TW201936597A - Process for the preparation of substituted (1H-1,2,4-triazol-1-yl)alcohols - Google Patents

Process for the preparation of substituted (1H-1,2,4-triazol-1-yl)alcohols Download PDF

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TW201936597A
TW201936597A TW107136304A TW107136304A TW201936597A TW 201936597 A TW201936597 A TW 201936597A TW 107136304 A TW107136304 A TW 107136304A TW 107136304 A TW107136304 A TW 107136304A TW 201936597 A TW201936597 A TW 201936597A
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克里斯托夫 斯裘泰斯
曼弗雷德 梅耶
埃克 海爾曼
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德商拜耳廠股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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Abstract

The present invention relates to a process for preparing substituted (1H-1,2,4-triazol-1-yl)alcohols of formula (I) wherein R1, R4, m and Y are defined as disclosed in the specification, by reacting 1H-1,2,4-triazole and an oxirane of formula (II) in the presence of a base and polyalkylene glycol. Also disclosed are particular crystalline forms of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl)propan-2-ol, a compound available by said process.

Description

製備經取代之(1H-1,2,4-***-1-基)醇類之方法 Method for preparing substituted (1H-1,2,4-triazol-1-yl)ol

本發明關於製備經取代之(1H-1,2,4-***-1-基)醇類之方法。 This invention relates to a process for the preparation of substituted (1H-1,2,4-triazol-1-yl)ols.

已知特定的經取代之(1H-1,2,4-***-1-基)醇類有用於作物保護領域中，特別作為殺真菌劑。WO 2017/029179 A1揭示此等經取代之(1H-1,2,4-***-1-基)醇類及合成彼等的許多途徑。該等途徑之一係在WO 2017/029179 A1中以方法B提及且包含適合的環氧乙烷衍生物之開環，其係藉由將該環氧乙烷衍生物與1H-1,2,4-***在鹼及視需要的有機溶劑存在下反應。此等程序提供到達標的(1H-1,2,4-***-1-基)醇類之入口。然而，希望進一步改進該方法以容許以工業規模有效的合成，例如在產率、純度及/或使用環境可承受溶劑方面。 Particular substituted (1H-1,2,4-triazol-1-yl)ols are known to be useful in the field of crop protection, particularly as fungicides. WO 2017/029179 A1 discloses such substituted (1H-1,2,4-triazol-1-yl)ols and many ways of synthesizing them. One of these routes is mentioned in Method B in WO 2017/029179 A1 and comprises a ring opening of a suitable oxirane derivative by reacting the oxirane derivative with 1H-1,2 The 4-triazole is reacted in the presence of a base and an optional organic solvent. These procedures provide access to the target (1H-1,2,4-triazol-1-yl) alcohol. However, it is desirable to further improve the process to allow for efficient synthesis on an industrial scale, for example in terms of yield, purity and/or environmentally acceptable solvent.

因此，本發明之目的係提供合成經取代之(1H-1,2,4-***-1-基)醇類之改進方法。 Accordingly, it is an object of the present invention to provide an improved process for the synthesis of substituted (1H-1,2,4-triazol-1-yl)ols.

驚訝地發現(1H-1,2,4-***-1-基)醇類可藉由適合的環氧乙烷衍生物與1H-1,2,4-***在鹼及聚烷二醇的存在下反應而以高產率合成。 Surprisingly, it was found that (1H-1,2,4-triazol-1-yl)ols can be obtained by using suitable oxirane derivatives with 1H-1,2,4-triazole in bases and polyalkylene glycols. The reaction is carried out in the presence of a high yield.

據此，本發明之目的為製備式(I)化合物之方法 其中R1 代表氫、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C3-C8-環烷基、C3-C8-環烷基-C1-C4-烷基或C6-C14-芳基，其中R1之脂族部分(排除環烷基部分)可攜有1、2、3或至多最大可能的數量之相同或不同的基團Ra，該等彼此獨立地選自鹵素、CN、硝基、苯基、C1-C4-烷氧基和C1-C4-鹵烷氧基，其中苯基可經1、2、3、4或5個彼此獨立地選自鹵素、CN、硝基、C1-C4-烷基、C1-C4-烷氧基、C1-C4-鹵烷基、C1-C4-鹵烷氧基之取代基取代，且其中R1之環烷基及/或C6-C14-芳基部分可攜有1、2、3、4、5或至多最大可能的數量之相同或不同的基團Rb，該等彼此獨立地選自鹵素、CN、硝基、C1-C4-烷基、C1-C4-烷氧基、C1-C4-鹵烷基和C1-C4-鹵烷氧基；各R4彼此獨立地代表鹵素、CN、硝基、C1-C4-烷基、C1-C4-鹵烷基、C1-C4-烷氧基、C1-C4-鹵烷氧基、C1-C4-烷基羰基、經羥基取代之C1-C4-烷基、五氟-λ6-氫硫基、C3-C6-環烷基、C3-C6-鹵素環烷基、C1-C4-烷基-C3-C6-環烷基、C2-C6-烯基、C2-C6-鹵素烯基、C2-C6-炔基、C2-C6-鹵素炔基、C1-C4-烷基氫硫基、C1-C4-鹵烷基氫硫基、C1-C6-烷基磺醯基、C6-C10-芳基磺醯基、C1-C6-烷基-SO2NH-、C6-C10-芳基-SO2NH-、甲醯基、含有至多4個選自N、O和S的雜原子之5-、6-或7-員飽和雜環烷基、或-C(R4a)=N-OR4b，其中R4a和R4b彼此獨立地代表氫、C1-C6-烷基或苯基；m 為整數且為0、1、2、3、4或5；Y 代表選自下列的6員芳族雜環： Accordingly, the object of the invention is a process for the preparation of a compound of formula (I) Wherein R 1 represents hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 - ring Alkyl-C 1 -C 4 -alkyl or C 6 -C 14 -aryl, wherein the aliphatic moiety of R 1 (excluding the cycloalkyl moiety) can carry 1, 2, 3 or up to the maximum possible number The same or different groups R a , which are independently of each other selected from the group consisting of halogen, CN, nitro, phenyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy, wherein phenyl 1, 2, 3, 4 or 5 independently of one another selected from the group consisting of halogen, CN, nitro, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -halide Substituted with a substituent of an alkyl group, a C 1 -C 4 -haloalkoxy group, and wherein the cycloalkyl group and/or the C 6 -C 14 -aryl moiety of R 1 can carry 1, 2, 3, 4, 5 Or at most the largest possible number of the same or different groups R b , independently of one another selected from the group consisting of halogen, CN, nitro, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl and C 1 -C 4 -haloalkoxy; each R 4 independently of one another represents halogen, CN, nitro, C 1 -C 4 -alkyl, C 1 -C 4 -halide alkyl group, C 1 -C 4 - alkoxy, C 1 -C 4 - haloalkoxy C 1 -C 4 - alkylcarbonyl group, the hydroxy-substituted C 1 -C 4 - alkyl, pentafluoro -λ 6 - mercapto, C 3 -C 6 - cycloalkyl, C 3 -C 6 - halo Cycloalkyl, C 1 -C 4 -alkyl-C 3 -C 6 -cycloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl , C 2 -C 6 -halothynyl, C 1 -C 4 -alkylthiol, C 1 -C 4 -haloalkylthio, C 1 -C 6 -alkylsulfonyl, C 6 -C 10 -arylsulfonyl, C 1 -C 6 -alkyl-SO 2 NH-, C 6 -C 10 -aryl-SO 2 NH-, formamyl, containing up to 4 selected from N, a 5-, 6- or 7-membered saturated heterocycloalkyl group of a hetero atom of O and S, or -C(R 4a )=N-OR 4b , wherein R 4a and R 4b independently of each other represent hydrogen, C 1 - C 6 -alkyl or phenyl; m is an integer and is 0, 1, 2, 3, 4 or 5; Y represents a 6-membered aromatic heterocyclic ring selected from the group consisting of:

其中Y係經由以「U」標識之鍵連接O，及Y係經由以「V」標識之鍵連接CR1部分，其中R 代表氫、C1-C2-鹵烷基、C1-C2-鹵烷氧基、C1-C2-烷基羰基或鹵素；各R3彼此獨立地代表鹵素、CN、硝基、C1-C4-烷基、C1-C4-鹵烷基、C1-C4-烷氧基或C1-C4-鹵烷氧基；及n 為整數且為0或1；該方法係藉由將1H-1,2,4-***與式(II)之環氧乙烷 其中R1、R4、m和Y係如式(I)所定義；在鹼及聚烷二醇的存在下反應。 Wherein Y is linked to O via a bond identified by "U", and Y is linked to the CR 1 moiety via a bond identified by "V", where R represents hydrogen, C 1 -C 2 -haloalkyl, C 1 -C 2 a haloalkoxy group, a C 1 -C 2 -alkylcarbonyl group or a halogen; each R 3 independently of one another represents halogen, CN, nitro, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl , C 1 -C 4 -alkoxy or C 1 -C 4 -haloalkoxy; and n is an integer and 0 or 1; the method is carried out by using 1H-1,2,4-triazole (II) ethylene oxide Wherein R 1 , R 4 , m and Y are as defined in formula (I); and are reacted in the presence of a base and a polyalkylene glycol.

該方法容許生產呈至少部分晶型之式(I)化合物。 This process permits the production of compounds of formula (I) in at least a partial crystalline form.

式(I)提供根據本發明之方法可獲得的***衍生物之概括定義。在上下文所示之式的較佳基團定義於下文給出。該等定義適用於式(I)之最終產物且同樣適用於所有的析出物及中間物，例如式(II)之環氧乙烷。 Formula (I) provides a general definition of the triazole derivatives obtainable by the process of the invention. Preferred groups of the formula shown in the context are defined below. These definitions apply to the final product of formula (I) and are equally applicable to all precipitates and intermediates, such as the ethylene oxide of formula (II).

R1 較佳地代表氫、C1-C4-烷基、C2-C6-烯基、C2-C6-炔基、環丙基或C6-C10-芳基，其中R1之脂族部分(排除環烷基部分)可攜有1、2、3或至多最大可能的數量之相同或不同的基團Ra，該等彼此獨立地選自鹵素、CN、硝基、苯基、C1-C4-烷氧基和C1-C4-鹵烷氧基，其中苯基可經1、2、3、4或5個彼此獨立地選自鹵素、CN、硝基、C1-C4-烷基、C1-C4-烷氧基、C1-C4-鹵烷基、C1-C4-鹵烷氧基之取代基取代，且其中R1之環烷基及/或C6-C10-芳基部分可攜有1、2、3、4、5或至多最大可能的數量之相同或不同的基團Rb，該等彼此獨立地選自鹵素、CN、硝基、C1-C4-烷基、C1-C4-烷氧基、C1-C4-鹵烷基和C1-C4-鹵烷氧基。 R 1 preferably represents hydrogen, C 1 -C 4 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, cyclopropyl or C 6 -C 10 -aryl, wherein R The aliphatic moiety of 1 (excluding the cycloalkyl moiety) can carry 1, 2, 3 or up to the largest possible number of the same or different radicals R a independently selected from the group consisting of halogen, CN, nitro, a phenyl group, a C 1 -C 4 -alkoxy group and a C 1 -C 4 -haloalkoxy group, wherein the phenyl group may be independently selected from the group consisting of halogen, CN, nitro via 1, 2, 3, 4 or 5 Substituted with a substituent of C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy, and wherein R 1 The cycloalkyl and/or C 6 -C 10 -aryl moiety may carry 1, 2, 3, 4, 5 or up to the largest possible number of the same or different groups R b , which are independently selected from each other Halogen, CN, nitro, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl and C 1 -C 4 -haloalkoxy.

R1 更佳地代表氫、C1-C4-烷基、C2-C6-烯基、C2-C6-炔基、環丙基或苯基，其中R1之脂族部分(排除環烷基部分)可攜有1、2、3或至多最大可能的數量之相同或不同的基團Ra，該等彼此獨立地選自鹵素、CN、硝基、苯基、C1-C4-烷氧基和C1-C4-鹵烷氧基，其中苯基可經1、2、3、4或5個彼此獨立地選自鹵素、CN、硝基、C1-C4-烷基、C1-C4-烷氧基、C1-C4-鹵烷基、C1-C4-鹵烷氧基之取代基取代，且其中R1之環烷基及/或苯基部分可攜有1、2、3、4、5或至多最大可能的數量之相同或不同的基團Rb，該等彼此獨立地選自鹵素、CN、硝基、C1-C4-烷基、C1-C4-烷氧基、C1-C4-鹵烷基和C1-C4-鹵烷氧基。 R 1 more preferably represents hydrogen, C 1 -C 4 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, cyclopropyl or phenyl, wherein the aliphatic moiety of R 1 Excluding the cycloalkyl moiety) can carry 1, 2, 3 or up to the largest possible number of the same or different groups R a , which are independently selected from halogen, CN, nitro, phenyl, C 1 - a C 4 -alkoxy group and a C 1 -C 4 -haloalkoxy group, wherein the phenyl group may be independently selected from halogen, CN, nitro, C 1 -C 4 via 1, 2, 3, 4 or 5 Substituted with a substituent of an alkyl group, a C 1 -C 4 -alkoxy group, a C 1 -C 4 -haloalkyl group, a C 1 -C 4 -haloalkoxy group, and wherein a cycloalkyl group of R 1 and/or The phenyl moiety can carry 1, 2, 3, 4, 5 or up to the largest possible number of identical or different groups R b , which are independently selected from the group consisting of halogen, CN, nitro, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl and C 1 -C 4 -haloalkoxy.

R1 更佳地代表氫、甲基、乙基、丙基、異丙基、丁基、環丙基、烯丙基、CH2C≡C-CH3或CH2C≡CH，其中脂族基團R1可攜有1、2、3或至多最大可能的數量之相同或不同的基團Ra，該等彼此獨立地選自鹵素、CN、硝基、苯基、C1-C4-烷氧基和C1-C4-鹵烷氧基，其中苯基可經1、2、3、4或5個彼此獨立地選自鹵素、CN、硝基、C1-C4-烷基、C1-C4-烷氧基、C1-C4-鹵烷基、C1-C4-鹵烷氧基之取代基取代。 R 1 more preferably represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, allyl, CH 2 C≡C-CH 3 or CH 2 C≡CH, wherein aliphatic The radical R 1 may carry 1, 2, 3 or up to the largest possible number of identical or different radicals R a , independently of one another selected from the group consisting of halogen, CN, nitro, phenyl, C 1 -C 4 Alkoxy and C 1 -C 4 -haloalkoxy, wherein the phenyl group may be independently selected from halogen, CN, nitro, C 1 -C 4 -alkane by 1, 2, 3, 4 or 5 Substituted by a substituent of a C 1 -C 4 -alkoxy group, a C 1 -C 4 -haloalkyl group, or a C 1 -C 4 -haloalkoxy group.

R1 更佳地代表氫或未經取代之甲基、乙基、丙基、異丙基、丁基、環丙基、CF3、苯甲基、烯丙基、CH2C≡C-CH3或CH2C≡CH。 R 1 more preferably represents hydrogen or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, CF 3 , benzyl, allyl, CH 2 C≡C-CH 3 or CH 2 C≡CH.

R1 更佳地代表氫、甲基或乙基。 R 1 more preferably represents hydrogen, methyl or ethyl.

R1 更佳地代表氫或甲基。 R 1 more preferably represents hydrogen or methyl.

R1 最佳地代表甲基。 R 1 best represents a methyl group.

