 substituents. 与这些R7基团有关的术语“任选地取代”指未取代或至少具有一个非氢取代基的基团，所述取代基不使未取代的类似物所具有的无脊椎害虫防治活性消失。 These terms and R7 groups related "optionally substituted" means unsubstituted or having at least one non-hydrogen substituent group, the substituent group not to invertebrate pest control activity possessed by the unsubstituted analog disappears. 还注意下面的j_i至J-4指5或6元杂芳环。 Also pay attention to the following j_i to J-4 refers to a 5 or 6-membered heterocyclic aromatic ring. 被I至3个R9任选地取代的苯基环的实例是在示意图I中所示的J-5,其中r为O至3的整数。 I to 3 R9 is an optionally substituted phenyl ring are examples of J-5 as shown in Scheme I, wherein r is an integer from O to 3. 被I至3个R9任选地取代的苯基环的实例是在示意图I中所示的J-6，其中r为O至3的整数。 I to 3 R9 is an optionally substituted phenyl ring are examples of J-6 as shown in Scheme I, wherein r is an integer from O to 3. 被I至3个R9任选地取代的萘基环体系的实例是在示意图I中所示的J-59,其中r为O至3的整数。 Examples I to 3 is R9 optionally substituted naphthyl ring system is J-59 as shown in Scheme I, wherein r is an integer of O 3. 被I至3个R9任选地取代的5或6元杂芳环的实例包括在示意图I中所示的J-7至J-58,其中r为O至3的整数。 Examples of 5- or 6-membered heteroaromatic ring 3 R9 is optionally substituted by I to cover shown in Scheme I J-7 through J-58, where r is an integer from O to 3. 注意J-7至J-26是JI的实例，J-27至J-41是J-2的实例，而J-46至J-58是J-3和J-4的实例。 Note that J-7 through J-26 are examples of JI, J-27 through J-41 are examples of J-2, and J-46 through J-58 are examples of J-3 and J-4's. 需要取代以满足其化合键的氮原子被H或R9取代。 Required to meet a substituted nitrogen atom which is substituted with a compound bond H or R9. 注意一些J基可以仅被少于3个R9基团取代(例如J-19、J-20、J-23至J-26和J-37至J-40可以仅被一个R9取代)。 Note that some of the J group can only be less than 3 R9 substituted (for example, J-19, J-20, J-23 to J-26 and J-37 through J-40 can only be substituted with an R9). 被I至3个R9任选地取代的芳香性8、9或10元稠合杂双环体系的实例包括在示意图I中所示的J-60至J-90，其中r为O至3的整数。 I to 3 R9 is optionally substituted aromatic 8, 9 or 10-membered fused bicyclic heteroaryl systems include the J-60 as shown in Scheme I through J-90, where r is an integer from O to 3, . 虽然R9显示在J-5至J-90结构中，但注意它们并不是必须存在的，因为它们是任选的取代基。 While R9 is displayed in the J-5 through J-90 structure, but note that they are not necessarily exist, since they are optional substituents. 注意当(R%与J基团之间的连接点表示为不固定时，（R9X可以连接于J基团的任合存在的碳原子上。注意当J基团上的连接点表示为不固定时，J基团可以通过取代H原子而通过J基团上的任何存在的碳连接于式I的其余部分。 Note that when the attachment point (R% and J groups is expressed as not fixed, (R9X can be attached to a carbon atom of the J group present in any combination. Note that when the attachment point on the J group is represented as not fixed When, J H group may be substituted by any of the carbon atoms present in the J group is connected to the remainder of Formula I.

15 15

可以使用下述路线1-22中所描述的一种或多种方法和变体制备式I的化合物。 The method of one or more compounds of formula I and variants prepared from 1-22 following the route described can be used. 在下面式2-40的化合物中，A、B和Ri至R9如在发明内容中所定义，除非另有说明。 In the compound of the following formula 2-40, A, B, and Ri to R9 are as defined in the Summary of the Invention, unless otherwise indicated. 式Ia-d、2a-d、3a、4a-d、5a-b、17a-c、183和323七的化合物是式1、2、3、4、5、17、18和32的化合物的不同亚类，Het为如下所示的基团： 2a-d 4a-d 17a-c compound of Formula Ia-d,, 3a,, 5a-b,, 183, and 323 are seven different compounds of formula 1,2,3,4,5,17,18 and 32 subclasses, Het is a group as shown below:

制备式Ia的化合物的典型方法如路线I所描述。 A typical process for preparing a compound of formula Ia as described in Scheme I.

路线I的方法包括在酸清除剂存在下偶联式2的胺与式3的酰氯，产生式Ia的化合物。 Route I approach include the presence of an acid scavenger amine coupling type 2 and type 3, chloride, resulting in a compound of Formula Ia. 典型的酸清除剂包括胺碱，如三乙胺、N，N-二异丙基乙胺和吡啶；其它清除剂包括氢氧化物，如氢氧化钠和氢氧化钾， 以及碳酸盐，如碳酸钠和碳酸钾。 Typical acid scavengers include amine bases such as triethylamine, N, N- diisopropylethylamine and pyridine; other scavengers include hydroxides such as sodium hydroxide and potassium hydroxide, and carbonates, e.g. sodium carbonate and potassium carbonate. 在某些情况下，采用聚合物载酸清除剂，如聚合物结合的况#-二异丙基乙胺和聚合物结合的4-(二甲基氨基)吡啶》偶联可以在适合的惰性溶剂，如四氢呋喃、二噁炼、乙醚或二氯甲烷中进行，获得式Ia的酰基苯胺。 In some cases, the use of an acid scavenger polymer carrier, such as a polymer-bound condition # - diisopropylethylamine and polymer-bound 4- (dimethylamino) pyridine "can be conjugated in a suitable inert solvent such as tetrahydrofuran, dioxane refining, ether or dichloromethane, to obtain the anilide of Formula Ia.

通过用多种标准硫转移试剂之一处理，可以在随后的步骤中从相应的式Ia的酰胺获得式Ib的硫代酰胺，所述硫转移试剂包括五硫化二碟和Lawesson试剂（2,4- 二（4-甲氧基苯基）-1,3- 一硫-2，4-diphosphetane-2,4-二硫化物) By one of the many standard sulfur transfer reagent, of Formula Ib can be obtained from the corresponding thioamide of formula Ia amide in a subsequent step, the sulfur transfer agent comprises Singles pentasulfide and Lawesson's reagent (2,4 - bis (4-methoxyphenyl) -1,3-sulfur -2,4-diphosphetane-2,4- disulfide)

如路线2所示，制备式Ia的化合物的另一方法包括在脱水剂存在下偶联式2的胺与式4的酸，所述脱水剂如二环己基碳二亚胺(DCC)、1，1'-羰基-二咪挫、二(2-氧-3-噁唑烷基)次磷酰氯或苯并三唑-1 -基氧-三(二甲基氨基)磷鎗六氟磷酸盐。 Such route, another method for preparing compounds of formula Ia comprises shown in the presence of coupling an amine of Formula 2 with an acid of formula 4 dehydrating agent, the dehydrating agent such as dicyclohexyl carbodiimide (DCC), 1 , 1'-carbonyl - two microphone frustration, bis (2-oxo-3-oxazolidinyl) phosphinic chloride or benzotriazol -1-- yloxy - tris (dimethylamino) phosphonium hexafluorophosphate gun .

路线2 Route 2

聚合物载剂在这里也有用，如聚合物结合的环己基碳二亚胺。 Polymeric carrier is also useful here, such as polymer-bound cyclohexyl carbodiimide. 偶联可在适合的惰性溶剂，如二氯甲烷或二甲基甲酰胺中进行。 Coupling can be in a suitable inert solvent, such as dichloromethane or dimethyl formamide. 路线I和2的合成万法是用于制备式I的化合物的多柙偶肤万法的代表性买例;这类偶联反应的合成文献很多。 Representative synthetic methodology course I 2 are the compounds of formula I are prepared even for a multi-pen methodology to buy cases of skin; a lot of the synthesis document of such coupling reaction.

本领域技术人员还将认识到，可以通过多种熟知的方法由式4的酸制备式3的酰氯。 Those skilled in the art will also recognize that, through a variety of well-known methods by the type of acid chloride of formula 4 3. 例如，可以通过在催化量的汉界二甲基甲酸胺.存在下，在如甲苯或二氯甲烷的惰性溶剂中，使式4的羧酸与亚硫酰氯或乙二酰氯反应而容易埤由式4的羧酸制得式3的酰氯。 For example, by a catalytic amount of dimethyl formamide Chinese community. Presence, in an inert solvent such as toluene or methylene chloride, sulfuryl chloride or oxalyl carboxylic acid chloride of formula 4 with the sub readily Pi carboxylic acid of formula 4 is prepared acid chloride of Formula 3.

如路线3所示，式2a的胺通常通过硝基的催化加氢而由相应的式5的2-硝基苯甲酰胺得到。 As shown in Scheme 3, amines of Formula 2a are typically obtained from the corresponding 2- nitrobenzamide formula 5 by catalytic hydrogenation of the nitro group.

典型的方法包括在金属催化剂如销/碳或氧化钯存在下，在轻基溶剂如乙醇和异丙醇中用氢还原。 Typical methods include a metal catalyst such as a pin / carbon or palladium oxide in the presence, in a light-based solvent such as ethanol and isopropanol with hydrogen reduction. 式2a的胺也可以通过在醋酸中用锌还原而制得。 Amine of Formula 2a can also be prepared by reduction with zinc acetate. 这些方法已发表于化学文献中。 These methods have been published in the chemical literature. R1取代基，如C1-C6烧基可以在此阶段通过熟知的方法，包括直接烷基化或通过胺的还原烷基化的一般优选的方法而引入。 R1 substituent group, is generally preferred method of firing groups such as C1-C6 by well-known methods, including direct alkylation at this stage, or by reductive alkylation of the amine introduced. 如路线3中进一步所示，通常采用的方法是在还原剂如氰基硼氢化钠存在下混合苯胺2a与乙醛，产生式2b的化合物，其中R1SC1-C6烷基。 As further shown in line 3, the method generally used is a reducing agent such as sodium cyanoborohydride in the presence of mixed aniline 2a with acetaldehyde, the compound of formula 2b, wherein R1SC1-C6 alkyl.

路线4显示在碱如氢化钠或正丁基锂存在下，在惰性溶剂如四氢呋喃或Ayv-二甲基甲酰胺中，可以用适合的烷基化剂或酰化剂，如烷基卤或氯甲酸烷基酯或酰氯将化合物Ic烷基化或酰化，得到式Id的酰基苯胺，其中R1不是H。 Route 4 shows a base such as sodium hydride or n-butyllithium, in an inert solvent such as tetrahydrofuran or dimethylformamide Ayv-, you can use a suitable alkylating agent or acylating agent, such as an alkyl halide or chlorine acid alkyl ester or acid chloride compound Ic alkylated or acylated to afford the anilide of Formula Id wherein R1 is not H.

式5a的中间体敢胺容易地从可商购的2-硝基苯甲酸制备。 Amine intermediates of Formula 5a dare easily from commercially available 2-nitro-benzoic acid. 可以使用形成酰胺的典型方法》如路线5中所示，这些方法包括使用例如 A typical method may be used amide-forming "as shown in Scheme 5, these methods include the use of e.g.

DCC直接脱水偶联式6的酸与式7的胺，并将酸转化成活化形式如酰氯或酸酐，接着与胺偶联，形成式5a的酰胺。 Direct dehydration DCC coupling an acid of formula 6 with an amine of formula 7, and is converted to an activated form such as an acid chloride or anhydride, followed by coupling with an amine to form amides of Formula 5a.

氯甲酸炼基酯，如氯甲酸乙酯或氯甲酸异丙酯，对于涉及酸活化的这类反应是特别有用的试剂。 Lian chloroformate ester, such as ethyl chloroformate or isopropyl chloroformate, for this type of reaction involving acid-activated are particularly useful reagents. 关于酰胺形成的方法的化学文献很多。 A lot of methods for amide formation of the chemical literature. 通过使用可商购的硫转移试剂，如五氯化二憐和Lawesson试剂而容易地将式5a的酰胺转化成式5b的硫代酰胺。 By using a commercially available sulfur transfer reagent, such as two pentachloride and Lawesson's reagent pity readily be converted to the amides of Formula 5a is thioamide of formula 5b.

式2c或2d的中间体邻氨基苯甲酰胺也可以分别由式8或9的靛红酸酐制备，如路线6所示。 The intermediates of Formula 2c or 2d may also be anthranilamide as shown in Scheme 6 are prepared from the isatoic anhydrides of Formula 8 or 9.

典型的方法包括在极性非质子溶剂如吡啶和A^iV-二甲基甲酰胺中，在室温至IOiTC的温度下混合等摩尔量的胺Ί与靛红酸酐。 Typical methods include in a polar aprotic solvent such as pyridine and A ^ iV- dimethyl formamide, at a temperature of from room temperature to IOiTC mixing equimolar amounts of amine Ί with isatoic anhydride. R1取代基如烷基和取代的烷基可以通过靛红酸酐8的碱催化的烷基化来引入，所述焼基化用已知的烷基化试剂R1-Lg (其中Lg为可亲核取代的离去基团，如卤素、烷基或芳基磺酸酯或烷基硫酸酯)进行，产生烷基取代的中间体9。 R1 substituents such as alkyl and substituted alkyl may be introduced by isatoic anhydride 8 base-catalyzed alkylation, glycosylation of the firing by known alkylating agent R1-Lg (wherein Lg is a nucleophilically substituted leaving group such as halogen, alkyl or aryl sulfonates or alkyl sulfates) carried produce alkyl substituted intermediate 9. 式8的靛红酸酐可以通过在Coppola, Synthesis 1980,505-36中所描述的方法来制备。 Isatoic anhydride of Formula 8 may be a method in Coppola, Synthesis 1980,505-36 prepared as described by.

如在路线7中所示，用于制备特定的式Ic的化合物的的另一方法包括胺7与式10的苯并噁嗪酮的反应。 Another method as shown in line 7 in the preparation of compounds of formula Ic of particular used include amines 7 and benzo Formula 10 oxazinone response.

路线7 Route 7

醚、吡啶、二氯甲烷或氯仿中，于室温至溶剂回流的最佳温度下进行。 Ethers, pyridine, methylene chloride or chloroform, at an optimum temperature at room temperature to the solvent refluxing. 苯并噁嗉酮与胺的一般反应产生邻氨基苯甲酰胺，这在化学文献中有很多记载。 Benzoxazin crop one with amines general reaction anthranilamide, which are well documented in the chemical literature. 关于苯并曙嗪酮化学的综述，参见Jakobsen等人，Biofganicand Medicinal Chemistry, 2000, 8，2095-2103 以及其中引用的文献。 For a review of benzo Shu oxazinone chemistry see Jakobsen et al., Biofganicand Medicinal Chemistry, 2000, 8,2095-2103 and references cited therein. 还参见Coppola, J, Heterocyclic Chemistry 1999, 36，563-588。 See also Coppola, J, Heterocyclic Chemistry 1999, 36,563-588.

可以通过多种方法制备式10的苯并噁嗪酮。 It can be prepared by a variety of methods Benzo 10 oxazinone. 在路线8-9中详述的两种方法是特别有用的》在路线8中，通过偶联式4a的吡唑羧酸与式11的邻氨基苯甲酸而直接制备式10的苯并噁嗪酮。 In both methods detailed route 8-9 are particularly useful "in line 8, by coupling pyrazole carboxylic acid of Formula 4a with 11 of anthranilic acid of formula directly benzoxazine of formula 10 one.

这包括在叔胺如三乙胺或吡啶存在下，将甲磺酰氯顺序加入式4a的吡唑羧酸中，随后加入式11的邻氨基苯甲酸，然后第二次加入叔胺和甲磺酰氯。 This includes a tertiary amine such as triethylamine or pyridine, the sequential addition of methanesulfonyl chloride of Formula 4a in the pyrazole carboxylic acid, anthranilic acid of Formula 11 is then added, and then a second addition of tertiary amine and methanesulfonyl chloride . 该方法通常提供良好的苯并噁嗪酮收率，并且在实施例6和8中进行更详细的说明。 The method generally provides good yield benzoxazinone, and described in more detail in Examples 6 and 8.

路线9描述了制备式10的苯并噁嗪酮的另一方法，包括偶联式3a的吡唑酰氯与式8的靛红酸酐，直接得到式10的苯并噁嗪酮。 Scheme 9 describes another process for preparing benzo formula 10 oxazinone, comprising coupling the pyrazole acid chloride of Formula 3a with the isatoic anhydride of Formula 8, Formula 10 directly benzo oxazinone.

溶剂如吡啶或吡啶/乙腈适合于该反应。 Solvent such as pyridine or pyridine / acetonitrile suitable for this reaction. 式3a的酰氯可以通过各种合成方法如用亚硫酰氯或乙二酰氯氯化而由相应的式4a的酸得到。 The acid chloride of Formula 3a can be obtained e.g. from the corresponding acids of Formula 4a with thionyl chloride or oxalyl chloride chloride by a variety of synthetic methods.

式8的靛红酸酐可以由式13的靛红制得，如在路线10中所述。 Isatoic anhydride of Formula 8 may be prepared from isatoic system Formula 13, as described in Scheme 10.

路线10 Route 10

使用文献中记载的方法由式12的苯胺衍生物获得式13的靛红。 Using the method described in the literature by the aniline derivative obtained isatin of Formula 12 Formula 13. 用过氧化氢氧化靛红13通常提供相应的靛红酸酐8的良好收率 Oxidation with hydrogen peroxide Isatoic 13 generally provide good yields of isatoic anhydride 8

Chem. Int. Ed. Engl.mO, 19, 222-223)。 Chem. Int. Ed. Engl.mO, 19, 222-223). 靛红酸酐也可以通过许多已知的方法由邻氨基苯甲酸11得到，所述方法包栝11与光气或光气等价物反应。 Isatoic anhydride can also be obtained from a number of known methods anthranilate 11, said method Gua 11 with phosgene or phosgene equivalents.

式4的代表性酸的合成在路线11-16中描述。 Representative acid synthesis formula 4 is described in Scheme 11-16. 式4a的吡唑的合成在路线11中显示。 Synthesis of pyrazoles of Formula 4a displayed on the route 11.

在路线11中的式4a的化合物的合成包括作为关键步骤的，通过用式15的化合物(其中Lg是如上定义的离去基团)焼基化或芳基化式14的吡唑而引入R7取代基。 Synthesis of Compound of Formula 11 in Scheme 4a comprises as a key step, the compound of formula 15 (wherein Lg is a leaving group as defined above) of the firing group of formula or arylation of pyrazole 14 introduced R7 substituents. 甲基的氧化产生吡®羧酸。 ® methyl pyridine carboxylic acid oxidation. 一些更优选的R6基包括齒烧基。 Some of the more preferred R6 groups include groups burn teeth.

式4a的吡唑的合成也显示在路线12中。 Pyrazole of Formula 4a is also shown in Scheme 12.

路线U Route U

这些酸可以通过将式18的化合物金属化和作为关键步骤羧化而制备。 These acids can be produced by a compound of formula 18 and the metal as a key step carboxylate ester. R7基以类似于路线U的方式引入，即通过用式15的化合物烧基化或芳基化。 R7 group U in a manner analogous to routes incorporated, i.e. by reacting a compound of formula 15 with a group of burning or arylation. 代表性的R6基包括例如氰基、卤烷基和卤素。 Representative R6 groups include e.g. cyano, haloalkyl and halogen.

该方法对于如路线13所示制备式4b的1-(2-吡啶_吡唑羧酸尤其有用。 This method is particularly useful for route 13 as shown in Formula 4b of 1- (2-pyridyl _ pyrazole carboxylic acid.

路线13 Route 13

式17的吡唑与式15a的2，3-二齒代吡啶的反应获得式18a的I-吡啶基吡唑的良好收率，其对所需区域化学具有良好的特异性。 The reaction pyrazole of Formula 15a of formula 17 2,3-tooth generation of pyridine of formula 18a of I- pyridyl pyrazole good yield, their chemical desired area with good specificity. 用二异丙基酰胺锂(LDA)将18a金属化，然后用二氧化碳使锂盐骤冷，得到式4b的1-(2-_^基)吡唑羧酸。 With lithium diisopropylamide (LDA) to metalization 18a, a lithium salt with carbon dioxide and then quenched formula 4b 1- (2 -_ ^ yl) pyrazole carboxylic acid. 这些方法的另外的细节在实施例I、3、 Further details of these methods in Example I, 3,

6、8和10中给出。 6, 8 and 10 below.

式4c的吡唑的合成在路线14中描述。 Pyrazole of Formula 4c is described in Scheme 14.

26 26

路线14涉及式19的任选地取代的苯肼与式20的酮基丙酮酸盐反应，生成式21的吡唑酯。 Route 14 of formula 19, optionally substituted phenyl hydrazine with a ketone of formula 20 reactive groups pyruvate, pyrazole ester of formula (21). 酯水解产生式4c的吡唑酸。 4c ester hydrolysis production pyrazole acid. 该方法对于制备R7为任选地取代的苯基而R6为卤烧基的化合物特别有用。 This method is an optionally substituted phenyl group and R6 is burned halogen compound is particularly useful for the preparation of R7.

式4c的吡唑酸的另一合成在路线15中描述。 Another synthesis of pyrazole acids of Formula 4c is described in Scheme 15.

路线15的方法涉及适当地取代的亚胺基卤化物22与式23的取代的丙块酸酯或式25的丙烯酸酯的3+2环加成。 3 + 2 loop approach route 15 relates to substituted imino halide appropriately substituted propionic acid ester block 22 and type 23 or type 25 esters of acrylic acid addition. 用丙烯酸酯的环加成需要附加的将中间体吡哩琳氧化成吡唑。 Cycloaddition with acrylate requires additional oxidation of the intermediate topiramate miles Lynn to pyrazole. 酯水解产生式4c的吡唑酸。 4c ester hydrolysis production pyrazole acid. 该反应优选的亚胺基卤包括式26的三氟甲基亚胺基氯和式27的亚胺基二溴。 The reaction is preferably imino halides include formula 26 trifluoromethanesulfinic chlorine and formula 27 amino imino dibromo. 诸如26的化合物是已知的(■/· Heterocycl Chem. 1985，22(2)，40, 2605)。 Compounds such as 26 are known (■ / · Heterocycl Chem. 1985,22 (2), 40, 2605). 这些方法对于制备其中R7为任选地取代的苯基而R6为卤烷基或溴的化合物特别有用。 These methods for the preparation of wherein R7 is optionally substituted phenyl and R6 is haloalkyl are particularly useful compound or bromine.

式17的起始吡唑是已知化合物或者可以根据已知方法制备。 Starting pyrazole of Formula 17 are known compounds or may be prepared according to known methods. 式17a的吡唑(式17的化合物，其中R6为CF3而R8为H)可以通过文献方法制备(/. F/wortwe aeTK. 1991, 53(1), 61-70)。 The pyrazole of Formula 17a (the compound of formula 17, wherein R6 CF3 and R8 is H is) can be prepared by literature methods (/. F / wortwe aeTK. 1991, 53 (1), 61-70). 式17c 的吡唑(式17的化合物，其中R6为Cl或Br而R8为H)也可以通过文献方法制^{Chem. Ber. 1966, 99(10), 335O-I 在路线I6 中描述了制备化合物17c的另一有用方法。 The pyrazole of Formula 17c (compounds of Formula 17 wherein R6 is Cl or Br and R8 is H) can also be prepared by literature methods ^ {Chem. Ber. 1966, 99 (10), 335O-I is described in the route I6 Another useful method for preparing a compound of 17c.

路线16 Route 16

在路线16的方法中，用正丁基锂将式28的氨磺酰毗挫金属化，随后用六氯乙烷(R6为Cl)或1,2-二溴四氯乙烧(R6为Br)直接卤化阴离子，产生式29的卤化衍生物。 In the process of Route 16, with n-butyl lithium ammonia formula sulfonamide border fell 28 metallization, followed by hexachloroethane (R6 is Cl) or 1,2-dibromo acetic burn tetrachloride (R6 is Br ) direct halide anion production halogenated derivatives 29. 在室温下用三氟醋酸(TFA)除去氨磺酰基进行得很完全，并以良好收率产生式17c的吡唑。 At room temperature with trifluoroacetic acid (TFA) to remove sulfamoyl be very complete and in good yield production pyrazole 17c. 本领域技术人员将认识到，式17c是式17b的互变异构体。 Those skilled in the art will recognize that Formula 17c is a tautomer of Formula 17b thereof. 这些方法的进一步实验细节在实施例8和10中描述。 Further experimental details of these methods in Examples 8 and 10 are described.

式4d的吡唑羧酸，其中R6为H、C1-C6烧基或C1-C6卤烧基，可以通过概述于路线17中的方法制备。 The pyrazole carboxylic acid of Formula 4d wherein R6 is H, C1-C6 burn halo group or C1-C6 firing group, may be prepared by the route outlined Method 17 in.

在适合的有机溶剂中使式30的化合物，其中1113为C1-C4烷基，与适合的碱反应，在用酸如乙酸中和后产生式31的环化产物。 In an organic solvent a compound of formula 30 suitable where 1113 is C1-C4 alkyl, is reacted with a suitable base, after neutralization with an acid such as acetic acid to produce the cyclized product of Formula 31. 适合的碱可以为，例如但不限于，氢化钠、叔丁醇钾、dimsyl钠(CH3S(O)CH2Tia+),碱金属(例如锂、钠或钾)碳酸盐或氢氧化物、四烷基(例如甲基、乙基或丁基)铵氟化物或氢氧化物或2-叔丁基亚氨基-2-二乙氨基-1,3-二甲基-全氢-1,3,2-二氮杂膦(diazaphosphonine)。 Suitable base may be, for example, but not limited to, sodium hydride, potassium t-butoxide, dimsyl sodium (CH3S (O) CH2Tia +), alkali metals (e.g. lithium, sodium or potassium) carbonates or hydroxides, tetraalkyl (e.g. methyl, ethyl or butyl) ammonium fluorides or hydroxides, or 2-amino-2-diethylamino-t-butyl-1,3-dimethyl - perhydro-1,3,2- diaza phosphine (diazaphosphonine). 适合的有机溶剂可以为，例如但不限于，丙酮、乙腈、四氢呋喃、二氯甲烷、二甲亚砜或况见二甲基甲酰胺。 Suitable organic solvents can, for example, but not limited to, acetone, acetonitrile, tetrahydrofuran, methylene chloride, dimethyl sulfoxide or dimethylformamide see conditions. 环化反应通常在约O至120°C的温度范围内进行。 The cyclization reaction is usually carried out within about O to to 120 ° C temperature range. 溶剂、碱、温度和加成时间的作用都是相互依赖的，并且选择反应条件对于减少副产物形成是重要的。 The solvent, base, temperature and addition time are all interdependent effects, and choose the reaction conditions for reducing the formation of by-products is important. 优选的碱是氟化四丁基铵。 A preferred base is tetrabutylammonium fluoride.

式31的化合物的脱水给出式32的化合物，随后将羧酸酷官能团转化为羧酸，得到式4d的化合物。 Dehydrating a compound of formula 32 to give compounds of Formula 31, followed by conversion of the carboxylic acid to a carboxylic acid functional group cool, to give a compound of Formula 4d. 脱水通过用催化量的适合的酸处理而实现。 Dehydration with a suitable acid treatment is achieved by a catalytic amount. 这里催化酸可以为，例如但不限于，硫酸。 Here catalytic acid can be, for example, but not limited to, sulfuric acid. 通常使用有机溶剂进行该反应。 Typically the reaction is carried out using an organic solvent. 本领域技术人员将认识到，脱水反应可以在约O至200Ό,更优选约O至100Ό的温度范围内，在多种溶剂中进行。 Those skilled in the art will recognize, the dehydration reaction can be from about O to 200Ό, more preferably from about O to 100Ό temperature range, carried out in a variety of solvents. 对的。 Right. 可以通过多种方法将羧酸酯化合物转化为羧酸化合物，所述方法包括在无水条件下的亲核裂解或涉及使用酸或碱的水解方法(参见TW Greene 和PGM Wuts，Protective Groups in Organic Synthesis,2nd ed., John Wiley & Sons, Inc., New York, 1991, pp. 224-269的方法综述)。 There are several ways the carboxylic acid ester compound into a carboxylic acid compound, said method comprising under anhydrous conditions nucleophilic cleavage or involve the use of an acid or alkali hydrolysis method (see TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York, 1991, pp. 224-269 Summary of the method). 对于路线17的方法，碱催化的水解方法是优选的。 Method for route 17, base-catalyzed hydrolytic methods are preferred. 适合的碱包括碱金属(例如锂、钠或钾)氢氧化物。 Suitable bases include alkali metal (e.g. lithium, sodium or potassium) hydroxides. 例如，可以将酯溶解在水和醇如乙醇的混合物中。 For example, the ester is dissolved in a mixture of water and an alcohol such as ethanol. 在用氢氧化钠或氢氧化钾处理时，酯皂化，提供羧酸的钠盐或钾盐。 When treated with sodium hydroxide or potassium hydroxide, the ester is saponified to provide the sodium or potassium salts of carboxylic acids. 用强酸如盐酸或硫酸酸化，产生式4d的羧酸。 With a strong acid such as hydrochloric acid or sulfuric acid, to produce carboxylic acid of formula (4d). 可以通过本领域技术人员已知的方法，包括结晶、萃取和蒸馏来分离羧酸。 It can be known by those skilled in the methods, including crystallization, extraction and distillation to separate the carboxylic acid.

式30的化合物可以通过概述于路线^8中的方法制备。 Compounds of formula 30 can be prepared by methods outlined 8 ^ in the route.

路线18 ' Route 18 '

其中R6为H、C1-C4烷基或C1-C6卤烷基，而R13为C1-C4烷基。 Wherein R6 is H, C1-C4 alkyl or C1-C6 haloalkyl, and R13 is C1-C4 alkyl. 在诸如水、甲醇或乙酸的溶剂中用式34的酮处理式33的肼化合物，得到式35的腙。 Hydrazine compounds such as water, methanol or acetic acid solvent with a ketone of formula 34 by treatment of 33, to give the hydrazone of formula 35. 本领域技术人员将认识到，该反应可能需要用任选的酸催化，并且也可能需要升高的温度，这取决于式35的腙的分子取代模式。 Those skilled in the art will recognize, the reaction may require catalysis by an optional acid and may also require elevated temperatures depending on the molecular substitution hydrazone of formula 35 mode. 在适合的有机溶剂，例如但不限于，二氯甲烷或四氢呋喃中，在酸清除剂如三乙胺存在下，式35的腙与式36的化合物反应，生成式30的化合物。 In a suitable organic solvent, such as, but not limited to, dichloromethane or tetrahydrofuran in the presence of an acid scavenger such as triethylamine compounds, hydrazone of Formula 35 with a compound of formula 36, ​​formula 30. 该反应通常在约P至100Ό的温度下进行。 The reaction is usually carried out at a temperature of about P to 100Ό. 路线18的方法的进一步实验细节在实施例17中说明。 Further experiments described in Example 17 details of the methods of Route 18 in the implementation. 式33的肼化合物可以通过标准方法制备，如通过使相应的式15a的卤代化合物与肼 Hydrazine compound of Formula 33 may be prepared by standard methods, such as by reacting the corresponding halo compound of Formula 15a with hydrazine

30式4d的吡唑竣酸，其中R6为卤素，可以通过概述于路线19中的方法制备。 30 Formula 4d pyrazole carboxylic acid, wherein R6 is halogen, may be prepared Route 19 by methods outlined in.

式37化合物的氧化作用任选地在酸存在的条件下进行，生成式32的化合物，随后将羧酸酯官能团转化为羧酸，生成式4d的化合物。 Oxidation of a compound of Formula 37 optionally in the presence of an acid under conditions carried out, the compound of formula 32, followed by conversion of the carboxylic ester function to the carboxylic acid, the compound of Formula 4d. 氧化剂可以为过氧化氢、有机过氧化物、过硫酸钾、过硫酸钠、过硫酸铵、过硫酸氢钾(例如Oxone®)或高锰酸钾。 The oxidizing agent can be hydrogen peroxide, organic peroxides, potassium persulfate, sodium persulfate, ammonium persulfate, potassium hydrogen sulfate (e.g., Oxone®) or potassium permanganate. 为了获得完全的转化，至少应当使用相对于式37的化合物而言为I当量的氧化剂，优选约I 至2当量。 To obtain complete conversion, at least it should be used relative to the compound of formula I 37 is the equivalent of an oxidizing agent, preferably about I to 2 equivalents. 该氧化通常在溶剂存在下进行。 The oxidation is typically carried out in the presence of a solvent. 溶剂可以为醚，如四氢呋喃、对二嘿烧等，有机酯，如乙酸乙醋、碳酸二甲酯等，或极性非质子有机溶剂如汉见二甲基甲酰胺、乙腈等。 The solvent can be an ether, such as tetrahydrofuran, p-Hey burning, etc., organic esters, such as ethyl acetate, dimethyl carbonate, etc., or a polar aprotic organic solvent such as dimethylformamide, see Han, acetonitrile and the like. 适用于氧化步骤的酸包括无机酸，如硫酸、磷酸等，以及有机酸，如乙酸、苯甲酸等。 Applicable to the oxidation step include inorganic acids such as sulfuric acid, phosphoric acid, etc., and organic acids such as acetic acid, benzoic acid and the like. 当使用时，所用的酸相对于式37的化合物而言应大于0.1当量。 When used, the acid phase used for the compound of Formula 37 should be greater than 0.1 equivalents. 为了获得完全的转化，可以使用I至5当量的酸。 To obtain complete conversion, you can use I to 5 equivalents of acid. 优选的氧化剂是过硫酸钾， 并且氧化优选在硫酸存在下进行。 The preferred oxidizing agent is potassium persulfate and the oxidation is preferably carried out in the presence of sulfuric acid. 反应可以通过在所需的溶剂和如果使用的话，在酸中混合式37的化合物而进行。 The reaction solvent may be required and, if used, the acid compound mixed carried out at 37. 然后可以便利的速度.加入氧化剂。 May then be convenient speed oxidizing agent is added. 为了获得合理的反应时间以完成反应，反应温度通常在低至约(TC到髙至溶剂的沸点内变化，反应时间优选低于8小时。所需的产物，式32的化合物，可以通过本领域技术人员已知的方法分的羧酸的方法己在路线17中得到描述。路线19的方法的进一步实验细节在实施例12和13中说明。 In order to obtain a reasonable reaction time to complete the reaction, the reaction temperature is usually as low as about (TC Gao to change to the boiling point of the solvent, the reaction time is preferably less than 8 hours. The product is the desired compound of formula 32 can be in the art Methods already known to the skilled method points acids are described in Scheme 17. Further experimental details for the method of Scheme 19 Examples 12 and 13 described.

式37的化合物可以由相应的式38的化合物制备，如路线20中所示。 Compounds of formula 37 may be prepared from the corresponding compound of formula 38, such as line 20 in FIG.

路线20 Route 20

其中R13为C1-C4焼基，而R6为卤素》 Wherein R13 is C1-C4 firing group, and R6 is halo "

用卤化试剂处理式38的化合物，通常在溶剂存在下进行，产生相应的式37的菌代化合物。 With a compound of formula 38 a halogenating reagent, usually in the presence of a solvent, producing bacteria substituting the corresponding compound of formula 37. 可以使用的卤化剂包括卤氧化磷、三卤化磷、五卤化磷、亚硫酰氯、二卤三烷基正膦、二卤二苯基正膦、草酰氯和光气。 Halogenating agent may be used include phosphorus oxyhalides, phosphorus trihalides, phosphorus pentahalide, thionyl chloride, n-dihalo trialkyl phosphine, diphenyl-n-phosphine dihalide, oxalyl chloride and phosgene. 优选为卤氧化磷和五卤化磷。 Preferably phosphorus oxyhalides and phosphorus pentahalide. 为了获得完全转化，相对于式38的化合物而言，至少应使用0.33当量的窗氧化磷(即卤氧化磷与式18的摩尔比至少为0.33),优选约0.33至1.2当量。 To obtain complete conversion, relative to the compound of formula 38, using at least 0.33 equivalents of phosphorus oxide window (i.e., phosphorus oxyhalide of the formula is at least 18 molar ratio of 0.33), preferably from about 0.33 to 1.2 equivalents. 为了获得完全转化，相对于式38的化合物而言，至少应使用0.20当量的五卤化憐，优选约0.20至1.0当量。 To obtain complete conversion, relative to the compound of formula 38, at least 0.20 equivalents of use pentahalide pity, preferably about 0.20 to 1.0 equivalents. 该反应中R13为C1-C4焼基的式38的化合物是优选的。 This reaction R13 is C1-C4 firing base compound of formula 38 is preferable. 用于该齒化的典型溶剂包括卤代烷烃，如二氯甲烷、氯仿、氯丁烧等，芳族溶剂，如苯、二甲苯、氯苯等，醚，如四氢呋喃、对二噁烷、乙醚等，以及极性非质子溶剂如乙腈、AW-二甲基甲酰胺等。 Typical solvents used include the teeth of the halogenated alkanes, such as methylene chloride, chloroform, chloroprene burning, etc., aromatic solvents such as benzene, xylene, chlorobenzene, etc., ethers such as tetrahydrofuran, p-dioxane, diethyl ether, etc. and a polar aprotic solvent such as acetonitrile, AW- dimethylformamide and the like. 任选地，可以加入有机碱，如三乙胺、吡啶、W-二甲基苯胺等。 Optionally, an organic base may be added, such as triethylamine, pyridine, W- dimethylaniline and the like. 力α入催化剂，如AUV-二甲基甲酷胺，也是一种选择。 Α into force catalyst, such as dimethylformamide cool AUV- amine, is also an option. 优选该方法中的溶剂是乙腈并且碱不存在。 The preferred method of solvent is acetonitrile and the base does not exist. 通常，当使用乙腈溶剂时，既不需要碱也然后在方便的时间内加入卤化试剂，并在所需的温度下放置混合物，直到反应完全。 Typically, when using an acetonitrile solvent, it does not require a base are then added over a convenient time halogenating agent, and the mixture is placed at the desired temperature until the reaction was complete. 反应温度通常在2(TC至乙腈的沸点之间，并且反应时间通常低于2小时。然后用无机碱，如碳酸氢钠、氢氧化纳等，或有机碱，如乙酸钠中和反应物料。所需的产物，式37的化合物，可以通过本领域技术人员已知的方法，包括结晶、萃取和蒸馏而得到分离。 The reaction temperature is generally between 2 (TC to the boiling point of acetonitrile, and the reaction time is usually less than 2 hours. Then treated with an inorganic base, such as sodium bicarbonate, sodium hydroxide, etc., or an organic base, such as sodium acetate and the reaction mass. The desired product, a compound of Formula 37, can be accomplished by methods known to the skilled person, including crystallization, extraction and distillation separation is obtained.

或者，R6为卤素的式37的化合物可以通过用适合的It化氢处理相应的式37的化合物而制备，所述的相应的式37的化合物中R6为不同的卤素(例如Cl,用于构成R3为Br的式37)或磺酸酯基，如对甲苯磺酸酯、苯磺酸酯和甲磺酸酯。 Alternatively, R6 halo of the compound of formula 37 with a suitable compound can be hydrogen It treating the corresponding formula 37 is prepared, the corresponding compound of formula 37 wherein R6 is a different halogen (e.g. Cl, for forming Formula 37 wherein R3 is Br) or a sulfonate group such as p-toluenesulfonate, benzenesulfonate and methanesulfonate. 通过该方法，式37起始化合物上的R6卤素或磺酸酯取代基分别被，例如来自溴化氣或氯化氢的Br或Cl取代。 By this method, R6 halogen or sulfonate of Formula 37 starting compound of the substituents are respectively, e.g. Br or Cl from hydrogen chloride or bromide gas substitution. 反应在适合的溶剂，如二溴甲烷、二氯甲烷或乙腈中进行。 Reaction in a suitable solvent, such as dibromomethane, dichloromethane or acetonitrile. 反应可在大气压或接近大气压下进行，或者可以在压力容器中在高于大气压下进行。 The reaction can be conducted at or near atmospheric pressure, or may be carried out at higher than atmospheric pressure in a pressure vessel. 当式37的起始化合物中的R6为卤素如Cl时，反应优选以这样的方式进行，即通过啧射或其它适合的方式除去反应产生的卤化氢。 When the starting compound of the formula 37 R6 is halogen such as Cl, the reaction is preferably carried out in such a way that the hydrogen halide generated by the reaction was removed by Tut shot or other suitable means. 反应可以在约O至IOOO下进行，最方便地在接近环境温度(例如约10至40Ό)下进行，并且更优选在约20至30Ό下进行。 The reaction can be carried out from about O to IOOO, most conveniently near ambient temperature (for example, about 10 to 40Ό) below, and more preferably from about 20 to 30Ό conduct. 加入路易斯酸催化剂(例如用于制备R6为Br的式37的三溴化培)可以促进反应。 Add a Lewis acid catalyst (e.g., R6 is tribromide for preparing Formula 37 culture Br) can facilitate the reaction. 通过本领域技术人员已知的常规方法，包括萃取，蒸馏和结晶来分离式37的产物。 By conventional methods known to the skilled person, including extraction, distillation and crystallization of the isolated product of Formula 37. 该方法的进一歩细节在实施例14中说明。 Into a ho details of the method described in Example 14 in.

R6为Cl或Br的式37的起始化合物可以由已经描述的相应的式38的化合物制备。 R6 starting compound of formula 37 Cl or Br may be prepared from the corresponding compound of formula 38 as already described. 通过标准方法，如在适合的溶剂如二氯甲烷中，用磺酰氯(例如对甲苯磺酸氯)和碱如叔胺(例如三乙胺)处理，可以由相应的式38的化合物同样地制备R6为磺酸酯基的式37的起始化合物；该方法的进一步细节在实施例15中说明。 By standard methods, such as in a suitable solvent such as dichloromethane, with a sulfonyl chloride (e.g., p-toluenesulfonic acid chloride) and base such as a tertiary amine (e.g. triethylamine) processing, can also be prepared from the corresponding compound of formula 38 sulfonate group of the starting compound of the formula R6 is 37; Example 15 Further details of the method described in the embodiment.

R6为C1-C4焼氧基或C1-C4齒综氧基的式4d的吡唑羧酸也可以通 R6 is C1-C4 firing groups or C1-C4 tooth mechanized group type pyrazolecarbonyl 4d may be through

33 33

其中R13为CrC4烧基，而X为离去基团。 Wherein R13 is CrC4 burn group and X is a leaving group.

在该方法中，代替如路线20中所示的被ΐϋ化，式38的化合物被氧化成式32a的化合物。 In this method, instead of the line of ΐϋ as is shown in 20, the compound of Formula 38 is oxidized to the compound of Formula 32a. 该氧化的反应条件己在路线19中描述过，用于将式37的化合物转化成式32的化合物》 The oxidation reaction conditions already described in Scheme 19 for the compound of formula 37 is converted to the compound of formula 32 '

然后通过使式32a的化合物在碱存在下与烷基化剂CF3CH2X (39)接触而将其烷基化，形成式32b的化合物。 Then by reacting a compound of formula 32a in the presence of a base with an alkylating agent CF3CH2X (39) contacting the alkylated to form a compound of formula 32b. 在烷基化剂39中，X是亲核反应离去基团，如卤素(例如Br、I)、OS(O)2CH3 (甲磺酸酯)、OS(O)2CF3> OS(O)2Ph-P-CH3 (对甲苯磺酸SI)等；甲磺酸酯效果良好。 In the alkylating agent 39, X is a nucleophilic reaction leaving group such as halogen (such as Br, I), OS (O) 2CH3 (mesylate), OS (O) 2CF3> OS (O) 2Ph- P-CH3 (p-toluenesulfonate SI) and the like; mesylate good effect. 反应在至少一当量的碱存在下进行。 The reaction carried out in the presence of at least one equivalent of a base. 适合的碱包括无机碱，如碱金属(如锂、钠或钾)碳酸盐和氢氧化物，以及有机碱，如三乙胺、二异丙基乙胺和1,8-二氮杂二环[5.4.0]H—碳-7-烯。 Suitable bases include inorganic bases, such as alkali metal (such as lithium, sodium or potassium) carbonates and hydroxides, and organic bases, such as triethylamine, diisopropylethylamine and 1,8-diazabicyclo ring [5.4.0] H--7-ene. 反应通常在溶剂中进行，所述溶剂可以包含醇，如甲醇和乙醇，卤代院经，如二氯甲烷，芳族溶剂，如苯、甲苯和氯苯，醚，如四氢呋喃，以及极性非质子溶剂，如乙腈、JV1JV-二甲基甲酰胺等。 The reaction is usually conducted in a solvent, the solvent may contain alcohol, such as methanol and ethanol, halogenated hospital classics, such as methylene chloride, aromatic solvents such as benzene, toluene and chlorobenzene, ethers, such as tetrahydrofuran, and polar non- protic solvents, such as acetonitrile, JV1JV- dimethylformamide and the like. 醇和极性非质子溶剂优选与无机碱一起使用。 Alcohols and polar aprotic solvents preferably used together with an inorganic base. 碳酸钾作为碱而乙腈作为溶剂是优选的。 Potassium carbonate as base and acetonitrile as solvent are preferred. 反应通常在约O至150Ό下进行，最通常在室温至100°C下进行。 The reaction is generally from about O to the next 150Ό conducted, most usually carried out at room temperature to 100 ° C under. 式32b的产物可以通过常规技术，如萃取而分离。 The product of Formula 32b can be by conventional techniques, such as extraction and separation. 然后可以通过已在路线17中描述过的用于将式32转化成式4d的方法来将式32b的酯转化成式4d的羧酸。 You can then have been described in the Route 17 over-32 for the type of formula 4d conversion process to be esters of formula 32b is converted to carboxylic acids of Formula 4d. 路线21的方法的进一步实验细节在实施例16中说明。 Further experimental details Route 21 method described in Example 16 implementation.

