WO2019012161A1 - Process for the preparation of substituted (1h-1,2,4-triazol-1-yl)alcohols - Google Patents

Abstract

The present invention relates to a process for preparing (1H-1,2,4-triazol-1-yl) substituted alcohols of formula (I), wherein R ¹ , R ⁴ , m and Y are as defined in the description by reaction of 1H-1,2,4-triazole and oxirane of formula (II) in the presence of a base and polyalkylene glycol. The invention also relates to 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 according to said method.

Description

Process for the preparation of substituted (lH-l,2,4-triazol-l-yl)alcohols

The present invention relates to a process for preparing substituted (lH-l,2,4-triazol-l-yl)alcohols.

Certain substituted (lH-l,2,4-triazol-l-yl)alcohols are known to be useful in the field of crop protection, in particular as fungicides. WO 2017/029179 Al discloses such substituted (lH-l,2,4-triazol-l-yl)alcohols and several routes to synthesize those. One of said routes is referred to in WO 2017/029179 Al as process B and comprises ring-opening of suitable oxirane derivatives by reacting said oxirane derivatives with 1H- 1 ,2,4-triazole in the presence of a base and optionally an organic solvent. Such procedure provides access to the target (lH-l,2,4-triazol-l-yl)alcohols. However, to allow efficient synthesis in an industrial scale further improvement of the process, e.g. in terms of yield, purity and/or use of environmental sustainable solvents, is desirable.

Hence, object of the invention is providing an improved process for the synthesis of substituted ( 1H- 1,2,4- triazol- 1 -yl)alcohols.

Surprisingly, it has been found that (lH-l,2,4-triazol-l-yl)alcohols can be synthesized in high yield by reacting suitable oxirane derivatives with lH-l,2,4-triazole in the presence of a base and polyalkylene glycol.

Accordingly, subject of this invention is a process for preparing compounds of formula (I)

wherein

R¹ represents hydrogen, Ci-C6-alkyl, C₂-C6-alkenyl, C₂-C6-alkynyl, Cs-Cs-cycloalkyl, C3-C8- cycloalkyl-Ci-C₄-alkyl or C6-Ci₄-aryl, wherein the aliphatic moieties, excluding cycloalkyl moieties, of R¹ may carry 1 , 2, 3 or up to the maximum possible number of identical or different groups R^a which independently of one another are selected from halogen, CN, nitro, phenyl, Ci-C₄-alkoxy and Ci-C₄-halogenalkoxy, wherein the phenyl may be substituted by 1, 2, 3, 4 or 5 substituents selected independently from each other from halogen, CN, nitro, Ci-C₄-alkyl, Ci-C₄-alkoxy, Ci-C₄-halogenalkyl, C₁-C4- halogenalkoxy, and wherein the cycloalkyl and/or C6-Ci₄-aryl moieties of R¹ may carry 1, 2, 3, 4, 5 or up to the maximum number of identical or different groups R^b which independently of one another are selected from halogen, CN, nitro, Ci-C₄-alkyl, Ci-C₄-alkoxy, Ci-C₄-halogenalkyl and C₁-C₄- halogenalkoxy; each R⁴ represents independently of one another halogen, CN, nitro, Ci-C₄-alkyl, Ci-C₄-halogenalkyl, Ci-C₄-alkoxy, Ci-C₄-halogenalkoxy, Ci-C₄-alkylcarbonyl, hydroxy-substituted Ci-C₄-alkyl, pentafluoro- ⁶-sulfanyl, C3-C6-cycloalkyl, C3-C6-halogencycloalkyl, Ci-C₄-alkyl-C3-C6-cycloalkyl, C₂-C6-alkenyl, C₂-C6-halogenalkenyl, C₂-C6-alkynyl, C₂-C6-halogenalkynyl, Ci-C₄-alkylsulfanyl, Ci-C₄-halogenalkylsulfanyl, Ci-C6-alkylsulfonyl, C6-Cio-arylsulfonyl, Ci-C6-alkyl-S0₂NH-, Ce-Cio- aryl-S0₂NH-, formyl, 5-, 6- or 7-membered saturated heterocycloalkyl containing up to 4 heteroatoms selected from N, O and S, or -C(R^4a)=N-OR^4b, wherein R^4a and R^4b represent independently from each other hydrogen, Ci-C6-alkyl or phenyl; m is an integer and is 0, 1 , 2, 3, 4 or 5;

Y represents a 6-membered aromatic heterocycle selected from

wherein Y is connected to the O via the bonds identified with "U" and Y is connected to the CR¹ moiety via the bonds identified with "V" and wherein

R represents hydrogen, Ci-C₂-halogenalkyl, Ci-C₂-halogenalkoxy, Ci-C₂-alkylcarbonyl or halogen; each R represents independently from each other halogen, CN, nitro, Ci-C4-alkyl, C1-C4- halogenalkyl, Ci-C4-alkoxy or Ci-C4-halogenalkoxy; and - - n is an integer and is 0 or 1 ; by reacting lH-l,2,4-triazole and an oxirane of formula (II)

wherein

R¹, R⁴, m and Y are defined as in formula (I); in the presence of a base and polyalkylene glycol.

The process allows producing compounds of formula (I) in at least partially crystalline form.

Formula (I) provides a general definition of the triazole derivatives obtainable by the process according to the invention. Preferred radical definitions for the formulae shown above and below are given below. These definitions apply to the end products of formula (I) and likewise to all educts and intermediates, e.g. the oxiranes of formula (II).

R¹ preferably represents hydrogen, Ci-C4-alkyl, C₂-C6-alkenyl, C₂-C6-alkynyl, cyclopropyl or Ce-Cio- aryl, wherein the aliphatic moieties, excluding the cycloalkyl moieties, of R¹ may carry 1 , 2, 3 or up to the maximum possible number of identical or different groups R^a which independently of one another are selected from halogen, CN, nitro, phenyl, Ci-C4-alkoxy and Ci-C4-halogenalkoxy, wherein the phenyl may be substituted by 1, 2, 3, 4 or 5 substituents selected independently of one another from halogen, CN, nitro, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-halogenalkyl, C1-C4- halogenalkoxy, and wherein the cycloalkyl and/or C6-Cio-aryl moieties of R¹ may carry 1, 2, 3, 4, 5 or up to the maximum number of identical or different groups R^b which independently of one another are selected from halogen, CN, nitro, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-halogenalkyl and C1-C4- halogenalkoxy.

R¹ more preferably represents hydrogen, Ci-C₄-alkyl, C₂-C6-alkenyl, C₂-C6-alkynyl, cyclopropyl or phenyl, wherein the aliphatic moieties, excluding the cycloalkyl moieties, of R¹ may carry 1 , 2, 3 or up to the maximum possible number of identical or different groups R^a which independently of one another are selected from halogen, CN, nitro, phenyl, Ci-C4-alkoxy and Ci-C4-halogenalkoxy, wherein the phenyl may be substituted by 1, 2, 3, 4 or 5 substituents selected independently of one another from halogen, CN, nitro, Ci-C₄-alkyl, Ci-C₄-alkoxy, Ci-C₄-halogenalkyl, C₁-C₄- halogenalkoxy, and wherein the cycloalkyl and/or phenyl moieties of R¹ may carry 1, 2, 3, 4, 5 or up to the maximum number of identical or different groups R^b which independently of one another are selected from halogen, CN, nitro, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-halogenalkyl and C1-C4- halogenalkoxy.

R¹ more preferably represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, allyl, CH₂C≡C-CH₃ or CH₂C≡CH, wherein the aliphatic groups R¹ may carry 1 , 2, 3 or up to the maximum possible number of identical or different groups R^a which independently of one another are selected from halogen, CN, nitro, phenyl, Ci-C4-alkoxy and Ci-C4-halogenalkoxy, wherein the phenyl may be substituted by 1, 2, 3, 4 or 5 substituents selected independently of one another from halogen, CN, nitro, Ci-C₄-alkyl, Ci-C4-alkoxy, Ci-C4-halogenalkyl, Ci-C4-halogenalkoxy.

R¹ more preferably represents hydrogen or non-substituted methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, CF₃, benzyl, allyl, CH₂C≡C-CH₃ or CH₂C≡CH.

