Method for producing chlorosubstituted phenyltrifluoromethyl ketones

Abstract

This invention provides a method for producing intermediate chlorosubstituted phenyltrifluoromethyl ketones. [Solution] The following general formula (4) JPEG2026062955000020.jpg35170 Compounds represented by the following formula (5) are reacted with trifluoromethane to obtain the compound shown in the following general formula (5). JPEG2026062955000021.jpg35170 A method for producing chlorosubstituted phenyltrifluoromethyl ketones represented by [formula] is used.

Description

[Technical Field]

[0001] The present invention relates to a method for producing chlorosubstituted phenyltrifluoromethyl ketones, intermediates such as Efavirenz, which is used as an HIV infection preventive and HIV infection treatment agent, and lotilaner, sarolaner, fluralaner, fluxametamide, isocycloseram, and afoxolaner, which are used as insecticides.

[0002] Chlorosubstituted phenyltrifluoromethyl ketones are useful compounds as intermediates for Efavirenz, which is used as a preventative and therapeutic agent for HIV infection, and for insecticides such as lotilaner, sarolaner, fluralaner, fluxametamide, isocycloseram, and afoxolaner.

[0003] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [Background technology]

[0004] As a prior art, a method for producing Efavirenz (1) is known, as shown below, which involves reacting 1,4-dichlorobenzene with n-butyllithium and then reacting it with methyl trifluoroacetate to obtain 1-(2,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one (a) as an intermediate (Patent Document 1).

[0005] [ka]

[0006] Furthermore, a method for producing Efavirenz analogs (2) is known, as shown below, which involves using 1-(5-chloro-2-nitrophenyl)-2,2,2-trifluoroethane-1-one (b), obtained by reacting 2-chloro-5-nitrobenzaldehyde with trifluoromethyltrimethylsilane, as an intermediate (Non-Patent Literature 1). Furthermore, another method for producing the intermediate 1-(5-chloro-2-nitrophenyl)-2,2,2-trifluoroethane-1-one (b) is known, as shown below, which involves introducing a nitro group by reacting 1-(5-chlorophenyl)-2,2,2-trifluoroethane-1-one with a mixed acid of fuming nitric acid / sulfuric acid (Patent Document 2).

[0007] [ka]

[0008] Furthermore, a method for producing fluralaner (3) is known, which involves using 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one (c) as an intermediate, as shown below (Non-Patent Literature 2). Also, as methods for producing the intermediate 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethan-1-one (c), a method of reacting methyl 3,5-dichlorobenzoate with trifluoromethyltrimethylsilane and a method of reacting 1-bromo-3,5-dichlorobenzene with n-butyllithium and then reacting with ethyl trifluoroacetate are known (Patent Document 3 and Patent Document 4).

[0009]

Chemical formula

[0010] The methods described in Patent Document 1 and Patent Document 4 have problems in terms of safety when implemented on an industrial scale because they use an alkyllithium reagent with high pyrophoricity. The methods described in Non-Patent Document 1 and Patent Document 3 require a more inexpensive trifluoromethyl anion source because the trifluoromethyltrimethylsilane used is relatively expensive. The method described in Patent Document 2 has problems in terms of safety when implemented on an industrial scale because explosive compounds may be by-produced due to the introduction of multiple nitro groups.

Prior Art Documents

Patent Documents

[0011]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Non-Patent Documents

[0012]

Non-Patent Document 1

[0013] In view of the above problems, the present invention provides a method for economically and safely producing chloro-substituted phenyltrifluoromethyl ketones, which are key intermediates for pharmaceuticals and agrochemicals such as Efavirenz, lotilaner, sarolaner, fluralaner, fluxametamide, isocycloseram, and afoxolaner, by generating a trifluoromethyl anion from trifluoromethane as a raw material and reacting it with ester compounds. [Means for solving the problem]

[0014] The present inventors diligently investigated methods for producing intermediates of pharmaceuticals and agrochemicals such as Efavirenz, lotilaner, sarolaner, fluralaner, fluxametamide, isocycloseram, and afoxolaner. As a result, they discovered that by using a glyme-based solvent and / or N,N-dimethylformamide as the reaction solvent, and reacting trifluoromethane as a raw material with ester compounds using potassium hexamethyldisilazide and / or potassium tert-butoxide, they were able to obtain chloro-substituted phenyltrifluoromethyl ketones, which are intermediates, thus completing the present invention.