式38的化合物可以由式33的化合物制备，如路线22所示》 Compounds of formula 38 may be prepared from compounds of formula 33, as shown in line 22 "

其中R13SC1-C4烧基。 Which R13SC1-C4 burn group.

在该方法中，在碱和溶剂存在下使式33的肼化合物与式40的化合物(可以使用富马酸酯或马来酸酯或它们的混合物)接触。 In this method, a base and a solvent in the presence of a compound of formula 33 with a hydrazine compound of Formula 40 (which can be used fumarate or maleate ester or a mixture thereof) in contact. 碱通常为金属醇盐，如甲醇钠、甲醇钾、乙醇钠、乙醇钾、叔丁醇钾、叔丁醇锂等。 Typically an alkali metal alkoxide such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide and the like. 相对于式33化合物而言，应使用高于0.5当量的碱，优选为0.9至1.3当量。 Relative to the compound of Formula 33 should be used more than 0.5 equivalents of base, preferably 0.9 to 1.3 equivalents. 应使用髙于1.0当量的式40的化合物，优选为1.0至1.3当量。 1.0 equivalents of the compound of Formula 40 should be used in Gao, preferably 1.0 to 1.3 equivalents. 可以使用极性质子和极性非质子溶剂，如醇、乙腈、四氢呋喃、汉界二甲基甲酰胺、二甲基亚砜等。 You can use the polar protic and aprotic polar solvents such as alcohols, acetonitrile, tetrahydrofuran, Chinese community dimethyl formamide, dimethyl sulfoxide and the like. 优选的溶剂是醇，如甲醇和乙醇。 Preferred solvents are alcohols such as methanol and ethanol. 特别优选醇与构成富马酸醋或马来酸酯，以及醇盐的醇相同。 Particularly preferred alcohols constituting the fumarate or maleate vinegar, and the same alcohol alkoxides. 反应通常通过在溶剂中混合式33的化合物和碱而进行。 The reaction is usually carried out in a solvent by mixing a compound of formula 33 and a base is performed. 可以将混合物加热或冷却至所需的温度，并且在一段时间内加入式40的化合物。 The mixture can be heated or cooled to a desired temperature and the compound of Formula 40 added over a period of time. 通常反应温度在0Ό至所用溶剂的沸点之间。 The reaction temperature is usually in 0Ό to the boiling point of the solvent used. 反应可以在高于大气压下进行，以提高溶剂的沸点。 The reaction can be carried out at higher than atmospheric pressure, in order to increase the boiling point of the solvent. 约30至90°C的温度通常是优选的。 A temperature of about 30 to to 90 ° C are generally preferred. 加入的时间可与热传递所允许的一样快。 The time can be added as fast as the heat transfer allows. 通常的加入的时间为I分钟至2小时。 Typically the time I added minutes to 2 hours. 最佳的反应温度和加入的时间随式33和式40的化合物的特性而变。 Optimum reaction temperature and time with added properties of the compounds of Formula 33 and Formula 40 and change. 在加入后，可以将反应混合物在反应温度下放置一段时间。 After the addition, the reaction mixture may be a period of time at the reaction temperature. 取决于反应温度，所需的放置时间可以为O至2小时。 Depending on the reaction temperature, the required time may be placed O to 2 hours. 通常的放置时间是10至60分钟。 The standing time is usually from 10 to 60 minutes. 然后通过加入有机酸，如醋酸等，或无机酸，如盐酸、硫酸等而酸化反应物料。 Then by adding an organic acid, such as acetic acid, or inorganic acids, such as hydrochloric acid, sulfuric acid, etc. The reaction mass is acidified. 取决于反应条件和分离方法，式38的化合物上的-CO2R13官能团可以逢7_Κ解成-CO2H;例如，在反应混合物中有水存在可以促进这种水解。 Depending on the reaction conditions and the isolation method, -CO2R13 functional groups on the compound of formula 38 can be decomposed into every 7_Κ -CO2H; for example, the presence of water can promote such hydrolysis reaction mixture. 如果形成羧酸(-C02H)，可 If you form a carboxylic acid (-C02H), may

35M IX厂Tg十识切仏⑴口, 才々I 丄、yv、^〜4 35M IX plant knowledge Tg ten cut Fo ⑴ mouth before 々 I Shang, yv, ^ ~4

烧基。 Burning group. 所需的产物，式38的化合物可以通过本领域技术人员已知的方法，如结晶、萃取或蒸馏而得到分离。 The desired product, a compound of formula 38 may be prepared by those skilled in the known methods, such as crystallization, extraction or distillation to obtain a separation.

应认识到，上述用于制备式I的化合物的一些试剂和反应条件可能与中间体中存在的某些官能团不相容。 It should be appreciated that some reagents and reaction conditions described above for the preparation of compounds of formula I may be present in the intermediates incompatible with certain functional groups. 在这些情况下，在合成中引入保护/脱保护程序或官能团互变将有助于获得所需的产物。 In these cases, the introduction of protection / deprotection or functional group interconversion procedures will help to obtain the desired product in the synthesis. 保护基的使用和选择对于化学合成技术人员而言是清楚的(参见，例如，Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis,2nded.； Wiley： New York, 1991)。 Use and choice of protecting groups for chemical synthesis techniques will be clear to persons (see, e.g., Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 2nded .; Wiley: New York, 1991). 本领域技术人员将认识到，在某些情况下，在如在任何单个路线中所示引入给定试剂后，可能需要进行未详细描述的其它常规合成步骤，以完成式I的化合物的合成。 Those skilled in the art will recognize that, in some cases, after the introduction of a given reagent as shown in any single route, it may be necessary to perform additional routine synthetic steps not described in detail, in order to perfect the compounds I of the synthesis. 本领域技术人员还将认识到，为了制备式I的化合物，可能需要将上述路线中所示的步骤以不同于所示的特定顺序的顺序组合进行。 Those skilled in the art will also recognize that, for the preparation of a compound of Formula I, may be necessary to route in the step shown in the above-described composition is different from the order shown in a particular order will be.

相信最大限度地使用前面的描述，本领域技术人员能够制备本发明的式I的化合物。 I believe that maximizing the use of the foregoing, the compounds of formula I of the present invention can be prepared by the skilled person. 因此，以下实施例仅是说明性的，其不以任何方式限制本发明。 Thus, the following examples are illustrative only, it does not in any way limit the present invention. 除了对于色谱溶剤混合物而言或另有说明外，百分比指重量百分比。 Except for chromatographic solvent mixture Ji terms or as otherwise indicated, the percentage refers to the percentage by weight. 除非另有说明，份和色谱溶剂混合物的百分比是体积比。 Unless otherwise indicated, parts and percentages for chromatographic solvent mixtures are by volume. 1HNMR谱以自四甲基甲桂烧的ppm低磁场报告；s表示单峰，d表示双峰，t表示兰重峰，q表示四重峰，m表示多重峰，dd表示双峰的双峰，dt表示三重峰的双峰，br表示宽单峰。 1HNMR spectrum of self-tetramethyl Jia Gui burning ppm downfield report; s singlet, d doublet, t represents blue doublet, q is quartet, m is multiplet, dd doublet of doublet , dt triplet of doublet, br indicates a broad singlet.

实施例I Example I

2-[1-乙基-3-三氟甲基吡唑-5-基氨基甲酰基]-3-甲基-ΛΚ1-甲基乙基)苯 2- [1-ethyl-3-trifluoromethyl-pyrazol-5-ylcarbamoyl] -3-methyl -ΛΚ1- methylethyl) benzene

甲酰胺的制备·步骤A: 3-甲基-ΛΓ-Π-甲某乙基V2-硝基苯甲酰胺的制备将在25 ml 二氯甲烷中的3-甲基-2-硝基苯甲酸(2.00 g, 11.0 mmol)和三乙胺(1.22 g, 12.1 mmol)溶液冷却至10Ό。 · Carboxamide Step A: 3- nitrobenzamide methyl -ΛΓ-Π- Jiamou V2- ethyl 3-methyl-2-nitrobenzoic acid in 25 ml of methylene chloride (2.00 g, 11.0 mmol) and triethylamine (1.22 g, 12.1 mmol) was cooled to 10Ό. 小心加入氯甲酸乙酯， Ethyl chloroformate was carefully added,

36^VuVCo IWT yj TTVR , 1U.V iiiiiiuiyi ΊτΤ 36 ^ VuVCo IWT yj TTVR, 1U.V iiiiiiuiyi ΊτΤ

到均相溶液。 To the homogeneous solution. 将该反应再搅拌I小时，并将其倒入水中，用乙酸乙酯萃取。 The reaction was stirred for I hour, poured into water and extracted with ethyl acetate. 用水洗涤有机萃取物，用硫酸镁干燥并减压蒸发，产生1.96 g所需的中间体，为白色固体，其在126-128Ό熔化。 The organic extract was washed with water, dried over magnesium sulfate and evaporated under reduced pressure to produce 1.96 g of the desired intermediate as a white solid, melting at 126-128Ό.

1H NMR (CDCl3) δ 1.24 (d, 6H), 2.38 (s, 3H), 4.22 (m, IH), 5.80 (brs, IH), 7.4 (m, 3H)» 1H NMR (CDCl3) δ 1.24 (d, 6H), 2.38 (s, 3H), 4.22 (m, IH), 5.80 (brs, IH), 7.4 (m, 3H) »

步骤B: 2-氣基-3-甲基-Wl-甲某乙基)苯甲酰胺的制备 Preparation of 2-methyl-3--Wl- gas Jiamou ethyl) benzamide: Step B

在5% PdyC上，40 ml乙醇中，于50psi下，将步骤A的2-硝基苯甲酰胺(1.70 g，7.6 mmol)氢化。 On 5% PdyC, 40 ml of ethanol, to 50psi at the step A 2-nitrobenzamide (1.70 g, 7.6 mmol) hydrogenation. 在停止氧气摄入时，通过Celite®桂藻土助滤剂过滤反应物，并用乙醚洗涤Celite®。 When it stops oxygen uptake, washed with ether Celite® reaction was filtered through diatomaceous earth filter aid Celite® Guangxi and. 减压蒸发滤液，得到1.41 g标题化合物，该化合物为固体，在149-151Γ熔化。 The filtrate was evaporated under reduced pressure, to give 1.41 g of the title compound, the compound as a solid, melting at 149-151Γ.

1H NMR (CDCl3) δ 1.24 (dd, 6H), 2.16 (s, 3H), 4.25 (m, IH), 5.54(brs, 2H), 5.85 (br s, 1H)，6.59 (t, IH), 7.13 (d, IH), 7.17 (d, 1H)。 1H NMR (CDCl3) δ 1.24 (dd, 6H), 2.16 (s, 3H), 4.25 (m, IH), 5.54 (brs, 2H), 5.85 (br s, 1H), 6.59 (t, IH), 7.13 (d, IH), 7.17 (d, 1H). 步骤C: I-乙基-3-三氟甲基吡唑-5-基羧酸的制备 Step C: I- ethyl-3-trifluoromethyl-pyrazol-5-yl-carboxylic acid

在30 ml N,N-二甲基甲酰胺中搅拌3-三氟甲基毗唑(5 g, 37 nunol)和粉末状碳酸钾(10 g，72 mmol)的混合物，滴加碘乙烷(8 g, 51 mmol)到混合物中。 In 30 ml N, N- dimethylformamide was stirred 3-trifluoromethyl adjacent azole (5 g, 37 nunol) and powdered potassium carbonate (10 g, 72 mmol) was dropwise iodine ethane ( 8 g, 51 mmol) to the mixture. 温和放热后，在室温下将反应物搅拌过夜》反应混合物在100 ml乙酸和100 ml水间分配。 After a mild exotherm, the reaction was stirred at room temperature overnight. "The reaction mixture was partitioned between 100 ml of acetic acid and 100 ml of water. 分离乙醚层并用水(3X)和盐水洗涤，用硫酸镁干燥。 The ether layer was separated and washed with water (3X) and brine, dried over magnesium sulfate. .真空中蒸去溶剂得到4 g油。 . The solvent was evaporated in vacuo to give 4 g oil.

在氮气保护下，在干冰/丙酮浴中，3.8 g上述油在40 ml的四氢呋喃中搅拌，滴加17 ml四氢呋喃(43 mmol)中的2.5 M正丁基锂溶液，将溶液在-78°C下搅拌20分钟。 Under nitrogen, in a dry ice / acetone bath, 3.8 g of the above oil in 40 ml of tetrahydrofuran was stirred, 17 ml of tetrahydrofuran was added dropwise (43 mmol) of 2.5 M n-butyllithium solution, at -78 ° C and the solution stirred 20 minutes. 以中等的速度往搅拌的溶液中通入过量的二氧化碳气10分钟。 A moderate speed to a stirred solution leads to an excess of carbon dioxide gas for 10 minutes. 加入二氧化碳后，使反应物慢慢达到室温并搅拌过夜。 After addition of carbon dioxide, the reaction was slowly brought to room temperature and stirred overnight. 反应混合物在乙醚(100 ml)和0.5 N氢氧化钠水溶液(100ml)间分配。 The reaction mixture diethyl ether (100 ml) and 0.5 N aqueous sodium hydroxide solution (100ml) partitioned between. 分离碱层，用浓盐酸酸化至pH2-3。 A base layer separated, acidified to pH2-3 with concentrated hydrochloric acid. 用乙酸乙酯(IOOml)萃取含水混合物，用水和盐水洗涤有机萃取物，并用硫酸镁干燥。 The aqueous mixture was extracted, washed with water and brine and the organic extracts were washed with ethyl acetate (IOOml), and dried over magnesium sulfate. 真空中蒸去溶剂后留下的油状残存物在少量I-氯丁烷中研磨成固体》过 Vacuo to an oily residue was left after evaporation of the solvent in a small amount of I- chlorobutane was triturated to a solid "too

3717心,iw I MC/R > Ί寸i- 密-J-二邦、丁 夕—恐汉敗PR 3717 heart, iw I MC / R> Ί inch i- -J- two secret state, Ding Xi - fear Han defeated PR

(l.4g),为宽熔点固体。 (L.4g), as a solid m.p. wide.

lHNMR(CDCl3)SljUt, 3H), 4.68 (q, 2H), 7.23 (s, 1H), 9.85 (brs，1H)。 lHNMR (CDCl3) SljUt, 3H), 4.68 (q, 2H), 7.23 (s, 1H), 9.85 (brs, 1H).

步骤P: 2-「l-乙基-3-三氟甲基吡哞-5-某氨某甲酰基1-3-甲基-#-Π-甲基乙基)苯甲酰胺的制备. Step P: 2- "l- ethyl-3-trifluoromethyl-pyrazol moo person A certain amino acid methyl -5- 1-3- - # - Π- methylethyl) benzamide.

将草酰氯(1.2 ml, 14 mmol)加到I-乙基-3-三氟甲基-吡唑-5基羧酸(即步骤C的产物）（0.5 g, 2.4 mmol)在20 ml 二氯甲烷中搜拌的溶液中。 Oxalyl chloride (1.2 ml, 14 mmol) was added ethyl 3-trifluoromethyl-I- - pyrazol-5-yl-carboxylic acid (i.e. the product of Step C) (0.5 g, 2.4 mmol) in 20 ml dichloro- methane mix in search of a solution. 刚一加入2滴二甲基甲酿胺，即产生泡沫和气泡。 Just a 2 drops of dimethyl amine wine, which produce foam and bubbles. 反应混合物回流加热I小时，成为黄色溶液。 The reaction mixture was heated at reflux for I h, the solution became yellow. 冷却后，真空除去溶剂，所得残留物溶解于20 ml四氢呋喃中。 After cooling, the solvent was removed in vacuo, the resulting residue was dissolved in 20 ml of tetrahydrofuran. 添加2-氨基-3-甲基-N-(l-甲基乙基)苯甲酸胺(即步骤B的产物)(0.7 g, 3.6 mol)至搅拌的溶液中，然后滴加况抓二异丙基乙胺(3 ml, 17 mmol)。 2-amino-3-methyl -N- (l- methylethyl) benzoic acid amine (i.e. product of Step B) (0.7 g, 3.6 mol) to a stirred solution, followed by dropwise addition of diisopropyl grasping condition propyl amine (3 ml, 17 mmol). 在室温下搅拌过夜后，反应混合物在乙酸乙酯(100 ml)和IN盐酸水溶液(75 ml)间分配。 After stirring at room temperature overnight, the reaction mixture was partitioned between ethyl acetate (100 ml) and IN aqueous hydrochloric acid (75 ml) between. 用水和盐水洗涤分离的有机层，用硫酸镁干燥。 The organic layer was separated and washed with water and brine, dried over magnesium sulfate. 真空蒸发得到白色固体残留物，通过闪蒸硅胶柱色谱(2 : I己烷/乙酸乙酯)纯化得到0.5 g标题化合物，本发明的化合物，在223-226Ό熔化。 And evaporated in vacuo to give a white solid residue by flash column chromatography on silica gel (2: I hexane / ethyl acetate) to give 0.5 g of the title compound, a compound of the present invention, in 223-226Ό melted.

1HNMR(DMSO-Cid)S 1.06 (d，6H), 1.36 (t, 3H), 2.45 (S，3H), 3.97(m, 1H), 4.58 (q, 2H)，7.43-7.25 (m, 3H), 7.45 (s, IH), 8.05 (d,1H), 10.15 (s, 1Η)ο 1HNMR (DMSO-Cid) S 1.06 (d, 6H), 1.36 (t, 3H), 2.45 (S, 3H), 3.97 (m, 1H), 4.58 (q, 2H), 7.43-7.25 (m, 3H) , 7.45 (s, IH), 8.05 (d, 1H), 10.15 (s, 1Η) ο

实施例2 Example 2

iV-[2-甲基-6-[[(l-甲基乙基)氨基■基]苯基]-I-苯基-3-(三氟甲基)-1Η-吡唑-5-酰胺的制备步骤A: 2-甲基-I-苯某-4-f三氟甲基VIH-Ptf：唑的制备 iV- [2- methyl -6 - [[(l- methylethyl) amino ■ yl] phenyl] -I- phenyl-3- (trifluoromethyl) -1Η- pyrazole-5-carboxamide Preparation of Step A: Preparation of oxazole: 2-methyl-phenyl -I- -4-f a trifluoromethyl VIH-Ptf

用冰/水浴将1，1，1-三氟戊烷-2，4-二酮(20.0 g, 0.130 mol)在冰醋酸(60 ml)中的溶液冷却至7*C。 With an ice / water bath 1,1,1-trifluoro-pentane-2,4-dione (20.0 g, 0.130 mol) was cooled to 7 * C in glacial acetic acid (60 ml) in. 在60分钟内滴加苯肼(14.1 g,0.130 mol)。 Solution of phenylhydrazine (14.1 g, 0.130 mol) over 60 minutes. 仕训八以枉亇，汉但初科反TT玉13匕。 Ma Shi Xun eight in vain, but the early Chinese jade Section 13 anti-TT dagger. 主姐Γ Main sister Γ

保持60分钟。 Maintained for 60 minutes. 在浴温65Γ的旋转蒸发仪上提馏除去大部分乙酸。 Stripping to remove most of acetic acid on a rotary evaporator at a bath temperature 65Γ of. 残留物溶解在二氯甲烷C150 ml)中。 The residue was dissolved in dichloromethane C150 ml) in. 用碳酸氢钠水溶液(在50 ml水中3 g)洗漆该溶液。 With sodium bicarbonate solution (50 ml of water at 3 g) and the solution washed paint. 分出紫红色有机层，用活性炭(2 g)和MgSO4处理，然后过滤。 Purple-red organic layer was separated, treated with charcoal and MgSO4 (2 g), and then filtered. 在旋转蒸发仪上除去挥发物。 Removed on a rotary evaporator volatiles. 粗产物由28.0 g玫瑰色油组成，其含有〜89%所需产物和.11%的I-苯基-5-(三氟甲基)-3-甲基吡唑。 The crude product was purified by 28.0 g rose oil composition containing ~89% and .11% of the desired product I- phenyl-5- (trifluoromethyl) -3-methylpyrazole.

'H NMR (DMSO-Jtf) δ 2.35 (s, 3H)，6.76 (s, IH), 7.6-7.5 (m，5H)。 'H NMR (DMSO-Jtf) δ 2.35 (s, 3H), 6.76 (s, IH), 7.6-7.5 (m, 5H). 步骤B: I-苯基-3-(三氟甲基Vlg-吡啤-5-羧酸的制备 Step B: Preparation of I- phenyl-3- (trifluoromethyl Vlg- beer pyrazole 5-carboxylic acid

将粗2-甲基-I-苯基-4-(三氟甲基)-1丑-吡唑(即步骤A的产物）（〜89%, 50.0 g, 0.221 mol)的样品与水(400 ml)和十六病基三甲基氯化铵(4.00 g，0.011 mol)混合》混合物加热到95°C。 The crude -I- phenyl-4-methyl-2- (trifluoromethyl) -1 ugly - pyrazole (i.e. the product of Step A) (~89%, 50.0 g, 0.221 mol) and water samples (400 ml) and hexadecyl trimethyl ammonium chloride disease (4.00 g, 0.011 mol) mixed "mixture is heated to 95 ° C. 以8分钟的间隔， 把高锰酸钾以10等份加入。 At 8 minute intervals, aliquots of the potassium permanganate was added to 10. 在此期间反应物料保持在95-100Ό。 During this period the reaction mass is maintained at 95-100Ό. 在最后一份加入后，该混合物在95-100'C下保持〜15分钟，此时紫色，高锰酸钾的颜色消失。 After the last one was added and the mixture was maintained at ~ 15 minutes 95-100'C, when the color purple, potassium permanganate disappears. 在热的时候(〜75Ό),通过150〜ml粗的玻璃料漏斗中的I cm厚的Ce】iie®硅藻土助滤剂过滤反应物料。 In the heat of the day (~75Ό), by 150~ml coarse frit funnel I cm thick Ce] iie® diatomaceous earth filter aid material response. 滤饼用温水(〜50°C) (3 X100 ml)洗漆。 The filter cake was washed with warm water paint (~50 ° C) (3 X100 ml). 用乙醚(2 X 100 ml)萃取合并的滤液和洗液，除去少量黄色的，非水溶性物质。 With ether (2 X 100 ml) The combined filtrate and washings were extracted to remove a small amount of yellow, water-insoluble material. 水层用氮气吹洗除去残留的乙醚。 The aqueous layer was purged with nitrogen to remove residual ether. 通过滴加浓盐酸酸化清亮、无色的碱溶液，直至pH达到〜1.3 (28g，0.28 mol)。 Acidified by dropwise addition of concentrated hydrochloric clear, colorless alkaline solution, until the pH reached ~1.3 (28g, 0.28 mol). 在加前三分之二酸的过程中，气体激烈释放。 During the first two-thirds increase in the acid gas intense release. 经过滤收集产品，用水洗涤(3X40ml),然后在55Ό真空中干燥过夜。 The product was collected by filtration, washed with water (3X40ml), then dried overnight in a vacuum 55Ό. 产物含有11.7 g白色结晶粉末，经1HNMR检测产物基本纯净。 The product contains 11.7 g of white crystalline powder, substantially pure product by 1HNMR detection.

1H NMR (CDCl3) δ 7.33 (s, IH), 7.4-7.5 (m，5H)。 1H NMR (CDCl3) δ 7.33 (s, IH), 7.4-7.5 (m, 5H).

步骤C: I-苯基-3-f三氟甲某Vlff·吡啐-5-酰氯的制备 Step C: I- phenyl -3-f trifluoroacetic Jiamou Vlff · pyridine -5 chloride spit

将粗I-苯基-3-(三氟甲基吡唑-5-竣酸(即步骤B的产物)(4.13 g,16.1 mmol)的样品溶解在二氯甲烷(45ml)中。用草酸氯(1.80ml, 20.6mmol)处理该溶液，随后用况iV·二甲基甲酰胺(0.010 ml, 0.13 mmol)处理该溶液。在加入二甲基甲酷胺催化剂后片刻，开始气体释 The crude sample I- phenyl-3- (trifluoromethyl pyrazole-5-carboxylic acid (i.e. product of Step B) (4.13 g, 16.1 mmol) was dissolved in dichloromethane (45ml) in. With oxalyl chloride (1.80ml, 20.6mmol) treating the solution, followed by conditions iV ·-dimethylformamide (0.010 ml, 0.13 mmol) treating the solution. After addition of dimethylformamide cool amine catalyst moment, start gas release

39λχ。 39λχ. 仕冲項;米什仟汉战庇η卿〜热后如热芏凹狐力w Shi Chong items; mish thousand Chinese war shelter η State - heat, such as hot Du concave fox force w

钟。 Minutes. 通过在浴温55Ό的旋转蒸发仪上提馏反应混合物，除去挥发物。 By on a rotary evaporator at a bath temperature 55Ό of stripping the reaction mixture to remove volatiles. 产物由4.43 g浅黄色油组成，通过1HNMR观察到的仅有杂质为N,N-二甲基甲酰胺。 4.43 g product as a pale yellow oil by the composition, was observed only by 1HNMR impurity N, N- dimethylformamide.

1H NMR (CDCl3)S 7.40 (m, IH), 7.42 (s, IH), 7.50-7.53 (m, 4H)。 1H NMR (CDCl3) S 7.40 (m, IH), 7.42 (s, IH), 7.50-7.53 (m, 4H). 步骤D:A^2-甲基-6-「「(l-甲基乙基愾基■基I苯基1-1-苯基-3-(三氟甲基Vlff-吡唑-5-酰胺的制备 Step D: A ^ 2- methyl-6 - "'(l- methylethyl group ■ anger I phenyl 1-1- yl-phenyl-3- (trifluoromethyl Vlff- pyrazole-5-carboxamide Preparation

用I-苯基-3-(三氟甲基吡唑)-5-酿氯(即步骤C的产物)(0.55 g, 1.9mmol)处理部分溶解在吡啶(4.0 ml)中的3-甲基靛红酸酐(0.30 g, 1.7nrnol)样品。 With I- phenyl-3- (trifluoromethyl pyrazole) -5- brewing chloride (i.e. the product of Step C) (0.55 g, 1.9mmol) was dissolved in pyridine processing portion (4.0 ml) of 3-methyl- isatoic anhydride (0.30 g, 1.7nrnol) samples. 混合物被加热至〜95°C 2小时。 The mixture was heated to ~95 ° C 2 hours. 所得橙色溶液冷却至29Ό,然后用异丙铵(1.00 g，16.9 mmol)处理。 The resulting orange solution was cooled to 29Ό, then treated with isopropyl ammonium (1.00 g, 16.9 mmol). 反应物料放热至39Ό。 Exothermic reaction mass to 39Ό. 再加热至55Ό 30分钟，即形成许多沉淀。 And then heated to 55Ό 30 minutes, that form a plurality of precipitates. 反应物料溶解在二氯甲烷(150 ml)中。 The reaction mass was dissolved in dichloromethane (150 ml) in. 用酸水溶液(5 ml浓HCl在45 ml水中)，然后用碱水溶·液(2 g碳酸钠在50 ml水中)洗涤该溶液。 With an acid aqueous solution (5 ml of concentrated HCl in 45 ml of water), then (2 g in 50 ml water and sodium carbonate) and the solution was washed with an aqueous alkaline solution *. 有机层用MgSO4干燥，过滤，然后在旋转蒸发伩上浓缩》减至〜4ml时，已形成产物结晶。 The organic layer was dried over MgSO4, filtered, and then concentrated on a rotary evaporator 伩 "is reduced ~4ml, already formed product crystallized. 浆液用〜10 ml乙醚稀释，即有更多的产物沉淀。 The slurry was diluted with ~10 ml of ether, that is the product of more precipitation. 过滤分离产物，用乙醚(2X10 ml)洗漆，然后用水(2X50 ml)洗涤。 The product was isolated by filtration, washed with ether paint (2X10 ml), then washed with water (2X50 ml) and washed. 湿饼在70Ό真空中千燥30分钟。 Dry wet cake in a vacuum thousand 70Ό 30 minutes. 产物，本发明的化合物，由0.52 g乳白色的粉末组成，在260-262°C熔化。 The product, a compound of the present invention, the composition of 0.52 g milky white powder, melting at 260-262 ° C.

1H NMR (DMSO-Cii) δ 1.07 (d, 6H), 2.21 (s, 3H), 4.02 (octet, IH),7.2-7.4 (m, 3H), 7.45-7.6 (m, 6H), 8.10 (d, IH), 10.31 (s, 1H)。 1H NMR (DMSO-Cii) δ 1.07 (d, 6H), 2.21 (s, 3H), 4.02 (octet, IH), 7.2-7.4 (m, 3H), 7.45-7.6 (m, 6H), 8.10 (d , IH), 10.31 (s, 1H).

实施例3 Example 3

从[2-甲基-6-[[(l-甲基乙基)氨基]羰基]苯基]-3_(三氟甲基)-1-[3_(三氟甲基)-2-吡啶基]-1丑-吡唑-5-酰胺的制备步驟A: 3-三氟甲某-243-f三氟甲基Vlff-吡唑-I-基I批啶的制备 From [2-methyl -6 - [[(l- methylethyl) amino] carbonyl] phenyl] -3_ (trifluoromethyl) -1- [3_ (trifluoromethyl) -2-pyridinyl Preparation of 3-trifluoromethyl Jiamou -243-f trifluoromethyl-pyrazol Vlff- -I- piperidin yl I batch of: preparing pyrazole-5-carboxamide Step A -] -1 Ugly

将2-氯-3-三氟甲基吡啶(3.62 g,21 mmol),3-三氟甲基吡唑(2.7 g, 2-Chloro-3-trifluoromethyl pyridine (3.62 g, 21 mmol), 3- trifluoromethyl pyrazole (2.7 g,

40^ UIIUUiuuiiuij口、jf比口切j iuu 匕yjw?<^ ιο ,j、w，j ο 40 ^ UIIUUiuuiiuij mouth, jf j iuu than mouth cut dagger yjw? <^ Ιο, j, w, j ο

冷却的混合物加到冰/水(100ml)中。 The cooled mixture was added to ice / water (100ml) in. 混合物用乙醚(100ml)萃取两次，并且用水(100 ml)洗涤合并的乙醚萃取液'两次。 Mixture was extracted with diethyl ether (100ml) and extracted twice, and washed with water (100 ml) The combined ether extracts were washed "twice. 用硫酸镁干燥有机层，并且浓缩至油。 The organic layer was dried over magnesium sulfate, and concentrated to an oil. 通过硅胶色谱，用己烷：乙酸乙酯8 : I至4 : I作为洗脱剂，得到油状标题化合物(3.5 g)。 By chromatography on silica gel, using hexane: ethyl acetate 8: I to 4: I as the eluent to give the title compound as an oil (3.5 g).

1H NMR (CDCl3)S 6.75 (m, IH), 7.5 (m, IH), 8.2 (m, 2H), 8.7 (m,1H)。 1H NMR (CDCl3) S 6.75 (m, IH), 7.5 (m, IH), 8.2 (m, 2H), 8.7 (m, 1H).

步骤B: 3-Γ三氟甲某νΐ-『3-ί三氟甲基V2-吡啶基I-Itf•吡唑-5-羧酸的制釜 Step B: 3-Γ trifluoromethyl Jiamou νΐ- "3-ί trifluoromethyl V2- pyridyl I-Itf • pyrazole-5-carboxylic acid prepared autoclave

将实施例3，步骤A的标题化合物的混合物(3.4 g, 13 mmol)溶解在四氢呋喃(30 ml)中，并冷却至-70°C»加入二异丙基酰胺锂(2 N 在庚烧/四氢呋喃中，（Aldrich) 9.5 ml, 19 mmol),所得的暗色混合物搅拌10分钟。 3, the mixture (3.4 g, 13 mmol) of the title compound of Step A of Example was dissolved in tetrahydrofuran (30 ml) and cooled to -70 ° C »Add lithium diisopropylamide (2 N in heptane burning / tetrahydrofuran, (Aldrich) 9.5 ml, 19 mmol), the resulting dark mixture was stirred for 10 minutes. 干燥的二氧化碳通入到混合物中15分钟。 Dry carbon dioxide introduced into the mixture for 15 minutes. 让混合物热至23°C,用水(50ml)和I #氢氧化钠(10ml)处理。 The mixture was heated to 23 ° C, washed with water (50ml) and I # NaOH (10ml) treated. 先用乙醚(IOOml),然后用乙酸乙酯(100ml)萃取含水混合物。 First with diethyl ether (IOOml), then (100ml) The aqueous mixture was extracted with ethyl acetate. 7K层用6iV盐酸酸化至pH1-2,再用二氯甲烷萃取两次。 7K 6iV layer was acidified to pH1-2, and extracted twice with dichloromethane. 有机层用硫酸镁干燥，浓缩得到标题化合物(1.5 g)。 The organic layer was dried over magnesium sulfate, and concentrated to give the title compound (1.5 g). ^ ^

1H NMR (CDCl3) δ 7.6 (m, IH), 7.95 (m，IH), 8.56 (m, 1H), 8.9 (m, 1H NMR (CDCl3) δ 7.6 (m, IH), 7.95 (m, IH), 8.56 (m, 1H), 8.9 (m,

IH), 14.2 (br, 1H)。 IH), 14.2 (br, 1H).

步骤C: iV-[2-甲某-6-mi-甲基乙基)氨基I羰基I苯基1-3-(三氟甲基V】-丨3-f三氟甲基V2-吡啶基〗-1开-吡唑·5-酿胺的制备 Step C: iV- [2- Jiamou -6-mi- methylethyl) amino carbonyl group I I phenyl 1-3- (trifluoromethyl V] - 3-f trifluoromethyl Shu V2- pyridyl 〗 -1 open - pyrazole · 5- stuffed amine

用三乙胺(0.9 ml)处理实施例3，步骤B的标题化合物(0.54 g，1.1mmol),实施例I,步骤B的标题化合物(0.44 g, 2.4 mmol)和BOP氯化物(双(2-氧-噁唑烷基)膦酰氯，0.54 g, 2.1 mmol)在乙腈(13 ml)中的混合物。 The title compound (0.44 g, 2.4 mmol) of the title compound with triethylamine (0.9 ml) treated in Example 3, Step B (0.54 g, 1.1mmol), Example I, Step B and BOP chloride (bis (2 - oxo - oxazolidinyl) phosphinic chloride, 0.54 g, 2.1 mmol) in acetonitrile (13 ml) in. 该混合物在密闭的闪烁瓶中摇.动18小时。 The mixture in a closed scintillation vial shake. Move 18 hours. 反应物在乙酸乙酯(100 ml)和IV盐酸间分配。 The reaction was partitioned between ethyl acetate (100 ml) and inter-IV hydrochloric acid. 乙酸乙酯层相继用IiV盐酸(50 ml)、I#氢氧化钠(50 ml)和饱和氯化钠溶液(50 ml)洗潘。 The ethyl acetate layer was washed successively with IiV hydrochloric acid (50 ml), I # sodium hydroxide (50 ml) and saturated sodium chloride solution (50 ml) wash pan. 有机层用硫酸镁干 The organic layer was dried with magnesium

41休，TT处1J小巧日O双田切红社;iXdil·百往，/■« Cl抓/^Li敗G日日、）：i王：）： 41 Hugh, TT at 1J small daily O double Tian cut red society; iXdil · one hundred to, / ■ «Cl catch / ^ Li defeated G day,): i king :):

I)作为洗脱剂。 I) as the eluent. 分离到标题化合物(0.43 g), —种本发明的化合物，为白色固体，mp227-23(TC。 To isolate the title compound (0.43 g), - compounds of the present invention, as a white solid, mp227-23 (TC.

'H NMR (CDCl3) δ 1.2 (m, 6H), 4.l5(m, IH), 5.9 (brd, IH), 7.1 (m, 'H NMR (CDCl3) δ 1.2 (m, 6H), 4.l5 (m, IH), 5.9 (brd, IH), 7.1 (m,

IH), 7.2 (tn, 2H), 7.4 (s，1Η), 7.6 (m, 1H), 8.15 (m, 1H), 8.74 (m, IH), 7.2 (tn, 2H), 7.4 (s, 1Η), 7.6 (m, 1H), 8.15 (m, 1H), 8.74 (m,

I Η), 10.4 (br, 1H)。 I Η), 10.4 (br, 1H).

实施例4 Example 4

I -(3-氯-2-吡啶基)-Λ42-甲基-6-[[(1 -甲基乙基)氨基]羰基]-苯基]-3-(三氟甲基)-1怀吡唑-5-酰胺的制备步骤A: 3-氯-2-「3-(三氟甲基VlH-吡唑-I-基I吡啶的制备· I - (3- chloro-2-pyridinyl) -Λ42- methyl-6 - [[(l - methylethyl) amino] carbonyl] - phenyl] -3- (trifluoromethyl) -1 pregnant Preparation of pyrazole-5-carboxamide Step A: 3- chloro-2- '3- (trifluoromethyl VlH- pyrazol-I-yl pyridine prepared -I- ·

将碳酸钾(166.0 g, 1.2 mol)加入到2，3-二氯吡啶(99.0 g, 0.67 mol)和3-(三氟甲基H比唑(83 g, 0.61 mol)在干燥N，N-二甲基甲酰胺(300ml)中的混合物中，然后该反应加热至110-125Ό 48小时。反应冷却至100Ό，并且通过Celite®硅藻助滤剂过滤除去固体。大气压下蒸馆除去汉#-二甲基甲酰胺和过量的二氯吡啶。减压(bp 139-14rC,7mm)蒸馆产物得到所需的中间体，为清亮的黄色油(113.4 g)。 Potassium carbonate (166.0 g, 1.2 mol) was added to 2,3-dichloropyridine (99.0 g, 0.67 mol) and 3- (trifluoromethyl H ratio azole (83 g, 0.61 mol) in dry N, N- (300ml) in a mixture of dimethylformamide and then the reaction was heated to 110-125Ό 48 hours of reaction was cooled to 100Ό, and the solid was removed by filtration through Celite® diatomaceous filter aid was distilled at atmospheric pressure to remove Kan Han #. - dimethylformamide and excess dichloropyridine. under reduced pressure (bp 139-14rC, 7mm) to give the desired product was distilled Kan intermediate as a clear yellow oil (113.4 g).

1HNMR (CDCl3) δ 6.78 (s, IH), 7.36 (t, IH), 7.93 (d, IH), 8.15 (s, 1HNMR (CDCl3) δ 6.78 (s, IH), 7.36 (t, IH), 7.93 (d, IH), 8.15 (s,

IH), 8.45 (d, 1H)。 IH), 8.45 (d, 1H).

步骤B: IG-氯-2-吡陡基)-3-(三氟甲基Vlff-吡啐-5-羧酸的制备 Step B: IG- steep Chloro-2-yl) -3- (trifluoromethyl Vlff- pyrazole 5-carboxylic acid prepared spit

将-30°C干燥四氢呋喃(300 ml)中的二异丙基酰胺锂(425 m mol)溶液经套管加入到中在-75°C干燥四氢呋喃(700 ml)中的3-氯_2_[3-(三氟甲基吡唑-I-基]卩比啶(即步骤A的产物)(105.0 g, 425 mmol)溶液中。深红色溶液搅拌15分钟，此后在-63O下通入二氧化碳直到溶液变成浅黄色，并且停止放热。反应再搅拌20分钟，然后用水(20 ml)骤冷。减压下除去溶剂，反应混合物在乙醚和0.5 JV氢氧化钠水溶液间分配。用乙醚(3X)洗涤水萃取物，经Celite®硅藻土助滤剂过滤除 The -30 ° C in dry tetrahydrofuran (300 ml) of lithium diisopropylamide (425 m mol) was added via cannula to a solution at -75 ° C in dry tetrahydrofuran (700 ml) of 3-chloro-_2_ [ 3- (trifluoromethyl-pyrazol -I- yl] pyridine Jie ratio (i.e. the product of Step A) (105.0 g, 425 mmol) solution. deep red solution was stirred for 15 minutes, after which the carbon dioxide fed in until -63O The solution turned pale yellow, and stops exothermic. The reaction was stirred for 20 minutes, then washed with water (20 ml) was quenched. The solvent was removed under reduced pressure, the reaction mixture was partitioned between diethyl ether and aqueous sodium hydroxide 0.5 JV with ether (3X ) The extract was washed with water, was removed by filtration through Celite® diatomaceous earth filter aid

42含水混合物并再加入酸以降低pH至2.5-3。 42 aqueous mixture and then adding an acid to lower the pH to 2.5-3. 橙色油凝结成颗粒固体，经过滤，相继用水和I JV盐酸洗涤，并在50°C真空中干燥，得到标题产物，为乳白色固体(130 g)。 Orange oil condensed into particulate solids, was filtered, washed successively with water and hydrochloric acid by I JV, at 50 ° C and dried in vacuo to give the title product as a cream solid (130 g). （来自根据类似方法的另一次操作的产物在175-176Ό熔化。） (According to a similar manner from the product of another run in 175-176Ό melted.)

1H NMR (DMSO-^i) 5 7.61 (s, IH), 7.76 (dd, IH), 8.31 (d, IH), 8.60(d, IH)» 1H NMR (DMSO- ^ i) 5 7.61 (s, IH), 7.76 (dd, IH), 8.31 (d, IH), 8.60 (d, IH) »

步骤C: 8-甲基-2F-3.1-苯并噁嗉-2.4(1/A-二酮的制备 Step C: 8- methyl -2F-3.1- benzoxazin crop -2.4 (Preparation 1 / A- dione

将干燥1，4-二噁烷(50 ml)中三氯甲基氯甲酸酯(8 ml)溶液滴加到干燥1,4-二曝院(50 ml)中的2-氨基-3-甲基苯甲酸(6 g)溶液中，用冰水冷却以保持反应温度低于25V。 The dried 1,4-dioxane (50 ml) of trichloromethyl chloroformate (8 ml) was added dropwise 1,4-dried exposure homes (50 ml) of 2-amino-3- methylbenzoic acid (6 g) was cooled with ice water to keep the reaction temperature below 25V. 滴加期间开始形成白色沉淀物。 A white precipitate began during the addition. 反应混合物在室温下搅拌过夜。 The reaction mixture was stirred at room temperature overnight. 过滤除去沉淀固体，用1，4-二噁烷(2X20 ml)和己烷(2X 15 ml)洗涤，并且风干得到6.51 g乳白色固体。 The precipitated solid was filtered, using 1,4-dioxane (2X20 ml) in hexane (2X 15 ml) was removed and washed, and air dried to give 6.51 g cream solid.

1H NMR (DMSO-Ji) δ 2.33 (s, 3H), 7.18 (t, IH), 7.59 (d, IH), 7.78(d，1H), 11.0 (brs, 1H)。 1H NMR (DMSO-Ji) δ 2.33 (s, 3H), 7.18 (t, IH), 7.59 (d, IH), 7.78 (d, 1H), 11.0 (brs, 1H).