R¹ more preferably represents hydrogen, methyl or ethyl.

R¹ more preferably represents hydrogen or methyl.

R¹ most preferably represents methyl.

Each R⁴ preferably represents independently from each other methyl, ethyl, n-propyl, iso-propyl, CF₃, OCF3, Br, CI, pentafluoro^⁶-sulfanyl, cyclopropyl, 1 -halogencyclopropyl, l-Ci-C₄-alkylcyclopropyl, C₂-C6-alkenyl, C₂-C6-halogenalkenyl, C₂-C6-alkynyl, C₂-C6-halogenalkynyl, Ci-C₄-alkylsulfanyl, Ci-C₄-halogenalkylsulfanyl, Ci-C₄-alkylsulfonyl, phenylsulfonyl, Ci-C₄-alkyl-S0₂NH-, phenyl- S0₂NH-, formyl, aziridinyl, pyrrolidinyl, dihydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomoφholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, pyranyl, isoxazolidinyl, isoxazolinyl, pyrazolinyl, dihydropyrrolyl, tetrahydropyridinyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithiolanyl, dithianyl, or -C(R^4a)=N-OR^4b, wherein R^4a and R^4b represent independently from each other hydrogen, Ci-C6-alkyl or phenyl.

Each R⁴ more preferably represents independently from each other CF3, OCF3, Br, CI, pentafluoro-λ - sulfanyl, cyclopropyl, 1-fluorocyclopropyl, 1 -chlorocyclopropyl, 1 -methylcyclopropyl, vinyl, allyl, ethynyl, prop-2-ynyl, SCH₃, SCH₂CH₃, SCH₂F, SCHF₂, SCF₃, methylsulfonyl, phenylsulfonyl, methyl-S0₂NH-, phenyl-S0₂NH-, formyl, dioxolanyl, dioxanyl, or -C(R^4a)=N-OR^4b, wherein R^4a and R^4b represent independently from each other hydrogen or Ci-C4-alkyl, preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert. -butyl, more preferably hydrogen or methyl.

Each R⁴ more preferably represents independently from each other CF3, OCF3, Br, CI, pentafluoro-λ - sulfanyl, cyclopropyl, l-fluorocyclopropyl, 1 -chlorocyclopropyl, 1 -methylcyclopropyl, vinyl, allyl, ethynyl, prop-2-ynyl, SCH₃, SCH₂CH₃, SCH₂F, SCHF₂, SCF₃, formyl, l,3-dioxolan-2-yl, or -C(R^4a)=N-OR^4b, wherein R^4a represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert. -butyl, preferably hydrogen or methyl, R^4b represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert. -butyl, preferably hydrogen or methyl.

Each R⁴ more preferably represents independently from each other CF₃, OCF₃, Br, CI, pentafluoro-λ⁶- sulfanyl, cyclopropyl, ethynyl, SCH₃, SCF₃, formyl, l,3-dioxolan-2-yl, or -C(R^4a)=N-OR^4b, wherein R^4a represents hydrogen, and R^4b represents hydrogen.

Each R⁴ more preferably represents independently from each other CF₃, OCF₃, Br, CI, pentafluoro-λ - sulfanyl, cyclopropyl, ethynyl, SCH₃, SCF₃, formyl, or -CH=N-OH.

Each R⁴ more preferably represents independently from each other CF₃, OCF₃, Br, CI or pentafluoro- 6-sulfanyl. Each R⁴ most preferably represents independently from each other Br or CI.

Preferably, R⁴ is located in the 2- and/or 4-position of the phenyl moiety of formula (I).

More preferably, R⁴ is located in the 4-position of the phenyl moiety of formula (I). m preferably is 1, 2 or 3. m more preferably is 1 or 2. m most preferably is 1.

Y preferably represents a 6-membered aromatic heterocycle selected from

wherein Y is connected to the O via the bonds identified with "U" and Y is connected to the CR¹ moiety via the bonds identified with "V" and wherein R, R³ and n are defined as mentioned above for formula (I).

Y more preferably represents a 6-membered aromatic heterocycle selected from

wherein Y is comiected to the O via the bonds identified with "U" and Y is connected to the CR¹ moiety via the bonds identified with "V" and wherein R, R¹ and n are defined as mentioned above for formula (I).

Y more preferably represents a 6-membered aromatic heterocycle selected from

wherein Y is connected to the O via the bonds identified with "U" and Y is connected to the CR¹ moiety via the bonds identified with "V" and wherein R, R and n are defined as mentioned above for formula (I).

Y most preferably represents

wherein Y is connected to the O via the bonds identified with "U" and Y is connected to the CR¹ moiety via the bonds identified with "V" and wherein R, R³ and n are defined as mentioned above for formula (I). R preferably represents hydrogen, Ci-C2-halogenalkyl or halogen.

R more preferably represents hydrogen, Ci-halogenalkyl, F or CI.

R more preferably represents Ci-halogenalkyl, F or CI.

R more preferably represents CF3 or CI.

R most preferably represents CF3. Each R³ preferably represents independently from each other F, CI, Br, CN, nitro, methyl, CF₃, methoxy or OCF3. n preferably is 0.

The radical definitions and explanations given above in general terms or stated within preferred ranges can be combined with one another as desired, i.e. including between the particular ranges and preferred ranges. They apply both to the end products and correspondingly to educts and intermediates. In addition, individual definitions may not apply.

Preference is given to those cases in which each of the radicals have the abovementioned preferred definitions.

Particular preference is given to those cases in which each of the radicals have the abovementioned more and/or most preferred definitions.

Hence, particular preferred is a process for preparing a compound of formula (I), wherein

R¹ represents methyl,

R⁴ represents Br or CI; m is 1 ; and - -

Y represents

wherein Y is connected to the O via the bond identified with "U" and Y is connected to the CR¹ moiety via the bond identified with "V".

In the definitions of the symbols given in the above and below formulae, collective terms were used which are generally representative of the following substituents:

The definition Ci-C6-alkyl comprises the largest range defined here for an alkyl radical. Specifically, this definition comprises the meanings methyl, ethyl, n-, isopropyl, n-, iso-, sec-, tert-butyl, and also in each case all isomeric pentyls and hexyls, such as methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 -methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 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-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1, 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, 1- ethylbutyl, 2-ethylbutyl, l-ethyl-3-methylpropyl, in particular 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-methylpentyl. A preferred range is Ci-C4-alkyl, such as methyl, ethyl, n-, isopropyl, n-, iso-, sec-, tert-butyl. The definition Ci-C₂-alkyl comprises methyl and ethyl.

The definition halogen comprises fluorine, chlorine, bromine and iodine.

Halogen-substituted alkyl - e.g. referred to as halogenalkyl, halogenoalkyl or haloalkyl, e.g. C1-C4- halogenalkyl or Ci-C₂-halogenalkyl - represents, for example, Ci-C4-alkyl or Ci-C₂-alkyl as defined above substituted by one or more halogen substituents which can be the same or different. Preferably C₁-C4- halogenalkyl represents chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, 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-l -methylethyl, 2- fluoro- 1 , 1 -dimethylethyl, 2-fluoro- 1 -fluoromethyl- 1 -methylethyl, 2-fluoro- 1 , 1 -di(fluoromethyl)-ethyl, 1 - chlorobutyl. Preferably Ci-C₂-halogenalkyl represents chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, 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.

Mono- or multiple fluorinated Ci-C4-alkyl represents, for example, Ci-C4-alkyl as defined above substituted by one or more fluorine substituent(s). Preferably mono- or multiple fluorinated Ci-C4-alkyl represents fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 1 -fluoro- l-methylethyl, 2-fluoro- l , l-dimethylethyl, 2-fluoro- l - fluoromethyl- 1 -methylethyl, 2-fluoro- l, l -di(fluoromethyl)-ethyl, l -methyl-3-trifluoromethylbutyl, 3- methyl- 1 -trifluoromethylbutyl.

The definition C2-C6-alkenyl comprises the largest range defined here for an alkenyl radical. Specifically, this definition comprises the meanings ethenyl, n-, isopropenyl, n-, iso-, sec-, tert-butenyl, and also in each case all isomeric pentenyls, hexenyls, 1 -methyl- 1-propenyl, 1 -ethyl- 1 -butenyl. Halogen-substituted alkenyl - referred to as C2-C6-haloalkenyl - represents, for example, C2-C6-alkenyl as defined above substituted by one or more halogen substituents which can be the same or different.

