TW201936597A - 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 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

Method for preparing substituted (1H-1,2,4-triazol-1-yl)ol

This invention relates to a process for the preparation of substituted (1H-1,2,4-triazol-1-yl)ols.

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.

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.

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.

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:

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.

This process permits the production of compounds of formula (I) in at least a partial crystalline form.

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).

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.

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.

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.

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.

R ^{1 more} preferably represents hydrogen, methyl or ethyl.

R ^{1 more} preferably represents hydrogen or methyl.

R ¹ best represents a methyl group.

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.

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.

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.

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.

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.

Each R ^{4 more} preferably independently of one another represents CF ₃ , OCF ₃ , Br, Cl or pentafluoro-λ ⁶ -hydrogenthio.

Each R ⁴ optimally represents Br or Cl independently of each other.

R ^{4 is} preferably located at the 2- and/or 4-position of the phenyl moiety of formula (I).

R ^{4 is more} preferably located at the 4-position of the phenyl moiety of formula (I).

m is preferably 1, 2 or 3.

m is preferably 1 or 2.

m is optimally 1.

Y preferably 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 bond identified by "V", and wherein R, R ³ and n are as defined above by formula (I) .

Y more preferably 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 bond identified by "V", and wherein R, R ³ and n are as defined above by formula (I) .

Y more preferably 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 bond identified by "V", and wherein R, R ³ and n are as defined above by formula (I) .

Y best represents

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 preferably represents hydrogen, C ₁ -C ₂ -haloalkyl or halogen.

R more preferably represents hydrogen, C ₁ -haloalkyl, F or Cl.

R more preferably represents C ₁ -haloalkyl, F or Cl.

R more preferably represents CF ₃ or Cl.

R best represents CF ₃ .

Each R ³ preferably independently of one another represents F, Cl, Br, CN, nitro, methyl, CF ₃ , methoxy or OCF ₃ .

n is preferably 0.

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.

Preference is given to those examples in which each of the groups has the above preferred definition.

Particular preference is given to those examples in which each of the groups has the above-described better and/or best definition.

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

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".

In the definition of the symbols given in the upper and lower formulas, a collective term that summarizes the following substituents is used:

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.

The halogen is defined to include fluorine, chlorine, bromine and iodine.

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 .

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.

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.

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.

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.

The aryl group is defined to include an aromatic mono-, bi- or tricyclic ring such as phenyl, naphthyl, anthracenyl (anthryl), phenanthracenyl (phenanthryl).

The process according to the invention is carried out in the presence of a polyalkylene glycol.

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.

R ² preferably represents an exoethyl, n-propyl or tetramethylene group, more preferably an exoethyl group.

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.

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.

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).

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.

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.

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.

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.

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.

The process according to the invention 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, 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).

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.

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.

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.

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).

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.

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.

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.

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-triazole is readily available from market sources.

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.

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:

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.

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.

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.

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.

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.

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).

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

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.

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.

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).

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' preferably represents a C ₁ -C ₂ -haloalkyl group or a C ₁ -C ₂ -haloalkoxy group.

R' more preferably represents a C ₁ -haloalkyl group.

R' more preferably represents CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , OCHF ₂ or OCH ₂ F.

R' best represents CF ₃ .

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.

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.

R ^{1 'more} preferably represents methyl, ethyl, propyl, isopropyl, butyl or cyclopropyl.

R ^{1 'more} preferably represents methyl or ethyl.

R ^{1 'is} best represented by a methyl group.

Z best represents chlorine.

R'' preferably represents a C ₁ -C ₄ -alkyl group or a C ₂ -C ₆ -cycloalkyl group.

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

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

R'' best represents isopropyl.

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.

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.

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).

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.

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.

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.

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.

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. .

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.

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

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).

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.

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).

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 .

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.

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.

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).

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.

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.

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.

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).

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. .

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.

Step E) is preferably carried out in the presence of water, dimethyl sulfide or a mixture thereof.

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.

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.

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.

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.

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).

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.

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.

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.

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

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".

Polymorph A can be obtained by applying specific crystallization conditions.

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.

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.

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-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:

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 °.

Polymorph A is further characterized by an X-ray powder diffraction pattern as depicted in Figure 1a.

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:

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-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:

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.

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.

Polymorph B can be obtained by applying specific crystallization conditions.

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.

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.

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-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:

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 °.

Polymorph B is further characterized by an X-ray powder diffraction pattern as depicted in Figure 2a.

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:

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-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:

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-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.

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

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

Example

Example 1

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).

Comparative Example 1:

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>>

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.

Example 2:

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).

Comparative Example 2:

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).

This shows that in the absence of PEG, the purity of the target compound is not comparable to the method according to the invention.

Example 3:

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).

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-Bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-1-(1H-1,2,4-triazol-1-yl)propane-2 - polymorph of alcohol

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

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°.

Raman

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

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)

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. 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. 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. 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. 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. The method according to at least one of claims 1 to 5, wherein R represents CF ₃ or Cl, and/or n is 0. 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". 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. The method according to claim 8, wherein R ² represents an ethyl group. 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. 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. 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. 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. 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. 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.