步骤D: 2-ΓΗ3-氯-2-吡啶基V3-(三氟甲基VliJ-吡唑-5-基1-8-甲基-477-3.1 -苯并噁嗪-4-酮的制备 Step D: 2-ΓΗ3- -477-3.1-chloro-2-methyl-pyridyl V3- (trifluoromethyl pyrazol-5-yl 1-8- VliJ- - benzoxazin-4-one was prepared

将W-二甲基甲酰胺(20滴)和草酰氯(67 ml, 750 mmol)以每份约5-ml在约2小时内加入到二氯甲烷(约2 L)中的步骤B制得的羧酸产物(146g, 500mmol)悬浮液中。 The W- dimethylformamide (20 drops) and oxalyl chloride (67 ml, 750 mmol) in approximately 5-ml per period of about 2 hours was added to a dichloromethane (approximately 2 L) obtained in step B The carboxylic acid product (146g, 500mmol) suspension. 在加入期间气体剧烈释放。 Violent release of gas during the addition. 反应混合物在室温下搅拌过夜。 The reaction mixture was stirred at room temperature overnight. 真空下浓缩反应混合物得到粗酰氯，为不透明橙色混合物。 The reaction mixture was concentrated in vacuo to give the crude acid chloride as an opaque orange mixture. 该材料溶解在二氯甲烷中，过滤除去某些固体，然后再浓缩，无进一步纯化下使用》粗酰氯溶解在乙腈(250 ml)中，并加入到乙腈(400ml)中的步骤C的产物的悬浮液中。 This material was dissolved in dichloromethane, filtered to remove some solids, then concentrated, without further purification using the "crude acid chloride was dissolved in acetonitrile (250 ml) in and added to the product of acetonitrile (400ml) in step C, the suspension. 加入吡唆(250ml)，混合物室温下搅拌15分钟，然后升温回流3小时。 Instigate topiramate was added (250ml), the mixture was stirred at room temperature for 15 minutes, then warmed at reflux for 3 hours. 所得混合物冷却至室温并搅拌过夜得到固体物料。 The resulting mixture was cooled to room temperature and stirred overnight to give a solid material. 再加入乙腈，混合该混合物形成稠浆料。 Acetonitrile was added, and the mixture was mixed to form a condensed slurry. 收集固体并用冷乙腈洗涤。 The solid was collected and washed with cold acetonitrile. 风干固_体并90Ό真空中干燥5小吋 _ Dried solid body and vacuum dried for 5 hours 90Ό inch

43以伢到广星H4.« g HS闽件。 43 Ya to Seng H4. «G HS Min pieces.

1H NMR (CDCl3) 5 1.84 (s, 3H), 7.4 (t, 1H), 7.6 (m, 3H), 8.0 (dd,1H), 8.1 (s，1H), 8.6 (d，lH)o 1H NMR (CDCl3) 5 1.84 (s, 3H), 7.4 (t, 1H), 7.6 (m, 3H), 8.0 (dd, 1H), 8.1 (s, 1H), 8.6 (d, lH) o

步骤E: 1-(3-氯-2-吡啶基VJV-『2-甲基-6-m-甲基乙基)氨基機基I苯基1-3-(三氟甲基Vli/-吡呻-5-酰胺的制备 Step E: 1- (3- chloro-2-pyridinyl VJV- "2-methyl -6-m- methylethyl) amino dryer group I phenyl 1-3- (trifluoromethyl Vli / - pyrazol Preparation of amides groan -5-

在室温下将异丙胺(76 ml，900 mmol)滴加至二氯甲烷(500 ml)中的步骤D的苯并嚼嗪酮产物(124 g，300 mmol)的悬浮液中。 A solution of isopropylamine (76 ml, 900 mmol) was added dropwise to benzo dichloromethane (500 ml) in step D oxazinone chew product (124 g, 300 mmol) in suspension. 在滴加期间，反应混合物的温度上升，悬浮液变稀。 During the dropwise addition, the temperature of the reaction mixture rises, the suspension thinned. 然后反应混合物升温至回流1.5小时。 The reaction mixture was then warmed to reflux for 1.5 hours. 形成新的悬浮液。 The new suspension formed. 反应混合物冷却至室温并且加入乙醚(1.3L),将该混合物在室温下搅拌过夜。 The reaction mixture was cooled to room temperature and add diethyl ether (1.3L), and the mixture was stirred at room temperature overnight. 用乙醚洗涤收集的固体。 The collected solid was washed with diethyl ether. 风干固体，然后在90°C真空中干燥5小时得到122 g标题化合物，本发明的化合物，为松软的白色固体，在194-196°C熔化。 Solid was air-dried, then dried for 5 hours to obtain 122 g of the title compound at 90 ° C in vacuo, the compounds of the present invention, as a fluffy white solid, melting at 194-196 ° C. iHNMR(CDCl3)S 1.23 (d, 6H)，2.21 (s, 3H), 4.2(m, 1H), 5.9 (d,1H), 7.2 (t, 1H)，7.3 (m, 2H), 7.31 (s, 1H), 7.4 (m，1H), 7.8 (d,1H), 8.5 (d, 1H), 10.4 (s, 1H)。 iHNMR (CDCl3) S 1.23 (d, 6H), 2.21 (s, 3H), 4.2 (m, 1H), 5.9 (d, 1H), 7.2 (t, 1H), 7.3 (m, 2H), 7.31 (s , 1H), 7.4 (m, 1H), 7.8 (d, 1H), 8.5 (d, 1H), 10.4 (s, 1H).

实施例5 Example 5

1-(3-氯-2-吡啶基)-界[2-甲基-6-[[(l-甲基乙基)氨基]羰基]-苯基]-3-(三氟甲基)-IH-吡唑-5-酰胺的另一制备将iW-二甲基甲酿胺(12滴)和草酰氯(15.8 g, 124 mmol)加入到二氯甲烷(240 ml)中的实施例4,步骤B制备的甲酸产物(28 g, 96mmol)溶液中。 1- (3-chloro-2-pyridyl) - bound [2-methyl -6 - [[(l- methylethyl) amino] carbonyl] - phenyl] -3- (trifluoromethyl) - Another IH- pyrazole-5-carboxamide Preparation of the amine brewing iW- dimethylformamide (12 drops) and oxalyl chloride (15.8 g, 124 mmol) was added to a methylene chloride Example 4 (240 ml) of, acid The product prepared in Step B (28 g, 96mmol) solution. 反应混合物在室温下搅拌，直至气体释放停止(约1.5小时)。 The reaction mixture was stirred at room temperature until gas evolution ceased (about 1.5 hours). 真空下浓缩反应混合物得到粗酰氯，为油状，不作进一步纯化直接使用。 The reaction mixture was concentrated in vacuo to give the crude acid chloride as an oil, used directly without further purification. 粗酰氯溶解在乙腈(95 ml)中，并且加入到乙腈(95 ml)中的实施例4，步骤C制备的苯并噁嗪-2,4-二酮溶液中。 The crude acid chloride was dissolved in acetonitrile (95 ml), and acetonitrile was added to Example (95 ml) of 4-benzoxazine-2,4-dione prepared in Step C in solution. 在室温下搜拌所得混合物(约30分钟)。 Search mix resulting mixture at room temperature (about 30 minutes). 加入吡啶(95 ml),混合物加热至约9(TC(约lh)。反应混合物冷却至约35°C，加入异丙胺(25 ml)。在加入期间反 Pyridine (95 ml), the mixture was heated to about 9 (TC (about lh). The reaction mixture was cooled to about 35 ° C, was added isopropylamine (25 ml). During the addition the anti-

44入冰水中并搅拌。 44 into ice water and stirred. 过滤收集所得沉淀物，用水洗涤，在真空中干燥过夜，得到37.5 g标题化合物，一种本发明的化合物，为棕黄色固体。 Collected by filtration, washed with water and the precipitate was dried under vacuum overnight to give 37.5 g of the title compound, a compound of the present invention, as a tan solid. 1H NMR (CDCl3) 5 1.23 (d, 6H), 2.21 (s, 3H), 4.2 (m, 1H), 5.9 (d, 1H), 7.2 (t, 1H), 7.3 (m, 2H), 7.31 (s, 1H), 7.4 (m, 1H), 7.8 (d, 1H), 8.5 (d，1H), 10.4 (s, 1H)。 1H NMR (CDCl3) 5 1.23 (d, 6H), 2.21 (s, 3H), 4.2 (m, 1H), 5.9 (d, 1H), 7.2 (t, 1H), 7.3 (m, 2H), 7.31 ( s, 1H), 7.4 (m, 1H), 7.8 (d, 1H), 8.5 (d, 1H), 10.4 (s, 1H).

实施例6 Example 6

从[4-氯-2-甲基-6-[[(l-甲基乙基)氣基]羰基]苯基]小(3_氯_2_吡啶基)-3-(三氟甲基)-m•吡唑-5-酰胺的制备步骤A: 2-氨基-3-甲基-5-氯苯甲酸的制备 From [4-chloro-2-methyl -6 - [[(l- methylethyl) gas-yl] carbonyl] phenyl] Small (3_ chloro _2_ pyridinyl) -3- (trifluoromethyl ) -m • Preparation of pyrazole amide Step A -5-: 2- amino-3-methyl-5-chlorobenzoic acid Preparation of

将N-氯丁二酷亚胺(13.3 g，99.2 mmol)加入到汉iV-二甲基甲酰胺(50ml)中的2-氣基-3-甲基苯甲酸(Aldrich, 15.0 g, 99.2 mmol)溶液中， 反应混合物加热至I0(TC 30分钟。停止加热，冷却该反应至室温并保持过夜。然后将反应混合物慢慢倒至冰水(250 ml)中以沉淀白色固体。过滤固体并用水洗潘四次，然后溶解在乙酸乙酯(900 ml)中。用硫酸镁干燥乙酸乙酯溶液，减压下蒸发，乙醚洗涤残留固体，得到所需中间体，为白色固体(13.9 g)。 Cool the imine N- chlorosuccinimide (13.3 g, 99.2 mmol) was added to the Chinese iV- dimethylformamide (50ml) in air-3-methylbenzoic acid 2- (Aldrich, 15.0 g, 99.2 mmol ) solution, the reaction mixture was heated to I0 (TC 30 minutes heating was stopped, the reaction was cooled to room temperature and kept overnight. The reaction mixture was then slowly poured into ice water (250 ml) to precipitate a white solid. The solid was filtered and washed with water Pan four times, and then dissolved in ethyl acetate (900 ml) in. The ethyl acetate solution dried over magnesium sulfate, evaporated under reduced pressure, the residual solid was washed with diethyl ether to give the desired intermediate as a white solid (13.9 g).

1H NMR (DMSO-^is) 2.11 (s, 3H), 7.22 (s, 1H), 7.55 (s, 1H)。 1H NMR (DMSO- ^ is) 2.11 (s, 3H), 7.22 (s, 1H), 7.55 (s, 1H). 步骤B: 3-氯-2-「3-(•三氟甲基VIff-吡唑-I-基I啦啶的制备 Preparation of 3-chloro-2- '3- (• trifluoromethyl VIff- pyrazolo pyridine friends -I- group I: Step B

将碳酸钾(166.0 g, 1.2mol)加入到干燥AW-二甲基甲酰胺(300 ml) 中的2,3-二氯吡啶(99.0 g,0.67 mol)和3-三氟甲基吡唑(83 g,0.61 mol) 混合物中，然后加热该反应至110-125°C 48小时。 Potassium carbonate (166.0 g, 1.2mol) was added to a dried AW- dimethylformamide (300 ml) of 2,3-dichloropyridine (99.0 g, 0.67 mol) and 3-trifluoromethyl pyrazole ( 83 g, 0.61 mol) in the mixture, and the reaction was then heated to 110-125 ° C 48 hours. 反应冷却至100 V,通过Celite®桂藻土助滤剂过滤反应物除去固体。 The reaction was cooled to 100 V, the reaction was filtered through Celite® to remove solids Gui diatomaceous earth filter aid. 大气压下蒸馈除去二甲基甲酰胺和过量的二氯吡啶。 Feeding was distilled at atmospheric pressure to remove dimethylformamide and excess dichloropyridine. 减压(bpl39-14rC，7mm) Decompression (bpl39-14rC, 7mm)

'蒸馏产物，得到标题化合物，为清亮的黄色油(113.4 g)。 'The product was distilled to give the title compound as a clear yellow oil (113.4 g).

1H NMR (CDCl3) 5 6.78 (s, 1H), 7.36 (t, 1H), 7.93 (d, 1H), 8.15 (S， 1H NMR (CDCl3) 5 6.78 (s, 1H), 7.36 (t, 1H), 7.93 (d, 1H), 8.15 (S,

45步骤C: 1-(3-氯-2-吡啶基)-3-(三氟甲基Vlff-吡唑-5-羧酸的制备将-30°C的干燥四氧B夫喃中(300 ml)的二异丙基酰胺锂(425 mmol)溶液经套管加入到在-75'C的干燥四氢呋喃(700 ml)中的步骤B的吡唑产物(105.0 g, 425 mmol)溶液中。搅拌深红色溶液15分钟后，在-63°C下通入二氧化碳直到溶液变成浅黄色，并且停止放热。反应再搅拌20分钟，然后用水(20 ml)骤冷。在减压下除去溶剂，反应混合物在乙醚和0.5 N氢氧化钠水溶液间分配。用乙醚(3 X)洗涤水萃取物，经Celite®挂藻土助滤剂过滤除去残留固体，然后酸化至pH约4,在该点形成橙色油。剧烈搅拌该含水混合物并再加入酸以降低pH至2.5-3»橙色油凝结成颗粒固体，经过滤，相继用水和IN盐酸洗涤，并在50°C真空中干燥，得到标题产物，为乳白色固体(130 g)。（来自根据类似方法的另一操作的产物在175-176°C熔化。） 45 Step C: 1- (3- chloro-2-pyridinyl) -3- (trifluoromethyl Vlff- pyrazole-5-carboxylic acid -30 ° C in dry oxygen B fu furans in four (300 ml) of lithium diisopropylamide (425 mmol) was added via cannula to a solution of pyrazole product in dry tetrahydrofuran (700 ml) at -75'C in Step B (105.0 g, 425 mmol) was stirred After 15 minutes a deep red solution at -63 ° C under carbon dioxide through until the solution became light yellow, and stops exothermic. The reaction was stirred for 20 minutes, then washed with water (20 ml) was quenched. The solvent was removed under reduced pressure, The reaction mixture was partitioned between diethyl ether and 0.5 N aqueous sodium hydroxide. The extract was washed with water and with ether (3 X), linked through Celite® diatomaceous earth filter aid to remove residual solids, and then acidified to a pH of about 4, is formed at the point orange oil. The aqueous mixture was stirred vigorously and then acid is added to lower the pH to 2.5-3 »orange oil condense into particulate solids, was filtered, washed successively with water and IN hydrochloric acid after, at 50 ° C and dried in vacuo to give the title product, as a cream solid (130 g). (product from another operating according to a similar manner to the melt in the 175-176 ° C.)

1H NMR (DMSO-^) 8 7.61 (s, 1H), 7.76 (dd, 1H), 8.31 (d, 1H), 8.60(d, 1H)。 1H NMR (DMSO- ^) 8 7.61 (s, 1H), 7.76 (dd, 1H), 8.31 (d, 1H), 8.60 (d, 1H).

步骤D: 6-氯-2-「1-(3-氯-2-吡啶某)-3-(~三氟甲某~1-1丑-吡啤-5-基1-8-甲基苯并噁嗪-4-酮的制备 Step D: 6- chloro-2 '1- (3-chloro-2-pyridyl a) -3 (~ trifluoromethyl Jiamou ~ 1-1 ugly - beer pyrazol-5-methyl benzene 1-8- and the evil-4-one hydrochloride was prepared

在0-5°C,将乙腈(75 ml；)中的步骤C的甲酸产物(7.5 g,27.0 mmol)和三乙胺(3.75 ml, 27.0mmol)混合物滴加到乙腈(75ml)中的甲磺酰氯(2.2 ml, 28.3 mmol)溶液中。 At 0-5 ° C, acetonitrile (75 ml;) acid product of Step C (7.5 g, 27.0 mmol) and triethylamine (3.75 ml, 27.0mmol) was added dropwise to a mixture of acetonitrile (75ml) of methyl sulfonyl chloride (2.2 ml, 28.3 mmol) solution. 然后在相继加入试剂过程中，反应温度保持在(TC。搅拌20分钟后，加入步骤A的2-氨基-3-甲基-5-氯苯甲酸(5.1g, 27.0nmiol)后再继续搅拌5分钟。然后滴加乙腈(15 ml)中的三乙胺(7_5ml, 54.0 mmol)溶液，反应混合物搜拌45分钟，随后加入甲磺酰氯(2.2 ml, 28.3 mmol)。然后反应混合物升至室温并搅拌过夜。加入约75 ml的水以沉淀5.8 g的黄色固体。通过萃取从滤液中分离到额外的Ig产物，得到总计6.8 g标题化合物，为黄色固体。 Then during successive addition of reagents, the reaction temperature was maintained at (TC. After stirring for 20 minutes, Step A was added 2-amino-3-methyl-5-chlorobenzoic acid (5.1g, 27.0nmiol) and then stirring was continued for 5 minutes then added dropwise acetonitrile (15 ml) in triethylamine (7_5ml, 54.0 mmol) added and the reaction mixture was stirred for 45 minutes found, followed by the addition of methanesulfonyl chloride (2.2 ml, 28.3 mmol). The reaction mixture was warmed to room temperature and then It was stirred overnight. Add about 75 ml of water to precipitate 5.8 g of a yellow solid was isolated from the filtrate to additional Ig purified by extraction to give a total of 6.8 g of the title compound as a yellow solid.

1H NMR (CDCl3) 5 1.83 (s, 3H), 7.50 (s，1H), 7.53 (m，2H)，7.99(m, 1H NMR (CDCl3) 5 1.83 (s, 3H), 7.50 (s, 1H), 7.53 (m, 2H), 7.99 (m,

462H), 8.58 (d，IH)= 462H), 8.58 (d, IH) =

步骤E: 7V-「4-氯-2-甲基-6-17(1-甲基乙基愾基機基I苯基1-1-(3-氯-2-吡啶基V3-(三氟甲基VlH-吡哞-5-酰胺的制备 Step E: 7V- "-6-17 4-chloro-2-methyl (1-methylethyl group dryer group I anger phenyl 1-1- (3-chloro-2-pyridinyl V3- (trifluoro Preparation of methyl VlH- topiramate amide moo -5-

在室温下，将四氢呋喃(10 ml)中的异丙胺(2.9 ml, 34.0 mmol)滴加到四氢呋喃(35 ml)中的步骤D的苯并噁嗪酮产物(5.0 g，11.3 mmol)溶液中。 At room temperature, in tetrahydrofuran (10 ml) in isopropylamine (2.9 ml, 34.0 mmol) was added dropwise to tetrahydrofuran (35 ml) of benzo oxazinone Step D product (5.0 g, 11.3 mmol) solution. 然后反应混合物升温直到固体溶解，再搅拌5分钟，在硅胶薄层色谱上的点证实反应完成。 The reaction mixture was then heated until the solids dissolved, and then stirred for five minutes, the point thin layer chromatography on silica gel confirmed completion of the reaction. 减压下蒸发四氢呋喃溶剂，采用硅胶色谱纯化残留固体，随后用乙醚/己焼研制，得到标题化合物，本发明的化合物，为固体(4.6g),在195-196X：培化。 Tetrahydrofuran solvent was evaporated under reduced pressure, the residual solid was purified by silica gel chromatography, followed by ether / firing has developed, to give the title compound, a compound of the present invention, as a solid (4.6g), in 195-196X: Culture of.

1HNMR(CDCi3)S 1.21 (d, 6H), 2.17 (s, 3H), 4.16 (m, 1H), 5.95 (brd, 1H), 7.1-7.3 (m, 2H), 7.39 (s, 1H), 7.4 (m, 1H), 7.84 (d, 1H),8.50 (d, 1H), 10.24 (br s，1HQ。 1HNMR (CDCi3) S 1.21 (d, 6H), 2.17 (s, 3H), 4.16 (m, 1H), 5.95 (brd, 1H), 7.1-7.3 (m, 2H), 7.39 (s, 1H), 7.4 (m, 1H), 7.84 (d, 1H), 8.50 (d, 1H), 10.24 (br s, 1HQ.

实施例7 Example 7

iV-[4-氯-2-甲基-6-[(甲基氨基)裁基]苯基]-1-(3-氯-2-吡啶基)-3-(三氟甲基> I丑-吡唑-5-酰胺的制备将甲胺(在THF中的2.0 M溶液，15 ml, 30.0 mtnol)滴加到在四氣咲喃(THF, 70ml)中的实施例6,步骤D的苯并噁嗪酮产物(4.50 g, iV- [4- chloro-2-methyl-6 - [(methylamino) CD-yl] phenyl] -1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl> I ugly - Example of Preparation of pyrazole-5-carboxamide Methylamine (2.0 M solution in THF, 15 ml, 30.0 mtnol) was added dropwise to the four gas Misaki furans (THF, 70ml). 6, Step D benzene and oxazinone product (4.50 g,

10.18 _ol)溶液中，在室温下反应混合物搅拌5分钟。 10.18 _ol), stirred for 5 minutes at room temperature the reaction mixture. 减压下蒸发四氢呋喃溶剂，并且釆用硅胶色谱纯化残留固体，得到4.09 g标题化合物，本发明的化合物，为白色固体，在185-186°C焰化。 Tetrahydrofuran solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography preclude the use of a solid, to obtain 4.09 g of the title compound, a compound of the present invention, as a white solid, in the flame of 185-186 ° C.

1H NMR (DMSO-Jrf) 5 2.17 (s, 3H), 2.65 (d, 3H), 7.35 (d, 1H), 7.46(dd, 1H), 7.65 (dd, 1H)，7.74 (s' 1H), 8.21 (d, 1H), 8.35 (br q,1H), 8.74 (d, 1H), 10.39 (s, 1H)。 1H NMR (DMSO-Jrf) 5 2.17 (s, 3H), 2.65 (d, 3H), 7.35 (d, 1H), 7.46 (dd, 1H), 7.65 (dd, 1H), 7.74 (s' 1H), 8.21 (d, 1H), 8.35 (br q, 1H), 8.74 (d, 1H), 10.39 (s, 1H).

473-氯-Al[4-氯-2-甲基-6-[[(l-甲基乙基)氨基]羰基]苯基]-I-(3-氯-2-吡啶基)-1丑-吡唑-5-酰胺的制备步骤A: 3-氯-AW■二甲基-Iif-吡唑-I-磺酰胺的制备 473- chloro -Al [4- chloro-2-methyl -6 - [[(l- methylethyl) amino] carbonyl] phenyl] -I- (3- Chloro-2-pyridyl) -1 ugly - Preparation of pyrazole-5-carboxamide Step A: Preparation of 3-chloro-dimethyl -Iif- -AW ■ -I- pyrazole-sulfonamide

温度保持在-65°C下，将己综中的2.5 M正丁基锂(472 ml, 1.18mol)溶液滴加到在-78°C下干燥四氢呋Pi(1500 ml)中的iV•二甲基氨磺酰吡唑(188.0 g, 1.07 mol)溶液中。 Maintaining the temperature at -65 ° C, a solution of 2.5 M has been mechanized n-butyl lithium (472 ml, 1.18mol) was added dropwise at -78 ° C under dry tetrahydrofuran Pi (1500 ml) of iV • dimethyl sulfamoyl pyrazole (188.0 g, 1.07 mol) solution. 加入完成后，反应混合物再保持在-78°C 45分钟，然后滴加四氢呋喃(120 ml)中的六氯乙炼(279 g, After the addition was complete, the reaction mixture was kept at -78 ° C 45 minutes and then a solution of tetrahydrofuran (120 ml) of hexachloroplatinic acid refining (279 g,

1.18 mol)溶液。 1.18 mol) was added. 该反应混合物在-78°C下保持I小时，升温至-20°C,然后用水(IL)骤冷。 The reaction mixture was kept at -78 ° C in I hour, allowed to warm to -20 ° C, and then washed with water (IL) quenched. 二氯甲烷(4X500ml)萃取反应混合物；用硫酸镁干燥有机萃取物并浓缩。 Dichloromethane (4X500ml) extraction of the reaction mixture; the organic extracts were dried over magnesium sulfate and concentrated. 通过桂胶色谱进一步纯化粗产物，用二氯甲焼作为洗脱剂，得到标题产物化合物，为黄色油(160 g)。 Further purification by gel chromatography Gui crude product with methylene firing as eluent to give the title product compound as a yellow oil (160 g).

1H NMR (CDCl3) 5 3.07 (d, 6H), 6.33 (s, 1H), 7.61 (S，1H)» 1H NMR (CDCl3) 5 3.07 (d, 6H), 6.33 (s, 1H), 7.61 (S, 1H) »

步骤B: 3-氯吡唑的制备 Step B: Preparation of 3-chloro-pyrazole

将步骤A的氯吡唑产物(160 g)滴加到三氟乙酸(290 ml)中，室温下反应混合物搅拌1.5小时，然后减压浓缩。 Chlorine pyrazole product of Step A (160 g) was added dropwise trifluoroacetic acid (290 ml), and the reaction mixture was stirred at room temperature for 1.5 hours, then concentrated under reduced pressure. 残留物溶解在己烷中，过滤出不溶性固体，并浓缩己嫁，得到油状的粗产物。 The residue was dissolved in hexane, insoluble solids were filtered off, and concentrated already married, to give a crude product oil. 粗产物用硅胶色谱进一步纯化，用乙醚/己烷(40: 60)作为洗脱剂，得到标题产物，为黄色油(64.44 g)。 The crude product was further purified by chromatography on silica gel using ether / hexane (40: 60) as eluent to give the title product as a yellow oil (64.44 g).

1H NMR (CDCl3) 5 6.39 (s, 1H), 7.66 (s, 1H), 9.6 (brs，1H)。 1H NMR (CDCl3) 5 6.39 (s, 1H), 7.66 (s, 1H), 9.6 (brs, 1H).

步骤C: 3•氯-2-(3-氯-I啤-I-基Vtt啶的制备 Step C: 3 • chloro-2- (3-chloro--I -I- beer pyridine base Vtt Preparation

将碳酸钾(147.78 g, 1.06 mol)加入到二甲基甲酰胺(400 ml)中的2,3-二氯吡啶(92.60 g, 0.629 mol)和3-氯吡唑(即步骤B的产物）(64.44 g, 0.629 mol)的混合物中，然后反应混合物加热至100°C 36小时。 Potassium carbonate (147.78 g, 1.06 mol) was added to dimethylformamide (400 ml) of 2,3-dichloropyridine (92.60 g, 0.629 mol) and 3-chloro-pyrazole (i.e. the product of Step B) (64.44 g, 0.629 mol) in the mixture, and then the reaction mixture was heated to 100 ° C 36 hours. 反应混合物冷却至室温并缓慢倒入冰水中。 The reaction mixture was cooled to room temperature and slowly poured into ice water. 过滤沉淀固体并用水洗涤。 The precipitated solid was filtered and washed with water. 固体滤饼溶解在乙酸乙酯中，用硫酸镁干燥并进行浓缩。 The solid cake was dissolved in ethyl acetate, dried over magnesium sulfate and concentrated. 粗固体产物在桂胶上层析，用20%乙酸乙酯/己烷作为洗脱剂，得到标 The crude solid product in Guangxi gel eluting with 20% ethyl acetate / hexane as eluent to give

481H NMR (CDCl3) 5 6.43 (s，1H)，7.26 (1x1，1H), 7.90 (d, 1H), 8.09 (s,1H), 8.41 (d, 1H)。 481H NMR (CDCl3) 5 6.43 (s, 1H), 7.26 (1x1,1H), 7.90 (d, 1H), 8.09 (s, 1H), 8.41 (d, 1H).

步骤D: 3-氯-1-0-氯-2-晰啶基)-1丑-吡啤-5-羧酸 Step D: 3- chloro-2-chloro--1-0- Xi pyridyl) -1 ugly - beer pyridine-5-carboxylate

将四氢呋喃中的2.0M 二异丙基酰胺锂(93 ml, 186 mmol)溶液滴加到在-78°C下干燥四氢呋喃(400 ml)中的步骤C的吡唑产物(39.75 g,186mmol)溶液中。 The pyrazole product of 2.0M lithium diisopropylamide (93 ml, 186 mmol) was added dropwise at -78 ° C in dry tetrahydrofuran (400 ml) in tetrahydrofuran Step C (39.75 g, 186mmol) solution in. 在该琥珀色溶液中通入二氧化碳14分钟，随后该溶液变成浅褐黄色。 In this amber solution with carbon dioxide 14 minutes, after which the solution turns pale yellow brown. 用IN氢氧化钠水溶液使反应呈碱性，并用乙醚(2X500ml)萃取。 The reaction with IN aqueous sodium hydroxide solution was made basic and extracted with ether (2X500ml). 用6N盐酸酸化含水萃取物，并用乙酸乙酯(3X500ml)萃取。 , And extracted with ethyl acetate (3X500ml) and acidified with 6N hydrochloric acid aqueous extract. 用硫酸镁干燥乙酸乙酯萃取物并进行浓缩，得到标题产物，为乳白色固体(42.96 g)。 The ethyl acetate extract was dried over magnesium sulfate and concentrated to give the title product as a cream solid (42.96 g). （来自根据类似方法的另一操作的产物在198-199°C熔化。） (Product from another operating according to a similar manner to the melt in the 198-199 ° C.)

1H NMR (DMSO-dtf) 5 6.99 (s, 1H), 7.45 (m, 1H), 7.93 (d, 1H), 8.51·(d, 1H)。 1H NMR (DMSO-dtf) 5 6.99 (s, 1H), 7.45 (m, 1H), 7.93 (d, 1H), 8.51 · (d, 1H).

步骤E: 6-氯-2-丨3-氲-IG-氯-2-吡啶基Vlif-吡啤-5-基1-8-甲基-4g-3,l-苯并噁嗪-4-酮的制备 Step E: 6- chloro-2- Shu Yun -IG- 3- chloro-2-pyridinyl Vlif- beer pyrazol-5-methyl-1-8- -4g-3, l- benzoxazin-4 -one

在-5°C下，将乙腈(150 ml)中的步骤D的甲酸产物(15.0 g, 58.16mrnol)和三乙胺(5.88 g, 58.16 mmol)的混合物滴加到乙腈(150 ml)中的甲磺酰氯(6.96 g, 61.06 mmol)溶液中。 At -5 ° C, a solution of the product of formic acid in acetonitrile (150 ml) of Step D (15.0 g, 58.16mrnol) and triethylamine (5.88 g, 58.16 mmol) was added dropwise to a mixture of acetonitrile (150 ml) of Methanesulfonyl chloride (6.96 g, 61.06 mmol) solution. 然后该反应混合物在(TC搅拌30分钟。然后'加入实施例6,步骤A的2-氨基-3-甲基-5-氯苯甲酸(10.79 g, 58.16 mmol),并再继续搅拌10分钟。然后滴加乙腈中的三乙胺(11.77 g, H6.5 mmol)溶液，同时保持10°C以下的温度。反应混合物在0°C搅拌60分钟，然后加入甲磺酰氯(6.96 g, 61.06 mmol)。随后将反应混合物升温至室温并再搅拌2小时。然后浓缩反应混合物，粗产物在桂胶上层析，用二氯甲烧作为洗脱剂，得到标题产物，为黄色固体(9.1 g)。 - The reaction mixture is then stirred at (TC 30 min, then 'Save Example 6, Step A 2-amino-3-methyl-5-chlorobenzoic acid (10.79 g, 58.16 mmol), and stirring was continued for 10 minutes. acetonitrile was then added dropwise triethylamine (11.77 g, H6.5 mmol) was added dropwise while maintaining the temperature below 10 ° C. The reaction mixture was stirred at 0 ° C 60 min, then methanesulfonyl chloride (6.96 g, 61.06 mmol ). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was then concentrated and the crude product was chromatographed on Gui gel, with methylene burning as eluent to give the title product as a yellow solid (9.1 g) -

1HNMr(CDCI3)S 1.81 (s，3H), 7.16 (s, 1H), 7.51 (m, 2H), 7.98 (d, 1HNMr (CDCI3) S 1.81 (s, 3H), 7.16 (s, 1H), 7.51 (m, 2H), 7.98 (d,

492H)，8.56 (d, 1H)。 492H), 8.56 (d, 1H). 步骤F: 3-氯-#-「4-氯-2-甲基-6-ITn-甲基乙基)氨基I羰基I苯基氯-2-吡啶基VlH•-吡哞-5-酰胺的制备 Step F: 3- Chloro - # - "4-chloro-2-methyl -6-ITn- methylethyl) amino carbonyl I I-chloro-phenyl-2-pyridinyl VlH • - pyrazol moo -5- amide preparation

将异丙胺(4.23 g, 72.74 mmol)加入到四氢呋喃(100 ml)中的步骤E的苯并噁嗪酮产物(6.21 g，15.21 rrnnol)的溶液中，然后反应混合物加热至60°C,搅拌I小时，然后冷却至室温。 Solution of diisopropylamine (4.23 g, 72.74 mmol) was added to a tetrahydrofuran (100 ml) of Step E benzoxazinone product (6.21 g, 15.21 rrnnol), and then the reaction mixture was heated to 60 ° C, stirred for I hours, then cooled to room temperature. 在减压下蒸发四氢呋喃溶剂，并且残留固体经硅胶色谱纯化，得到标题化合物，本发明的化合物，为白色固体(5.05 g),在173-175°C溶化。 Tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by silica gel chromatography to give the title compound, a compound of the present invention, as a white solid (5.05 g), melting at 173-175 ° C.

1H NMR (CDCl3) 8 1.23 (d, 6H), 2.18 (s, 3H), 4.21 (m, 1H), 5.97 (d,1H), 7.01 (m, 1H)，7.20 (s, 1H), 7.24 (s, 1H), 7.41 (d, 1H), 7.83(d, 1H), 8,43 (d，1H), 10.15 (brs, 1H)。 1H NMR (CDCl3) 8 1.23 (d, 6H), 2.18 (s, 3H), 4.21 (m, 1H), 5.97 (d, 1H), 7.01 (m, 1H), 7.20 (s, 1H), 7.24 ( s, 1H), 7.41 (d, 1H), 7.83 (d, 1H), 8,43 (d, 1H), 10.15 (brs, 1H).

实施例9 Example 9

3-氯-#-[4-氯-2-甲基-6-[(甲基氨基)撰基]苯基]-1-(3-氯-2-敝啶基>1乐吡唑-5-酸胺的制备将甲胺(在THF中的2.0 M溶液，38 ml, 77.38 mmol)加入到四氢呋喃(50 ml)中的实施例8,步骤E的苯并嚼凑酮产物(6.32 g, 15.47mmol)溶液中，并且反应混合物加热至6(TC，搅拌I小时，然后冷却至室温。在减压下蒸发四氢呋喃溶剂，残留固体经硅胶色谱纯化，得到标题化合物，本发明的化合物，为白色固体(4.57 g),在225-226T；熔化。 3-chloro - # - [4-chloro-2-methyl-6 - [(methylamino) essays yl] phenyl] -1- (3-chloro-2-piperidyl spacious> 1 Le pyrazole -5 - Preparation of acid amine methylamine (2.0 M solution in THF, 38 ml, 77.38 mmol) was added to tetrahydrofuran (50 ml) of Example 8, Step E benzo chew Minato ketone product (6.32 g, 15.47 mmol) solution and the reaction mixture was heated to 6 (TC, stirred for I h, then cooled to room temperature in tetrahydrofuran solvent was evaporated under reduced pressure, the solid residue was purified by silica gel chromatography to give the title compound, a compound of the present invention, as a white solid (4.57 g), in 225-226T; melted.

1HNMr(CDCI3) 5 2.15 (s, 3H), 2.93 (s，3H), 6.21 (d, IH), 7.06 (s,1H), 7.18 (s, 1H), 7.20 (s，1H)，7.42 (m, 1H)，7.83 (d, 1H), 8.42(d, 1H), 10.08 (brs, 1H)。 1HNMr (CDCI3) 5 2.15 (s, 3H), 2.93 (s, 3H), 6.21 (d, IH), 7.06 (s, 1H), 7.18 (s, 1H), 7.20 (s, 1H), 7.42 (m , 1H), 7.83 (d, 1H), 8.42 (d, 1H), 10.08 (brs, 1H).

503-溴善[4-氯-2-甲基-6-[[(l-甲基乙基)氣基]羰基]苯基]-1-(3-氯-2-卩比睡基)-1乐吡唑-5-酰胺的制备步骤A: 3-逭-W-二甲基-I丑-吡啐-I-磺酰胺的制备 503- Good bromo [4-chloro-2-methyl -6 - [[(l- methylethyl) gas-yl] carbonyl] phenyl] -1- (3-chloro-2-Jie ratio sleep-yl) - 1 Le pyrazole-5-amide preparation steps A: 3- escape dimethyl -I ugly -W- - pyridine sulfonamide prepared spit -I-

温度保持低于-60°C,将正丁基锂(2.5 M在己烷中，105.5 ml, 0.264mol)滴加到-78°C下干燥四氢呋喃(500 ml)中的iV-二甲基氨磺酰吡唑(44.0 g, 0.251 mol)溶液中。 Maintaining the temperature below -60 ° C, n-butyllithium (2.5 M in hexanes, 105.5 ml, 0.264mol) was added dropwise at -78 ° C in dry tetrahydrofuran (500 ml) of iV- dimethylsulfamoyl sulfonyl pyrazole (44.0 g, 0.251 mol) solution. 滴加期间形成稠密的固体。 Forming a dense solid during the addition. 滴加完成后，反应混合物再保持15分钟，然后温度保持在-70°C以下，滴加四氢呋喃(150 ml)中的1，2-二溴四氯乙烧(90 g，0.276mol)溶液。 After completion of the dropwise addition, the reaction mixture was held for 15 minutes and then the temperature was maintained at -70 ° C or less, was added dropwise tetrahydrofuran (150 ml) of ethyl 1,2-dibromo-tetrachloro burning (90 g, 0.276mol) was added. 反应混合物变成清亮的植色;再持续搅拌15分钟。 The reaction mixture became a clear color explant; stirring was continued for 15 minutes. 除去-78"C浴并且反应用水(600ml)骤冷。二氯甲烷(4X)萃取反应混合物，用硫酸镁干燥有机萃取物并进行浓缩。粗产物经硅胶色谱进一步纯化，用二氯甲烷/己烷(50 : 50)作为洗脱剂，得到标题化合物，为清亮的无色油(57.04 g)。 Removing -78 "C water bath and the reaction (600ml) quenched dichloromethane (4X) the reaction mixture was extracted, the organic extracts were dried over magnesium sulfate and concentrated. The crude product was further purified by chromatography on silica gel using dichloromethane / hexyl alkyl (50: 50) as eluent to give the title compound as a clear colorless oil (57.04 g).

1H NMR (CDCl3) 8 3.07 (d, 6H), 6.44 (m, 1H), 7.62 (m, 1H)。 1H NMR (CDCl3) 8 3.07 (d, 6H), 6.44 (m, 1H), 7.62 (m, 1H).

步骤B: 3-漳吡唑的制备 Step B: Preparation of 3 Zhang pyrazole

将步骤A的溴吡哩产物(57.04 g)缓慢加入到三氟乙酸(70 ml)中。 The pyridostigmine mile product of Step A (57.04 g) was slowly added to trifluoroacetic acid (70 ml) in. 室温下搅拌反应混合物30分钟，然后在减压下浓缩。 The reaction mixture was stirred at room temperature for 30 minutes, then concentrated under reduced pressure. 残留物溶解在己炼中，过滤不溶性固体，蒸发己烷，得到油状粗产物。 The residue is dissolved in hexyl refining, the insoluble solid was filtered, evaporated with hexane to afford an oily crude product. 粗产物经用乙酸乙酯/二氯甲烷(10: 90)作为洗脱剂的硅胶色谱进一步纯化，得到油状物。 The crude product was purified by using ethyl acetate / dichloromethane: silica gel chromatography (10 to 90) as an eluent and further purified to give an oil. 将该油溶解在二氯甲烷中，用碳酸氧铀水溶液中和，二氯甲烷(3X)萃取，用硫酸镁干燥并进行浓缩，得到标题产物，为白色固体(25.9 g), mp61-64'C。 The oil was dissolved in dichloromethane, washed with an aqueous solution of uranyl carbonate and dichloromethane (3X) was extracted, dried over magnesium sulfate and concentrated to give the title product as a white solid (25.9 g), mp61-64 ' C.

1HNMR(CDCl3) S 6.37(d, 1H), 7.59 (d, 1H), 12.4 (brs, 1H)。 1HNMR (CDCl3) S 6.37 (d, 1H), 7.59 (d, 1H), 12.4 (brs, 1H).

步骧C： 2-G-湟-Ii/-吡啤某V3-氯吡啶的制备 Step Xiang C: 2-G- Huang -Ii / - Preparation of topiramate beer a V3- chloropyridine

将碳酸钾(48.6 g, 352 mmol)加入到干燥N,N-二甲基甲酰胺(88 ml)中的2,3-二氯吡啶(27.4 g, 185 mmol)和3-漠败唑(即步骤B的产物）(25.4 g, 176 mmol)的混合物中，并且反应混合物加热至125°C 18小 Potassium carbonate (48.6 g, 352 mmol) was added to the dried N, N- dimethylformamide (88 ml) of 2,3-dichloropyridine (27.4 g, 185 mmol) and 3-yl desert failure (i.e. product of Step B) (25.4 g, 176 mmol) in the mixture and the reaction mixture was heated to 125 ° C 18 Small

51沉淀搅拌1.5小时，过滤并用水(2X IOO ml)洗涤。 51 The precipitate was stirred for 1.5 hours, filtered and washed with water (2X IOO ml) and washed. 固体滤饼溶解在二氯甲烷中并相继用水、IN盐酸、饱和碳酸氢钠水溶液和盐水洗涤。 The solid cake was dissolved in methylene chloride and washed successively with water, IN hydrochloric acid, saturated aqueous sodium bicarbonate and brine. 然后用硫酸镁干燥有机萃取物并进行浓缩，得到39.9 g粉红色固体。 Then the organic extracts were dried over magnesium sulfate and concentrated to give 39.9 g of pink solid. 将粗固体产物悬浮在己烷中并剧烈搅拌I小时。 The crude solid product was suspended in hexane and stirred vigorously for I hour. 过滤固体，用己烷洗涤并干燥，得到标题产物，为乳白色粉末(30.4 g),经NMR测定达到>94%纯度。 The solid was filtered, washed with hexane and dried to give the title product as a milky white powder (30.4 g), measured by NMR reached> 94% purity. 该物质不做进一步纯化用于步骤D中。 This material was used without further purification Step D.

1H NMR (CDCl3) 5 6.52 (s, 1H), 7.30 (dd, 1H)，7.92 (d, 1H), 8.05 (s,1H), 8.43 (d，1H)。 1H NMR (CDCl3) 5 6.52 (s, 1H), 7.30 (dd, 1H), 7.92 (d, 1H), 8.05 (s, 1H), 8.43 (d, 1H).

步骤D: 3-溴-IG-氯-2-吡啶基Vlff-吡呻-5-羧酸的制备 Step D: Preparation of pyrazole 5-carboxylic acid groan -IG--chloro-3-bromo-2-pyridinyl Vlff-

以将温度保持在-7rc以下的速度，将四氢呋喃中的二异丙基酰胺锂溶液滴加到-76°C下千燥四氢呋喃(250 ml)中的步骤C的吡唑产物(30.4 g，118 mmol)溶液中。 In keeping the temperature below -7rc speed, the tetrahydrofuran solution of lithium diisopropylamide was added dropwise at -76 ° C was dry tetrahydrofuran pyrazole product (250 ml) of Step C (30.4 g, 118 mmol) solution. 反应混合物在-76°C下搅拌15分钟，然后通入二氧化碳10分钟，导致升温至-57°C。 The reaction mixture was stirred at -76 ° C for 15 minutes, then purged with carbon dioxide for 10 minutes, warmed to lead to -57 ° C. 反应混合物升温至-20°C并用水骤冷。 The reaction mixture was warmed to -20 ° C and quenched with water. 浓缩反应混合物并在水(IL)和乙醚(500 ml)中溶解，然后加入氢氧化钠水溶液(IN, 20 ml)。 The reaction mixture was concentrated and dissolved in water (IL) and ether (500 ml), followed by aqueous sodium hydroxide solution (IN, 20 ml). 用乙醚洗涤水萃取物并用盐酸酸化。 The extract was washed with ether and water and acidified with hydrochloric acid. 过滤沉淀固体，用水洗涤并干燥，得到标题产物，为棕黄色固体(27.7 g)。 The precipitated solid was filtered, washed with water and dried to give the title product as a tan solid (27.7 g). （来自根据类似方法的另一操作的产物在200-201°C熔化。） (Product from another operating according to a similar manner to the melt in the 200-201 ° C.)

1H NMR (DMSO-^) 8 7.25 (s, 1H), 7.68 (dd, 1H), 8.24 (d, 1H), 8.56(d, 1H)。 1H NMR (DMSO- ^) 8 7.25 (s, 1H), 7.68 (dd, 1H), 8.24 (d, 1H), 8.56 (d, 1H).

步骤E: 2-「3-溴-IG-氯-2-吡聢基Vlff-吡啤-5-基1-6-氯-8-甲基-4//-3.1-苯并嚷嚷-4-丽的制备 Step E: 2- "-IG- chloro-3-bromo-2-yl Vlff- Ding beer pyrazol-5-chloro-8-methyl-1-6- // - 3.1 Benzo yell -4- Preparation Korea

采用类似于实施例6,步骤D的方法，将实施例10,步骤D的吡唑甲酸产物(1.5 g, 4.96 mmol)和2-氨基-3-甲基-5-氯苯甲酸(0.92 g，4.96mmol)转化成标题产物，为固体(1.21 g)。 Using similar to Example 6, Step D, Example 10, pyrazole carboxylic acid product of Step D (1.5 g, 4.96 mmol) and 2-amino-3-methyl-5-chlorobenzoic acid (0.92 g, 4.96mmol) converted to the title product as a solid (1.21 g).