各R4較佳地彼此獨立地代表甲基、乙基、正丙基、異丙基、CF3、OCF3、Br、Cl、五氟-λ6-氫硫基、環丙基、1-鹵素環丙基、1-C1-C4-烷基環丙基、C2-C6-烯基、C2-C6-鹵烯基、C2-C6-炔基、C2-C6-鹵炔基、C1-C4-烷基氫硫基、C1-C4-鹵烷基氫硫基、C1-C4-烷基磺醯基、苯基磺醯基、C1-C4-烷基-SO2NH-、苯基-SO2NH-、甲醯基、氮丙環基(aziridinyl)、吡咯啶基、二氫吡啶基、哌啶基、哌基、嗎啉基、硫代嗎啉基、四氫呋喃基、四氫硫代呋喃基、四氫吡喃基、吡喃基、異唑啶基、異唑啉基、吡唑啉基、二氫吡咯基、四氫吡啶基、二氧環戊烷基(dioxolanyl)、二 烷基、氧硫雜環戊烷基(oxathiolanyl)、氧硫基、二噻基、二噻基或-C(R4a)=N-OR4b，其中R4a和R4b彼此獨立地代表氫、C1-C6-烷基或苯基。 Each R 4 preferably independently of one another represents methyl, ethyl, n-propyl, isopropyl, CF 3 , OCF 3 , Br, Cl, pentafluoro-λ 6 -hydrothio, cyclopropyl, 1- Halogen cyclopropyl, 1-C 1 -C 4 -alkylcyclopropyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 - C 6 -halynyl, C 1 -C 4 -alkylthiomethyl, C 1 -C 4 -haloalkylthio, C 1 -C 4 -alkylsulfonyl, phenylsulfonyl, C 1 -C 4 -alkyl-SO 2 NH-, phenyl-SO 2 NH-, methoxymethyl, aziridinyl, pyrrolidinyl, dihydropyridyl, piperidinyl, piperidine Base, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, pyranyl, iso Zymididine Oxazolinyl, pyrazolinyl, dihydropyrrolyl, tetrahydropyridyl, dioxolylyl, di Alkyl, oxathiolanyl, oxysulfide Dithiophene Dithiophene Or a group -C(R 4a )=N-OR 4b , wherein R 4a and R 4b independently of each other represent hydrogen, C 1 -C 6 -alkyl or phenyl.

各R4更佳地彼此獨立地代表CF3、OCF3、Br、Cl、五氟-λ6-氫硫基、環丙基、1-氟環丙基、1-氯環丙基、1-甲基環丙基、乙烯基、烯丙基、乙炔基、丙-2-炔基、SCH3、SCH2CH3、SCH2F、SCHF2、SCF3、甲基磺醯基、苯基磺醯基、甲基-SO2NH-、苯基-SO2NH-、甲醯基、二氧環戊烷基、二烷基或-C(R4a)=N-OR4b， 其中R4a和R4b彼此獨立地代表氫或C1-C4-烷基，較佳為氫、甲基、乙基、正丙基、異丙基、正丁基、異丁基或三級丁基，更佳為氫或甲基。 Each R 4 more preferably independently of one another represents CF 3 , OCF 3 , Br, Cl, pentafluoro-λ 6 - thiol, cyclopropyl, 1-fluorocyclopropyl, 1-chlorocyclopropyl, 1- Methylcyclopropyl, vinyl, allyl, ethynyl, prop-2-ynyl, SCH 3 , SCH 2 CH 3 , SCH 2 F, SCHF 2 , SCF 3 , methylsulfonyl, phenylsulfonate Sulfhydryl, methyl-SO 2 NH-, phenyl-SO 2 NH-, methionyl, dioxolcycloalkyl, di Alkyl or -C(R 4a )=N-OR 4b , wherein R 4a and R 4b independently of each other represent hydrogen or C 1 -C 4 -alkyl, preferably hydrogen, methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl or tert-butyl, more preferably hydrogen or methyl.

各R4更佳地彼此獨立地代表CF3、OCF3、Br、Cl、五氟-λ6-氫硫基、環丙基、1-氟環丙基、1-氯環丙基、1-甲基環丙基、乙烯基、烯丙基、乙炔基、丙-2-炔基、SCH3、SCH2CH3、SCH2F、SCHF2、SCF3、甲醯基、1,3-二氧環戊烷-2-基或-C(R4a)=N-OR4b， 其中R4a代表氫、甲基、乙基、正丙基、異丙基、正丁基、異丁基或三級丁基，較佳為氫或甲基，R4b代表氫、甲基、乙基、正丙基、異丙基、正丁基、異丁基或三級丁基，較佳為氫或甲基。 Each R 4 more preferably independently of one another represents CF 3 , OCF 3 , Br, Cl, pentafluoro-λ 6 - thiol, cyclopropyl, 1-fluorocyclopropyl, 1-chlorocyclopropyl, 1- Methylcyclopropyl, vinyl, allyl, ethynyl, prop-2-ynyl, SCH 3 , SCH 2 CH 3 , SCH 2 F, SCHF 2 , SCF 3 , formazan, 1,3-di Oxycyclopentan-2-yl or -C(R 4a )=N-OR 4b , wherein R 4a represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tri a butyl group, preferably hydrogen or methyl, and R 4b represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably hydrogen or base.

各R4更佳地彼此獨立地代表CF3、OCF3、Br、Cl、五氟-λ6-氫硫基、環丙基、乙炔基、SCH3、SCF3、甲醯基、1,3-二氧環戊烷-2-基或-C(R4a)=N-OR4b，其中R4a代表氫，及R4b代表氫。 Each R 4 more preferably independently of one another represents CF 3 , OCF 3 , Br, Cl, pentafluoro-λ 6 -hydrothiol, cyclopropyl, ethynyl, SCH 3 , SCF 3 , formazan, 1,3 - Dioxocyclopentan-2-yl or -C(R 4a )=N-OR 4b , wherein R 4a represents hydrogen, and R 4b represents hydrogen.

各R4更佳地彼此獨立地代表CF3、OCF3、Br、Cl、五氟-λ6-氫硫基、環丙基、乙炔基、SCH3、SCF3、甲醯基或-CH=N-OH。 Each R 4 more preferably independently of one another represents CF 3 , OCF 3 , Br, Cl, pentafluoro-λ 6 -hydrothiol, cyclopropyl, ethynyl, SCH 3 , SCF 3 , formamyl or -CH= N-OH.

各R4更佳地彼此獨立地代表CF3、OCF3、Br、Cl或五氟-λ6-氫硫基。 Each R 4 more preferably independently of one another represents CF 3 , OCF 3 , Br, Cl or pentafluoro-λ 6 -hydrogenthio.

各R4最佳地彼此獨立地代表Br或Cl。 Each R 4 optimally represents Br or Cl independently of each other.

R4較佳地位於式(I)之苯基部分的2-及/或4-位置上。 R 4 is preferably located at the 2- and/or 4-position of the phenyl moiety of formula (I).

R4更佳地位於式(I)之苯基部分的4-位置上。 R 4 is more preferably located at the 4-position of the phenyl moiety of formula (I).

m 較佳為1、2或3。 m is preferably 1, 2 or 3.

m 更佳為1或2。 m is preferably 1 or 2.

m 最佳為1。 m is optimally 1.

Y 較佳地代表選自下列的6員芳族雜環： Y preferably represents a 6-membered aromatic heterocyclic ring selected from the group consisting of:

其中Y係經由以「U」標識之鍵連接O，及Y係經由以「V」標識之鍵連接CR1部分，及其中R、R3和n係如上文述及之式(I)所定義。 Wherein Y is connected to O via a key identified by "U", and Y is connected to the CR 1 portion via a bond identified by "V", and wherein R, R 3 and n are as defined above by formula (I) .

Y 更佳地代表選自下列的6員芳族雜環： Y more preferably represents a 6-membered aromatic heterocyclic ring selected from the group consisting of:

其中Y係經由以「U」標識之鍵連接O，及Y係經由以「V」標識之鍵連接CR1部分，及其中R、R3和n係如上文述及之式(I)所定義。 Wherein Y is connected to O via a key identified by "U", and Y is connected to the CR 1 portion via a bond identified by "V", and wherein R, R 3 and n are as defined above by formula (I) .

Y 更佳地代表選自下列的6員芳族雜環： Y more preferably represents a 6-membered aromatic heterocyclic ring selected from the group consisting of:

其中Y係經由以「U」標識之鍵連接O，及Y係經由以「V」標識之鍵連接CR1部分，及其中R、R3和n係如上文述及之式(I)所定義。 Wherein Y is connected to O via a key identified by "U", and Y is connected to the CR 1 portion via a bond identified by "V", and wherein R, R 3 and n are as defined above by formula (I) .

Y 最佳地代表 Y best represents

Y係經由以「U」標識之鍵連接O，及Y係經由以「V」標識之鍵連接CR1部分，及其中R、R3和n係如上文述及之式(I)所定義。 Y is connected to O via a key identified by "U", and Y is connected to the CR 1 portion via a key identified by "V", and wherein R, R 3 and n are as defined in the above formula (I).

R 較佳地代表氫、C1-C2-鹵烷基或鹵素。 R preferably represents hydrogen, C 1 -C 2 -haloalkyl or halogen.

R 更佳地代表氫、C1-鹵烷基、F或Cl。 R more preferably represents hydrogen, C 1 -haloalkyl, F or Cl.

R 更佳地代表C1-鹵烷基、F或Cl。 R more preferably represents C 1 -haloalkyl, F or Cl.

R 更佳地代表CF3或Cl。 R more preferably represents CF 3 or Cl.

R 最佳地代表CF3。 R best represents CF 3 .

各R3較佳地彼此獨立地代表F、Cl、Br、CN、硝基、甲基、CF3、甲氧基或OCF3。 Each R 3 preferably independently of one another represents F, Cl, Br, CN, nitro, methyl, CF 3 , methoxy or OCF 3 .

n 較佳為0。 n is preferably 0.

在上文以概括術語給出或在較佳的範圍內陳述之基團定義及解釋亦可依要求彼此組合，亦即包括在介於特定的範圍與較佳的範圍之間。該等同時適用於最終產物與相應的析出物及中間物。另外，個別的定義可能不適用。 The group definitions and explanations set forth above in the general terms or in the preferred ranges may also be combined with each other as desired, that is, included between the specific range and the preferred range. These apply to both the final product and the corresponding precipitates and intermediates. In addition, individual definitions may not apply.

優先選擇為那些其中基團中之各者具有上述較佳的定義之例子。 Preference is given to those examples in which each of the groups has the above preferred definition.

特別優先選擇為那些其中基團中之各者具有上述更佳及/或最佳的定義之例子。 Particular preference is given to those examples in which each of the groups has the above-described better and/or best definition.

因此，特別佳的是製備式(Ia)化合物之方法，其中R1 代表甲基，R4 代表Br或Cl；m 為1；及Y 代表 Therefore, particularly preferred is a process for the preparation of a compound of formula (Ia) wherein R 1 represents a methyl group, R 4 represents Br or Cl; m is 1; and Y represents

其中Y係經由以「U」標識之鍵連接O，及Y係經由以「V」標識之鍵連接CR1部分。 Wherein Y is connected to O via a key identified by "U", and Y is connected to the CR 1 portion via a key identified by "V".

在上下式中所給出之符號的定義中，使用概括代表下列取代基之集合術語： In the definition of the symbols given in the upper and lower formulas, a collective term that summarizes the following substituents is used:

定義C1-C6-烷基包含在此就烷基所定義之最大範圍。特定言之，此定義包含下列含義：甲基、乙基、正丙基、異丙基、正丁基、異丁基、二級 丁基、三級丁基及亦於各例子中包含所有的異構性戊基和己基，諸如甲基、乙基、丙基、1-甲基乙基、丁基、1-甲基丙基、2-甲基丙基、1,1-二甲基乙基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、1,2-二甲基丙基、1,1-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、正己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基、1,1,2-三甲基丙基、1,2,2-三甲基丙基、1-乙基丁基、2-乙基丁基、1-乙基-3-甲基丙基，特別為丙基、1-甲基乙基、丁基、1-甲基丁基、2-甲基丁基、3-甲基丁基、1,1-二甲基乙基、1,2-二甲基丁基、1,3-二甲基丁基、正戊基、1-甲基丁基、1-乙基丙基、己基、3-甲基戊基。較佳的範圍為C1-C4-烷基，諸如甲基、乙基、正丙基、異丙基、正丁基、異丁基、二級丁基、三級丁基。定義C1-C2-烷基包含甲基和乙基。 The definition C 1 -C 6 -alkyl includes the maximum range defined herein for the alkyl group. In particular, this definition includes the following meanings: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, dibutyl, tert-butyl and also included in each case. Isomers pentyl and hexyl, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethyl Base, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2 - dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-di Methyl butyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-di Methyl butyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-3- Methyl propyl, especially propyl, 1-methylethyl, butyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylethyl 1,2-dimethylbutyl, 1,3-dimethylbutyl, n-pentyl, 1-methylbutyl, 1-ethylpropyl, hexyl, 3- Methyl amyl. A preferred range is C 1 -C 4 -alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tert-butyl. Definitions C 1 -C 2 -alkyl includes methyl and ethyl.

定義鹵素包含氟、氯、溴和碘。 The halogen is defined to include fluorine, chlorine, bromine and iodine.

經鹵素取代之烷基(例如以鹵烷基(halogenalkyl)、鹵烷基(halogenoalkyl)或鹵烷基(haloalkyl)提及，例如C1-C4-鹵烷基或C1-C2-鹵烷基)代表經一或多個可相同或不同的鹵素取代基取代之如上文定義之例如C1-C4-烷基或C1-C2-烷基。C1-C4-鹵烷基較佳地代表氯甲基、二氯甲基、三氯甲基、氟甲基、二氟甲基、三氟甲基、氯氟甲基、二氯氟甲基、氯二氟甲基、1-氟乙基、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、2-氯-2-氟乙基、2-氯-2,2-二氟乙基、2,2-二氯-2-氟乙基、2,2,2-三氯乙基、1,1-二氟乙基、五氟乙基、1-氟-1-甲基乙基、2-氟-1,1-二甲基乙基、2-氟-1-氟甲基-1-甲基乙基、2-氟-1,1-二(氟甲基)-乙基、1-氯丁基。C1-C2-鹵烷基較佳地代表氯甲基、二氯甲基、三氯甲基、氟甲基、二氟甲基、三氟甲基、氯氟甲基、二氯氟甲基、氯二氟甲基、1-氟乙基、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、2-氯-2-氟乙基、2-氯-2,2-二氟乙基、2,2-二氯-2-氟乙基、2,2,2-三氯乙基、1,1-二氟乙基、五氟乙基。 A halogen-substituted alkyl group (for example, a haloalkyl, a halotoalkyl or a haloalkyl group such as a C 1 -C 4 -haloalkyl group or a C 1 -C 2 -halogen) the alkyl group as defined above) substituted with one or more representatives may be the same or different halo substituents for example of C 1 -C 4 - alkyl or C 1 -C 2 - alkyl. C 1 -C 4 -haloalkyl preferably represents chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoro , chlorodifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-Chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 1,1-difluoroethyl, pentafluoroethyl , 1-fluoro-1-methylethyl, 2-fluoro-1,1-dimethylethyl, 2-fluoro-1-fluoromethyl-1-methylethyl, 2-fluoro-1,1 - bis(fluoromethyl)-ethyl, 1-chlorobutyl. C 1 -C 2 -haloalkyl preferably represents chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoro , chlorodifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-Chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 1,1-difluoroethyl, pentafluoroethyl .

單或多氟化C1-C4-烷基代表經一或多個氟取代基取代之如上文定義之例如C1-C4-烷基。單或多氟化C1-C4-烷基較佳地代表氟甲基、二氟甲基、三氟甲基、1-氟乙基、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、五氟乙基、 1-氟-1-甲基乙基、2-氟-1,1-二甲基乙基、2-氟-1-氟甲基-1-甲基乙基、2-氟-1,1-二(氟甲基)-乙基、1-甲基-3-三氟甲基丁基、3-甲基-1-三氟甲基丁基。 Mono- or polyfluorinated C 1 -C 4 -alkyl represents, for example, C 1 -C 4 -alkyl as defined above, substituted by one or more fluoro substituents. Mono- or polyfluorinated C 1 -C 4 -alkyl preferably represents fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethane Base, 2,2,2-trifluoroethyl, pentafluoroethyl, 1-fluoro-1-methylethyl, 2-fluoro-1,1-dimethylethyl, 2-fluoro-1-fluoro Methyl-1-methylethyl, 2-fluoro-1,1-di(fluoromethyl)-ethyl, 1-methyl-3-trifluoromethylbutyl, 3-methyl-1-tri Fluoromethylbutyl.

