Method for producing 4-ketobenzamide derivative and 4-ketobenzoic acid derivative

Abstract

To provide a method for producing 4-ketobenzamide derivatives and 4-ketobenzoic acid derivatives.SOLUTION: The present invention provides a method for producing a 4-ketobenzamide compound represented by formula (2), by amidating a compound represented by formula (1), which is obtained through cyanation of a compound represented by formula (3), as well as a method for producing a 4-ketobenzoic acid derivative represented by formula (6), by hydrolyzing the compound represented by formula (1) or the compound represented by formula (2), and a method for producing a 4-ketobenzoic acid ester derivative represented by formula (5), by esterifying the compound represented by formula (2), wherein R1 represents a C1-C6 alkyl group or the like, R2 represents a C1-C6 alkyl group or the like, R3 represents a C1-C6 alkyl group or the like, X represents a halogen atom or the like, Y represents a C1-C6 alkyl group or the like, and n represents an integer of 0-3.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a 4-ketobenzamide derivative or a 4-ketobenzoic acid derivative, which is useful as an intermediate in the production of pharmaceuticals and agrochemicals. [Background technology]

[0002] Known methods for synthesizing 4-ketobenzamide derivatives from 4-ketobenzonitrile derivatives include, for example, methods such as those described in Non-Patent Documents 1 to 5. Also, known methods for synthesizing 2-methyl-4-ketobenzoic acid derivatives, which are useful as intermediates for pharmaceuticals and agrochemicals, include, for example, methods such as those described in Patent Document 1 and Non-Patent Document 6. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2009 / 001942 [Non-patent literature]

[0004] [Non-Patent Document 1] Angewandte Chemie, International Edition, 2004, 1576 contributions [Non-Patent Document 2] Chemistry-A European Journal, 2008, 6601 contributions [Non-Patent Document 3] Organic Letters, 2009, 5598 contributions [Non-Patent Document 4] Tetrahedron Letters, 2010, 1639 contributions [Non-Patent Document 5] Journal of Chemical Society, Chemical Communications, 2009, 3258 contributions [Non-Patent Document 6] Journal of the American Chemical Society, 1975, 2107 contributions Summary of the Invention [Problem to be solved by the invention]

[0005] When attempting to produce a 4-ketobenzamide derivative by the methods described in Non-Patent Documents 1 to 3, it is necessary to use an expensive transition metal catalyst. Moreover, the method described in Non-Patent Document 4 relies on an enzyme reaction, and the method described in Non-Patent Document 5 requires the use of a supported catalyst that is time-consuming to prepare, and therefore these methods are not satisfactory as industrial production methods.

[0006] In addition, when attempting to produce a 4-ketobenzoic acid derivative having an alkyl group at the 2-position, the method described in Non-Patent Document 6 synthesizes 4-acetyl-2-methylbenzoic acid by a Fludel-Crafts reaction with a cobalt nonacarbonyl complex followed by an oxidation reaction, and since a stoichiometric amount of a cobalt complex is used, there are problems with the cost of waste disposal and the like as an industrial production method. In addition, the method described in Patent Document 1 synthesizes 4-acetyl-2-methylbenzoic acid by a reaction of 4-bromo-2-methylbenzoic acid with vinyl ethers using a palladium catalyst, and a carbon monoxide insertion reaction of 4-bromo-3-methylacetophenone using a palladium catalyst, but since palladium catalysts are expensive, there are problems with the cost of using them in industrial production. As described above, there are no known industrial production methods for 4-ketobenzamide derivatives having a substituent at the 2-position and 4-ketobenzoic acid derivatives having an alkyl group at the 2-position, which do not use heavy metals and use only economically satisfactory and inexpensive reaction reagents. In addition, since the contamination of pharmaceutical and agrochemical intermediates with heavy metals may affect the quality of the final product, an industrial production method that does not use heavy metals is desired. [Means for solving the problem]

[0007] In view of such circumstances, the present inventors have conducted intensive research and have found an industrial production method for a 4-ketobenzoic acid derivative having a substituent at the 2-position, which comprises producing a 4-ketobenzamide derivative from a 4-ketobenzonitrile derivative having a substituent at the 2-position using only inexpensive reaction reagents without using heavy metals, and further esterifying and hydrolyzing the 4-ketobenzamide derivative, thereby completing the present invention. That is, the present invention relates to the following [1] to

[10] . [1] Formula (1):

[0008] [ka]

[0009] (In the formula, R 1 represents C1-C6 alkyl or C3-C8 cycloalkyl; R 2 represents a halogen atom, a C1-C6 alkyl, a C1-C6 haloalkyl, or nitro; Y is a halogen atom, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylcarbonyl, phenyl or (Z) p1 represents a phenyl substituted by When n is an integer of 2 or more, each Y may be the same as or different from each other; Further R 2 If and Y are adjacent, the two adjacent R 2 and Y form -CH=CHCH=CH-, R 2 and Y may form a 6-membered ring together with the carbon atom to which they are bonded, and in this case, a hydrogen atom bonded to each carbon atom forming the ring may be optionally replaced by Z, and when the ring is replaced by two or more Z's at the same time, each Z may be the same or different from each other; Z represents a halogen atom, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio or C1-C6 alkylcarbonyl; n represents an integer of 0, 1, 2 or 3; p1 represents an integer of 1, 2, 3, 4 or 5. With an acid or a base, a 4-ketobenzonitrile compound represented by the formula (2):