1H NMR (CDCl3) 5 2.01 (s, 3H), 7.29 (s, 1H), 7.42 (d, 1H), 7.95 (d, 1H NMR (CDCl3) 5 2.01 (s, 3H), 7.29 (s, 1H), 7.42 (d, 1H), 7.95 (d,

52步骤F: 3-溴善「4_氯-2-甲基-6-「f(l-甲基乙基愾基懺基I苯基1-1-(3-氯-2-吡啶基Vlg-吡啤-5-酰胺的制备 52 Step F: 3- bromo-good "4_-chloro-2-methyl-6-" f (l- methyl ethyl anger phenyl group I repent group 1-1- (3-chloro-2-pyridyl Vlg - Preparation of topiramate amide beer -5-

将异丙胺(0.122 ml, 1.42 mmol)加入到四氢呋喃中的步骤E的苯并噁嗪酮产物(0.20 g, 0.44 mmol)溶液中，反应混合物加热至60°C 90分钟，然后冷却至室温。 The isopropylamine (0.122 ml, 1.42 mmol) was added to a tetrahydrofuran Step E benzoxazinone product (0.20 g, 0.44 mmol) solution, the reaction mixture was heated to 60 ° C 90 minutes and then cooled to room temperature. 减压下蒸发四氢呋喃溶剂，用乙醚研制残余固体，过滤，并干燥，得到标题化合物，本发明的化合物，为固体(150mg), mpl59-161°C。 Tetrahydrofuran solvent was evaporated under reduced pressure, the residual solid was triturated with ether, filtered and dried to give the title compound, a compound of the present invention, as a solid (150mg), mpl59-161 ° C.

1H NMR (CDCl3) 5 1.22 (d, 6H), 2.19 (S，3H)，4.21 (m，1H), 5.99 (m，1H), 7.05 (m，1H), 7.22 (m, 2H), 7.39 (m, IH), 7.82 (d, 1H), 8.41(d, 1H)。 1H NMR (CDCl3) 5 1.22 (d, 6H), 2.19 (S, 3H), 4.21 (m, 1H), 5.99 (m, 1H), 7.05 (m, 1H), 7.22 (m, 2H), 7.39 ( m, IH), 7.82 (d, 1H), 8.41 (d, 1H).

实施例11 3-溴-jV-「4-氯-2-甲某-6-K甲某氣某I餓基I苯基I-1 -(3-氯-2-吡啶某VIH-吡哞-5-酰胺的制备将甲胺(在THF.中的2.0M溶液，0.514ml，1.02 mmol)加入到四氢呋喃中的实施例10,步骤E的苯并囉嗪酮产物(0.20 g，0.44 mmol)溶液中，反应混合物加热至60°C 90分钟，然后冷却至室温。减压下蒸发四氢呋喃溶剂，用乙醚研制残留固体，过滤，并干燥得到标题化合物，本发明的化合物，为固体(40mg), mpl62-164°C。 Example 11 3-Bromo -jV- "4-chloro-Jiamou -6-K Jiamou gas I was hungry for a phenyl group I I-1 - (3- chloro-2-pyridyl a VIH- topiramate moo - Preparation of 5 mg of methylamine (2.0M solution in THF. The, 0.514ml, 1.02 mmol) in tetrahydrofuran was added to Example 10, Step E benzo-triazin La ketone product (0.20 g, 0.44 mmol) solution of The reaction mixture was heated to 60 ° C 90 minutes and then cooled to room temperature. The solvent tetrahydrofuran was evaporated under reduced pressure, the residual solid was triturated with ether, filtered and dried to give the title compound, a compound of the present invention, as a solid (40mg), mpl62 -164 ° C.

1H NMR (CDCl3) 8 2.18 (s, 3H), 2.95 (s, 3H), 6.21 (m, 1H), 7.10 (s,1H), 7.24 (m, 2H), 7.39 (m, 1H), 7.80 (d, 1H), 8.45 (d, 1H)。 1H NMR (CDCl3) 8 2.18 (s, 3H), 2.95 (s, 3H), 6.21 (m, 1H), 7.10 (s, 1H), 7.24 (m, 2H), 7.39 (m, 1H), 7.80 ( d, 1H), 8.45 (d, 1H).

下面的实施例12说明了另一种制备3-氯-l-(3-氯-2-B比啶基)-LH■-吡唑-5-羧酸的方法， 通过实施例8和9所述的进一步的步骤，该化合物可用于制备，例如，3-氯-N_[4-氯-2-甲基-6-[[(l-甲基乙基)氨基]羰基]苯基]-1-(3-氯-2-吡啶基)-lH-吡唑-5-酰胺和3-氯-N-[4-氯-2-甲基-6-[(甲基氨基)羰基]苯基]-1-(3-氯-2-B比啶基)-lH-卩比唑-5-醜胺。 The following Example 12 illustrates an alternative (3-chloro -2-B ratio piperidinyl) -LH ■ Preparation of 3-chloro -l- - Method pyrazole-5-carboxylic acid, Examples 8 and 9 further steps described below, the compound can be used to prepare, for example, 3-chloro -N_ [4- chloro-2-methyl -6 - [[(l- methylethyl) amino] carbonyl] phenyl] -1 - (3-chloro-2-pyridinyl) -lH- pyrazole-5-carboxamide and 3-chloro -N- [4- chloro-2-methyl-6 - [(methylamino) carbonyl] phenyl] 1- (3-chloro -2-B ratio pyridyl) -lH- Jie ugly than-5-amine.

53头她例Yi 53 She Cases Yi

3-氯-1-(3-氯-2-吡啶基)-lH-吡唑-5-羧酸的制备步骤A: 2-(3-氯-2-吡啶基V5-氧-3-吡哞烷羧酸乙酯f另一个命名是1-0-氯-2-B比啶基V3-批唑烷酮-5-羧酸乙酯)的制备 3-chloro-1- (3-chloro-2-pyridinyl) -lH- pyrazole-5-carboxylic acid Step A: 2- (3- chloro-2-oxo-3-pyridinyl V5- pyrazol moo alkyl carboxylate f another named 1-0- chloro -2-B ratio piperidinyl V3- approved oxazolidinone-5-carboxylate) Preparation

在装有机械搅拌器、温度计、加液漏斗、回流冷凝器和氮气入口的2-L四颈烧瓶中装入无水乙醇(250 ml)和乙氧基钠的乙醇溶液(21%，190 ml, 0.504 mol)。 Equipped with a mechanical stirrer, thermometer, addition funnel, reflux condenser and nitrogen inlet 2-L four-necked flask was charged with absolute ethanol (250 ml) and sodium ethoxide in ethanol solution (21%, 190 ml , 0.504 mol). 混合物加热至约83°C回流。 The mixture was heated to about 83 ° C to reflux. 然后用3-氯-2(lii)-R比淀酮腙(pyridinone hydrazone) (68.0 g, 0.474 mol)处理混合物。 Then 3-chloro -2 (lii) -R than starch hydrazone (pyridinone hydrazone) (68.0 g, 0.474 mol) mixture was treated. 混合物再加热至回流5分钟。 The mixture was then heated to reflux for 5 minutes. 然后用马来酸二乙酯(88.0 ml, 0.544mol)滴加处理黄色浆料5分钟。 Then with diethyl maleate (88.0 ml, 0.544mol) was added dropwise a yellow slurry was treated 5 minutes. 在滴加期间，回流速度显著上升。 During the addition, the reflux rate increased significantly. 在结束滴加时，所有起始物质都已溶解。 At the end of the addition, all the starting material had dissolved. 所得橘红色溶液回流10分钟。 The resulting orange solution was refluxed for 10 minutes. 然后冷却至65°C,用冰醋酸(50.0ml, 0.873 mol)处理反应混合物。 Then cooled to 65 ° C, the reaction mixture was treated with glacial acetic acid (50.0ml, 0.873 mol). 形成沉淀。 A precipitate formed. 用水(650 ml)稀释混合物，使得沉淀溶解。 Washed with water (650 ml) the mixture was diluted such that the precipitate dissolved. 橙色溶剂在冰浴中冷却。 Orange solvent cooled in an ice bath. 产物在28°C开始沉淀。 The product began to precipitate at 28 ° C. 浆料置于约2°C 2小时。 Slurry to about 2 ° C 2 hours. 产物经过滤分离，用含水乙醇(40%, 3X50ml)洗涤，然后在过滤器上风干约I小时。 The product was isolated by filtration, washed with aqueous ethanol (40%, 3X50ml) washed and then air-dried on the filter for about I hour. 得到标题化合物，为高度结晶，淡橙色粉末(70.3 g, 55%收率)。 To give the title compound as a highly crystalline, light orange powder (70.3 g, 55% yield). 经1H NMR检测无显著杂质。 By 1H NMR detected no significant impurities.

1H NMR (DMSO-Jtf) S 1.22 (t, 3H), 2.35 (d, 1H)，2.91 (dd, 1H), 4.20(q, 2H), 4.84 (d, 1H), 7.20 (dd, 1H), 7.92 (d, IH), 8.27 (d, 1H), 1H NMR (DMSO-Jtf) S 1.22 (t, 3H), 2.35 (d, 1H), 2.91 (dd, 1H), 4.20 (q, 2H), 4.84 (d, 1H), 7.20 (dd, 1H), 7.92 (d, IH), 8.27 (d, 1H),

10.18 (s，1H)。 10.18 (s, 1H).

步骤B: 3-氯-1-(3-氯-I-批啶基V4.5-二氢-IH-吡唑-5-羧酸乙酯域者命名为1-(3-氯-2-吡啶基V3-氯-2-吡唑啉-5-羧酸乙酯)的制备将乙腈(1000 ml)、2-(3-氯-2-吡啶基)-5-氧-3-吡哩焼羧酸乙酯(即步骤A 的产物）(91.0 g，0.337 mol)和磷酰氯(35.0 ml, 0.375 mol)装入装有机械搅拌器、温度计、回流冷凝器和氣气入口的2-L的四颈烧瓶中。一加入磷酰氯，混合物即自身放热从22°C至25°C并形成沉淀。淡黄色浆料加热至83T：回流35分钟，沉淀即溶解。所得橙色溶液回流45 Step B: 3- chloro-1- (3-chloro -I- batch piperidinyl V4.5- dihydro -IH- pyrazole-5-carboxylate by domain name is 1- (3-chloro- pyridyl V3--chloro-2-pyrazoline-5-carboxylate) A mixture of acetonitrile (1000 ml), 2- (3- chloro-2-pyridinyl) -5-oxo-3-pyrazol firing miles carboxylate (i.e. the product of Step A) (91.0 g, 0.337 mol) and phosphorus oxychloride (35.0 ml, 0.375 mol) is loaded with mechanical stirrer, thermometer, reflux condenser and gas inlet of the 2-L four- The neck flask, a phosphorus oxychloride was added, the mixture that is self-heating from 22 ° C to 25 ° C and a precipitate formed pale yellow slurry was heated to 83T:.. under reflux for 35 minutes, the precipitate will dissolve the resulting orange solution was refluxed 45

54yj ^Tf 广口然^田;日 别：令汉， 54yj ^ Tf ^ Tian Ran wide mouth; day do not: make the Han,

去650 ml溶剂。 To 650 ml solvent. 在装有机械搅拌器的另一个2-L四颈烧瓶中装入碳酸氯钠(130 g, 1.55 mol)和水(400 ml)。 Chloro charged sodium carbonate (130 g, 1.55 mol) and water (400 ml) equipped with a mechanical stirrer, another 2-L four-necked flask. 在15分钟时间内，将浓缩的反应混合物加入到碳酸氢钠楽料中。 Within 15 minutes, the reaction mixture was added to a concentrated sodium bicarbonate yue compound. 将所得到的两相混合物剧烈搅拌20分钟，此时气体释放停止。 The resulting two-phase mixture was vigorously stirred for 20 minutes at which time gas evolution stopped. 用二氯甲烷(250 ml)稀释混合物，然后搅拌50分钟。 The mixture was diluted with dichloromethane (250 ml), followed by stirring for 50 minutes. 用Celite®5.45硅藻土助滤剂(I〗g)处理混合物，然后过滤除去黑色的、焦油状的物质，该物质抑制相分离。 Celite®5.45 diatomaceous earth filter aid with (I〗 g) processing the mixture, then filtered to remove a black, tarry substance that inhibited phase separation. 从滤液慢慢地分离成不同的相开始，用二氯甲烷(200 ml)和水(200ml)稀释之，并用更多的Celite®545 (15 g)处理之。 From the filtrate slowly separated into different phases started, diluted with dichloromethane (200 ml) and water (200ml), and treated with more Celite®545 (15 g) of the treated. 过滤混合物，滤液转入分离漏斗。 The mixture was filtered, the filtrate was transferred to a separatory funnel. 分离出更重的、深绿色有机层。 Isolated heavier, deep green organic layer. 再过滤碎层(rag layer) (50 ml),然后将其加入到有机层中。 Refiltered broken layer (rag layer) (50 ml), then added to the organic layer. 用硫酸镁(30 g)和硅胶(12 g)处理有机溶液(800ml),磁力搅拌浆料30分钟。 With magnesium sulfate (30 g) and silica gel (12 g) processing the organic solution (800ml), the slurry was stirred magnetically for 30 minutes. 过滤浆料以除去己变成深蓝绿色的硫酸镁和硅胶。 The slurry was filtered to remove the magnesium sulfate had become deep blue-green and silicone. 用二氯甲烷(100ml)洗涤滤饼。 (100ml) The filter cake was washed with dichloromethane. 滤液在旋转蒸发仪上浓缩。 The filtrate was concentrated on a rotary evaporator. 产物由黑琥珀色油(93.0 g，93%收率)组成。 The product from black amber oil (93.0 g, 93% yield) composition. 经1HNMR观测到的杂质仅有I %起始物质和0.7%的乙腈。 Impurities observed by 1HNMR only I% starting material and 0.7% acetonitrile.

1H NMR (DMSOtfl5)S 1.15 (t，3H), 3.26 (dd, 1H), 3.58 (dd, 1H), 1H NMR (DMSOtfl5) S 1.15 (t, 3H), 3.26 (dd, 1H), 3.58 (dd, 1H),

4.11 (q, 2H), 5.25 (dd, 1H), 7.00 (dd, IH), 7.84 (d, 1H), 8.12 (d,1H)。 4.11 (q, 2H), 5.25 (dd, 1H), 7.00 (dd, IH), 7.84 (d, 1H), 8.12 (d, 1H).

步骤C: 3-氯-M3-氯-2-吡啶基VlH-吡唑-5-羧酸乙酯f或者命名为1-(3-氯-2-吡啶基V3-氯吡啐-5-羧酸乙酯)的制备 Step C: 3- chloro-chloro-2-pyridinyl VlH- -M3- pyrazole-5-carboxylate f or named 1- (3-chloro-2-pyridyl V3- chloro-5-carboxymethyl topiramate spit ethyl) Preparation of

在装有机械搅拌器、温度计、回流冷凝器和氮气入口的2-L四颈烧瓶中装入3-氯-1-(3-氯-I-吡啶基>4,5-二氢-IH-吡唑-5-竣酸乙酷(即步骤B的产物）（95%纯，99.5 g，0.328 mol),乙腈(1000 ml)和硫酸(98%, 35.0ml，0.661 mol)。一加入硫酸，混合物即自身放热从22°C至35°C。在搅拌几分钟后，过硫酸钾(140 g, 0.518mol)处理混合物。浆料加热至84"C回流4.5小时。将所得橙色浆料在仍温(50-65'C)时过滤，除去细小的白色沉淀。乙腈(50ml)洗涤滤饼。滤液在旋转蒸发仪 Charged with 3-chloro-1- (3-chloro-pyridyl -I-> equipped with a mechanical stirrer, thermometer, reflux condenser and nitrogen inlet 2-L four-necked flask, 4,5-dihydro--IH- pyrazole-5-carboxylic acid ethyl cool (ie the product of Step B) (95% pure, 99.5 g, 0.328 mol), acetonitrile (1000 ml) and sulfuric acid (98%, 35.0ml, 0.661 mol). A sulfuric acid was added That mixture of self-heating from 22 ° C to 35 ° C. After stirring for a few minutes, potassium persulfate (140 g, 0.518mol) processing the mixture. The slurry is heated to 84 "C under reflux for 4.5 hours. The resulting orange slurry still warm (50-65'C) filtration to remove fine white precipitate. acetonitrile (50ml) washing the filter cake. The filtrate was rotary evaporator

55上浓玴芏约5U0mlo在装有机棚现扦器的另一个2-L四颂货瓶甲装入水(1250ml)。 55 Du concentrated 玴 about 5U0mlo pretending now stick in the organic shed another 2-L four-song A bottle filled with water goods (1250ml). 在约5分钟时间内，将该浓缩的反应物料加入到水中。 In about 5 minutes, the reaction mass was added to the concentrated water. 经过滤分离产物，用含水乙腈(25%, 3X125 ml)洗涤，用水(100 ml)洗涤一次，然后在室温下真空干燥过夜。 The product was isolated by filtration, washed with aqueous acetonitrile (25%, 3X125 ml) and washed with water (100 ml), washed once, and then dried in vacuo at room temperature overnight. 产物由结晶橙色粉末(79.3 g,82%收率)组成。 The crystalline product was an orange powder (79.3 g, 82% yield) components. 经1H NMR观测到的杂质仅有约1.9%的水和0.6%的乙腈。 Observed by 1H NMR impurities only about 1.9% water and 0.6% acetonitrile.

1H NMR (DMSO-^5) 5 1.09 (t, 3H), 4.16 (q, 2H), 7.31 (s, 1H), 7.71(dd, 1H), 8.38 (d, 1H), 8.59 (d, 1H)。 1H NMR (DMSO- ^ 5) 5 1.09 (t, 3H), 4.16 (q, 2H), 7.31 (s, 1H), 7.71 (dd, 1H), 8.38 (d, 1H), 8.59 (d, 1H) .

步骤D: 3-氯-1-(3-氯-2-吡啶某Vl//-吡啤-5-羧酸〔或者命名为1-(3-氯-2-j比啶基)-3-氯吡唑-5-羧酸)的制备 Step D: 3- chloro-1- (3-chloro-2-pyridyl certain Vl // - pyrazol beer or named 5-carboxylic acid [1- (3-chloro -2-j ratio piperidinyl) -3- chloro-pyrazole-5-carboxylic acid) was prepared

在装有机械搅拌器、温度计和氮气入口的IL四颈烧瓶中装入3-氯-1-(3-氯-2-吡啶基)-1丑-吡哇-5-羧酸乙酯(即步骤C的产(97.5%纯，79.3 g，0.270 mol)、甲醇(260 ml)、水(140 ml)和氢氧化钠片(13.0g, 0.325 mol)。一加入氢氧化钠，混合物即自身放热从22°C至35°C，并且起始物质开始溶解。在环境条件下搅拌45分钟后，所有起始物质都已溶解。所得深橘红-褐色溶液在旋转蒸发仪上浓缩至约250 ml。然后浓缩的反应混合物用水(400 ml)稀释。用乙醚(200 ml)萃取含水溶液。将水层转移至装有磁力搅拌器的IL锥形瓶中。溶液用浓盐酸(36.0 g, 0.355 mol)滴加处理约10分钟。经过滤分离产物，用水(2X200 ml)使其再成为浆料，用水(100 ml)覆盖洗漆(cover wash)—次，然后在过滤器上风干1.5小时。产物由结晶淡褐色粉末(58.1 g, 83%收率)组成。经1HNMR观测到的杂质仅有约0.7%的乙醚。 Charged with 3-chloro-equipped with a mechanical stirrer, thermometer, and nitrogen inlet IL four-necked flask -1- (3-chloro-2-pyridyl) -1 ugly - wow pyrazole-5-carboxylate (i.e. Step C yield (97.5% pure, 79.3 g, 0.270 mol), methanol (260 ml), water (140 ml) and sodium hydroxide pellets (13.0g, 0.325 mol). a solution of sodium hydroxide, the mixture was put itself i.e. heat from 22 ° C to 35 ° C, and the starting material began to dissolve under ambient conditions for 45 minutes, all of the starting material had dissolved resulting dark orange. - brown solution was concentrated to about 250 ml on a rotary evaporator . The reaction mixture is then concentrated water (400 ml) was diluted with ether (200 ml) and extracted aqueous solution. The aqueous layer was transferred to a IL equipped with a magnetic stirrer Erlenmeyer flask. was treated with concentrated hydrochloric acid (36.0 g, 0.355 mol .) was added dropwise for about 10 minutes the product was isolated by filtration, washed with water (2X200 ml) it was reslurried with water (100 ml) to wash the paint cover (cover wash) -. times and then air-dried on the filter 1.5 hours product the crystalline light brown powder (58.1 g, 83% yield) components. 1HNMR observed by only about 0.7% of impurities ether.

1H NMR(DMSO-A) S 7.20 (s, 1H), 7.68 (dd, 1H), 8.25 (d, 1H), 8.56(d, 1H), 13.95 (brs, 1H)。 1H NMR (DMSO-A) S 7.20 (s, 1H), 7.68 (dd, 1H), 8.25 (d, 1H), 8.56 (d, 1H), 13.95 (brs, 1H).

下面的实施例13说明3-溴-1-(3-氯-2-P比啶基)-1丑-吡唑-5-羧酸的另一制备，通过实施例10和11所述的进一步的步骤，该化合物可用于制备，例如，3-溴各[4-氯-2-甲基-6-[[(1■甲基乙基)氨基]羰基]苯 The following Example 13 illustrates 3- bromo-1- (3-chloro -2-P ratio piperidinyl) -1 ugly - pyrazole-5-carboxylic acid of the other, Examples 10 and 11 by the further step, the compound can be used to prepare, for example, 3-bromo-all [4-chloro-2-methyl -6 - [[(1 ■ methylethyl) amino] carbonyl] benzene

56密執-Z-HfUH儿空尸叹O-既胶J-裸_IN_1/K录h厶干空-0-[^〒 56 Michigan -Z-HfUH children dead sigh empty plastic J- O- both bare _IN_1 / K h were recorded Si dry air -0 - [^ 〒

基氨基)羰基]苯基]-1-(3-氯-2-批啶基)-lH-吡唑-5-酰胺。 Ylamino) carbonyl] phenyl] -1- (3-chloro-2-piperidyl batch) -lH- pyrazole-5-carboxamide.

实施例13 Example 13

3-溴-1-(3-氯-2-吡啶基)-lH-吡唑-5-羧酸的制备步骤Al:使用三溴氧化磯制备3-溴-IG-氯-2-吡啶基V4.5-二氢-Iff-吡哩-5-豫酸乙酯If或者侖名为IG-氯-2-妣啶某V3-簿-2-吡唑啉-5-羧酸 3-bromo-1- (3-chloro-2-pyridinyl) -lH- pyrazole-5-carboxylic acid prepared in Step Al: Use oxybromide Angeles Preparation of 3-bromo-chloro-2-pyridinyl V4 -IG- .5- dihydro -Iff- topiramate miles -5- Lun Yu called IG- If either ethyl chloro-2-pyridine deceased mother V3- book a 2-pyrazoline-5-carboxylate

ZM ZM

在装有机械搅拌器、温度计、回流冷凝器和氮气入口的IL四颈烧瓶中装入乙腈(400 ml)、2-(3-氯-2-吡啶基)-5-氧-3-吡唑烷羧酸乙酯(即实施例12,步骤A的产物）(50.0 g, 0.185 mol)和三溴氧化磷(34.0g，0.119 mol)。 Charged acetonitrile (400 ml) equipped with a mechanical stirrer, thermometer, reflux condenser and a nitrogen inlet IL four-necked flask, 2- (3-chloro-2-pyridinyl) -5-oxo-3-pyrazol- carboxylic acid ethyl ester (i.e., Example 12, the product of Step A) (50.0 g, 0.185 mol) and phosphorus oxybromide (34.0g, 0.119 mol). 橙色衆料加热至83°C回流超过20分钟。 Orange congregation is heated to 83 ° C under reflux for more than 20 minutes. 将所得的混浊的、橙色溶液回流75分钟，此时形成獨的棕黄色结晶沉淀。 The orange cloudy solution was refluxed for 75 minutes, then form a separate brown crystalline precipitate. 用蒸馏头替代回流冷凝器，并且收集混浊的无色馏出液(300 ml)。 Alternatively reflux condenser with a distillation head and collection turbid colorless distillate (300 ml). 在装有机械搅拌器的另一个IL四颈瓶中装入碳酸氢钠(45 g, 0.54 mol)和水(200 ml)。 Equipped with a mechanical stirrer was charged to another four-necked flask IL sodium bicarbonate (45 g, 0.54 mol) and water (200 ml). 在5分钟的时间内将浓缩的反应混合物加入到碳酸氢钠浆料中。 Within five minutes of the time the reaction mixture was concentrated sodium bicarbonate was added to the slurry. 所得的两相混合物剧烈搅拌5分钟，此时气体释放停止。 The resulting two-phase mixture was stirred vigorously for 5 minutes at which time gas evolution stopped. 用二氯甲烷(200 ml)稀释馄合物，然后搅拌75分钟。 Ravioli compound diluted with dichloromethane (200 ml), then stirred for 75 minutes. 用5 g的Cdite®545硅藻土助滤剂处理混合物，过滤除去褐色的、焦油状物质。 Cdite®545 with 5 g of a mixture of diatomaceous earth filter aid treatment and filtered to remove a brown, tarry substance. 将滤液转移入分液漏斗。 The filtrate was transferred into a separating funnel. 分离出褐色的有机层(400 ml)，并且然后用硫酸镁(15g)和DarcO®G60活性炭(2.0 g)处理。 Brown organic layer was separated (400 ml), and then treated with magnesium sulfate (15g) and DarcO®G60 activated carbon (2.0 g). 所得楽料磁力搅拌15分钟，然后过滤除去硫酸镁和活性炭。 The resulting material yue magnetic stirring for 15 minutes, then filtered to remove the magnesium sulfate and charcoal. 用硅胶(3 g)处理绿色的滤液并搅拌几分钟。 The filtrate was treated with silica gel green (3 g) and stirred for several minutes. 过滤除去深蓝绿色硅胶，在旋转蒸发仪上浓缩滤液。 Blue green silica gel was removed by filtration, the filtrate was concentrated on a rotary evaporator. 产物由淡琥珀色油(58.6 g, 95%收率)组成，在放置后结晶。 The product from light amber oil (58.6 g, 95% yield) composed of the crystallized on standing. 经1H NMR观测到的杂质仅有0.3%的乙腈。 Observed by 1H NMR impurity only 0.3% acetonitrile.

1H NMR (DMSO-rftf) 5 1.15 (t, 3H), 3.29 (dd, 1H)，3.60 (dd, 1H), 1H NMR (DMSO-rftf) 5 1.15 (t, 3H), 3.29 (dd, 1H), 3.60 (dd, 1H),

4.11 (q, 2H), 5.20 (dd, 1H), 6.99 (dd, 1H), 7.84 (d，1H), 8.12 (d， 4.11 (q, 2H), 5.20 (dd, 1H), 6.99 (dd, 1H), 7.84 (d, 1H), 8.12 (d,

57IHjo 57IHjo

步骤A2:使用五湟化磷制备3-漳-IG-氣-2-吡啶基V4.5-二氢-IH-妣唑-5-羧酸乙酯 Step A2: Use the 5 Huang Zhang -IG- phosphorus preparation of 3-2-pyridyl V4.5- gas -IH- deceased mother dihydro-5-carboxylate

在装有机械搅拌器、温度计、回流冷凝器和氮气入口的IL四颈烧瓶中装入乙腈(33Q ml)、2-(3-氯-2-卩比啶基)-5-氧-3-吡唑烷羧酸乙酯(即实施例12,步骤A的产物）（52.0 g，0.193 mol)和五溴化磷(41.0 g,0.0952 mol)。 Charged acetonitrile (33Q ml) equipped with a mechanical stirrer, thermometer, reflux condenser and a nitrogen inlet IL four-necked flask, 2- (3-chloro-Jie ratio piperidyl) -5-oxo-3 pyrazolidine-carboxylate (i.e., Example 12, the product of Step A) (52.0 g, 0.193 mol) and phosphorus pentabromide (41.0 g, 0.0952 mol). 橙色浆料加热至84°C回流20分钟。 Orange slurry was heated to 84 ° C under reflux for 20 minutes. 将所得的砖红色混合物回流90分钟，此时形成稠的棕黄色结晶沉淀。 The resulting brick-red mixture was refluxed for 90 minutes, then form a thick brown crystalline precipitate. 用蒸馏头替代回流冷凝器，并且收集混浊的无色馏出液(220 ml)。 Alternatively reflux condenser with a distillation head and collection turbid colorless distillate (220 ml). 在装有机械搅拌器的另一个IL四颈瓶中装入碳酸氢钠(40 g, 0.48 mol)和水(200 ml)。 Equipped with a mechanical stirrer was charged to another four-necked flask IL sodium bicarbonate (40 g, 0.48 mol) and water (200 ml). 在5分钟的时间内将浓缩的反应混合物加入到碳酸氧铀浆料中。 Within 5 minutes the reaction mixture was concentrated uranyl carbonate was added to the slurry. 将所得的两相混合物剧烈搅拌10分钟，此时气体释放停止。 The resulting two-phase mixture was stirred vigorously for 10 minutes at which time gas evolution stopped. 用二氯甲烷(200 ml)稀释混合物，然后搅拌10分钟。 The mixture was diluted with dichloromethane (200 ml), then stirred for 10 minutes. 用Celite®545硅藻土助滤剂(5 g)处理混合物，然后过滤除去紫色的、焦油状物质。 The mixture was treated with Celite®545 diatomaceous earth filter aid (5 g), then filtered to remove a purple, tarry substance. 用二氯甲烷(50ml)洗涤滤饼。 (50ml) The filter cake was washed with dichloromethane. 将滤液转移入分液漏斗。 The filtrate was transferred into a separating funnel. 分离出紫红色有机层(400 ml),然后用硫酸镁(15 g)和Darco®G60活性炭(2.2 g)处理。 The organic layer was separated fuchsia (400 ml), then (2.2 g) was treated with magnesium sulfate (15 g) and Darco®G60 activated carbon. 浆料剧烈搅拌40分钟。 Slurry was stirred vigorously for 40 minutes. 浆料过滤以除去硫酸镁和活性炭。 Slurry was filtered to remove the magnesium sulfate and charcoal. 在旋转蒸发仪上浓缩滤液。 The filtrate was concentrated on a rotary evaporator. 产物由深玻珀色油(61.2 g, 95%收率)组成，在放置后结晶。 Bose product from deep amber color oil (61.2 g, 95% yield), with the crystallized on standing. 经1HNMR观测到的杂质仅有0.7%的匕腈。 1HNMR observed by only 0.7 per cent of impurities dagger nitrile.

1H NMR (DMSO-£?tf) 5 1.15 (t, 3H), 3.29 (dd, 1H), 3.60 (dd, 1H), 1H NMR (DMSO- £? Tf) 5 1.15 (t, 3H), 3.29 (dd, 1H), 3.60 (dd, 1H),

4.11 (q, 2H), 5.20 (dd, 1H)，6.99 (dd, 1H), 7.84 (d, 1H), 8.12 (d,1H)。 4.11 (q, 2H), 5.20 (dd, 1H), 6.99 (dd, 1H), 7.84 (d, 1H), 8.12 (d, 1H).

步骤B:3-溴-l-f3-氯-2-吡啶基VlH-吡啤-5-羧酸乙酯(或者命名为IG-氯-2-吡啶基V3-簿吡唑-5-羧酸乙酯)的制备 Step B: 3- bromo -l-f3- chloro-2-pyridinyl VlH- beer pyrazole-5-carboxylate (or named IG- chloro-2-pyridinyl-pyrazole-5-carboxylic acid V3- workbook ethyl) Preparation of

在装有机械搅拌器^温度计、回流冷凝器和氮气入口的IL四颈烧瓶中装入3-溴-1-(3-氯-2-¾啶基)-4，5-二氢-IH-吡唑-5-羧酸乙酷(即步骤Al 和A2 的产物)(40.2 g, 0.121 mol),乙腈(300 ml)和硫酸(98%, Charged with 3-bromo ^ equipped with a mechanical stirrer a thermometer, a reflux condenser and a nitrogen inlet IL four-necked flask -1- (3-chloro -2-¾ piperidinyl) -4,5-dihydro--IH- pyrazole-5-carboxylic acid ethyl cool (i.e. the product of Step Al and A2) (40.2 g, 0.121 mol), acetonitrile (300 ml) and sulfuric acid (98%,

58nu, uz^o moijo 一/«/、侧敗，即曰：a•取SS/AU王 58nu, uz ^ o moijo a / «/, the side lost, that said: a • Take SS / AU king

°C。 ° C. 在搅拌几分钟后，用过硫酸钾(48.0 g, 0.178 mol)处理混合物。 After stirring for several minutes, the used potassium persulfate (48.0 g, 0.178 mol) mixture was treated. 浆料加热至在84°C回流.2小时。 The slurry was heated to reflux at 84 ° C .2 hours. --将所得的橙色浆料在仍温(50-65°C)时过滤，以除去白色沉淀。 - The resulting orange slurry while still warm (50-65 ° C) filtration to remove a white precipitate. 用乙腈(2X50 ml)洗涤滤饼。 With acetonitrile (2X50 ml) and washed cake. 将滤液在旋转蒸发仪上浓缩至约200 mlo在装有机械撹拌器的另一个IL四颈瓶中装入水(400 ml)。 The filtrate was concentrated on a rotary evaporator to about 200 mlo equipped with a mechanical stirrer of another IL Jiao four-necked flask was charged with water (400 ml). 在约5分钟的时间内将浓缩的反应物料加入到水中。 In about 5 minutes and the concentrated reaction mass was added to the water. 经过滤分离产物，相继用含水乙腈(20%, 100 ml)和水(75 ml)洗涤，然后在过滤器上风干I小时。 The product was isolated by filtration, washed successively with aqueous acetonitrile (20%, 100 ml) and water (75 ml), then dried on the filter I hour. 产物由结晶橙色粉末(36.6 g, 90%收率)组成。 The crystalline product was an orange powder (36.6 g, 90% yield) components. 经1H NMR观测到仅有的杂质为约I %未知物质和0.5%乙腈。 By 1H NMR observed only about I% unknown impurity material and 0.5% acetonitrile.

1H NMR (DMSO-^tf) 6 1.09 (t, 3H)，4.16 (q, 2H), 7.35 (s, 1H), 7.72 (dd, 1H)，8.39 (d, 1H), 8.59 (d, 1H)。 1H NMR (DMSO- ^ tf) 6 1.09 (t, 3H), 4.16 (q, 2H), 7.35 (s, 1H), 7.72 (dd, 1H), 8.39 (d, 1H), 8.59 (d, 1H) .

步骤C: 3-漠-IG-氯-2-吡啶基VlH-吡唑-5-羧酸域者命名为IG-氯-2-吡啶基V3-溴吡哞-S-羧酸)的制备 Preparation of 3-chloro-2-pyridinyl desert -IG- VlH- pyrazole-5-carboxylic acid by the domain name IG- bromo-chloro-2-pyridinyl V3- moo -S- pyrazole carboxylic acid): Step C

在装有机械搅拌器、温度计和氮气入口的300-mL四颈烧瓶中装A 3-溴-1-(3-氯-2-吡啶基)-lH-吡唑-5-羧酸乙酯(即步骤B的产物）(98.5%纯，25.0 g，0.0756 mol),甲醇(75 ml),水(50 ml)和氢氧化钠片(3.30 g，0.0825 tnol)。 Equipped with a mechanical stirrer, a thermometer and a nitrogen inlet 300-mL four-neck flask installed with A 3- bromo-1- (3-chloro-2-pyridinyl) -lH- pyrazole-5-carboxylate ( i.e. the product of Step B) (98.5% pure, 25.0 g, 0.0756 mol), methanol (75 ml), water (50 ml) and sodium hydroxide pellets (3.30 g, 0.0825 tnol). 一加入氧氧化钠，混合物即自身放热从29.°C至34°C并且起始物质开始溶解。 An added oxygen sodium oxide, a mixture that is self-heating from 29. ° C to 34 ° C and the starting material began to dissolve. 在环境条件下搅拌90分钟后，所有的起始物质都已溶解。 Was stirred at ambient conditions for 90 minutes, all the starting material had dissolved. 在旋转蒸发仪上浓缩所得深植色溶液至约90 ml。 And concentrated on a rotary evaporator and the resulting color solution rooted to about 90 ml. 然后用水(160 ml)稀释浓缩的反应混合物。 Then washed with water (160 ml) was diluted reaction mixture was concentrated. 用乙醚(100 ml)萃取含水溶液。 With diethyl ether (100 ml) and extracted aqueous solution. 然后将水层转移入装有磁力搅拌器的500-ml锥形瓶中。 The aqueous layer was then equipped with a magnetic stirrer, transferred into a 500-ml Erlenmeyer flask. 用浓盐酸(8.50 g, 0.0839 mol)滴加处理溶液约10分钟。 With concentrated hydrochloric acid (8.50 g, 0.0839 mol) was added dropwise a solution treatment for about 10 minutes. 经过滤分离产物，用水(2X40 ml)使其再成为浆料，用水(25 ml)覆盖洗涤一次，然后在过滤器上风干2小时。 The product was isolated by filtration, washed with water (2X40 ml) it was reslurried with water (25 ml) cover washed once, and then air-dried on the filter for 2 hours. 产物由晶体状的、棕黄色粉末(20.9 g，91%收率)组成。 Product by the crystal-shaped, brown-yellow powder (20.9 g, 91% yield) components. 经1H NMR观测到的仅有杂质为约0.8%未知物质和0.7%乙醚。 By 1H NMR observed only about 0.8% of impurities and 0.7% ether unknown substance.

59▲丄丄lATAi、if V4-QJ <J / 山~t XXXJf A J y^C/1 Ot IXXJt \Jix±jt 59 ▲ Shang Shang lATAi, if V4-QJ <J / Mountain ~ t XXXJf AJ y ^ C / 1 Ot IXXJt \ Jix ± jt

8.25 (d, 1H), 7.68 (dd, IH)= 8.25 (d, 1H), 7.68 (dd, IH) =

下面的实施例14说明3-溴-1-(3-氯-2-吡啶基)-4,5-二氢-Iif-吡唑-5-羧酸乙酯的另一制备，该物质可以用于制备，例如，3-溴-1-(3-氯-2-吡啶基>1F-吡唑-5-羧酸乙酯(即实施例13,步骤B的产物)》 The following Example 14 illustrates the 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro--Iif- pyrazole-5-carboxylic acid ethyl ester another, the substance can be used in the preparation of, e.g., 3-bromo-1- (3-chloro-2-pyridyl> 1F- pyrazole-5-carboxylate (i.e. 13, the product of Step B in Example) "

实施例14 Example 14

使用溴化氢由3-氯-1-(3-氯-2-吡啶基)-4，5-二氢-IH-卩比唑-5-羧酸乙酯制备3-溴-1 -(3 -氯-2-吡啶基)-1H-吡唑-5-羧酸乙酯将溴化氢通入二溴甲烷(85 ml)中的3-溴-1-(3-氯-2-吡啶基)-4,5-二氢-IH-吡唑-5-羧酸乙酯(即实施例12,步骤B的产物)(8.45 g, 29.3mmol)溶液中。 Hydrogen bromide from 3-chloro-1- (3-chloro-2-pyridinyl) -4,5-dihydro-Jie -IH- than-5-carboxylate Preparation of 3-bromo-1 - (3 - chloro-2-pyridinyl) -1H- pyrazole-5-carboxylate Hydrogen bromide passed into dibromomethane (85 ml) of 3-bromo-1- (3-chloro-2-pyridinyl) -IH- pyrazole-4,5-dihydro-5-carboxylate (i.e. the product of Example 12, Step B embodiment) (8.45 g, 29.3mmol) solution. 90分钟后，停止通入气体，用碳酸氢钠水溶液(100 ml) 洗涤反应混合物。 After 90 minutes, the gas was stopped, with aqueous sodium bicarbonate (100 ml) the reaction mixture was washed. 干燥有机相，并在减压下蒸发，得到油状的标题产物(9.7g, 99%收率;)，该产物在放置后结晶。 The organic phase was dried and evaporated under reduced pressure to give the title product as an oil (9.7g, 99% yield;), after which the product crystallized on standing.

1HNMR(CDCi3)S 1.19 (t, 3H), 3.24 (在ABX 模式中的AB 的1/2, J= 9.3，17.3 Hz, 1H), 3.44(在ABX 模式中的AB 的1/2, J= 11.7,17.3 Hz, 1H), 4.18 (q, 2H), 5.25 (ABX 的X, IH, /=9.3, 11.9 Hz),6.85 (dd, /=4.7, 7.7 Hz, 1H), 7.65 (dd, J= 1.6, 7.8 Hz, 1H), 8.07(dd, J= 1.6, 4.8 Hz, 1H)。 1HNMR (CDCi3) S 1.19 (t, 3H), 3.24 (AB in ABX pattern of the 1/2, J = 9.3,17.3 Hz, 1H), 3.44 (AB in ABX pattern of the 1/2, J = 11.7,17.3 Hz, 1H), 4.18 (q, 2H), 5.25 (ABX of X, IH, /=9.3, 11.9 Hz), 6.85 (dd, /=4.7, 7.7 Hz, 1H), 7.65 (dd, J = 1.6, 7.8 Hz, 1H), 8.07 (dd, J = 1.6, 4.8 Hz, 1H).

下面的实施例15说明I-(3-氯-2-卩比啶基)-4,5-二氢-3-[[(4-甲基苯基)磺酰基]氧]-IH-吡唑-5-羧酸乙酯的制备，通过与实施例14中描述的类似方法，该物质可用于制备3-溴-1-(3-氯-2-批啶基>4，5-二氢-IH-吡唑-5-羧酸乙酯。 The following Example 15 illustrates I- (3- chloro-2-Jie ratio piperidinyl) -4,5-dihydro-3 - [[(4-methylphenyl) sulfonyl] oxy] -IH- pyrazole -5-carboxylate, by a similar method described in Example 14, the material can be used for the preparation of 3-bromo-1- (3-chloro-2 batches piperidyl> 4,5-dihydro - IH- pyrazole-5-carboxylate.

实施例15 Example 15

1-(3-氯-2-吡啶基)-4,5-二氢-3-[[(4-甲基苯基)磺酰基]轻基HH-吡哩-5- 1- (3-chloro-2-pyridinyl) -4,5-dihydro-3 - [[(4-methylphenyl) sulfonyl] -5- light-yl HH- pyrazol miles

羧酸乙酯的制备 Carboxylic acid ethyl ester

60中的2-(3-氯-2-卩比啶基)-5-氧-3-卩比唑烷羧酸乙酯(即实施例12,步骤A的产物）（10.0 g, 37.1 mmol)和对甲苯磺酰氯(7.07 g, 37.1 mmol)的混合物中。 60 2- (3-chloro-Jie ratio piperidyl) -5-oxo-3-oxazolidine carboxylate Jie ratio (i.e., Example 12, the product of Step A) (10.0 g, 37.1 mmol) and a mixture of p-toluenesulfonyl chloride (7.07 g, 37.1 mmol) in. 再加入对甲苯磺酰氯(0.35 g, 1.83 mmol)和三乙胺(0.19 g, Was added p-toluenesulfonyl chloride (0.35 g, 1.83 mmol) and triethylamine (0.19 g,

I.88mmol)。 I.88mmol). 然后让反应混合物升温至室温并搅拌过夜。 The reaction mixture was then allowed to warm to room temperature and stirred overnight. 用二氯甲烷(200ml)稀释混合物并用水(3X70ml)洗涤。 The mixture was diluted with dichloromethane (200ml) and washed with water (3X70ml) and washed. 干燥有机相并蒸发，以留下油状的标题产物(13.7 g, 87%收率)，该产物缓慢形成晶体。 The organic phase was dried and evaporated to leave the title product as an oil (13.7 g, 87% yield), which was slowly formed crystals. 从乙酸乙酯/己烷重结晶的产物在99.5-100°C熔化。 From the product from ethyl acetate / hexane recrystallized melted at 99.5-100 ° C.