The definition C2-C6-alkynyl comprises the largest range defined here for an alkynyl radical. Specifically, this definition comprises the meanings ethynyl, n-, isopropynyl, n-, iso-, sec-, tert-butynyl, and also in each case all isomeric pentynyls, hexynyls. Halogen-substituted alkynyl - referred to as C2-C6-haloalkynyl - represents, for example, C2-C6-alkynyl as defined above substituted by one or more halogen substituents which can be the same or different.

The definition Cs-Cs-cycloalkyl comprises monocyclic saturated hydrocarbyl groups having 3 to 8 carbon ring members, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The definition aryl comprises aromatic, mono-, bi- or tricyclic ring, for example phenyl, naphthyl, anthracenyl (anthryl), phenanthracenyl (phenanthryl).

The process according to the invention is performed in the presence of polyalkylene glycol. Preferably, the polyalkylene glycol is selected from polyalkylene glycols of formula (III)

wherein

R² represents C2-C4-alkylene, and o is an integer from 2 to 200; - - and mixtures thereof.

R² preferably represents ethylene, n-propylene or tetramethylene, more preferably represents ethylene.

0 preferably is an integer from 2 to 150, more preferably from 2 to 100, even more preferred 2 to 50, 3 to 40, 4 to 30, 4 to 20, or 4 to 15, most preferred 4 to 10. It is possible to use just one particular polyalkylene glycol, however, also mixtures of different polyalkylene glycols differing in R² and/or o can be used. Preferably, the polyalkylene glycols used differ only in o, i.e. the number of repeating units.

Particularly preferred the polyalkylene glycol is selected from tetraethylene glycol and the polyethylene glycol commercially available as PEG 400. The latter is a mixture of compounds of formula (III), wherein R² is ethylene and the average number of repeating units is about 8.2 to 9.1, resulting in an average molecular weight M_n of about 380 to 420 g/mol (gel permeation chromatography (GPC), polystyrol standard).

Preferably, the polyalkylene glycol is present in an amount of at least 2 % by weight based on the total weight of the reaction mixture, more preferred in an amount of 3 to 80 % by weight, even more preferred in an amount of 4 to 20 % by weight, and most preferred in an amount of 5 to 15 % by weight, each time based on the total weight of the reaction mixture. In case more than one polyalkylene glycol is present the given amounts refer to the sum of the amounts of all polyalkylene glycols.

It is possible to conduct the process without addition of any solvent, in particular, if a polyalkylene glycol being liquid under the process conditions is used. However, it is preferred to perform the process according to the invention in the presence of a Ci-Cio- alcohol, preferably n-butanol, n-propanol, isopropanol, ethanol, methanol, or mixtures thereof, particularly preferred n-butanol.

Preferably, the volumetric ratio of polyalkylene glycol and Ci-Cio-alcohol is 1 : 1 to 1 : 40, more preferred

1 : 2 to 1 : 20, and most preferred 1 : 3 to 1 : 10. In case more than one polyalkylene glycol and/or more than one Ci-Cio-alcohol is/are present the given ratios refer to the sum of the volumes of all polyalkylene glycols and the sum of the volumes of all Ci-Cio-alcohols.

It is possible to carry out the process according to the invention in the presence of an additional organic solvent, preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2- methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, teri-butyl methyl ether, toluene, N- methylpyridione (NMP), dimethylformamide (DMF) and mixtures thereof. However, preferably, no additional organic solvent is present, i.e. besides polyalkylene glycol only Ci-Cio-alcohol is present as organic solvent. The process according to the invention is performed in the presence of a base.

These preferably include alkali metal or alkaline earth metal acetates, amides, carbonates, hydrogencarbonates, hydrides, hydroxides or alkoxides, for example sodium acetate, potassium acetate or calcium acetate, lithium amide, sodium amide, potassium amide or calcium amide, 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, sodium hydroxide, potassium hydroxide or calcium hydroxide, n-butyllithium, sec- butyllithium, tert-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium methoxide, ethoxide, n- or i-propoxide, n-, i-, s- or t-butoxide or potassium methoxide, ethoxide, n- or i- propoxide, n-, i-, s- or t-butoxide; and also basic organic nitrogen compounds, for example trimethylamine, triethylamine, tripropylamine, tributylamine, ethyldiisopropylamine, N,N-dimethylcyclohexylamine, dicyclohexylamine, ethyldicyclohexylamine, Ν,Ν-dimethylaniline, N,N-dimethylbenzylamine, pyridine, 2- methyl-, 3-methyl-, 4-methyl-, 2,4-dimethyl-, 2,6-dimethyl-, 3,4-dimethyl- and 3,5-dimethylpyridine, 5- ethyl-2-methylpyridine, 4-dimethylaminopyridine, N-methylpiperidine, l,4-diazabicyclo[2.2.2]-octane (DABCO), l,5-diazabicyclo[4.3.0]-non-5-ene (DBN) or l,8-diazabicyclo[5.4.0]-undec-7-ene (DBU).

Preferably the base is selected from Na₂C0₃, K₂C0₃, Cs₂C0₃, NaOH, KOH, KOtBu, NaH and mixtures thereof, more preferably from KOH, K2CO3, CS2CO3 and mixtures thereof.

In a particular embodiment of the process according to the invention, a sodium or potassium salt of 1H- 1,2,4-triazole is used as base. Said sodium or potassium salt can be prepared by reacting lH-l,2,4-triazole and a sodium or potassium base, preferably selected from NaOH, NaH and Na-alcoholates or KOH and K- alcoholates, respectively. In this embodiment the sodium or potassium salt of lH-l,2,4-triazole acts as base and lH-l,2,4-triazole, i.e. lH-l,2,4-triazole and base are partially or fully replaced by the sodium or potassium salt of lH-l,2,4-triazole. In this embodiment, preferably lH-l,2,4-triazole and base are fully replaced by the sodium or potassium salt of lH-l,2,4-triazole. Preferably, the molar ratio of base and oxirane of formula (II) is 0.1 : 1 to 2 : 1, more preferred 0.2 : 1 to 0.6 : 1, and most preferred 0.35 : 1 to 0.45 : 1. In case more than one oxirane of formula (II) and/or more than one base is/are present the given ratios refer to the sum of the molar amounts of all oxiranes of formula (II) and the sum of the molar amounts of all bases.

Preferably, the lH-l,2,4-triazole and the oxirane of formula (II) are reacted in a molar ratio of 0.8 : 1 to 4 : 1, more preferred 0.9 : 1 to 3 : 1, most preferred 1 : 1 to 2 : 1. In case more than one oxirane of formula (II) is present the given ratios refer to the sum of the molar amounts of all oxiranes of formula (II).

Preferably, the process is carried out at a temperature of 20°C to 150°C, more preferred 120°C to 150°C, and most preferred 120°C to 140°C. The reaction time of the process according to the invention varies depending on the scale of the reaction and the reaction temperature, but is generally between a few, e.g. 5, minutes and 48 hours.

The process according to the invention is generally performed under standard pressure (1 arm). However, it is also possible to work under elevated or reduced pressure. The reaction mixture resulting from the process according to the invention can be worked-up 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 re-dissolved in a suitable organic solvent like ethyl acetate. Water is added and the pH (room temperature) is adjusted to about 6 by introduction of a strong acid like concentrated aqueous hydrochloric acid. The aqueous phase is extracted with a suitable organic solvent like ethyl acetate, and the combined organic phases are dried, preferably over magnesium sulfate. Preferably, the organic solvent is removed and the resulting crude product further purified by known techniques, for example recrystallization or chromatography. lH-l,2,4-triazole is readily available from commercial sources.

Oxiranes of formula (II) can be obtained by various routes in analogy to prior art processes known, in particular by process B disclosed in WO 2017/029179 Al .