[0010] [ka]

[0011] (In the formula, R 1 , R 2 , Y and n are as defined above. A method for producing a 4-ketobenzamide compound represented by the following formula: [2] Formula (3):

[0012] [ka]

[0013] {where, R 1 , R 2 , Y and n have the same meanings as described in [1] above, X represents a halogen atom, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy. The method for producing the 4-ketobenzamide compound according to the above-mentioned [1], wherein the 4-ketobenzonitrile compound (1) according to the above-mentioned [1] is obtained by cyanating a 4-ketobenzene compound represented by the following formula (1): [3] Y is a halogen atom, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylcarbonyl, phenyl or (Z)p1 represents a phenyl substituted by The method for producing a 4-ketobenzamide compound according to the above item [1] or [2], wherein when n represents an integer of 2 or more, each Y may be the same as or different from each other. [4] R 1 represents C1-C6 alkyl, R 2 represents C1-C6 alkyl, The method for producing a 4-ketobenzamide compound according to the above [1] or [2], wherein n represents 0. [5] R 1 represents C1-C6 alkyl, R 2 represents C1-C6 alkyl, X represents a halogen atom; The method for producing a 4-ketobenzamide compound according to the above [2], wherein n represents 0. [6] The 4-ketobenzamide compound represented by formula (2) described in [1] above is reacted in the presence of an acid, Formula (4):

[0014] [ka]

[0015] [In the formula, R 3 represents a C1-C6 alkyl group. With an alcohol represented by formula (5):

[0016] [ka]

[0017] {where, R 1 , R 2 , R 3 , Y and n have the same meanings as described in [1] above.} A method for producing a 4-ketobenzoic acid ester compound represented by the following formula: [7] A method for producing a 4-ketobenzoic acid ester compound represented by formula (5) described in [6] above, which is obtained by reacting a 4-ketobenzonitrile compound represented by formula (1) described in [1] above with an alcohol represented by formula (4) described in [6] above. [8] Formula (3) described in [2] above:

[0018] [ka]

[0019] [In the formula, R 2 represents a halogen atom, a C1-C6 alkyl, a C1-C6 haloalkyl, or nitro; Y is a halogen atom, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylcarbonyl, phenyl or (Z) p1 represents a phenyl substituted by When n is an integer of 2 or more, each Y may be the same as or different from each other; R 1 , X, Z, n and p1 have the same meanings as described in [1] above.] The compound represented by the formula (1):

[0020] [ka]

[0021] [In the formula, R 1 , R 2 , Y and n are as defined above.] A method for producing a 4-ketobenzonitrile compound represented by the formula: [9] The 4-ketobenzamide compound represented by formula (2) described in [1] above is hydrolyzed with an acid or a base to obtain a compound represented by formula (6):

[0022] [ka]

[0023] [In the formula, R 1 , R 2 , Y and n have the same meanings as described in [1] above.] A method for producing a 4-ketobenzoic acid compound represented by the formula:

[10] A 4-ketobenzonitrile compound represented by formula (1) described in [1] above. [In the formula, R 1 , R 2 , Y and n have the same meanings as described in [1] above (except for R 2 (excluding halogen atoms).] with an acid or a base. Effect of the Invention

[0024] INDUSTRIAL APPLICABILITY The present invention provides a method useful for the industrial production of 4-ketobenzamide derivatives and 4-ketobenzoic acid derivatives, which are useful as intermediates for pharmaceuticals, agrochemicals, and various other chemical products. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] The present invention will be described in detail below.

[0026] In this specification, n- means normal, i- means iso, s- means secondary, and t- means tertiary. The designation "halo" herein refers to fluorine, chlorine, bromine, and iodine atoms.

[0027] In this specification, C a ~C bThe notation of alkyl represents a linear or branched hydrocarbon group having a to b carbon atoms, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, an s-butyl group, a t-butyl group, an n-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1-ethylpropyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a 2,2-dimethylpropyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 1,1-dimethylbutyl group, and a 1,3-dimethylbutyl group, and each of the specified ranges of the number of carbon atoms is selected.

[0028] In this specification, C a ~C b The notation of cycloalkyl represents a cyclic hydrocarbon group having a to b carbon atoms, and can form a single ring or a composite ring structure having 3 to 6 members. In addition, each ring may be optionally substituted with an alkyl group within the range of the specified number of carbon atoms. For example, cyclopropyl group, 1-methylcyclopropyl group, 2-methylcyclopropyl group, 2,2-dimethylcyclopropyl group, 2,2,3,3-tetramethylcyclopropyl group, cyclobutyl group, cyclopentyl group, 2-methylcyclopentyl group, 3-methylcyclopentyl group, cyclohexyl group, 2-methylcyclohexyl group, 3-methylcyclohexyl group, 4-methylcyclohexyl group, bicyclo[2.2.1]heptan-2-yl group, etc. are listed as specific examples, and each is selected within the range of the specified number of carbon atoms.