IR(nujol)v 1740, 1638, 1576, 1446, 1343，1296, 1228, 1191, 1178,1084，1027, 948, 969, 868, 845 cm-1 IR (nujol) v 1740, 1638, 1576, 1446, 1343,1296, 1228, 1191, 1178,1084,1027, 948, 969, 868, 845 cm-1

1H NMR (CDCl3) 5 1.19 (t, 3H), 2.45 (S，3H), 3.12 (在ABX 模式中的AB 的1/2，J= 17.3, 9 Hz, 1H)，3.33 (在ABX 模式中的AB 的1/2, /=17.5, 11.8 Hz, 1H), 4.16 (q, 2H), 5.72 (ABX 的X，7=9, 1H NMR (CDCl3) 5 1.19 (t, 3H), 2.45 (S, 3H), 3.12 (AB in ABX pattern of the 1/2, J = 17.3, 9 Hz, 1H), 3.33 (ABX mode in AB, 1/2, /=17.5, 11.8 Hz, 1H), 4.16 (q, 2H), 5.72 (ABX of X, 7 = 9,

II.8 Hz, 1H), 6.79 (dd, J = 4.6, 7.7 Hz, 1H), 7.36 (d, /=8.4 Hz,2H), 7.56 (dd, J= 1.6, 7.8 Hz, 1H), 7.95 (d, 7 =8.4 Hz, 2H), 8.01(dd, J= 1.4, 4.6Hz, 1H)。 II.8 Hz, 1H), 6.79 (dd, J = 4.6, 7.7 Hz, 1H), 7.36 (d, /=8.4 Hz, 2H), 7.56 (dd, J = 1.6, 7.8 Hz, 1H), 7.95 ( d, 7 = 8.4 Hz, 2H), 8.01 (dd, J = 1.4, 4.6Hz, 1H).

实施例16 Example 16

Af-[4_氯-2-甲基-6-[(甲基氨基)裁基]苯基]-1-(3-氯-2-吡啶基)-3-(2,2,2-三氟乙氧基)-Ii/-吡唑-5-酰胺的制备步骤A: 1-C3-氯-2-吡啶基V2.3-二氢-3-氧-Iff-吡啤-5-羧酸乙酷的制备将硫酸(20 g, 200ramol)—次加入到干燥乙腈(200 ml)中经搅拌的 Af- [4_ chloro-2-methyl-6 - [(methylamino) CD-yl] phenyl] -1- (3-chloro-2-pyridinyl) -3- (2,2,2- fluoro-ethoxy) -Ii / - pyrazole-5-carboxamide Preparation of Step A: 1-C3--chloro-2-pyridinyl V2.3- dihydro-3-oxo-5-carboxylate -Iff- pyrazol beer Cool the production of acetic acid (20 g, 200ramol) - was added to the dry acetonitrile (200 ml) in a stirred

2-(3-氯-2-吡啶基)-5-氧-3-卩比唑烷羧酸乙醋(即实施例12，步骤A的产物)(27g, 100mmol)悬浮液中。 2- (3-chloro-2-pyridinyl) -5-oxo-3-Jie-carboxylic acid ethyl ester oxazolidine ratio (i.e., Example 12, the product of Step A) (27g, 100mmol) suspension. 反应混合物变稀形成淡绿色，接近清彻的溶液，然后变稠形成淡黄色悬浮液。 The reaction mixture was thinning formed light green, nearly clear solution before thickening is formed as a pale yellow suspension. 一次加入过硫酸钾(33 g, 120mmol),然后反应混合物加热至温和回流3.5小时。 Was added potassium persulfate (33 g, 120mmol), and then the reaction mixture was heated to a gentle reflux for 3.5 hours. 在用冰浴冷却后，过滤除去白色固体沉淀并弃去。 After cooling in an ice bath, a white solid precipitate was removed by filtration and discarded. 用水(400 ml)稀释滤液，然后用乙醚 Washed with water (400 ml) and the filtrate was diluted, with diethyl ether and then

61使得出现乳白色固体沉淀(3.75 g),过滤收集之。 61 so that the solid precipitate appears milky (3.75 g), was collected by filtration. 进一步浓缩乙醚母液产生第二部分乳白色沉淀物(4.2 g),再次过滤收集沉淀。 Ether mother liquor was further concentrated to produce a milky white precipitate a second portion (4.2 g), the precipitate was collected by filtration again. 乳白色固体也由水相沉淀；过滤收集该固体(4.5 g),合并得到总计为12.45的标题化合物。 Cream solid also precipitated from the aqueous phase; the solid was collected by filtration (4.5 g), to give the title compound combined total of 12.45.

1HNMR(DMSo-^)S 1.06 (t, 3H), 4.11 (q, 2H), 6.34 (s, 1H), 7.6 (t,1H), 8.19 (d, 1H), 8.5 (d, 1H), 10.6 (s，1H)。 1HNMR (DMSo - ^) S 1.06 (t, 3H), 4.11 (q, 2H), 6.34 (s, 1H), 7.6 (t, 1H), 8.19 (d, 1H), 8.5 (d, 1H), 10.6 (s, 1H).

步骤B: IG-氯-2-吡啶某V3-C2.2.2-三氟乙氧某VlH-吡唑-5-羧酸乙酯的制备 Step B: IG--chloro-2-trifluoromethyl pyridin a V3-C2.2.2- a VlH- ethoxycarbonyl-pyrazole-5-carboxylate Preparation of

将碳酸钾(0.85 g, 6.15 _01)加入到-5°C的干燥乙腈(15 ml)中经搅拌的1-(3-氯-2-吡啶基)-2，3-二氢-3-氧-IH-吡唑-5-羧酸乙酯(即步骤A的产物）(0.8 g, 3 mmol)悬浮液中。 Potassium carbonate (0.85 g, 6.15 _01) -5 ° C was added to the dry acetonitrile (15 ml) in a stirred solution of 1- (3-chloro-2-pyridinyl) -2,3-dihydro-3-oxo- -IH- pyrazole-5-carboxylate (i.e. the product of Step A) (0.8 g, 3 mmol) suspension. 悬浮液在2(TC下搅拌15分钟。然后将经搅拌的悬浮液冷却至5°C,并滴加2，2，2-三氟乙基三氟甲烷磺酸酯(0.8 g, 3.45 mmol)O反应混合物升温至室温，然后加热至回流，此时薄层色谱显示反应完全。加水(25 ml)至反应混合物，然后用乙醚萃取。用硫酸镁干燥乙醚萃取物并浓缩以产生标题产物化合物(1.05g)，为淡黄色油。 The suspension was stirred at 2 (under TC 15 minutes and then stirred suspension was cooled to 5 ° C, and a solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.8 g, 3.45 mmol) O The reaction mixture was allowed to warm to room temperature and then heated to reflux, when TLC showed the reaction was complete. Water was added (25 ml) to the reaction mixture, and then extracted with ether. The ether extract was dried over magnesium sulfate and concentrated to yield the title product compound ( 1.05g), as a pale yellow oil.

1HNMr(CDCI3)S 1.21 (t, 3H)，4:20 (q，2H), 4.63 (q，2H), 6.53 (s,1H), 7.4 (t, 1H), 7.9 (d, 1H), 8.5 (d, 1H)。 1HNMr (CDCI3) S 1.21 (t, 3H), 4: 20 (q, 2H), 4.63 (q, 2H), 6.53 (s, 1H), 7.4 (t, 1H), 7.9 (d, 1H), 8.5 (d, 1H).

步骤C: 1-0-氯-2-吡啶基V3-(2.2.2-三氟乙氣某VlH-毗唑-5-羧酸的制备 Step C: 1-0--chloro-2-pyridyl preparation V3- (2.2.2- TFA gas a VlH- border-5-carboxylic acid

将水(5 ml)加入甲醇(15 ml)中的1-(3-氯-2-吡啶基)-3-(2,2，2-三氟乙氧基)-lH-吡唑-5-竣酸乙酯(即步骤B的产物）（0.92 g, 2.8 mmol)的经搅拌的溶液中，这使得反应混合物变得混浊。 Water (5 ml) was added methanol (15 ml) of 1- (3-chloro-2-pyridinyl) -3- (2,2,2-trifluoroethoxy) -lH- pyrazol-5 carboxylic acid ethyl ester (i.e. the product of Step B) (0.92 g, 2.8 mmol) in a stirred solution, which makes the reaction mixture became cloudy. 滴加氢氧化钠水溶液(50%, 1.5 g, 19.2 mmol),并且在室温下将反应混合物搅拌30分钟，其间反应混合物又变清亮。 Was added dropwise aqueous sodium hydroxide (50%, 1.5 g, 19.2 mmol), and the reaction mixture was stirred at room temperature for 30 minutes, during which the reaction mixture becomes clear yet. 加入水(20 ml),并用乙醚萃取反应混合物，弃去萃取物。 Was added water (20 ml), and the reaction mixture was extracted with diethyl ether, the extract discarded. 用浓盐酸将水相酸化至pH 2，然后用乙酸乙酯(50 ml) With concentrated hydrochloric acid and the aqueous phase was acidified to pH 2, then with ethyl acetate (50 ml)

62并浓缩，得到标题化合物，分离为白色固体(0.8 g)。 62 and concentrated to give the title compound, isolated as a white solid (0.8 g).

1H NMR (DMSO-^) 5 4.9 (q, 2H)，6.75 (s，1H), 7.6 (t，1H), 8.2 (d,1H), 8.55 (d, 1H), 13.7 (bs, 1H). 1H NMR (DMSO- ^) 5 4.9 (q, 2H), 6.75 (s, 1H), 7.6 (t, 1H), 8.2 (d, 1H), 8.55 (d, 1H), 13.7 (bs, 1H).

步骤D: 6-氯-8-甲基-2//-3.1-苯并噁唪-2.4nflV二酮的制备 Step D: 6- chloro-methyl-2 // -8- - Preparation of 3.1-benzoxazine dione chant -2.4nflV

将氯甲酸三氯甲酯(63 g，320 mmol)滴加到室温的干燥二噁烷(750 ml)中经搅拌的2-氨基-3-甲基-5-氯苯甲酸(即实施例6,步骤A的产物)的悬浮液中。 The trichloromethyl chloroformate (63 g, 320 mmol) was added dropwise at room temperature in dry dioxane (750 ml) in a stirred solution of 2-amino-3-methyl-5-chlorobenzoic acid (i.e., Example 6 , the product of Step A) suspension. 反应混合物放热缓慢升温至42°C,固体几乎完全溶解，之后又形成稠的悬浮液。 The reaction mixture exothermed slowly warmed to 42 ° C, the solid is almost completely dissolved, and then forming a thick suspension. 将该悬浮液在环境温度下撹拌2.5小时后，过滤分离标题化合物，用乙醚洗涤，并干燥，得到标题化合物，为白色固体(98 g)。 The suspension was stirred at ambient temperature for 2.5 hours after Jiao, the title compound was isolated by filtration, washed with diethyl ether, and dried to give the title compound as a white solid (98 g).

1H NMR (DMSO-^) 5 2.3 (s, 3H), 7.70 (s, 1H)，7.75 (s，1H), 11.2 (s, 1H)。 1H NMR (DMSO- ^) 5 2.3 (s, 3H), 7.70 (s, 1H), 7.75 (s, 1H), 11.2 (s, 1H).

步骤E: 6-氯-2-HG-氯-2-吡啶某V3-f2.2:2-三氟乙氧基VIi/-吡哩-5-基1-8-甲某-4ff-3,l-苯并噁嗪-4-酮的制备 Step E: 6- chloro-2-chloro-pyridin -2-HG- a V3-f2.2: 2- trifluoroethoxy VIi / - pyrazol-5-yl 1-8- mile Jiamou -4ff-3, Preparation of l- benzoxazin-4-one

将iVW-二甲基甲酰胺(4滴)加入在二氯甲烷(100 ml)中经搅拌的1-(3-氯-2-吡啶基)-3-(2,2,2-三氟乙氧基)-lH-吡唑-5-羧酸(即步骤C的产物)(7.9 g, 24 mmol)的悬浮液中。 The iVW- dimethylformamide (4 drops) in methylene chloride (100 ml) in a stirred solution of 1- (3-chloro-2-pyridinyl) -3- (2,2,2-trifluoroethyl yloxy) -lH- pyrazole-5-carboxylic acid (i.e. the product of Step C) (7.9 g, 24 mmol) suspension. 在45分钟的时间内滴加草酸氯(4.45 g，35 mmol)。 Oxalyl chloride was added dropwise over 45 minutes (4.45 g, 35 mmol). 将所得溶液在室温下撹拌4小时，然后真空浓缩。 The resulting solution was stirred at room temperature Jiao four hours, then concentrated under vacuum. 将分离的酰氯溶解在干燥的乙腈(10ml)中'并加入在干燥乙腈(14 ml)中经搅拌的6-氯-8-甲基-2H-3,1-苯并噁嗪-2,4(1//)-二酮(即步骤D的产物)(4.9 g, 23_ol)的悬浮液中。 The isolated acid chloride was dissolved in dry acetonitrile (10ml) was' added and dry acetonitrile (14 ml) in a stirred solution of 6-chloro-8-methyl -2H-3,1- benzoxazin-2,4 (1 //) - dione (i.e. the product of Step D) (4.9 g, 23_ol) suspension. 加入吡啶(10 ml),将溶液加热回流6小时。 Was added pyridine (10 ml), the solution was heated at reflux for 6 hours. 用冰浴冷却后，收集白色固体沉淀(9.15 g)。 After cooling with an ice bath, the precipitate was collected as a white solid (9.15 g). 所收集的沉淀的1H NMR谱显示由标题化合物和残留的6-氯-8-甲基-2H-3,1-苯并噁嗪-2，4(1切-二酮起始物质组成的波峰。将收集的沉淀的一小部分从乙腈中重结晶，得到纯的标题产物，该产物在178-18(TC熔化。 The precipitate was collected by 1H NMR spectra indicated by the title compound and residual 6-chloro-8-methyl -2H-3,1- benzoxazine-2,4 (1 cut - dione starting material consisting of peaks . A small portion of the collected precipitate was recrystallized from acetonitrile to give the pure title product which at 178-18 (TC melt.

1H NMR (DMSO-Jtf) 5 1.72 (s, 3H)，4.96 (q, 2H), 7.04 (s，1H), 7.7 1H NMR (DMSO-Jtf) 5 1.72 (s, 3H), 4.96 (q, 2H), 7.04 (s, 1H), 7.7

63步骤F: iV-丨4-氲-2-甲基-6-丨(甲基氨基)羰基I苯基1-1-(3-氯-2-吡啶基)-3-(2.2.2-三氟乙氧某Vlff-吡唑-5-酰胺的制备 63 Step F: iV- 4- Shu Shu Yun -2- methyl-6- (methylamino) carbonyl-I-phenyl 1-1- (3-chloro-2-pyridinyl) -3- (2.2.2- Preparation of a Vlff- trifluoromethyl pyrazole-5-ethoxycarbonyl amide

将甲胺(THF中的2.0 M溶液，IlmU 22 mmol)滴加到在四氢呋喃(15 ml)中的6-氯-2-[l-(3-氯-2-吡啶基)-3-(2,2,2-三氟乙氧基)-111-吡唑-5-基]各甲基-4H-3，1-苯并噁嗪-4-酮(即步骤E的沉淀产物)(3.53 g, The methylamine (THF solution of 2.0 M, IlmU 22 mmol) was added dropwise to tetrahydrofuran (15 ml) in 6-chloro -2- [l- (3- chloro-2-pyridinyl) -3- (2 , 2,2-trifluoroethoxy) -111- pyrazol-5-yl] -4H-3,1- each methyl benzoxazin-4-one (i.e. precipitate product of Step E) (3.53 g ,

7.5 mmol)的悬浮液中，并将所得溶液在室温下搅拌45分钟。 7.5 mmol) suspension, and the resulting solution was stirred at room temperature for 45 minutes. 然后薄层色谱表明反应完全。 Then TLC showed complete reaction. 加入乙醚(100 ml),将反应混合物搅拌2小时，同时形成沉淀。 Was added diethyl ether (100 ml), and the reaction mixture was stirred for 2 hours while a precipitate formed. 过滤收集沉淀,然后由乙腈重结晶，得到白色固体(0.82g)。 The precipitate was collected by filtration, and then recrystallized from acetonitrile to give a white solid (0.82g). 由乙腈母液沉淀第二批白色固体(0.35 g),并经过滤收集之。 Acetonitrile mother liquor by the second batch of white solid precipitate (0.35 g), and collected by filtration. 将最初的乙醚/四氢呋喃母液浓缩至干，残留固体由乙腈重结晶，得到第三批白色固体(0.95 g)。 The initial ether / tetrahydrofuran mother liquor was concentrated to dryness, the residual solid was recrystallized from acetonitrile to give a third batch of a white solid (0.95 g). 合并三批产物，总计2.12 g (干燥后)的标题化合物，本发明的化合物，分离为白色固体，在195-197°C熔化。 The combined product batches totaling 2.12 g (after drying) of the title compound, compounds of the invention, isolated as a white solid, melting at 195-197 ° C.

1H NMR (CDCl3) 5 2.18 (S，3H), 2.92 (d, 3H), 4.66 (q, 2H), 6.15 (q, 1H), 6.6 (s，1H), 7.2 (s, 1H), 7.25 (S，1H), 7.35 (t, 1H), 7.8 (d,1H), 8.45 (d, 1H), 10.0 (s, 1H)。 1H NMR (CDCl3) 5 2.18 (S, 3H), 2.92 (d, 3H), 4.66 (q, 2H), 6.15 (q, 1H), 6.6 (s, 1H), 7.2 (s, 1H), 7.25 ( S, 1H), 7.35 (t, 1H), 7.8 (d, 1H), 8.45 (d, 1H), 10.0 (s, 1H).

下面的实施例17说明1-(3-氯-2-卩比啶基)-3-(三氟甲基)-IH-吡唑-5-竣酸的另一制备，通过实施例4中所述的进一步的步骤，该物质可用于制备，例如，1-(3-氯-2-吡啶基)-N-[2-甲基-6-[[(l-甲基乙基)氨基]裁基]苯基]-3-(三氟甲基比唑-5-酿胺。 The following examples illustrate 17 1- (3-chloro-2-Jie ratio pyridyl) -3- (trifluoromethyl) -IH- another pyrazole-5-carboxylic acid was prepared by the Examples 4 further steps described below, can be used to prepare the material, e.g., 1- (3-chloro-2-pyridinyl) -N- [2- methyl -6 - [[(l- methylethyl) amino] CD yl] phenyl] -3- (trifluoromethyl than-5-amine brewing.

实施例17 Example 17

1-(3-氯-2-吡啶基)-3-(三氟甲基)-1开-吡唑-5-羧酸的制备步骤A: 3-氯-2(1別-批啶酮(2.2.2-三氟-I-甲基亚乙基)腙的制备 1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl) -1 open - pyrazole-5-carboxylic acid Step A: 3- chloro-2 (respectively 1 - Batch piperidone ( trifluoromethyl -I- methylethylidene) hydrazone preparation 2.2.2

在20-25°C下，将1,1，1-三氟丙酮(7.80 g, 69.6 mmol)加入3-氯-2(lifH比啶酮腙(或者命名为(3-氯-n比啶-2基)-腙）(10 g, 69.7 mmol)中。加入完成后，将混合物搅拌约10分钟。减压除去溶剂，使混合 At 20-25 ° C, a solution of 1,1,1-trifluoroacetone (7.80 g, 69.6 mmol) was added 3-chloro -2 (lifH of pyridine hydrazone (or named (3-chloro--n of pyridine - 2-yl) - hydrazone) (10 g, 69.7 mmol) After addition was complete, the mixture was stirred for about 10 minutes the solvent was removed under reduced pressure, mixed.

64勒仕6敗和恢股W爪格很（iuu 卞；机层并蒸发。硅胶层析(用乙酸乙酯洗脱)给出乳白色固体产物(II g, 66%收率)，mp 64-64.5°C(在从乙酸乙酯/己烷结晶后)。 64 Leshi 6 W defeat and restore stocks claw grid is (iuu Bian; layer and evaporation of silica gel (eluted with ethyl acetate) to give a cream solid product (II g, 66% yield), mp 64-. 64.5 ° C (after from ethyl acetate / hexane).

IR(Xiujol)V 1629, 1590, 1518, 1403, 1365, 1309, 1240, 1196，1158,1100, 1032, 992, 800 cm-1 IR (Xiujol) V 1629, 1590, 1518, 1403, 1365, 1309, 1240, 1196,1158,1100, 1032, 992, 800 cm-1

1HNMR(CDQ3) 52.12 (s, 3H), 6.91-6.86 (m, 1H), 7.64-7.61 (m,1H)，8.33-8.32 (m，2H)。 1HNMR (CDQ3) 52.12 (s, 3H), 6.91-6.86 (m, 1H), 7.64-7.61 (m, 1H), 8.33-8.32 (m, 2H).

MS m/z 237 (M+) MS m / z 237 (M +)

步骤B:乙基氢乙二酯(3-氯-2-吡啶基V2.2.2-三氟-I-甲基亚乙基基)腙(•或者命名为乙基氢乙二酯(3-氯-2-吡啶某V2.2.2-三氟-I-甲某亚乙基基I腺)的制备 Step B: Ethyl hydrogen terephthalate (3-chloro-2-pyridyl V2.2.2- trifluoromethyl -I- methylimino ethyl group) hydrazone (• or named as ethyl hydrogen terephthalate (3-chloro -I- Jiamou a V2.2.2- trifluoromethyl pyridine ethylene radical I gland) of -2

在(TC下，将三乙胺(20.81 g, 0.206 mmol)加入在二氯甲烷(6S ml)中的3-氯-2(m)-B比啶酮(2,2,2-三氟-I-甲基亚乙基)踪(即步骤A的产物）(32.63 g, 0.137 mol)中。在(TC下，将在二氯甲烷(69 ml)中的氯氧乙酸乙酯(18.75 g, 0.137 mol)滴加到该混合物中。使该混合物在约2小时内升温至25°C。使该混合物冷却至(TC并进一步滴加在二氯甲烷(14ml)中的氯氧乙酸乙酯(3.75 g, 27.47 mmol)。再过约I小时后，用二氯甲烷(约450 ml)稀释该混合物，用水(2X150 ml)洗涤该混合物。干燥有机层并蒸发。硅胶层析(用I ： I乙酸乙酯-己烷洗脱)给出固体产物(42.06 g, 90%收率)，mp 73.0-73.5°C(从乙酸乙酯/己烷结晶后)。IR(Iiujol)V 1751, 1720，1664, 1572, 1417, 1361, 1330, 1202, 1214,1184, 1137，1110, 1004，1043, 1013, 942, 807, 836 cm'11HNMr(DMSC)-A, 115-C)1.19(t, 3H), 1.72(brs, 3H)，4.25 (q,2H), 7.65 (dd, /=8.3, 4.7 Hz, 1H), 8.20 (dd, / = 7.6, 1.5 Hz, 1H),8.55 (d, /=3.6 Hz, 1H)。 In (case TC, triethylamine (20.81 g, 0.206 mmol) was added in dichloromethane (6S ml) of 3-chloro -2 (m) -B ratio piperidone (2,2,2-trifluoro - I- methylethylidene) track (ie the product of Step A) (32.63 g, 0.137 mol) In (at TC, in dichloromethane (69 ml) of ethyl oxychloride (18.75 g, 0.137 mol) was added dropwise to the mixture. The mixture was heated in about 2 hours to 25 ° C. The mixture was cooled to (TC and further dropped in dichloromethane (14ml) of ethyl oxychloride ( 3.75 g, 27.47 mmol) after another for about I hour, the mixture was diluted with dichloromethane (approximately 450 ml), washed with water (2X150 ml) and the mixture was washed organic layer was dried and evaporated to silica gel chromatography (with I:... I ethyl acetate - hexane) to give the solid product (42.06 g, 90% yield), mp 73.0-73.5 ° C (from ethyl acetate / hexane) .IR (Iiujol) V 1751, 1720, 1664, 1572, 1417, 1361, 1330, 1202, 1214,1184, 1137,1110, 1004,1043, 1013, 942, 807, 836 cm'11HNMr (DMSC) -A, 115-C) 1.19 (t, 3H) , 1.72 (brs, 3H), 4.25 (q, 2H), 7.65 (dd, /=8.3, 4.7 Hz, 1H), 8.20 (dd, / = 7.6, 1.5 Hz, 1H), 8.55 (d, /=3.6 Hz, 1H).

步骤C: IG-氯-2-吡啶基V4.5-二氢-5-羟基-3-f三氟甲基VlH-吡挫-5- Step C: IG--chloro-2-pyridyl V4.5--dihydro-5-hydroxy -3-f trifluoromethyl VlH- topiramate setback -5-

羧酸乙酯的制备 Carboxylic acid ethyl ester

65yUL o 'wj Ka^nnx一t*巫juijt 口u —曰日、j-东、-厶-h^u 65yUL o 'wj Ka ^ nnx a witch juijt mouth t * u - said date, j- East - Si -h ^ u

啶基)(2，2，2-三氟-I-甲基亚乙基)腙(即步骤B的产物)(5 g, 14.8 mmol)加入在二甲亚砜(25 ml)中的氟化四丁基铵水合物(10 g)*。 Piperidinyl) (2,2,2-trifluoro -I- methylethylidene) hydrazone (i.e. the product of Step B) (5 g, 14.8 mmol) was added fluoride dimethylsulfoxide (25 ml) at room tetrabutyl ammonium hydrate (10 g) *. 当加入完成时，将混合物倒入醋酸(3.25 g)7]C溶液(25 ml)中。 When the addition was complete, the mixture was poured into acetic acid (3.25 g) 7] C solution (25 ml) in. 在25°C下搅拌过夜后，用甲苯(4X25 ml)萃取该混合物，并用水(50 ml)洗涤合并的甲苯萃取物，千燥并蒸发，得到固体。 After stirring overnight at 25 ° C with toluene (4X25 ml) and the mixture was extracted and washed with water (50 ml) The combined extracts were washed with toluene, it was dry and evaporated to give a solid. 硅胶层析(用I : 2的乙酸乙酯-己烷洗涤)给出固体产物(2.91 g, 50%收率，含有约5%的3-氯-2(1H)-吡啶酮(2,2，2-三氟-I-甲基亚乙基)腙)，mp 78-78.5°C(从乙酸乙酷/己烧结晶后)。 Silica gel chromatography (with I: 2 ethyl acetate - hexane washed) to give solid product (2.91 g, 50% yield, containing about 5% of 3-chloro -2 (1H) - pyridone (2,2 , 2-trifluoromethyl -I- methylethylidene) hydrazone), mp 78-78.5 ° C (from ethyl acetate cool / had burned crystallized).

IR (nujol) V 3403, 1726, 1618, 1582, 1407, 1320，1293, 1260, 1217，1187, 1150, 1122, 1100, 1067, 1013, 873，829 cm'11HNMR(CDCl3) S 1.19 (s, 3H), 3.20 (ABZ 模式的1/2，7= 18 Hz,1H), 3.42 (ABZ 模式的1/2，J= 18 Hz, 1H), 4.24 (q, 2H), 6.94 (dd, /=7.9, 4.9 Hz, 1H), 7.74 (dd, J =1.1, 1.5 Hz, 1H), 8.03 (dd, J =4.7, 1.5 Hz, 1H)。 IR (nujol) V 3403, 1726, 1618, 1582, 1407, 1320,1293, 1260, 1217,1187, 1150, 1122, 1100, 1067, 1013, 873,829 cm'11HNMR (CDCl3) S 1.19 (s, 3H ), 3.20 (ABZ Mode 1 / 2,7 = 18 Hz, 1H), 3.42 (ABZ Mode 1/2, J = 18 Hz, 1H), 4.24 (q, 2H), 6.94 (dd, /=7.9 , 4.9 Hz, 1H), 7.74 (dd, J = 1.1, 1.5 Hz, 1H), 8.03 (dd, J = 4.7, 1.5 Hz, 1H).

MSm/z319(M+) MSm / z319 (M +)

步骤D: M3-氯-2-吡啶基V3-f三氟甲基VlF-吡唑-5-羧酸乙酯的制备将硫酸(浓，2滴)加入在醋酸(10 ml)中的1-(3-氯-2-吡啶基>4,5-二氢-5-@基-3-(三氟甲基)-1丑-吡唑-5-羧酸乙酯(即步骤C的产物）(Ig, 2.96 mmol)中，并使混合物升温至65°C约I小时。让混合物冷却至25aC,并在减压下除去大部分醋酸。使混合物在饱和碳酸钠水溶'^(100 ml)和乙酸乙酯(100 ml)间分配。用乙酸乙酯(100 ml)进一步萃取水层。干燥合并的有机萃取层并浓缩，得到油状产物(0.66 g，77%收率)。 Step D: M3--chloro-2-pyridinyl V3-f trifluoromethyl VlF- pyrazole-5-carboxylate Sulfuric acid (concentrated, 2 drops) was added acetic acid (10 ml) of 1- (3-chloro-2-pyridyl> @ 4,5-dihydro-5-yl-3- (trifluoromethyl) -1 ugly - pyrazole-5-carboxylate (i.e. the product of Step C) (Ig, 2.96 mmol), and the mixture was heated to 65 ° C for about I hour. The mixture was cooled to 25aC, and most of the acetic acid was removed under reduced pressure. The mixture was saturated sodium carbonate aqueous' ^ (100 ml) and Ethyl acetate (100 ml) was partitioned between with ethyl acetate (100 ml) and the aqueous layer was further extracted. The organic layer was extracted dried and concentrated to give an oily product (0.66 g, 77% yield).

IR (neat) v 3147, 2986, 1734, 1577, 1547, 1466，1420, 1367, 1277,1236, 1135, 1082, 1031, 973, 842, 802 cm'1iHNMR(CDCI3)S 1.23 (t, 3H), 4.25 (q, 2H)，7.21 (s, 1H), 7.48 (dd, IR (neat) v 3147, 2986, 1734, 1577, 1547, 1466,1420, 1367, 1277,1236, 1135, 1082, 1031, 973, 842, 802 cm'1iHNMR (CDCI3) S 1.23 (t, 3H), 4.25 (q, 2H), 7.21 (s, 1H), 7.48 (dd,

66^ = oi,外./ nz, mj, ^aa. J — oo, l nz, mj, a.Di (,aa, j = a, 66 ^ = oi, outside ./ nz, mj, ^ aa J -. Oo, l nz, mj, a.Di (, aa, j = a,

1.5 Hz, 1H)。 1.5 Hz, 1H).

MSmz^lSI(M+) MSmz ^ lSI (M +)

步骤E: IG-氯-2-吡啶基V3-(三氟甲基VlH-吡哞-5-羧酸的制备 Step E: IG--chloro-2-pyridinyl V3- (trifluoromethyl VlH- pyrazole 5-carboxylic acid moo

将氢氧化钾(0.5 g, 85%, 2.28 mmol：)水溶液(I ml)加入在乙醇(3 ml)中的1-(3-氯-2-卩比啶基)-3-(三氟甲基比唑-5-竣酸乙酯(即步骤D的产物)(0.66 g, 2.07 mmol)中。约30分钟后，减压除去溶剂，并将混合物溶解在水(40 ml)中。用乙酸乙酯(20 ml)洗搽溶液。用浓盐酸酸化水层并用乙酸乙酯(3 X20 ml)萃取。干燥合并的萃取物并蒸发，得到固体产物(0.53 g，93%收率)，178-179°C(从己烷-乙酸乙酯结晶后)。 Potassium hydroxide (0.5 g, 85%, 2.28 mmol :) aqueous solution (I ml) was added in ethanol (3 ml) of 1- (3-chloro-Jie ratio piperidinyl) -3- (trifluoromethyl than-5-yl carboxylic acid ethyl ester (i.e. the product of Step D) (0.66 g, 2.07 mmol) in. After about 30 minutes, the solvent was removed under reduced pressure, and the mixture was dissolved in water (40 ml) in. with acetic acid ethyl ester (20 ml) to wash the paint solution. The aqueous layer was acidified with concentrated hydrochloric acid with ethyl acetate (3 X20 ml) and extracted. The combined extracts were dried and evaporated to give a solid product (0.53 g, 93% yield), 178- 179 ° C (from hexane - ethyl acetate crystallized).

IR (nujol) V 1711, 1586, 1565, 1550, 1440，1425，1292，1247, 1219，1170, 1135, 1087, 1059, 1031, 972, 843，816 cm'11H NMR (DMSO-Js) 5 7.61 (s, 1H), 7.77 (m, 1H), 8.30 (d，1H), 8.60(s, IH)。 IR (nujol) V 1711, 1586, 1565, 1550, 1440,1425,1292,1247, 1219,1170, 1135, 1087, 1059, 1031, 972, 843,816 cm'11H NMR (DMSO-Js) 5 7.61 ( s, 1H), 7.77 (m, 1H), 8.30 (d, 1H), 8.60 (s, IH).

实施例18和19说明在实施例10,步骤E和实施例8,步骤E中分别描述的反应条件的备选方案。 Examples 18 and 19 illustrate alternative 10, Step E and Example 8, Step E, respectively, the reaction conditions described embodiments.

实施例18 Example 18

2-[3-漠-1-(3-氯-2-吡啶基)-lH-吡唑-5-基]-6-氯-8-甲基-4H-3，1-苯并噁 2- [3- desert -1- (3-chloro-2-pyridinyl) -lH- pyrazol-5-yl] -6-chloro-8-methyl -4H-3,1- benzoxazin

嚷-4-嗣的制备 -4-Heir shout

将甲磺酰氯(1.0 ml, 1.5 g, 13 mmol)溶解在乙腈(10ml)中，并将该混合物冷却至-5°C。 Methanesulfonyl chloride (1.0 ml, 1.5 g, 13 mmol) was dissolved in acetonitrile (10ml) was added and the mixture was cooled to -5 ° C. 在-5至(TC下，在5分钟内滴加在乙腈(10 ml)中的3-溴-1-(3-氯-2-11比啶基)-lH-吡哩-5-羧酸(即实施例10,步骤D的吡唑羧酸产物)(3.02 g，10 mmol)和吡啶(1.4 ml, 1.4 g, I7Inmol)溶液中。在滴加期间形成浆料。将混合物在同样的温度下搅拌5分钟，然后加入在乙腈(10 ml)中2-氨基-3-甲基-5-氯苯甲酸(即实施例6步骤A At -5 to (at TC, was added dropwise over 5 minutes in acetonitrile (10 ml) of 3-bromo-1- (3-chloro -2-11 ratio piperidinyl) -lH- pyrazole-5-carboxylate miles (i.e., Example 10, pyrazole carboxylic acid product of Step D) (3.02 g, 10 mmol) and pyridine (1.4 ml, 1.4 g, I7Inmol) solution. During the dropwise addition to form a slurry. The mixture at the same temperature stirred 5 minutes, then added in acetonitrile (10 ml) of 2-amino-3-methyl-5-chlorobenzoic acid (i.e., Example 6, Step A

67WJr-WJ (1.0(3 g, iummoi)冲則CL呢(z.js 血，厶/g, 67WJr-WJ (1.0 (3 g, iummoi) rushed the CL it (z.js blood, Si / g,

用更多的乙腈(5 ml)淋洗。 With more acetonitrile (5 ml) rinse. 将混合物在-5至0°C下搅拌15分钟，然后在-5至(TC下在5分钟内滴加在乙腈(5 ml)中的甲磺酰氯(I .OmL 1.5ml, 13 mmol)溶液。在该温度下将反应混合物再掼拌15分钟，然后让其缓慢升温至室温，并搅拌4小时。滴加水(20 ml),并将该混合物搅拌15分钟。然后过滤该混合物，用2 : I乙腈-水(3X3 ml)洗涤固体，然后用乙腈(2 X 3 ml)洗涤，在氮气下干燥，得到标题产物，为淡黄色粉末，4.07 g (90.2%粗收率)，在203-205-C熔化。使用Zorbax®RX-C8色谱柱(4.6 mmX 25 cm,洗脱剂25-95%乙腈/pH3水)，产物的HPLC显示相应于标题化合物的主峰，并占总色谱峰面积的95.7%。 The mixture was stirred for 15 minutes at -5 to 0 ° C, and then at -5 to (at TC was added dropwise over 5 minutes in acetonitrile (5 ml) of methanesulfonyl chloride (I .OmL 1.5ml, 13 mmol) solution of The reaction mixture was then whipped stirred at this temperature for 15 minutes and then allowed to warm slowly to room temperature and stirred for 4 hours dropwise addition of water (20 ml), and the mixture was stirred for 15 minutes and then the mixture was filtered with 2: I acetonitrile - water (3X3 ml) washed solid was then washed with acetonitrile (2 X 3 ml), dried under nitrogen and dried to give the title product as a pale yellow powder, 4.07 g (90.2% crude yield), at 203-205 -C melted using Zorbax®RX-C8 column (4.6 mmX 25 cm, eluent 25-95% acetonitrile / pH3 water), HPLC of the product showed a peak corresponding to the title compound, and the total peak area of ​​95.7 %.

'H NMR (DMSO-^) 8 1.72 (s, 3H), 7.52 (s, 1H), 7.72-7.78 (m, 2H),7.88 (m, 1H), 8.37 (dd, 1H), 8.62 (dd, 1H)。 'H NMR (DMSO- ^) 8 1.72 (s, 3H), 7.52 (s, 1H), 7.72-7.78 (m, 2H), 7.88 (m, 1H), 8.37 (dd, 1H), 8.62 (dd, 1H). 实施例19 Example 19

6-氯-2-f3-氯-1-(3-氯-2-吡啶某VlH-吡哗-5-某1-8-甲基-4H-3.1-苯并噁嚷-4-丽的制备 6-chloro -2-f3--chloro-1- (3-chloro-2-pyridyl a VlH- topiramate Wow -5- a 1-8- methyl -4H-3.1- benzoxazin -4- Li shouted preparation

将甲磺酰氯(1.0 ml, 1.5 g, 13 mmol)溶解在乙腈(10 ml)中，并将混合物冷却至-5°C。 Methanesulfonyl chloride (1.0 ml, 1.5 g, 13 mmol) was dissolved in acetonitrile (10 ml) and the mixture was cooled to -5 ° C. 在-5至0"C下，在5分钟内滴加在乙腈(10 ml)中的3-氯-1-(3-氯-2-吡啶基)-lH-吡唑-5-羧酸(即实施例8，步骤D的羧酸产物）(2.58g, 10 mmol)和吡啶(1.4 ml，1.4 g, 17 mmol)溶液中。在滴加期间形成浆料。将该混合物在该温度下搅拌5分钟，然后一次加入所有的2-氨基-3-甲基-5-氯苯甲酸(即实施例6,步骤A的产物)(1.86g, 10 mmol)。然后在-5至(TC下，在5分钟内滴加在乙腈(10 ml)中的吡啶(2.8 ml，2.1%, 35 mmol)溶液。将混合物在-5至0°C下搅拌15分钟，然后在-5至0°C下，在5分中内滴加在乙腈(5 ml)中的甲磺酰氯(1.0 ml, 1.5 ml, 13 mmol)溶液。将反应混合物在该温度下搅拌15分钟，然后让其缓慢升温至室温，并搅拌4小时。滴加水(15 ml),并 At -5 to 0 "C under added dropwise over 5 minutes in acetonitrile (10 ml) of 3-chloro-1- (3-chloro-2-pyridinyl) -lH- pyrazole-5-carboxylic acid ( i.e. Example 8, the carboxylic acid product of Step D) (2.58g, 10 mmol) and pyridine (1.4 ml, 1.4 g, 17 mmol) was. added dropwise during form a slurry. The mixture was stirred at this temperature 5 minutes, then added all at once all the 3-methyl-5-chloro-2-amino benzoic acid (i.e., Example 6, the product of Step A) (1.86g, 10 mmol). Then at -5 to (lower TC, was added dropwise over 5 minutes in acetonitrile (10 ml) in pyridine (2.8 ml, 2.1%, 35 mmol) was added. The mixture was stirred for 15 minutes at -5 to 0 ° C, and then at -5 to 0 ° C under , was added dropwise over 5 minutes in acetonitrile (5 ml) of methanesulfonyl chloride (1.0 ml, 1.5 ml, 13 mmol) was added. The reaction mixture was stirred for 15 minutes at this temperature, then allowed to slowly warm to room temperature, and stirred for 4 hours. Water was added dropwise (15 ml), and

68U 。 68U. 热后以 升用2. ： I A 3 ml) After the heat to rise by 2.: I A 3 ml)

洗涤固体，然后用乙腈(2 X 3 ml)洗涤，在氮气下干燥，得到标题产物，为淡黄色粉末,3.83 g (94.2%粗收率)，在199-201 °C熔化。 The solid was washed, and then with acetonitrile (2 X 3 ml), dried under nitrogen and dried to give the title product as a pale yellow powder, 3.83 g (94.2% crude yield), melting at 199-201 ° C. 使用Zorbax®RX-C8色谱柱(4.6_X25cm,洗脱剂25-95%乙腈/pH3水)，产物的HPLC显示相应于标题化合物的主峰，并占总色谱峰面积的97.8%。 Use Zorbax®RX-C8 column (4.6_X25cm, eluent 25-95% acetonitrile / pH3 water), HPLC showed the product peak corresponds to the title compound and 97.8% of total chromatogram peak area. 1H NMR (DMSO-Jtf) 5 1.72 (s, 3H), 7.48 (s, 1H), 7.74-7.80 (m，2H),7.87 (m, 1H), 8.37 (dd, IH), 8.62 (dd, IH)。 1H NMR (DMSO-Jtf) 5 1.72 (s, 3H), 7.48 (s, 1H), 7.74-7.80 (m, 2H), 7.87 (m, 1H), 8.37 (dd, IH), 8.62 (dd, IH ).

通过本文描述的方法，以及本领域已知的方法，可以制备以下表1-6的化合物。 By the methods described herein, and methods known in the art, the following compounds can be prepared in Table 1-6. 在表中采用的缩写如下：t表示叔，s表示仲，n表示正，i表示异，Me表示甲基，Et表示乙基，Pr表示丙基，i-Pr表示异丙基，而Bu表示丁基。 Abbreviations used in the table as follows: t represents tertiary, s means secondary, n represents normal, i means iso, Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, i-Pr represents isopropyl, and Bu represents butyl.

R R

93 93

的化首卿主友胃屮的穿和根，以便E们也得到俅铲。 The Friends of the stomach of the first main Cao Qing wear and root for E are also Qiu shovel.