定義C2-C6-烯基包含在此就烯基所定義之最大範圍。特定言之，此定義包含下列含義：乙烯基、正丙烯基、異丙烯基、正丁烯基、異丁烯基、二級丁烯基、三級丁烯基及亦於各例子中包含所有的異構性戊烯基、己烯基、1-甲基-1-丙烯基、1-乙基-1-丁烯基。經鹵素取代之烯基(以C2-C6-鹵烯基提及)代表經一或多個可相同或不同的鹵素取代基取代之如上文定義之例如C2-C6-烯基。 The definition C 2 -C 6 -alkenyl embraces the maximum range defined herein for alkenyl. In particular, this definition includes the following meanings: vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, secondary butenyl, tert-butenyl and also includes all variants in each case. Constructed pentenyl, hexenyl, 1-methyl-1-propenyl, 1-ethyl-1-butenyl. Alkenyl group substituted with halogen (in C 2 -C 6 - haloalkenyl and mentioned for) by one or more representatives may be the same or different halogen substituents of the group as hereinbefore defined, for example, C 2 -C 6 - alkenyl.

定義C2-C6-炔基包含在此就炔基所定義之最大範圍。特定言之，此定義包含下列含義：乙炔基、正丙炔基、異丙炔基、正丁炔基、異丁炔基、二級丁炔基、三級丁炔基及亦於各例子中包含所有的異構性戊炔基、己炔基。經鹵素取代之炔基(以C2-C6-鹵炔基提及)代表經一或多個可相同或不同的鹵素取代基取代之如上文定義之例如C2-C6-炔基。 The definition C 2 -C 6 -alkynyl embraces the maximum range defined herein for alkynyl groups. In particular, this definition includes the following meanings: ethynyl, n-propynyl, isopropynyl, n-butynyl, isobutynyl, di-butynyl, tert-butynyl and also in each case Contains all isomeric pentynyl, hexynyl groups. As hereinbefore defined by one or more of the representative may be the same or different halogen substituents, for example, the C 2 -C 6 - alkynyl group substituted with halogen (halides and alkynyl Kittim to C 2 -C 6) - alkynyl.

定義C3-C8-環烷基包含具有3至8個碳環員的單環飽和烴基，諸如環丙基、環丁基、環戊基、環己基、環庚基和環辛基。 The C 3 -C 8 -cycloalkyl group is defined to include a monocyclic saturated hydrocarbon group having 3 to 8 carbon ring members such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

定義芳基包含芳族單、雙或三環狀環，例如苯基、萘基、蒽基(anthracenyl)(蒽基(anthryl))、菲基(phenanthracenyl)(菲基(phenanthryl))。 The aryl group is defined to include an aromatic mono-, bi- or tricyclic ring such as phenyl, naphthyl, anthracenyl (anthryl), phenanthracenyl (phenanthryl).

根據本發明之方法係在聚烷二醇的存在下進行。 The process according to the invention is carried out in the presence of a polyalkylene glycol.

聚烷二醇較佳地選自式(III)之聚烷二醇 其中R2 代表C2-C4-伸烷基，及o 為從2至200之整數；及其混合物。 The polyalkylene glycol is preferably selected from the group consisting of polyalkylene glycols of formula (III) Wherein R 2 represents a C 2 -C 4 -alkylene group, and o is an integer from 2 to 200; and mixtures thereof.

R2 較佳地代表伸乙基、正伸丙基或四亞甲基，更佳地代表伸乙基。 R 2 preferably represents an exoethyl, n-propyl or tetramethylene group, more preferably an exoethyl group.

o 較佳為從2至150，更佳為從2至100，甚至更佳為2至50、3至40、4至30、4至20或4至15，最佳為4至10之整數。 o is preferably from 2 to 150, more preferably from 2 to 100, even more preferably from 2 to 50, from 3 to 40, from 4 to 30, from 4 to 20 or from 4 to 15, most preferably from 4 to 10.

有可能僅使用一種特定的聚烷二醇，然而亦可使用具有不同的R2及/ 或o之不同的聚烷二醇之混合物。所使用之聚烷二醇較佳地具有不同的o，亦即重複單元數目。 It is possible to use only one specific polyalkylene glycol, but it is also possible to use a mixture of polyalkylene glycols having different R 2 and/or o differences. The polyalkylene glycols used preferably have different o, i.e. the number of repeating units.

特別佳的聚烷二醇係選自四乙二醇及市場上以PEG 400取得的聚乙二醇。後者為式(III)化合物之混合物，其中R2為伸乙基及平均的重複單元數目為約8.2至9.1，得到約380至420克/莫耳之平均分子量Mn(凝膠滲透層析術(GPC)，聚苯乙烯標準物)。 A particularly preferred polyalkylene glycol is selected from the group consisting of tetraethylene glycol and polyethylene glycol commercially available as PEG 400. The latter is a mixture of compounds of formula (III), wherein R 2 is ethyl, and extending the average number of repeating units is from about 8.2 to 9.1, to obtain about 380-420 g / mole average molecular weight of M n (gel permeation chromatography technique (GPC), polystyrene standards).

聚烷二醇較佳地以反應混合物總重量為基準計至少2重量%之量存在，更佳為3至80重量%之量，甚至更佳為4至20重量%之量，及最佳為5至15重量%之量，每次係以反應混合物總重量為基準計。如果有超過一個以上的聚烷二醇存在，則所給出之量係指所有的聚烷二醇量之總和。 The polyalkylene glycol is preferably present in an amount of at least 2% by weight, based on the total weight of the reaction mixture, more preferably from 3 to 80% by weight, even more preferably from 4 to 20% by weight, and most preferably The amount is from 5 to 15% by weight, based on the total weight of the reaction mixture. If more than one polyalkylene glycol is present, the amount given is the sum of all of the polyalkylene glycol amounts.

有可能進行本方法而不添加任何溶劑，特別地若使用在方法條件下為液體的聚烷二醇。 It is possible to carry out the process without adding any solvent, in particular if a polyalkylene glycol which is liquid under the process conditions is used.

然而，較佳的是在C1-C10-醇的存在下進行根據本發明之方法，該醇較佳為正丁醇、正丙醇、異丙醇、乙醇、甲醇或其混合物，特別佳為正丁醇。 However, it is preferred to carry out the process according to the invention in the presence of a C 1 -C 10 -alcohol, preferably n-butanol, n-propanol, isopropanol, ethanol, methanol or mixtures thereof, particularly preferably It is n-butanol.

聚烷二醇及C1-C10-醇之體積比較佳為1：1至1：40，更佳為1：2至1：20，及最佳為1：3至1：10。如果有超過一個以上的聚烷二醇及/或有超過一個以上的C1-C10-醇存在，則所給出之比係指所有的聚烷二醇類之體積總和及所有的C1-C10-醇類之體積總和。 The volume of the polyalkylene glycol and the C 1 -C 10 -alcohol is preferably from 1:1 to 1:40, more preferably from 1:2 to 1:20, and most preferably from 1:3 to 1:10. If more than one polyalkylene glycol is present and/or more than one C 1 -C 10 -alcohol is present, the ratio given is the sum of all the polyalkylene glycols and all C 1 -C 10 - the sum of the volumes of the alcohols.

有可能在額外的有機溶劑存在下進行根據本發明之方法，該溶劑較佳地選自四氫呋喃、甲基四氫呋喃(特別為2-甲基四氫呋喃、二***、環戊基甲醚、三級丁基甲醚、甲苯、N-甲基吡咯啶酮(NMP)、二甲基甲醯胺(DMF)及其混合物。然而，較佳地沒有額外的有機溶劑存在，亦即除了聚烷二醇以外，僅C1-C10-醇係作為有機溶劑存在。 It is possible to carry out the process according to the invention in the presence of an additional organic solvent, preferably selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran (especially 2-methyltetrahydrofuran, diethyl ether, cyclopentyl methyl ether, tertiary butyl methyl ether) , toluene, N-methylpyrrolidone (NMP), dimethylformamide (DMF), and mixtures thereof. However, preferably no additional organic solvent is present, ie, except for the polyalkylene glycol, only C The 1 -C 10 -alcohol is present as an organic solvent.

根據本發明之方法係在鹼的存在下進行。 The process according to the invention is carried out in the presence of a base.

該等鹼較佳地包括鹼金屬或鹼土金屬乙酸鹽、胺化物、碳酸鹽、碳酸氫鹽、氫化物、氫氧化物或醇鹽，例如乙酸鈉、乙酸鉀或乙酸鈣、胺化鋰、胺化鈉、胺化鉀或胺化鈣、碳酸鈉、碳酸鉀或碳酸鈣、碳酸氫鈉、碳酸氫鉀或碳酸氫鈣、氫化鋰、氫化鈉、氫化鉀或氫化鈣、氫氧化鋰、氫氧化鈉、氫氧化鉀或氫氧化鈣、正丁基鋰、二級丁基鋰、三級丁基鋰、二異丙基胺 化鋰、雙(三甲基矽基)胺化鋰、甲醇鈉、乙醇鈉、正或異丙醇鈉、正丁醇鈉、異丁醇鈉、二級丁醇鈉或三級丁醇鈉或甲醇鉀、乙醇鉀、正或異丙醇鉀、正丁醇鉀、異丁醇鉀、二級丁醇鉀或三級丁醇鉀；及亦包括鹼性有機氮化合物，例如三甲胺、三乙胺、三丙胺、三丁胺、乙基二異丙胺、N,N-二甲基環己胺、二環己胺、乙基二環己胺、N,N-二甲基苯胺、N,N-二甲基苯甲胺、吡啶、2-甲基吡啶、3-甲基吡啶、4-甲基吡啶、2,4-二甲基吡啶、2,6-二甲基吡啶、3,4-二甲基吡啶和3,5-二甲基吡啶、5-乙基-2-甲基吡啶、4-二甲基胺基吡啶、N-甲基哌啶、1,4-二氮雜雙環[2.2.2]-辛烷(DABCO)、1,5-二氮雜雙環[4.3.0]-壬-5-烯(DBN)或1,8-二氮雜雙環[5.4.0]-十一-7-烯(DBU)。 The bases preferably include alkali metal or alkaline earth metal acetates, amines, carbonates, hydrogencarbonates, hydrides, hydroxides or alkoxides such as sodium acetate, potassium acetate or calcium acetate, lithium amination, amines Sodium, potassium or calcium amination, sodium carbonate, potassium carbonate or calcium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or calcium hydrogencarbonate, lithium hydride, sodium hydride, potassium hydride or calcium hydride, lithium hydroxide, hydroxide Sodium, potassium hydroxide or calcium hydroxide, n-butyllithium, secondary butyllithium, tertiary butyllithium, diisopropylamine Lithium, lithium bis(trimethyldecyl) amination, sodium methoxide, sodium ethoxide, sodium or isopropoxide, sodium n-butoxide, sodium isobutoxide, sodium secondary butoxide or sodium butoxide or Potassium methoxide, potassium ethoxide, potassium or isopropoxide, potassium n-butoxide, potassium isobutoxide, potassium secondary butanolate or potassium butoxide; and basic organic nitrogen compounds such as trimethylamine, triethyl Amine, tripropylamine, tributylamine, ethyldiisopropylamine, N,N-dimethylcyclohexylamine, dicyclohexylamine, ethyldicyclohexylamine, N,N-dimethylaniline, N,N - dimethyl benzylamine, pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2,4-dimethylpyridine, 2,6-lutidine, 3,4- Lutidine and 3,5-lutidine, 5-ethyl-2-methylpyridine, 4-dimethylaminopyridine, N-methylpiperidine, 1,4-diazabicyclo[ 2.2.2]-octane (DABCO), 1,5-diazabicyclo[4.3.0]-non-5-ene (DBN) or 1,8-diazabicyclo[5.4.0]- eleven -7-ene (DBU).

鹼較佳地選自Na2CO3、K2CO3、Cs2CO3、NaOH、KOH、KOtBu、NaH及其混合物，更佳地選自KOH、K2CO3、Cs2CO3及其混合物。 The base is preferably selected from the group consisting of Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH, KOtBu, NaH and mixtures thereof, more preferably selected from the group consisting of KOH, K 2 CO 3 , Cs 2 CO 3 and mixture.

在根據本發明之方法特別的具體例中，使用1H-1,2,4-***之鈉或鉀鹽作為鹼。該鈉或鉀鹽可藉由將1H-1,2,4-***與鈉或鉀鹼反應而製備，該鈉或鉀鹼較佳地分別選自NaOH、NaH及Na-醇化物或KOH及K-醇化物。在此具體例中，1H-1,2,4-***之鈉或鉀鹽係作為鹼及1H-1,2,4-***起作用，亦即1H-1,2,4-***及鹼部分或完全以1H-1,2,4-***之鈉或鉀鹽替換。在此具體例中，1H-1,2,4-***及鹼較佳地部分以1H-1,2,4-***之鈉或鉀鹽替換。 In a particular embodiment of the process according to the invention, the sodium or potassium salt of 1H-1,2,4-triazole is used as the base. The sodium or potassium salt can be prepared by reacting 1H-1,2,4-triazole with a sodium or potassium base, preferably selected from the group consisting of NaOH, NaH and Na-alcohol or KOH, respectively. K-alcoholate. In this specific example, the sodium or potassium salt of 1H-1,2,4-triazole acts as a base and 1H-1,2,4-triazole, ie 1H-1,2,4-triazole The base is partially or completely replaced with sodium or potassium salt of 1H-1,2,4-triazole. In this embodiment, the 1H-1,2,4-triazole and base are preferably partially replaced with the sodium or potassium salt of 1H-1,2,4-triazole.

鹼及式(II)之環氧乙烷的莫耳比較佳為0.1：1至2：1，更佳為0.2：1至0.6：1，及最佳為0.35：1至0.45：1。如果有超過一個以上的式(II)之環氧乙烷及/或有超過一個以上的鹼存在，則所給出之比係指所有的式(II)之環氧乙烷的莫耳量總和及所有的鹼的莫耳量總和。 The molar ratio of the base and the ethylene oxide of the formula (II) is preferably from 0.1:1 to 2:1, more preferably from 0.2:1 to 0.6:1, and most preferably from 0.35:1 to 0.45:1. If more than one of the ethylene oxides of formula (II) and/or more than one base are present, the ratio given is the sum of the molar amounts of all of the ethylene oxides of formula (II). And the sum of the molar amounts of all the bases.

1H-1,2,4-***與式(II)之環氧乙烷較佳地以0.8：1至4：1，更佳地以0.9：1至3：1.，最佳地以1：1至2：1之莫耳比反應。如果有超過一個以上的式(II)之環氧乙烷存在，則所給出之比係指所有的式(II)之環氧乙烷的莫耳量總和。 The 1H-1,2,4-triazole and the ethylene oxide of the formula (II) are preferably from 0.8:1 to 4:1, more preferably from 0.9:1 to 3:1, most preferably 1 : 1 to 2:1 molar ratio reaction. If more than one ethylene oxide of formula (II) is present, the ratio given is the sum of the molar amounts of all of the ethylene oxides of formula (II).

本方法較佳地在20℃至150℃，更佳為120℃至150℃，及最佳為120℃至140℃之溫度下進行。 The process is preferably carried out at a temperature of from 20 ° C to 150 ° C, more preferably from 120 ° C to 150 ° C, and most preferably from 120 ° C to 140 ° C.

根據本發明之方法的反應時間係取決於反應規模及反應溫度而不等， 但是通常介於幾分鐘(例如5分鐘)與48小時之間。 The reaction time according to the method of the present invention varies depending on the reaction scale and the reaction temperature. But usually between a few minutes (for example 5 minutes) and 48 hours.