A preferred process to obtain certain oxiranes of formula (II) is outlined below. Preferably, in the process according to the invention oxiranes of formula (Ila) obtained by this procedure are used:

In step A) of this process a compound of formula (IV)

wherein

Pv' represents hydrogen, Ci-C₂-halogenalkyl, Ci-C₂-halogenalkoxy, Ci-C₂-alkylcarbonyl, fluorine chlorine; and

X represents fluorine or chlorine; is prepared by reacting a compound of formula (V)

- - wherein

R' is defined as in formula (IV); with hydrogen chloride in the presence of dinitrogen trioxide or an organic nitrite.

Preferably, gaseous hydrogen chloride is used. This means the hydrogen chloride is added in gaseous state and remains in the gaseous state under the specific reaction conditions.

Step A) is preferably conducted at a temperature of from 0 to 30 °C and a pressure of from 0.5 to 2 bar.

Preferably, step A) is carried out in the presence of an solvent, preferably selected from dichloromethane, trichloromethane, tetrachloromethane, 1 ,2-dichloroethane, 1 , 1 , 1 -trichloroethane, 1 , 1 ,2-trichloroethane, cyclohexane, methylcyclohexane, heptane, hexane, trifluoromethylbenzene, 4- chloro-trifluoromethylbenzene, chlorobenzene, 1 ,2-dichlorobenzene, 1 ,3-dichlorobenzene, acetic acid, trifluoroacetic acid, nitrobenzene, tetrahydrofuran, methyltetrahydrofuran, in particular 2- methyltetrahydrofuran, dioxane, acetonitrile, diethylether, cyclopentyl methyl ether, teri-butyl methyl ether, toluene, dimethylformamide (DMF) and mixtures thereof, more preferably selected from dichloromethane, 1 ,2-dichloroethane, cyclohexane, nitrobenzene, chlorobenzene, dioxane, trifluoromethylbenzene, 4-chloro-trifluoromethylbenzene, 2-methyltetrahydrofuran, acetic acid, cyclopentyl methyl ether and mixtures thereof.

The organic nitrite is preferably selected from methyl nitrite, ethyl nitrite, isopropyl nitrite, isobutyl nitrite and teri-butyl nitrite. Preferred is teri-butyl nitrite.

Thereafter, a compound of formula (VI)

wherein

R¹ represents Ci-C6-alkyl, C₂-C6-alkenyl, C₂-C6-alkynyl, Cs-Cs-cycloalkyl, Cs-Cs-cycloalkyl-Ci-C/r alkyl, phenyl, phenyl-Ci-C4-alkyl, phenyl-C₂-C4-alkenyl or phenyl-C₂-C4-alkynyl; and

Pv' and X are defined as in formula (IV); is prepared by reacting the compound of formula (IV) in a first step B) with a compound of formula (VII) - -

R"MgZ (VII), wherein

R represents Ci-C6-alkyl or Cs-Cs-cycloalkyl; and Z represents chlorine or bromine; and reacting the resulting product in step C) with an anhydride of formula (VIII)

wherein

R¹ is defined as in formula (VI).

In step B) the compound of formula (IV) is reacted with a Grignard reagent. The Grignard reagent is represented by formula (VII). However, as generally known to the skilled person, Grignard compounds undergo a solvent-dependent equilibrium between different magnesium compounds that can be described by the so-called Schlenck equilibrium. The Schlenck equilibrium for the Grignard reagent according to formula (VII) can be schematically illustrated as follows:

2 R"MgZ (R")₂ g + MgZ^ (R")₂Mg ^* MgZ₂ Furthermore, it is known, that solvent molecules, in particular ethers such as diethylether or THF, which are commonly used for reactions with Grignard reagents, can add to the magnesium of the Grignard reagent thereby forming etherates. Hence, formula (VII) encompasses not only the structures as depicted, but also the structures resulting from the Schleck equilibrium as well as the respective solvent adducts.

For general information regarding structures of Grignard reagents, see also Milton Orchin, Journal of Chemical Education, Volume 66, Number 7, 1999, pp 586 to 588.

Finally, the compound of formula (VI) is further reacted to an oxirane derivative of formula (Ila)

₅ wherein

R' and R¹ are defined as in formula (VI); and R⁴ and m are defined as in formula (I); wherein the reaction of the compound of formula (VI) to the oxirane derivative of formula (Ila) comprises the following steps : step D): reacting the compound of formula (VI) with a phenol derivative of formula (IX)

wherein

R⁴ and m are defined as in formula (I); in the presence of a base to a compound of formula (X)

wherein

R\ R^1', R⁴ and m are defined as in formula (Ila); and step E): reacting the compound of formula (X) with a trimethylsulfoxonium halide, a trimethylsulfonium halide, trimethylsulfoxonium methylsulfate or trimethylsulfonium methylsulfate to the epoxide of formula (Ila).

Formulae given above provide a general definition of the compounds involved in the process to obtain oxiranes of formula (Ila). Preferred radical definitions for said formulae regarding R⁴ and m are given above and regarding R', R¹ , Z and R" below. These definitions apply to the oxiranes of formula (Ila) and likewise to all educts and intermediates bearing the respective radical(s). R' preferably represents Ci-C2-halogenalkyl or Ci-C₂-halogenalkoxy.

R' more preferably represents Ci-halogenalkyl.

R' more preferably represents CF₃, CHF₂, CH₂F, OCF₃, OCHF₂ or OCH₂F. R' most preferably represents CF₃.

R¹ preferably represents Ci-C₄-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, cyclopropyl, phenyl, benzyl, phenylethenyl or phenylethinyl.

R¹ more preferably represents methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, CF₃, allyl, CH₂C≡C-CH₃ or CH₂C≡CH.

R¹ more preferably represents methyl, ethyl, propyl, isopropyl, butyl or cyclopropyl.

R¹ more preferably represents methyl or ethyl.

R¹ most preferably represents methyl.

Z most preferably represents chlorine.

R' ' preferably represents G-C₄-alkyl or C₂-C6-cycloalkyl.

R' ' more preferably represents methyl, ethyl, propyl, isopropyl, butyl or cyclopropyl.

R' ' more preferably represents methyl, ethyl, propyl, isopropyl or butyl.

R' ' most preferably represents isopropyl.

In step B) Grignard compounds may be formed, which are represented by formula (IV-Gr) and/or (IV-Br)

wherein R', X and Z are defined as outlined above.

As outlined above with regard to the Grignard reagents of formula (VII), Grignard compounds generally undergo a solvent-dependent equilibrium between different magnesium compounds that can be described by the so-called Schlenck equilibrium. The respective remarks above apply for compounds of formulae (IV-Gr) and (IV-Br) mutatis mutandis. - 7 -

Generally, one may work-up the reaction product resulting from step B) for example in order to isolate, concentrate, dilute or purify the Grignard compound or a solution or suspension thereof. However, it is preferred to conduct step B) and step C) without any treatment like isolation or purification of the reaction product resulting from step B). It is particularly preferred to add the reaction mixture resulting from step B) to the anhydride of formula (VIII).

Preferably, steps B) and C) are carried out in the presence of an aprotic solvent, preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, ieri-butyl methyl ether, toluene and mixtures thereof, more preferably from tetrahydrofuran, toluene and mixtures thereof. Preferably, steps B) and C) are carried out at a temperature of -30°C to 50°C, preferably - 10°C to 10°C.

Preferably, the compound of formula (IV) and the compound of formula (VII) are reacted in a molar ratio of 1 : 0.8 to 1 : 1.5, more preferred 1 : 0.9 to 1 : 1.4, more preferred about 1 : 1 to 1 : 1.3, most preferred 1 : 1 to 1 : 1.1.

The Grignard reagent of formula (VII) is preferably used as solution in an aprotic solvent, in particular as solution in tetrahydrofuran, particularly preferred as a 1.0 to 3.0 molar solution in tetrahydrofuran.

Typically, the Grignard reagent of formula (VII) is added as solution in an aprotic solvent, preferably tetrahydrofuran, to a reaction vessel or flask containing the compound of formula (IV) and an aprotic solvent, preferably toluene.

Preferably, the molar ratio of compound of formula (IV) and anhydride of formula (VIII) is 1 : 1 to 1 : 2, more preferred 1 : 1.05 to 1 : 1.8, more preferred 1 : 1.1 to 1 : 1.5, most preferred 1 : 1.1 to 1 : 1.3.

Preferably, step B) and step C) are carried out under anhydrous conditions, preferably under argon atmosphere.