[0015] In other words, the present invention relates to the following invention. [1] The following general formula (4) [ka] (In formula (4), R 1 and R 2Each of these independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a trifluoromethyl group, or a nitro group, and R 3 (This indicates a methyl group or an ethyl group.) The ester compounds represented by the following general formula (5) are reacted with trifluoromethane in a glyme solvent and / or N,N-dimethylformamide in the presence of potassium hexamethyldisilazide and / or potassium tert-butoxide, characterized by the reaction of ester compounds represented by the following general formula (5). [ka] (In formula (5), R 1 and R 2 Each of these independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a trifluoromethyl group, or a nitro group. A method for producing chlorosubstituted phenyltrifluoromethyl ketones represented by [the specified formula]. [2] The method for producing chlorosubstituted phenyltrifluoromethyl ketones according to [1], characterized in that the glyme solvent is triglyme and / or tetraglyme. [3] A method for producing chlorosubstituted phenyltrifluoromethyl ketones according to [1] or [2], characterized in that the trifluoromethyl group substitution reaction of ester compounds represented by formula (4) is carried out at -60°C to 0°C. [4] A method for producing chlorosubstituted phenyltrifluoromethyl ketones according to any one of [1] to [3], characterized by using 1.0 molar equivalent to 5.0 molar equivalents of potassium hexamethyldisilazide and / or potassium tert-butoxide with respect to ester compounds represented by formula (4). [5] A method for producing chlorosubstituted phenyltrifluoromethyl ketones according to any one of [1] to [4], characterized by using 1.0 molar equivalent or more of trifluoromethane with respect to ester compounds represented by formula (4). [6] A method for producing a chlorosubstituted phenyltrifluoromethyl ketone hydrate according to any one of [1] to [5], characterized in that the solvent is N,N-dimethylformamide and the base is potassium tert-butoxide.

[0016] The chlorosubstituted phenyltrifluoromethyl ketone represented by formula (5) above exists in equilibrium with ketone bodies and ketone hydrates. Ketone bodies are hydrated by moisture contained in the air or solution. On the other hand, ketone hydrates can be converted to ketone bodies by azeotropic dehydration using heptane or the like. Therefore, the chlorosubstituted phenyltrifluoromethyl ketone represented by formula (5) includes chlorosubstituted phenyltrifluoromethyl ketone hydrate and its equilibrium mixture. [Effects of the Invention]

[0017] The present invention provides an industrial method for producing chloro-substituted phenyltrifluoromethyl ketones, which are intermediates for ester compounds such as Efavirenz, used as a therapeutic agent for HIV infection, and lotilaner, sarolaner, fluralaner, fluxametamide, isocycloseram, and afoxolaner, used as insecticides, using inexpensive trifluoromethane. [Modes for carrying out the invention]