如本公开中所称，术语“无脊椎害虫”包括作为害虫具有经济重要性的节肢类、腹足类和线虫类。 As referred to in this disclosure, the term "invertebrate pest" includes as pests of economic importance arthropods, gastropods and nematodes. 术语“植食性无脊椎害虫”指通过在植物上摄食，如通过食用叶(foliage)、茎、叶(leaf)、果实或种子组织，或者通过吸取植物维管汁液而导致其损伤的无脊椎害虫。 The term "phytophagous invertebrate pest" means by feeding on the plant, such as by eating the leaves (foliage), stems and leaves (leaf), fruit or seed tissue or vascular plants by sucking the sap and cause the damage of invertebrate pests . 术语“节肢类〃包括昆虫、螨、蜈蚁、百足虫、鼠妇和综合纲(symphylans)。术语“腹足类”包括蜗牛、蛞蝓和其它有柱腹足目。术语“线虫类”包括植食性线虫(线虫门或纲)。经济上重要的植食性无脊椎害虫包括：鳞翅目幼虫，如夜蛾科的栗蚕蛾幼虫、切根虫、尺蠖和heliothixies(例如草地粘虫(Spodoptera JUgiperda JE Smith)、甜菜夜蛾(Spodoptera exigua Hllbner)> 小地蚕切57_/0/2 Hufhagel)、粉纹夜^,(Trichoplusia ni Htlbner)、燕夜蛾(¾/妨virescens Fabricius))；螟蛾科的姓虫、鞘蛾、结网毛虫、conev/orms、cabbageworms (例如玉米螟nubilalis Htlbne)、脐橙螟transitella Walker)、玉米根草螟caliginosellus Clemens) 苍螺(iiierp咖grizmma licarsisalis Walker))；卷蛾科的卷叶虫、卷叶蛾、seed worms 和fruitworms (例如苹果蠹蛾pomonella L. (L 指Linnaeus))、葡萄小食心虫(Endopiza viteana Clemens)、梨小食心虫（ΟαρΛο/to molestaBusck));以及许多其它经济上重要的鱗翅目（例如菜蛾xylostella L·)、棉红铃虫(PeMwopAora gossypiella Saunders)、舞毒蛾(Lymantria dispar L.))o銷翅目的摄叶幼虫和成虫，包括长角象虫科、豆象科和象虫科的象鼻虫(例如棉铃象鼻虫(Anthonomus grandisBoheman)^ 稻水象虫oryzophilus Kuschel)、米象鼻虫(Sitophilus oryzaeL.));叶甲科的跳甲、黄守瓜、食虫、叶甲、薯虫和潜叶虫(例如马铃薯甲虫(i职zViotoM decemlineata Say)、玉米根叶甲(Diabrotica virgifera LeConte));金龟子和scaribaeidae 的其它甲虫(例如日本丽金龟(Popiiha japonica Newman)和欧金龟(Rhizotrogus The term "arthropod 〃 including insects, mites, centipede ants, centipedes, pillbugs and integrated classes (symphylans). The term" gastropod "includes snails, slugs and other pillared Mesogastropoda term" nematode "includes plant . feeding nematodes (nematode door or classes) of herbivorous economically important invertebrate pests include: larvae of Lepidoptera, such as chestnut Noctuidae moth larvae, cutworms, looper and heliothixies (for example, fall armyworm (Spodoptera JUgiperda JE Smith), beet armyworm (Spodoptera exigua Hllbner)> Small cutworms cut 57_ / 0/2 Hufhagel), Trichoplusia night ^, (Trichoplusia ni Htlbner), Yan armyworm (¾ / harm virescens Fabricius)); Pyralidae surname insects, Casebearer, networking caterpillar, conev / orms, cabbageworms (such as corn borer nubilalis Htlbne), Orange moth transitella Walker), corn borer blades of grass caliginosellus Clemens) Cang screw (iiierp coffee grizmma licarsisalis Walker)); Meyrick Branch leaf beetle, leaf rollers, seed worms and fruitworms (such as codling moth pomonella L. (L means Linnaeus)), grape fruit moth (Endopiza viteana Clemens), pear borer (ΟαρΛο / to molestaBusck)); and many others economically important Lepidoptera (eg, diamondback moth xylostella L ·), pink bollworm (PeMwopAora gossypiella Saunders), gypsy moth (Lymantria dispar L.)) o pin fin purpose camera leaf larvae and adults, including the Longhorn Curculionidae , Bruchidae and Curculionidae weevils (such as boll weevil (Anthonomus grandisBoheman) ^ rice water weevil oryzophilus Kuschel), rice weevil (Sitophilus oryzaeL.)); jump Chrysomelidae of armor, yellow melon, food insect, leaf beetle, potato beetle and leaf miner (eg potato beetle (i grade zViotoM decemlineata Say), corn rootworm (Diabrotica virgifera LeConte)); scaribaeidae scarab beetles and other (for example, Japanese beetles Korea (Popiiha japonica Newman) and the European beetles (Rhizotrogus

96tnujum x^uumuwT釋肛,J、龜竹fTJ,J、蟲；平翅目的成虫和幼虫，包括球螋科的蠼螋(例如欧洲蠼螋(ForWcwkauricularia L·)、black earwig (Chelisoches morio Fabricius));半翅目和同翅目的成虫和幼虫，如盲蝽科的盲蝽、蝉科的蝉、大叶蝉科的叶蝉(例如spp.)、赌姆科和飞虱科的飞風、角婢科的角蜂、木風科的木虱、粉虱科的粉虱、蚜科的蚜虫、根瘤蚜科的根瘤蚜、粉阶科的粉阶、蚧科、盾蚧科和绵蚧科的介壳虫(scales)、网蝽科的网赌、蝽科的蝽象、长蝽科的麦长蝽(例如双spp.)和其它实蝽、沬蝉科的沫蝉、缘蝽科的南瓜缘蝽，以及红蝽科的红椿和棉红蝽；螨目的成虫和幼虫，如叶螨科的蛛螨和红蝴蛛(例如欧洲红蝴蛛(PawonjvcAws ulmiKoch)、红獅蛛(re/m«少diuy urticae Koch)、McDaniel 螨(7Wm^yc/zwimcdaniele McGregor))、毛足蛛科(tenuipalpidae)的flat mite (例如桔短须蠘Iewisi McGregor)) > 瘿螨科(Erophyidae)的梧叶刺瘿螨和bud mites，以及其它摄叶螨；直翅目的成虫和幼虫，包括蚱蜢、·蝗虫和蛾摔(例如迁徙炸猛(例如Melanoplus sanguinipes Fabricius/MAifferentialis Thomas)、美洲蚱猛（例如Schistocerca americanaDrury)、妙猿蜂{Schisiocerca gregana Forskal)、迁徙蝗虫(LocWWflmigratoria L.)>鱗蛄(G/7W她命spp.》；双翅目的成虫和幼虫，包括潜叶虫、蠓、果姆(实媽科)、瑞典杆绳(例如Oscinellafrit L,)、soii maggot以及其它长角亚目；缨翅目的成虫和幼虫，包括葱萄马(Thrips tabaciLindeman)和其它摄叶蓟马；蚰蜒目的綠蛇；线虫门或纲的成员，包括如下重要的农业害虫，如根结线虫(矶/0/而gyne)属的根癌线虫、短体线虫属的根斑线虫、毛刺线虫属的粗短根线虫。 96tnujum x ^ uumuwT release anus, J, turtle bamboo fTJ, J, insects; adults and larvae flat wings purpose, including ball Sou family earwigs (such as the European earwig (ForWcwkauricularia L ·), black earwig (Chelisoches morio Fabricius)) ; (for example spp) Hemiptera and Homoptera adults and larvae, as MIRIDAE of the bugs, cicadas cicada family, leafhoppers large CICADELLIDAE and fly bet 姆科 and Delphacidae wind angle angle bee family servant, psyllids wood wind Division, whiteflies whiteflies and aphids aphids Branch, Division of phylloxera phylloxera, powder pink rank-order division, Coccidae, Diaspididae and cotton Kuwana Section scale insects (scales), Tingidae net gambling, PENTATOMIDAE of stinkbug, long wheat Pentatomidae, chinch bugs (such as double spp.) and other real bug, pumpkin edge droplets of spittle bugs Cicadidae, Coreidae of bugs, and red bugs Section toon and cotton red bugs; mites aim adults and larvae, as Tetranychidae of spider mites and red butterfly spider (such as the European red butterfly spider (PawonjvcAws ulmiKoch), Red Lion spider (re / m «less diuy urticae Koch), McDaniel mite (7Wm ^ yc / zwimcdaniele McGregor)), gross foot spider families (tenuipalpidae) of flat mite (such as orange short hair Jie Iewisi McGregor))> Eriophyidae (Erophyidae) of Wuye thorn gall mites and bud mites, spider mites and other camera; adults and larvae Orthoptera, including grasshoppers, locusts and moths fall * (such as migratory fried Meng (eg Melanoplus sanguinipes Fabricius / MAifferentialis Thomas), American grasshopper Meng (eg Schistocerca americanaDrury), wonderful ape Bee {Schisiocerca gregana Forskal), migratory locust (LocWWflmigratoria L)> scales mantis (G / 7W her life spp ";.. Diptera adults and larvae, including leaf miners, midges, fruit Farm (real mother Branch), Sweden rod string (for example Oscinellafrit L,), soii maggot and other horned suborder; Thysanoptera adults and larvae purpose, including onions grapes horse (Thrips tabaciLindeman) and other camera leaf thrips; Youyan purpose green snake; nematode door or Gang members, including the following important agricultural pests, such as root-knot nematode (Rocky / 0 / and gyne) belong to root knot nematodes, genus Pratylenchus spot root nematodes, genus Trichodorus stubby root nematodes.

本领域技术人员将认识到，并非所有的化合物对所有的害虫有相同的效力。 Those skilled in the art will recognize that not all compounds have the same effect on all pests. 本发明的化合物对下列目的害虫具有特别高的活性：鱗翅目(例如棉叶波纹夜蛾argillacea HUbner)%果黄卷蛾(如咖沐 The compounds of the invention for the following purposes pests particularly high activity: Lepidoptera (such as cotton leaf Spodoptera littoralis argillacea HUbner)% fruit moth yellow paper (such as coffee Mu

97argyrospua Walker)、huropean Iear roller (A. rosana L,)祁具匕貢卷蛾(Archips)种、二化螺(Chilo suppressalis Walker)、稻纵卷叶螟(Cnaphalocrosis medinalis Guenee)、玉米根草螟{CrambusClemens)、早熟禾草螺(Cnmtoy 如Zincken)、苹果蠹蛾(Q^/αpomonella L.)、鼎点金刚钻(£^rfay insulana Boisduval)s埃及金刚钻(Earias vittella Fabricius)、Ammerican bollworm(Helicoverpa armigera HUbner)^ 玉米穗蛾(Z/e/fcove/pazeiS Boddie)、薛夜鐵(Heliothis virescens Fabricius)、苍娱(Herpetogramma licarsisalisWalker)、葡萄小食心虫botrana Denis Sc SchiffermUller)、棉红铃虫{Pectinophora gossypiella Saunders)、梧细潜蛾tPhyliocnistiscitrella Stainton)、大菜粉蝶brassicae L.)、小菜粉蝶rapaeL.)、菜蛾(P/wteMa L.)、甜菜夜蛾exf^wfllMmer)、 97argyrospua Walker), huropean Iear roller (A. rosana L,) Qi Gong with dagger moth (Archips) species, two of the screw (Chilo suppressalis Walker), medinalis (Cnaphalocrosis medinalis Guenee), blades of grass corn borer { CrambusClemens), precocious grass snail (Cnmtoy as Zincken), codling moth (Q ^ / αpomonella L.), Ding-point diamond (£ ^ rfay insulana Boisduval) s Egypt diamond (Earias vittella Fabricius), Ammerican bollworm (Helicoverpa armigera HUbner ) ^ corn earworm (Z / e / fcove / pazeiS Boddie), Xue night iron (Heliothis virescens Fabricius), dark green entertainment (Herpetogramma licarsisalisWalker), vine borer botrana Denis Sc SchiffermUller), pink bollworm {Pectinophora gossypiella Saunders) , Wu fine leafminer tPhyliocnistiscitrella Stainton), large Pieris brassicae L.), small Pieris rapaeL.), moth (P / wteMa L.), beet armyworm exf ^ wfllMmer),

斜纹夜蛾(Spodoptera litura Fabricius)、草地粘虫{Spodopterafrugiperda JE Siriith)、粉纹夜蛾(TWc/io/i/w·?。ni Hubner)和tomatoleafminer {Tuta absoluta))0本发明的化合物对同翅目的成员也具有商业上重要的活性，所述同翅目包括：豌豆跑(jqyrA/吨pisumHarris)、虹豆礙craccivwa Koch)、蚕豆癖Scopoli)、棉姆(却gossypii Glover)、苹崎(々?Αώ· pomi De Geer)、锈线菊觀{Aphis spiraecola Patch)、指顶花无网厨(Aulacorthum solaniKaltenbach)、草莓中瘤钉毛癖Cockerell)、俄罗斯麦长管礙(Diwrqpito noxia Kurdjumov/Mordvilko)、车前圆尾礙(Dysaphis plantaginea Paaserini)、苹绵跑(Eriosoma IanigerumHausmann)、桃大尾蚁pruni Geoffiroy)、完菁极(Zij?aphise/>^>wiKaltenbach)、答锻(Meiopolophium dirrhodumWa^ef^ 马铃薯长管赔(Mac/Osz>wm euphorbtae Thomas)、桃厨(JVfyzwspersiaze Sulzer)、莴苣衲长管野(Atocwovfiz ribisnigri Mosley)、根礙和葡糖根抚蚊{Pemphigus spp.)> 玉米概(Rhopalosiphum maidis Fitch)、bird cherry-oatα^/iULl \J\ftUyUlU^ljJrlUiil yClill L·/. J、夕_ —- i%4 yjC/ilZCipiil^ QrTllflUTrl Common cutworm (Spodoptera litura Fabricius), S.frugiperda {Spodopterafrugiperda JE Siriith), Trichoplusia ni (TWc / io / i / w ·? .ni Hubner) and tomatoleafminer {Tuta absoluta)) compounds of the invention on the same 0 wing members of the order also has important commercial activity, the Homoptera include: peas run (jqyrA / t pisumHarris), Hong beans hinder craccivwa Koch), beans addiction Scopoli), Cotton Farm (but gossypii Glover), Ping Qi ( 々? Αώ · pomi De Geer), Spiraea concept {Aphis spiraecola Patch), foxglove no net kitchen (Aulacorthum solaniKaltenbach), strawberry gross tumor nail addiction Cockerell), Eluosimai long tube obstruction (Diwrqpito noxia Kurdjumov / Mordvilko ), before the round tail obstruction (Dysaphis plantaginea Paaserini), Ping Mian run (Eriosoma IanigerumHausmann), Peach tail ant pruni Geoffiroy), End Jing pole (Zij? aphise /> ^> wiKaltenbach), A. forging (Meiopolophium dirrhodumWa ^ ef ^ Potato long tube compensation (Mac / Osz> wm euphorbtae Thomas), peach kitchen (JVfyzwspersiaze Sulzer), wild lettuce cassock long tube (Atocwovfiz ribisnigri Mosley), and glucose root root hinder ask mosquito {Pemphigus spp.)> Corn Overview (Rhopalosiphum maidis Fitch), bird cherry-oatα ^ / iULl \ J \ ftUyUlU ^ ljJrlUiil yClill L · / J, evening _ -. i% 4 yjC / ilZCipiil ^ QrTllflUTrl

Rondani)、麦长管跑(StoZi/cw avenae Fabricius)、苜猜斑頓(77^π·θβρ/^maculaia Buckton)、梧声赔(Tbxopiera aurantii Boyer de Fonscolombe)、热带梧二贫citricida Kirkaldy)；球蜂(Zi/e/ge? spp)；美核桃根瘤驗(P/^//oxenz devasiatrix Pergande)；烟草粉虱tabaciGennadius)、甘薯粉風(5e即argentifolii Bellows Sc Perring)、相梧粉MiDialeurodes citri Ashmead)和温室粉虱(7Ha/ewrc*i/es vaporariorumWestwood)；马铃薯微叶蝉(Empoasca fabae Harris)、小揭稻虱(Laodelphax striatellus Fallen)> 六点叶蝶(Mzcroteto quadrilineatusForbes)、茶微叶辉助c cinticeps Uhler)、黑尾叶蝉(汾坤扣过故nigropictns Stal)、稻褐飞虱(Nilaparvata lugens Stil)、玉米蜡蜂(Peregrinus maidis Ashmead)> 白背稻虱furcifera Horvath)^rice delphacid (Sogatodes orizicola Muir)^ 苹白小叶蝶pomaria McAtee)> 葡糖斑叶蝉spp.);期婢(MagicWcwfcseptendecim L.)、吹绵蚁(Icerya purchasi Maskell)；梨圆盾阶(Quadraspidiotus perniciosus Comstock)；批桔粉蚁citriRisso)；其它粉蚁复合体{Pseudococcus spp.)；梨黄木SI (CacopsylIapyricola Foerster)^ 柿木風(TWoza iSospyn'Ashmead)。 Rondani), Sitobion run (StoZi / cw avenae Fabricius), clover guess spot Dayton (77 ^ π · θβρ / ^ maculaia Buckton), Wu sound compensation (Tbxopiera aurantii Boyer de Fonscolombe), tropical Wu two poor citricida Kirkaldy); ball bee (Zi / e / ge spp?); the US walnut nodule posterior (P / ^ // oxenz devasiatrix Pergande); tobacco whitefly tabaciGennadius), Sweet Potato Flour wind (5e ie argentifolii Bellows Sc Perring), with Wu powder MiDialeurodes citri Ashmead) and greenhouse whitefly (7Ha / ewrc * i / es vaporariorumWestwood); potato leafhopper (Empoasca fabae Harris), a small mortgage planthopper (Laodelphax striatellus Fallen)> six leaf butterfly (Mzcroteto quadrilineatusForbes), tea micro Ye Hui help c cinticeps Uhler), black-tailed leafhopper (Fen Kun buckle so nigropictns Stal), brown rice planthopper (Nilaparvata lugens Stil), bee wax corn (Peregrinus maidis Ashmead)> white-backed planthopper furcifera Horvath) ^ rice delphacid (Sogatodes orizicola Muir) ^ apple white leaflets butterfly pomaria McAtee)> glucose leafhopper spp);. of servant (MagicWcwfcseptendecim L.), Icerya ant (Icerya purchasi Maskell); pears Buckler Order (Quadraspidiotus perniciosus Comstock); Batch orange powder ant citriRisso); other ant powder composites {Pseudococcus spp);. pear yellow wood SI (CacopsylIapyricola Foerster) ^ persimmon wood wind (TWoza iSospyn'Ashmead). 这些化合物还对半翅目的成员有活性，所述半翅目包括：稻绿蝽(Aro^erm/m MareSay)、南瓜绿蝽(^/ziwa tristis De Geer)、麦长赌(5/bms1 leucopierusSay)、棉网蝽gossypii Fabricius)、tomato bug (Cyrtopeltismodesta Distant)、棉黑翅红蝽suturellus Herrich-Schaffer)>掲美蝽(Euchistus servus Say)、一点褐蝽(-EwcAi1Siw1S variolarius PalisotdeBeauvois)、地长蝽属(Gmpiasi/ieiws spp)、松籽險缘螓corculus Say)> 牧草盲嬉(L_ygus/ineo/aris Palisot deBeauvois)、稻绿蝽(Nezara viridula L.)、稻褐蟮(OebaZus pugnax Fabricius)、大马利筋长蝽(Oncopehus fasciatuf Dallas) ^ 棉跳盲蝽(ftewifotowaycefty seriatus These compounds are also active members of the order Hemiptera, the Hemiptera include: rice green stink bug (Aro ^ erm / m MareSay), pumpkin green stink bug (^ / ziwa tristis De Geer), Sitobion bet (5 / bms1 leucopierusSay ), cotton lace bug gossypii Fabricius), tomato bug (Cyrtopeltismodesta Distant), black-winged red cotton bug suturellus Herrich-Schaffer)> kei beauty bug (Euchistus servus Say), a little brown bugs (-EwcAi1Siw1S variolarius PalisotdeBeauvois), belongs to a long bug (Gmpiasi / ieiws spp), pine dangerous edge cicada corculus Say)> tarnished play (L_ygus / ineo / aris Palisot deBeauvois), southern green stink bug (Nezara viridula L.), brown rice significantly less (OebaZus pugnax Fabricius), Malaysia Lee tendons chinch bugs (Oncopehus fasciatuf Dallas) ^ cotton jump MIRIDAE (ftewifotowaycefty seriatus

99AvcuuviyZO UJ 个W：J Mi 口150 ΙΙϋ fcbJJSs R Ci3Cl攻姐H、I^lJ >μ 曰·《!百葡马(FrankHnieHa occidentalis Pergande)、檢实爾马(Scirthothrips citriMoulton)、大丑蓟马{Sericothrips variabilis Beach)和葱莉马(Thripstabaci Lindeman))，以及鞘翅目（例如马铃薯甲虫{Leptinotarsadecemlineata Say)、墨西哥显瓢虫varivestis Mulsant)和Agriotes λ Athous 或Iiwonius 属的金针虫)。 99AvcuuviyZO UJ a W: J Mi port 150 ΙΙϋ fcbJJSs R Ci3Cl attack Sister H, I ^ lJ> μ saying · "Best Portuguese horse (FrankHnieHa occidentalis Pergande), check the real Palma (Scirthothrips citriMoulton), big ugly thrips {Sericothrips! variabilis Beach) and onions Lima (Thripstabaci Lindeman)), and Coleoptera (eg potato beetle {Leptinotarsadecemlineata Say), Mexico was ladybug varivestis Mulsant) and Agriotes λ Athous or Iiwonius genus wireworms).

本发明的方法实际上可用于所有植物品种。 The method of the present invention can be used in virtually all plant species. 可处理的种子包括，例如小麦(TVzYfa洲aestivum L,)、硬质小麦(ThWcwm durum Desf.)、大轰(Hordeum vulgare L.)、燕麦sativa L.)、黑麦(Secafe cerealeL·)、玉米(Zea may L·)、高梁(Sorghum vulgare?ers.)、稻(Oryza saiivaL_)、菱白(Ζώβ/η*α aquatica L,)、綿花(Gossypium barbadense L 和G.hirsutum L)、亚麻(Zmwm usitatissimum L.)、向曰蔡{Helianthus annuusL.)、大豆(Glycine max Merr.)、四季豆(PAaseo/iw vulgaris L.)、菜豆(Phaseolus limensis Mac£)、蚕豆(Vida faba L_)、碗豆(P&w/n sativum L.)、花生(Arachis hypogaes L)、甜菜(5故！vulgaris L_)、莴苣(Laciwoz sativa L.)、油菜籽(5rcwsz_ca rapa L.和B.napus L.)>甘蓝作物如卷心菜、花揶菜和椰菜L.)、宪菁(Brassica rapa L.)、芥菜juncea Coss.)、黑芥(历*awzbsnigra Koch)、.^(Lycopersicon esculentum Mill)、马镑慕(Solanumtuberosum L·.)、^^(Capsicum frutescens L··)、M~f{Solanum melongenaL·)、烟草(Mcc^awa tabacum L.)、黄瓜(Cucumis sativus L.)、香瓜{Cucumis melo L.)、西瓜(CzYnrf/ws vulgaris Schrad)、南瓜pepo Li C. moschata Duchesne 和C, maxima Duchesne)、胡萝卜(Daucus carota L.)、百日菊(Zfnnfa elegans Jacq.)、大波斯菊(例如Cosmos bipinnatus Cav.)、菊花(Chrysanthemum spp·)、非洲菊(SatWasaatropurpurea L·)、金鱼草（^«iz>rAz>iww majus L·)、大了草(Gerberajamesonii Bolus)> 满夭星JjGypsophUa paniculata L.，G. repens L.和G· Seeds can be handled include, for example, wheat (TVzYfa Island aestivum L,), durum wheat (ThWcwm durum Desf.), Big bang (Hordeum vulgare L.), oat sativa L.), rye (Secafe cerealeL ·), corn (Zea may L ·), sorghum (Sorghum vulgare? ers.), rice (Oryza saiivaL_), Bai Ling (Ζώβ / η * α aquatica L,), cotton flower (Gossypium barbadense L and G.hirsutum L), flax (Zmwm usitatissimum L.), to said Cai {Helianthus annuusL.), soybean (Glycine max Merr.), green beans (PAaseo / iw vulgaris L.), common bean (Phaseolus limensis Mac £), beans (Vida faba L_), peas (P & w / n sativum L.), peanuts (Arachis hypogaes L), sugar beet (5 it! vulgaris L_), lettuce (Laciwoz sativa L.), rapeseed (5rcwsz_ca rapa L. and B.napus L.)> cabbage crops such as cabbage, broccoli flowers and coconut dish L.), Xian Jing (Brassica rapa L.), mustard juncea Coss.), black mustard (calendar * awzbsnigra Koch),. ^ (Lycopersicon esculentum Mill), Lm Mu (Solanumtuberosum L ·.), ^^ (Capsicum frutescens L · ·), M ~ f {Solanum melongenaL ·), tobacco (Mcc ^ awa tabacum L.), cucumbers (Cucumis sativus L.), melon {Cucumis melo L.), Watermelon (CzYnrf / ws vulgaris Schrad), pumpkins pepo Li C. moschata Duchesne and C, maxima Duchesne), carrot (Daucus carota L.), Zinnia (Zfnnfa elegans Jacq.), cosmos (such as Cosmos bipinnatus Cav. ), chrysanthemum (Chrysanthemum spp ·), gerbera (SatWasaatropurpurea L ·), snapdragon (^ «iz> rAz> iww majus L ·), a big grass (Gerberajamesonii Bolus)> Full yao Star JjGypsophUa paniculata L., G. repens L. and G ·

100Kuntze)、矮百合(例如印如加Willd·，L.pycnostachya Michx.,L. scariosa Willd)、洋梧梗(例如Eustoma grandiflorum (Raf.) Shinn)、西洋蓍草(例如Achillea filipendulina Lam" A.millefolium L.)、万寿菊(例如Tagetespatula L., T. erecta L.)、三色堇(例如Viola cornuta L.，V. /rzVo/or L.)、凤仙花(例如Impatiens balsamina L.)、矮牵牛花(Peiwmhspp.)、天竺葵(Geranium spp.)和紫锦苏（例如Solenostemonscutellarioides (L.) Codd)。不仅种子，而且它们的根萎、块莲、鱗莲或球茎，包括活的插条，均可根据本发明进行处理，如来自马铃薯{Solanum tuberosum L·)、^M{Ipomoea batatas L··)、山药(Dioscoreacayenensis Lam.和D. roundata Poir)、洋葱(例如Allium cepa L.)、郁金香(Tulipa spp.)、唐葛蒲(Gladiolus spp.)、合(IMium spp·)、水仙{Narcissus spp.)、大丽花（例如Dahlia pinnata Cav.) λ 鸾尾(frisgermanica L.和其它品种)、藏红花(Crocus spp.)、银莲花spp.)、风信子(Ifyacini/i spp.)、磨香兰(Miwan· spp.)、小苍兰(例如Freesia refracta Klatt.» F. armstrongii W. Wats)、观赏洋葱、(Allium·spp.)、酢楽草spp.)、红海葱(见7/(3/^?1^^7^乙.和其它品种)、仙客来(CJyc/awew persicum Mill.和其它品种)、四尊齿草(C/iiom^oxizluciliae Boiss 和其它品种)、条纹紅海葱(Puschkinia scilloides Adams)、水芋百合(calla U\y)(Zantedeschia aethiopica Spreng., Ζ· elliottianaEngler 和其它品种)、大岩桐(Sinnigia speciosa Benth. Sc Hood.)和块莲状秋海棠(Begonia fuber/iybrfda Voss.)。 100Kuntze), dwarf lily (such as printing such as adding Willd ·, L.pycnostachya Michx., L. Scariosa Willd), Yang Wu Terrier (such as Eustoma grandiflorum (Raf.) Shinn), yarrow (for example Achillea filipendulina Lam "A. millefolium L.), marigold (eg Tagetespatula L., T. erecta L.), pansy (such as Viola cornuta L., V. / rzVo / or L.), Impatiens (such as Impatiens balsamina L.) , Petunia (Peiwmhspp.), geranium (Geranium spp.) and purple Jin Su (eg Solenostemonscutellarioides (L.) Codd). Not only the seeds, but their roots wilt, block lotus, lotus or bulb scales, including live cuttings, can be treated according to the present invention, such as those from potato {Solanum tuberosum L ·), ^ M {Ipomoea batatas L · ·), yam (Dioscoreacayenensis Lam. and D. roundata Poir), onion (Allium cepa L. e.g. ), tulips (Tulipa spp.), Tangge Po (Gladiolus spp.), close (IMium spp ·), Narcissus {Narcissus spp.), dahlias (such as Dahlia pinnata Cav.) λ Luan tail (frisgermanica L. and other species ), saffron (Crocus spp.), Anemone spp.), Hyacinth (Ifyacini / i spp.), grinding Pandan (Miwan · spp.), freesia (eg, Freesia refracta Klatt. »F. armstrongii W. Wats), ornamental onion, (Allium · spp.), Health yue grass spp.), Red onions (see 7 / (3 / ^? ^ 1 ^ ^ 7 B. and other species), cyclamen (CJyc / awew persicum Mill., and other species), four teeth grass (C / iiom ^ oxizluciliae Boiss and other species), striped Red onions (Puschkinia scilloides Adams), calla lily (calla U \ y) (Zantedeschia aethiopica Spreng., Ζ · elliottianaEngler and other species), gloxinia (Sinnigia speciosa Benth. Sc Hood.) and a block lotus-like begonia (Begonia fuber / iybrfda Voss.). 可以根据本发明处理莲插，包括来自如下植物的莲插：甘鹿(iSacc^zrwm officinarum L.)、香石竹(Dianthus caryophyllus L·)、florists chrysanthemum {Chrysanthemummortifolium Ramat.)^ 秋海棠spp.)、天竺葵(Geramwzn spp.)、紫锦苏（例如Soienostemon scutellarioides (L.) Codd)和一品红{Euphorbiapulcherrima Willd.)。 Lotus plug can be treated according to the invention, including the lotus plant is inserted from the following: Gan Lu (iSacc ^ zrwm officinarum L.), carnation (Dianthus caryophyllus L ·), florists chrysanthemum {Chrysanthemummortifolium Ramat) ^ Begonia spp), geranium. (Geramwzn spp.), purple Jin Su (eg Soienostemon scutellarioides (L.) Codd) and poinsettia {Euphorbiapulcherrima Willd.). 可以根据本发明处理的叶插包括来自 According to the present invention can be inserted leaf processing comprises from

101>·Η I P -J JAs jtq · yCzV\JJti^U/llCi ~{卜V Il VW iJLltillJJUUllCl 101> · Η IP -J JAs jtq · yCzV \ JJti ^ U / llCi ~ {Bu V Il VW iJLltillJJUUllCl

ionantha Wendl.)和景天(Sedum spp.)。 ionantha Wendl.) and sedum (Sedum spp.). 上面列举的谷类、蔬菜、观赏植物(包括花)和果实作物是说明性的，不应认为它们以任何方式限制本发明。 Listed above cereals, vegetables, ornamental plants (including flowers) and fruit crops are illustrative, it should not be considered in any way limiting the present invention. 因为无脊椎害虫防治谱和经济重要性，棉花、玉米、大豆和稻的种子处理，马铃薯、甘薯、洋葱、郁金香、水仙、番红花和风信子的块茎和鳞茎处理是本发明的优选实施方案。 Because of invertebrate pest control spectrum and economic importance, seed cotton, corn, soybeans and rice processing, potato, sweet potato, onion, tulips, daffodils, crocuses and hyacinths tubers and bulbs deal is a preferred embodiment of the present invention.

可以通过多种不同方法来用式I的化合物处理繁殖体的场所。 Place propagules can be handled with a compound of formula I by means of various methods. 所需的全部就是生物有效量的式I的化合物，其被施加于或足够靠近繁殖体，从而使其能被该繁殖体吸收》式I的化合物可以通过以下方法施用：用式I的化合物的溶液或分散体浸透包含繁殖体的生长介质，混合式I的化合物与生长介质并在经处理的生长介质中种植该繁殖体(例如育苗箱处理)，或者各种形式的繁殖体处理，其中在将繁殖体种植在生长介质中之前将式I的化合物施用于繁殖体。 All that is biologically effective amount of a compound of formula I required, which is applied to propagules or sufficiently close, so that it can absorb the propagules "compound of Formula I may be administered by the following method: using a compound of formula I saturated solution or dispersion containing growth medium propagules, the compounds of Formula I mixed with the growth medium and grow the propagules (such as nursery box treatment) in the growth medium treated, or propagules of various forms of treatment, which in The compound propagules planted in growth media prior to formula I is administered to propagules.

在这些方法中，式I的化合物将通常与农业上适宜的载体一起以配方或组合物来施用，所述适宜的载体包含至少一种液体稀释剂、固体稀释剂或表面活性剂。 In these methods, the compounds of formula I will generally be together to be administered formulation or composition with an agriculturally suitable carrier, said carrier comprising at least one suitable liquid diluent, a solid diluent or a surfactant. 多种配方适用于本发明，最适宜的配方取决于施用方法。 A variety of formulations suitable for the present invention, the most suitable method of administration depends on the recipe. 如本领域技术人员熟知的，配方的目的是提供安全和便利的转运、测量、分配作物保护化学品的方式，还有优化其生物功效。 As well known to those skilled in the purpose of formulation is to provide a safe and convenient transport, measuring, crop protection chemicals are allocated, as well as to optimize the biological efficacy.

取决于施用方法，有用的配方包括液体如溶液剂(包括乳状浓缩物)、混悬剂、乳剂(包括微乳和/或悬乳(suspoemulsions))等，它们可以任选地被浓缩成凝胶。 Depending on the method of application useful formulations include liquids such as solutions (including emulsion concentrates), suspensions, emulsions (including microemulsions and / or suspended milk (suspoemulsions)), etc., which may optionally be concentrated to a gel . 有用的配方进一步包括固体如粉剂、散剂、颗粒剂、丸剂、片剂、膜剂等，它们可以是水分散性的（“可湿性的”）或水溶性的。 Useful formulations further include solids such as dusts, powders, granules, pellets, tablets, films, etc., which may be water-dispersible ("wettable") or water-soluble. 可以将有效成分(微)胶囊化并进一步形成混悬剂或固体配方；或者可以将有效成分的整个配方胶囊化(或“包衣”）。 The active ingredient can be (micro) encapsulated and further formed a suspension or solid formulation; or it can be the whole formulation of the active ingredient encapsulated (or "coating"). 胶囊化可以控制或延缓有效成分的释放。 Encapsulated to control or delay release of the active ingredient. 可喷雾的配方可以在适宜的介质中提供，使用的喷雾体积为每公顷约一百至几百升。 Sprayable formulations can be provided in a suitable medium, using a spray volume per hectare is about one hundred to several hundred liters. 高强度组合物主要用作进一步配方的中间体。 High strength compositions are primarily used as intermediates for further formulation.

102万通芾苜有有双重的嘀效成分、柿梓刑和表囬沽饪刑，大约在如下范围内，它们总和为100重量％。 102 Wantong Fei has a double tick clover have active ingredients, persimmon Azusa punishment and torture table back to put Ning, approximately in the following ranges, they sum to 100% by weight.

重量百分比有效成分稀释剂 表面活性剂水分散性和水溶性颗粒5-90 0-94 1-15齐U、片剂和散剂混悬剂、乳剂、溶液剂5-50 40-95 0-15(包括乳状浓缩物） The percentage by weight of the active ingredient Diluent Surfactant Water-dispersible and water-soluble granules 5-900-941-15 homogeneous U, tablets, and powders, suspensions, emulsions, solutions 5-5040-950-15 ( include emulsion concentrates)

粉末1-25 70-99 0-5 颗粒剂与丸剂0.01-99 5-99.99 0-15 1-2570-990-5 powder granules and pellets 0.01-99 5-99.99 0-15

高强度组合物卯-99 0-10 0-2 High strength compositions Mao -990-100-2

典型的固体稀释剂在"Watkins 等人，Handbook of Insecticide Dust Typical solid diluents are described in "Watkins, et al., Handbook of Insecticide Dust

Diluents and Carriers,第二版，Dorland Books，Caldwell, New Jersey Diluents and Carriers, Second Edition, Dorland Books, Caldwell, New Jersey

中有描述。 It is described. 典型的液体稀释剂在Marsden, Solvents Guide,第二版， Typical liquid diluents in Marsden, Solvents Guide, Second Edition,

Interscience, New York, 1950 中有描述。 Interscience, New York, 1950 are described. McCutcheon's Emulsifiers and McCutcheon's Emulsifiers and

Detergents and McCutcheon's Functional Materials (North America and Detergents and McCutcheon's Functional Materials (North America and

International Edition, 2001)，The Manufactuing Confection Publ Co.， International Edition, 2001), The Manufactuing Confection Publ Co.,

Glen Rock, New Jersey,以及Sisely and Wood, Encyclopedia of Surface Glen Rock, New Jersey, as well as Sisely and Wood, Encyclopedia of Surface

Active Agents, 'Chemical Publ. Co., Inc., New York, 1964 列出了表面活性剂和推荐的应用。 Active Agents, 'Chemical Publ. Co., Inc., New York, 1964 lists the surfactants and recommended application. 所有配方都可以含有少量添加剂以减少泡沫。 All formulations can contain minor amounts of additives to reduce foam. 结块、腐蚀、微生物生长等，或者含有增稠剂以增加粘度。 Caking, corrosion, microbiological growth and the like, or contain a thickening agent to increase the viscosity.

表面活性剂包括，例如，乙氧基化醇、乙氧基化烧基酚、乙氧基化脱水山梨糖醇脂肪酸酯、乙氧基化胺、乙氧基化脂肪酸、酯和油、 Surfactants include, for example, ethoxylated alcohols, ethoxylated phenol burn, ethoxylated sorbitan fatty acid esters, ethoxylated amines, ethoxylated fatty acids, esters and oils,

磺基丁二酸二综基酯、烷基硫酸盐、烷基芳基横酸盐、有机硅酮、 Fully sulfosuccinate dimethyl ester, alkyl sulfates, alkyl aryl cross salts, organic silicone,

MiV-二烷基牛磺酸盐、乙二醇酯、磷酸酯、木质素磺酸盐、萘磺酸盐甲醛缩合物、聚羧酸盐和包括聚氧乙稀/聚氧丙烯嵌段共聚物在内的嵌段共聚物。 MiV- two alkyl taurates, glycol esters, phosphate esters, lignin sulfonates, naphthalene sulfonate formaldehyde condensates, polycarboxylates, and polyoxyethylene comprising ethylene / polyoxypropylene block copolymers including block copolymers. 固体稀释剂包括，例如，粘土如膨润土、蒙脱石、硅镁土和高岭土、淀粉、糖、二氧化桂、滑石、硅藻土、尿素、碳酸齊、 Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, starch, sugar, Gui dioxide, talc, diatomaceous earth, urea, carbonate Qi,

碳酸钠和碳酸氢钠，以及硫酸钠。 Sodium carbonate and sodium bicarbonate, and sodium sulfate. 液体稀释剂包括，例如，水、KN- Liquid diluents include, for example, water, KN-

二甲基甲酸胺、二甲基亚砜、N-焼基B比咯烧酮、乙二醇、聚丙二醇、 Dimethyl formamide, dimethyl sulfoxide, N- firing group B than slightly burned ketone, ethylene glycol, polypropylene glycol,

103日、一夕L·日目、qitr曰、进;μ. 103 days, overnight L · day project, qitr said, into; μ.

麻籽油、桐油、芝麻油、玉米油、花生油、棉籽油、大豆油、菜籽油和椰子油、脂肪酸酯、酮类如环己酮、2-庚酮、异佛乐酮和4-羟基-4-甲基-2-戊酮，以及醇类如甲醇、环己醇、十二烷基醇、苄醇和四氢呋喃醇。 Hemp seed oil, tung oil, sesame oil, corn oil, peanut oil, cottonseed oil, soybean oil, rapeseed oil and coconut oil, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy 4-methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, lauryl alcohol, benzyl alcohol and tetrahydrofurfuryl alcohol.

溶液，包括乳状浓缩物，可以简单地通过混合各组分来制备。 Solution, including emulsion concentrates, can be prepared by simply mixing the ingredients. 细粉和粉末可以通过混合，并且通常在锤式粉碎机或流能磨中进行研磨而制备。 Powder and powder can be mixed and prepared generally ground in a hammer mill or fluid energy mill. 悬浮剂通常通过湿磨而制备；参见例如，US 3，060，084。 The suspending agent is usually prepared by wet milling; see e.g., US 3,060,084. 颗粒剂和丸剂可以通过将活性物质喷在预制成的颗粒载体上或者通过团聚技术来制备。 Granules and pellets can be prepared by spraying the active material on preformed granular carriers or prepared by agglomeration techniques. 参见Browning, “Agglomeration”，ChemicalEngineering, 1967 年12 月4 曰，第147-48 页；Perry's ChemicalEngineer's Handbook,第四版，McGraw-Hill, New York, 1963 8-57 页和下述的，以及.PCT公开WO 91/13546。 See Browning, "Agglomeration", ChemicalEngineering, 1967 December 4, saying, pp. 147-48; Perry's ChemicalEngineer's Handbook, Fourth Edition, McGraw-Hill, New York, 1963 8-57 and the following pages, and .PCT Publication WO 91/13546. 丸剂的制备如US4,172,714中所描述。 Preparation of pills as described in US4,172,714. 水分散性和水溶性粒剂可以根据US 4,144,050、US 3,920,442和DE 3,246,493所教导而制备。 Water-dispersible and water-soluble granules can be prepared according to US 4,144,050, US 3,920,442 and DE 3,246,493 teaches. 片剂可以根据US5,180,587、US 5,232,701 和US 5,208,030 所教导而制备。 The tablets may be prepared according to US5,180,587, US 5,232,701 and US 5,208,030 taught. 膜剂可以根据GB 2,095,558和US 3,299,566所教导而制备。 Agent can be prepared according to GB 2,095,558 and US 3,299,566 taught.

有关配方技术的更多信息，参见TS Woods，“The FormulatorsSToolbox - Product Forms for Modem Agriculture”，收于PesticideChemistry and Bioscience, The Food-Environment Challenge, T. Brooks和TR Roberts 编著，Proceedings of the 9th International Congress onPesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999,pp. 120-133。 For more information about the formulation technology, see TS Woods, "The FormulatorsSToolbox - Product Forms for Modem Agriculture", to close at PesticideChemistry and Bioscience, The Food-Environment Challenge, T. Brooks and TR Roberts eds., Proceedings of the 9th International Congress onPesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999, pp. 120-133. 另外参见US3，235，361,第6栏第16行至第7栏第19行及实施例10-41； US 3,309,192,第5栏第43行至第7栏第62行及实施例8、12、15、39、41、52、53、58、132、138-140、162-164、166、167 和169-182; US 2,891,855,第3 栏第66 行至第5 栏第17行及实施例1-4； KIingman. Weed Control as a Science, John Wiley and See also US3,235,361, column 6, line 16 through Col. 7, line 19 and Examples 10-41; US ​​3,309,192, line 43 to column 7, column 5, line 62 and Examples 8, 12 , 15,39,41,52,53,58,132,138-140,162-164,166,167 and 169-182; US 2,891,855, column 3, line 66 to column 5, line 17 and Examples 1-4;. KIingman Weed Control as a Science, John Wiley and

104mu iNcw i υΐΛ.» ι^υι > οι-yO ;从队naiiuc 守r yyana ^uniroi . 104mu iNcw i υΐΛ »ι ^ υι> οι-yO; from the team naiiuc keep r yyana ^ uniroi

Handbook,第8 版，Blackwell Scientific Publications，Oxford, 1989。 Handbook, Version 8, Blackwell Scientific Publications, Oxford, 1989.