Preferably, step C) is conducted in the absence of a copper catalyst, more preferred in the absence of any catalyst. Even more preferred also in step B) no catalyst is present. The reaction mixture resulting from step C) can be worked-up by procedures generally known in the art. Preferably, after completion of the reaction, the reaction mixture is quenched by addition of water and/or saturated aqueous ammonium chloride solution, the resulting organic and aqueous phases are separated, the aqueous phase is extracted with an organic solvent, preferably toluene, and the combined organic phases are washed, preferably with a saturated aqueous NaCl solution, dried, preferably over magnesium sulfate, and filtered. The resulting solution of the compound of formula (VI) can be directly used 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. The process yields the compounds of formula (VI) in high purity. However, if desired, the compounds of formula (VI) may be further purified by known techniques, for example distillation or chromatography.

Step D) is carried out in the presence of a base. These preferably include alkali metal or alkaline earth metal acetates, amides, carbonates, hydrogencarbonates, hydrides, hydroxides or alkoxides, for example sodium acetate, potassium acetate or calcium acetate, lithium amide, sodium amide, potassium amide or calcium amide, 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, sodium hydroxide, potassium hydroxide or calcium hydroxide, n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium methoxide, ethoxide, n- or i-propoxide, n-, i-, s- or t-butoxide or potassium methoxide, ethoxide, n- or i-propoxide, n-, i-, s- or t-butoxide; and also basic organic nitrogen compounds, for example trimethylamine, triethylamine, tripropylamine, tributylamine, ethyldiisopropylamine, Ν,Ν-dimethylcyclohexylamine, dicyclohexylamine, ethyldicyclohexylamine, N,N- dimethylaniline, N,N-dimethylbenzylamine, pyridine, 2-methyl-, 3 -methyl-, 4-methyl-, 2,4-dimethyl-, 2,6- dimethyl-, 3,4-dimethyl- and 3,5-dimethylpyridine, 5-ethyl-2-methylpyridine, 4-dimethylaminopyridine, N-methylpiperidine, l,4-diazabicyclo[2.2.2]-octane (DABCO), l,5-diazabicyclo[4.3.0]-non-5-ene (DBN) or l,8-diazabicyclo[5.4.0]-undec-7-ene (DBU).

Preferably the base is selected from Na₂C0₃, K₂C0₃, Cs₂C0₃, NaOH, NaOMe, KOMe, KOtBu, NaH and mixtures thereof, more preferably form NaOMe, KOMe, K₂CO3, CS₂CO3 and mixtures thereof. Particular preferred the base is selected from KOMe and K₂CO3.

The phenolate nucleophile can be generated in-situ by use of the abovementioned bases or prepared from the phenol derivative of formula (IX) and the base and possibly isolated prior to the reaction. When NaOMe or KOMe are used as bases to achieve this, the generated MeOH is preferably distilled off together with all or a portion of any present solvent. Preferably, step D) is carried out in the presence of a solvent, preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, tert-buiyl methyl ether, methyl isobutyl ketone, methyl ethyl ketone, toluene, dimethylformamide (DMF), 1-propanol, 2-propanol, 1-butanol, polyalkylene glycol, in particular polyethylene glycol (PEG), and mixtures thereof. More preferably step D) is carried out in the presence of methyl isobutyl ketone, methyl ethyl ketone, toluene, 1-propanol, 2-propanol, 1-butanol, PEG 400 or mixtures thereof. Most preferably the reaction is carried out in the presence of toluene, 1-propanol, 2-propanol, 1-butanol, PEG 400 or any mixture thereof. - -

The reaction is completed faster in the presence of a suitable catalyst. Hence, preferably step D) is carried out in the presence of a catalyst, preferably l,4-diazabicyclo[2.2.2]-octane (DABCO). Preferably, the catalyst is present in an amount of from 1 to 20 mol%, based on the amount of compound of formula (VI).

Preferably, the reagents used in step D) are mixed at room temperature (23 °C). After mixing the reagents, preferably the temperature is increased. Preferably, step D) is carried out at an elevated temperature from 30°C to 150°C, preferably 50°C to 100°C.

The reaction mixture resulting from step D) can be worked-up by procedures generally known in the art. Preferably, after completion of the reaction, the reaction mixture is quenched by addition of water and/or saturated aqueous ammonium chloride solution, the resulting organic and aqueous phases are separated, the aqueous phase is extracted with an organic solvent, preferably toluene, and the combined organic phases are washed, preferably with a saturated aqueous NaCl solution, dried, preferably over magnesium sulfate, and filtered. The resulting solution of the compound of formula (X) or the crude product obtained by evaporation of the organic solvent can be directly used in step E). However, if desired, the compounds of formula (X) may be further purified by known techniques, for example recrystallization or chromatography.

In step E) compounds of formula (X) are converted into epoxides of formula (Ila) by reaction with a trimethylsulfoxonium halide, a trimethylsulfonium halide, trimethylsulfoxonium methylsulfate or trimethylsulfonium methylsulfate, preferably trimethylsulfoxonium chloride, trimethylsulfonium chloride, trimethylsulfoxonium methylsulfate or trimethylsulfonium methylsulfate. It is possible to prepare the trimethylsulfoxonium halide, trimethylsulfonium halide, trimethylsulfoxonium methylsulfate or trimethylsulfonium methylsulfate separately before using it in step E). However, it is also possible to prepare said reagents in situ, e.g. trimethylsulfonium methylsulfate from a mixture of dimethylsulfide and dimethylsulfate, preferably in the presence of a base such as sodium hydroxide or potassium hydroxide.

The trimethylsulfoxonium halide, trimethylsulfonium halide, trimethylsulfoxonium methylsulfate or trimethylsulfonium methylsulfate is preferably used in an amount of 1.1 to 2.5, in particular 1.2 to 2, more preferred 1.3 to 1.6 mole equivalents per 1 mole of compound of formula (X).

Preferably, trimethylsulfonium methylsulfate is used. Particularly preferred an aqueous solution of trimethylsulfonium methylsulfate is used, preferably an aqueous solution containing 38 to 40 wt%, preferably 38 to 39.5 wt%, more preferred 38 to 39.0 wt% of trimethylsulfonium kation. Preferably, step E) is carried out at a temperature of -30°C to 50°C, preferably - 10°C to 40°C, particularly preferred 20°C to 40°C.

Step E) is preferably conducted in the presence of water, dimethylsulfide or a mixture thereof. It is preferably carried out in the presence of a base. Preferably the base is selected from Na₂CC>3, K₂CO3, Cs₂C0₃, NaOH, KOH, KOtBu, NaH and mixtures thereof, more preferably the base is KOH.

The reaction mixture resulting from step E) can be worked-up by procedures generally known in the art. Preferably, after completion of the reaction, the reaction mixture is quenched by addition of water. Resulting organic and aqueous phases are separated, the aqueous phase is extracted with an organic solvent, preferably teri-butyl methyl ether. The resulting solution of the compound of formula (Ila) or the crude product obtained by evaporation of the organic solvent and other volatile components can be directly used in the process according to the invention. However, if desired, the compounds of formula (Ila) may be further purified by known techniques, for example recrystallization or chromatography. The reaction time of each of the steps of the process outlined above varies depending on the scale of the reaction and the reaction temperature, but is generally between a few, e.g. 5, minutes and 48 hours.

If not defined otherwise, the process steps are generally performed under standard pressure (1 atm). However, it is also possible to work under elevated or reduced pressure.

As outlined above, the process according to the invention allows producing compounds of formula (I) in solid form, in particular in at least partially crystalline form. It has now be found that the compound of formula (I) 2- [6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3 -yl] - 1 -( 1 H- 1 ,2,4-triazol- 1 -yl)propan-2- ol occurs in different polymorphic forms (herein also named as polymorphs or crystalline forms).