[0018] The present invention will be described in detail below. Ester compounds represented by general formula (4) applicable to the present invention, R 3Examples of those with a methyl group include, specifically, methyl 3-chloro-2-fluorobenzoate, methyl 5-chloro-2-fluorobenzoate, methyl 3-chloro-4-fluorobenzoate, methyl 3-chloro-5-fluorobenzoate, methyl 2,3-dichlorobenzoate, methyl 2,5-dichlorobenzoate, methyl 3,4-dichlorobenzoate, methyl 3,5-dichlorobenzoate, methyl 3-chloro-2-trifluoromethylbenzoate, methyl 5-chloro-2-trifluoromethylbenzoate, methyl 3-chloro-4-trifluoromethylbenzoate, and methyl 3-chloro -5-trifluoromethylbenzoate methyl, 3-chloro-2-nitrobenzoate methyl, 5-chloro-2-nitrobenzoate methyl, 3-chloro-4-nitrobenzoate methyl, 3-chloro-5-nitrobenzoate methyl, 3-chloro-2,4-difluorobenzoate methyl, 3-chloro-2,5-difluorobenzoate methyl, 3-chloro-2,6-difluorobenzoate methyl, 3-chloro-4,5-difluorobenzoate methyl, 3-chloro-4,6-difluorobenzoate methyl, 3-chloro-5,6-difluorobenzoate methyl, 2,3,4-trichlorobenzoate Methyl benzoate, 2,3,5-trichlorobenzoate methyl, 2,3,6-trichlorobenzoate methyl, 2,4,5-trichlorobenzoate methyl, 3,4,5-trichlorobenzoate methyl, 3-chloro-2,4-bis(trifluoromethyl)benzoate methyl, 3-chloro-2,5-bis(trifluoromethyl)benzoate methyl, 3-chloro-2,6-bis(trifluoromethyl)benzoate methyl, 3-chloro-4,5-bis(trifluoromethyl)benzoate methyl, 3-chloro-4,6-bis(trifluoromethyl)benzoate methyl, 3-chloro-5, 6-Bis(trifluoromethyl)methyl benzoate, 3-chloro-2,4-dinitrobenzoate methyl, 3-chloro-2,5-dinitrobenzoate methyl, 3-chloro-2,6-dinitrobenzoate methyl, 3-chloro-4,5-dinitrobenzoate methyl, 3-chloro-4,6-dinitrobenzoate methyl, 3-chloro-5,6-dinitrobenzoate methyl, 3,4-dichloro-2-fluorobenzoate methyl, 3,5-dichloro-2-fluorobenzoate methyl, 3,6-dichloro-2-fluorobenzoate methyl, 4,5-dichloro-2-fluorobenzoate methyl,5,6-Dichloro-2-fluorobenzoate methyl, 2,3-Dichloro-4-fluorobenzoate methyl, 3,5-Dichloro-4-fluorobenzoate methyl, 3,6-Dichloro-4-fluorobenzoate methyl, 2,3-Dichloro-5-fluorobenzoate methyl, 3,4-Dichloro-5-fluorobenzoate methyl, 3,6-Dichloro-5-fluorobenzoate methyl, 3,4-Dichloro-2-trifluoromethylbenzoate methyl, 3,5-Dichloro-2-trifluoromethylbenzoate methyl, 3,6-Dichloro-2-trifluoromethylbenzoate methyl, 4,5- Methyl dichloro-2-trifluoromethylbenzoate, 5,6-dichloro-2-trifluoromethylbenzoate, 2,3-dichloro-4-trifluoromethylbenzoate, 3,5-dichloro-4-trifluoromethylbenzoate, 3,6-dichloro-4-trifluoromethylbenzoate, 2,3-dichloro-5-trifluoromethylbenzoate, 3,4-dichloro-5-trifluoromethylbenzoate, 3,6-dichloro-5-trifluoromethylbenzoate, 3,4-dichloro-2-nitrobenzoate, 3,5-dichloro -2-methyl nitrobenzoate, 3,6-dichloro-2-nitrobenzoate, 4,5-dichloro-2-nitrobenzoate, 5,6-dichloro-2-nitrobenzoate, 2,3-dichloro-4-nitrobenzoate, 3,5-dichloro-4-nitrobenzoate, 3,6-dichloro-4-nitrobenzoate, 2,3-dichloro-5-nitrobenzoate, 3,4-dichloro-5-nitrobenzoate, 3,6-dichloro-5-nitrobenzoate, 3-chloro-2-fluoro-4-trifluoromethylbenzoate, 3-chloro- 2-Fluoro-5-trifluoromethylbenzoate methyl, 3-chloro-2-fluoro-6-trifluoromethylbenzoate methyl, 3-chloro-4-fluoro-2-trifluoromethylbenzoate methyl, 3-chloro-4-fluoro-5-trifluoromethylbenzoate methyl, 3-chloro-4-fluoro-6-trifluoromethylbenzoate methyl, 3-chloro-5-fluoro-2-trifluoromethylbenzoate methyl, 3-chloro-5-fluoro-4-trifluoromethylbenzoate methyl, 3-chloro-5-fluoro-6-trifluoromethylbenzoate methyl,5-chloro-2-fluoro-3-trifluoromethylbenzoate methyl, 5-chloro-2-fluoro-4-trifluoromethylbenzoate methyl, 5-chloro-2-fluoro-6-trifluoromethylbenzoate methyl, 3-chloro-2-fluoro-4-nitrobenzoate methyl, 3-chloro-2-fluoro-5-nitrobenzoate methyl, 3-chloro-2-fluoro-6-nitrobenzoate methyl, 3-chloro-4-fluoro-2-nitrobenzoate Methyl, 3-chloro-4-fluoro-5-nitrobenzoate methyl, 3-chloro-4-fluoro-6-nitrobenzoate methyl, 3-chloro-5-fluoro-2-nitrobenzoate methyl, 3-chloro-5-fluoro-4-nitrobenzoate methyl, 3-chloro-5-fluoro-6-nitrobenzoate methyl, 5-chloro-2-fluoro-3-nitrobenzoate methyl, 5-chloro-2-fluoro-4-nitrobenzoate methyl, 5-chloro-2-fluorine Examples include methyl 6-chloromethylbenzoate, 3-chloro-2-nitro-4-trifluoromethylbenzoate, 3-chloro-2-nitro-5-trifluoromethylbenzoate, 3-chloro-2-nitro-6-trifluoromethylbenzoate, 3-chloro-4-nitro-2-trifluoromethylbenzoate, 3-chloro-4-nitro-5-trifluoromethylbenzoate, 3-chloro-4-nitro-6-trifluoromethylbenzoate, 3-chloro-5-nitro-2-trifluoromethylbenzoate, 3-chloro-5-nitro-4-trifluoromethylbenzoate, 3-chloro-5-nitro-6-trifluoromethylbenzoate, 5-chloro-2-nitro-3-trifluoromethylbenzoate, 5-chloro-2-nitro-4-trifluoromethylbenzoate, and 5-chloro-2-nitro-6-trifluoromethylbenzoate.

