Production method for tafamidis or salt thereof

Abstract

The present invention provides a method with which it is possible to produce tafamidis or a salt thereof with high yield.　This production method for tafamidis or a salt thereof comprises a cyclization step for obtaining a compound represented by formula (2) by cyclization of a compound represented by formula (1) in the presence of an amine ligand, a base, and at least one copper catalyst selected from among copper halides, copper carboxylates, copper sulfates, and copper oxides. [In formula (1), R1 represents a linear or branched alkyl group, and X represents a halogen atom.] [In formula (2), R1 is the same as defined above.]

Description

Method for producing tafamidis or a salt thereof

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

[0002] Tafamidis meglumine is a drug whose efficacy or effect is to inhibit the progression of peripheral neuropathy in transthyretin familial amyloid polyneuropathy and to treat transthyretin cardiac amyloidosis. In recent years, cardiomyopathy due to transthyretin amyloidosis has been added as an efficacy or effect, and demand is expected to increase.

[0003] Known methods for producing tafamidis meglumine include amidating 3,5-dichlorobenzoyl chloride with 3-hydroxy-4-aminobenzoic acid in the presence of pyridine and cyclizing the resulting amide compound in the presence of p-toluenesulfonic acid to obtain a benzoxazole derivative (Patent Documents 1 and 2). However, the methods described in Patent Documents 1 and 2 suffer from the problem of requiring complicated purification due to the tendency for side reactions to occur during amidation, resulting in low selectivity and yield. Another problem is that 3-hydroxy-4-aminobenzoic acid is expensive, resulting in high costs. In particular, the method described in Patent Document 1 requires methyl esterification of the carboxy group derived from 3-hydroxy-4-aminobenzoic acid for purification, which requires column purification, which is difficult to commercialize. Furthermore, the method described in Patent Document 1 and the method described in Patent Document 2 require liquid volumes of 187 v / w and 170 v / w, respectively, resulting in poor production efficiency. Furthermore, the filterability of the intermediate N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide makes industrialization even more difficult.

[0004] On the other hand, it has been proposed to use bis(1,5-cyclooctadiene)diiridium(I) dichloride (hereinafter also simply referred to as iridium catalyst) as a catalyst when N-(2-bromo-5-nitrophenyl)benzamide is cyclized (C—O 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 tafamidis) was obtained in a yield of 52% by carrying out the cyclization reaction using the iridium catalyst for 48 hours.

[0005] JP 2006-511612 A JP 2021-517118 A

[0006] Tetrahedron Letters 2019,60,151082

[0007] 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 (0.01 mmol) and a copper iodide catalyst ((CuI) 0.20 mmol), respectively. When the above-mentioned iridium catalyst was used, a benzoxazole derivative was obtained in a yield of 74% without producing a by-product (debrominated product). However, when a copper iodide catalyst was used, the yield of the benzoxazole derivative was only 24%, and a large amount of the by-product (debrominated product) was confirmed to be produced (61%). Therefore, in terms of improving the efficiency of cyclization by a C—O coupling reaction, an iridium catalyst was considered to be more useful than a copper catalyst such as a copper iodide catalyst.

[0008] Furthermore, as a result of studies by the present inventors, it was found that although the above-mentioned iridium catalyst efficiently cyclizes N-(2-bromo-5-nitrophenyl)benzamide, there is a problem in that the cyclization yield is insufficient when a synthetic intermediate of tafamidis having an alkoxycarbonylphenyl group in the molecule, such as N-[2-bromo-4-(methoxycarbonyl)phenyl]-3,5-dichlorobenzamide, is used as a substrate.An object of the present invention is to provide a method for producing tafamidis or a salt thereof in high yield.

[0009] The present inventors have conducted extensive research using various catalysts on the cyclization reaction of N-[2-halo-4-(alkoxycarbonyl)phenyl]-3,5-dichlorobenzamide and have surprisingly found that tafamidis or a salt thereof can be produced in high yield and at low cost by a method comprising a cyclization step of cyclizing N-[2-halo-4-(alkoxycarbonyl)phenyl]-3,5-dichlorobenzamide in the presence of one or more copper catalysts selected from copper halide, copper carboxylate, copper sulfate, and copper oxide, a base, and an amine ligand, thereby completing the present invention.

