WO2019048526A1

WO2019048526A1 - Process for the preparation of 1-[6-halogeno-3-pyridyl]ketones

Info

Publication number: WO2019048526A1
Application number: PCT/EP2018/073963
Authority: WO
Inventors: Christoph SCHOTES
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 2017-09-11
Filing date: 2018-09-06
Publication date: 2019-03-14
Anticipated expiration: 2020-03-11
Also published as: TW201920106A

Abstract

The present invention relates to a process for preparing a compound of formula (I) wherein R represents hydrogen, C₁-C₂-halogenalkyl, C₁-C₂-halogenalkoxy, C₁-C₂-alkylcarbonyl, fluorine or chlorine, R¹ represents C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, phenyl, phenyl-C₁-C₄-alkyl, phenyl-C₂-C₄-alkenyl or phenyl-C₂-C₄-alkynyl and X represents fluorine or chlorine; by reacting a compound of formula (II) in a first step A) with a compound of formula R'MgY (III), wherein R represents C₁-C₆-alkyl or C₃-C₈-cycloalkyl; and Y represents chlorine or bromine; and in step B) with an anhydride of formula (IV) and optionally further reacting the compound of formula (I) to a triazole derivative of formula (VI).

Description

Process for the preparation of l-r6-halogeno-3-pyridyl1ketones

The present invention relates to a process for preparing l-[6-halogeno-3-pyridyl]ketones, and optionally further reacting such ketones to triazole derivatives. It further relates to l -[6-halogeno-3-pyridyl]ketones and to 3-bromo-6-chloro-2-(trifluoromethyl)pyridine. l-[6-halogeno-3-pyridyl]ketones are known to be valuable intermediates in the synthesis of compounds useful in the field of crop protection. WO 2017/029179 Al discloses respective triazole compounds and several routes to synthesize those. One of those routes is referred to in WO 2017/029179 Al as process B and comprises synthesis of l -[6-halogeno-3-pyridyl]ketones which are converted in several steps to triazole derivatives. According to said process B l -[6-halogeno-3-pyridyl]ketones are formed by converting dihalogenated pyridine derivatives into Grignard compounds and subsequently reacting such Grignard compounds with acyl chlorides to the desired ketones. The acylation step is performed in the presence of a catalyst, in particular a catalyst selected from copper chloride, aluminum chloride or lithium chloride. Although such procedure provides access to the target ketones it has certain drawbacks. The necessary presence of a catalyst entails need of costly and inconvenient removal of catalyst. In particular, if a copper catalyst is used additional steps for removal and safe deposit of any copper residuals need to be taken to ensure that such residuals do not get into the environment. Moreover, yields need to be further improved to allow efficient synthesis in an industrial scale.

Hence, object of the invention is provision of an improved process for the synthesis of l-[6-halogeno-3- pyridyl]ketones. Surprisingly, it has been found that l -[6-halogeno-3-pyridyl]ketones can be synthesized in high yield and without the need of adding any catalyst by converting dihalogenated pyridine derivatives into Grignard reagents and further reacting those with acyl anhydrides.

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

wherein

R represents hydrogen, Ci-C₂-halogenalkyl, Ci-C₂-halogenalkoxy, Ci-C₂-alkylcarbonyl, fluorine chlorine;

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

X represents fluorine or chlorine; characterized in that a compound of formula (II)

wherein

R and X are defined as in formula (I); is reacted in a first step A) with a compound of formula (III)

R'MgY (III), wherein

R represents Ci-C6-alkyl or Cs-Cs-cycloalkyl; and Y represents chlorine or bromine; and the resulting product is reacted in step B) with an anhydride of formula (IV)

wherein

R¹ is defined as in formula (I).

In step A) the compound of formula (II) is reacted with a Grignard reagent. The Grignard reagent is represented by formula (III). 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 (III) can be schematically illustrated as follows:

2 R'MgY (R')₂Mg + MgY, ^ (R')₂Mg ^* MgY₂

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 (III) 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.

Formula (I) provides a general definition of the ketones obtainable by the process according to the invention. Preferred radical definitions for fonnula (I) shown above and below are given below. These definitions apply to the end products of formula (I) and likewise to all educts and intermediates bearing the respective radical(s).

R preferably represents Ci-C2-halogenalkyl or G-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 G-C4-alkyl, C₂-Ce-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.