[0029] In this specification, C a ~C bThe term "haloalkyl" refers to a linear or branched hydrocarbon group having a to b carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom, and in this case, when substituted with two or more halogen atoms, those halogen atoms may be the same or different from each other. For example, a fluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, a chlorofluoromethyl group, a dichloromethyl group, a bromofluoromethyl group, a trifluoromethyl group, a chlorodifluoromethyl group, a dichlorofluoromethyl group, a trichloromethyl group, a bromodifluoromethyl group, a bromochlorofluoromethyl group, a dibromofluoromethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2,2-difluoroethyl group, a 2-chloro-2-fluoroethyl group, a 2,2-dichloroethyl group, a 2-bromo-2-fluoroethyl group, a 2,2,2-trifluoroethyl group, a 2-chloro-2,2-difluoroethyl group, a 2,2-dichloro-2-fluoroethyl group, a 2,2,2-trichloroethyl group, a 2-bromo-2,2-difluoroethyl group, a 2-bromo-2-chloro-2-fluoroethyl group, a 2-bromo-2,2-dichloroethyl group, a 1,1,2,2-tetrafluoro ...,2-dichloroethyl group, a 2-bromo-2,2-dichloroethyl group, a 1,1,2,2-tetrafluoroethyl group, a 2-bromo-2,2-difluoroethyl group, a 2-bromo-2,2-dichloroethyl group, a 2-bromo-2,2-dichloroethyl group, a 2-bromo-2,2-dichloroethyl group, a 1,1,2,2-tetrafluoroethyl group, a 2-bro trifluoroethyl group, pentafluoroethyl group, 1-chloro-1,2,2,2-tetrafluoroethyl group, 2-chloro-1,1,2,2-tetrafluoroethyl group, 1,2-dichloro-1,2,2-trifluoroethyl group, 2-bromo-1,1,2,2-tetrafluoroethyl group, 2-fluoropropyl group, 2-chloropropyl group, 2-bromopropyl group, 2-chloro-2-fluoropropyl group, 2,3-dichloropropyl group, 2-bromo-3-fluoropropyl group, fluoropropyl group, 3-bromo-2-chloropropyl group, 2,3-dibromopropyl group, 3,3,3-trifluoropropyl group, 3-bromo-3,3-difluoropropyl group, 2,2,3,3-tetrafluoropropyl group, 2-chloro-3,3,3-trifluoropropyl group, 2,2,3,3,3-pentafluoropropyl group, 1,1,2,3,3,3-hexafluoropropyl group, heptafluoropropyl group, 2,3-dichloro-1,1,2,3,3-pentafluoropropyl group, 2-fluoro-1-methylethyl group, 2-chloro-1-methylethyl group, 2-bromo-1-methylethyl group, 2,2,2-trifluoro-1-(trifluoromethyl)ethyl group, 1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl group, 2-fluorobutyl group, 2-chlorobutyl group, 2,2,3,3,4,4-hexafluorobutyl group, 2,2,3,4,4,4-hexafluorobutyl group, 2,2,3,3,4,4-hexafluorobutyl group, 2,2,3,3,4,4-heptafluorobutyl group, Specific examples include 1,1,2,2,3,3,4,4-octafluorobutyl group, nonafluorobutyl group, 4-chloro-1,1,2,2,3,3,4,4-octafluorobutyl group, 2-fluoro-2-methylpropyl group, 1,2,2,3,3,3-hexafluoro-1-(trifluoromethyl)propyl group, 2-chloro-1,1-dimethylethyl group, 2-bromo-1,1-dimethylethyl group, 5-chloro-2,2,3,4,4,5,5-heptafluoropentyl group, and tridecafluorohexyl group, each of which is selected within the range of the number of carbon atoms specified.

[0030] In this specification, C a ~C b The notation of alkoxy represents the above-mentioned alkyl-O- group having a to b carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, an n-propyloxy group, an i-propyloxy group, an n-butyloxy group, an i-butyloxy group, an s-butyloxy group, and a t-butyloxy group, each of which is selected within the range of the specified number of carbon atoms.

[0031] In this specification, C a ~C b The notation of alkylthio represents the above-mentioned alkyl-S- group having a to b carbon atoms, and specific examples thereof include a methylthio group, an ethylthio group, an n-propylthio group, an i-propylthio group, an n-butylthio group, an i-butylthio group, an s-butylthio group, a t-butylthio group, an n-pentylthio group, and an n-hexylthio group, each of which is selected within the range of the specified number of carbon atoms.

[0032] In this specification, C a ~C b The notation of haloalkoxy represents a haloalkyl-O- group having the above-mentioned meaning and containing a to b carbon atoms, and examples thereof include a difluoromethoxy group, a trifluoromethoxy group, a chlorodifluoromethoxy group, a bromodifluoromethoxy group, a 2-fluoroethoxy group, a 2-chloroethoxy group, a 2,2,2-trifluoroethoxy group, a 1,1,2,2-tetrafluoroethoxy group, a 2-chloro-1,1,2-trifluoroethoxy group, a 2-bromo-1,1,2-trifluoroethoxy group, a pentafluoroethoxy group, a 2,2-dichloro-1, Specific examples include a 1,2-trifluoroethoxy group, a 2,2,2-trichloro-1,1-difluoroethoxy group, a 2-bromo-1,1,2,2-tetrafluoroethoxy group, a 2,2,3,3-tetrafluoropropyloxy group, a 1,1,2,3,3,3-hexafluoropropyloxy group, a 2,2,2-trifluoro-1-(trifluoromethyl)ethoxy group, a heptafluoropropyloxy group, and a 2-bromo-1,1,2,3,3,3-hexafluoropropyloxy group, and the like, each of which is selected within the range of the number of carbon atoms specified for each group.