Polymorphism is the ability of a compound to crystallize in different crystalline phases with different arrangements and/or conformations of the molecules in the crystal lattice. Hence, polymorphs are different crystalline forms of the same pure chemical compound. On account of the different arrangement and/or conformation of molecules, polymorphs exhibit different physical, chemical and biological properties. Properties which may be affected include but are not limited solubility, dissolution rate, stability, optical and mechanical properties, etc. The relative stability of a polymorph depends on its free energy, i.e. a more stable polymorph has a lower free energy. Under a defined set of experimental conditions only one polymorph has the lowest free energy. This polymorph is the thermodynamically stable form and all other polymorph(s) is (are) termed metastable form(s). A metastable form is one that is thermodynamically unstable but can nevertheless be prepared, isolated and analyzed as a result of its relatively slow rate of transformation.

The occurrence of active substances in different polymorphic forms is of decisive importance for the production in industrial scale as well as for the development of formulations containing the active substance, as unwanted phase change can lead to thickening and potentially solidification of the formulation and/or large crystals, which can lead to blockages in application equipment, e.g. in spray nozzles in agricultural application machinery. The knowledge of the existence of crystalline modifications and their properties is thus of high relevance. Each polymorph is characterized by a specific, uniform packing and arrangement of the molecules in the solid state. Nevertheless, it is generally not predictable whether a given chemical compound forms polymorphs at all and if so, which physical and biological properties the different polymorphs may have.

In addition pseudopolymophic forms, named hydrates or solvates, can occur. A solvate is a crystalline molecular compound in which molecules of the solvent of crystallisation are incorporated into the host lattice, consisting of unsolvated molecules. A hydrate is a special case of a solvate, when the incorporated solvent is water. The presence of solvent molecules in the crystal lattice influences the intermolecular interactions and confers unique physical properties to each solvate. A solvate thus has its own characteristic values of internal energy, enthalpy, entropy, Gibbs free energy, and thermodynamic activity. In the following a crystalline form A of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH- 1 ,2,4-triazol- 1 -yl)propan-2-ol is disclosed. 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]- 1 - (lH-l,2,4-triazol-l-yl)propan-2-ol is the compound of formula (I), wherein

R¹ represents methyl,

R⁴ represents Br; m is 1 ; and

Y represents

wherein Y is connected to the O via the bond identified with "U" and Y is connected to the CR¹ moiety via the bond identified with "V".

The polymorphic form A can be obtained by applying specific crystallisation conditions.

For example, it is obtained by a process comprising the following steps: a) diluting and/or suspending 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4- triazol- 1 -yl)propan-2-ol in a mixture of 4 parts by volume of acetone and 1 part by volume of water; b) heating the same to boiling temperature of the solvent mixture; c) cooling the solution or slurry obtained in step b) to about 50°C; and d) keeping the solution or slurry at said temperature until all solvent has been evaporated.

Crystals of polymorphic form A of suitable size and quality for crystallographic studies are for example obtained by diluting and/or suspending 400 mg 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-

1- (lH- l,2,4-triazol-l-yl)propan-2-ol in 40 ml of a mixture of 4 parts by volume of acetone and 1 part by volume of water followed by process steps b) to d) described above.

2- [6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]- 1 -(1H- 1 ,2,4-triazol- 1 -yl)propan-2-ol in step a) can essentially be any known form of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH- 1 ,2,4-triazol- 1 -yl)propan-2-ol. This means that 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]- l-(lH-l,2,4-triazol-l-yl)propan-2-ol can be used in amorphous form or in a mixture of different polymorphic forms or in a mixture containing an amorphous and one or more different polymorphic forms.

The polymorphic form A of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4- triazol- 1 -yl)propan-2-ol can be characterized by X-ray powder diffractometry on the basis of the respective diffraction diagrams, which are recorded at 25°C and with Cu-Κα 1 radiation (1.5406 A). The polymorphic form A displays at least 3, often at least 5, in particular at least 7, more particularly at least 10, and especially all of the reflections quoted in the following as values:

Table 1: X-ray reflections of polymorphic form A

The polymorphic form A is in particular characterized by at least the reflections, quoted as 2Θ value ± 0.2°, 14.2±0.2°, 14.9±0.2° and 18.8±0.2°, more particularly by at least the reflections 14.2±0.2°, 14.9±0.2°, 18.8±0.2°, 23.3±0.2° and 28.0±0.2°, more particularly by at least the reflections 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 by at least the reflections 14.2±0.2°, 14. 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° and 28.0±0.2°.

The polymorphic form A is further characterized by the X-ray powder diffractogram depicted in Fig. la.

The polymorphic form A of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4- triazol- 1 -yl)propan-2-ol can be characterized by Raman spectroscopy on the basis of the respective spectrum, which are recorded at 25°C and with a laser wavelength of 1064 nm and a resolution of 2 cm . The polymorphic form A displays at least 3, often at least 5, in particular at least 7, and especially all of the bands quoted in the following as peak maxima:

Table 2: Raman bands of polymorphic form A

Fig. lb shows the FT Raman spectrum of polymorphic form A of 2-[6-(4-bromophenoxy)-2- (trifluoromethyl)pyridin-3-yl]- 1 -(1H- 1 ,2,4-triazol- 1 -yl)propan-2-ol.

The polymorphic form A of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4- triazol- 1 -yl)propan-2-ol can be characterized by infrared spectroscopy on the basis of the respective spectrum, which are recorded at 25°C using an universal diamond ATR device and a resolution of 4 cm⁴. The polymorphic form A displays at least 3, often at least 5, in particular at least 7, and especially all of the bands quoted in the following as peak maxima: - - Table 3: IR bands of polymorphic form A

Fig. lc shows the IR spectrum of polymorphic form A of 2-[6-(4-bromophenoxy)-2- (trifluoromethyl)pyridin-3-yl]- 1 -(1H- 1 ,2,4-triazol- 1 -yl)propan-2-ol. In addition to the polymorphic form A of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l- (lH- l,2,4-triazol-l-yl)propan-2-ol a polymorphic form B of 2-[6-(4-bromophenoxy)-2- (trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4-triazol-l-yl)propan-2-ol as well as an amorphous form have been identified, which are further characterized in the following.

The polymorphic form B can be obtained by applying specific crystallisation conditions. For example, it is obtained by a process comprising the following steps: a) diluting and/or suspending 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4- triazol- 1 -yl)propan-2-ol in a suitable solvent or solvent mixture, selected from ethylacetate, ethylacetate / n- heptane (1 : 10 parts by volume) and methanol; b) heating the same to boiling temperature of the solvent or solvent mixture; and c) cooling the solution or slurry obtained in step b) to a temperature of less than 25°C.

Crystals of polymorphic form B of suitable size and quality for crystallographic studies are for example obtained by diluting and/or suspending 100 mg 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]- l-(lH-l,2,4-triazol-l-yl)propan-2-ol in 10 ml methanol, heating the same to boiling temperature, cooling the obtained solution to 25°C whilst adding 100 ml water, storing the resulting suspension at 25°C for 24 hours, before filtration and evaporation of the adsorbed solvent at 25°C. - 5 -

2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]- 1 -(1H- 1 ,2,4-triazol- 1 -yl)propan-2-ol in step a) can essentially be any known form of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH- 1 ,2,4-triazol- 1 -yl)propan-2-ol. This means that 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]- l-(lH-l,2,4-triazol-l-yl)propan-2-ol can be used in amorphous form or in a mixture of different polymorphic forms or in a mixture containing an amorphous and one or more different polymorphic forms.

The polymorphic form B of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4-triazol- 1 -yl)propan-2-ol can be characterized by X-ray powder diffractometry on the basis of the respective diffraction diagrams, which are recorded at 25°C and with Cu-Κα 1 radiation (1.5406 A). The polymorphic form B displays at least 3, often at least 5, in particular at least 7, more particularly at least 10, and especially all of the reflections quoted in the following as values:

Table 4: X-ray reflections of polymorphic form B

The polymorphic form B is in particular characterized by at least the reflections, quoted as 2Θ value ± 0.2°, 18.3±0.2°, 24.5±0.2° and 26.8±0.2°, more particularly by at least the reflections 18.3±0.2°, 21.7±0.2°, 21.8±0.2°, 24.5±0.2° and 26.8±0.2°, more particularly by at least the reflections 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 by at least the reflections 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° and 26.8±0.2°.