[0019] Ester compounds represented by general formula (4) applicable to the present invention, R 3Examples of those with an ethyl group include, specifically, ethyl 3-chloro-2-fluorobenzoate, ethyl 5-chloro-2-fluorobenzoate, ethyl 3-chloro-4-fluorobenzoate, ethyl 3-chloro-5-fluorobenzoate, ethyl 2,3-dichlorobenzoate, ethyl 2,5-dichlorobenzoate, ethyl 3,4-dichlorobenzoate, ethyl 3,5-dichlorobenzoate, ethyl 3-chloro-2-trifluoromethylbenzoate, ethyl 5-chloro-2-trifluoromethylbenzoate, ethyl 3-chloro-4-trifluoromethylbenzoate, and ethyl 3-chloro -5-trifluoromethylbenzoate ethyl, 3-chloro-2-nitrobenzoate ethyl, 5-chloro-2-nitrobenzoate ethyl, 3-chloro-4-nitrobenzoate ethyl, 3-chloro-5-nitrobenzoate ethyl, 3-chloro-2,4-difluorobenzoate ethyl, 3-chloro-2,5-difluorobenzoate ethyl, 3-chloro-2,6-difluorobenzoate ethyl, 3-chloro-4,5-difluorobenzoate ethyl, 3-chloro-4,6-difluorobenzoate ethyl, 3-chloro-5,6-difluorobenzoate ethyl, 2,3,4-trichlorobenzoate Ethyl benzoate, 2,3,5-trichlorobenzoate ethyl, 2,3,6-trichlorobenzoate ethyl, 2,4,5-trichlorobenzoate ethyl, 3,4,5-trichlorobenzoate ethyl, 3-chloro-2,4-bis(trifluoromethyl)benzoate ethyl, 3-chloro-2,5-bis(trifluoromethyl)benzoate ethyl, 3-chloro-2,6-bis(trifluoromethyl)benzoate ethyl, 3-chloro-4,5-bis(trifluoromethyl)benzoate ethyl, 3-chloro-4,6-bis(trifluoromethyl)benzoate ethyl, 3-chloro-5, 6-Bis(trifluoromethyl)ethyl benzoate, 3-chloro-2,4-dinitrobenzoate ethyl ethyl 3-chloro-2,5-dinitrobenzoate ethyl 3-chloro-2,6-dinitrobenzoate ethyl 3-chloro-4,5-dinitrobenzoate ethyl 3-chloro-4,6-dinitrobenzoate ethyl 3-chloro-5,6-dinitrobenzoate ethyl 3,4-dichloro-2-fluorobenzoate ethyl 3,5-dichloro-2-fluorobenzoate ethyl 3,6-dichloro-2-fluorobenzoate ethyl 4,5-dichloro-2-fluorobenzoate ethyl,5,6-Dichloro-2-fluorobenzoate ethyl, 2,3-Dichloro-4-fluorobenzoate ethyl, 3,5-Dichloro-4-fluorobenzoate ethyl, 3,6-Dichloro-4-fluorobenzoate ethyl, 2,3-Dichloro-5-fluorobenzoate ethyl, 3,4-Dichloro-5-fluorobenzoate ethyl, 3,6-Dichloro-5-fluorobenzoate ethyl, 3,4-Dichloro-2-trifluoromethylbenzoate ethyl, 3,5-Dichloro-2-trifluoromethylbenzoate ethyl, 3,6-Dichloro-2-trifluoromethylbenzoate ethyl, 4,5- Ethyl dichloro-2-trifluoromethylbenzoate, ethyl 5,6-dichloro-2-trifluoromethylbenzoate, ethyl 2,3-dichloro-4-trifluoromethylbenzoate, ethyl 3,5-dichloro-4-trifluoromethylbenzoate, ethyl 3,6-dichloro-4-trifluoromethylbenzoate, ethyl 2,3-dichloro-5-trifluoromethylbenzoate, ethyl 3,4-dichloro-5-trifluoromethylbenzoate, ethyl 3,6-dichloro-5-trifluoromethylbenzoate, ethyl 3,4-dichloro-2-nitrobenzoate, ethyl 3,5-dichloro -2-Ethyl nitrobenzoate, 3,6-Dichloro-2-nitrobenzoate ethyl, 4,5-Dichloro-2-nitrobenzoate ethyl, 5,6-Dichloro-2-nitrobenzoate ethyl, 2,3-Dichloro-4-nitrobenzoate ethyl, 3,5-Dichloro-4-nitrobenzoate ethyl, 3,6-Dichloro-4-nitrobenzoate ethyl, 2,3-Dichloro-5-nitrobenzoate ethyl, 3,4-Dichloro-5-nitrobenzoate ethyl, 3,6-Dichloro-5-nitrobenzoate ethyl, 3-Chloro-2-fluoro-4-trifluoromethylbenzoate ethyl, 3-Chloro- 2-Fluoro-5-trifluoromethylbenzoate ethyl, 3-chloro-2-fluoro-6-trifluoromethylbenzoate ethyl, 3-chloro-4-fluoro-2-trifluoromethylbenzoate ethyl, 3-chloro-4-fluoro-5-trifluoromethylbenzoate ethyl, 3-chloro-4-fluoro-6-trifluoromethylbenzoate ethyl, 3-chloro-5-fluoro-2-trifluoromethylbenzoate ethyl, 3-chloro-5-fluoro-4-trifluoromethylbenzoate ethyl, 3-chloro-5-fluoro-6-trifluoromethylbenzoate ethyl,Ethyl 5-chloro-2-fluoro-3-trifluoromethylbenzoate, ethyl 5-chloro-2-fluoro-4-trifluoromethylbenzoate, ethyl 5-chloro-2-fluoro-6-trifluoromethylbenzoate, ethyl 3-chloro-2-fluoro-4-nitrobenzoate, ethyl 3-chloro-2-fluoro-5-nitrobenzoate, ethyl 3-chloro-2-fluoro-6-nitrobenzoate, ethyl 3-chloro-4-fluoro-2-nitrobenzoate Ethyl, 3-chloro-4-fluoro-5-nitrobenzoate ethyl, 3-chloro-4-fluoro-6-nitrobenzoate ethyl, 3-chloro-5-fluoro-2-nitrobenzoate ethyl, 3-chloro-5-fluoro-4-nitrobenzoate ethyl, 3-chloro-5-fluoro-6-nitrobenzoate ethyl, 5-chloro-2-fluoro-3-nitrobenzoate ethyl, 5-chloro-2-fluoro-4-nitrobenzoate ethyl, 5-chloro-2-fluorinated Examples include ethyl 6-chloromethylbenzoate, ethyl 3-chloro-2-nitro-4-trifluoromethylbenzoate, ethyl 3-chloro-2-nitro-5-trifluoromethylbenzoate, ethyl 3-chloro-2-nitro-6-trifluoromethylbenzoate, ethyl 3-chloro-4-nitro-2-trifluoromethylbenzoate, ethyl 3-chloro-4-nitro-5-trifluoromethylbenzoate, ethyl 3-chloro-4-nitro-6-trifluoromethylbenzoate, ethyl 3-chloro-5-nitro-2-trifluoromethylbenzoate, ethyl 3-chloro-5-nitro-4-trifluoromethylbenzoate, ethyl 3-chloro-5-nitro-6-trifluoromethylbenzoate, ethyl 5-chloro-2-nitro-3-trifluoromethylbenzoate, ethyl 5-chloro-2-nitro-4-trifluoromethylbenzoate, and ethyl 5-chloro-2-nitro-6-trifluoromethylbenzoate.