[0033] In this specification, C a ~C b The notation of alkylcarbonyl represents the above-mentioned alkyl-C(O)- group having a to b carbon atoms, and specific examples thereof include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a 2-methylbutanoyl group, a pivaloyl group, and a hexanoyl group, each of which is selected within the range of the specified number of carbon atoms.

[0034] Examples of solvents that can be used in the cyanation process of the compound represented by formula (1) from the compound represented by formula (3) according to the present invention include aromatics such as toluene, benzene, chlorobenzene, orthodichlorobenzene, nitrobenzene, and trifluoromethylbenzene, hydrocarbons such as hexane, heptane, octane, and nonane, polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, and water, alcohol solvents such as methanol, ethanol, n-propanol, i-propanol, n-butanol, ethylene glycol, and propylene glycol, halogen-based solvents such as dichloromethane, chloroform, and 1,2-dichloroethane, ether solvents such as diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, and methyl-t-butyl ether, ester solvents such as methyl acetate, ethyl acetate, and butyl acetate, and mixtures of these solvents can also be used. Among these, polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide are particularly preferred.

[0035] The amount of the solvent used in the cyanation step of converting the compound represented by formula (1) from the compound represented by formula (3) according to the present invention is in the range of 0 to 100 parts by weight, preferably 1 to 10 parts by weight, per part by weight of the compound represented by formula (3) as the raw material.

[0036] In the cyanation process of the compound represented by formula (1) from the compound represented by formula (3) according to the present invention, it may be preferable to add a phase transfer catalyst from the viewpoint of shortening the reaction time and suppressing by-products. Examples of the phase transfer catalyst that can be used include quaternary ammonium salts such as tetraethylammonium chloride, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, and benzyltrimethylammonium chloride, and quaternary phosphonium salts such as tetraethylphosphonium bromide, tetra-n-butylphosphonium bromide, and tetra-n-butylphosphonium chloride. Among these, tetra-n-butylammonium bromide is particularly preferred.

[0037] Examples of the cyanating agent that can be used in the cyanation step of converting the compound represented by formula (3) according to the present invention into the compound represented by formula (1) include sodium cyanide, potassium cyanide, copper cyanide, zinc cyanide, etc. Among these, sodium cyanide is particularly preferred. In addition, it is preferable to use a cyanating agent that is as fine as possible (for example, powdery) in terms of shortening the reaction time and suppressing by-products.

[0038] The amount of the cyanating agent used in the cyanation step of converting the compound represented by formula (3) according to the present invention into the compound represented by formula (1) is within a range of 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of the compound represented by formula (1) as the raw material.

[0039] The reaction temperature in the cyanation step of converting the compound represented by formula (3) according to the present invention into the compound represented by formula (1) may be set in any temperature range of 0°C or higher and 200°C or lower, for example, in the range of 50°C or higher and 150°C or lower, and preferably 80°C or higher and 130°C or lower.

[0040] The cyanation process of the compound represented by formula (1) from the compound represented by formula (3) according to the present invention is preferably carried out under an atmosphere of an inert gas such as air, oxygen, nitrogen, argon, xenon, etc. From the viewpoint of shortening the reaction time and suppressing by-products, it is preferable to maintain a certain concentration of a certain inert gas (e.g., oxygen, etc.). For example, the method of bubbling an inert gas or the method of supplying a constant amount of an inert gas during the reaction can be mentioned.

[0041] Solvents that can be used in the amidation step of converting the compound represented by formula (1) to the compound represented by formula (2) according to the present invention include alcoholic solvents such as methanol, ethanol, n-propanol, i-propanol, n-butanol, ethylene glycol, and propylene glycol, aromatics such as toluene, benzene, chlorobenzene, orthodichlorobenzene, nitrobenzene, and trifluoromethylbenzene, hydrocarbons such as hexane, heptane, octane, and nonane, polar solvents such as nitromethane, N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, and water, and halogenated solvents such as dichloromethane, chloroform, and 1,2-dichloroethane, and mixtures of these solvents can also be used. Among these, aromatics such as toluene, alcoholic solvents such as methanol, and polar solvents such as dimethylsulfoxide are preferred.

[0042] The amount of the solvent used in the amidation step of converting the compound represented by formula (1) according to the present invention into the compound represented by formula (2) is in the range of 0 to 100 parts by weight, preferably 1 to 20 parts by weight, per 1 part by weight of the compound represented by formula (2).

[0043] In the amidation step of converting the compound represented by formula (1) to the compound represented by formula (2) according to the present invention, an acid or a base can be used, and examples of the acid that can be used include sulfuric acid, hydrochloric acid, trifluoroacetic acid, acetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, etc., and examples of the base that can be used include sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium phosphate, etc., and an aqueous solution of these may also be used. Of these, sulfuric acid and sodium hydroxide are particularly preferred.

[0044] When the amidation step of converting the compound represented by formula (1) to the compound represented by formula (2) according to the present invention is carried out using a base, it may be preferable to use an oxidizing agent in the presence of the same. Examples of the oxidizing agent that can be used include aqueous hydrogen peroxide, urea-hydrogen peroxide adduct, and m-chloroperbenzoic acid.

[0045] When an oxidizing agent is used in the amidation step of converting the compound represented by formula (1) to the compound represented by formula (2) according to the present invention, the amount of the oxidizing agent is in the range of 0.1 to 100 equivalents, preferably 1 to 10 equivalents, relative to the compound represented by formula (1). The amidation step of the compound represented by formula (1) according to the present invention to produce a compound represented by formula (2) is preferably carried out at a temperature of -20°C or higher and 100°C or lower, more preferably at a temperature of -20°C or higher and 50°C or lower.