The polymorphic form B is further characterized by the X-ray powder diffractogram depicted in Fig. 2a The polymorphic form B of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4-triazol- l-yl)propan-2-ol can be characterized by Raman spectroscopy on the basis of the respective spectrum, which are recorded at 25°C and with a laser wavelength of 1064 nm and a resolution of 2 cm . The polymorphic form B displays at least 3, often at least 5, in particular at least 7, and especially all of the bands quoted in the following as peak maxima:

Table 5: Raman bands of polymorphic form B

Fig. 2b shows the FT Raman spectrum of polymorphic form B of 2-[6-(4-bromophenoxy)-2- (trifluoromethyl)pyridin-3-yl]- 1 -(1H- 1 ,2,4-triazol- 1 -yl)propan-2-ol.

The polymorphic form B of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4-triazol- 1 -yl)propan-2-ol can be characterized by infrared spectroscopy on the basis of the respective spectrum, which are recorded at 25°C using an universal diamond ATR device and a resolution of 4 cm^"1. The polymorphic form B displays at least 3, often at least 5, in particular at least 7, and especially all of the bands quoted in the following as peak maxima:

Table 6: IR bands of polymorphic form B

IR band [peak maxima in cm^"1]

Form B

3142 1470 1 156 933 650

3113 1454 1 133 900 610

2997 1396 1092 874

2970 1375 1065 843

1739 1333 1043 818

1604 1280 1019 787

1580 1240 101 1 750 - 7 -

Fig. 2c shows the IR spectrum of polymorphic form B of 2-[6-(4-bromophenoxy)-2- (trifluoromethyl)pyridin-3-yl]- 1 -(1H- 1 ,2,4-triazol- 1 -yl)propan-2-ol.

The amorphous form of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4-triazol- l- yl)propan-2-ol can be obtained by melting crystals of polymorphic form B of 2-[6-(4-bromophenoxy)-2- (trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4-triazol- l-yl)propan-2-ol at 150°C and storing the melt at 25°C to let it cool to that temperature.

The amorphous form is characterized by the IR spectrum depicted in Fig. 3a

The invention is illustrated by the examples below. However, the invention is not limited to the examples.

- -

Examples

Example 1 :

6-(4-bromophenoxy)-3-(2-methyloxiran-2-yl)-2-(trifluoromethyl)pyridine (225 g, 0.575 mol, 1 equivalent (in 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). 60.6 g of lH-l,2,4-triazole (0.862 mol, 1.5 equiv) and 15.2 g of K2CO3 (0.23 mol, 0.4 equiv) were added and the mixture was heated to 100 °C for 13 h. The solvent was removed under reduced pressure until a viscous light-brown oil remained. 3 L of ethyl acetate were added together with 1.5 L of water and 18 mL of concentrated aqueous hydrochloric acid. The phases were separated and the organic phase was washed with water. The organic phase was dried over Na2S04 and the solvent was removed under reduced pressure. The remaining oily residue crystallized quickly and was triturated 3 times with cyclohexane. The wet product was filtered and dried, yielding 240 g of beige crystals of 90%a/a HPLC purity (84.7% yield). The crystals were dissolved in 760 mL of isopropanol at 82 °C. 1 170 mL of water were added and after stirring at 80 °C for 5 minutes, the mixture was let cool down to room temperature overnight. The suspension was further cooled down to 10-15 °C, filtered and washed with 800 mL of water. The product was dried under vacuum at 50 °C to obtain 202 g of light-beige crystals of 97.9%a/a HPLC purity (77.6% yield).

Comparative example 1 :

To 800 mL of 1 -methyl-2-pyrrolidone were added 14.2 g of KOH (0.22 mol, 0.4 equiv.) and 45.4 g (1.2 equiv) of lH-l,2,4-triazole (0.644 mol, 1.2 equiv). Half of the solvent was removed in order to strip the generated water from the reaction mixture. To this clear solution, 6-(4-bromophenoxy)-3-(2-methyloxiran- 2-yl)-2-(trifluoromethyl)pyridine (225 g, 0.575 mol, 1 equiv) was added and the mixture was heated to 85 °C for 11 h. The solvent was removed under reduced pressure until a viscous brown oil remained. 3 L of ethyl acetate were added together with 1.5 L of water and 18 mL of concentrated aqueous hydrochloric acid. The phases were separated and the organic phase was washed with water. The organic phase was dried over Na2S04 and the solvent was removed under reduced pressure. The remaining oily residue crystallized slowly when seeded. The residue was triturated 3 times with cyclohexane. The wet product was filtered and dried, yielding 175 g of beige crystals of 89%a/a HPLC purity (64.8 % yield). The crystals were dissolved in 560 mL of isopropanol at 82 °C. 850 mL of water were added and after stirring at 70 °C for 5 minutes, the mixture was let cool down to room temperature overnight. The suspension was further cooled down to 10-15 °C, filtered and washed with 400 mL of water. The product was dried under vacuum at 45 °C to obtain 140 g of beige crystals of 98%a/a HPLC purity (57.7% yield).

This shows that process B known from WO 2017/029179 Al is inferior to the process according to the invention in terms of yield of the target compound. - -

Example 2:

6-(4-bromophenoxy)-3-(2-methyloxiran-2-yl)-2-(trifluoromethyl)pyridine of 91.7% purity (40 g, 98 mmol, 1 equiv) was added to a 80:20 v/v mixture of n-butanol and PEG400 (commercially available from Merck under the name Polyethylene glycol 400) (40 mL). 10.2 g of lH-l,2,4-triazole (147 mmol, 1.5 equiv) and 7.4 g of K₂CO3 (54 mmol, 0.55 equiv) were added and the mixture was heated to 118-120 °C for 3 h. The solvent was removed under reduced pressure and water was added to further remove the solvent azeotropically. The residue was brought to room temperature, filtered, and washed with water to obtain a crude product of 84%a/a of target compound and 8% of its 4N-isomer. 45 mL of toluene were added to the crude product and the mixture was heated to 70 °C. After cooling to 50 °C, some seeding crystals were added and the mixture was further cooled to 5 °C. The suspension was filtered, washed with mother liquor, cold toluene and with petrol ether and finally dried to obtain 31.7 g of target compound of 95.5%a/a HPLC purity (69.7% yield).

Comparative example 2:

6-(4-bromophenoxy)-3-(2-methyloxiran-2-yl)-2-(trifluoromethyl)pyridine of 98% purity (40 g, 105 mmol, 1 equiv) was added to n-butanol (40 mL). 10.9 g of lH-l,2,4-triazole (157 mmol, 1.5 equiv) and 8 g of K2CO3 (58 mmol, 0.55 equiv) were added and the mixture was heated to 118-120 °C for 3 h. The solvent was removed under reduced pressure and water was added to further remove the solvent azeotropically. The residue was brought to room temperature, filtered, and washed with water to obtain a crude product of 82%a/a of target compound and 18% of its 4N-isomer. 45 mL of toluene were added to the crude product and the mixture was heated to 70 °C. After cooling to 50 °C, some seeding crystals were added and the mixture was further cooled to 5 °C. The suspension was filtered, washed with mother liquor, cold toluene and with petrol ether and finally dried to obtain 39.9 g of target compound of 81.2%a/a HPLC purity (69.8% yield).

This shows that the process in the absence of PEG is inferior to the process according to the invention in terms of purity of the target compound.

Example 3:

6-(4-bromophenoxy)-3-(2-methyloxiran-2-yl)-2-(trifluoromethyl)pyridine of 94.4% purity (40 g, 100,9 mmol, 1 equiv) was added to 120 mL of PEG400 (commercially available from Merck under the name Polyethylene glycol 400). 10.5 g of lH-l,2,4-triazole (151.4 mmol, 1.5 equiv) and 5.6 g of K2CO3 (40.4 mmol, 0.4 equiv) were added and the mixture was heated to 110-120 °C for 4 h. After cooling the reaction mixture to room temperature, water (1.5 L) was added and the mixture was stirred thoroughly. The precipitated solid was filtered using a suction strainer and remaining smeary residues were triturated with more water until they turned solid, whereupon they were added to the filter cake on the suction strainer. After washing with water and further straining, 73.73 g wet crude product of 92.1%a/a HPLC purity were obtained as beige solid. The material was dissolved in 110 mL of isopropanol at 78 °C, stirred for 10 min and 160 mL of water were added. After stirring at 70 °C for 10 minutes, the mixture was let cool down to room temperature overnight. The suspension was filtered and the product was dried to obtain 35 g of off- white crystals of 97.6%a/a HPLC purity (76.4% yield). This shows that using PEG as sole solvent provides the target compound in high yield and purity even in the absence of a co-solvent.