[0020] The chlorosubstituted phenyltrifluoromethyl ketones represented by general formula (5) that can be produced by the present invention include, specifically, 1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethane-1-one, 1-(5-chloro-2-fluorophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-4-fluorophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-5-fluorophenyl)-2,2,2-trifluoroethane-1-one, and 1-(2,3-dichlorophenyl)-2,2,2-trifluoro Ethane-1-one, 1-(2,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one, 1-(3,4-dichlorophenyl)-2,2,2-trifluoroethane-1-one, 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-2-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(5-chloro-2-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-4-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one Lifluoroethane-1-one, 1-(3-chloro-5-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-2-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(5-chloro-2-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-4-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-5-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-2,4-difluorophenyl)-2 ,2,2-trifluoroethane-1-one, 1-(3-chloro-2,5-difluorophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-2,6-difluorophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-4,5-difluorophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-4,6-difluorophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-5,6-difluorophenyl)-2,2,2-trifluoroethane-1-one, 1-(2,3,4-trichlorophenyl)-2,2,2-trifluoroethane-1-one, 1-(2,3,5-trichlorophenyl)-2,2,2-trifluoroethane-1-one, 1-(2,3,6-trichlorophenyl)-2,2,2-trifluoroethane-1-one, 1-(2,4,5-trichlorophenyl)-2,2,2-trifluoroethane-1-one, 1-(3,4,5-trichlorophenyl)-2,2,2-trifluoroethane-1-one, 1-[3-chloro-2,4-bis(trifluoromethyl)phenyl]-2,2,2-trifluoroethane -1-one, 1-[3-chloro-2,5-bis(trifluoromethyl)phenyl]-2,2,2-trifluoroethane-1-one, 1-[3-chloro-2,6-bis(trifluoromethyl)phenyl]-2,2,2-trifluoroethane-1-one, 1-[3-chloro-4,5-bis(trifluoromethyl)phenyl]-2,2,2-trifluoroethane-1-one, 1-[3-chloro-4,6-bis(trifluoromethyl)phenyl]-2,2,2-trifluoroethane-1-one, 1-[3-chloro-5,6-bis(trifluoromethyl)phenyl ]-2,2,2-trifluoroethane-1-one, 1-(3-chloro-2,4-dinitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-2,5-dinitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-2,6-dinitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-4,5-dinitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3 -chloro-5,6-dinitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3,4-dichloro-2-fluorophenyl)-2,2,2-trifluoroethane-1-one, 1-(3,5-dichloro-2-fluorophenyl)-2,2,2-trifluoroethane-1-one, 1-(3,6-dichloro-2-fluorophenyl)-2,2,2-trifluoroethane-1-one, 1-(4,5-dichloro-2-fluorophenyl)-2,2,2-trifluoroethane-1-one, 1-(5,6-dichloro-2-fluorophenyl)-2,22-trifluoroethane-1-one, 1-(2,3-dichloro-4-fluorophenyl)-2,2,2-trifluoroethane-1-one, 1-(3,5-dichloro-4-fluorophenyl)-2,2,2-trifluoroethane-1-one, 1-(3,6-dichloro-4-fluorophenyl)-2,2,2-trifluoroethane-1-one, 1-(2,3-dichloro-5-fluorophenyl)-2,2,2-trifluoroethane-1-one, 1-(3,6- Dichloro-5-fluorophenyl)-2,2,2-trifluoroethane-1-one, 1-(3,4-dichloro-2-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3,5-dichloro-2-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3,6-dichloro-2-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(4,5-dichloro-2-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(5,6-dichloro -2-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(2,3-dichloro-4-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3,5-dichloro-4-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3,6-dichloro-4-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(2,3-dichloro-5-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3,4-dichloro (L-5-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, (3,6-dichloro-5-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, (3,4-dichloro-2-nitrophenyl)-2,2,2-trifluoroethane-1-one, (3,5-dichloro-2-nitrophenyl)-2,2,2-trifluoroethane-1-one, (3,6-dichloro-2-nitrophenyl)-2,2,2-trifluoroethane-1-one, (4,5-dichloro-2-nitrophenyl)-2,22-trifluoroethane-1-one, 1-(5,6-dichloro-2-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(2,3-dichloro-4-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3,5-dichloro-4-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3,6-dichloro-4-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(2,3-dichloro-5-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3,4-dichloro-5 -nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3,6-dichloro-5-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-2-fluoro-4-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-2-fluoro-5-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-2-fluoro-6-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 3-chloro-4-fluoro- 2-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-4-fluoro-5-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-4-fluoro-6-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-5-fluoro-2-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-5-fluoro-4-trifluoromethylphenyl)-2,2,2-trifluoroethane-1 -one, 1-(3-chloro-5-fluoro-6-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(5-chloro-2-fluoro-3-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(5-chloro-2-fluoro-4-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(5-chloro-2-fluoro-6-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-2-fluoro-4-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-2-fluoro-5-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-2-fluoro-6-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-4-fluoro-2-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-4-fluoro-5-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-4-fluoro-6-nitrophenyl)-2, 2,2-trifluoroethane-1-one, 1-(3-chloro-5-fluoro-2-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-5-fluoro-4-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-5-fluoro-6-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(5-chloro-2-fluoro-3-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(5-chloro-2-fluoro-4-nitrophenyl)- 2,2,2-trifluoroethane-1-one, 1-(5-chloro-2-fluoro-6-nitrophenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-2-nitro-4-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-2-nitro-5-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-2-nitro-6-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-4 -Nitro-2-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-4-nitro-5-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-4-nitro-6-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-5-nitro-2-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(3-chloro-5-nitro-4-trifluoromethylphenyl)-2,22-trifluoroethane-1-one, 1-(3-chloro-5-nitro-6-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(5-chloro-2-nitro-3-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(5-chloro-2-nitro-4-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one, 1-(5-, Chloro-2-nitro-6-trifluoromethylphenyl)-2,2,2-trifluoroethane-1-one is one example.