[0046] Acids that can be used in the esterification step of the compounds represented by formulas (1) and (2) according to the present invention to the compounds represented by formula (5) include sulfuric acid, hydrochloric acid, trifluoroacetic acid, acetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, etc., and aqueous solutions of these acids may be used. Of these, sulfuric acid is particularly preferred.

[0047] The amount of the acid used in the esterification step of the compounds represented by formulas (1) and (2) to the compound represented by formula (5) according to the present invention is in the range of 0.1 to 100 parts by weight, preferably 1 to 20 parts by weight, based on the compounds represented by formulas (1) and (2).

[0048] The amount of the alcohol represented by formula (4) used in the esterification step of the compounds represented by formulas (1) and (2) according to the present invention to the compound represented by formula (5) is in the range of 1 to 100 parts by weight, preferably 1 to 20 parts by weight, based on the compounds represented by formulas (1) and (2).

[0049] In the esterification process of the compounds represented by formulas (1) and (2) to the compounds represented by formula (5) according to the present invention, it may be better to add water in some cases. The amount of water added is preferably in the range of 0.01 to 100 parts by weight based on the compounds represented by formulas (1) and (2).

[0050] The esterification step of the present invention from the compounds represented by formula (1) and formula (2) to the compound represented by formula (5) is preferably carried out at a temperature of 0°C or higher and 200°C or lower, more preferably at a temperature of 50°C or higher and 200°C or lower.

[0051] The esterification step of the present invention from the compounds represented by formula (1) and formula (2) to the compound represented by formula (5) is preferably carried out at a pressure of 1 atm or more and 100 atm or less.

[0052] Solvents that can be used in the hydrolysis step of the compounds represented by formula (1) and formula (2) of the present invention include alcoholic solvents such as methanol, ethanol, n-propanol, i-propanol, n-butanol, ethylene glycol, and propylene glycol; aromatic solvents such as toluene, benzene, chlorobenzene, ortho-dichlorobenzene, nitrobenzene, and trifluoromethylbenzene; hydrocarbons such as hexane, heptane, octane, and nonane; polar solvents such as nitromethane, N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, and water; halogenated solvents such as dichloromethane, chloroform, and 1,2-dichloroethane; and ether solvents such as diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, and methyl-t-butyl ether. Mixtures of these solvents can also be used.

[0053] The amount of the solvent used in the hydrolysis step of the compounds represented by formula (1) and formula (2) according to the present invention is in the range of 0 to 100 parts by weight, preferably 1 to 20 parts by weight, per part by weight of the compounds represented by formula (1) and formula (2).

[0054] In the hydrolysis step of the compounds represented by formula (1) and formula (2) according to the present invention, an acid or a base can be used. Examples of the acid that can be used include sulfuric acid, hydrochloric acid, and acetic acid. Examples of the base that can be used include sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide. An aqueous solution of these may also be used.

[0055] The amounts of the acid and base used in the hydrolysis step of the compounds represented by formula (1) and formula (2) according to the present invention are in the range of 0.1 to 300 equivalents, preferably 1 to 50 equivalents, relative to the compounds represented by formula (1) and formula (2).

[0056] Some of the compounds represented by formula (3), which are the raw materials of the present invention, are known compounds, and some of them are commercially available. Others can be synthesized according to general synthetic methods for substituted ketobenzenes described in the literature. EXAMPLES

[0057] The present invention will be described in detail below by specifically describing synthesis examples of the compounds of the present invention as examples, but the present invention is not limited to these.

[0058] The analyses by high performance liquid chromatography (hereinafter abbreviated as HPLC) described in the examples were carried out under the conditions described below. Column: Inertstain C8, 4.6×250mm, 5μm (GL Science) Eluent: acetonitrile: water: acetic acid = 1:1:0.001 (volume ratio) Oven temperature: 40℃ Flow rate: 0.75~1.00ml / min Detection wavelength: 254 nm [Quantitative analysis] The quantitative analysis using HPLC was carried out under the same measurement conditions as above, using the internal standard method with 2-nitrobiphenyl as the internal standard substance.

[0059] Example 1 Synthesis of 4-cyano-3-methylacetophenone Part 1 To a solution of 15.2 g (100 mmol) of 4-fluoro-3-methylacetophenone in 30.4 g of dimethyl sulfoxide, 5.88 g (120 mmol) of sodium cyanide and 6.44 g (20 mmol) of tetra-n-butylammonium bromide were added and stirred at 115° C. for 10 hours. After the reaction was completed, the mixture was cooled to room temperature, 152 g of water was added, and the mixture was extracted with toluene (91.2 g). The organic layer obtained was quantitatively analyzed by HPLC, and the content of the target substance was 13.0 g (yield 82%).

[0060] Example 2 Synthesis of 4-cyano-3-methylacetophenone Part 2 To a solution of 1.11 g (7.0 mmol) of 4-fluoro-3-methylacetophenone in 3.2 g of dimethylacetamide, 191 mg (1.4 mmol) of 1,4-dimethoxybenzene was added as an internal standard substance for reaction tracking. Furthermore, 412 mg (8.4 mmol) of sodium cyanide and 45.1 mg (1.4 mmol) of tetra-n-butylammonium bromide were added under air and stirred at 120 ° C for 15 hours. After the reaction was completed, the mixture was cooled to room temperature and a water:acetonitrile = 1:1 (volume ratio) solution was added to make 87.2 g of a homogeneous solution. The obtained solution was quantitatively analyzed by HPLC, and the content of the target substance was 891 mg (yield 80%).

