Method for producing chlorbuconazole or salt thereof

Abstract

Provided is a method with which it is possible to produce chlorprazole acid or a salt thereof at a high yield. The present invention relates to a method for producing chlorbenazolic acid or a salt thereof, the method comprising a cyclization step for obtaining a compound represented by formula (2) by cyclizing a compound represented by formula (1) in the presence of one or more copper catalysts selected from the group consisting of copper halides, copper carbonate, copper sulfate and copper oxide, a base and an amine ligand: # imgabs0 # (in formula (1), R1 represents a linear or branched alkyl group, R2 represents a linear or branched alkyl group, and R3 represents a linear or branched alkyl group; and X represents a halogen atom) # imgabs1 # (In formula (2), R1 is as defined above).

Description

Technical Field

[0001] The present invention relates to a method for producing tamiprofen or a salt thereof, and more particularly to a method for producing tamiprofen or a salt thereof and a synthetic intermediate thereof. Background Art

[0002] Lofamifluan meglumine is a drug that inhibits the progression of peripheral nerve disorders in transthyretin-type familial amyloid polyneuropathy and has transthyretin-type cardiac amyloidosis as its function or effect. In recent years, cardiomyopathy caused by transthyretin amyloidosis has been added as a function or effect, and demand is expected to increase.

[0003] As a method for producing clofazoline meglumine, for example, a method is known in which 3,5-dichlorobenzoyl chloride and 3-hydroxy-4-aminobenzoic acid are amidated in the presence of pyridine and the resulting amide compound is cyclized in the presence of p-toluenesulfonic acid to obtain a benzoxazole derivative (Patent Documents 1 and 2).

[0004] However, the methods described in Patent Documents 1 to 2 are prone to side reactions during amidation, and the selectivity and yield are low, so there is a problem of requiring complicated purification. In addition, there is also the problem of high price and high cost of 3-hydroxy-4-aminobenzoic acid. In particular, in the method described in Patent Document 1, in order to purify, the carboxyl group from 3-hydroxy-4-aminobenzoic acid must be methylated, thereby performing column purification that is difficult to industrialize. In addition, since the method described in Patent Document 1 requires a liquid volume of 187 v / w and the method described in Patent Document 2 requires a liquid volume of 170 v / w, the production efficiency is poor. In addition, since the intermediate N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide has poor filterability, industrialization is even more difficult.

[0005] On the other hand, it has been proposed to use bis(1,5-cyclooctadiene)diiridium(I) dichloride (hereinafter also referred to as iridium catalyst) as a catalyst when cyclizing N-(2-bromo-5-nitrophenyl)benzamide (CO coupling reaction) to obtain a benzoxazole derivative (Non-Patent Document 1). Furthermore, Non-Patent Document 1 describes that methyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylate (methyl ester of chlorobenzazole) was obtained in a yield of 52% by performing a cyclization reaction using the iridium catalyst for 48 hours.

[0006] Prior art literature

[0007] Patent Literature

[0008] Patent Document 1: Japanese Patent Application No. 2006-511612

[0009] Patent Document 2: Japanese Patent Application Publication No. 2021-517118

[0010] Non-patent literature

[0011] Non-patent literature 1: Tetrahedron Letters 2019, 60, 151082 Summary of the invention

[0012] Problems to be solved by the invention

[0013] In the above-mentioned non-patent document 1, the cyclization reaction of N-(2-Bromo-5-nitrophenyl)cinnamamide was carried out using the above-mentioned iridium catalyst (0.01mmol) and copper iodide catalyst ((CuI) 0.20mmol), respectively. When the above-mentioned iridium catalyst was used, no by-product (debrominated product) was generated, and a benzoxazole derivative was obtained with a yield of 74%.

[0014] However, when copper iodide catalyst was used, the yield of benzoxazole derivative was maintained at 24%, and the formation of a large amount of by-products (debrominated products) (61%) was confirmed. Therefore, iridium catalysts are considered to be more useful than copper catalysts such as copper iodide catalysts in improving the efficiency of cyclization by CO coupling reaction.

[0015] In addition, the results of the studies conducted by the present inventors show that although the above-mentioned iridium catalyst allows N-(2-bromo-5-nitrophenyl)benzamide to be efficiently cyclized, there is a problem of insufficient cyclization yield when a synthetic intermediate of chlorobenzamide having an alkoxycarbonylphenyl group in the molecule such as N-[2-bromo-4-(methoxycarbonyl)phenyl]-3,5-dichlorobenzamide is used as a substrate.

[0016] An object of the present invention is to provide a method for producing tamiprofen or a salt thereof in high yield.

[0017] Means for solving problems

[0018] The present inventors have conducted intensive studies on the cyclization reaction of N-[2-halogeno-4-(alkoxycarbonyl)phenyl]-3,5-dichlorobenzamide using various catalysts. As a result, they have surprisingly found that clofentacil or a salt thereof can be produced in high yield and at low cost by a method including a cyclization step of cyclizing N-[2-halogeno-4-(alkoxycarbonyl)phenyl]-3,5-dichlorobenzamide in the presence of one or more copper catalysts selected from copper halides, copper carbonate, copper sulfate and copper oxide, a base and an amine ligand, thereby completing the present invention.

[0019] That is, the present invention provides the following <1> to <14>.

[0020] <1> A method for producing clofazoline or a salt thereof (hereinafter also referred to as the production method of the present invention), comprising a step of cyclizing a compound represented by the following formula (1) in the presence of one or more copper catalysts selected from copper halides, copper carbonate, copper sulfate and copper oxide, a base and an amine ligand to obtain a compound represented by the following formula (2).

[0021]

[0022] [In formula (1), R 1 represents a linear or branched alkyl group, and X represents a halogen atom]

[0023]

[0024] [In formula (2), R 1 Same definition as above].

[0025] <2> The production method according to <1>, further comprising an amidation step of subjecting the compound represented by the following formula (3) and the compound represented by the following formula (4) to an amidation reaction in the presence of a base, and using the compound represented by the formula (1) obtained in the step for the cyclization step.

[0026]

[0027] [In formula (3), Y represents a halogen atom]

[0028]

[0029] [In formula (4), R 1 and X are defined the same as above].

[0030] <3> The production method according to <2>, further comprising a halogenation step of subjecting the compound represented by the following formula (5) to a halogenation reaction, and using the compound represented by the formula (4) obtained in the step for the amidation step.

[0031]

[0032] In formula (5), R 1 Same definition as above]

[0033] <4> The production method according to <2>, further comprising an esterification step of subjecting a compound represented by the following formula (11) and a compound represented by the following formula (12) to a dehydration condensation reaction, and using the compound represented by the formula (4) obtained in the step for the amidation step,

[0034]

[0035] [In formula (11), X has the same definition as above]

[0036] R 1 OH (12)

[0037] [In formula (12), R 1 Same definition as above].

[0038] <5> The production method according to any one of <1> to <4>, further comprising a hydrolysis step of esterifying the compound represented by formula (2) obtained in the cyclization step.