根据本发明，可以通过一种方法保护繁殖体或从其生长的植物免受无脊椎害虫侵害，所述方法包括使该繁殖体或该繁殖体的场所与包含生物有效量的式I的化合物、其N-氧化物或农业上适用的盐的组合物接触。 According to the present invention can be protected by a method propagule or a plant grown therefrom from an invertebrate pests, said method comprising the breeding places of the body or the propagation body comprising a biologically effective amount of a compound of formula I, Suitable salts of the compositions contacting the N- oxide thereof, or agriculture. 本发明包括与包含生物有效量的式I的化合物、其N-氧化物或农业上适用的盐，以及有效量的至少一种其它生物活性化合物或试剂的组合物接触的繁殖体。 The present invention comprises a biologically effective amount of a compound comprising the formula I, their N- oxides or agriculturally suitable salt thereof, and an effective amount of at least one propagules other biologically active compounds or agents in contact with the composition. 根据本发明用于处理繁殖体(或从其生长的植物)的组合物也可以包含(除式I的成分之外)有效量的一种或多种其他生物活性化合物或试剂。 According to the present invention for treating propagules (or plant grown therefrom) composition may also contain (in addition to the Formula I component) an effective amount of one or more other biologically active compounds or agents. 适宜的其它化合物或试剂包括杀虫剂、杀菌剂、杀线虫剂、杀细菌剂、杀螨剂、生长调节剂如生根刺激剂、化学不育剂、半化学药物(semiochemical)、拒虫剂、诱虫剂、外激素、·取食刺激剂、其它生物活性化合物或昆虫致病细菌、病毒或真菌，以形成多组分杀虫药，所述杀虫药给出更宽的农业效用谱。 Suitable other compounds or agents including insecticides, fungicides, nematicides, bactericides, acaricides, growth regulators such as rooting stimulants, chemosterilant, semi-chemical drugs (semiochemical), insect repellent, insect attractant, pheromones, · feeding stimulants, other biologically active compounds or entomopathogenic bacteria, viruses or fungi to form a multi-component insecticide, the insecticide is given a broader spectrum of agricultural utility. 这些可与本发明的化合物一起配方的生物活性化合物或试剂的实例为：杀虫剂如阿维菌素、乙酰甲胺磷、吡虫清、amidoflument (S-1955)、齐墩螨素、艾扎丁、谷硫磷、氟氯菊酯、binfenazate、噻嗪酮、呋喃丹、氟唑虫清、定虫隆、毒死蜱、甲基毒死蜱、环虫酰肼(chromafenozide)、噻虫胺、百树菊酯、β-氟氯氰菊酯、氯氟氰菊酯、λ-氯氟氰菊醋、氯氰菊酯、灭蝇胺、溴氰菊酯、杀螨硫隆、二嗪农、氟脲杀、乐果、噁茂醚、依马菌素、硫丹、高氰戊菊酯、ethiprole、苯硫威、双氧威、甲氰菊酯、唑螨酯、杀灭菊酯、锐劲特、flonicamid、氟氰戊菊酯、氟胺氰菊酯、flufenerim (UR-50701)、氟虫脲、地虫磷、特丁苯酰肼、氟铃脲、吡虫啉、嚼二唑虫、丙胺憐、氟丙氧脲、马拉硫磷、蜗牛敌、甲胺磷、杀扑磷、灭多虫、蒙五一五、甲氧滴滴涕、久效憐、甲氧苯酰肼、硝虫噻曉、双苯氟脲、noviilumuron (XDE-007)、甲氨叉威、对硫磷、甲基对硫磷、氯菊酯、甲拌磷、伏杀磷、亚胺硫磷、磷胺、抗 Examples of these agents or bioactive compounds with compounds of this invention formulated together: insecticides such as abamectin, acephate, acetamiprid, amidoflument (S-1955), abamectin, Ai Zhading, azinphos-methyl, bifenthrin, binfenazate, buprofezin, carbofuran, chlorfenapyr, chlorfluazuron, chlorpyrifos, chlorpyrifos-methyl, ring tebufenozide (chromafenozide), clothianidin, one hundred tree permethrin, β- cyfluthrin, cyhalothrin, λ- cyhalothrin chrysanthemum vinegar, cypermethrin, cyromazine, deltamethrin, mites sulfur Long, diazinon, fluorouracil kill, dimethoate, evil Mao ether, according to Ma streptozotocin, endosulfan, esfenvalerate, ethiprole, benzene, sulfur Granville, fenoxycarb, Fenpropathrin, Fenpyroximate, fenvalerate, fipronil, flonicamid, fluorine cyanide amyl pyrethroids, fluvalinate, flufenerim (UR-50701), flufenoxuron, FONOFOS, halofenozide, hexaflumuron, imidacloprid, chewing oxadiazole insects, propylamine pity, fluorine propoxyphene urea, Ma Pull parathion, metaldehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, long effect pity, methicillin hydrazine nitrate insect thiophene dawn, novaluron, noviilumuron ( XDE-007), carbamoyl fork Wei, parathion, methyl parathion, permethrin, phorate, phosalone, phosmet, phosphamidon, anti-

105spiromesifm(BSN2060).乙丙硫磷、双苯酰肼、伏虫隆、七氟菊酯、特丁磷、杀虫畏、噻虫啉(thiacloprid)、噻虫嘆(thiamethoxam)、硫双灭多威、杀虫双、四溴菊酯、敌百虫和杀虫隆；杀菌剂如噻二唑素、腈嘧菌酯、苯菌灵、灭瘟素、波尔多液(碱式硫酸铜)、糠菌唑、氯环丙酿胺、敌菌丹、克菌丹、多菌灵、地茂散、百菌清、王铜、铜盐、cyflufenamid^清菌服、环唑醇、环丙嘧淀、（S)-3，5-二氯-N-(3-氯-1-乙基-I-甲基-2-氧丙基)-4-甲基苯甲酰胺(RH7281)、双氯氰菌胺(diclocymet) (S-2900)、哒菌清、氯硝胺、噁咪唑、（S)-3,5-二氢-5-甲基-2-(甲硫基)-5-苯基-3-(苯氨基)-4H-咪唑-4-酮(RP 407213)、烯酰吗啉、dimoxystrobin、烯唑醇、稀唑醇-M、多果定、克瘟散、氧唑菌、 105spiromesifm (BSN2060). EPR parathion, tebufenozide, teflubenzuron, tefluthrin, terbufos, tetrachlorvinphos, thiacloprid (thiacloprid), clothianidin sigh (thiamethoxam), sulfur double methomyl Granville, Bisultap, tralomethrin, trichlorfon and insecticidal Long; fungicides such as acibenzolar, azoxystrobin, benomyl, blasticidin, Bordeaux mixture (basic copper sulfate), bran ipconazole, chlorine cyproterone stuffed amine, captafol, captan, carbendazim, to Mao San, chlorothalonil, copper king, copper, cyflufenamid ^ clear bacteria clothes, cyproconazole, cyproterone ethyl starch, (S) -3,5- dichloro -N- (3- chloro-1-ethyl -I- methyl-2-oxopropyl) -4-methylbenzamide (RH7281), bis cyanuric chloride bacteria amine (diclocymet) (S-2900), da clear bacteria, clonazepam amine, oxpoconazole, (S) -3,5- dihydro-5-methyl-2- (methylthio) -5-phenyl - 3- (phenylamino) -4H- imidazole-4-one (RP 407213), dimethomorph, dimoxystrobin, diniconazole, dilute Hexaconazole -M, dodine, g blast scattered, epoxiconazole,

P惡哩酮菌、咪挫菌酮(fenamidone)、异喃菌醇、腈苯唑、fencaramid(SZX0722)、拌种咯、苯锈淀、丁苯吗啉、薯瘟锡、毒菌锡、氟啶胺、氟噁菌、氟联苯菌(RJPA 403397)、flumorfiOumorlin (SYP-L190)、fluoxastrobin (HEC5725)、喹唑菌酮、氟硅唑、氟酰胺、粉唑醇、灭菌丹、藻菌磷、咲氣丙灵、扶Π比挫灵(fbrametapyr) (S-82658)、已哩醇、环戊唑醇、异稻瘟净、异丙定、稻瘟灵、春雷霉素、亚胺菌、代森锰锌、代森锰、mefenxam、丙氧灭绣胺、甲霜灵、环戊唑菌、叉氨苯酰胺(SSF-126)、metrafenone (AC375839)、腈菌唑、田安甲胂铁(甲基胂酸铁)、nicobifen (BAS 510), orysastrobin、囉霜灵、戊菌哩、戊菌隆、噻菌灵、丙氯灵、百维灵、丙环唑、proquinazid (DPX-KQ926)、prothioconazole (JAU6476)、唆斑西、pyradostrobin、二甲啼菌胺、略喹酮、喹氧灵、螺嚷茂胺、硫、戊唑醇、氟醚唑、涕必灵、溴氟唑菌、甲基托布津、福美双、tiadinil、三唑酮、唑菌醇、三环唑、肟菌酯(trifloxystrobin)、戊叉唑菌、有效霉素和稀菌酮；杀线虫剂如涕灭威、甲氨叉威和克线磷；杀细菌剂如链霉素；杀螨剂如虫蠘脒、灭螨猛、乙醋杀螨醇(chlorobenzilate)、三环锡、开乐散、除螨灵、特苯曙哩、 P evil one mile bacteria, microphone fell cycloheximide (fenamidone), isopropyl alcohol furans bacteria, fenbuconazole, fencaramid (SZX0722), fenpiclonil, fenpropidin lake, fenpropimorph, potato plague tin, toadstool tin, fluorine piperidinamine, fluorine bad bacteria, flurbiprofen bacteria (RJPA 403397), flumorfiOumorlin (SYP-L190), fluoxastrobin (HEC5725), quinazoline cycloheximide, flusilazole, flutolanil, flutriafol, folpet, phycomycetes phosphorus, Misaki gas propionate spirit, help Π ratio fell Spirit (fbrametapyr) (S-82658), has miles alcohol, cyclopentanol Hexaconazole, Iprobenfos, isopropyl set, Isoprothiolane, kasugamycin, imine bacteria , mancozeb, maneb, mefenxam, propoxyphene off embroidered amine, metalaxyl, metconazole, fork benzamide (SSF-126), metrafenone (AC375839), myclobutanil, Tian An iron armor arsine (monomethylarsenic acid iron), nicobifen (BAS 510), orysastrobin, La frost spirit, amyl bacteria miles pencycuron, thiabendazole, prochloraz, Broadway spirit, propiconazole, proquinazid (DPX-KQ926) , prothioconazole (JAU6476), instigate spot west, pyradostrobin, dimethyl amine cry bacteria, slightly methaqualone, quinoxyfen, screw cried Mao amines, sulfur, tebuconazole, fluorine difenoconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram, tiadinil, triadimefon, Triadimenol, tricyclazole, trifloxystrobin (trifloxystrobin), E fork yl bacteria, validamycin and dilute cycloheximide; nematicides such as aldicarb, carbamoyl fork K and g fenamiphos; bactericides such as streptomycin; acaricides such as insect Jie amidine, Chinomethionate, ethyl acetate mites alcohol (chlorobenzilate), cyhexatin, dicofol, in addition to mites, especially benzene Shu miles,

106螨胺；和生物试剂如包括苏云金杆菌a和苏云金杆菌k在内的苏云金杆菌，苏云金杆菌δ-内毒素、杆状病毒，以及昆虫致病细菌、病毒和真菌。 106 mites amine; and biological agents such as Bacillus thuringiensis including a Bacillus thuringiensis and Bacillus thuringiensis including k, within δ- endotoxin of Bacillus thuringiensis, baculovirus, and entomopathogenic bacteria, viruses and fungi.

有关这些农用保护剂的通用参考文献是The Pesticide Manual,第十二版，CDS Tomlin, Ed., British Crop Protection Council, Famham,Surrey, U. K-, 2000。 Agricultural protection agents about these common references is The Pesticide Manual, Twelfth Edition, CDS Tomlin, Ed., British Crop Protection Council, Famham, Surrey, U. K-, 2000.

用于与式I的化合物混合的优选杀虫剂和杀螨剂包括拟除虫菊酯类如氯氰菊酯、氯氟氰菊酯、百树菊酯和β-氟氯氰菊酯、高氰戊菊酯、杀灭菊酯和四溴菊酯；氨基甲酸酯类如苯硫威、灭多虫、甲氨叉威和硫双灭多威；新烟碱类(neonicotinoids)如噻虫胺、批虫啉和噻虫啉；神经纳通道阻断剂如噁二唑虫，杀虫大环内酯如艾克敌105、阿维菌素、齐壤螨素、依马菌素；γ-氨基丁酸(GABA)拮抗剂如硫丹、ethiprole和锐劲特；杀虫脲类如氟虫脲和杀虫隆；保幼激素模拟物如噁茂醚和蚊蝇醚；拒嗪酮；和虫螨脒。 Preferably insecticides and acaricides for mixing with compounds of formula I include pyrethroids such as cypermethrin, cyhalothrin, cyfluthrin and β- cyfluthrin, esfenvalerate, killing chrysanthemum esters and tralomethrin; carbamates such as benzene sulfur Viagra, methomyl, carbamoyl fork K methomyl and thiodicarb; neonicotinoids (neonicotinoids) as clothianidin, approved insect morpholine and thiacloprid ; sodium channel blockers, such as nerve oxadiazole insects, insecticidal macrocyclic lactone such as spinosad, avermectin, soil mites Su Qi, according to Ma streptozotocin; γ- aminobutyric acid (GABA) antagonists such as endosulfan, ethiprole and fipronil; insecticidal ureas such as flufenoxuron and insecticidal Long; juvenile hormone mimics such as dioxolyl ether and pyriproxyfen; pymetrozine; and amitraz. 用于与本发明的化合物混合的优选生物试剂包括苏云金杆菌和苏云金杆菌δ-内毒素，以及天然存在的和遗传改良的病毒杀虫剂，包括杆状病毒科的成员和昆虫致病真菌。 Preferably biological agents for mixing with compounds of this invention include Bacillus thuringiensis and Bacillus thuringiensis within δ- endotoxin, and a naturally occurring virus and genetic improvement of pesticides, including family members of the baculovirus and insect pathogenic fungi.

在用于处理茎插的组合物中与式I的化合物混合的优选的植物生长调节剂是I私卩引噪-3-乙酸、1/ί-别噪-3-丁酸和I-萘乙酸，以及它们的农业上适用的盐、酯和酰胺衍生物，如I-萘乙酰胺。 In the plant growth regulator used to process stem cutting composition is mixed with a compound of formula I is preferred that I cited private Jie noise 3-acetic acid, 1 / ί- other noise 3-butyric acid and I- naphthylacetate and the agriculturally suitable salts thereof, the ester and amide derivatives, such as I- naphthyl amide. 用于与式I的化合物混合的优选杀菌剂包括用作种子处理的杀菌剂如福美双、代森锰、代森锰锌和克菌丹。 Preferably fungicides for mixing with the compound of Formula I include fungicide used as a seed treatment, such as thiram, maneb, mancozeb and captan.

在以下实施例中，所有百分比均以重量计，并且所有配方都用常规方法制备。 In the following examples, all percentages are by weight and all formulations are prepared by conventional methods. 化合物号指索引表A中的化合物。 A compound numbers refer to the compound index table.

实施例A Example A

可湿性散剂 Wettable powders

化合物208 65.0%I——>兀巫明浓匕一Δ.\)70 Compound 208 65.0% I -.> Wu Wu Ming concentrated dagger a Δ \) 70

木质素磺酸钠 4.0% Lignin sulfonate 4.0%

硅铝酸钠 6.0% 6.0% sodium aluminosilicate

蒙脱石(煅烧的） 23.0% Montmorillonite (calcined) 23.0%

实施例B Example B

颗粒剂 Granules

化合物486 10.0% Compound 486 10.0%

硅镁土颗粒(低挥发物，0.71/0.30 mm; 90.0% Attapulgite granules (low volatiles, 0.71 / 0.30 mm; 90.0%

USS No. 25-50 筛） USS No. 25-50 mesh)

实施例C Example C

挤压丸 Extrudates

化合物509 25.0% Compound 509 25.0%

无水硫酸钠 10.0% Anhydrous sodium sulfate 10.0%

粗木质素磺酸钙 5.0% Crude calcium ligninsulfonate 5.0%

烷基萘磺酸钠 1.0% Sodium alkylnaphthalenesulfonate 1.0%

钓/镁膨润土 59.0% Fishing / magnesium bentonite 59.0%

实施例D Example D

乳状浓缩物 Emulsion concentrates

化合物516 20.0% Compound 516 20.0%

油溶性磺酸盐和聚氧乙烯醚混合物 10.0% The oil soluble sulfonates and polyoxyethylene ethers mixture of 10.0%

异佛乐酮 70.0% Isophorone 70.0%

对于生长介质浸液，配方需要，通常在用水稀释后，提供在溶液中的或小到足以在液体中保持分散的颗粒的形式的式I的化合物。 For the growth medium infusion, formulations need, usually after dilution with water, to provide the compound in solution or in the form of dispersed particles small enough to formula I kept in the liquid. 水分散性或水溶性散剂、颗粒剂、片剂、乳状浓缩物、含水混悬剂浓缩物等是适于生长介质水浸液的配方。 Water-soluble or water-dispersible powders, granules, tablets, emulsion concentrates, aqueous suspension concentrates and the like are suitable for growing medium flooding liquid formulation. 对于处理具有相对高的孔隙率的生长介质，如轻质土壤，或包含多孔物质的人工生长介质，如泥煤苔、 珍珠岩、蛭石等，浸液是最令人满意的。 Growth media for dealing with a relatively high porosity, such as light soil, or artificial growth medium comprising a porous material, such as peat moss, perlite, vermiculite, immersion is the most satisfactory. 也可以将包含式I的化合物的浸液加入液体生长介质中(即水培)，这使得式I的化合物成为液体■生长介质的一部分。 Infusion of compounds of formula I may also be added to a liquid containing growth medium (i.e. hydroponics), which makes the compounds of Formula I become part of a liquid ■ growth medium. 本领域技术人员将理解，无脊椎害虫防治功效所需的浸液中的式I的化合物的量(即生物有效量)将随繁殖体的类型、 式I的化合物、所需的植物保护的持续时间和范围、要防治的无脊椎 Those skilled in the art will appreciate that the amount of compound types (ie biologically effective amount) of the desired compound invertebrate pest control efficacy of immersion of formula I will be with propagules of formula I, the required duration of plant protection timing and extent of invertebrate to be controlled

108軎丑和外境因隶向变。 108 Wei Li ugly and outside the territory due to the change. 浸液中式I的化合物的浓度通常为约0.01 ppm至10000 ppm,更通常为约I ppm至100 ppm。 The infusion concentration of the compound of formula I is generally from about 0.01 ppm to 10000 ppm, more typically from about I ppm from 100 ppm. 本领域技术人员能够容易地确定所需的植食性无脊椎害虫防治水平所需的生物有效浓度。 Those skilled in the art can easily determine the required phytophagous invertebrate pest control level desired biological effective concentration.

对于处理生长介质，也可以通过混合式I的化合物和干燥的散剂或颗粒剂配方而施用之。 For treatment the growth medium and to be administered and the compound of the dried powder or granules of the formula I mixed. 由于该施用方法不需要首先分散或溶解在水中，因此干燥的散剂或颗粒剂配方不需要具有高分散性或溶解性。 Since this method of administration without first dispersed or dissolved in water, so the drying of powders or granules formulation does not need to have high solubility or dispersibility. 尽管在育苗箱中可以处理所有的生长介质，但在农田中由于环境和成本原因，通常仅处理繁殖体附近的泥土。 Although in a nursery box can handle all the growth media, but in the fields due to environmental and cost reasons, generally deal only with propagules nearby soil. 为了将施用劳动和费用最小化，式I的化合物的配方施用与繁殖体种植(例如播种)同时进行最有效。 In order to minimize the cost of labor and administration, Fertilizers and planting propagules (eg sowing) compounds of formula I are most effective at the same time. 对于沟中施用，将式I配方(最便利地为颗粒剂配方)直接施用于种植者鞋后。 For ditch administration the formula I formulation (most conveniently a granule formulation) is applied directly to the growers after the shoe. 对于T带施用，将式I配方施用在种植者鞋后和压力机轮后或通常在其前面的行的带》本领域技术人员将理解，无脊椎害虫防治功效所需的生长介质场所中的式I的化合物的量(即生物有效量)将随繁殖体类型、式I的化合物、所需的植物保护的持续时间和范围、要防治的无脊椎害虫和环境因素而变。 For T with administration of the formula I Fertilizers growers in the shoe and the rear wheels or the press usually with their front line, "skilled in the art will appreciate that the desired invertebrate pest control efficacy in the growth medium places amount (ie biologically effective amount) of a compound of formula I will vary with the type of reproduction, the compounds of formula I, the duration and scope of the required plant protection, and environmental factors invertebrate pest to be controlled and changed. 在繁殖体的生长介质场所中的式·I的化合物的浓度通常为约0.0001 ppm至100 ppm,更通常为约0.01ppm至10 ppm。 Concentration of the compound in the growth medium in place propagules Formula · I is typically about 0.0001 ppm to 100 ppm, more typically from about 0.01ppm to 10 ppm. 本领域技术人员能够容易地确定所需的植食性无脊椎害虫防治水平所需的生物有效量。 Those skilled in the art can easily determine the required phytophagous invertebrate pest control levels of biologically effective amount necessary.

可以通过在式I的化合物溶液或分散体中浸泡繁殖体而直接处理之。 It can be a solution or dispersion of the compound of Formula I soak propagules handle it directly. 尽管该施用方法可用于所有类型的繁殖体，但对于给发育中的植物提供无脊椎害虫防治而言,处理大种子(例如平均直径至少为3 mm)比处理小种子更有效。 Although this method of administration for all types of propagules, but to the developing plants provide invertebrate pest control, the handling of large seeds (for example, an average diameter of at least 3 mm) is more effective than treatment of small seeds. 处理繁殖体如块茎、鳞基、球芸、根莖、茎插和叶插，除了提供繁殖体处理以外，还能有效处理发育中的植物。 Processing propagules such as tubers, scales base, the ball Yun, roots, stems and leaves inserted plug, in addition to providing treatment propagules outside, but also to deal effectively with the developing plants. 用于生长介质浸液的配方通常也可用于浸泡处理。 Formulations for immersion liquid growth medium may also be used generally soaking. 浸泡介质包含非植物毒性液体，通常为水基的，尽管其可以包含非植物毒性量的其它溶剂如甲醇、乙醇、异丙醇、乙二醇、丙二醇、碳酸丙烯、苄醇、二元酯、丙酮、乙酸甲酯、乙酸乙酯、环己酮、二甲基亚砜和从甲基吡咯烷 Soaking medium comprises a non-phytotoxic liquid, typically water-based, although other solvents which may contain non-phytotoxic amount, such as methanol, ethanol, isopropanol, ethylene glycol, propylene glycol, propylene carbonate, benzyl alcohol, dibasic esters, acetone, methyl acetate, ethyl acetate, cyclohexanone, dimethylsulfoxide and from methylpyrrolidine

109WJ，匕^…用丁從同八丄的^百脚的报赃'比以汉谬边进八系沮件。 109WJ, dagger ^ ... With eight Shang Ding from the same newspaper of ^ centipede stolen goods' than the absurd side of Han Ju pieces into the eight lines. 衣面活性剂可以促进繁殖体湿润和式I的化合物的渗透。 Clothing surfactant can facilitate wetting and penetration of the compound of Formula I propagules of. 本领域技术人员将理解，无脊椎害虫防治功效所需的浸泡介质中的式Γ的化合物的…量(即生物有效量)将随繁殖体的类型、式I的化合物、所需的植物保护的持续时间和范围、要防治的无脊椎害虫和环境因素而变。 Those skilled in the art will appreciate that the desired invertebrate pest control efficacy immersion medium of a compound of formula Γ ... amount (ie biologically effective amount) will vary with the type of propagule, the compounds of formula I, the required plant protection the duration and scope of invertebrate pest to be controlled and environmental factors change. 浸泡液中式I的化合物的浓度通常为约0.01 ppm至IOOOOppm之间，更通常为约I ppm至100 ppm。 The concentration of compound of formula I infusions usually about 0.01 ppm to between IOOOOppm, more typically from about I ppm from 100 ppm. 本领域技术人员能够容易地确定所需的植食性无脊椎害虫防治水平所需的生物有效浓度。 Those skilled in the art can easily determine the required phytophagous invertebrate pest control level desired biological effective concentration. 浸泡时间可以为I分钟至I天甚至更长》实际上可以在繁殖体萌芽或发芽时将其保持在处理液中(例如直接播种前稻种的发芽)。 I soak time may be days or more minutes to I "actually sprout or germinate in propagules when it is held in the treatment liquid (such as direct sowing rice seeds before germination). 由于枝条和根的形成经由种皮，因此枝条和根直接与包含式I的化合物的溶液接触。 Since the formation of shoot and root, shoot and root so that the contact directly with a compound of formula I contains a solution through the seed coat. 对于处理大播种作物如稻的发芽种子，处理时间为约8至48小时，如约24小时，是通常的。 For handling large germinated seeds sown crops such as rice, the processing time is about 8-48 hours, such as about 24 hours, is the usual. 对于处理小种子，更短的时间最有用。 For the treatment of small seeds, the most useful shorter time.

也可以用包含生物有效量的式I的化合物的组合物涂覆繁殖体。 The composition may also be coated propagule comprising a biologically effective amount of a compound of formula I. 本发明的涂层能够通过扩散到繁殖体和周围介质中而实现式I的化合物的缓慢释放。 Slow release coating of the present invention can be produced by the body and spread to the surrounding medium reproduction achieved formula I compounds. 涂层包括通过粘结剂如甲基纤维素或阿拉伯胶的作用而粘附到繁殖体上的干粉或粉末。 Coating comprises an adhesive such as methyl cellulose or acacia action while adhering to a dry powder or powder propagules on. 也可由悬浮在水中的混悬剂浓缩物、水分散性粉末或乳剂，在滚筒装置中将其喷到繁殖体上，然后干燥，而制备涂层。 May also be suspended in water suspension concentrates, water-dispersible powders or emulsions, in the apparatus in which the drum is sprayed onto the propagules, followed by drying, to prepare the coating. 可以将溶解在溶剂中的式I的化合物喷在翻转的繁殖体上，然后蒸发溶剂。 The compound may be dissolved in a solvent of formula I sprayed on the propagules flip, and then the solvent was evaporated. 这些组合物优选包括促进涂层粘附到繁殖体的成分。 These compositions preferably comprise a coating adhered to promoting component propagules. 该组合物还可以含有促进繁殖体湿润的表面活性剂。 The composition may also contain propagules promote wetting surfactant. 所用溶剂必须对繁殖体无植物毒性；通常用水，但其它具低植物毒性的挥发性溶剂如甲醇、乙醇、乙酸甲酯、乙酸乙酯、丙酮等可以单独或组合使用。 The solvent must be non-toxic to plants with propagules; usually water, but other volatile solvents with low toxicity of the plant, such as methanol, ethanol, methyl acetate, ethyl acetate, acetone, etc. may be used alone or in combination. 挥发性溶剂为正常沸点低于约lOOt：的溶剂。 Volatile solvents are normal boiling below about lOOt: solvent. 干燥必须以不伤害繁殖体或诱导过早萌发或发芽的方式进行。 Drying must be carried out so as not to harm propagules or induce premature germination or sprouting way.

涂层厚度从粘附粉至薄膜至丸剂层约0.5至5 mm厚而变。 Powder coating thickness from adhering to the film to about 0.5 to 5 mm thick layer of variable pills. 本发明的繁殖体涂层可以包含多于一种粘合层，其中仅一层需包含式I的 Propagule coating of the present invention may comprise more than one adhesive layer, which should contain only one layer of the Formula I

HO'丨七口切。 HO 'Shu seven cut. Λ·」J Zrrr 丁丨丨IJ5,遇币凡則疋取々V、俩思U、J,四刀匕択生物有效量的式I的化合物的能力不受种子表面积的限制，并且粒化小种子也有利于种子运输和栽培工作。 Λ · "J Zrrr small 丨 丨 IJ5, the case where the currency Cloth take 々 V, both think U, J, ability of the compounds of four knives dagger Ze biologically effective amount of formula I is not limited by the surface area of ​​the seeds, and small granulated Seed is also conducive to seed transport and cultivation work. 由于更大尺寸和表面积，大种子和鳞茎、±夬茎、球茎、根茎和它们的活插条通常不进行粒化，而用粉末或薄膜涂覆代替。 Due to the larger size and surface area, large seeds and bulbs, ± Jue stems, corms, rhizomes and their viable cuttings are not usually granulated and coated with a powder or a film instead.

与本发明的式I的化合物接触的繁殖体包括种子。 Formula I of the present invention comprises contacting a compound of propagules seed. 适宜的种子包括下列植物的种子：小麦、硬质小麦、大麦、燕麦、黑麦、玉米、高梁、稻、茭白、棉花、亚麻、向日葵、大豆、四季豆、菜豆、蚕豆、豌豆、花生、苜稽、甜菜、窝宦、油菜籽、甘蓝、宪菁、叶芥菜、黑芥、番茄、马铃薯、胡椒、茄子、烟草、黄瓜、香瓜、西瓜、南瓜、胡萝卜、百日菊、大波斯菊、菊花、松虫草、金鱼草、非洲菊、满天·星、补血草、矮百合、洋梧梗、西洋蓍草、万寿菊、三色堇、凤仙花、矮牵牛花、天竺葵和紫锦苏。 Suitable seeds include seeds of the following plants: wheat, durum wheat, barley, oats, rye, corn, sorghum, rice, wild rice, cotton, flax, sunflower, soy, beans, beans, beans, peas, peanuts, clover JI, beets, Wo Huan, rapeseed, kale, Xian Jing, leaf mustard, black mustard, tomato, potato, pepper, eggplant, tobacco, cucumbers, melons, watermelons, squash, carrot, zinnia, cosmos, chrysanthemum pine caterpillar fungus, snapdragons, gerbera, sky * Star, blood grass, dwarf lily, Wu Yang terrier, yarrow, marigold, pansy, impatiens, petunias, geraniums and purple Jin Su . 重要的是棉花、玉米、大豆和稻的种子。 It is important cotton, corn, soybeans and rice seed. 根据本发明与式I的化合物接触的繁殖体还包括根茎、块茎、鳞茎和球茎，或它们的活的分割部分。 Reproduction of the compounds according to the present invention in contact with the formula I also include rhizomes, tubers, bulbs and corms, or a live split part. 适宜的根茎、块垄、鱗基和球茎，或它们的活的分割部分包括下列植物的：马铃薯、甘薯、山药、洋葱、郁金香、唐菖蒲、百合、水仙、大丽花、鸾尾、藏红花、银莲花、风信子、麝香兰、小苍兰、观赏洋葱、酢浆草、红海葱、仙客来、四萼齿草，条纹红海葱、水芋百合、大岩桐和块茎状秋海棠。 Suitable rhizomes, block ridge, scales group and bulbs, or a live split section includes the following plants: potato, sweet potato, yam, onion, tulip, gladiolus, lilies, daffodils, dahlias, phoenix tail, saffron, Anemone , hyacinth, musk orchid, freesia, ornamental onion, sorrel, Red onions, cyclamen, four calyx teeth grass, striped Red onions, calla lily, gloxinia and tuberous begonia. 重要的是马铃薯、马铃薯、甘薯、洋葱、郁金香、黄水仙、藏红花和风信子的根茎、块莲、鱗茎和球茎，或它们的活的分割部分。 It is important potato, potato, sweet potato, onion, tulip, daffodil, crocus and hyacinth roots, block lotus, bulbs and corms, or a live split part. 根据本发明与式I的化合物接触的繁殖体还包括茎插和叶插。 Reproduction of the compounds according to the present invention in contact with the formula I also include stems and leaf cutting insert.

与式I的化合物接触的繁殖体的一个实施方案是用包含式I的化合物、其N-氧化物或农业上适用的盐和成膜剂或粘合剂涂覆的繁殖体。 An embodiment of propagules with a compound of formula I is in contact with a compound comprising Formula I for the N- oxide or a salt thereof and a film former agriculture or propagules adhesive coated. 包含生物有效量的式I的化合物、其N-氧化物或农业上适用的盐和成膜剂或粘合剂的本发明的组合物可以进一步包含有效量的至少一种其它生物活性化合物或试剂。 Comprising a biologically effective amount of a compound of formula I, N- oxide or a composition thereof agriculturally suitable salt thereof and a film former or adhesive of the present invention may further comprise an effective amount of at least one additional biologically active compound or agent . 重要的组合物包含(除式I组分和 Important compositions comprising (in addition to the component of formula I and

111/认/伏力UMT口口 口'J；^： ΪΜΚ^^·3^Ε305^、安V1^S1T 111 / recognize / volt power UMT mouth mouth 'J; ^: ΪΜΚ ^^ · 3 ^ Ε305 ^, Ann V1 ^ S1T

酸酯类、新烟碱类、神经元钠通道阻断剂类、杀虫大环内酯类，γ-氨基丁酸(GABA)拮抗剂类、杀虫脲类和保幼激素模拟物类。 Esters, neonicotinoids, neuronal sodium channel blockers, insecticidal macrolides, γ- aminobutyric acid (GABA) antagonists, insecticidal ureas and juvenile hormone mimics class. 同样重要的是组合物包含(除式I组分和成膜剂或粘合剂以外)至少一种选自下组的其它生物活性化合物或试剂阿维菌素、乙酰甲胺磷、吡虫清、amidoflument (S-1955)、齐墩螨素、艾扎丁、谷硫磷、氟氯菊酯、binfenazate、噻嗪酮、呋喃丹、氟哇虫清、定虫隆、毒死蜱、甲基毒死蜱、环虫酰肼、噻虫胺、百树菊酯、β-氟氯氰菊酯、氯氟氰菊酯、λ-氯氟氰菊酯、氯氰菊酯、灭蝇胺、溴氰菊酯、杀螨硫隆、二嗪农、氟脲杀、乐果、H惡茂醚、依马菌素、硫丹、髙氰戊菊酿、ethiprole、苯硫威、双氧威、甲氰菊酷、唑_醋、杀灭菊酯、锐劲特、flonicamid,氟氰戊菊酯、氟胺氰菊酯、flufenerim (UR-50701)、氟虫脲、地虫磷、特丁苯酰肼、氟铃脲、吡虫啉、噁二唑虫、丙胺磷、氟丙氧脲、马拉硫磷、蜗牛敌、甲胺磷、杀扑磷、灭多虫、蒙五一五、甲氧滴滴涕、久效磷、甲氧苯酰肼、硝虫噻嗪、双苯氟脲、noviflumuron(XDE-007)>甲氨叉威、对硫磷、甲基对硫磷、氯菊酯、甲拌磷、伏杀磷、亚胺硫磷、磷胺、抗®威、丙溴磷、拒嗪酮、pyridalyl、蚊绳醚、鱼藤酮、艾克敌105、spiromesifin (BSN2060)、乙丙硫磷、双苯醜肼、伏虫隆、七氟菊酯、特丁磷、杀虫畏、噻虫啉、噻虫嗪、硫双灭多威、杀虫双、四漠菊酯、敌百虫和杀虫隆、涕灭威、甲氨叉威、克线磷、虫螨脒、灭瞒猛、乙酯杀螨醇、三环锡、开乐散、除螨灵、特苯噁唑、喹螨醚、杀螨锡、甲氰菊酯、唑螨酯、噻螨酮、克螨特、哒螨酮、吡螨胺：和生物试剂如包括苏云金杆菌a和苏云金杆菌k在内的苏云金杆菌，苏云金杆菌δ-内毒素、杆状病毒，以及昆虫致病细菌、病毒和真菌。 Equally important is the composition comprises other biologically active compounds or agents avermectin (except Formula I component and a film adhesive or outside) at least one member selected from the group consisting of acephate, acetamiprid , amidoflument (S-1955), abamectin, Yi Zhading, azinphos-methyl, bifenthrin, binfenazate, buprofezin, carbofuran, fluorine wow ACETAMIPRID, chlorfluazuron, chlorpyrifos, chlorpyrifos-methyl, Central Tebufenozide, clothianidin, cyfluthrin, β- cyfluthrin, cyhalothrin, λ- cyhalothrin, cypermethrin, cyromazine, deltamethrin, mites sulfur-long, two Diazinon, fluorouracil kill, dimethoate, H dioxol ether, according to Ma streptozotocin, endosulfan, Gao E-ju stuffed cyanide, ethiprole, benzene, sulfur Granville, fenoxycarb, methyl cyanide Ju cool, azole _ vinegar, kill permethrin, fipronil, flonicamid, flucythrinate, fluvalinate, flufenerim (UR-50701), flufenoxuron, FONOFOS, halofenozide, hexaflumuron, imidacloprid, oxadiazole azole insects, propylamine phosphorus, fluorine propoxyphene urea, malathion, metaldehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, monocrotophos, methicillin hydrazide, nithiazine, novaluron, noviflumuron (XDE-007)> carbamoyl fork Wei, parathion, methyl parathion, permethrin, phorate, phosalone, phosmet, phosphorus amines, anti-Viagra ®, profenofos, pymetrozine, pyridalyl, mosquito rope ether, rotenone, spinosad 105, spiromesifin (BSN2060), ethylene-propylene parathion, double benzene ugly hydrazine, teflubenzuron, tefluthrin , terbufos, tetrachlorvinphos, thiacloprid, thiamethoxam, thiodicarb methomyl insecticide double, four desert permethrin, trichlorfon and insecticidal Long, aldicarb, methyl ammonia fork K, g fenamiphos, amitraz, eliminate hiding fierce, mites, ethyl alcohol, cyhexatin, dicofol, in addition to mites, especially benzoxazole, Fenazaquin, mites tin, Fenpropathrin, Fenpyroximate , hexythiazox, propargite, pyridaben, tebufenpyrad: and biological agents such as Bacillus thuringiensis including a Bacillus thuringiensis and Bacillus thuringiensis including k, within δ- endotoxin of Bacillus thuringiensis, baculovirus, and entomopathogenic bacteria, viruses and fungi. 同样重要的组合物包含(除式I组分和成膜剂或粘合剂以外)至少一种选自下组的杀菌剂的其它生物活性化合物或试剂：噻二唑素、腈嘧菌酯、苯菌灵、灭瘟素、波尔多液(碱式硫酸铜)、糠菌唑、氯环丙酰胺、敌困7T、凡困7Τ、夕困火、mjxsx-. H 困W、土WJ、Wliff、cyiiuienamid、 Equally important, the composition comprises at least one fungicide selected from the group (except Formula I component and the film former or adhesive outside) the other biologically active compound or agent: acibenzolar, azoxystrobin, benomyl, blasticidin, Bordeaux mixture (basic copper sulfate), bromuconazole, chlorine cyproterone amide enemy trapped 7T, where the storm 7Τ, sleepy evening fire, mjxsx-. H sleepy W, soil WJ, Wliff, cyiiuienamid,

清菌脲、环唑醇、环丙嘧啶、（S)-3,5-二氯-N-(3-氯-I-乙基-I-甲基-2- --氧丙基->4-甲基苯甲酰胺(RH7281)、-'双氯氰菌胺(S-2900)、'-哒菌清、氯硝胺、嚼咪唑、(S)-3，5-二氢-5-甲基-2_(甲硫基)-5-苯基-3-(苯氨基>4H- 咪哩-4-酮(RP 407213)、稀酰吗啉、dimoxystrobin、煤哩醇、稀挫醇-Μ、 多果定、克瘟散、氧唑菌、噁唑酮菌、咪唑菌酮、异嘧菌醇、腈苯唑、 fencaramid (SZX0722)、拌种咯、苯锈啶、丁苯吗啉、薯瘟锡、毒菌锡、氟唆胺、氟嚼菌、氟联苯菌(RPA 403397)、flumorf/flumorlin (SYP-L190)、fluoxastrobin (HEC5725)、喹唑菌酮、氟硅唑、氟酰胺、 粉唑醇、灭菌丹、藻菌磷、呋氨丙灵、呋吡脞灵(S-82658)、已唑醇、 环戊脞醇、异稻瘟净、异丙定、稻疽灵、春雷霉素、亚胺菌、代森锰锌、代森锰、mefenxam、丙氧灭绣胺、甲霜灵、环戊唑菌、叉氨苯酰胺(SSF-126)、metrafenone (AC375839),腈菌唑、田安甲胂铁(甲基胂酸铁)、nicobifen (BAS 510)、orysastrobin、嘿霜灵、戊菌挫、戊菌隆、噻菌灵、丙氯灵、百维灵、丙环哩、proquinazid (DPX-KQ926)、 prothioconazole (JAU6476)、淀斑西、pyraclostrobin、二甲喃菌胺、略喹酮、喹氧灵、螺噁茂胺、硫、戊唑醇、氟醚唑、涕必灵、溴氟唑菌、 甲基托布津、福美双、tiadinil、三唑酮、唑菌醇、三环唑、肟菌酯、 戊叉唑菌、有效霉素和烯菌酮(尤其是其中至少一种其它生物活性的化合物或试剂是选自福美双、代森锰、代森锰锌和克菌丹的杀菌剂的组合物)。 Cymoxanil, cyproconazole, cyclopropylmethyl pyrimidine, (S) -3,5- dichloro -N- (3- chloro -I- -I- methyl ethyl -2--- oxopropyl -> 4 - methylbenzamide (RH7281), - 'double cyanuric bacteria amine (S-2900),' - da bacteria clean, clonazepam amine, chewing imidazole, (S) -3,5- dihydro-5- yl -2_ (methylthio) -5-phenyl-3- (phenylamino> 4H- imidazol-4-one mile (RP 407213), dilute acid morpholine, dimoxystrobin, coal mile alcohol, diluted alcohol fell -Μ, Dodine, g blast scattered, epoxiconazole, oxazolone bacteria, fenamidone, iso triarimol, fenbuconazole, fencaramid (SZX0722), fenpiclonil, fenpropidin, fenpropimorph, potato plague tin, toadstool tin, fluorine instigate amine fluoride chewing bacteria, flurbiprofen bacteria (RPA 403397), flumorf / flumorlin (SYP-L190), fluoxastrobin (HEC5725), quinazoline cycloheximide, flusilazole, flutolanil, pink Hexaconazole, folpet, phycomycetes phosphorus, furosemide metalaxyl, furosemide topiramate trifles Spirit (S-82658), has Hexaconazole, cyclopentyl trifles alcohol, Iprobenfos, isopropyl fixed, rice gangrene spirit, Jubilee mold Su, imide bacteria, mancozeb, maneb, mefenxam, propoxyphene off embroidered amine, metalaxyl, metconazole, fork benzamide (SSF-126), metrafenone (AC375839), myclobutanil Tian An iron armor arsine (monomethylarsenic acid iron), nicobifen (BAS 510), orysastrobin, hey frost spirit, amyl bacteria setback, pencycuron, thiabendazole, prochloraz, Broadway spirit, propiconazole miles, proquinazid (DPX-KQ926), prothioconazole (JAU6476), spot West Lake, pyraclostrobin, dimethyl amine furans bacteria, slightly methaqualone, quinoxyfen, screw dioxol amines, sulfur, tebuconazole, fluorine difenoconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram, tiadinil, triadimefon, Triadimenol, tricyclazole, trifloxystrobin, amyl fork yl bacteria, validamycin and allyl cycloheximide (especially where at least one other biologically active compounds or agents selected from thiram, composition maneb, mancozeb and captan fungicides).

通常本发明的繁殖体涂层包含式I的化合物、成膜剂或粘合剂。 Typically propagules coating of the present invention comprises a compound of formula I, a film former or adhesive. 涂层可以进一步包含配方助剂如分散剂、表面活性剂、载体和任选的消泡剂和染料。 The coating may further comprise formulation aids such as dispersants, surfactants, carriers, and optionally antifoam and dye. 本领域技术人员将理解，无脊椎害虫所需功效所需的涂层中的式I的化合物的量(即生物有效量)将随繁殖体的类型、式I 的化合物、所需的植物保护的持续时间和范围、要防治的无脊椎害虫和环境因素而变。 Those skilled in the art will appreciate that amount (ie biologically effective amount) of the desired compound invertebrate pest desired effect in the coating will vary with the type of formula I propagules, the compounds of formula I, the required plant protection the duration and scope of invertebrate pest to be controlled and environmental factors change. 涂层需要不抑制繁殖体的发芽或萌芽，并应当在目 Coating need not inhibit germination or sprouting propagules, and should in the head

113q/j、円/| -f3? -p· 口Ji /pj □»! 义/].Η >Τ</Μ<Λ1 177 P] I ·ί5ζ_丨Oj 口ίί^-"Ή λα. VQlC fJ/ α_Β Λί/ΐ ? 113q / j, yen / | -f3 -p · mouth Ji / pj □ »meaning /].Η> Τ </ Μ <Λ1 177 P] I · ί5ζ_ Shu Oj mouth ίί ^ -" Ή λα VQlC!. fJ / α_Β Λί / ΐ

损伤。 Damage. 包含足够的式I的化合物的涂层可以提供无脊椎害虫防治保护达约120天或者甚至更久。 Coatings containing compounds of formula I may be sufficient to provide invertebrate pest control protection for about 120 days or even longer. 通常式I的化合物的量为繁殖体重量的约0.001-50%,对于种子而言，更通常为种子重量的约0.01-50°/。 Amount of a compound of formula I generally ranges from about 0.001 to 50% by weight of the propagules, for seed, the seed weight and more typically about 0.01-50 ° /. ，对大种子而言，最通常为种子重量的约0.1-10%。 For large seeds, the most typically about 0.1 to 10% by weight of the seed. 然而，更高量,达约100%或更高是有利的，特别是对于延长无脊椎害虫防治保护用的粒化小种子而言。 However, higher amounts, up to about 100% or more is advantageous, especially for extended invertebrate pest control protection in terms of granulated small seeds. 对于繁殖体如根茎、块莲、鱗茎和球垄和它们的活插条，以及茎插和叶插而言，通常式I的化合物的量为繁殖体重量的约0.001-5%,更高的百分比用于更小的繁殖体。 For propagules such as roots, block lotus, bulbs and balls ridge and their live cuttings, and stem and leaf cutting insert, the amount of the compound of formula I generally ranges from about 0.001 to 5% by weight of propagules and higher percentage for smaller propagules. 本领域技术人员能够容易地确定所需的植食性无脊椎害虫防治水平所需的生物有效量。 Those skilled in the art can easily determine the required phytophagous invertebrate pest control levels of biologically effective amount necessary.

繁殖体涂层的成膜剂或粘合剂组分优选由粘合剂聚合物组成，所述粘合剂聚合物可以是天然或合成的，并且对要涂覆的繁殖体无植物毒性作用。 Propagule coating film-forming agent or binder component preferably consists of a binder polymer, the binder polymer may be natural or synthetic, and the propagule to be coated on the non-phytotoxic effects. 成膜剂或粘合剂可以选自乙酸乙烯酯、聚乙酸乙烯醋共聚物、水解的聚乙酸乙烯酯、聚乙烯吡略烧酮-乙酸乙烯酯共聚物、聚乙烯醇、聚乙烯醇共聚物、聚乙烯基甲基醚、聚乙烯基甲基醚-马来酸酐共聚物、蜡、胶乳聚合物、包括乙基纤维素和甲基纤维素、羟甲基纤维素、羟丙基纤维素、羟甲基丙基纤维素的纤维素、聚乙烯吡咯烷酮、藻酸盐、糊精、麦芽糖糊精、多糖、脂肪、油、蛋白质、刺梧桐树胶、加尔胶、黄蓍胶、多糖胶、胶浆、阿拉伯胶、虫胶、偏二氯乙烯聚合物和共聚物、大豆基蛋白聚合物和共聚物、木质素磺酸盐、丙烯酸共聚齓淀粉、聚丙烯酸乙烯酯、玉米醇溶蛋白、明胶、羧甲基纤维素、脱乙酰壳多糖、聚环氧乙烷、丙烯酰亚胺聚合物和共聚物、聚丙烯酸羟乙酯、甲基丙烯酰亚胺单体、藻酸盐、乙基纤维素、聚氯丁二烯和糖浆或它们的混合物。 Film formers or binders may be selected from vinyl acetate, polyethylene-vinyl acetate copolymers, hydrolyzed polyvinyl acetate, polyvinyl ketones slightly burned - vinyl acetate copolymer, polyvinyl alcohol, polyvinyl alcohol copolymer , polyvinyl methyl ether, polyvinyl methyl ether - maleic anhydride copolymer, waxes, latex polymers, including ethyl cellulose and methyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxymethylpropylcellulose cellulose, polyvinylpyrrolidone, alginate, dextrin, maltodextrin, polysaccharides, fats, oils, proteins, karaya gum, gum Senegal, tragacanth, gum, mucilage , gum arabic, shellac, polyvinylidene chloride polymers and copolymers, soybean-based protein polymers and copolymers, lignin sulfonate, acrylic copolymer Chen starch, polyacrylic acid, vinyl acetate, zein, gelatin, carboxymethylcellulose methyl cellulose, chitosan, polyethylene oxide, acrylimide polymers and copolymers, polyacrylic acid, hydroxyethyl acrylate, methacrylic imide monomers, alginate, ethylcellulose, polychloroprene and syrups or mixtures thereof. 优选的成膜剂和粘合剂包括乙酸乙烯酯的聚合物和共聚物、聚乙烯吡咯烷酮-乙酸乙烯酯共聚物和水溶性蜡。 Preferred film formers and binders include polymers and copolymers of vinyl acetate, polyvinyl pyrrolidone - vinyl acetate copolymer and water-soluble waxes. 特别优选的是聚乙烯吡咯烷酮-乙酸乙烯酯共聚物和水溶性蜡。 Especially preferred are polyvinyl pyrrolidone - vinyl acetate copolymer and water-soluble waxes. 上述聚合物包括那些本领域已知的以及例如Agrimer® VA 6和 Above polymers include those well known in the art such as Agrimer® VA 6 and

114i.icowax- KSi o He；万甲昍现臊刑谀相甘刑的重通芾刃重的约 114i.icowax- KSi o He; Wan Xuan A flatter now bashfulness criminal punishment phase Gan Tong Fu edge heavy weight about

0.001-100%,对于大种子而言，成膜剂或粘合剂的量通常为种子重量的约0.05-5%;对于小种子而言，该量通常为约1-100%，但在粒化中可高于种子重量的100%。 0.001 to 100%, for large seeds, the amount of film formers or binders is usually about 0.05 to 5% by weight of seed; for small seed is concerned, the amount is usually about 1 to 100%, but in the grain It may be higher than 100% of the weight of the seed. 对于其它繁殖体而言，成膜剂或粘合剂的量通常为繁殖体重量的约0.001-2%。 For other propagules, the amount of film former or adhesive is usually about 0.001 to 2% by weight of the propagule.