[0061] Example 3 Synthesis of 4-cyano-3-methylacetophenone Part 3 377 mg (7.7 mmol) of sodium cyanide was added to a solution of 1.10 g (7.0 mmol) of 4-fluoro-3-methylacetophenone in 5.3 g of dimethylacetamide under air and stirred at 115 ° C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature and a water:acetonitrile = 1:1 (volume ratio) solution was added to obtain a homogeneous solution of 113.1 g. The obtained solution was quantitatively analyzed by HPLC, and the content of the target substance was 915 mg (yield 82%).

[0062] Example 4 Synthesis of 4-cyano-3-methylacetophenone Part 4 377 mg (7.7 mmol) of sodium cyanide was added to a solution of 1.10 g (7.0 mmol) of 4-fluoro-3-methylacetophenone in 5.3 g of dimethylacetamide, and the mixture was stirred at 115°C for 24 hours while blowing in air at 0.6 mL / min. After the reaction was completed, the mixture was cooled to room temperature, and a water:acetonitrile = 1:1 (volume ratio) solution was added to make 118.6 g of a homogeneous solution. The result of quantitative analysis of the obtained solution by HPLC showed that the content of the target substance was 900 mg (yield 81%).

[0063] Example 5 Synthesis of 4-acetyl-2-methylbenzamide, Part 1 To a solution of 12.5 g (79 mmol) of 4-cyano-3-methylacetophenone in 62.5 g of methanol, 6.25 g of dimethyl sulfoxide and 10.5 g (79 mmol) of 30% by mass aqueous caustic soda were added, and the mixture was stirred at 20°C for 15 minutes. Then, 26.7 g (237 mmol) of 30% by mass aqueous hydrogen peroxide was added dropwise, and the mixture was stirred at the same temperature for 2 hours. After the reaction was completed, 9.06 g of concentrated hydrochloric acid was added to make the reaction solution acidic, and then 29.9 g (237 mmol) of sodium sulfite was added, and the mixture was stirred at 30°C for 1 hour. After the stirring was completed, methanol was distilled off under reduced pressure, and then 62.5 g of water was added, and the mixture was stirred at 0°C for 2 hours. The crystals were collected by filtration from the obtained slurry and dried under reduced pressure, and 12.9 g of the target product was obtained as white crystals. (Yield 93%) Example 6 Synthesis of 4-acetyl-2-methylbenzamide, Part 2 To a solution of 797 mg (5 mmol) of 4-cyano-3-methylacetophenone in 2.39 g of toluene, 3.20 g of methanol and 678 mg (5 mmol) of 30% by mass aqueous caustic soda solution were added and stirred at 10°C for 15 minutes. Then, 2.42 g (25 mmol) of 30% by mass aqueous hydrogen peroxide was added dropwise and stirred at the same temperature for 5 hours. After the reaction was completed, a water:acetonitrile = 1:1 (volume ratio) solution was added to make a 95.4 g homogeneous solution. The result of quantitative analysis of the obtained solution by HPLC showed that the content of the target substance was 867 mg (yield 97.7%).

[0064] Example 7 Synthesis of methyl 4-acetyl-2-methylbenzoate Part 1 A solution of 10.0 g (56.5 mmol) of 4-acetyl-2-methylbenzamide in 40 g of methanol was cooled to below 10°C, and 20 g of concentrated sulfuric acid was added dropwise so that the temperature of the reaction solution did not exceed 10°C. The mixture was then stirred under reflux for 30 hours and cooled to room temperature. 50 g of toluene and 50 g of water were added, and methanol was distilled off under reduced pressure. The aqueous layer was separated, and a portion of the resulting organic layer was sampled and quantitatively analyzed by HPLC, revealing that the content of the target product was 9.07 g (yield 84%).

[0065] Example 8 Synthesis of methyl 4-acetyl-2-methylbenzoate Part 2 2.0 g of water was added to a solution of 10.0 g (56.5 mmol) of 4-acetyl-2-methylbenzamide in 60 g of methanol. After the addition was completed, the reaction solution was cooled to 10°C or less, and 30 g of concentrated sulfuric acid was added dropwise so that the temperature of the reaction solution did not exceed 10°C. After the addition was completed, the mixture was stirred under heating and reflux for 30 hours, and then cooled to room temperature. A portion of the resulting reaction solution was sampled and analyzed by HPLC, and the relative area value of the target substance was 90.2%.

[0066] Example 9 Synthesis of methyl 4-acetyl-2-methylbenzoate Part 3 A solution of 0.354 g (2 mmol) of 4-acetyl-2-methylbenzamide in 3.54 g of methanol was cooled to below 10°C in a pressure-resistant reaction vessel, and 1.77 g of concentrated sulfuric acid was added dropwise so that the temperature of the reaction solution did not exceed 10°C. The vessel was then sealed and stirred at 100°C for 8 hours. After cooling to room temperature, the reaction solution was analyzed by HPLC, and the relative area value of the target compound was 92.9%.