[0039] <6> The production method according to any one of <1> to <5>, wherein one or more selected from copper (I) iodide, copper (II) iodide, copper (I) bromide, copper (II) bromide, copper (I) chloride, copper (II) chloride, copper (I) acetate, copper (II) acetate, copper trifluoroacetate, copper pentafluoropropionate, copper oxalate, copper (I) sulfate, copper (II) sulfate, copper (I) oxide and copper (II) oxide is used as the copper catalyst.

[0040] <7> The production method according to any one of <1> to <5>, wherein the copper catalyst is one or more copper catalysts selected from copper halide, copper carbonate, and copper sulfate.

[0041] <8> The production method according to any one of <1> to <5>, wherein a copper halide is used as the copper catalyst.

[0042] <9> The production method according to <8>, wherein the copper halide is one or more copper halides selected from copper (I) iodide, copper (I) bromide and copper (I) chloride.

[0043] <10> The production method according to any one of <1> to <9>, wherein an amine ligand selected from a monoamine ligand and a diamine ligand is used as the amine ligand.

[0044] <11> The production method according to any one of <1> to <10>, wherein X is a chlorine atom or a bromine atom.

[0045] <12> A compound represented by the following formula (1) (hereinafter also referred to as a specific compound of the present invention).

[0046]

[0047] [In formula (1), R 1 represents a linear or branched alkyl group, and X represents a fluorine atom, a bromine atom or an iodine atom].

[0048] <13> The compound according to <12>, wherein R 1 It is ethyl.

[0049] <14> The compound according to <12> or <13>, wherein X is a bromine atom or an iodine atom.

[0050] Effects of the Invention

[0051] According to the present invention, tamiprofen or a salt thereof can be produced in high yield and at low cost.

[0052] The specific compound of the present invention is useful as a synthetic intermediate of clofazodone or a salt thereof. DETAILED DESCRIPTION

[0053] The production method of the present invention is characterized in that it includes the following cyclization step: in the presence of a copper catalyst selected from one or more of copper halides, copper carbonate, copper sulfate and copper oxide, a base and an amine ligand, a compound represented by the following formula (1) (hereinafter also referred to as compound (1)) is cyclized to obtain a compound represented by the following formula (2) (hereinafter also referred to as compound (2)). The cyclization step in the production method of the present invention is not prone to produce side reactions, and can quantitatively produce high-purity compound (2), so the production method of the present invention is an industrially excellent production method. In addition, the amount of liquid required for the cyclization step in the production method of the present invention (the maximum amount of liquid required until the product is separated) is small, and it is easy to compress the production equipment required for the production of clofentoxane.

[0054]

[0055] [In formula (1), R 1 represents a linear or branched alkyl group, and X represents a halogen atom]

[0056]

[0057] [In formula (2), R 1 Same definition as above].

[0058] (Cyclization process)

[0059] In formula (1), R 1 represents a linear or branched alkyl group. From the viewpoint of availability and reaction efficiency, the number of carbon atoms in the alkyl group is preferably 1 to 12, more preferably 1 to 8, further preferably 1 to 4, and particularly preferably 1 to 2. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc. Among them, methyl and ethyl are preferred, and ethyl is more preferred.

[0060] Examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Among them, from the viewpoint of reaction efficiency and suppression of by-products, a chlorine atom, a bromine atom and an iodine atom are preferred, and a chlorine atom and a bromine atom are more preferred.

[0061] Examples of compound (1) include N-[2-bromo-4-(methoxycarbonyl)phenyl]-3,5-dichlorobenzamide, N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide, N-[2-bromo-4-(n-propoxycarbonyl)phenyl]-3,5-dichlorobenzamide, N-[2-bromo-4-(isopropoxycarbonyl)phenyl]-3,5-dichlorobenzamide, N-[2-chloro-4-(methoxycarbonyl)phenyl]-3,5-dichlorobenzamide, and N-[2-chloro-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide. Dichlorobenzamide, N-[2-chloro-4-(n-propoxycarbonyl)phenyl]-3,5-dichlorobenzamide, N-[2-chloro-4-(isopropoxycarbonyl)phenyl]-3,5-dichlorobenzamide, N-[2-iodo-4-(methoxycarbonyl)phenyl]-3,5-dichlorobenzamide, N-[2-iodo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide, N-[2-iodo-4-(n-propoxycarbonyl)phenyl]-3,5-dichlorobenzamide, N-[2-iodo-4-(isopropoxycarbonyl)phenyl]-3,5-dichlorobenzamide, and the like.

[0062] The cyclization step uses one or more copper catalysts selected from copper halide, copper carbonate, copper sulfate and copper oxide. By using this copper catalyst, the cyclization reaction can be carried out efficiently. Among them, from the viewpoint of reaction efficiency and suppression of by-products, one or more copper catalysts selected from copper halide, copper carbonate and copper sulfate are preferred.

[0063] As the copper catalyst, from the viewpoint of reaction efficiency and suppression of by-products, one or more of copper iodide (I), copper iodide (II), copper bromide (I), copper bromide (II), copper chloride (I), copper chloride (II), copper acetate (I), copper acetate (II), copper trifluoroacetate, copper pentafluoropropionate, copper oxalate, copper sulfate (I), copper sulfate (II), copper oxide (I) and copper oxide (II) are preferred, and more preferably copper iodide (I), copper iodide (II), copper bromide (I), copper bromide (II), chloride One or more of copper (I), copper (II) chloride, copper (I) acetate, copper (II) acetate, copper (I) sulfate, copper (II) sulfate, copper (I) oxide and copper (II) oxide, more preferably one or more of copper (I) iodide, copper (I) bromide, copper (I) chloride, copper (I) acetate, copper (II) sulfate and copper (II) oxide, more preferably one or more of copper (I) iodide, copper (I) bromide, copper (I) chloride, copper (I) acetate and copper (II) sulfate, particularly preferably copper (I) iodide.

[0064] The amount of one or more copper catalysts selected from copper halides, copper carbonate, copper sulfate and copper oxide used is usually in the range of 0.1 to 500 mol, preferably in the range of 0.5 to 100 mol, more preferably in the range of 1 to 50 mol, based on 100 mol of compound (1), from the viewpoint of reaction efficiency and production cost.

[0065] As the base used in the cyclization step, an inorganic base is preferred. Examples of the base include alkali metal carbonates such as potassium carbonate, sodium carbonate, and lithium carbonate; alkali metal bicarbonates such as potassium bicarbonate, sodium bicarbonate, and lithium bicarbonate; and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. The base may be used alone or in combination of two or more.

[0066] From the viewpoint of reaction efficiency and production cost, the amount of the base used in the cyclization step is preferably in the range of 10 to 1000 mol, more preferably 100 to 750 mol, particularly preferably 200 to 500 mol, based on 100 mol of compound (1).

[0067] Examples of the amine ligand used in the cyclization step include monoamine ligands such as ethanolamine, and diamine ligands such as tetramethylethylenediamine, N,N'-dimethylethylenediamine, N,N'-dicyclohexylethylenediamine, 2,2'-bipyridine, 1,10-phenanthroline, 2,9-diphenyl-1,10-phenanthroline, ethylenediamine, N,N,N',N'-tetramethyl-1,3-propylenediamine, 2,2'-bis[2-oxazoline], 1,2-cyclohexanediamine, N,N'-di-tert-butylethylenediamine, ethylenebis(diethylamine), and N,N'-diphenylethylenediamine. Among the monoamine ligand and the diamine ligand, the diamine ligand is preferred from the viewpoint of reaction efficiency and production cost. The amine ligand may be used alone or in combination of two or more.