[0021] The amount of potassium hexamethyldisilazide and / or potassium tert-butoxide applicable to this invention is 1.0 to 5.0 moles per mole of ester compounds in the reaction.

[0022] The amount of trifluoromethane applicable to this invention can be 1.0 molar equivalent or more per mole of ester compounds used in the reaction. However, since trifluoromethane is a gas and has low solubility in various solvents, it may be supplied to the reaction system in excess by bubbling at an amount of 5.0 molar or more. The excess trifluoromethane supplied may be recovered and reused.

[0023] Glyme-based solvents and / or N,N-dimethylformamide can be used as solvents applicable to the present invention. Examples of glyme-based solvents include diglyme, ethyl diglyme, butyl diglyme, methyl ethyl diglyme, triglyme, and tetraglyme. Among these, triglyme, tetraglyme, and N,N-dimethylformamide are preferred for their good yield, and the amount used should be 5 to 200 times the weight of the ester compounds involved in the reaction. Furthermore, as long as it is inert to the reaction, it may be used in mixture with glyme solvents and N,N-dimethylformamide. Examples of the solvents that can be used in mixture include aliphatic hydrocarbons such as pentane, hexane, and octane; aromatic hydrocarbons such as benzene, toluene, ethylbenzene, and xylene; ethers such as diethyl ether, diisopropyl ether, methyl-tert-butyl ether, methylcyclopentyl ether, and anisole; and halogenated aliphatic hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform.