已知为配方助剂的物质也可以用于本发明的用于无脊椎害虫防治的繁殖体处理涂层中，并且这是本领域技术人员所熟知的。 A substance known as formulation aids can also be used in the present invention is used propagules invertebrate pest control treatment coating, and it is to those skilled in the art. 配方助剂有助于繁殖体处理的产生或加工，包括但不限于分散剂、表面活性剂、载体、消泡剂和染料。 Formulation aids helps produce propagules treatment or processing, including but not limited to dispersants, surfactants, carriers, antifoams and dyes. 有用的分散剂可以包括高水溶性明离子表面活性剂，如Borresperse™ CA、Morwet® D425等。 Useful dispersants can include highly water-soluble ionic surfactants described, such as Borresperse ™ CA, Morwet® D425 and the like. 有用的表面活性剂可以包括高水溶性非离子表面活性剂，如Pluronk®F108、Brij®78等。 Useful surfactants can include highly water-soluble nonionic surfactants, such as Pluronk®F108, Brij®78 like. 有用的载体可以包括液体如水和油，它们是水溶性的，如醇。 Useful carriers can include liquids such as water and oils, which are water soluble, such as alcohol. 有用的载体还可以包括填料如木粉、粘土、活性炭、硅藻土、细粒无机固体、碳酸钙等。 Useful carriers can also include fillers such as wood flour, clay, activated carbon, diatomaceous earth, fine inorganic solids, calcium carbonate and the like. 可以使用的粘土和无机固体包括钙膨润土、高岭土、陶土、滑石、珍珠岩、云母、蛭石、二氧化硅、石英粉、蒙脱石及它们的混合物。 Clays and inorganic solids which may be used include calcium bentonite, kaolin, clay, talc, perlite, mica, vermiculite, silicas, quartz powder, montmorillonite and mixtures thereof. 消泡剂可以包括包含聚有机硅氧烷如Rhodorsil® 416的水分散性液体。 Antifoaming agents may comprise water-dispersible polyorganosiloxane containing liquids such as Rhodorsil® 416 a. 染料可以包括水分散性液体着色剂组合物如Pro-lzed®Colorant Redo本领域技术人员将理解，这是非穷尽的助剂列举，并且根据要涂覆的繁殖体和用于涂覆的式I的化合物，可以使用经认可的其它物质。 Dyes can include water dispersible liquid colorant compositions such as Pro-lzed®Colorant Redo skilled in the art will appreciate that this is a non-exhaustive enumeration additives, and according to the propagule coated Formula I for the coating of compounds, other substances approved. 适宜的配方助剂的实例包括本文和由MC PublishingCompany 出版的McCutcheon, s 2001» Volume 2： Functional Materials,中所列的。 Suitable formulation aids include article and published by the MC PublishingCompany McCutcheon, s 2001 »2 Volume: Functional Materials, listed. 配方助剂的用量可以变化，但通常该组分的重量将为繁殖体重量的约0.001-10000%, 100%以上的百分比主要用于粒化小种子。 The amount of additive formulations may vary, but generally granulated small seed weight of the component will be about 0.001-10000% propagules weight, the percentage of more than 100% of the principal for. 对于未粒化的种子，配方助剂的量通常为种子重量的约0.01-45%,通常为种子重量的约0.1-15%。 For non-pelletized seed, the amount of formulation aids is usually about 0.01-45% seed weight, generally from about 0.1 to 15% by weight of the seed. 对于除种子以外的繁殖体，配方助剂的量通常为繁殖体重量的约0.001-10%。 For propagules other than seeds, the amount of formulation aids generally is about 0.001 to 10% by weight of the propagule.

施用种子涂层的常规方法可以用于进行本发明的涂覆。 Conventional methods for applying seed coatings may be coated with the present invention. 细粉或粉 Powder or powder

115>μ rmm si使得细粉或粉末粘附于该繁殖体，并且在包装或运输期间不脱落.细粉或粉末也可以如下施用：将细粉或粉末直接加入繁殖体滚筒床，随后将载体液体喷到种子上并干燥。 115> μ rmm si making flour or powder adhered to the propagation body, and do not fall off during packaging or transport powder or powder may also be administered as follows: The powder or powder directly into the roller bed of propagules, followed by the carrier liquid is sprayed onto the seed and dried. 包含式I的化合物的细粉和粉末也可以如下施用：用任选地包含粘合剂溶剂，如水处理(例如浸渍)至少一部分繁殖体，并将经处理的部分浸入所提供的干燥细粉或粉末中。 And fine powder of a compound of formula I may also be contained administered as follows: with a solvent optionally containing a binder, such as water treatment (e.g., dipping), at least a portion of propagules and partially dried powder is immersed or treated provided powder. 该方法用于涂覆茎插特别有用。 This method is particularly useful for coating stem cutting. 也可以将繁殖体浸入包含式I可湿性粉、溶液、悬乳剂、乳状浓缩物和在水中的乳剂的配方中，然后干燥或直接种植在生长介质中。 Also propagules of formula I may be immersed in a wettable powder comprising, solutions, suspensions emulsions, emulsion concentrates and emulsions in water formulation, and then dried or directly planted in a growth medium. 繁殖体如鳞茎、块茎、球茎、根茎通常仅需要单一涂层来提供生物有效量的式I的化合物。 Propagules such as bulbs, tubers, corms, rhizomes typically need only a single coating layer to provide a biologically effective amount of a compound of formula I.

也可以通过直接将悬浮液浓缩物喷在繁殖体滚筒床中，然后干燥繁殖体而涂覆繁殖体。 It can also direct the suspension concentrate sprayed propagules roller bed and then dried and coated propagules propagules. 或者，可以将其它配方类型，如可湿性粉末、溶液剂、悬乳剂、乳状浓缩物和在水中的乳剂喷到繁殖体上》该方法对于将膜施用于种子而言特别有用。 Alternatively, the other formulation types, such as wettable powders, solutions, suspoemulsions, "The method is particularly useful for the film is applied to the seed in terms of emulsion concentrates and emulsions in water is sprayed onto the propagules. 本领域技术人员可利用多种涂覆机械和方法。 Those skilled in the art can take advantage of a variety of coating machinery and methods. 适宜的方法包括在P. Kosters等，Seed Treatment：Progress and Prospects, 1994 BCPC Monograph No.57 和其中列出的参考文献中所列的。 Suitable methods include in P. Kosters, etc., Seed Treatment: Progress and Prospects, 1994 BCPC Monograph No.57 references and lists those listed in. 三种熟知的技术包括使用滚筒涂覆器、流化床技术和喷动床。 Three kinds of well known techniques including the use of roller coating, fluidized bed technology and spouted bed. 在涂覆前可对繁殖体如种子预先按大小分级。 Before coating may be pre-graded by size of propagules such as seeds. 涂覆后，干燥繁殖体，随后任选地通过转移至分级机而根据大小分级。 After coating, drying propagules, optionally followed by transfer to a grading machine grading according to size. 这些机械是本领域已知的，例如用于工业中按大小分级玉米种子的典型机械。 These machines are known in the art, such as used in the industry by size grading of corn seed typical mechanical.

对于涂覆种子，种子和涂覆物质在任何多种常规种子涂覆装置中混合。 For coating seed, seed and coating material is mixed in any variety of conventional seed coating apparatus. 滚动速率和涂层施用取决于种子。 Scrolling speed and coating application depends on seeds. 对于大的长方形种子如棉花的种子，令人满意的种子涂覆装置包括具有提升轮叶的旋转型盘，提升轮叶转动的rpm足以保持种子滚动，促进均一覆盖。 For large oblong seeds such as cotton seed, seed satisfying coating device comprises a lifting vane rotary plate, lifting vanes rotating rpm is sufficient to maintain seed roll, promote uniform coverage. 对于以液体施用的种子涂覆配方，种子涂层必须施用足够的时间来千燥，以使种子结块最小化。 For seed coating liquid administration formulations, seed coating must be applied to dry in sufficient time to allow the seeds to minimize agglomeration. 使用强迫通风或加热强迫通风可以提高施用速度。 The use of forced ventilation or forced air heating can increase application rates. 本领 Ability

116ΑΙΧ·/卜y、火XU何以疋刀：杜铁広。 116ΑΙΧ · / Bu y, fire XU why Piece Goods knife: Du iron Hiroshima. 乂、”1口曰示的，连续法让种子在整个产物运转期间连续流动。新种子在稳定流中进入盘中，以替代从盘中流出的经涂覆的种子。 Qe, "said one shown, so that the seed in a continuous process throughout the product run continuous flow of new seeds into the pan in a steady stream to replace coated seeds outflow from the disc.

本发明的种子涂覆方法不限于薄膜涂覆，也可以包括种子粒化。 Seed coating methods of the present invention is not limited to thin film coating, the seeds may comprise granulation. 粒化方法通常提高种子重量2-4倍，也可以用于改善种子的形状，以用于播种机中。 Granulation process is usually 2-4 times increase seed weight, can also be used to improve the shape of the seed for the planter. 粒化组合物通常含有固体稀释剂，其通常为不溶性颗粒物质，如粘土、重质碳酸钙、粉末二氧化硅等，以提供除粘合剂以外的大部分，所述粘合剂如人造聚合物(例如聚乙烯醇、水解聚乙酸乙烯酯、聚乙烯基甲基醚、聚乙烯基甲基醚-马来酸酐共聚物，和聚乙烯吡咯烷酮)或天然聚合物(例如藻酸盐、刺梧桐树胶、加尔胶、黄蓍胶、多糖胶、粘胶)。 Granulated compositions generally contain a solid diluent, it is generally insoluble particulate matter, such as clay, calcium carbonate, silica powder, etc., in order to provide the most part, other than the adhesive binder addition polymerization such as artificial (e.g., polyvinyl alcohol, hydrolyzed polyvinyl acetate, polyvinyl methyl ether, polyvinyl methyl ether - maleic anhydride copolymers, and polyvinylpyrrolidone) or natural polymers (e.g., alginate, karaya gums, Gard gum, tragacanth gum, gum, glue). 在构建足够多的层后，干燥涂层并进行丸粒分级。 After building a sufficient number of layers were dried coating and pellets grading. 生产丸剂的方法描述于Agrow, The Seed. Treatment Market,Chapter 3, PJB Publiction Ltd., 1994。 The method of producing pellets is described in Agrow, The Seed. Treatment Market, Chapter 3, PJB Publiction Ltd., 1994.

适于用式I的化合物涂覆繁殖体的组合物组分和方法的进一步描述见美国专利4,443,637、5,494,709、5,527,760, 5,834,006、5,849,320、5,876,739、6,156,699、6,199,318、6,202,346 和6,230,438,以及欧洲专利公开EP-1，078,563-A1。 Further description of composition components and methods suitable for coating with the compound of formula I see U.S. Patent propagules 4,443,637,5,494,709,5,527,760, 5,834,006,5,849,320,5,876,739,6,156,699,6,199,318,6,202,346 and 6,230,438, and European Patent Publication EP- 1,078,563-A1.

以下实施例EH说明涂覆种子的方法。 The following examples illustrate the coated seed EH approach. 化合物号指索引表A中的化合物。 A compound numbers refer to the compound index table.

实施例E Example E

包含化合物208的组合物涂覆的棉籽批的制备步骤I ：包含化合物208的易流动的悬浮液的制备制备含有表7中所列成分的易流动的悬浮液 Flowable suspension containing compound 208 Preparation of flowable suspension containing the ingredients listed in Table 7: Preparation of a compound comprising the step of cottonseed batches coated with composition I-208

117MJ. 117MJ.

Agrimer® VA 6是软化点为106°C的高水溶性的成膜粘合剂，其包含聚乙稀卩比咯烧酮-乙酸乙稀酿共聚物，由International Specialty Product Agrimer® VA 6 is a softening point of 106 ° C is highly water soluble film-forming binder, which contains polyethylene Jie burn slightly more than one - acetate ethylene copolymer stuffed by International Specialty Product

(ISP)销售。 (ISP) sales. Licowax® KST是液滴形成(drop fomiing)点为59°C的高水溶性的成膜粘合剂，其包含褐煤蜡酸、聚乙二醇酯，由Clariant销售。 Licowax® KST is droplet formation (drop fomiing) point of 59 ° C is highly water soluble film-forming binder comprising montan wax acid, polyethylene glycol, sold by Clariant.

Borresperse™ CA是软化点为132Ό的高水溶性阴离子分散剂，其包含去糖木质素磺酸韩，由Borregaard LignoTech销售。 Borresperse ™ CA is a softening point of 132Ό of highly water soluble anionic dispersing agent comprising sugar to Korea ligninsulfonate by Borregaard LignoTech sales. Pluronic® F-108 Pluronic® F-108

是培化点为57Ό的高水溶性非离子分散剂，其包含聚氧丙烯-聚氧乙烯嵌段共聚物，由BSAF销售。 Is the point of training is 57Ό high water-soluble nonionic dispersant comprising polyoxypropylene - polyoxyethylene block copolymer consisting BSAF sales. Brij® 78是倾点为38Ό的高水溶性非离子分散剂，其包含十八烷醇(POE 20),由Uniqema销售。 Brij® 78 is a high pour point 38Ό water-soluble nonionic dispersant comprising stearyl alcohol (POE 20), sold by the Uniqema. Rhodorsil® Rhodorsil®

416是水分散性液体消泡剂，其包含聚硅氧综和乳化剂，由Rhodia 416 is a water dispersible liquid defoamers, comprising a silicone emulsifier mechanized and by Rhodia

销售。 Sales. Pro-lzed® Colorant Red是水分散性液体着色剂组合物，其包含红色着色剤、高岭土和非离子表面活性剂，由Gustafson销售。 Pro-lzed® Colorant Red is a water-dispersible liquid colorant composition comprising a red colorant Ji, kaolin and nonionic surfactants, marketed by Gustafson.

如下制备悬浮液载体(253.20 g)：首先将Brij® 78 (6.00 g)溶解在温水(210.48 g)中，随后剧烈混合在Agrimer® VA 6 (15.00 g)、Licowax®KST (15.00 g)、Borresperse™ CA (3.00 g)、Pluronic® F-108 (3.00 g)、Brij® 78 (6.00 g)、Rhodorsil® 416 (0.6 g)和Pro-lzed® Colorant Red (0.12g)中。 Suspension vehicle were prepared as follows (253.20 g): First, Brij® 78 (6.00 g) was dissolved in warm water (210.48 g), followed by vigorously mixing in Agrimer® VA 6 (15.00 g), Licowax®KST (15.00 g), Borresperse ™ CA (3.00 g), Pluronic® F-108 (3.00 g), Brij® 78 (6.00 g), Rhodorsil® 416 (0.6 g) and Pro-lzed® Colorant Red in (0.12g). 将化合物208 (15.6 g)加入烧杯中，随后加入部分经完全混合的悬浮液载体(84.4 g),用刮勺将化合物208混入该悬浮液载体中》 Compound 208 (15.6 g) added to the beaker, followed by adding some completely mixed suspension carrier (84.4 g), with a spatula to compound 208 mixed into the suspension carrier "

118i^· naμ IV nun piuuc^q*j ruiyuun Jo] 118i ^ · naμ IV nun piuuc ^ q * j ruiyuun Jo]

速旋转定片分散器(由Brinkman Instruments Inc., Cantiague Rd.,Westbury, NYl 1590 USA销售)将混合物进一步均化，使化合物208聚集体碎裂。 Speed ​​rotary stator disperser (manufactured by Brinkman Instruments Inc., Cantiague Rd., Westbury, NYl 1590 USA sales) and the mixture was further homogenized, the compound 208 aggregate fragmentation.

然后将所得浆料转移入运转着的磨中，该磨装有80%容量的0.5-mm,单一大小的(mopo-sized)高密度陶瓷研磨介质，通过使冷的33%乙二醇水溶液通过磨室的冷却套管而将其冷却。 The resulting slurry is then transferred into the operation of the mill, the mill is equipped with 80% of the capacity of 0.5-mm, single-size (mopo-sized) high density ceramic grinding media, by cold 33% aqueous solution of ethylene glycol by grinding chamber cooling jacket and cooled. 在搅拌器在4300rpm旋转下，使浆料再循环通过磨室13分钟》然后从磨进料漏斗移动循环管端至收集瓶，得到最终的粉红色高度可倾注的易流动的悬浮液(89.5 g)。 By rotating the agitator at 4300rpm, the slurry is recirculated through the grinding chamber 13 minutes "and then move into the mill hopper circulation pipe end to collect bottles to get the final pink highly pourable flowable suspension (89.5 g ).

用激光衍射仪分析悬浮液中经微粉化(磨制)的颗粒的直径。 Analysis of the diameter of the suspension micronized (milled) particles with a laser diffractometer. 使用两次测量的平均值，算术平均粒径为2.03 μιπ, 90%的颗粒粒径小于5.21 μπι, 10%的颗粒粒径小于0.30 μτη,中值粒径为Ι.Ομιη。 Using the average of two measurements, the arithmetic average particle diameter of 2.03 μιπ, 90% of the particle size is less than 5.21 μπι, 10% of the particle size is less than 0.30 μτη, median diameter Ι.Ομιη.

步骤2:用包含化合物208的组合物涂覆棉籽 Step 2: using a composition comprising a compound 208 is coated cottonseed

将棉籽(Stoneville 4793 RR, 122.5 g)加入含有两个相反的提升叶片的不锈钢罐(12 cm id, 11 cm深)中，所述提升叶片随罐转动而提升种子。 The Cottonseed (Stoneville 4793 RR, 122.5 g) was added two opposing lifting vanes comprising a stainless steel pot (12 cm id, 11 cm deep), said lifting blades rotate with the tank and lifting the seed. 罐的方向与水平成40-45°角，并以640rpm机械旋转，这在罐内导致良好的混合和翻转运动。 Direction and level tank into a 40-45 ° angle, and 640rpm mechanical rotation, which leads to good mixing and flipping motion in the tank.

将步骤I中制备的易流动的悬浮液直接喷到种子的翻转床上，气压供给为10-11 psi (69-76 kPa)，以产生细小微滴。 The flowable suspension prepared in step I is directly sprayed onto the seed bed inverted, the supply pressure of 10-11 psi (69-76 kPa), to produce fine droplets. 通过测量容器的重量可以测定喷在种子上的易流动的悬浮液的量。 You can determine the amount of flowable suspension sprayed on the seeds by weight measurement container. 随着种子翻转，将手控雾化器指向罐的内部，以直接喷在种子翻转床的中心。 With seed flip, it will hand control point to the internal tank atomizer to spray directly in the center of the bed flipping seed. 喷雾继续到种子表面发粘，导致种子结块。 Continue to spray seed sticky surface, resulting in seed clumping. 然后关闭雾化器，通过在室温下从装备以控制罐内气流方向的喷嘴将低压气体吹到种子上而快速干燥种子涂层。 Then close the nebulizer, through equipment at room temperature from the tank to control the direction of airflow nozzle pressure gas is blown onto the seeds and seed coating fast drying. 翻转的种子的声音提高提供可听到的信号，即种子涂层充分干燥。 Flip voice rose seeds provide audible signal that the seed coating is fully dry. 然后关闭干燥气流，重新开始用手控雾化器喷雾。 Then close the drying gas, restart by a manual atomizer spray. 重复喷雾和干燥循环，直到已将所需量的易流动的悬浮液施用于种子上。 Repeat spraying and drying cycle until you have the desired amount of flowable suspension applied to the seed. 然后通 Then pass

119通过在珠磨(bead mill)中将每粒种子浸软，然后加入乙腈萃取溶剂而测定施加于来自每批的十粒种子的化合物208的重量。 119 through the bead mill (bead mill) will each seed soaked, then acetonitrile extraction solvent and measuring the weight applied to 十粒 seeds from each batch of compound 208. 离心萃取液，并将等分试样的上清液稀释10000: I,然后通过LC/MS分析》分析结果列于表8。 The extract was centrifuged, and the supernatant was diluted aliquot 10000: I, and then by LC / MS analysis. "The results are shown in Table 8.

表8 Table 8

用化合物208组合物涂覆的棉籽的测量 208 composition is coated with a compound of cottonseed measurement

*基于10次重复测定 * Based on 10 replicate measurements

实施例F Example F

用包含化合物208、484、486、502、509或515的组合物涂覆的玉米 Corn coating composition comprising a compound of 208,484,486,502,509 or 515

种子批的制备步骤I:包含化合物208、484、486、502、509或515的易流动的悬浮液的制备 Preparing a compound 208,484,486,502,509 or 515 flowable suspension: preparing step seed lot I

使用下表9中显示的配方制备六种易流动的悬浮液，每种含有上述六种有效成分化合物中的一种。 9 shown in the following table used Six flowable formulation was prepared a suspension, each containing six active ingredient compounds above one. 衣y Clothes y

易流动的悬浮液中的成分的量 The amount of flowable suspension components

除有效成分化合物以外的所有成分都在实施例E中描述。 All the ingredients except the active ingredient compound are described in Examples E.

以实施例E,步骤I所描述的方法制备各化合物的易流动的悬浮液。 In Example E, the method steps I described for the preparation of flowable suspension of each compound. 悬浮液中的颗粒粒径(即Dia,在表10中)也通过实施例E，步骤 Suspension particle size (i.e. Dia, in Table 10) also by Example E, Step

I中描述的方法分析。 Analysis Method I described. 湿磨后获得的粒径分布显示于表10中。 Particle size distribution obtained after wet milling are shown in Table 10.

表10 Table 10

6种易流动的悬浮液的粒径 Particle size of 6 kinds of flowable suspension

*两次测量的平均值 * Average of two measurements

“<”表示小于步骤2:用包含化合物208、484、486、502或515的单独绀合物涂覆玉米种子 "<" Means less than Step 2: A coating composition comprising a compound of a single purple corn seed 208,484,486,502 or 515

将玉米种子(Pioneer 3146 Lot # C92FA (亲本)，65 g)加入含有两个相反的提升叶片的不锈钢罐(12 cm id，11 cm深)中，所述提升叶片随罐转动而提升种子。 Corn seeds (Pioneer 3146 Lot # C92FA (parent), 65 g) was added two opposing lifting vanes comprising a stainless steel pot (12 cm id, 11 cm deep), said lifting blades rotate with the tank and lifting the seed. 罐的方向与水平成40-45°角，并以IlOrpm机械旋转，这在罐内导致良好的混合和翻转运动。 Direction and level tank into a 40-45 ° angle, and IlOrpm mechanical rotation, which leads to good mixing and flipping motion in the tank. •J 乂Γ、Γ、：^Γ//ίϋ JlJj /y ^ ： W Ali m^yJ i/^.9 Ύ^ίν^ I 厂 ^ • J qe Γ, Γ,: ^ Γ // ίϋ JlJj / y ^:. W Ali m ^ yJ i / ^ 9 Ύ ^ ίν ^ I plant ^

种易流动的悬浮液各自直接喷到玉米种子的翻转床上。 Kind of free-flowing suspension is sprayed directly into the respective flip corn seed bed. 然后通过让种子在化学通风橱中干燥过夜而完成种子涂层的干燥。 Then let the seeds in a chemical fume hood overnight to complete the drying of the coating was dried seed. 玉米种子上每种微粉化的化合物的标称3重量％涂层如表11所示得以实现。 Nominal 3 wt micronized corn seed each compound coating as shown in Table 11% can be achieved. 表11 Table 11

用单独化合物组合物涂覆的玉米种子的测量 Measuring individual compounds composition is applied to corn seeds

*基于10次重复测定实施例G * Based on 10 replicate measurements Example G

用包含化合物208、276或483的组合物涂覆的棉籽批的制备步骤I:包含化合物208、276或483的易流动的悬浮液的制备使用与表9中显示相同的配方制备三种易流动的悬浮液，每种含有上述六种化合物中的一种。 Preparation of cottonseed batches step comprising a compound coating composition of 208,276 or 483 I: Table prepared using flowable suspension comprising compound 9 208,276 or 483 shown in the same three flowable formulation was prepared The suspension, each containing one of the six compounds. 以实施例E，步骤I所描述的方法制备各化合物的易流动的悬浮液。 In Example E, the method steps I described for the preparation of flowable suspension of each compound. 悬浮液中的颗粒粒径(即Dia，在表10中)也通过实施例E，步骤I中描述的方法分析。 Suspension particle size (i.e. Dia, in Table 10) is also the method described in step I analyzed by Example E,. 湿磨后获得的粒径分布显示于表12中。 Particle size distribution obtained after wet milling are shown in Table 12.

*两次测量的平均值 * Average of two measurements

“<”表示小于步骤2:用包含化合物208、276或483的单独组合物涂覆棉籽将棉籽(Stoneville 4793 RR, 33 g)加入含有两个相反的提升叶片的不锈钢罐(6.5 cm Ld., 7.5 cm深)中，所述提升叶片随罐转动而提升种子。 "<" Means less than Step 2: The coated cottonseed separate compositions comprising a compound of the 208,276 or 483 Cottonseed (Stoneville 4793 RR, 33 g) was added with two opposing lifting vanes stainless steel tanks (6.5 cm Ld,. 7.5 cm deep), said lifting blades rotate with the tank and lifting the seed. 罐的方向与水平成40-45°角，并以IOOrpm机械旋转，这在罐内导致良好的混合和翻转运动。 Direction and level tank into a 40-45 ° angle, and IOOrpm mechanical rotation, which leads to good mixing and flipping motion in the tank.

按照实施例E,步骤2中描述的常规方法，将步骤I中制备的3种易流动的悬浮液各自直接喷到翻转的棉籽批上。 According to the conventional method of Example E, as described in Step 2, Step I prepared three kinds of flowable suspension sprayed directly onto the cottonseed each batch flipped. 然后通过让种子在化学通风橱中干燥过夜而完成种子涂层的干燥。 Then let the seeds in a chemical fume hood overnight to complete the drying of the coating was dried seed. 棉籽上每种微粉化的化合物的标称3重量％涂层如表13所示得以实现。 On each cottonseed nominal 3 wt micronized% coating compound shown in Table 13 can be achieved.

表13 Table 13

*基于10次重复测定用包含化合物502的组合物涂覆的玉米种子批的制备步骤I:包含15% w/w化合物502的易流动的悬浮液的制备 Prepared containing 15% w / w compound 502 flowable suspension: * Based on 10 replicate measurements coated with a composition comprising a compound prepared in step 502 corn seed lot I

制备化合物502的15%易流动的悬浮液，除化合物以外，其含有实施例F,表9所列的相同成分。 Preparation of Compound 502 in 15% flowable suspension, except for compounds containing Example F, listed in Table 9 of the same composition. 以实施例E，步骤I所描述的方法制备化合物502的易流动的悬浮液。 In Example E, the method described in Step I of the preparation of compound 502 flowable suspension. 悬浮液中的颗粒粒径(即Dia,在表10中)也通过实施例B，步骤I中描述的方法分析。 Suspension particle size (i.e. Dia, in Table 10) is also the method described in step I analyzed by Example B,. 湿磨后获得的粒径分布显示于表14中。 Particle size distribution obtained after wet milling are shown in Table 14.

表14 Table 14

*两次测量的平均值“<”表示小于步骤2:用包含化合物502的组合物涂覆玉米种子 * Average of two measurements "<" means less than Step 2: A composition comprising a compound 502 corn seed coating

将玉米种子(Pioneer 34M94 Hybrid Field Com, 575 g)加入含有两个相反的提升叶片的不锈钢罐(17 cmi.d, 16 cm深)中，所述提升叶片随罐转动而提升种子。 Corn seeds (Pioneer 34M94 Hybrid Field Com, 575 g) was added two opposing lifting vanes comprising a stainless steel canister (17 cmi.d, 16 cm deep), said lifting blades rotate with the tank and lifting the seed. 罐的方向与水平成40*45°角，并以200ipm机械旋转，这在罐内导致良好的混合和翻转运动。 The horizontal direction the tank into 40 * 45 ° angle, and 200ipm mechanical rotation, which results in good mixing in the tank and the rollover motion.

按照实施例E，步骤2中描述的常规方法，将步骤I中制备的15%w/w易流动的悬浮液直接喷到各翻转的玉米种子批上。 According to the conventional method described in Example E, Step Example 2, Step I prepared 15% w / w flowable suspension sprayed directly onto the corn seed lots each flip. 然后通过让种子在化学通风橱中干燥过夜而完成种子涂层的干燥。 Then let the seeds in a chemical fume hood overnight to complete the drying of the coating was dried seed. 玉米种子上微粉化的化合物502的标称0.15、0.29、0.58、1.09. 1.75重量％涂层如表15所示得以实现。 Corn seed micronized compound nominal 0.15,0.29,0.58,1.09 502. 1.75 weight percent of the coating as shown in Table 15 can be achieved. 经涂覆的种子上化合物502的平均\\^%按照实施例E,步骤2中的方法通过LC/MS测量。 Seeds coated by a compound average \\ ^ 502% of cases according to E, the procedure of the second method by LC / MS measurements. 衣13 Clothing 13

用化合物502组合物涂覆的玉米种子的测量 Measuring 502 compound composition is applied to corn seeds

*基于10次重复测定 * Based on 10 replicate measurements

以下本发明的生物实施例中的试验说明本发明的方法和组合物对于保护植物免受特定节肢动物害虫侵害的功效。 Examples of test organisms described embodiment of the invention the following methods and compositions of the present invention are useful for protecting plants from specific arthropod pests effect. 然而，由这些化合物提供的害虫防治保护并不限于这些种类。 However, the pest control protection afforded by these compounds is not limited to these species. 关于化合物的说明，参见索引表A。 About compound instructions, see the index table A. 在以下索引表中使用的缩写如下：ί为叔，《为正，i为异， Abbreviations used in the following index table as follows: ί is tertiary, "it is normal, i is iso,

^为仲，c为环，Me为甲基，Et为乙基，Pr为丙基而Bu为丁基；相应地，i-Pr为异丙基，i-Bu为仲丁基等。 ^ Is secondary, c is a ring, Me is methyl, Et is ethyl, Pr is propyl and Bu is butyl; accordingly, i-Pr is isopropyl, i-Bu is butyl and the like. 缩写“Ex”表示“实施例”，其后跟着的数字表示该化合物在哪个实施例中制备。 Abbreviation "Ex" represents "Example", followed by the subsequent digital representation in which the compound prepared in the Examples.

除非特别指明，R1、R5和Rs为H;除非特别指明，B为O; “CN”通过碳而非氮键合；例如，“CN-Ph”指氰基苯基，不是异氰基苯基。 Unless otherwise indicated, R1, R5 and Rs are H; unless otherwise specified, B is O; "CN" is bonded through a carbon rather than nitrogen; for example, "CN-Ph" refers cyanophenyl, not different cyanophenylboronic .

583 H H 2-M&4-CI Br 2*U-4-F-Fh 229-229 583 H H 2-M & 4-CI Br 2 * U-4-F-Fh 229-229

584 i^r H 2-Me4-Q Br 2-a-4-F-Ph 189-190 584 i ^ r H 2-Me4-Q Br 2-a-4-F-Ph 189-190

585 ί-Btt H 2-Me^Q Br 2-Cl-4-F-Fh 247-249 585 ί-Btt H 2-Me ^ Q Br 2-Cl-4-F-Fh 247-249

586 ί-Pr H 2-Me^i-N02 CF3 2-Q-Ph * 586 ί-Pr H 2-Me ^ i-N02 CF3 2-Q-Ph *

587 Ph H 2-Me本a CF3 2-(3~Cl·吡啶莪） 243-244 587 Ph H 2-Me present a CF3 2- (3 ~ Cl · pyridine Curcuma) 243-244

588 2-Me-Ph H 2-Me-4-Q CF3 2»(3«Cl· 吡啶狴） 249-251 588 2-Me-Ph H 2-Me-4-Q CF3 2 »(3« Cl · pyridine jail) 249-251

589 /-Pr H 2-Me-*-N02 CF3 2#·0·吡啶驻） 170-172 589 / -Pr H 2-Me - * - N02 CF3 2 # · 0 · pyridine in) 170-172

590 ϊ-Ργ H 2-MM-N02 CF3 2<3-Cl-吡啶基） * 590 ϊ-Ργ H 2-MM-N02 CF3 2 <3-Cl- pyridyl) *

591 M^B为S H 2-Me CF3 2-Cl-Ph 164-167 591 M ^ B is S H 2-Me CF3 2-Cl-Ph 164-167

592 /-Pr H 2-N02 CF3 2-a-Ki · 592 / -Pr H 2-N02 CF3 2-a-Ki ·

593 ι-Pr H 2-Me-4-D OCHF2 2-Q-Ph 177-179 593 ι-Pr H 2-Me-4-D OCHF2 2-Q-Ph 177-179

594 Me Me 2,4-r-Br Q 2-(3^01-吡啶菡） 151-152 594 Me Me 2,4-r-Br Q 2- (3 ^ 01- pyridine Han) 151-152

595 CH(CH3)CH2OCH3 H 2'4·二-Br Cl 2·<3>0-吡啶基> 162-163 595 CH (CH3) CH2OCH3 H 2'4 · two -Br Cl 2 · <3> 0- pyridyl> 162-163

596 CH(CH3)CH2SCHb H 2,4·二-Br Cl ^<3-0-吡啶莪） 174-175 596 CH (CH3) CH2SCHb H 2,4 · two -Br Cl ^ <3-0- pyridyl Curcuma) 174-175

597 CH(CH3)CH2OH H 2,4-~-Br Cl 2»(3~Cl· 吡啶基> 148-149 597 CH (CH3) CH2OH H 2,4- ~ -Br Cl 2 »(3 ~ Cl · pyridyl> 148-149

142 142

a 1H NMR数据为ppm来自四甲基硅烷低磁场。 a 1H NMR data in ppm downfield from tetramethylsilane. 偶联用以下符号表示：(S)-单峰，（d)-双峰，（O-主重峰，（q)-四重峰，（m)-多重峰，（dd)-双重的双峰，（dt)-双重的三重峰，（brs)-宽单峰。 Coupled with the following symbols: (S) - singlet, (d) - doublet, (O- main quintet, (q) - quartet, (m) - multiplet, (dd) - double double peak, (dt) - double triplet, (brs) - br.

本发明的牛物实施例试验A Cattle embodiment of the present invention Test A

将如实施例E中所述制备的来自标称1%、标称2%和标称3%浓度批的用化合物208的组合物涂覆的棉籽和用以对照的未经处理的种子种植在无菌黄樟土(Sassafras soil)罐中，并在28°C 16小时光照和24°C 8小时黑暗和50%相对湿度的生长箱中生长。 Will be as prepared as described in Example E from a nominal 1%, 2% of the nominal and nominal untreated seed batches concentration of 3% compound 208 composition is applied to the control of cottonseed and grow in sterile sassafras soil (Sassafras soil) tank, and grown in 28 ° C 16 hours of light and 24 ° C 8 hours of darkness and 50% relative humidity in a growth chamber. 31天后，从每个种子批中选择都具有真叶的两株植物，除去它们的子叶。 After 31 days, choose from each seed lot have a leaf of two plants, remove their cotyledons. 将银叶粉虱(Bemisia 成虫加于植物上产卵，然后将罩有薄纸的塑料圆筒与罐适合。三天后，除去成虫，检査叶子以确定卵沉积。15天后(约卵孵化后六天)，从植物上除去受侵染的叶子，并通过计数叶子下面的死蛹和活蛹而确定49天结果。再将银叶粉虱成虫引入植物叶子的上面进行第二轮产卵，并且如前相同地将罩有薄纸的塑料圆筒与罐适合。三天后，除去成虫，检查叶子以确定卵沉积。十四天后(约卵孵化后六天)，从植物上除去受侵染的叶子，并通过计数叶子下面的死蛹和活蛹而确定66天的结果》两个级别时间的结果在表A中概括。通过用化合物208的组合物涂覆棉籽而防治银叶粉虱 The silverleaf whitefly (Bemisia adults is applied to the plants to lay eggs, then cover with plastic cylinder has a tissue tank for three days later to remove the adult, check the leaves to determine the egg deposition .15 days (approximately eggs hatch after six days), remove the leaves from the plants infested, and by counting the dead leaves below live pupa while pupae and 49 days to determine the result. Then silverleaf whitefly adults were introduced into the leaves of plants above the second round of spawning, and have the same manner as before the cover tissue plastic cylinder and tank for three days later to remove the adult leaves to determine the eggs deposited checks after fourteen days (eggs hatch after about six days), removed from the infested plants leaves, and by counting the dead leaves below live pupa while pupae and 66 days to determine the result of "two levels of time results are summarized in Table A, by using a coating composition comprising a compound 208 cottonseed and prevention of silverleaf whitefly

该试验表明本发明的种子涂层可以在播种后超过9周保护棉花植物免受同翅目害虫银叶粉虱的侵害。 The tests showed that the seed coating of the present invention may be more than nine weeks after sowing cotton to protect plants from pests homopteran silverleaf whitefly damage.

试验B Test B

将如实施例E描述的方法制备的来自标称1%、标称2%和标称3%浓度的用化合物208的组合物涂覆的棉籽和用作对照的未经处理的种子种植在10-cm的无菌黄樟土罐中，并在25Ό下16小时光照和8小时黑暗和50%相对湿度的生长箱中生长。 The method described in Example E was prepared from the nominal 1%, 2% of the nominal concentration of 3% and a nominal untreated seed was coated with the composition of the compound 208 and used as a control cottonseed planted in 10 -cm sterile sassafras soil in pots and grown in 25Ό 16 hours of light and 8 hours of darkness and 50% relative humidity in a growth chamber. 播种后14天，从一些植株上采集叶片，剪成3至4片，放置于生长箱中经覆盖的16孔(16-well)半透明塑料盘中，每孔放一片。 14 days after sowing, the number of plants collected from leaves, cut into 3-4, placed in a growth chamber through 16 holes covered (16-well) translucent plastic trays, each hole put one. 将烟草蚜虫(/ZetoitoWrejcens)的二龄幼虫加到叶片上(I幼虫/孔，6-10幼虫/处理/叶片类型)，侵染后48小时和96小时测定害虫死亡率。 The tobacco budworm (/ ZetoitoWrejcens) second instar larvae added to the blade (I larvae / well, 6-10 larvae / treatment / blade type), 48 hours and 96 hours post-infection was measured pest mortality. 播种64天后从其它植物采集叶片，剪成3-4片，放置于生长箱中经覆盖的16孔半透明塑料盘中，每孔放一片。 64 days after sowing collect leaves from other plants, cut into 3-4 pieces, placed in a growth chamber by covering the 16 holes translucent plastic trays, each put a hole. 将烟草蚜虫的二龄幼虫加到叶片上(I幼虫/孔，6-16幼虫/处理/叶片位置)，侵染后72小时和96小时测定害虫死亡率。 The second instar larvae of the tobacco budworm is applied to the blade (I larvae / well, 6-16 larvae / treatment / blade position), 72 hours and 96 hours post-infection was measured pest mortality. 结果概括于表BI和B2中。 The results are summarized in Table BI and B2.

*棉花植株上剪下叶片的位置。 * Cut blade position on cotton plants.

该试验表明，本发明的种子涂层可以保护棉花植物免受鱗翅目害虫烟草蚜虫的侵害超过播种后9周。 The tests showed that the seed coating of the present invention can protect cotton plants from 9 weeks after the tobacco budworm against lepidopteran pests than sowing.

试验C Test C

将如实施例E所述制备的用化合物208处理的棉籽(标称3%批）和如实施例G所述制备的用化合物276、486和502处理的棉籽，以及用作对照的未经处理的种子种植在无菌黄樟土或黑色石首鱼土(Drummer soil)耀中。 The cottonseed prepared as described in Example E treated with compound 208 (nominal 3% batch) and prepared as described in Example G using the compound of cottonseed processing 276,486 and 502, as well as untreated control The seeds were planted in sterile sassafras soil or black kingfish soil (Drummer soil) Yew Chung. 植物在温室中生长，当它们开始发芽(方形)时，取样。 Plants grown in a greenhouse, when they begin to sprout (square), the sampling. 从第二节点的叶和大于15 cm2的末端叶取样(植物约有5片叶>将来自各植株的经修剪的叶剪成4片，将各片置于具有一只烟草蚜虫 Leaves from the second point is greater than 15 cm2 end leaf samples (approximately 5 leaves of plants> The pruned leaves from each plant cut into four, each piece is placed has a tobacco budworm

156狀忏尼yo 勹TC习匕1~中。 156 yo-like Benny Chan Bao Xi dagger 1 to the TC.

表C Table C

试验P Test P

将如实施例F所述制备的用化合物208、484、486、502、509和515处理的玉米种子种植在黄樟土罐中。 As described in Example F was prepared using the compound 208,484,486,502,509 and 515 corn seed treatment sassafras planted in clay pots. 植株在温室中生长至轮生体高度(第9片叶)，用25只草地粘虫(一龄幼虫)侵染轮生体。 Plants grown in the greenhouse to whorl height (9th leaf), with 25 fall armyworm (first instar larvae) infested whorls. 侵染后六天，记录与摄食相关的植株损伤。 Six days after infection, the recording and feeding plants related damage. 植株损害以0-100%评定(O表示未摄食)。 Plant damage assessment of 0-100% (O means no feeding).

试验E Test E

将如实施例H所述制备的以五级(标称1.75%、1.09%、0.58%、0.29%和0.15%)用化合物502处理的玉米种子种植在邻近Newark,DE和Donna, TX的农田中。 Corn seeds as described in Example H prepared to five (nominal 1.75%, 1.09%, 0.58%, 0.29% and 0.15%) treated with compound 502 were planted in neighboring Newark, DE and Donna, TX farmland . 当植株生长的第5片叶至少10 cm长时，将其剪下。 When the plant growth in the first 5 leaves at least 10 cm long, it was cut. 从至少16株植物每级取一片经修剪的叶，并置于具有一只二龄草地粘虫幼虫的孔中。 At least 16 plants from each grade to take a leaf trimmed and placed S.frugiperda having a second instar larvae bore in. 侵染后72小时记录幼虫死亡率。 72 hours after infection larval mortality was recorded.

测量Donna位点的玉米植株以确定植株生长。 Donna measurement sites to determine the plants grow corn plants. 将叶片叠近管中，记录管中由地面至叶片最顶端的高度。 The blade stacked near tube, recording the tube from the ground to the top of the blade height.

表El 在用化合物502处理的种子的玉米的第5片叶上摄食弓丨起的幼虫死亡率 Table El in the seed corn treated with compound 502 5th leaf feeding larvae mortality from bow 丨

表E2 Table E2

在Donna，TX用化合物502处理种子的玉米的植株高度种子处理I 未经处|0·15% I 0.29°/。 In Donna, TX processing I plant height with untreated seed compound 502 corn seed treatment | 0 · 15% I 0.29 ° /. 0.58% L09% 1.75% " 0.58% L09% 1.75% "

(标称级） 理____—_____ (Nominal level) manager ____-_____

高度(英寸）41.64 40.76 4236~ 44.28~ 45.32~ 48.32~从表E2可以看'出，在该试验中用化合物502处理似乎促进植株生长。 Height (inches) 41.64 40.76 4236 - 44.28 - 45.32 - 48.32 - you can see from Table E2 'out with the test compound (502) appears to promote plant growth.