[0067] Example 10 Synthesis of 3-chloro-4-cyanoacetophenone 0.877g of sodium cyanide was added to a solution of 3.0g of 3-chloro-4-fluoroacetophenone in 28ml of dimethylformamide, and the mixture was stirred at 45°C for 2 hours, followed by stirring at 100°C for 2 hours. After the reaction was completed, the reaction mixture was allowed to cool to room temperature, then gradually poured into ice-cooled aqueous ammonia solution, and the temperature was raised to room temperature. After extraction with ethyl acetate (60ml x 2), the mixture was washed with water, saturated saline, and anhydrous sodium sulfate in this order, dried, and the solvent was distilled off under reduced pressure. The obtained crude product was washed with diethyl ether-hexane to obtain 2.43g of the target product as a white solid.

[0068] Example 11 Synthesis of 3-bromo-4-cyanoacetophenone 0.66 g of 3-bromo-4-fluoroacetophenone was dissolved in 4 ml of N,N-dimethylformamide, 0.16 g of sodium cyanide was added, and the mixture was stirred at 100° C. for 4 hours. After the reaction was completed, the reaction solution was cooled to 0° C., 15 ml of aqueous ammonia was added, and the mixture was extracted with 30 ml of ethyl acetate. The organic layer obtained was washed with 15 ml of water and 10 ml of saturated saline in this order, and then dried using sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residual solid was washed with diisopropyl ether to obtain 0.45 g of the target product as a yellow solid.

[0069] Example 12 Synthesis of 4-acetyl-2-methylbenzoic acid, part 1 To a solution of 1.59 g (10 mmol) of 4-cyano-3-methylacetophenone in 15.9 g of methanol, 0.80 g of dimethyl sulfoxide and 26.7 g (200 mmol) of 30% by mass aqueous caustic soda solution were added, and the mixture was stirred under heating and reflux for 6 hours. After stirring, the mixture was cooled to room temperature. Then, 22.9 g (220 mmol) of concentrated hydrochloric acid was added to neutralize the mixture, and methanol was distilled off under reduced pressure. Further, 13 g of toluene was added, and the mixture was stirred for 30 minutes, after which the aqueous layer was separated. A portion of the obtained organic layer was sampled and quantitatively analyzed by HPLC, and the content of the target substance was 1.41 g (yield 79%).

[0070] Example 13 Synthesis of 4-acetyl-2-methylbenzoic acid, part 2 19.0 g of acetic acid and 38.0 g of 50% by mass sulfuric acid were added to 3.18 g (20 mmol) of 4-cyano-3-methylacetophenone, and the mixture was stirred under heating and reflux for 17 hours. After cooling to 80°C, 31.8 g of toluene was added and the mixture was stirred for 30 minutes. The aqueous layer was separated, and a portion of the organic layer was sampled and quantitatively analyzed by HPLC, revealing that the content of the target substance was 2.74 g (yield 77%).

[0071] Example 14 Synthesis of 4-acetyl-2-methylbenzoic acid, part 3 44.3g of acetic acid and 88.5g of 50% by mass sulfuric acid were added to 8.85g (50mmol) of 4-acetyl-2-methylbenzamide, and the mixture was stirred at 100°C for 24 hours. 88.5g of toluene was added, and the mixture was stirred for 30 minutes, after which the aqueous layer was separated. A portion of the organic layer obtained was sampled and quantitatively analyzed by HPLC, revealing that the content of the target substance was 6.85g (yield 77%).

[0072] Example 15 Synthesis of 4-acetyl-2-methylbenzoic acid, part 4 To a solution of 0.354 g (2 mmol) of 4-acetyl-2-methylbenzamide in 3.54 g of methanol, 5.31 g (40 mmol) of 30% by mass aqueous sodium hydroxide solution was added and stirred for 5 hours under heating and reflux. After the stirring was completed, a part of the reaction solution was sampled and analyzed by HPLC, and the relative area value of the target substance was 85.2%.

[0073] [Reference example 1] Synthesis of 4-fluoro-3-methylacetophenone 40.0 g of aluminum chloride was added to 66.1 g (600 mmol) of 2-fluorotoluene and cooled to 0°C. While maintaining the temperature at 0-5°C, 23.5 g (300 mmol) of acetyl chloride was added dropwise, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was gradually added to 225 g of water under ice cooling, and then 96 g of toluene was added. After stirring for 30 minutes, the aqueous layer was separated. 128 g of 1 mol / L hydrochloric acid was added to the obtained organic layer and stirred, and the aqueous layer was separated. The obtained organic layer was further washed with a 5 mass % aqueous caustic soda solution, and the water layer was separated, and the toluene was distilled off under reduced pressure. The obtained oily crude product was subjected to reduced pressure distillation to separate the fraction at 1.3-1.5 kPa and 98°C-107°C, and 76.6 g of the target product was obtained (yield 98%).

[0074] [Reference example 2] Synthesis of 3-bromo-4-fluoroacetophenone 1.00g of 1-bromo-2-fluorobenzene was dissolved in 3.00g of 1,2-dichloroethane, and 0.90g of acetyl chloride was added. 1.52g of aluminum chloride was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour, then heated to 35°C to 45°C, and stirred at the same temperature for another 7 hours. After the reaction was completed, the reaction solution was poured into 30g of ice water, and extracted with 30g of 1,2-dichloroethane. The obtained organic layer was washed with 10ml of saturated saline, dried using sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.76g of the target product as an orange oil.