根據本發明之方法通常係在標準壓力下(1大氣壓)進行。然而，亦有可能在升壓或減壓下操作。 The process according to the invention is generally carried out under standard pressure (1 atm). However, it is also possible to operate under boost or decompression.

來自根據本發明之方法的所得反應混合物可以此項技術中概括已知的程序整理。較佳地在完成反應之後，將所有的揮發性化合物在減壓下蒸發且將殘餘物再溶解於適合的有機溶劑(如乙酸乙酯)中。添加水及pH(室溫)以引入強酸(如濃縮水性氫氯酸)調整至約6。將水相以適合的有機溶劑(如乙酸乙酯)萃取且將合併的有機相較佳經為經硫酸鎂乾燥。較佳地移除有機溶劑且將所得粗製產物以已知的技術進一步純化，例如再結晶或層析術。 The resulting reaction mixture from the process according to the invention can be prepared by procedures generally known in the art. Preferably, after completion of the reaction, all volatile compounds are evaporated under reduced pressure and the residue is redissolved in a suitable organic solvent such as ethyl acetate. Water and pH (room temperature) were added to introduce a strong acid (such as concentrated aqueous hydrochloric acid) to about 6. The aqueous phase is extracted with a suitable organic solvent such as ethyl acetate and the combined organic phases are preferably dried over magnesium sulfate. The organic solvent is preferably removed and the resulting crude product is further purified by known techniques, such as recrystallization or chromatography.

1H-1,2,4-***係自市場來源輕易地取得。 1H-1,2,4-triazole is readily available from market sources.

式(II)之環氧乙烷可以類似於已知的先前技術方法之各種途徑獲得，特別以WO 2017/029179 A1所揭示之方法B。 The ethylene oxide of the formula (II) can be obtained in a manner similar to the various routes of the known prior art methods, in particular the method B disclosed in WO 2017/029179 A1.

獲得特定的式(II)之環氧乙烷的較佳方法於下文概述。較佳地，在根據本發明之方法中，式(IIa)之環氧乙烷係使用此程序獲得： A preferred method of obtaining a particular ethylene oxide of formula (II) is outlined below. Preferably, in the process according to the invention, the ethylene oxide of formula (IIa) is obtained using this procedure:

在本方法之步驟A)中，式(IV)化合物之製備係如下： 其中R’ 代表氫、C1-C2-鹵烷基、C1-C2-鹵烷氧基、C1-C2-烷基羰基、氟或氯；及X 代表氟或氯；將式(V)化合物 其中R’ 係如式(IV)所定義；與氯化氫在三氧化二氮或有機亞硝酸酯的存在下反應。 In step A) of the process, the preparation of the compound of formula (IV) is as follows: Wherein R' represents hydrogen, C 1 -C 2 -haloalkyl, C 1 -C 2 -haloalkoxy, C 1 -C 2 -alkylcarbonyl, fluoro or chloro; and X represents fluoro or chloro; (V) compound Wherein R' is as defined in formula (IV); it is reacted with hydrogen chloride in the presence of dinitrogen trioxide or an organic nitrite.

較佳地使用氣態氯化氫。這意指氯化氫係以氣態添加且在特定的反應 條件下維持在氣態。 Gaseous hydrogen chloride is preferably used. This means that hydrogen chloride is added in a gaseous state and in a specific reaction. Maintained in a gaseous state under conditions.

步驟A)較佳地在從0至30℃之溫度及從0.5至2巴之壓力下進行。 Step A) is preferably carried out at a temperature of from 0 to 30 ° C and a pressure of from 0.5 to 2 bar.

步驟A)較佳地在溶劑的存在下進行，該溶劑較佳地選自二氯甲烷、三氯甲烷、四氯甲烷、1,2-二氯乙烷、1,1,1-三氯乙烷、1,1,2-三氯乙烷、環己烷、甲基環己烷、庚烷、己烷、三氟甲基苯、4-氯-三氟甲基苯、氯苯、1,2-二氯苯、1,3-二氯苯、乙酸、三氟乙酸、硝苯、四氫呋喃、甲基四氫呋喃(特別為2-甲基四氫呋喃)、二烷、乙腈、二***、環丙基甲醚、三級丁基甲醚、甲苯、二甲基甲醯胺(DMF)及其混合物，更佳地選自二氯甲烷、1,2-二氯乙烷、環己烷、硝苯、氯苯、二烷、三氟甲基苯、4-氯-三氟甲基苯、2-甲基四氫呋喃、乙酸、環丙基甲醚及其混合物。 Step A) is preferably carried out in the presence of a solvent, preferably selected from the group consisting of dichloromethane, chloroform, tetrachloromethane, 1,2-dichloroethane, 1,1,1-trichloroethane. Alkane, 1,1,2-trichloroethane, cyclohexane, methylcyclohexane, heptane, hexane, trifluoromethylbenzene, 4-chloro-trifluoromethylbenzene, chlorobenzene, 1, 2-Dichlorobenzene, 1,3-dichlorobenzene, acetic acid, trifluoroacetic acid, nifedipine, tetrahydrofuran, methyltetrahydrofuran (especially 2-methyltetrahydrofuran), two Alkane, acetonitrile, diethyl ether, cyclopropyl methyl ether, tertiary butyl methyl ether, toluene, dimethylformamide (DMF) and mixtures thereof, more preferably selected from dichloromethane, 1,2-dichloroethane , cyclohexane, nifedipine, chlorobenzene, two Alkanes, trifluoromethylbenzene, 4-chloro-trifluoromethylbenzene, 2-methyltetrahydrofuran, acetic acid, cyclopropyl methyl ether, and mixtures thereof.

有機亞硝酸酯較佳地選自亞硝酸甲酯、亞硝酸乙酯、亞硝酸異丙酯、亞硝酸異丁酯和亞硝酸三級丁酯。較佳為亞硝酸三級丁酯。 The organic nitrite is preferably selected from the group consisting of methyl nitrite, ethyl nitrite, isopropyl nitrite, isobutyl nitrite and tertiary butyl nitrite. Preferred is butyl nitrite.

隨後，式(VI)化合物之製備係如下： 其中R1’ 代表C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C3-C8-環烷基、C3-C8-環烷基-C1-C4-烷基、苯基、苯基-C1-C4-烷基、苯基-C2-C4-烯基或苯基-C2-C4-炔基；及R和X 係如式(IV)所定義；將式(IV)化合物在第一步驟B)中與式(VII)化合物反應R’’MgZ (VII)，其中R’’ 代表C1-C6-烷基或C3-C8-環烷基；及Z 代表氯或溴；且將步驟C)的所得產物與式(VIII)之酐反應 其中R1’ 係如式(VI)所定義。 Subsequently, the preparation of the compound of formula (VI) is as follows: Wherein R 1 ' represents C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkane -C 1 -C 4 -alkyl, phenyl, phenyl-C 1 -C 4 -alkyl, phenyl-C 2 -C 4 -alkenyl or phenyl-C 2 -C 4 -alkynyl; and R and X are as based formula (IV) as defined above; a compound of formula (IV) the reaction R''MgZ (VII) with a compound of formula (VII) in a first step) B, where R '' represents C 1 -C 6 -alkyl or C 3 -C 8 -cycloalkyl; and Z represents chlorine or bromine; and reacts the obtained product of step C) with an anhydride of formula (VIII) Wherein R 1 ' is as defined in formula (VI).

在步驟B)中，將式(IV)化合物與格任亞(Grignard)試劑反應。格任亞試劑係以式(VII)代表。然而，如熟習此項技術者概括已知，格任亞化合物在不同的鎂化合物之間經歷溶劑依賴性平衡，其可以所謂的史蘭克(Schlenck)平衡說明。根據式(VII)之格任亞試劑的史蘭克平衡可如下以流程例證：2 R"MgZ(R")2Mg+MgZ2 (R")2Mg * MgZ2 In step B), the compound of formula (IV) is reacted with a Grignard reagent. The Grenya reagent is represented by the formula (VII). However, as is generally known to those skilled in the art, the Grenium compound undergoes a solvent-dependent equilibrium between different magnesium compounds, which can be illustrated by the so-called Schlenck equilibrium. The Rank balance according to the formula (VII) can be as follows: 2 R"MgZ (R") 2 Mg+MgZ 2 (R") 2 Mg * MgZ 2

此外，已知常用於與格任亞試劑反應的溶劑分子(特別為醚，諸如二***或THF)可添加至格任亞試劑之鎂中，由此形成醚化物。因此，式(VII)不僅包含如描述之結構，且亦包含起因於史蘭克平衡以及各個溶劑加成物之結構。 Further, it is known that a solvent molecule (particularly an ether such as diethyl ether or THF) which is commonly used for the reaction with a genomic reagent can be added to the magnesium of the genomic reagent, thereby forming an etherate. Therefore, the formula (VII) includes not only the structure as described, but also the structure resulting from the balance of the slant and the respective solvent adducts.

關於格任亞試劑之結構的概括訊息，亦參見Milton Orchin,Journal of Chemical Education,Volume 66,Number 7,1999，第586至588頁。 For a summary of the structure of the Grenada reagent, see Milton Orchin, Journal of Chemical Education, Volume 66, Number 7, 1999, pp. 586-588.

最後，式(VI)化合物進一步反應成式(IIa)之環氧乙烷衍生物 其中R’和R1’ 係如式(VI)所定義；及R4和m 係如式(I)所定義；其中式(VI)化合物反應成式(IIa)之環氧乙烷衍生物包含下列步驟：步驟D)：將式(VI)化合物與式(IX)之酚衍生物 其中R4和m 係如式(I)所定義；在鹼的存在下反應成式(X)化合物 其中R’、R1’、R4和m 係如式(IIa)所定義；及步驟E)：將式(X)化合物與鹵化三甲基氧化鋶(sulfoxonium)、鹵化三甲基鋶、甲基硫酸三甲基氧化鋶或甲基硫酸三甲基鋶反應成式(IIa)之環氧化物。 Finally, the compound of formula (VI) is further reacted to the ethylene oxide derivative of formula (IIa). Wherein R' and R 1 ' are as defined in formula (VI); and R 4 and m are as defined in formula (I); wherein the compound of formula (VI) is reacted to form an oxirane derivative of formula (IIa) comprising The following steps: Step D): a compound of formula (VI) and a phenol derivative of formula (IX) Wherein R 4 and m are as defined in formula (I); reacting in the presence of a base to form a compound of formula (X) Wherein R', R 1 ' , R 4 and m are as defined in formula (IIa); and step E): compound of formula (X) with trimethylsulfoxonium halide, trimethylsulfonium halide, a The trimethyl sulfonium sulfate or trimethyl sulfonium methyl sulfate is reacted to form an epoxide of the formula (IIa).

上文所給出之式提供在獲得式(IIa)之環氧乙烷之方法中所涉及的化合物之概括定義。該式關於R4和m之較佳的基團定義係於上文給出及關於R’、R1’、Z和R’’之較佳的基團定義係於下文給出。該等定義適用於攜有各個基團的式(IIa)之環氧乙烷且同樣適用於所有的析出物及中間物。 The formula given above provides a general definition of the compounds involved in the process for obtaining the ethylene oxide of formula (IIa). Preferred group definitions for R 4 and m are given below and the preferred group definitions for R', R 1 ' , Z and R'' are given below. These definitions apply to the ethylene oxide of formula (IIa) carrying the various groups and are equally applicable to all precipitates and intermediates.

R’ 較佳地代表C1-C2-鹵烷基或C1-C2-鹵烷氧基。 R' preferably represents a C 1 -C 2 -haloalkyl group or a C 1 -C 2 -haloalkoxy group.

R’ 更佳地代表C1-鹵烷基。 R' more preferably represents a C 1 -haloalkyl group.

R’ 更佳地代表CF3、CHF2、CH2F、OCF3、OCHF2或OCH2F。 R' more preferably represents CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 or OCH 2 F.

R’ 最佳地代表CF3。 R' best represents CF 3 .

R1’ 較佳地代表C1-C4-烷基、C2-C6-烯基、C2-C6-炔基、環丙基、苯基、苯甲基、苯基乙烯基或苯基乙炔基。 R 1 ' preferably represents C 1 -C 4 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, cyclopropyl, phenyl, benzyl, phenylvinyl or Phenylethynyl.

R1’ 更佳地代表甲基、乙基、丙基、異丙基、丁基、環丙基、CF3、烯丙基、CH2C≡C-CH3或CH2C≡CH。 R 1 'more preferably represents methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, CF 3 , allyl, CH 2 C≡C-CH 3 or CH 2 C≡CH.

R1’ 更佳地代表甲基、乙基、丙基、異丙基、丁基或環丙基。 R 1 'more preferably represents methyl, ethyl, propyl, isopropyl, butyl or cyclopropyl.

R1’ 更佳地代表甲基或乙基。 R 1 'more preferably represents methyl or ethyl.

R1’ 最佳地代表甲基。 R 1 'is best represented by a methyl group.

Z 最佳地代表氯。 Z best represents chlorine.

R’’ 較佳地代表C1-C4-烷基或C2-C6-環烷基。 R'' preferably represents a C 1 -C 4 -alkyl group or a C 2 -C 6 -cycloalkyl group.

R’’ 更佳地代表甲基、乙基、丙基、異丙基、丁基或環丙基。 R'' more preferably represents methyl, ethyl, propyl, isopropyl, butyl or cyclopropyl.

R’’ 更佳地代表甲基、乙基、丙基、異丙基或丁基。 R'' more preferably represents methyl, ethyl, propyl, isopropyl or butyl.

R’’ 最佳地代表異丙基。 R'' best represents isopropyl.

在步驟B)中，可形成以式(IV-Gr)及/或(IV-Br)代表的格任亞化合物， 其中R’、X和Z係如上文概述所定義。 In the step B), a genino compound represented by the formula (IV-Gr) and/or (IV-Br) may be formed. Wherein R', X and Z are as defined above in the Summary.

如上文關於式(VII)之格任亞試劑所概述，格任亞化合物通常在不同的鎂化合物之間經歷溶劑依賴性平衡，其可以所謂的史蘭克平衡說明。上述各個標註就實際情況適用於式(IV-Gr)和(IV-Br)化合物。 As outlined above with respect to the sub-reagent of formula (VII), the Grenium compound typically undergoes a solvent-dependent equilibrium between the different magnesium compounds, which can be illustrated by the so-called Schalke equilibrium. The above various labels apply to the compounds of the formulae (IV-Gr) and (IV-Br) as appropriate.

通常可整理來自步驟B)的所得反應產物，例如以便於分離、濃縮、稀釋或純化格任亞化合物或其溶液或懸浮液。然而，較佳的是進行步驟B)和步驟C)而無需任何處理，如分離或純化來自步驟B)的所得反應產物。特別佳的是添加來自步驟B)的所得反應混合物至式(VIII)之酐中。 The resulting reaction product from step B) can generally be trimmed, for example, to facilitate separation, concentration, dilution or purification of the Grenium compound or a solution or suspension thereof. However, it is preferred to carry out step B) and step C) without any treatment, such as separation or purification of the resulting reaction product from step B). It is especially preferred to add the resulting reaction mixture from step B) to the anhydride of formula (VIII).

步驟B)和C)較佳地在非質子性溶劑的存在下進行，該溶劑較佳地選自四氫呋喃、甲基四氫呋喃(特別為2-甲基四氫呋喃)、二***、環丙基甲醚、三級丁基甲醚、甲苯及其混合物，更佳為四氫呋喃、甲苯及其混合物。 Steps B) and C) are preferably carried out in the presence of an aprotic solvent, preferably selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran (particularly 2-methyltetrahydrofuran), diethyl ether, cyclopropyl methyl ether, Tert-butyl butyl methyl ether, toluene and mixtures thereof, more preferably tetrahydrofuran, toluene and mixtures thereof.

步驟B)和C)較佳地在-30℃至50℃，較佳為-10℃至10℃之溫度下進行。 Steps B) and C) are preferably carried out at a temperature of from -30 ° C to 50 ° C, preferably from -10 ° C to 10 ° C.