[0024] The reaction temperature and time of the present invention are -100°C to 0°C, and the reaction is carried out for 1 hour to 48 hours. There are no particular regulations for the post-treatment after the reaction of the present invention, and it can be carried out by well-known methods. For example, after neutralization with dilute hydrochloric acid, extraction with an organic solvent such as dichloromethane, drying with a desiccant such as anhydrous sodium sulfate, filtration, and concentration to obtain the target product as a crude product, and further purification by silica gel column chromatography or the like to obtain the purified target product. Furthermore, the hydrate may be converted into the ketone form by azeotropic dehydration using heptane or the like.

Examples

[0025] Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited only to these examples. The following instruments were used for analysis. 1 H-NMR (300 MHz), 19 F-NMR (282 MHz): Varian Mercury 300 and Bruker Avance 500.

[0026] In the identification of the compounds, the data described in the following literature were referred to. Example 1: Correia, C.A. et al., Angew. Chem. Int. Ed., 2015, 54, 4945-4948. Example 2: Cai, H. et al., J. Org. Chem., 2014, 79, 5484-5493. Example 3: PCT Int.Appl., WO2018009751.

[0027] Example 1 Preparation of 1-(2,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one (a) [ka] 82.0 mg, 0.4 mmol of methyl 2,5-dichlorobenzoate and 0.7 mL of triglime were placed in a test tube equipped with a stirring bar. Trifluoromethane (9.9 mL, 1.1 eq.) was added using a syringe while cooling the container with liquid nitrogen. Next, a solution of potassium hexamethyl disilazide (160 mg, 0.8 mmol, 2.0 eq.) dissolved in triglime (0.3 mL) was added to a test tube cooled to -40°C, and the reaction was carried out at the same temperature for 4 hours. After the reaction was complete, 1.0 mL of 1 M hydrochloric acid was added, the aqueous layer was extracted with dichloromethane (1.0 mL x 3), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 9 / 1 (vol / vol)) to obtain the target 1-(2,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one (a) as a colorless transparent liquid (63.2 mg, 0.260 mmol, yield 65%).

[0028] The analysis results were as follows: 1 H-NMR (300MHz, CDCl3) δ: 7.66 (s, 1H), 7.55-7.47 (m, 2H) ppm. 19 F-NMR (282MHz, CDCl3)δ: -71.22(s,3F)ppm.

[0029] Example 2 Preparation of 1-(5-chloro-2-nitrophenyl)-2,2,2-trifluoroethane-1-one (b) [ka] 86.2 mg (0.4 mmol) of methyl 5-chloro-2-nitrobenzoate and 0.7 mL of triglime were placed in a test tube equipped with a stirring bar. Trifluoromethane (9.9 mL, 1.1 eq.) was added using a syringe while cooling the container with liquid nitrogen. Next, a solution of potassium hexamethyl disilazide (160 mg, 0.8 mmol, 2.0 eq.) dissolved in triglime (0.3 mL) was added to a test tube cooled to -40°C, and the reaction was carried out at the same temperature for 4 hours. After the reaction was complete, 1.0 mL of 1 M hydrochloric acid was added, the aqueous layer was extracted with dichloromethane (1.0 mL x 3), and the organic layers were combined and dried over anhydrous sodium sulfate. The crude product was then filtered and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 9 / 1 (vol / vol)) to obtain the target 1-(5-chloro-2-nitrophenyl)-2,2,2-trifluoroethane-1-one (b) as a white solid (56.8 mg, 0.224 mmol, yield 56%).

[0030] The analysis results were as follows: 1 H-NMR (300MHz, CDCl3) δ:8.27(d,J=8.8Hz,1H),7.77(dd,J=8.8,2.3Hz,1H),7.51(d,J=2.1Hz,1H)ppm. 19 F-NMR (282MHz, CDCl3)δ: -76.21(s,3F)ppm.

[0031] Example 3 Preparation of a mixture of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one (c) and 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1,1-diol (d) [ka] 82.0 mg, 0.4 mmol of methyl 3,5-dichlorobenzoate and 0.7 mL of triglyme were placed in a test tube equipped with a stirring bar. Trifluoromethane (9.9 mL, 1.1 eq.) was added using a syringe while cooling the container with liquid nitrogen. Next, a solution of potassium hexamethyl disilazide (160 mg, 0.8 mmol, 2.0 eq.) dissolved in triglyme (0.3 mL) was added to a test tube cooled to -40°C, and the reaction was carried out at the same temperature for 4 hours. After the reaction was complete, 1.0 mL of 1 M hydrochloric acid was added, the aqueous layer was extracted with dichloromethane (1.0 mL x 3), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by silica gel column chromatography to obtain a mixture of the target 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one (c) and 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1,1-diol (d) as a colorless, transparent liquid (49.6 mg, yield 50%, (c):(d)=1:2.3).