[0068] Among them, from the viewpoint of reaction efficiency and production cost, tetramethylethylenediamine, N,N'-dimethylethylenediamine, N,N'-dicyclohexylethylenediamine, 2,2'-bipyridine, 1,10-phenanthroline, 2,9-diphenyl-1,10-phenanthroline, ethylenediamine, ethanolamine, N,N,N',N'-tetramethyl-1,3-propylenediamine, 2,2'-bis[2-oxazoline], and 1,2-cyclohexyldiamine are preferred, and tetramethylethylenediamine, N,N'-dimethylethylenediamine, N,N'-dicyclohexylethylenediamine, 2,2'-bipyridine, 1,10-phenanthroline, and 2,9-diphenyl-1,10-phenanthroline are more preferred.

[0069] From the viewpoint of reaction efficiency and production cost, the amount of the amine ligand used in the cyclization step is preferably 0.1 to 1000 mol, more preferably 0.5 to 200 mol, particularly preferably 1 to 100 mol, based on 100 mol of compound (1).

[0070] From the viewpoint of reaction efficiency and production cost, the cyclization step is preferably carried out in the presence of a solvent, more preferably in the presence of an organic solvent.

[0071] Examples of the organic solvent include aromatic hydrocarbon solvents such as benzene, toluene, and xylene; aliphatic hydrocarbon solvents such as propane, n-butane, isobutane, n-pentane, isopentane, and n-hexane; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, dichloromethane, and chloroform; ether solvents such as diethyl ether, dibutyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; ester solvents such as ethyl acetate, and N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide. The solvents may be used alone or in combination of two or more.

[0072] The amount of the solvent used is preferably in the range of 150 to 5000 parts by mass, more preferably 300 to 3000 parts by mass, based on 100 parts by mass of the compound (1).

[0073] The reaction temperature in the cyclization step is usually room temperature to the boiling point of the solvent, and preferably 50° C. to the boiling point of the solvent.

[0074] The reaction time of the cyclization step is usually 0.1 to 72 hours, preferably 1 to 48 hours.

[0075] In addition, the cyclization step can be carried out by a batch method, a semi-continuous method or a continuous method.

[0076] In addition, the compound (1) is preferably obtained by an amidation step of subjecting a compound represented by the following formula (3) (hereinafter also referred to as compound (3)) and a compound represented by the following formula (4) (hereinafter also referred to as compound (4)) to an amidation reaction in the presence of a base. The amidation step can be quantitatively performed and the required liquid amount can be controlled (up to the maximum liquid amount required to separate the product), and the subsequent treatment is also simple. Thus, by obtaining the compound through the amidation step, a higher yield and lower cost can be further achieved.

[0077] In addition, compound (4) can be obtained, for example, by a halogenation step of subjecting a compound represented by the following formula (5) (hereinafter also referred to as compound (5)) to a halogenation reaction, or by an esterification step of subjecting a compound represented by the following formula (11) (hereinafter also referred to as compound (11)) to a dehydration condensation reaction with a compound represented by the following formula (12) (hereinafter also referred to as compound (12)).

[0078] The halogenation step can be quantitatively carried out and the required liquid amount can be controlled (until the maximum liquid amount required for the separation product), and the subsequent treatment is also simple, and the compound (4) is obtained by the halogenation step, thereby further achieving high yield and low cost. In addition, compound (3) can use a commercial product, or a compound prepared by a known method can be used.

[0079]

[0080] [In formula (3), Y represents a halogen atom]

[0081]

[0082] [In formula (4), R 1 and X are defined as above].

[0083]

[0084] In formula (5), R 1 Same definition as above]

[0085]

[0086] [In formula (11), X has the same definition as above]

[0087] R 1 OH (12)

[0088] [In formula (12), R 1 Same definition as above].

[0089] Here, the halogenation step, the esterification step, and the amidation step are described in detail.

[0090] (Halogenation process)

[0091] Examples of compound (5) include methyl 4-aminobenzoate, ethyl 4-aminobenzoate, n-propyl 4-aminobenzoate, isopropyl 4-aminobenzoate, etc. Compound (5) is available at a low price and can be obtained from compound (4) by a halogenation step, thereby significantly reducing costs.

[0092] The halogenation step is preferably carried out in the presence of a halogenating agent.

[0093] Examples of the halogenating agent include bromine (Br 2 ), hydrogen bromide, N-bromosuccinimide, tetrabutylammonium tribromide, dibromoisocyanuric acid (DBI), 1,3-dibromo-5,5-dimethylhydantoin and other brominating agents; chlorine (Cl 2 ), thionyl chloride, N-chlorosuccinimide and other chlorinating agents; fluorine (F 2 ) and other fluorinating agents; iodine (I 2 ), iodine chloride (ICl), 1,3-diiodo-5,5-dimethylhydantoin, N-iodosuccinimide and other iodination agents, etc. The halogenating agent may be used alone or in combination of two or more.

[0094] From the viewpoint of reaction efficiency and production cost, the amount of the halogenating agent used is preferably in the range of 80 to 120 mol, more preferably 90 to 110 mol, and particularly preferably 95 to 105 mol, based on 100 mol of compound (5).

[0095] From the viewpoint of reaction efficiency and production cost, the halogenation step is preferably carried out in the presence of a solvent, more preferably in the presence of an organic solvent.

[0096] Examples of the organic solvent include ether solvents such as diethyl ether, dibutyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; amide solvents such as N,N-dimethylformamide; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, dichloromethane, and chloroform; nitrile solvents such as acetonitrile; and monohydric low alcohol solvents such as methanol and ethanol. The solvents may be used alone or in combination of two or more.

[0097] The amount of the solvent used is preferably in the range of 100 to 2000 parts by mass, more preferably 250 to 1000 parts by mass, based on 100 parts by mass of the compound (5).

[0098] The reaction temperature in the halogenation step is usually -15°C to the boiling point of the solvent, preferably 0 to 50°C.

[0099] The reaction time of the halogenation step is usually 0.1 to 24 hours, preferably 0.5 to 12 hours.

[0100] (Esterification process)

[0101] Examples of the compound (11) include 4-amino-3-chlorobenzoic acid, 4-amino-3-bromobenzoic acid, 4-amino-3-iodobenzoic acid, and 4-amino-3-fluorobenzoic acid.

[0102] Examples of the compound (12) include monohydric lower alcohols (specifically, monohydric alcohols having 1 to 4 carbon atoms) such as methanol, ethanol, n-propanol, and isopropanol.

[0103] From the viewpoint of reaction efficiency and production cost, the amount of compound (12) used is preferably in the range of 90 to 50,000 mol, more preferably 100 to 10,000 mol, based on 100 mol of compound (11).

[0104] The esterification step is preferably carried out in the presence of an esterification catalyst.

[0105] Examples of the esterification catalyst include inorganic acids such as sulfuric acid and phosphoric acid, inorganic oxides such as tin oxide and zinc oxide, and alkoxides. The esterification catalyst may be used alone or in combination of two or more.