Polymorphic forms of 2-[6-r4-bromophenoxy -2-rtrifluoromethyl pyridin-3-yll-l-ilH- 1.2.4-triazol-l- yl)propan-2-ol

All data which is part of the present application has been prepared according to the methods described below unless otherwise indicated. The samples used for measurement were directly used and did not undergo any further sample preparation.

XRPD

X-Ray diffraction patterns were recorded at room temperature using XRD -diffractometers X ert PRO (PANalytical) and STOE STADI-P (radiation Cu K alpha 1, wavelength 1.5406 A). All X-Ray reflections are quoted as °2Θ (theta) values (peak maxima) with a resolution of ±0.2°.

Raman

Raman spectra were recorded at room temperature using FT-Raman-spectrophotometers (model RFS 100 and MultiRam) from Bruker. Resolution was 2 cm . Measurements were performed in glass vials or aluminium discs.

IR

IR-ATR-spectra were recorded at room temperature using a FT-IR-spectrophotometer one with universal diamond ATR device from Perkin-Elmer. Resolution was 4 cm .

Claims

Claims

1. Process for preparing a com ound of formula (I)

wherein

R¹ represents hydrogen, Ci-C6-alkyl, C₂-C6-alkenyl, C₂-C6-alkynyl, C3-Cs-cycloalkyl, C3-C8- cycloalkyl-Ci-C₄-alkyl or C6-Ci₄-aryl, wherein the aliphatic moieties, excluding cycloalkyl moieties, of R¹ may carry 1, 2, 3 or up to the maximum possible number of identical or different groups R^a which independently of one another are selected from halogen, CN, nitro, phenyl, Ci-C₄-alkoxy and Ci-C4-halogenalkoxy, wherein the phenyl may be substituted by 1, 2, 3, 4 or 5 substituents selected independently from each other from halogen, CN, nitro, Ci-C₄-alkyl, Ci-C₄-alkoxy, Ci -C₄-halogenalkyl, Ci -C₄-halogenalkoxy, and wherein the cycloalkyl and/or C6-Ci₄-aryl moieties of R¹ may carry 1, 2, 3, 4, 5 or up to the maximum number of identical or different groups R^b which independently of one another are selected from halogen, CN, nitro, Ci-C₄-alkyl, Ci-C₄-alkoxy, Ci-C₄-halogenalkyl and Ci-C4-halogenalkoxy; each R⁴ represents independently of one another halogen, CN, nitro, Ci-C4-alkyl, C1-C4- halogenalkyl, Ci-C4-alkoxy, Ci-C4-halogenalkoxy, Ci-C4-alkylcarbonyl, hydroxy-substituted Ci-C₄-alkyl, pentafluoro- ⁶-sulfanyl, C3-C6-cycloalkyl, C3-C6-halogencycloalkyl, C₁-C₄- alkyl-C3-C6-cycloalkyl, C₂-C6-alkenyl, C₂-C6-halogenalkenyl, C₂-C6-alkynyl, C₂-C6- halogenalkynyl, Ci-C₄-alkylsulfanyl, Ci-C₄-halogenalkylsulfanyl, Ci-C6-alkylsulfonyl, Ce- Cio-arylsulfonyl, Ci-C6-alkyl-S0₂NH-, C6-Cio-aryl-SC>₂NH-, formyl, 5-, 6- or 7-membered saturated heterocycloalkyl containing up to 4 heteroatoms selected from N, O and S, or -C(R^4a)=N-OR^4b, wherein R^4a and R^4b represent independently from each other hydrogen, Ci-C6-alkyl or phenyl; m is an integer and is 0, 1 , 2, 3, 4 or 5;

Y represents a 6-membered aromatic heterocycle selected from

wherein Y is connected to the O via the bonds identified with "U" and Y is connected to the CR¹ moiety via the bonds identified with "V" and wherein

R represents hydrogen, Ci-C₂-halogenalkyl, Ci-C₂-halogenalkoxy, Ci-C₂-alkylcarbonyl or halogen; each R³ represents independently from each other halogen, CN, nitro, Ci-C4-alkyl, Ci- C4-halogenalkyl, Ci-C4-alkoxy or Ci-C4-halogenalkoxy; and n is an integer and is 0 or 1 ; by reacting lH-l,2,4-triazole and an oxirane of formula (II)

wherein

R^ R^ m and Y are defined as in formula (I); in the presence of a base, characterized in that the reaction is performed in the presence of polyalkylene glycol.

2. Process according to claim 1, wherein R¹ represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, CF₃, benzyl, allyl, CH₂C≡C-CH₃ or CH₂C≡CH.

3. Process according to at least one of claims 1 and 2, wherein each R⁴ represents independently from each other CF3, OCF3, Br, CI, pentafluoro- ⁶-sulfanyl, cyclopropyl, 1 -fluorocyclopropyl, 1 -chlorocyclopropyl, 1 -methylcyclopropyl, vinyl, allyl, ethynyl, prop-2-ynyl, SCH₃, SCH2CH3, SCH₂F, SCHF₂, SCF₃, methylsulfonyl, phenylsulfonyl, methyl-S02NH-, phenyl-S02NH-, formyl, dioxolanyl, dioxanyl, or -C(R^4a)=N-OR^4b, wherein R^4a and R^4b represent independently from each other hydrogen or Ci-C4-alkyl, preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert. -butyl, more preferably hydrogen or methyl, and/or m is 1.

4. Process according to at least one of claims 1 to 3, wherein

Y represents a 6-membered aromatic heterocycle selected from

wherein Y is connected to the O via the bonds identified with "U" and Y is connected to the CR¹ moiety via the bonds identified with "V" and wherein R, R³ and n are defined according to claim 1.

5. Process according to at least one of claims 1 to 4, wherein

Y represents

wherein Y is connected to the O via the bonds identified with "U" and Y is connected to the CR¹ moiety via the bonds identified with "V" and wherein R, R³ and n are defined according to claim 1.

Process according to at least one of claims 1 to 5, wherein

R represents CF3 or CI, and/or n is 0.

Process according to at least one of claims 1 to 6, wherein R¹ represents methyl, R⁴ represents Br or CI; m is 1 ; and Y represents

wherein Y is connected to the O via the bond identified with "U" and Y is connected to the CR¹ moiety via the bond identified with "V".

Process according to at least one of claims 1 to 7, wherein the polyalkylene glycol is selected from compounds of formula (III)

wherein

R² represents C2-C4-alkylene, and o is an integer from 2 to 200; and mixtures thereof.

9. Process according to claim 8, wherein R² represents ethylene.

10. Process according to at least one of claims 8 to 9, wherein o is an integer from 2 to 150, preferably from 2 to 100, more preferred 2 to 50, 3 to 40, 4 to 30, 4 to 20, 4 to 15, most preferred 4 to 10.

1 1. Process according to at least one of claims 1 to 10, wherein the base is selected from Na2C03, K2CO3, CS2CO3, NaOH, KOH, KOtBu, NaH and mixtures thereof, more preferably from KOH, K2CO3, CS2CO3 and mixtures thereof.

12. Process according to at least one of claims 1 to 11, wherein the lH-l,2,4-triazole and the oxirane of formula (II) are reacted in a molar ratio of 0.8 : 1 to 4 : 1, preferably 0.9 : 1 to 3 : 1, more preferred 1 : 1 to 2 : 1.

13. Process 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 in an amount of 3 to 80 % by weight, 4 to 20 % by weight, more preferred 5 to 15 % by weight, each time based on the total weight of the reaction mixture.

14. Process according to at least one of claims 1 to 13, wherein the reaction is performed in the presence of a Ci-Cio-alcohol, preferably n-butanol, n-propanol, isopropanol, ethanol, methanol, or mixtures thereof, particularly preferred n-butanol.

15. Process according to claim 14, wherein the volumetric ratio of polyalkylene glycol and C₁-C₁0- alcohol is 1 : 1 to 1 : 40, preferably 1 : 2 to 1 : 20, more preferred 1 : 3 to 1 : 10.