X 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. Y most preferably represents chlorine. - -

The radical definitions and explanations given above in general terms or stated within preferred ranges can, however, also 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 precursors 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 the compound of formula (la)

characterized in that the compound of formula (Ila)

is reacted in a first step A) with a compound of formula (III)

R'MgY (III), wherein

R represents Ci-C6-alkyl or C3-Cs-cycloalkyl, preferably isopropyl; and

Y represents chlorine or bromine, preferably chlorine; and the resulting product is reacted in step B) with the anhydride of formula (IVa)

(IVa). As outlined above, compounds of formula (I) are valuable intermediates in the synthesis of compounds useful in the field of crop protection, in particular the triazole compounds disclosed in WO 2017/029179 Al.

Therefore, in a particular aspect present invention refers to a process, wherein a compound of formula (I) is synthesized as outlined above and is further reacted to a triazole derivative of formula (VI)

wherein

R and R¹ are defined as in formula (I);

R⁴ represents halogen, CN, nitro, Ci-C4-alkyl, Ci-C4-halogenalkyl, Ci-C4-alkoxy, Ci-C4-halogenalkoxy, Ci-C₄-alkylcarbonyl, hydroxy-substituted Ci-C₄-alkyl or pentafluoro- ⁶-sulfanyl; and m is an integer and is 0, 1, 2, 3, 4 or 5; characterized in that the reaction of the compound of formula (I) to the triazole derivative of formula (VI) comprises the following steps : step C): reacting the compound of formula (I) with a phenol derivative of formula (VII)

wherein

R⁴ and m are defined as in formula (VI); in the presence of a base to a compound of formula (VIII) - -

wherein

R, R¹, R⁴ and m are defined as in formula (VI); step D): reacting the compound of formula (VIII) with a trimethylsulfoxonium halide, a trimethylsulfonium halide, trimethylsulfoxonium methylsulfate or trimethylsulfonium methylsulfate to an epoxide of formula (IX)

wherein

R, R¹, R⁴ and m are defined as in formula (VI); and step E): reacting the compound of formula (IX) with lH-l,2,4-triazole in the presence of a base to the triazole derivative of formula (VI).

R⁴ preferably represents halogen, CN, nitro, Ci-C4-alkyl, Ci-C4-halogenalkyl, Ci-C4-alkoxy, C1-C4- halogenalkoxy or pentafluoro- ⁶-sulfanyl. R⁴ more preferably represents CF3, OCF3, Br, CI or pentafluoro- ⁶-sulfanyl.

R⁴ more preferably represents CF₃, OCF₃, Br, CI or pentafluoro- ⁶-sulfanyl in the 4-position of the phenyl moiety.

R⁴ most preferably represents Br or CI, preferably in the 4-position of the phenyl moiety, m preferably is 1. 2 or 3. m more preferably is 1 or 2. m most preferably is 1.

Compounds of formula (II) are readily available by established synthesis routes. However, preferably the compound of formula (II) is prepared by reacting a compound of formula (V)

wherein

R is defined as in formula (I); 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.

The reaction is preferably conducted at a temperature of from 0 to 30 °C and a pressure of from 0.5 to 2 bar.

Preferably, this reaction 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, cyclopropyl methyl ether, ieri-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, cyclopropyl 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.

In the definitions of the symbols given in the above 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- 1,1 -dimethylethyl, 2-fluoro- 1- 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. In step A) of the process according to the present invention Grignard compounds may be formed, which are represented by formula (II-Gr) and/or (II-Br)

wherein R, X and Y are defined as outlined above.

As outlined above with regard to the Grignard reagents of formula (III), 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 (II- Gr) and (II-Br) mutatis mutandis.

Generally, one may work-up the reaction product resulting from step A) 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 A) and step B) without any treatment like isolation or purification of the reaction product resulting from step A). It is particularly preferred to add the reaction mixture resulting from step A) to the anhydride of formula (IV).

Preferably, step A) and step B) are carried out in the presence of an aprotic solvent, preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopropyl methyl ether, teri-butyl methyl ether, toluene and mixtures thereof, more preferably from tetrahydrofuran, toluene and mixtures thereof.

Preferably, step A) and step B) are carried out at a temperature of -30°C to 50°C, preferably -10°C to Preferably, the compound of formula (II) and the compound of formula (III) 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 (III) 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 (III) is added as solution in an aprotic solvent, preferably tetrahydrofuran, to a reaction vessel or flask containing the compound of formula (II) and an aprotic solvent, preferably toluene.

Preferably, the molar ratio of compound of formula (II) and anhydride of formula (TV) 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 A) and step B) are carried out under anhydrous conditions, preferably under argon atmosphere.