[0075] [Reference example 3] Synthesis of 4-acetyl-2-methylbenzoic acid To a solution of 9.07 g (47.2 mmol) of methyl 4-acetyl-2-methylbenzoate in 27.1 g of toluene, 45.3 g (56.6 mmol) of 5% by mass aqueous caustic soda solution was added and stirred at 80° C. for 8 hours. After stirring, the toluene layer was separated, 72.5 g of toluene was added, and 7.66 g of 35% by mass hydrochloric acid was added to neutralize, and the mixture was heated to 75° C. to separate the aqueous layer. The toluene layer was cooled to room temperature. The obtained slurry was filtered, and the resulting filter cake was dried to obtain 6.88 g of the target product (yield 82%). [Industrial Applicability]

[0076] The production method of the present invention is useful as a method for industrially producing 4-ketobenzamide derivatives or 4-ketobenzoic acid derivatives, which are useful as intermediates for pharmaceuticals and agrochemicals.

Claims

1. Formula (1): 【Chemistry 1】 (In the formula, R １ is C １ ~C ６ Alkyl or C ３ ~C ８ represents cycloalkyl, R ２ is a halogen atom, C １ ~C ６ Alkyl, C １ ~C ６ represents haloalkyl or nitro; Y is a halogen atom, nitro, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkylthio, C １ ~C ６ Alkylcarbonyl, phenyl or (Z) p1 represents a phenyl substituted by When n is an integer of 2 or more, each Y may be the same or different from each other; Further R 2 If and Y are adjacent, the two adjacent R 2 and Y form -CH=CHCH=CH-, R 2 and Y may form a 6-membered ring together with the carbon atom to which they are bonded, and in this case, a hydrogen atom bonded to each carbon atom forming the ring may be optionally replaced by Z, and when the ring is replaced by two or more Z's at the same time, each Z may be the same or different from each other; Z is a halogen atom, nitro, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkylthio or C １ ~C ６ represents alkylcarbonyl, n represents an integer of 0, 1, 2 or 3; p1 represents an integer of 1, 2, 3, 4 or 5. The compound represented by the formula (2): 【Chemistry 2】 (In the formula, R １ , R ２ , Y and n are as defined above.) A method for producing a 4-ketobenzamide compound represented by the following formula:

2. Formula (3): 【Chemistry 3】 (In the formula, R １ , R ２ , Y and n have the same meanings as defined in claim 1; X represents a halogen atom, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy. The method for producing the 4-ketobenzamide compound according to claim 1, wherein the 4-ketobenzonitrile compound (1) according to claim 1 obtained by cyanating a 4-ketobenzene compound represented by the following formula (1) is used as a raw material.

3. Y is a halogen atom, nitro, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkylthio, C １ ~C ６ Alkylcarbonyl, phenyl or (Z) p1 represents a phenyl substituted by 3. The method for producing a 4-ketobenzamide compound according to claim 1 or 2, wherein when n represents an integer of 2 or more, each Y may be the same as or different from each other.

4. R １ is C １ ~C ６ represents an alkyl group, R ２ is C １ ~C ６ represents an alkyl group, The method for producing a 4-ketobenzamide compound according to claim 1 or 2, wherein n represents 0.

5. R １ is C １ ~C ６ represents an alkyl group, R ２ is C １ ~C ６ represents an alkyl group, X represents a halogen atom; The method for producing a 4-ketobenzamide compound according to claim 2, wherein n represents 0.

6. The 4-ketobenzamide compound represented by formula (2) according to claim 1 is reacted with a compound represented by formula (4): 【Chemistry 4】 [In the formula, R ３ is C １ ~C ６ represents alkyl. With an alcohol represented by formula (5): 【Chemistry 5】 [In the formula, R １ , R ２ , R ３ , Y and n have the same meanings as defined in claim 1. The present invention relates to a method for producing a 4-ketobenzoic acid ester compound represented by the following formula:

7. A method for producing a 4-ketobenzoic acid ester compound represented by formula (5) according to claim 6, which is obtained by reacting a 4-ketobenzonitrile compound represented by formula (1) according to claim 1 with an alcohol represented by formula (4) according to claim 6.

8. Formula (3) according to claim 2: 【Chemistry 6】 [In the formula, R ２ is a halogen atom, C １ ~C ６ Alkyl, C １ ~C ６ represents haloalkyl or nitro; Y is a halogen atom, nitro, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkylthio, C １ ~C ６ Alkylcarbonyl, phenyl or (Z) p1 represents a phenyl substituted by When n is an integer of 2 or more, each Y may be the same or different from each other; R １ , X, Z, n and p1 have the same meanings as defined in claim 1. The compound represented by the formula (1): 【Chemistry 7】 [In the formula, R １ , R ２ , Y and n are as defined above. A method for producing a 4-ketobenzonitrile compound represented by the formula:

9. A compound represented by the formula (6): obtained by hydrolyzing the 4-ketobenzamide compound represented by the formula (2) according to claim 1 with an acid or a base: 【Chemistry 8】 [In the formula, R １ , R ２ , Y and n have the same meanings as defined in claim 1. The present invention relates to a method for producing a 4-ketobenzoic acid compound represented by the formula:

10. A 4-ketobenzonitrile compound represented by formula (1) according to claim 1. [In the formula, R １ , R ２ , Y and n have the same meanings as defined in claim 1. ２ and removing halogen atoms from the compound represented by formula (6) according to claim 9, wherein the compound is hydrolyzed with an acid or a base.

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