[0106] The amount of the esterification catalyst used in the esterification step is preferably in the range of 10 to 1000 mol, more preferably 50 to 300 mol, based on 100 mol of the compound (11), from the viewpoint of reaction efficiency and production cost.

[0107] Compound (12) is not only a substrate but also functions as a solvent. Therefore, the esterification step can be carried out without using a solvent other than compound (12). However, a solvent other than compound (12) may be used together with compound (12). Examples of the solvent other than compound (12) include the same ether solvents, halogenated hydrocarbon solvents, and nitrile solvents as those in the halogenation step.

[0108] The reaction temperature in the esterification step is usually 35° C. to the boiling point of the solvent.

[0109] The reaction time of the esterification step is usually 0.1 to 36 hours, preferably 0.5 to 12 hours.

[0110] (Amidation step)

[0111] Examples of compound (4) include methyl 4-amino-3-chlorobenzoate, methyl 4-amino-3-bromobenzoate, methyl 4-amino-3-iodobenzoate, ethyl 4-amino-3-chlorobenzoate, ethyl 4-amino-3-bromobenzoate, ethyl 4-amino-3-iodobenzoate, n-propyl 4-amino-3-chlorobenzoate, n-propyl 4-amino-3-bromobenzoate, n-propyl 4-amino-3-iodobenzoate, isopropyl 4-amino-3-chlorobenzoate, isopropyl 4-amino-3-bromobenzoate, and isopropyl 4-amino-3-iodobenzoate.

[0112] Examples of the halogen atom represented by Y include fluorine, chlorine, bromine and iodine atoms, of which chlorine, bromine and iodine atoms are preferred from the viewpoint of reaction efficiency and suppression of by-products, and chlorine and bromine atoms are more preferred.

[0113] Examples of the compound (3) include 3,5-dichlorobenzoyl chloride, 3,5-dichlorobenzoyl bromide, and 3,5-dichlorobenzoyl iodide.

[0114] From the viewpoint of reaction efficiency and production cost, the amount of compound (3) used is preferably 70 to 1000 mol, more preferably 90 to 500 mol, and particularly preferably 100 to 200 mol, based on 100 mol of compound (4).

[0115] As the base used in the amidation step, in addition to tertiary amine bases, alkali metal carbonates such as potassium carbonate and sodium carbonate; alkali metal hydroxides such as potassium hydroxide and sodium hydroxide can be listed. Among them, tertiary amine bases are preferred. Examples of such bases include pyridine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, etc. The base can be used alone or in combination of two or more.

[0116] From the viewpoint of reaction efficiency and production cost, the amount of the base used in the amidation step is preferably 70 to 1000 mol, more preferably 90 to 500 mol, particularly preferably 100 to 200 mol, based on 100 mol of compound (4).

[0117] From the viewpoint of reaction efficiency and production cost, the amidation step is preferably carried out in the presence of a solvent, and more preferably in the presence of an organic solvent.

[0118] Examples of the organic solvent include ether solvents such as diethyl ether, dibutyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, dichloromethane, and chloroform; nitrile solvents such as acetonitrile; ester solvents such as ethyl acetate; and aromatic hydrocarbon solvents such as benzene, toluene, and xylene. The solvents may be used alone or in combination of two or more.

[0119] The amount of the solvent used is preferably in the range of 150 to 3000 parts by mass, more preferably 300 to 1000 parts by mass, based on 100 parts by mass of the compound (4).

[0120] The reaction temperature in the amidation step is usually 3°C to the boiling point of the solvent, preferably 10 to 30°C.

[0121] The reaction time of the amidation step is usually 0.1 to 36 hours, preferably 0.5 to 12 hours.

[0122] Among the compounds (1) obtained in the amidation step, the compound in which X represents a fluorine atom, a bromine atom or an iodine atom (preferably a bromine atom or an iodine atom) is a novel compound and is useful as a synthetic intermediate of clofazodone or a salt thereof.

[0123] In addition, R in formula (1) 1 The same definition as above, preferably methyl or ethyl, more preferably ethyl.

[0124] In addition, the production method of the present invention preferably further comprises a hydrolysis step of esterifying the compound (2) obtained in the cyclization step. By performing such a hydrolysis step, tamifluan represented by the following formula (6) can be obtained.

[0125]

[0126] (Hydrolysis process)

[0127] The hydrolysis is preferably carried out in the presence of a base.

[0128] As the base used in the hydrolysis step, inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, and cesium hydroxide are preferred. The base may be used alone or in combination of two or more.

[0129] From the viewpoint of reaction efficiency and production cost, the amount of the base used in the hydrolysis step is preferably in the range of 70 to 750 mol, more preferably 90 to 500 mol, and particularly preferably 100 to 200 mol, based on 100 mol of compound (2).

[0130] From the viewpoint of reaction efficiency and production cost, the amount of water used in the hydrolysis step is preferably in the range of 75 to 2000 parts by mass, more preferably 100 to 800 parts by mass, based on 100 parts by mass of the compound (2).

[0131] In addition, an organic solvent miscible with water may be used together with water. Examples of such organic solvents include ether solvents such as diethyl ether, dibutyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; nitrile solvents such as acetonitrile; and monohydric low alcohol solvents such as methanol and ethanol. The solvents may be used alone or in combination of two or more.

[0132] The reaction temperature in the hydrolysis step is usually 10°C to the boiling point of the solvent, preferably 20 to 70°C.

[0133] The reaction time of the hydrolysis step is usually 1 to 96 hours, preferably 3 to 48 hours.

[0134] The salt of clofazoline can be obtained by a conventional method, for example, by a salt-making process in which an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, or an organic base such as methylamine, ethylamine, meglumine, ethanolamine, diethanolamine, dicyclohexylamine, benzylamine, or the like is brought into contact with clofazoline (6).

[0135] From the viewpoint of reaction efficiency and production cost, the amount of the base used in the salt-making step is preferably in the range of 70 to 750 mol, more preferably in the range of 90 to 500 mol, and particularly preferably in the range of 100 to 300 mol, relative to 100 mol of clofazodone (6).

[0136] The salt production process is preferably carried out in the presence of a solvent. Examples of the solvent include ether solvents such as diethyl ether, dibutyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; nitrile solvents such as acetonitrile; ester solvents such as ethyl acetate; monohydric low alcohol solvents such as methanol and ethanol; and water. The solvent may be used alone or in combination of two or more.

[0137] The reaction temperature in the salt production step is usually -10°C to the boiling point of the solvent, preferably 0 to 30°C.

[0138] The reaction time of the salt production step is usually 0.1 to 96 hours, preferably 1 to 48 hours.

[0139] Alternatively, the tautomer (6) obtained in the hydrolysis step may be separated and purified before being supplied to the salt-making step, or the tautomer (6) solution obtained in the hydrolysis step may be directly supplied to the salt-making step.

[0140] Furthermore, the reaction products obtained in the above-mentioned steps can be purified by separation means such as distillation, extraction, crystallization, washing, etc.

[0141] Then, according to the production method of the present invention, tamiprofen or its salt can be produced at high yield and low cost. In addition, the required amount of liquid in the cyclization step (the maximum amount of liquid required until the product is separated) is small, and it is easy to compress the production equipment required for producing tamiprofen.