式(IV)化合物與式(VII)化合物較佳地以1：0.8至1：1.5，更佳地以1：0.9至1：1.4，更佳地以約1：1至1：1.3，最佳地以1：1至1：1.1之莫耳比反應。 The compound of the formula (IV) and the compound of the formula (VII) are preferably from 1:0.8 to 1:1.5, more preferably from 1:0.9 to 1:1.4, still more preferably from about 1:1 to 1:1.3. The ground reacts with a molar ratio of 1:1 to 1:1.1.

式(VII)之格任亞試劑較佳地以非質子性溶劑中的溶液，特別地以四氫呋喃中的溶液，特別佳地以四氫呋喃中的1.0至3.0莫耳溶液使用。 The argon reagent of the formula (VII) is preferably used in a solution in an aprotic solvent, in particular in tetrahydrofuran, particularly preferably in a 1.0 to 3.0 molar solution in tetrahydrofuran.

式(VII)之格任亞試劑典型地以非質子性溶劑(較佳為四氫呋喃)中的溶液添加至含有式(IV)化合物及非質子性溶劑(較佳為甲苯)的反應容器或燒瓶中。 The arylene reagent of the formula (VII) is typically added to a reaction vessel or flask containing a compound of the formula (IV) and an aprotic solvent, preferably toluene, in a solution in an aprotic solvent, preferably tetrahydrofuran. .

式(IV)化合物及式(VIII)之酐的莫耳比較佳為1：1至1：2，更佳為1：1.05至1：1.8，更佳為1：1.1至1：1.5，最佳為1：1.1至1：1.3。 The molar amount of the compound of the formula (IV) and the anhydride of the formula (VIII) is preferably from 1:1 to 1:2, more preferably from 1:1.05 to 1:1.8, still more preferably from 1:1.1 to 1:1.5, most preferably It is 1:1.1 to 1:1.3.

步驟B)和步驟C)較佳地在無水條件下進行，較佳地在氬氣氛圍下。 Step B) and step C) are preferably carried out under anhydrous conditions, preferably under an argon atmosphere.

步驟C)較佳地在沒有銅觸媒的存在下進行，更佳地在沒有任何觸媒的存在下。甚至更佳的是亦沒有觸媒存在於步驟B)中。 Step C) is preferably carried out in the absence of a copper catalyst, more preferably in the absence of any catalyst. Even better, there is no catalyst present in step B).

來自步驟C)的所得反應混合物可以此項技術中概括已知的程序整理。 較佳地在反應完成之後，將反應混合物以添加水及/或氯化銨飽和水溶液淬滅，將所得有機相與水相分離，將水相以有機溶劑(較佳為甲苯)萃取，且將合併的有機相清洗(較佳地以NaCl飽和水溶液)，乾燥(較佳地經硫酸鎂)且過濾。所得式(VI)化合物溶液可直接用於步驟D)中。亦有可能分離式(VI)化合物，較佳地藉由蒸發有機溶劑，較佳地在減壓下。本方法得到高產率的式(VI)化合物。然而，若要求時，式(VI)化合物可以已知的技術進一步純化，例如蒸餾或層析術。 The resulting reaction mixture from step C) can be prepared by procedures generally known in the art. Preferably, after the reaction is completed, the reaction mixture is quenched with water and/or a saturated aqueous solution of ammonium chloride, the obtained organic phase is separated from the aqueous phase, and the aqueous phase is extracted with an organic solvent (preferably toluene), and The combined organic phases are washed (preferably with a saturated aqueous solution of NaCl), dried (preferably with magnesium sulfate) and filtered. The resulting solution of the compound of formula (VI) can be used directly in step D). It is also possible to isolate the compound of formula (VI), preferably by evaporation of the organic solvent, preferably under reduced pressure. This process yields a high yield of the compound of formula (VI). However, if desired, the compound of formula (VI) can be further purified by known techniques, such as distillation or chromatography.

步驟D)係在鹼的存在下進行。該等鹼較佳地包括鹼金屬或鹼土金屬乙酸鹽、胺化物、碳酸鹽、碳酸氫鹽、氫化物、氫氧化物或醇鹽，例如乙酸鈉、乙酸鉀或乙酸鈣、胺化鋰、胺化鈉、胺化鉀或胺化鈣、碳酸鈉、碳酸鉀或碳酸鈣、碳酸氫鈉、碳酸氫鉀或碳酸氫鈣、氫化鋰、氫化鈉、氫化鉀或氫化鈣、氫氧化鋰、氫氧化鈉、氫氧化鉀或氫氧化鈣、正丁基鋰、二級丁基鋰、三級丁基鋰、二異丙基胺化鋰、雙(三甲基矽基)胺化鋰、甲醇鈉、乙醇鈉、正或異丙醇鈉、正丁醇鈉、異丁醇鈉、二級丁醇鈉或三級丁醇鈉或甲醇鉀、乙醇鉀、正或異丙醇鉀、正丁醇鉀、異丁醇鉀、二級丁醇鉀或三級丁醇鉀；及亦包括鹼性有機氮化合物，例如三甲胺、三乙胺、三丙胺、三丁胺、乙基二異丙胺、N,N-二甲基環己胺、二環己胺、乙基二環己胺、N,N-二甲基苯胺、N,N-二甲基苯甲胺、吡啶、2-甲基吡啶、3-甲基吡啶、4-甲基吡啶、2,4-二甲基吡啶、2,6-二甲基吡啶、3,4-二甲基吡啶和3,5-二甲基吡啶、5-乙基-2-甲基吡啶、4-二甲基胺基吡啶、N-甲基哌啶、1,4-二氮雜雙環[2.2.2]-辛烷(DABCO)、1,5-二氮雜雙環[4.3.0]-壬-5-烯(DBN)或1,8-二氮雜雙環[5.4.0]-十一-7-烯(DBU)。 Step D) is carried out in the presence of a base. The bases preferably include alkali metal or alkaline earth metal acetates, amines, carbonates, hydrogencarbonates, hydrides, hydroxides or alkoxides such as sodium acetate, potassium acetate or calcium acetate, lithium amination, amines Sodium, potassium or calcium amination, sodium carbonate, potassium carbonate or calcium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or calcium hydrogencarbonate, lithium hydride, sodium hydride, potassium hydride or calcium hydride, lithium hydroxide, hydroxide Sodium, potassium hydroxide or calcium hydroxide, n-butyllithium, secondary butyllithium, tertiary butyllithium, lithium diisopropylamide, lithium bis(trimethyldecyl) amination, sodium methoxide, Sodium ethoxide, sodium or isopropoxide, sodium n-butoxide, sodium isobutoxide, sodium 2-butoxide or sodium butoxide or potassium methoxide, potassium ethoxide, potassium or potassium isopropoxide, potassium n-butoxide, Potassium isobutoxide, potassium 2-butoxide or potassium butoxide; and basic organic nitrogen compounds such as trimethylamine, triethylamine, tripropylamine, tributylamine, ethyldiisopropylamine, N,N - dimethylcyclohexylamine, dicyclohexylamine, ethyldicyclohexylamine, N,N-dimethylaniline, N,N-dimethylbenzylamine, pyridine, 2-methylpyridine, 3- methyl Pyridine, 4-methylpyridine, 2,4-dimethylpyridine, 2,6-lutidine, 3,4-dimethylpyridine and 3,5-lutidine, 5-ethyl-2 -methylpyridine, 4-dimethylaminopyridine, N-methylpiperidine, 1,4-diazabicyclo[2.2.2]-octane (DABCO), 1,5-diazabicyclo[ 4.3.0]-Indol-5-ene (DBN) or 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU).

鹼較佳地選自Na2CO3、K2CO3、Cs2CO3、NaOH、NaOMe、KOMe、KOtBu、NaH及其混合物，更佳地選自NaOMe、KOMe、K2CO3、Cs2CO3及其混合物。特別佳的鹼係選自KOMe和K2CO3。 The base is preferably selected from the group consisting of Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, NaOMe, KOMe, KOtBu, NaH and mixtures thereof, more preferably selected from NaOMe, KOMe, K 2 CO 3 , Cs 2 CO 3 and mixtures thereof. A particularly preferred base is selected from the group consisting of KOMe and K 2 CO 3 .

酚鹽親核劑可藉由使用上述鹼而現場產生或自式(IX)之酚衍生物及鹼製備且可能地在反應之前分離。當使用NaOMe或KOMe作為鹼以達成此製備時，則所產生的MeOH通常與所有或一部分的任何存在的溶劑一起蒸餾出。 The phenate nucleophile can be prepared in situ by using the above base or prepared from a phenol derivative of the formula (IX) and a base and possibly before the reaction. When NaOMe or KOMe is used as the base to achieve this preparation, the MeOH produced is usually distilled off together with all or a portion of any solvent present.

步驟D)較佳地在非質子性溶劑的存在下進行，該溶劑較佳地選自四氫呋喃、甲基四氫呋喃(特別為2-甲基四氫呋喃)、二***、環丙基甲醚、三級丁基甲醚、甲基異丁酮、甲基乙酮、甲苯、二甲基甲醯胺(DMF)、1-丙醇、2-丙醇、1-丁醇、聚烷二醇(特別為聚乙二醇(PEG))及其混合物。步驟D)更佳地在甲基異丁酮、甲基乙酮、甲苯、1-丙醇、2-丙醇、1-丁醇、PEG 400或其混合物存在下進行。反應最佳地在甲苯、1-丙醇、2-丙醇、1-丁醇、PEG 400或其任何混合物的存在下進行。 Step D) is preferably carried out in the presence of an aprotic solvent, preferably selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran (particularly 2-methyltetrahydrofuran), diethyl ether, cyclopropyl methyl ether, tertiary butyl group Ether, methyl isobutyl ketone, methyl ethyl ketone, toluene, dimethylformamide (DMF), 1-propanol, 2-propanol, 1-butanol, polyalkylene glycol (especially polyethylene Alcohol (PEG)) and mixtures thereof. Step D) is more preferably carried out in the presence of methyl isobutyl ketone, methyl ethyl ketone, toluene, 1-propanol, 2-propanol, 1-butanol, PEG 400 or a mixture thereof. The reaction is carried out optimally in the presence of toluene, 1-propanol, 2-propanol, 1-butanol, PEG 400 or any mixture thereof.

反應在適合的觸媒存在下更快完成。因此，步驟C)較佳地在觸媒的存在下進行，較佳為1,4-二氮雜雙環[2.2.2]-辛烷(DABCO)。觸媒較佳地以式(VI)化合物的量為基礎計從1至20莫耳%的量存在。 The reaction is completed faster in the presence of a suitable catalyst. Thus, step C) is preferably carried out in the presence of a catalyst, preferably 1,4-diazabicyclo[2.2.2]-octane (DABCO). The catalyst is preferably present in an amount of from 1 to 20 mol% based on the amount of the compound of formula (VI).

在步驟D)中所使用的試劑較佳地在室溫(23℃)下混合。在試劑混合之後，較佳地溫度增加。步驟D)較佳地在從30℃至150℃，較佳地在50℃至100℃之升溫下進行。 The reagent used in step D) is preferably mixed at room temperature (23 ° C). Preferably, the temperature increases after the reagents are mixed. Step D) is preferably carried out at a temperature of from 30 ° C to 150 ° C, preferably from 50 ° C to 100 ° C.

來自步驟D)的所得反應混合物可以此項技術中概括已知的程序整理。較佳地在反應完成之後，將反應混合物以添加水及/或氯化銨飽和水溶液淬滅，將所得有機相與水相分離，將水相以有機溶劑(較佳為甲苯)萃取，且將合併的有機相清洗(較佳地以NaCl飽和水溶液)，乾燥(較佳地經硫酸鎂)且過濾。所得式(X)化合物溶液或藉由蒸發有機溶劑而獲得的粗製產物可直接用於步驟E)中。然而，若要求時，式(X)化合物可以已知的技術進一步純化，例如再結晶或層析術。 The resulting reaction mixture from step D) can be prepared by procedures generally known in the art. Preferably, after the reaction is completed, the reaction mixture is quenched with water and/or a saturated aqueous solution of ammonium chloride, the obtained organic phase is separated from the aqueous phase, and the aqueous phase is extracted with an organic solvent (preferably toluene), and The combined organic phases are washed (preferably with a saturated aqueous solution of NaCl), dried (preferably with magnesium sulfate) and filtered. The resulting solution of the compound of the formula (X) or the crude product obtained by evaporation of the organic solvent can be used directly in the step E). However, if desired, the compound of formula (X) can be further purified by known techniques, such as recrystallization or chromatography.

在步驟E)中，式(X)化合物係藉由與鹵化三甲基氧化鋶、鹵化三甲基鋶、甲基硫酸三甲基氧化鋶或甲基硫酸三甲基鋶，較佳為氯化三甲基氧化鋶、氯化三甲基鋶、甲基硫酸三甲基氧化鋶或甲基硫酸三甲基鋶反應而轉化成式(IIa)之環氧化物。有可能分開製備鹵化三甲基氧化鋶、鹵化三甲基鋶、甲基硫酸三甲基氧化鋶或甲基硫酸三甲基鋶，然後於步驟E)中使用。然而，亦有可能現場製備該試劑，例如來自二甲硫醚與硫酸二甲酯之混合物的甲基硫酸三甲基鋶，較佳地在鹼的存在下，諸如氫氧化鈉或氫氧化鉀。 In the step E), the compound of the formula (X) is obtained by reacting with trimethylsulfoxonium halide, trimethylsulfonium halide, trimethylsulfonium methylsulfate or trimethylsulfonium methylsulfate, preferably chlorinated. The epoxide of the formula (IIa) is converted by reaction of trimethylsulfoxonium oxide, trimethylsulfonium chloride, trimethylsulfonium methylsulfate or trimethylsulfonium methylsulfate. It is possible to separately prepare a halogenated trimethylsulfoxonium oxide, a trimethylsulfonium halide, a trimethylsulfonium methylsulfate or a trimethylsulfonium methylsulfate, which is then used in step E). However, it is also possible to prepare the reagent in situ, such as trimethylsulfonium methylsulfate from a mixture of dimethyl sulfide and dimethyl sulfate, preferably in the presence of a base such as sodium hydroxide or potassium hydroxide.

鹵化三甲基氧化鋶、鹵化三甲基鋶、甲基硫酸三甲基氧化鋶或甲基硫 酸三甲基鋶的使用量較佳為以每1莫耳式(X)化合物計1.1至2.5，特別為1.2至2，更佳為1.3至1.6莫耳當量。 Halogenated trimethyl cerium oxide, trimethyl sulfonium halide, trimethyl sulfonium methyl sulfate or methyl sulphide The acid trimethylhydrazine is preferably used in an amount of from 1.1 to 2.5, particularly from 1.2 to 2, more preferably from 1.3 to 1.6 mol equivalent per 1 mol of the compound of the formula (X).

較佳地使用甲基硫酸三甲基鋶。特別佳地使用甲基硫酸三甲基鋶水溶液，較佳為含有38至40重量%，較佳為38至39.5重量%，更佳為38至39.0重量%之甲基硫酸三甲基鋶的水溶液。 Trimethyl sulfonium methyl sulfate is preferably used. It is particularly preferable to use an aqueous solution of trimethylsulfonium methylsulfate, preferably an aqueous solution containing 38 to 40% by weight, preferably 38 to 39.5% by weight, more preferably 38 to 39.0% by weight, of trimethylsulfonium methylsulfate. .

步驟E)較佳地在-30℃至50℃，較佳地在-10℃至40℃，特別佳地在20℃至40℃之溫度下進行。 Step E) is preferably carried out at a temperature of from -30 ° C to 50 ° C, preferably from -10 ° C to 40 ° C, particularly preferably from 20 ° C to 40 ° C.

步驟E)較佳地在水、二甲硫醚或彼之混合物的存在下進行。 Step E) is preferably carried out in the presence of water, dimethyl sulfide or a mixture thereof.