Preferably, step B) is conducted in the absence of a copper catalyst, more preferred in the absence of any catalyst. Even more preferred also in step A) no catalyst is present. The reaction mixture resulting from step B) 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 (I) can be directly used in step C) of the process according to the invention. It is also possible to isolate the compound of formula (I), preferably by evaporation of the organic solvent, preferably under reduced pressure. The process according to the invention yields the compounds of formula (I) in high purity. However, if desired, the compounds of formula (I) may be further purified by known techniques, for example distillation or chromatography.

Step C) 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 KOMe.

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

The reaction is completed faster in the presence of a suitable catalyst. Hence, preferably step C) 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 (I).

Preferably, the reagents used in step C) are mixed at room temperature (23°C). After mixing the reagents, preferably the temperature is increased. Preferably, step C) 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 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 (VIII) or the crude product obtained by evaporation of the organic solvent can be directly used in step D) of the process according to the invention. However, if desired, the compounds of formula (VIII) may be further purified by known techniques, for example recrystallization or chromatography.

In step D) compounds of formula (VIII) are converted into epoxides of formula (IX) 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 D). 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 (VIII).

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 D) 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 D) 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 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. Resulting organic and aqueous phases are separated, the aqueous phase is extracted with an organic solvent, preferably tert-buiyl methyl ether. The resulting solution of the compound of formula (IX) or the crude product obtained by evaporation of the organic solvent and other volatile components can be directly used in step E) of the process according to the invention. However, if desired, the compounds of formula (IX) may be further purified by known techniques, for example recrystallization or chromatography. Step E) 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, KOH, KOtBu, NaH and mixtures thereof, more preferably form KOH, K2CO3, CS2CO3 and mixtures thereof. In a particular embodiment of this step, a sodium or potassium salt of lH-l,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.

Preferably, step E) is carried out in the presence of an organic solvent, preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopropyl methyl ether, tert-buiyl methyl ether, toluene, n-butanol, n-propanol, isopropanol, ethanol, methanol, N- methylpyridione (NMP), dimethylformamide (DMF) and mixtures thereof, more preferably in the presence of n-butanol.

Preferably, step E) is carried out at a temperature of 20°C to 150°C, preferably 120°C to 150°C, particularly preferred 120°C to 140°C. The reaction mixture resulting from step E) 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. The reaction time of each of the steps 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.

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

The invention is particularly useful to produce compounds of formula (I)

wherein

R represents CF3;

R¹ represents Ci-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl; and

X represents fluorine or chlorine.

Preferred is the compound of formula (I), wherein

R represents CF3;

R¹ represents methyl; and

X represents chlorine.

A particularly useful educt is the compound of formula (Ila)

The invention is illustrated by the examples below. However, the invention is not limited to the examples. - 5 -

Examples

Example 1 :

Under a blanket of argon, 89 g of 3-bromo-6-chloro-2-(trifluoromethyl)pyridine (336,6 mmol) were added to 200 mL of toluene. The mixture was cooled to -5 °C and iPrMgCl (1.7M solution in THF, 336,6 mmol, 1 equivalent) was added dropwise while keeping the inner temperature at -5 °C. In a second vessel, 200 mL of toluene were added to 38.5 mL of acetic anhydride (41.7 g, 404 mmol, 1.2 equiv). The Grignard solution of the first vessel was added under cooling to the second vessel containing the acetic anhydride while keeping the inner temperature at -5 to 0 °C. After stirring for 1 hour (h) at that temperature the reaction was quenched with 150 mL of a saturated ammonium chloride solution in water. The phases were separated and the aqueous phase was extracted twice with toluene. The combined organic phases were washed with a saturated NaCl solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure, giving 80,7 g of l-[6-chloro-2-(trifluoromethyl)-3-pyridyl]ethanone in 82% purity (87.9% yield).

Comparative example 1 : According to process B known from WO 2017/029179 Al under a blanket of argon 20 g of 3-bromo-6- chloro-2-(trifluoromethyl)pyridine (75.5 mmol) were added to 50 mL of toluene. The mixture was cooled below -5 °C and iPrMgCl (1.7M solution in THF, 75.5 mmol, 1 equiv) was added dropwise over 60 minutes while keeping the inner temperature below -5 °C. In a second vessel, 40 mL of toluene were added to 0.37 g of copper(I) chloride (3.7 mmol, 0.05 equiv) and 6.45 mL of acetyl chloride (7.1 g, 90.6 mmol, 1.2 equiv) were introduced. The Grignard solution of the first vessel was added under cooling to the second vessel containing the acetic anhydride while keeping the inner temperature below 10 °C. After stirring for 30 min at that temperature the reaction was quenched with a saturated ammonium chloride solution in water (50 mL). The phases were separated and the aqueous phase was extracted twice with toluene. The combined organic phases were washed twice with water and twice with a saturated NaCl solution, then dried over magnesium sulfate, filtered and evaporated under reduced pressure, giving 16.28 g of l-[6-chloro-2-(trifluoromethyl)-3-pyridyl]ethanone in 78% purity (74.7% yield).