[0142] In addition, the amount of liquid required in the amidation step and the halogenation step (the maximum amount of liquid required to separate the product) is also small, so the production method of the present invention can easily compress the production equipment required for producing clofazodone even when it includes the amidation step and / or the halogenation step.

[0143] Example

[0144] Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited to these Examples.

[0145] Example 1 (Synthesis of clofazodone)

[0146] (1) Synthesis of ethyl 4-amino-3-bromobenzoate

[0147] 200 g (1.21 mol) of ethyl 4-aminobenzoate was dissolved in 1000 mL of tetrahydrofuran and stirred at an external temperature of 0°C. Subsequently, 218 g (1.22 mol) of N-bromosuccinimide was added and stirred for 1 hour. 1000 mL of water and 1000 mL of ethyl acetate were added to the reaction solution and separated. The organic layer was washed with 1000 mL of saturated saline, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. 460 mL of ethyl acetate and 1500 mL of n-heptane were added to the concentrate, stirred at an external temperature of 0°C for 1 hour, and the precipitated solid was filtered out. The filtered solid was dried under reduced pressure at an external temperature of 40°C to obtain 297 g (1.22 mol, yield 100%) of ethyl 4-amino-3-bromobenzoate as a slightly yellowish white solid.

[0148] 1 H-NMR (DMSO): δ / ppm=1.28 (t, 3H, J=7.2Hz), 4.22 (q, 2H, J=6.8Hz), 6.19 (s, 2H), 6.80 (d, 1H, J=8.4Hz), 7.65 (dd, 1H, J=2.0, 8.4Hz), 7.89 (d, 1H, J=2.0Hz)

[0149] (2) Synthesis of N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide

[0150] 290 g (1.19 mol) of the above-obtained ethyl 4-amino-3-bromobenzoate was dissolved in 2900 mL of tetrahydrofuran, and 141 g (1.79 mol) of pyridine was added. Then, 299 g (1.42 mol) of 3,5-dichlorobenzoyl chloride dissolved in 580 mL of tetrahydrofuran was added dropwise, and the mixture was stirred at an external temperature of 15°C for 19.5 hours. 3480 mL of water was added to the reaction solution, and after stirring at an external temperature of 0°C for 1 hour, the precipitated solid was filtered out. The filtered solid was dried under reduced pressure at an external temperature of 50°C to obtain 460 g (1.10 mol, yield 93%) of N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide as a white solid.

[0151] H -NMR(DMSO): δ / ppm=1.34(t,3H,J=7.2Hz), 4.34(q,2H,J=7.2Hz), 7.75(d,1H,J=8.4Hz), 7.93(t,1H , J=1.6Hz), 8.01 (dd, 1H, J=1.6, 7.6Hz), 8.01 (d, 2H, J=2.0Hz), 8.21 (1H, d, J=1.6Hz), 10.48 (1H, s)

[0152] (3) Synthesis of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate

[0153] 0.28 g (2.4 mmol) of N,N,N',N'-tetramethylethylenediamine, 0.23 g (1.2 mmol) of copper (I) iodide, 5.00 g (12.0 mmol) of N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide obtained above, and 4.97 g (36.0 mmol) of potassium carbonate were added to 50 mL of toluene, and stirred at an external temperature of 110°C for 5 hours. 25 mL of 10% aqueous ammonium chloride solution and 60 mL of tetrahydrofuran were added to the reaction solution, and the solution was separated. The organic layer was washed with 10% aqueous ammonium chloride solution and saturated brine, and then dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3.99 g (11.9 mmol, yield 99%) of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate as a light yellow solid.

[0154] 1 H-NMR (DMSO): δ / ppm=1.44(t,3H,J=7.2Hz), 4.43(q,2H,J=7.2Hz), 7.55(t,1H,J=2.0), 7.8 0 (d, 1H, J = 8.4Hz), 8.13 (dd, 1H, J = 2.0, 8.8Hz), 8.15 (d, 1H, J = 2.0Hz), 8.29 (d, 1H, J = 1.2Hz)

[0155] (4) Synthesis of clofazoline

[0156] 3.99 g (11.9 mmol) of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate and 0.70 g (16.6 mmol) of lithium hydroxide monohydrate obtained above were added to a mixture of 64 mL of tetrahydrofuran and 16 mL of water, and stirred overnight at an external temperature of 40°C. After cooling the reaction solution, 48 mL of water and 32 mL of 1 mol / L hydrochloric acid were added, and the precipitated solid was filtered out. The filtered solid was dried under reduced pressure at an external temperature of 50°C to obtain 3.17 g (10.3 mmol, yield 87%, total yield from ethyl 4-aminobenzoate 80%) of clofentoxane as a slightly yellowish white solid.

[0157] 1 H-NMR (DMSO): v / ppm=7.91 (d, 1H, J=8.4Hz), 7.94 (t, 1H, J=2.0Hz), 8.03 (dd, 1 H, 1.2, 8.0Hz), 8.13 (d, 2H, J = 2.0Hz), 8.26 (d, 1H, J = 0.8Hz), 13.28 (br-s, 1H)

[0158] Embodiment 2 (Synthesis of clofazodone)

[0159] 0.28 g (2.4 mmol) of N,N,N',N'-tetramethylethylenediamine, 0.17 g (1.2 mmol) of copper (I) bromide, 5.00 g (12.0 mmol) of N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide obtained by the same operation as in (1) and (2) of Example 1, and 4.97 g (36.0 mmol) of potassium carbonate were added to 50 mL of toluene, and stirred overnight at an external temperature of 110°C. 25 mL of a 10% aqueous solution of ammonium chloride and 60 mL of tetrahydrofuran were added to the reaction solution, and the layers were separated. The organic layer was washed with a 10% aqueous solution of ammonium chloride and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3.88 g (11.5 mmol, yield 96%) of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate as a light yellow solid. The obtained spectral data are consistent with the spectral data described in Example 1(3).

[0160] Then, the same operation as in Example 1(4) was carried out to obtain clofazoline as a slightly yellowish white solid with a yield of 87% (total yield from ethyl 4-aminobenzoate: 78%). The obtained spectral data were consistent with those described in Example 1(4).

[0161] Example 3 (Synthesis of clofazodone)

[0162] 0.28 g (2.4 mmol) of N,N,N',N'-tetramethylethylenediamine, 0.15 g (1.2 mmol) of copper (I) acetate, 5.00 g (12.0 mmol) of N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide obtained by the same operation as in (1) and (2) of Example 1, and 4.97 g (36.0 mmol) of potassium carbonate were added to 50 mL of toluene, and stirred at an external temperature of 110°C for 5 hours. 25 mL of a 10% aqueous solution of ammonium chloride and 60 mL of tetrahydrofuran were added to the reaction solution, and the solution was separated. The organic layer was washed with a 10% aqueous solution of ammonium chloride and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3.89 g (11.6 mmol, yield 96%) of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate as a grayish yellow solid. The obtained spectral data are consistent with the spectral data described in Example 1(3).