其較佳地在鹼的存在下進行。鹼較佳地選自Na2CO3、K2CO3、Cs2CO3、NaOH、KOH、KOtBu、NaH及其混合物，鹼更佳為KOH。 It is preferably carried out in the presence of a base. The base is preferably selected from the group consisting of Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH, KOtBu, NaH and mixtures thereof, and the base is more preferably KOH.

來自步驟E)的所得反應混合物可以此項技術中概括已知的程序整理。較佳地在反應完成之後，將反應混合物以添加水淬滅，將所得有機相與水相分離，將水相以有機溶劑(較佳為三級丁基甲醚)萃取。所得式(IIa)化合物溶液或藉由蒸發有機溶劑及其他的揮發性組份而獲得的粗製產物可直接用於根據本發明之方法中。然而，若要求時，式(IIa)化合物可以已知的技術進一步純化，例如再結晶或層析術。 The resulting reaction mixture from step E) can be prepared by procedures generally known in the art. Preferably, after completion of the reaction, the reaction mixture is quenched with the addition of water, the resulting organic phase is separated from the aqueous phase, and the aqueous phase is extracted with an organic solvent (preferably tri-butyl butyl ether). The resulting solution of the compound of the formula (IIa) or the crude product obtained by evaporating the organic solvent and other volatile components can be used directly in the process according to the invention. However, if desired, the compound of formula (IIa) can be further purified by known techniques, such as recrystallization or chromatography.

上文概述之方法的每一步驟之反應時間係取決於反應規模及反應溫度而不等，但是通常介於幾分鐘(例如5分鐘)與48小時之間。 The reaction time for each step of the method outlined above varies depending on the scale of the reaction and the reaction temperature, but is usually between a few minutes (e.g., 5 minutes) and 48 hours.

若沒有其他另外的定義，則本方法步驟通常係在標準壓力下(1大氣壓)進行。然而，亦有可能在升壓或減壓下操作。 If there are no other definitions, the method steps are usually carried out under standard pressure (1 atm). However, it is also possible to operate under boost or decompression.

如上文所概述，根據本發明之方法容許生產呈固體形式之式(I)化合物，特別地呈至少部分晶型。現已發現式(I)化合物2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇係呈不同的多晶型(在本文以稱為多晶型物或晶型)出現。 As outlined above, the process according to the invention permits the production of compounds of the formula (I) in solid form, in particular at least partially crystalline. The compound of formula (I) has been found to be 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazole The -1-yl)propan-2-ols are present in different polymorphic forms (referred to herein as polymorphs or crystal forms).

多晶型現象為化合物使分子在晶格中呈具有不同的排列及/或組構之不同的結晶相結晶之能力。因此，多晶型物為相同的純化學化合物之不同的晶型。由於分子之不同的排列及/或組構，使多晶型物展現不同的物理、化學及生物特性。可受影響的特性包括但不限於溶解度、溶解速率、穩定性、光學及機械特性等。多晶型物的相對穩定性係取決於其自由能而定， 亦即越穩定的多晶型物具有越低的自由能。在限定的實驗條件設定下，僅一種多晶型物具有最低的自由能。此多晶型物為熱力學穩定形式且所有其他的多晶型物被稱為亞穩定形式。亞穩定形式為一種熱力學不穩定形式，但是由於其相對緩慢的轉變速度，所以仍可製備、分離及分析。 Polymorphism is the ability of a compound to crystallize molecules in a crystal lattice with different alignments and/or different crystal phases. Thus, the polymorph is a different crystalline form of the same purified compound. Polymorphs exhibit different physical, chemical, and biological properties due to the different arrangement and/or organization of the molecules. Properties that can be affected include, but are not limited to, solubility, dissolution rate, stability, optical and mechanical properties, and the like. The relative stability of a polymorph depends on its free energy. That is, the more stable the polymorph has the lower free energy. Only one polymorph has the lowest free energy at a defined experimental condition setting. This polymorph is in a thermodynamically stable form and all other polymorphs are referred to as metastable forms. The metastable form is a thermodynamically unstable form, but due to its relatively slow rate of transformation, it can be prepared, isolated, and analyzed.

呈不同的多晶型之活性物質的出現對以工業規模的生產以及含有活性物質之調配物的開發具有決定性的重要性，因為不希望的相改變可導致調配物增稠及可能的固化及/或大的晶體，其可導致應用設備堵塞，例如在農業應用機械的噴嘴中。結晶修飾及彼等特性的現有知識因此具有高度實用性。各多晶型物係以呈固態的分子之特定、均勻的堆積及排列特徵化。不過，通常不可預測所給出之化學化合物是否完全形成多晶型物，且如果是，則不同的多晶型物可具有其物理及生物特性。 The emergence of active substances in different polymorphic forms is of decisive importance for the production of industrial scale production and formulations containing active substances, since undesired phase changes can lead to thickening of the formulation and possible curing and/or Or large crystals, which can cause blockage of the application equipment, for example in nozzles of agricultural applications. The prior knowledge of crystalline modifications and their properties is therefore highly practical. Each polymorph is characterized by a specific, uniform packing and arrangement of molecules in a solid state. However, it is generally unpredictable whether the given chemical compound completely forms a polymorph, and if so, the different polymorphs may have their physical and biological properties.

另外，可出現稱為水合物或溶劑合物之假多晶型。溶劑合物為其中結晶之溶劑分子併入由非溶劑化分子所組成之主體晶格中的結晶分子化合物。當併入的溶劑為水時，則水合物為溶劑合物的特殊例子。存在於晶格中的溶劑分子影響分子間交互作用且賦予各溶劑合物獨特的物理特性。溶劑合物因此具有內能、焓、熵、吉布斯(Gibbs)自由能及熱力學活性之其本身的特徵值。 Additionally, pseudopolymorphs known as hydrates or solvates may occur. A solvate is a crystalline molecular compound in which a solvent molecule of a crystal is incorporated into a host lattice composed of an unsolvated molecule. When the solvent to be incorporated is water, the hydrate is a special example of a solvate. Solvent molecules present in the crystal lattice affect the intermolecular interactions and impart unique physical properties to each solvate. The solvate thus has its own characteristic values of internal energy, enthalpy, entropy, Gibbs free energy and thermodynamic activity.

在下列揭示2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之晶型A。2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇為式(I)化合物，其中R1 代表甲基，R4 代表Br；m 為1；及Y 代表 2-[6-(4-Bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl) is disclosed below. Form A of propan-2-ol. 2-[6-(4-Bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl)propane-2 An alcohol is a compound of formula (I) wherein R 1 represents methyl, R 4 represents Br; m is 1; and Y represents

其中Y係經由以「U」標識之鍵連接O，及Y係經由以「V」標識之鍵連接CR1部分。 Wherein Y is connected to O via a key identified by "U", and Y is connected to the CR 1 portion via a key identified by "V".

多晶型A可藉由施予特定的結晶條件而獲得。 Polymorph A can be obtained by applying specific crystallization conditions.

例如，其係以包含下列步驟之方法獲得：a)將2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇稀釋及/或懸浮在4體積份丙酮與1體積份水之混合物中；b)將其加熱之溶劑混合物之沸騰溫度；c)將步驟b)獲得的溶液或漿液冷卻至約50℃；及d)保持溶液或漿液在該溫度下，直到所有的溶液已蒸發為止。 For example, it is obtained by a process comprising the steps of: a) 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1 , 2,4-triazol-1-yl)propan-2-ol is diluted and/or suspended in a mixture of 4 parts by volume of acetone and 1 part by volume of water; b) boiling temperature of the solvent mixture to be heated; c) The solution or slurry obtained in step b) is cooled to about 50 ° C; and d) the solution or slurry is maintained at this temperature until all of the solution has evaporated.

適合於結晶學研究之大小及品質的多晶型A之晶體係例如藉由以下方式獲得：將400毫克2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇稀釋及/或懸浮在4體積份丙酮與1體積份水之40毫升混合物中，接著進行上述之方法步驟b)至d)。 A polycrystalline Form A crystal system suitable for the size and quality of crystallographic studies is obtained, for example, by the following method: 400 mg of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridine 3-yl]-1-(1H-1,2,4-triazol-1-yl)propan-2-ol is diluted and/or suspended in a mixture of 4 parts by volume of acetone and 1 part by volume of water, 40 ml, The method steps b) to d) above are then carried out.

在步驟a)中的2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇基本上可為2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之任何已知的形式。這意指可使用呈非晶型或不同的多晶型之混合物或含有非晶型與一或多種不同的多晶型之混合物的2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇。 2-[6-(4-Bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazole-1) in step a) -yl)propan-2-ol can be substantially 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2, Any known form of 4-triazol-1-yl)propan-2-ol. This means that a mixture of amorphous or different polymorphs or 2-[6-(4-bromophenoxy)-2- which is a mixture of amorphous and one or more different polymorphs can be used. (Trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl)propan-2-ol.

2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之多晶型A可以在25℃下及以Cu-K α 1輻射(1.5406Å)記錄之各自的繞射圖為基礎之X射線粉末繞射法特徵化。多晶型A顯現至少3個，常為至少5個，特別為至少7個，更特別為至少10個，及尤其為所有下列以值引述之反射： 2-[6-(4-Bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl)propane-2 The polymorph A of the alcohol can be characterized by an X-ray powder diffraction method based on the respective diffraction pattern recorded by Cu-K α 1 radiation (1.5406 Å) at 25 ° C. Polymorph A exhibits at least 3, often at least 5, especially at least 7, more particularly at least 10, and especially all of the following reflections quoted by value:

多晶型A特別以至少以2θ值±0.2°引述之反射14.2±0.2°、14.9±0.2°和18.8±0.2°，更特別以至少反射14.2±0.2°、14.9±0.2°、18.8±0.2°、23.3±0.2°和28.0±0.2°，更特別以至少反射14.2±0.2°、14.9±0.2°、18.8±0.2°、20.2±0.2°、23.3±0.2°、26.1±0.2°和28.0±0.2°，及尤其以至少反射14.2±0.2°、14.9±0.2°、15.2±0.2°、18.8±0.2°、20.2±0.2°、22.2±0.2°、23.3±0.2°、23.8±0.2°、26.1±0.2°和28.0±0.2°特徵化。 Polymorph A specifically reflects 14.2 ± 0.2°, 14.9 ± 0.2° and 18.8 ± 0.2°, more particularly at least 14.2 ± 0.2°, 14.9 ± 0.2°, 18.8 ± 0.2°, quoted by at least 2θ value ± 0.2°. , 23.3 ± 0.2 ° and 28.0 ± 0.2 °, more particularly at least reflect 14.2 ± 0.2 °, 14.9 ± 0.2 °, 18.8 ± 0.2 °, 20.2 ± 0.2 °, 23.3 ± 0.2 °, 26.1 ± 0.2 ° and 28.0 ± 0.2 ° And especially at least reflect 14.2 ± 0.2 °, 14.9 ± 0.2 °, 15.2 ± 0.2 °, 18.8 ± 0.2 °, 20.2 ± 0.2 °, 22.2 ± 0.2 °, 23.3 ± 0.2 °, 23.8 ± 0.2 °, 26.1 ± 0.2 ° Characterized by 28.0 ± 0.2 °.

多晶型A進一步以圖1a描述之X射線粉末繞射圖特徵化。 Polymorph A is further characterized by an X-ray powder diffraction pattern as depicted in Figure 1a.

2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之多晶型A可以在25℃下及以1064奈米雷射波長和2公分-1解析度記錄之各自的光譜圖為基礎之拉曼光譜法特徵化。多晶型A顯現至少3個，常為至少5個，特別為至少7個，及尤其為所有下列以峰最大值引述之譜帶： 2-[6-(4-Bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl)propane-2 The polymorph A of the alcohol can be characterized by Raman spectroscopy based on the respective spectra recorded at a resolution of 1064 nm and a resolution of 2 cm -1 at 25 °C. Polymorph A exhibits at least 3, often at least 5, especially at least 7, and especially all of the following bands quoted as peak maxima:

圖1b顯示2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之多晶型A的FT拉曼光譜。 Figure 1b shows 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl) FT Raman spectrum of polymorph A of propan-2-ol.

2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之多晶型A可以在25℃下使用universal diamond ATR裝置和4公分-1解析度記錄之各自的光譜圖為基礎之紅外線光譜法特徵化。多晶型A顯現至少3個，常為至少5個，特別為至少7個，及尤其為所有下列以峰最大值引述之譜帶： 2-[6-(4-Bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl)propane-2 The polymorph A of the alcohol can be characterized by infrared spectroscopy based on the respective spectra of the universal diamond ATR apparatus and the 4 cm -1 resolution recorded at 25 °C. Polymorph A exhibits at least 3, often at least 5, especially at least 7, and especially all of the following bands quoted as peak maxima:

圖1c顯示2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之多晶型A的IR光譜。 Figure 1c shows 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl) IR spectrum of polymorph A of propan-2-ol.

除了2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之多晶型A以外，亦鑑定2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之多晶型B以及非晶型，該等係於下列進一步特徵化。 In addition to 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl)propene- In addition to the polymorph A of 2-alcohol, 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2, Polymorph B of 4-triazol-1-yl)propan-2-ol and amorphous form are further characterized as follows.

多晶型B可藉由施予特定的結晶條件而獲得。 Polymorph B can be obtained by applying specific crystallization conditions.

例如，其係以包含下列步驟之方法獲得：a)將2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇稀釋及/或懸浮在適合的溶劑或溶劑混合物中，該溶劑係選自乙酸乙酯、乙酸乙酯/正庚烷(1：10體積份)和甲醇；b)將其加熱至溶液或溶劑混合物之沸騰溫度；及c)將步驟b)獲得的溶液或漿液冷卻至低於25℃之溫度。 For example, it is obtained by a process comprising the steps of: a) 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1 , 2,4-triazol-1-yl)propan-2-ol is diluted and/or suspended in a suitable solvent or solvent mixture selected from ethyl acetate, ethyl acetate/n-heptane (1: 10 parts by volume) and methanol; b) heating to the boiling temperature of the solution or solvent mixture; and c) cooling the solution or slurry obtained in step b) to a temperature below 25 °C.

適合於結晶學研究之大小及品質的多晶型B之晶體係例如藉由以下方式獲得：將100毫克2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇稀釋及/或懸浮在10毫升甲醇中，將其加熱至沸騰溫度，將獲得的溶液冷卻至25℃，同時添加100毫升水，將所得懸浮液貯存在25℃下24小時，然後過濾及在25℃下蒸發所吸附之溶劑。 A polycrystalline B crystal system suitable for the size and quality of crystallographic studies is obtained, for example, by the following method: 100 mg of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridine -3-yl]-1-(1H-1,2,4-triazol-1-yl)propan-2-ol is diluted and/or suspended in 10 ml of methanol and heated to boiling temperature to obtain The solution was cooled to 25 ° C while 100 ml of water was added, and the resulting suspension was stored at 25 ° C for 24 hours, then filtered and the adsorbed solvent was evaporated at 25 ° C.

在步驟a)中的2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇基本上可為2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之任何已知的形式。這意指可使用呈非晶型或不同的多晶型之混合物或含有非晶型與一或多種不同的多晶型之混合物的2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇。 2-[6-(4-Bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazole-1) in step a) -yl)propan-2-ol can be substantially 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2, Any known form of 4-triazol-1-yl)propan-2-ol. This means that a mixture of amorphous or different polymorphs or 2-[6-(4-bromophenoxy)-2- which is a mixture of amorphous and one or more different polymorphs can be used. (Trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl)propan-2-ol.