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

Claims

1. Process for preparing a compound of formula (I)

wherein represents hydrogen, Ci-C₂-halogenalkyl, Ci-C₂-halogenalkoxy, Ci-C₂-alkylcarbonyl, fluorine or chlorine; represents Ci-C6-alkyl, C₂-C6-alkenyl, C₂-C6-alkynyl, Cs-Cs-cycloalkyl, Cs-Cs-cycloalkyl-Ci- C₄-alkyl, phenyl, phenyl-Ci-C₄-alkyl, phenyl-C₂-C₄-alkenyl or phenyl-C₂-C₄-alkynyl; and represents fluorine or chlorine; characterized in that a compound of formula (II)

wherein

R'MgY (III), wherein

R represents Ci-C6-alkyl or C3-Cs-cycloalkyl; and Y represents chlorine or bromine; and the resulting product is reacted in step B) with an anhydride of formula (IV)

wherein

R¹ is defined as in formula (I).

2. Process according to claim 1, wherein R represents Ci-C₂-halogenalkyl or Ci-C₂-halogenalkoxy.

3. Process according to at least one of claims 1 and 2, wherein R represents CF3, CHF2, CH2F, OCF3, OCHF2 or OCH2F, preferably CF₃.

4. Process according to at least one of claims 1 to 3, wherein R¹ represents Ci-C4-alkyl, C₂-C6-alkenyl, C₂-C6-alkynyl, cyclopropyl, phenyl, benzyl, phenylethenyl or phenylethinyl.

5. Process according to at least one of claims 1 to 4, wherein R¹ represents methyl, ethyl, propyl, isopropyl, butyl or cyclopropyl, preferably methyl.

6. Process according to at least one of claims 1 to 5, wherein X represents chlorine.

7. Process according to at least one of claims 1 to 6, wherein R represents methyl, ethyl, propyl, isopropyl or butyl, preferably isopropyl.

8. Process according to at least one of claims 1 to 7, wherein Y represents chlorine.

9. Process according to at least one of claims 1 to 8, wherein step A) and step B) are conducted without isolation or purification of the reaction product resulting from step A).

10. Process according to at least one of claims 1 to 9, wherein step A) and step B) are carried out in the presence of an aprotic solvent, preferably selected from tetrahydrofuran, toluene and mixtures thereof.

1 1. Process according to at least one of claims 1 to 10, wherein the process is carried out at a temperature of -30°C to 50°C, preferably -10°C to 10°C.

12. Process according to at least one of claims 1 to 11, wherein the compound of formula (II) and the compound of formula (III) are reacted in a molar ratio of 1 : 0.8 to 1 : 1.5, preferably 1 : 1 to 1 : 1.1.

13. Process according to at least one of claims 1 to 12, wherein the molar ratio of compound of formula (II) and anhydride of formula (IV) is 1 : 1 to 1 : 2, preferably 1 : 1.1 to 1 : 1.3.

14. Process according to at least one of claims 1 to 13, wherein the compound of formula (II) is prepared by reacting a compound of formula (V)

wherein R is defined as in any one of claims 1 to 3; with hydrogen chloride in the presence of dinitrogen trioxide or an organic nitrite.

15. Process according to at least one of claims 1 to 14, wherein compound of formula (I) is further reacted to a triazole derivative of formula (VI)

wherein

R and R¹ are defined as in any one of claims 1 to 5;

R represents halogen, CN, nitro, Ci-C4-alkyl, Ci-C4-halogenalkyl, Ci-C4-alkoxy, C1-C4- halogenalkoxy, Ci-C₄-alkylcarbonyl, hydroxy-substituted Ci-C4-alkyl or pentafluoro-λ⁶- sulfanyl; and m is an integer and is 0, 1, 2, 3, 4 or 5; characterized in that the reaction of the compound of formula (I) to the triazole derivative of formula (VI) comprises the following steps : step C): reacting the compound of formula (I) with a phenol derivative of formula (VII)

wherein

R and m are defined as in formula (VI); in the presence of a base to a compound of formula (VIII)

wherein

wherein