[0163] Then, the same operation as in Example 1(4) was carried out to obtain clofenac as an off-white solid with a yield of 87% (total yield from ethyl 4-aminobenzoate: 78%). The obtained spectral data were consistent with those described in Example 1(4).

[0164] Example 4 (Synthesis of clofazodone)

[0165] In 50 mL of toluene, 0.28 g (2.4 mmol) of N,N,N',N'-tetramethylethylenediamine, 0.19 g (1.2 mmol) of copper (II) sulfate, 5.00 g (12.0 mmol) of N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide obtained by the same operation as in (1) and (2) of Example 1, and 4.97 g (36.0 mmol) of potassium carbonate were added, and the mixture was stirred at an external temperature of 110° C. for 5 hours. 25 mL of a 10% aqueous solution of ammonium chloride and 60 mL of tetrahydrofuran were added to the reaction solution, and the mixture was separated. The organic layer was washed with a 10% aqueous solution of ammonium chloride and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3.89 g (11.6 mmol, yield 96%) of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate as a light yellow solid. The obtained spectral data are consistent with the spectral data described in Example 1(3).

[0166] Then, the same operation as in Example 1(4) was carried out to obtain clofazoline as a slightly yellowish white solid with a yield of 90% (total yield from ethyl 4-aminobenzoate 80%). The obtained spectral data were consistent with the spectral data described in Example 1(4).

[0167] Example 5 (Synthesis of clofazodone)

[0168] 0.28 g (2.4 mmol) of N,N,N',N'-tetramethylethylenediamine, 0.10 g (1.2 mmol) of copper (II) oxide, 5.00 g (12.0 mmol) of N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide obtained by the same operation as (1) and (2) of Example 1, and 4.97 g (36.0 mmol) of potassium carbonate were added to 50 mL of toluene, and stirred at an external temperature of 110°C for 24 hours. The reaction conversion rate at this time was 93%. 25 mL of 10% aqueous ammonium chloride solution and 60 mL of tetrahydrofuran were added to the reaction solution, and the solution was separated. The organic layer was washed with 10% aqueous ammonium chloride solution and saturated brine, then dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. 100 mL of ethyl acetate was added to the concentrate, and it was dissolved at an external temperature of 80°C, then cooled to room temperature, and the precipitated crystals were filtered out. The crystals were dried under reduced pressure at an external temperature of 50° C. to obtain 2.87 g (8.5 mmol, yield 71%) of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate as a white solid.

[0169] Then, the same operation as in Example 1(4) was carried out to obtain clofazoline as a slightly yellowish white solid with a yield of 97% (total yield from ethyl 4-aminobenzoate: 64%). The obtained spectral data were consistent with those described in Example 1(4).

[0170] Example 6 (Synthesis of clofazodone)

[0171] N-[2-chloro-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide was obtained by carrying out the same procedures as in (1) and (2) of Example 1 except that N-chlorosuccinimide was changed to N-bromosuccinimide.

[0172] 0.19 g (1.61 mmol) of N,N,N',N'-tetramethylethylenediamine, 0.10 g (0.8 mmol) of copper (I) acetate, 1.00 g (2.7 mmol) of N-[2-chloro-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide obtained above, and 1.11 g (8.1 mmol) of potassium carbonate were added to 10 mL of toluene, and stirred at an external temperature of 110°C for 22 hours. 5 mL of 10% aqueous ammonium chloride solution and 12 mL of tetrahydrofuran were added to the reaction solution, and the solution was separated. The organic layer was washed with 10% aqueous ammonium chloride solution and saturated brine, and then dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 0.91 g (2.7 mmol, yield 100%) of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate as a light yellow solid. The obtained spectral data were consistent with the spectral data described in Example 1 (3).

[0173] Then, the same operation as in Example 1(4) was carried out to obtain clofazoline as a slightly yellowish white solid at a yield of 93% (total yield from ethyl 4-aminobenzoate 86%). The obtained spectral data were consistent with the spectral data described in Example 1(4).

[0174] Example 7 (Synthesis of clofazoline)

[0175] (1) Synthesis of ethyl 4-amino-3-iodobenzoate

[0176] A mixture of 1 g (3.8 mmol) of 4-amino-3-iodobenzoic acid, 10 mL of ethanol and 0.48 g (4.9 mmol) of concentrated sulfuric acid was heated to reflux for 5 hours and concentrated under reduced pressure. 10 mL of saturated sodium bicarbonate water was added to the concentrate and the solid was filtered out. The filtered solid was dried under reduced pressure at an external temperature of 50° C. to obtain 0.77 g (2.6 mmol, yield 69%) of ethyl 4-amino-3-iodobenzoate as a slightly yellowish white solid.

[0177] 1 H-NMR (CDCl 3 ): δ / ppm=1.38(t,3H,J=7.2Hz), 4.33(q,2H,J=7.2Hz), 4.53(br-s,2H), 6.72(d,1H,J=8.4Hz), 7.84(dd,1H,J=2.0,8.4Hz), 8.35(d,1H,J=1.6Hz)

[0178] (2) Synthesis of N-[2-iodo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide

[0179] 0.7 g (2.4 mmol) of the above-obtained ethyl 4-amino-3-iodobenzoate was dissolved in 7 mL of tetrahydrofuran, and 0.29 g (3.6 mmol) of pyridine was added. Then, 0.6 g (2.9 mmol) of 3,5-dichlorobenzoyl chloride dissolved in 1.4 mL of tetrahydrofuran was added dropwise, and the mixture was stirred at an external temperature of 20°C for 5 hours. 11.9 mL of ethyl acetate was added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated saline, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. 5.6 mL of ethyl acetate was added to the concentrate, and the mixture was stirred at room temperature for 1 hour, and then the solid was filtered out. The filtered solid was dried under reduced pressure at an external temperature of 40°C to obtain 0.71 g (1.5 mol, yield 64%) of N-[2-iodo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide as a white solid.

[0180] 1 H-NMR (CDCl 3): δ / ppm=1.34(t,3H,J=7.2Hz), 4.34(q,2H,J=7.2Hz), 7.63(d,1H,J=8.4Hz), 7.86(d,1H ,J=1.6Hz),7.93(t,1H,J=1.6Hz),8.00-8.03(m,3H),8.43(d,1H,J=2.0Hz),8.57(s,1H)

[0181] (3) Synthesis of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate

[0182] 30.0 mg (0.26 mmol) of N,N,N',N'-tetramethylethylenediamine, 24.6 mg (0.13 mmol) of copper (I) iodide, 600 mg (1.29 mmol) of N-[2-iodo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide obtained above, and 536 mg (3.88 mmol) of potassium carbonate were added to 6 mL of toluene, and stirred at an external temperature of 110°C for 30 hours. 3 mL of 10% aqueous ammonium chloride solution and 7.2 mL of tetrahydrofuran were added to the reaction solution, and the solution was separated. The organic layer was washed with 10% aqueous ammonium chloride solution and saturated brine, and then dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 360 mg (1.07 mmol, yield 83%) of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate as a light yellow solid. The obtained spectral data were consistent with the spectral data described in Example 1 (3).

[0183] Then, the same operation as in Example 1 (4) was carried out to obtain clofazoline as a slightly yellowish white solid with a yield of 93% (total yield from 4-amino-3-iodobenzoic acid 34%). The obtained spectral data were consistent with the spectral data described in Example 1 (4).