2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之多晶型B可以在25℃下及以Cu-K α 1輻射(1.5406Å)記錄之各自的繞射圖為基礎之X射線粉末繞射法特徵化。多晶型B顯現至少3個，常為至少5個，特別為至少7個，更特別為至少10個，及尤其為所有下列以值引述之反射： 2-[6-(4-Bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl)propane-2 The polymorph B of the alcohol can be characterized by an X-ray powder diffraction method based on the respective diffraction pattern recorded by Cu-K α 1 radiation (1.5406 Å) at 25 ° C. Polymorph B exhibits at least 3, often at least 5, especially at least 7, more particularly at least 10, and especially all of the following reflections quoted by value:

多晶型B特別以至少以2θ值±0.2°引述之反射18.3±0.2°、24.5±0.2°和26.8±0.2°，更特別以至少反射18.3±0.2°、21.7±0.2°、21.8±0.2°、24.5±0.2°和26.8±0.2°，更特別以至少反射17.4±0.2°、18.3±0.2°、21.7±0.2°、21.8±0.2°、22.5±0.2°、24.5±0.2°和26.8±0.2°，及尤其以至少反射17.0±0.2°、17.4±0.2°、18.3±0.2°、19.2±0.2°、21.7±0.2°、21.8±0.2°、22.5±0.2°、24.5±0.2°、26.6±0.2°和26.8±0.2°特徵化。 Polymorph B is particularly characterized by reflections of at least 2θ values ± 0.2°, 18.3 ± 0.2°, 24.5 ± 0.2° and 26.8 ± 0.2°, more particularly at least 18.3 ± 0.2°, 21.7 ± 0.2°, 21.8 ± 0.2°. 24.5±0.2° and 26.8±0.2°, more particularly at least 17.4±0.2°, 18.3±0.2°, 21.7±0.2°, 21.8±0.2°, 22.5±0.2°, 24.5±0.2° and 26.8±0.2° And especially at least reflect 17.0 ± 0.2 °, 17.4 ± 0.2 °, 18.3 ± 0.2 °, 19.2 ± 0.2 °, 21.7 ± 0.2 °, 21.8 ± 0.2 °, 22.5 ± 0.2 °, 24.5 ± 0.2 °, 26.6 ± 0.2 ° Characterized by 26.8 ± 0.2 °.

多晶型B進一步以圖2a描述之X射線粉末繞射圖特徵化。 Polymorph B is further characterized by an X-ray powder diffraction pattern as depicted in Figure 2a.

2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之多晶型B可以在25℃下及以1064奈米雷射波長和2公分-1解析度記錄之各自的光譜圖為基礎之拉曼光譜法特徵化。多晶型B顯現至少3個，常為至少5個，特別為至少7個，及尤其為所有下列以峰最大值引述之譜帶： 2-[6-(4-Bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl)propane-2 The polymorph B of the alcohol can be characterized by Raman spectroscopy based on the respective spectra recorded at a wavelength of 1064 nm and a resolution of 2 cm -1 at 25 °C. Polymorph B exhibits at least 3, often at least 5, especially at least 7, and especially all of the following bands quoted as peak maxima:

圖2b顯示2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之多晶型B的FT拉曼光譜。 Figure 2b shows 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl) FT Raman spectrum of polymorph B of propan-2-ol.

2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之多晶型B可以在25℃下使用universal diamond ATR裝置和4公分-1解析度記錄之各自的光譜圖為基礎之紅外線光譜法特徵化。多晶型B顯現至少3個，常為至少5個，特別為至少7個，及尤其為所有下列以峰最大值引述之譜帶： 2-[6-(4-Bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl)propane-2 Polymorph B of alcohol can be characterized by infrared spectroscopy based on the respective spectra of the universal diamond ATR apparatus and 4 cm -1 resolution recorded at 25 °C. Polymorph B exhibits at least 3, often at least 5, especially at least 7, and especially all of the following bands quoted as peak maxima:

圖2c顯示2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之多晶型B的IR光譜。 Figure 2c shows 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl) IR spectrum of polymorph B of propan-2-ol.

2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之非晶型可藉由將of 2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之多晶型B晶體在150℃下熔融且將熔融物貯存在25℃下，讓其冷卻至該溫度而獲得。 2-[6-(4-Bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl)propane-2 - Amorphous form of alcohol by means of 2-(6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4 The polymorph B crystal of triazol-1-yl)propan-2-ol was obtained by melting at 150 ° C and storing the melt at 25 ° C and allowing it to cool to this temperature.

非晶型係以圖3a描述之IR光譜特徵化。 The amorphous form is characterized by the IR spectrum depicted in Figure 3a.

本發明係以下列實施例例證。然而，本發明不限於該等實施例。 The invention is illustrated by the following examples. However, the invention is not limited to the embodiments.

實施例 Example

實施例1 Example 1

將6-(4-溴苯氧基)-3-(2-甲基環氧乙烷-2-基)-2-(三氟甲基)吡啶(225克，0.575莫耳，1當量(equivalent)(下列以當量(equiv)))添加至608毫升正丁醇與68毫升PEG400(在市場上以聚乙二醇400之名稱取自Merck)之混合物中。添加60.6克1H-1,2,4-***(0.862莫耳，1.5當量)及15.2克K2CO3(0.23莫耳，0.4當量)且將混合物加熱至100℃經13小時。在減壓下移除溶劑，直到維持黏的淺棕色油為止。一起添加3公升乙酸乙酯與1.5公升水及18毫升濃縮水性氫氯酸。將相分離且將有機相以水清洗。將有機相經Na2SO4乾燥且在減壓下移除溶劑。剩餘油狀殘餘物快速結晶且以環己烷濕磨3次。將濕產物過濾且乾燥，得到240克米黃色晶體，90% a/a HPLC純度(84.7%產率)。將晶體於82℃下溶解在760毫升異丙醇中。添加1170毫升水，且在80℃下攪拌5分鐘之後，讓混合物經隔夜冷卻至室溫。將懸浮液進一步冷卻至10-15℃，過濾且以800毫升水清洗。將產物在真空下於50℃下乾燥，以獲得202克淺米黃色晶體，97.9% a/a HPLC純度(77.6%產率)。 6-(4-Bromophenoxy)-3-(2-methyloxiran-2-yl)-2-(trifluoromethyl)pyridine (225 g, 0.575 mol, 1 equivalent (equivalent) (The following equiv) was added to a mixture of 608 ml of n-butanol and 68 ml of PEG400 (commercially available from Merck under the name polyethylene glycol 400). Was added 1H-1,2,4- triazole 60.6 g (0.862 mole, 1.5 eq.) And 15.2 g K 2 CO 3 (0.23 mole, 0.4 eq.) And the mixture was heated to 100 deg.] C over 13 hours. The solvent was removed under reduced pressure until a sticky light brown oil remained. 3 liters of ethyl acetate and 1.5 liters of water and 18 ml of concentrated aqueous hydrochloric acid were added together. The phases were separated and the organic phase was washed with water. The organic phase was dried over Na 2 SO 4 and the solvent removed under reduced pressure. The remaining oily residue crystallized rapidly and was triturated 3 times with cyclohexane. The wet product was filtered and dried to give 240 g of beige crystals, 90% a/a HPLC purity (84.7% yield). The crystals were dissolved in 760 ml of isopropanol at 82 °C. After adding 1170 ml of water and stirring at 80 ° C for 5 minutes, the mixture was allowed to cool to room temperature overnight. The suspension was further cooled to 10-15 ° C, filtered and washed with 800 mL of water. The product was dried under vacuum at 50 ° C to give 202 g of pale beige crystals, 97.9% a/a HPLC purity (77.6% yield).

比較例1： Comparative Example 1:

將14.2克KOH(0.22莫耳，0.4當量)及45.4克(1.2當量)1H-1,2,4-***(0.644莫耳，1.2當量)添加至800毫升1-甲基-2-吡咯啶酮中。移除一半的溶劑，以便自反應混合物汽提所產生之水。將6-(4-溴苯氧基)-3-(2-甲基環氧乙烷-2-基)-2-(三氟甲基)吡啶(225克，0.575莫耳，1當量)添加至此澄清溶液中且將混合物加熱至85℃經11小時。在減壓下移除溶劑，直到維持黏的棕色油為止。一起添加3公升乙酸乙酯與1.5公升水及18毫升濃縮水性氫氯酸。將相分離且將有機相以水清洗。將有機相經Na2SO4乾燥且在減壓下移除溶劑。當接種時，剩餘油狀殘餘物緩慢結晶。將殘餘物以環己 烷濕磨3次。將濕產物過濾且乾燥，得到175克米黃色晶體，89% a/a HPLC純度(64.8%產率)。將晶體於82℃下溶解在560毫升異丙醇中。添加850毫升水，且在70℃下攪拌5分鐘之後，讓混合物經隔夜冷卻至室溫。將懸浮液進一步冷卻至10-15℃，過濾且以400毫升水清洗。將產物在真空下於45℃下乾燥，以獲得140克米黃色晶體，98% a/a HPLC純度(57.7%產率)。 14.2 grams of KOH (0.22 moles, 0.4 equivalents) and 45.4 grams (1.2 equivalents) of 1H-1,2,4-triazole (0.644 moles, 1.2 equivalents) were added to 800 ml of 1-methyl-2-pyrrolidine Ketone. Half of the solvent is removed to strip the water produced from the reaction mixture. Add 6-(4-bromophenoxy)-3-(2-methyloxiran-2-yl)-2-(trifluoromethyl)pyridine (225 g, 0.575 mol, 1 eq.) The solution was thus clarified and the mixture was heated to 85 ° C for 11 hours. The solvent was removed under reduced pressure until a sticky brown oil remained. 3 liters of ethyl acetate and 1.5 liters of water and 18 ml of concentrated aqueous hydrochloric acid were added together. The phases were separated and the organic phase was washed with water. The organic phase was dried over Na 2 SO 4 and the solvent removed under reduced pressure. When inoculated, the remaining oily residue slowly crystallized. The residue was triturated 3 times with cyclohexane. The wet product was filtered and dried to give 175 g of beige crystals, 89% a/a HPLC purity (64.8% yield). The crystals were dissolved in 560 ml of isopropanol at 82 °C. After adding 850 ml of water and stirring at 70 ° C for 5 minutes, the mixture was allowed to cool to room temperature overnight. The suspension was further cooled to 10-15 ° C, filtered and washed with 400 mL water. The product was dried under vacuum at 45 <0>C to afford <RTI ID=0.0>>

這顯示自WO 2017/029179 A1已知的方法B在標的化合物之產率方面比不上根據本發明之方法。 This shows that Process B, known from WO 2017/029179 A1, does not match the process according to the invention in terms of the yield of the target compound.

實施例2： Example 2:

將91.7%純度之6-(4-溴苯氧基)-3-(2-甲基環氧乙烷-2-基)-2-(三氟甲基)吡啶(40克，98毫莫耳，1當量)添加至正丁醇與PEG400(在市場上以聚乙二醇400之名稱取自Merck)之80：20v/v混合物(40毫升)中。添加10.2克1H-1,2,4-***(147毫莫耳，1.5當量)及7.4克K2CO3(54毫莫耳，0.55當量)且將混合物加熱至118-120℃經3小時。在減壓下移除溶劑且添加水，進一步經共沸移除溶劑。將殘餘物降到室溫，過濾且以水清洗，以獲得84% a/a之標的化合物及8%之其4N-異構物的粗製產物。將45毫升甲苯添加至粗製產物中且將混合物加熱至70℃。在冷卻至50℃之後，添加一些接種晶體且將混合物進一步冷卻至5℃。將懸浮液過濾，以母液、冷甲苯及石油醚清洗且最終乾燥，以獲得31.7克標的化合物，95.5% a/a HPLC純度(69.7%產率)。 91.7% purity of 6-(4-bromophenoxy)-3-(2-methyloxiran-2-yl)-2-(trifluoromethyl)pyridine (40 g, 98 mmol) , 1 equivalent) was added to an 80:20 v/v mixture (40 mL) of n-butanol and PEG 400 (available from Merck in the market under the name polyethylene glycol 400). 10.2 g of 1H-1,2,4-triazole (147 mmol, 1.5 eq.) and 7.4 g of K 2 CO 3 (54 mmol, 0.55 eq.) were added and the mixture was heated to 118-120 ° C for 3 hours. . The solvent was removed under reduced pressure and water was added, and the solvent was further removed by azeotropy. The residue was taken to room temperature, filtered and washed with water to give a crude material of <RTI ID=0.0>> 45 ml of toluene was added to the crude product and the mixture was heated to 70 °C. After cooling to 50 ° C, some inoculated crystals were added and the mixture was further cooled to 5 °C. The suspension was filtered, washed with a mother liquor, cold toluene and petroleum ether and then dried to afford 31.7 g of the title compound, 95.5% a/a HPLC purity (69.7% yield).

比較例2： Comparative Example 2:

將98%純度之6-(4-溴苯氧基)-3-(2-甲基環氧乙烷-2-基)-2-(三氟甲基)吡啶(40克，105毫莫耳，1當量)添加至正丁醇(40毫升)中。添加10.9克1H-1,2,4-***(157毫莫耳，1.5當量)及8克K2CO3(58毫莫耳，0.55當量)且將混合物加熱至118-120℃經3小時。在減壓下移除溶劑且添加水，進一步經共沸移除溶劑。將殘餘物降到室溫，過濾且以水清洗，以獲得82% a/a之標的化合物及18%之其4N-異構物的粗製產物。將45毫升甲苯添加至粗製產物中且將混合物加熱至70℃。在冷卻至50℃之後，添加一些接種晶體且 將混合物進一步冷卻至5℃。將懸浮液過濾，以母液、冷甲苯及石油醚清洗且最終乾燥，以獲得39.9克標的化合物，81.2% a/a HPLC純度(69.8%產率)。 98% pure 6-(4-bromophenoxy)-3-(2-methyloxiran-2-yl)-2-(trifluoromethyl)pyridine (40 g, 105 mmol) , 1 equivalent) was added to n-butanol (40 mL). 10.9 g of 1H-1,2,4-triazole (157 mmol, 1.5 equivalents) and 8 g of K 2 CO 3 (58 mmol, 0.55 equivalent) were added and the mixture was heated to 118-120 ° C for 3 hours. . The solvent was removed under reduced pressure and water was added, and the solvent was further removed by azeotropy. The residue was taken to room temperature, filtered and washed with water to give a crude compound of <RTI ID=0.0>> 45 ml of toluene was added to the crude product and the mixture was heated to 70 °C. After cooling to 50 ° C, some inoculated crystals were added and the mixture was further cooled to 5 °C. The suspension was filtered, washed with a mother liquor, cold toluene and petroleum ether and then dried to give 39.9 g of the title compound, 81.2% a/a HPLC purity (69.8% yield).

這顯示以PEG不存在之方法在標的化合物之純度方面比不上根據本發明之方法。 This shows that in the absence of PEG, the purity of the target compound is not comparable to the method according to the invention.

實施例3： Example 3:

將94.4%純度之6-(4-溴苯氧基)-3-(2-甲基環氧乙烷-2-基)-2-(三氟甲基)吡啶(40克，100,9毫莫耳，1當量)添加至120毫升PEG400(在市場上以聚乙二醇400之名稱取自Merck)中。添加10.5克1H-1,2,4-***(151.4毫莫耳，1.5當量)及5.6克K2CO3(40.4毫莫耳，0.4當量)且將混合物加熱至110-120℃經4小時。在反應混合物冷卻至室溫之後，添加水(1.5公升)且將混合物徹底攪拌。將沈澱之固體使用吸濾器過濾且將剩餘的沾黏殘留物以更多的水濕磨，直到該等變成固體為止，在此時將該等添加至吸濾器上的濾餅中。在以水清洗及進一步粗濾之後，獲得成為米黃色固體的73.73克粗製濕產物，92.1%a/a HPLC純度。將材料於78℃下溶解在110毫升異丙醇中，攪拌10分鐘且添加160毫升水。在70℃下攪拌10分鐘之後，讓混合物經隔夜冷卻至室溫。將懸浮液過濾且將產物乾燥，以獲得35克灰白色晶體，97.6% a/a HPLC純度(76.4%產率)。 94.4% pure 6-(4-bromophenoxy)-3-(2-methyloxiran-2-yl)-2-(trifluoromethyl)pyridine (40 g, 100, 9 m) Mohr, 1 equivalent) was added to 120 ml of PEG 400 (obtained from Merck on the market under the name polyethylene glycol 400). 10.5 g of 1H-1,2,4-triazole (151.4 mmol, 1.5 eq.) and 5.6 g of K 2 CO 3 (40.4 mmol, 0.4 eq.) were added and the mixture was heated to 110-120 ° C for 4 hours. . After the reaction mixture was cooled to room temperature, water (1.5 liters) was added and the mixture was thoroughly stirred. The precipitated solids were filtered using a suction filter and the remaining adherent residue was wet-milled with more water until the solids became solid, at which point the additions were added to the filter cake on the suction filter. After washing with water and further coarse filtration, 73.73 g of crude wet product was obtained as a beige solid, 92.1% a/a HPLC purity. The material was dissolved in 110 ml of isopropanol at 78 ° C, stirred for 10 minutes and 160 ml of water was added. After stirring at 70 ° C for 10 minutes, the mixture was allowed to cool to room temperature overnight. The suspension was filtered and the product was dried to give 35 g of pale white crystals, 97.6% a/a HPLC purity (76.4% yield).