[0032] The analysis results were as follows: 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one(c) 1 H-NMR (300MHz, CDCl3) δ: 7.71 (s, 2H), 7.93 (s, 1H) ppm. 19 F-NMR (282MHz, CDCl3)δ: -72.18(s,3F)ppm. 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1,1-diol(d) 1 H-NMR (300MHz, CDCl3) δ: 7.61 (s, 2H), 7.46 (s, 1H), 3.70-3.62 (m, 2H) ppm. 19 F-NMR (282MHz, CDCl3)δ: -85.08(s,3F)ppm.

[0033] Example 4 Preparation of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1,1-diol (d) [ka] In a test tube equipped with a stirring bar, methyl 3,5-dichlorobenzoate (41.0 mg, 0.2 mmol) and N,N-dimethylformamide (0.7 mL) were charged. Trifluoromethane (4.9 mL, 1.1 eq.) was added using a syringe while cooling the container with liquid nitrogen. Next, a solution of potassium tert-butoxide (44.9 mg, 0.4 mmol, 2.0 eq.) dissolved in dimethylformamide (0.3 mL) was added to a test tube cooled to -40°C, and the reaction was carried out at the same temperature for 4 hours. After the reaction was complete, saturated ammonium chloride aqueous solution (1.0 mL) was added, the aqueous layer was extracted with dichloromethane (1.0 mL x 3), the organic layers were washed together with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1,1-diol (d) (benzotrifluoride was used as an internal standard). 19 F-NMR yielded 36%, 18.8 mg, 0.072 mmol).

[0034] The analysis results were as follows: 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1,1-diol(d) 1 H-NMR (300MHz, CDCl3) δ: 7.61 (s, 2H), 7.46 (s, 1H), 3.70-3.62 (m, 2H) ppm. 19 F-NMR (282MHz, CDCl3)δ: -85.08(s,3F)ppm.

[0035] Examples 5-6 Preparation of various chlorosubstituted phenyltrifluoromethyl ketone hydrates Using the same reaction apparatus as in Example 4, the same procedure as in Example 4 was carried out, except that methyl 3,5-dichlorobenzoate was replaced with the ester compounds shown in Table 1, to obtain the target chloro-substituted phenyltrifluoromethyl ketone hydrate. The results are shown in Table 1.

[0036] [Table 1] [Industrial applicability]

[0037] The chloro-substituted phenyltrifluoromethyl ketones obtained by the method of the present invention are useful as intermediates for Efavirenz, which is used as an HIV prophylaxis and HIV infection treatment agent, and as intermediates for insecticides such as lotilaner, sarolaner, fluralaner, fluxametamide, isocycloseram, and afoxolaner.

Claims

1. The following general formula (4) 【Chemistry 17】 (In formula (4), R １ is a chlorine atom or a nitro group, R ２ R represents a hydrogen atom. ３ (This indicates a methyl group.) The ester compounds represented by the following general formula (5) are reacted with trifluoromethane in a glyme solvent and / or N,N-dimethylformamide in the presence of potassium hexamethyldisilazide and / or potassium tert-butoxide, characterized by the reaction of ester compounds represented by the following general formula (5). [Chemistry 18] (In formula (5), R １ is a chlorine atom or a nitro group, R ２ (This represents a hydrogen atom.) A method for producing chlorosubstituted phenyltrifluoromethyl ketones represented by [the specified formula].

2. A method for producing chlorosubstituted phenyltrifluoromethyl ketones according to claim 1, characterized in that the solvent is triglyme, tetraglyme, and / or dimethylformamide.

3. A method for producing chlorosubstituted phenyltrifluoromethyl ketones according to claim 1 or claim 2, characterized in that the trifluoromethyl group substitution reaction of ester compounds represented by formula (4) is carried out at -60°C to 0°C.

4. A method for producing chlorosubstituted phenyltrifluoromethyl ketones according to any one of claims 1 to 3, characterized in that 1.0 molar equivalent to 5.0 molar equivalents of potassium hexamethyldisilazide and / or potassium tert-butoxide are used with respect to ester compounds represented by formula (4).

5. A method for producing chlorosubstituted phenyltrifluoromethyl ketones according to any one of claims 1 to 4, characterized in that 1.0 molar equivalent or more of trifluoromethane is used with respect to ester compounds represented by formula (4).

6. A method for producing a chlorosubstituted phenyltrifluoromethyl ketone hydrate according to any one of claims 1 to 5, characterized in that the solvent is N,N-dimethylformamide and the base is potassium tert-butoxide.

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