[0184] Example 8 (Synthesis of Lofenac Meglumine)

[0185] 20 mL of 2-propanol, 5.5 mL of water, and 0.63 g of N-methyl-D-glucamine (3.25 mmol) were added to 1.00 g (3.25 mmol) of clofazoline obtained in Example 1, and the mixture was stirred at an external temperature of 80°C for 1 hour. The mixture was then cooled at an internal temperature of 10°C, and the precipitated solid was filtered out. The filtered solid was dried under reduced pressure at an external temperature of 50°C to obtain 1.26 g (2.50 mmol, yield 77%) of clofazoline meglumine as a white solid.

[0186] 1H-NMR (DMSO): δ / ppm=2.55 (s, 3H), 2.91-3.06 (m, 2H), 3.41-3.55 (m, 3H), 3.60 (dd, 1H, J= 3.2, 10.4Hz), 3.71 (dd, 1H, J= 1.2, 4.8 Hz), 3.94 (m, 1H), 7.77 (d, 1H, J = 8.4Hz), 7.92 (t, 1H, J = 2.0Hz), 8.03 (dd, 1H, J = 1.2, 8.4Hz), 8.15 (d, 2H, J = 2.0Hz), 8.19 (s, 1H)

[0187] Comparative Example 1 (Synthesis of clofazodone)

[0188] According to the method described in JP-A-2006-511612, clofazodone was synthesized.

[0189] (1) That is, 2.00 g (13.1 mmol) of 4-amino-3-hydroxybenzoic acid, 3.10 g (39.2 mmol) of pyridine, and 2.74 g (13.1 mmol) of 3,5-dichlorobenzoyl chloride were added to 200 mL of tetrahydrofuran, and the mixture was refluxed for 1 hour, and the reaction mixture was concentrated under reduced pressure. The obtained N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide was used in the next step without purification.

[0190] (2) Add 330 mL of xylene and 24.9 g (131 mmol) of p-toluenesulfonic acid monohydrate to the concentrate of N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide obtained above, and stir at an external temperature of 140°C for 14 hours. After cooling the reaction solution, add 131 mL (131 mmol) of 1 mol / L sodium hydroxide aqueous solution, and separate the organic layer. Add 1 mol / L hydrochloric acid to the aqueous layer to adjust its pH to 2, and extract 4 times with 200 mL of ethyl acetate. Combine the organic layers, dehydrate with anhydrous sulfuric acid, and concentrate under reduced pressure to obtain 2.31 g (7.5 mmol, yield 57.2%) of chlorobenzene as a reddish-white solid. In the method of Comparative Example 1, the yield is insufficient.

[0191] Test Example 1

[0192] The maximum liquid amount (mL) of 1 g of clofentoxane in each step of the method for obtaining Examples 1 to 7 and Comparative Example 1 was estimated by estimation. The liquid amount was the largest just before liquid separation in the halogenation step and the cyclization step, so the liquid amount just before liquid separation was estimated as the maximum liquid amount. The liquid amount was the largest just before filtration in the esterification step, the amidation step, and the hydrolysis step, so the liquid amount just before filtration was estimated as the maximum liquid amount. In addition, it was estimated in this way assuming that the specific gravity of the liquid was 1 g / mL and assuming that the solid was a liquid with a specific gravity of 1 g / mL.

[0193] In addition, among the maximum liquid amounts for obtaining 1 g of clofazodone in each step, the largest liquid amount was recorded as the "maximum value".

[0194] It can be said that the smaller the maximum liquid amount for obtaining 1 g of tamiprofen in each step and the value of the above-mentioned "maximum value", the easier it is to compress the production equipment required for producing tamiprofen. The results are shown in Table 1.

[0195] In addition, the following describes the estimation method for obtaining the maximum liquid amount (mL) of 1 g of clofentoxane in each process using Example 1 as an example. In Example 1, among the halogenation process, the amidation process, the cyclization process, and the hydrolysis process, the hydrolysis process has the largest liquid amount, which is 52 mL, so the "maximum value" among the maximum liquid amounts in each process is recorded as 52 mL.

[0196] The total liquid volume in the hydrolysis step of Example 1 is approximately 164.49 mL. Details: tetrahydrofuran (64 mL) + water (16 mL) + ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate (about 3.99 mL) + lithium hydroxide monohydrate (about 0.70 mL) + water (48 mL) + 1 mol / L hydrochloric acid (32 mL)

[0197] Then, the amount of tamifloxacin obtained through the hydrolysis step was 3.17 g, and the maximum amount of liquid for obtaining 1 g of tamifloxacin in the hydrolysis step of Example 1 was 164.49÷3.17≈52 mL.

[0198] The total liquid volume in the cyclization step of Example 1 is approximately 145.48 mL. Details: Toluene (50 mL) + N,N,N',N'-tetramethylethylenediamine (about 0.28 mL) + copper (I) iodide (about 0.23 mL) + N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide (about 5.00 mL) + potassium carbonate (about 4.97 mL) + 10% aqueous ammonium chloride solution (25 mL) + tetrahydrofuran (60 mL)

[0199] Then, the amount of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate obtained by the cyclization step was 3.99 g, and the amount of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate required to obtain 1 g of clofop-butyl was 3.99÷3.17≈1.26 g.

[0200] Therefore, the maximum amount of liquid used to obtain 1 g of clofazoline in the cyclization step of Example 1 is 145.48÷3.99×1.26≈46 mL.

[0201] The total liquid volume in the amidation step of Example 1 is approximately 7690 mL. Details: 4-amino-3-bromobenzoic acid ethyl ester (about 290 mL) + tetrahydrofuran (2900 mL) + pyridine (about 141 mL) + tetrahydrofuran (580 mL) + 3,5-dichlorobenzoyl chloride (about 299 mL) + water (3480 mL)

[0202] Then, the amount of N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide obtained by the amidation step was 460 g, and the amount of N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide required to obtain 1 g of clofop-butyl was 5.00÷3.99×1.26≈1.58 g.

[0203] Therefore, the maximum amount of liquid for obtaining 1 g of clofazoline in the amidation step of Example 1 is 7690÷460×1.58≈26 mL.

[0204] The total liquid volume in the halogenation step of Example 1 is approximately 3418 mL. Details: 4-aminobenzoic acid ethyl ester (about 200 mL) + tetrahydrofuran (1000 mL) + N-bromosuccinimide (about 218 mL) + water (1000 mL) + ethyl acetate (1000 mL)

[0205] Then, the amount of ethyl 4-amino-3-bromobenzoate obtained by the halogenation step was 297 g, and the amount of ethyl 4-amino-3-bromobenzoate required to obtain 1 g of clofentxadic acid was 290÷460×1.58≈0.99 g.

[0206] Therefore, the maximum amount of liquid for obtaining 1 g of clofazoline in the halogenation step of Example 1 is 3418÷297×0.99≈11 mL.

[0207] [Table 1]

[0208]

[0209] As shown in Table 1, by using the methods of Examples 1 to 7 for production, the production equipment required for producing tamifluacil can be compressed.