這顯示使用PEG作為唯一的溶劑提供具有高產率及純度之標的化合物，甚至在共溶劑不存在下。 This shows that the use of PEG as the sole solvent provides a standard compound with high yield and purity, even in the absence of a cosolvent.

2-[6-(4-溴苯氧基)-2-(三氟甲基)吡啶-3-基]-1-(1H-1,2,4-***-1-基)丙-2-醇之多晶型 2-[6-(4-Bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl)propane-2 - polymorph of alcohol

所有的數據(其為本發明之一部分)係根據下文所述之方法得出，除非另有其他指示。用於測量的樣品係直接使用且不經歷任何進一步的樣品準備。 All data, which is part of the invention, is derived according to the methods described below, unless otherwise indicated. The samples used for the measurements were used directly and did not undergo any further sample preparation.

XRPD XRPD

X射線繞射譜係在室溫下使用XRD-繞射儀X`Pert PRO(PANalytical)及STOE STADI-P(輻射Cu K α 1，波長1.5406Å)記錄。所有的X射線反射係以具有±0.2°解析度之°2θ(theta)值(峰最大值)引述。 The X-ray diffraction spectrum was recorded at room temperature using an XRD-diffuser X'Pert PRO (PANalytical) and STOE STADI-P (radiation Cu K α 1, wavelength 1.5406 Å). All X-ray reflections are quoted as °2 theta value (peak maximum) with a resolution of ±0.2°.

拉曼 Raman

拉曼光譜係在室溫下使用來自Bruker之FT拉曼光譜儀(型RFS 100及MultiRam)記錄。解析度為2公分-1。測量係在玻璃小瓶或鋁盤中進行。 Raman spectroscopy was recorded at room temperature using an FT Raman spectrometer (type RFS 100 and MultiRam) from Bruker. The resolution is 2 cm -1 . The measurement is carried out in a glass vial or aluminum pan.

IR IR

IR-ATR光譜係在室溫下使用來自Perkin-Elmer之一種具有universal diamond ATR裝置的FT-IR光譜儀記錄。解析度為4公分-1。 The IR-ATR spectrum was recorded at room temperature using an FT-IR spectrometer from Perkin-Elmer with a universal diamond ATR device. The resolution is 4 cm -1 .

Claims (15)

一種製備式(I)化合物之方法， 其中R1 代表氫、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C3-C8-環烷基、C3-C8-環烷基-C1-C4-烷基或C6-C14-芳基，其中R1之脂族部分(排除環烷基部分)可攜有1、2、3或至多最大可能的數量之相同或不同的基團Ra，該等彼此獨立地選自鹵素、CN、硝基、苯基、C1-C4-烷氧基和C1-C4-鹵烷氧基，其中苯基可經1、2、3、4或5個彼此獨立地選自鹵素、CN、硝基、C1-C4-烷基、C1-C4-烷氧基、C1-C4-鹵烷基、C1-C4-鹵烷氧基之取代基取代，且其中R1之環烷基及/或C6-C14-芳基部分可攜有1、2、3、4、5或至多最大可能的數量之相同或不同的基團Rb，該等彼此獨立地選自鹵素、CN、硝基、C1-C4-烷基、C1-C4-烷氧基、C1-C4-鹵烷基和C1-C4-鹵烷氧基；各R4彼此獨立地代表鹵素、CN、硝基、C1-C4-烷基、C1-C4-鹵烷基、C1-C4-烷氧基、C1-C4-鹵烷氧基、C1-C4-烷基羰基、經羥基取代之C1-C4-烷基、五氟-λ6-氫硫基、C3-C6-環烷基、C3-C6-鹵素環烷基、C1-C4-烷基-C3-C6-環烷基、C2-C6-烯基、C2-C6-鹵素烯基、C2-C6-炔基、C2-C6-鹵素炔基、C1-C4-烷基氫硫基、C1-C4-鹵烷基氫硫基、C1-C6-烷基磺醯基、C6-C10-芳基磺醯基、C1-C6-烷基-SO2NH-、C6-C10-芳基-SO2NH-、甲醯基、含有至多4個選自N、O和S的雜原子之5-、6-或7-員飽和雜環烷基、或-C(R4a)=N-OR4b，其中R4a和R4b彼此獨立地代表氫、C1-C6-烷基或苯基；m 為整數且為0、1、2、3、4或5；Y 代表選自下列的6員芳族雜環： 其中Y係經由以「U」標識之鍵連接O，及Y係經由以「V」標識之鍵連接CR1部分，及其中R 代表氫、C1-C2-鹵烷基、C1-C2-鹵烷氧基、C1-C2-烷基羰基或鹵素；各R3彼此獨立地代表鹵素、CN、硝基、C1-C4-烷基、C1-C4-鹵烷基、C1-C4-烷氧基或C1-C4-鹵烷氧基；及n 為整數且為0或1；該方法係藉由將1H-1,2,4-***與式(II)之環氧乙烷在鹼的存在下反應， 其中R1、R4、m和Y係如式(I)所定義；其特徵在於該反應係在聚烷二醇的存在下進行。 a method of preparing a compound of formula (I), Wherein R 1 represents hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 - ring Alkyl-C 1 -C 4 -alkyl or C 6 -C 14 -aryl, wherein the aliphatic moiety of R 1 (excluding the cycloalkyl moiety) can carry 1, 2, 3 or up to the maximum possible number The same or different groups R a , which are independently of each other selected from the group consisting of halogen, CN, nitro, phenyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy, wherein phenyl 1, 2, 3, 4 or 5 independently of one another selected from the group consisting of halogen, CN, nitro, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -halide Substituted with a substituent of an alkyl group, a C 1 -C 4 -haloalkoxy group, and wherein the cycloalkyl group and/or the C 6 -C 14 -aryl moiety of R 1 can carry 1, 2, 3, 4, 5 Or at most the largest possible number of the same or different groups R b , independently of one another selected from the group consisting of halogen, CN, nitro, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl and C 1 -C 4 -haloalkoxy; each R 4 independently of one another represents halogen, CN, nitro, C 1 -C 4 -alkyl, C 1 -C 4 -halide alkyl group, C 1 -C 4 - alkoxy, C 1 -C 4 - haloalkoxy C 1 -C 4 - alkylcarbonyl group, the hydroxy-substituted C 1 -C 4 - alkyl, pentafluoro -λ 6 - mercapto, C 3 -C 6 - cycloalkyl, C 3 -C 6 - halo Cycloalkyl, C 1 -C 4 -alkyl-C 3 -C 6 -cycloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl , C 2 -C 6 -halothynyl, C 1 -C 4 -alkylthiol, C 1 -C 4 -haloalkylthio, C 1 -C 6 -alkylsulfonyl, C 6 -C 10 -arylsulfonyl, C 1 -C 6 -alkyl-SO 2 NH-, C 6 -C 10 -aryl-SO 2 NH-, formamyl, containing up to 4 selected from N, a 5-, 6- or 7-membered saturated heterocycloalkyl group of a hetero atom of O and S, or -C(R 4a )=N-OR 4b , wherein R 4a and R 4b independently of each other represent hydrogen, C 1 - C 6 -alkyl or phenyl; m is an integer and is 0, 1, 2, 3, 4 or 5; Y represents a 6-membered aromatic heterocyclic ring selected from the group consisting of: Wherein Y is connected to O via a bond identified by "U", and Y is linked to the CR 1 moiety via a bond identified by "V", and wherein R represents hydrogen, C 1 -C 2 -haloalkyl, C 1 -C 2 -haloalkoxy, C 1 -C 2 -alkylcarbonyl or halogen; each R 3 independently of one another represents halogen, CN, nitro, C 1 -C 4 -alkyl, C 1 -C 4 -halane a C 1 -C 4 -alkoxy group or a C 1 -C 4 -haloalkoxy group; and n is an integer and 0 or 1; the method is carried out by 1H-1,2,4-triazole Ethylene oxide of formula (II) is reacted in the presence of a base, Wherein R 1 , R 4 , m and Y are as defined in formula (I); characterized in that the reaction is carried out in the presence of a polyalkylene glycol. 根據請求項1之方法，其中R1代表氫、甲基、乙基、丙基、異丙基、丁基、環丙基、CF3、苯甲基、烯丙基、CH2C≡C-CH3或CH2C≡CH。 The method according to claim 1, wherein R 1 represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, CF 3 , benzyl, allyl, CH 2 C≡C- CH 3 or CH 2 C≡CH. 根據請求項1及2中至少一項之方法，其中各R4彼此獨立地代表CF3、OCF3、Br、Cl、五氟-λ6-氫硫基、環丙基、1-氟環丙基、1-氯環丙基、1-甲基環丙基、乙烯基、烯丙基、乙炔基、丙-2-炔基、SCH3、SCH2CH3、SCH2F、SCHF2、SCF3、甲基磺醯基、苯基磺醯基、甲基-SO2NH-、苯基-SO2NH-、甲醯基、二氧環戊烷基、二烷基 或-C(R4a)=N-OR4b，其中R4a和R4b彼此獨立地代表氫或C1-C4-烷基，較佳為氫、甲基、乙基、正丙基、異丙基、正丁基、異丁基或三級丁基，更佳為氫或甲基，及/或m 為1。 The method according to at least one of claims 1 and 2, wherein each R 4 independently of one another represents CF 3 , OCF 3 , Br, Cl, pentafluoro-λ 6 -hydrothiol, cyclopropyl, 1-fluorocyclopropane , 1-chlorocyclopropyl, 1-methylcyclopropyl, vinyl, allyl, ethynyl, prop-2-ynyl, SCH 3 , SCH 2 CH 3 , SCH 2 F, SCHF 2 , SCF 3 , methylsulfonyl, phenylsulfonyl, methyl-SO 2 NH-, phenyl-SO 2 NH-, formazan, dioxolane, two Alkyl or -C(R 4a )=N-OR 4b , wherein R 4a and R 4b independently of each other represent hydrogen or C 1 -C 4 -alkyl, preferably hydrogen, methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl or tert-butyl, more preferably hydrogen or methyl, and/or m is 1. 根據請求項1至3中至少一項之方法，其中Y 代表選自下列的6員芳族雜環： 其中Y係經由以「U」標識之鍵連接O，及Y係經由以「V」標識之鍵連接CR1部分，及其中R、R3和n係根據請求項1所定義。 The method according to at least one of claims 1 to 3, wherein Y represents a 6-membered aromatic heterocyclic ring selected from the group consisting of: Wherein Y is connected to O via a key identified by "U", and Y is connected to the CR 1 portion via a key identified by "V", and wherein R, R 3 and n are defined according to claim 1. 根據請求項1至4中至少一項之方法，其中Y 代表 其中Y係經由以「U」標識之鍵連接O，及Y係經由以「V」標識之鍵連接CR1部分，及其中R、R3和n係根據請求項1所定義。 According to at least one of the claims 1 to 4, wherein Y represents Wherein Y is connected to O via a key identified by "U", and Y is connected to the CR 1 portion via a key identified by "V", and wherein R, R 3 and n are defined according to claim 1. 根據請求項1至5中至少一項之方法，其中R 代表CF3或Cl，及/或n 為0。 The method according to at least one of claims 1 to 5, wherein R represents CF 3 or Cl, and/or n is 0. 根據請求項1至6中至少一項之方法，其中R1 代表甲基，R4 代表Br或Cl；m 為1；及 Y 代表 其中Y係經由以「U」標識之鍵連接O，及Y係經由以「V」標識之鍵連接CR1部分。 The method according to at least one of claims 1 to 6, wherein R 1 represents a methyl group, R 4 represents Br or Cl; m is 1; and Y represents Wherein Y is connected to O via a key identified by "U", and Y is connected to the CR 1 portion via a key identified by "V". 根據請求項1至7中至少一項之方法，其中該聚烷二醇係選自式(III)化合物 其中R2 代表C2-C4-伸烷基，及o 為從2至200之整數；及其混合物。 The method according to at least one of claims 1 to 7, wherein the polyalkylene glycol is selected from the group consisting of a compound of the formula (III) Wherein R 2 represents a C 2 -C 4 -alkylene group, and o is an integer from 2 to 200; and mixtures thereof. 根據請求項8之方法，其中R2代表伸乙基。 The method according to claim 8, wherein R 2 represents an ethyl group. 根據請求項8至9中至少一項之方法，其中o為從2至150，較佳為從2至100，更佳為2至50、3至40、4至30、4至20、4至15，最佳為4至10之整數。 The method according to at least one of claims 8 to 9, wherein o is from 2 to 150, preferably from 2 to 100, more preferably from 2 to 50, from 3 to 40, from 4 to 30, from 4 to 20, from 4 to 15, the best is an integer from 4 to 10. 根據請求項1至10中至少一項之方法，其中該鹼係選自Na2CO3、K2CO3、Cs2CO3、NaOH、KOH、KOtBu、NaH其混合物，更佳地選自KOH、K2CO3、Cs2CO3及其混合物。 The method according to at least one of claims 1 to 10, wherein the base is selected from the group consisting of Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH, KOtBu, NaH, more preferably selected from KOH K 2 CO 3 , Cs 2 CO 3 and mixtures thereof. 根據請求項1至11中至少一項之方法，其中該1H-1,2,4-***與該式(II)之環氧乙烷係以0.8：1至4：1，較佳為0.9：1至3：1，更佳為1：1至2：1之莫耳比反應。 The method according to at least one of claims 1 to 11, wherein the 1H-1,2,4-triazole and the ethylene oxide of the formula (II) are from 0.8:1 to 4:1, preferably 0.9. : 1 to 3:1, more preferably a molar ratio of 1:1 to 2:1. 根據請求項1至12中至少一項之方法，其中該聚烷二醇係以該反應混合物總重量為基準計至少2重量%之量存在，較佳為3至80重量%，4至20重量%，更佳為5至15重量%之量，每次係以該反應混合物總重量為基準計。 The method according to at least one of claims 1 to 12, wherein the polyalkylene glycol is present in an amount of at least 2% by weight, based on the total weight of the reaction mixture, preferably from 3 to 80% by weight, from 4 to 20% by weight. More preferably, the amount is from 5 to 15% by weight, based on the total weight of the reaction mixture. 根據請求項1至13中至少一項之方法，其中該反應係在C1-C10-醇的存在下進行，該醇較佳為正丁醇、正丙醇、異丙醇、乙醇、甲醇或其混合物，特別佳為正丁醇。 The method according to at least one of claims 1 to 13, wherein the reaction is carried out in the presence of a C 1 -C 10 -alcohol, preferably n-butanol, n-propanol, isopropanol, ethanol, methanol Or a mixture thereof, particularly preferably n-butanol. 根據請求項14之方法，其中聚烷二醇及C1-C10-醇之體積比為1：1至1：40，較佳為1：2至1：20，更佳為1：3至1：10。 According to the method of claim 14, wherein the volume ratio of the polyalkylene glycol to the C 1 -C 10 -alcohol is from 1:1 to 1:40, preferably from 1:2 to 1:20, more preferably from 1:3 to 1:10.
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