[0210] Comparative Example 2 (Synthesis of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate)

[0211] In 12 mL of dimethyl sulfoxide, 4 g (9.6 mmol) of N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide, 0.064 g (0.12 mmol) of bis(1,5-cyclooctadiene)diiridium(I)dichloride, and 2.82 g (29 mmol) of potassium acetate were added, and the mixture was stirred at an external temperature of 100°C for 48 hours. The reaction conversion rate at this time was 51%. 20 mL of water was added to the reaction solution, and the mixture was extracted with a mixed solution of 60 mL of ethyl acetate and 20 mL of tetrahydrofuran. The organic layer was washed with saturated brine, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain 1.08 g (2.6 mmol, yield 34%) of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate as a light yellow solid. In the method of Comparative Example 2, the yield was insufficient.

[0212] As described above, in the case where the cyclization step of compound (1) was carried out in the presence of bis(1,5-cyclooctadiene)diiridium(I) dichloride (Comparative Example 2), the yield was 34%.

[0213] In contrast, the yield of the cyclization step of compound (1) in the presence of one or more copper catalysts selected from copper halide, copper carbonate, copper sulfate and copper oxide, a base and an amine ligand (Examples 1 to 7) is 71 to 100%. Here, in terms of improving the efficiency of cyclization by such a CO coupling reaction, iridium catalysts are considered to be more useful than copper catalysts such as copper iodide catalysts (Tetrahedron Letters 2019, 60, 151082), and it is unexpected that a significant improvement in yield is observed as described above when using one or more copper catalysts selected from copper halide, copper carbonate, copper sulfate and copper oxide, a base and an amine ligand.

[0214] Reference Example 1 (Synthesis of N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide)

[0215] N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide was synthesized with reference to the amidation reaction described in JP-A-2021-517118.

[0216] That is, 2.00 g (13.1 mmol) of 4-amino-3-hydroxybenzoic acid and 1.20 g (15.2 mmol) of pyridine were added to 74 mL of tetrahydrofuran, and the mixture was cooled to -12°C in an ice-salt bath. 2.68 g (12.8 mmol) of 3,5-dichlorobenzoyl chloride dissolved in 12 mL of tetrahydrofuran was added, the temperature was changed to room temperature, and the mixture was stirred for 40 minutes. 258 mL of 0.2 mol / L hydrochloric acid was added to the reaction solution, the precipitate was filtered out, and the mixture was dried under reduced pressure at an external temperature of 50°C. 98 mL of 0.5 mol / L sodium hydroxide aqueous solution was added to the obtained solid, the mixture was stirred at room temperature, and the insoluble matter was filtered out by filtration. The solution was washed with 48 mL of dichloromethane, and 1 mol / L hydrochloric acid was added to the aqueous layer to adjust the pH to 2 to 3. The precipitate was filtered out, and the mixture was dried under reduced pressure at an external temperature of 50°C. 122 mL of 1-butanol was added to the obtained solid, and the mixture was heated under reflux at an external temperature of 120° C. for 7 hours, and then stirred at an external temperature of 70° C. overnight, and the solid was filtered out. The obtained solid was dried under reduced pressure at an external temperature of 50° C. to obtain 2.64 g (8.1 mmol, yield 61.8%) of N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide as a light yellow solid.

[0217] Reference Example 2 (Synthesis of N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide)

[0218] N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide was synthesized with reference to the amidation reaction described in JP-A-2021-517118.

[0219] That is, 2.00 g (13.1 mmol) of 4-amino-3-hydroxybenzoic acid was dissolved in a mixture of 36 mL of tetrahydrofuran and 4 mL of water, 3.28 g (15.7 mmol) of 3,5-dichlorobenzoyl chloride was added, and the mixture was stirred at room temperature for 1 hour. 1.59 g (15.7 mmol) of triethylamine was added to the mixture, and the mixture was stirred at room temperature for 2 hours. 300 mL of 0.1 mol / L hydrochloric acid was added, and the precipitate was filtered out. 0.5 mol / L sodium hydroxide aqueous solution was added to the obtained solid, and the mixture was stirred at room temperature, and the insoluble matter was filtered out by filtration. The solution was washed with 100 mL of dichloromethane, 30 mL of 1 mol / L hydrochloric acid and 130 mL of acetonitrile were added to the water layer, the precipitate was filtered out, and it was dried under reduced pressure at an external temperature of 50°C to obtain N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide as an off-white solid. The yield is about 65%, similar to that described in Japanese Patent Application Laid-Open No. 2021-517118.

Claims

1. A method for producing clofazoline or a salt thereof, comprising the step of cyclizing a compound represented by the following formula (1) in the presence of one or more copper catalysts selected from copper halide, copper carbonate, copper sulfate and copper oxide, a base and an amine ligand to obtain a compound represented by the following formula (2), [In formula (1), R 1 represents a linear or branched alkyl group, and X represents a halogen atom] [In formula (2), R 1 Same definition as above].

2. The manufacturing method according to claim 1, wherein: The method further comprises the step of subjecting the compound represented by the following formula (3) to an amidation reaction with the compound represented by the following formula (4) in the presence of a base, and using the compound represented by the formula (1) obtained in the step for the cyclization step. [In formula (3), Y represents a halogen atom] [In formula (4), R 1 and X are defined as above].

3. The manufacturing method according to claim 2, wherein: The method further comprises a halogenation step of subjecting a compound represented by the following formula (5) to a halogenation reaction, and using the compound represented by the formula (4) obtained in the step in the amidation step. In formula (5), R 1 Same definition as above].

4. The manufacturing method according to claim 2, wherein: further comprising an esterification step of subjecting the compound represented by the following formula (11) and the compound represented by the following formula (12) to a dehydration condensation reaction, and using the compound represented by the formula (4) obtained in the step for the amidation step, [In formula (11), X has the same definition as above] R 1 OH (12) [In the formula (12), R1 has the same meaning as above].

5. The production method according to any one of claims 1 to 4, wherein The method further comprises a hydrolysis step of subjecting the compound represented by the formula (2) obtained in the cyclization step to ester hydrolysis.

6. The production method according to any one of claims 1 to 5, wherein As the copper catalyst, one or more selected from copper (I) iodide, copper (II) iodide, copper (I) bromide, copper (II) bromide, copper (I) chloride, copper (II) chloride, copper (I) acetate, copper (II) acetate, copper trifluoroacetate, copper pentafluoropropionate, copper oxalate, copper (I) sulfate, copper (II) sulfate, copper (I) oxide and copper (II) oxide are used.

7. The production method according to any one of claims 1 to 5, wherein As the copper catalyst, one or more copper catalysts selected from copper halide, copper carbonate and copper sulfate are used.

8. The production method according to any one of claims 1 to 5, wherein As the copper catalyst, copper halide is used.

9. The manufacturing method according to claim 8, wherein: As the copper halide, one or more copper halides selected from copper (I) iodide, copper (I) bromide and copper (I) chloride are used.

10. The production method according to any one of claims 1 to 9, wherein: As the above-mentioned amine ligand, an amine ligand selected from a monoamine ligand and a diamine ligand is used.

11. The production method according to any one of claims 1 to 10, wherein X is a chlorine atom or a bromine atom.

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