[0010] That is, the present invention provides the following items <1> to <14>: <1> A method for producing tafamidis or a salt thereof, comprising a cyclization 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 carboxylates, copper sulfates, and copper oxides, a base, and an amine ligand to obtain a compound represented by the following formula (2) (hereinafter also referred to as the production method of the present invention).

[0011]

[0012] [In formula (1), R 1 represents a linear or branched alkyl group, and X represents a halogen atom.

[0013]

[0014] [In formula (2), R 1 has the same meaning as above.]

[0015] <2> The production method according to <1>, further comprising an amidation step of amidating a compound represented by the following formula (3) with a compound represented by the following formula (4) in the presence of a base, and using the compound represented by formula (1) obtained in the amidation step in the cyclization step:

[0016]

[0017] [In formula (3), Y represents a halogen atom.]

[0018]

[0019] [In formula (4), R 1 and X have the same meanings as defined above.]

[0020] <3> The production method according to <2>, further comprising a halogenation step of halogenating a compound represented by the following formula (5), and using the compound represented by formula (4) obtained in the halogenation step in the amidation step:

[0021]

[0022] [In formula (5), R 1 has the same meaning as above.]

[0023] <4> The production method according to <2>, further comprising an esterification step of carrying out a dehydration condensation reaction between a compound represented by the following formula (11) and a compound represented by the following formula (12), and using the compound represented by formula (4) obtained in the esterification step in the amidation step:

[0024]

[0025] (In formula (11), X has the same meaning as defined above.)

[0026]

[0027] [In formula (12), R 1 has the same meaning as above.]

[0028] <5> The method according to any one of <1> to <4>, further comprising a hydrolysis step of ester hydrolyzing the compound represented by formula (2) obtained in the cyclization step.

[0029] <6> The method according to any one of <1> to <5>, wherein the copper catalyst is 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. <7> The method according to any one of <1> to <5>, wherein the copper catalyst is one or more selected from copper halides, copper carboxylates, and copper sulfate. <8> The method according to any one of <1> to <5>, wherein the copper catalyst is a copper halide. <9> The method according to <8>, wherein the copper halide is one or more selected from copper(I) iodide, copper(I) bromide, and copper(I) chloride.

[0030] <10> The method according to any one of <1> to <9>, wherein the amine ligand is an amine ligand selected from a monovalent amine ligand and a diamine ligand. <11> The method according to any one of <1> to <10>, wherein X is a chlorine atom or a bromine atom.

[0031] <12> A compound represented by the following formula (1) (hereinafter also referred to as a specific compound of the present invention). [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.

[0032] <13> R 1 <14> The compound according to <12> or <13>, wherein X is a bromine atom or an iodine atom.

[0033] According to the present invention, tafamidis or a salt thereof can be produced in high yield and at low cost. The specific compound of the present invention is useful as a synthetic intermediate for tafamidis or a salt thereof.

[0034] The production method of the present invention is characterized by comprising a cyclization step of cyclizing a compound represented by the following formula (1) (hereinafter also referred to as compound (1)) in the presence of one or more copper catalysts selected from copper halide, copper carboxylate, copper sulfate, and copper oxide, a base, and an amine ligand 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 less likely to cause side reactions and can produce compound (2) with high purity quantitatively, making the production method of the present invention an extremely excellent production method from an industrial perspective. Furthermore, the cyclization step in the production method of the present invention requires a small amount of liquid (the maximum amount of liquid before separation of the product), making it easy to compact the production equipment required for producing tafamidis.

[0035]

[0036] [In formula (1), R 1 represents a linear or branched alkyl group, and X represents a halogen atom.

[0037]

[0038] [In formula (2), R 1 has the same meaning as above.]

[0039] (Cyclization step) In formula (1), R 1represents a linear or branched alkyl group. From the viewpoints of availability and reaction efficiency, the number of carbon atoms in the alkyl group is preferably 1 to 12, more preferably 1 to 8, even more preferably 1 to 4, and particularly preferably 1 to 2. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. Among these, a methyl group and an ethyl group are preferred, and an ethyl group is more preferred. Examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among these, from the viewpoints 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. 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. , 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.

[0040] The cyclization step uses one or more copper catalysts selected from copper halides, copper carboxylates, copper sulfates, and copper oxides. By using this copper catalyst, the cyclization reaction can proceed with high efficiency. Among these, one or more copper catalysts selected from copper halides, copper carboxylates, and copper sulfates are preferred from the viewpoints of reaction efficiency and by-product suppression. As the copper catalyst, from the viewpoints of reaction efficiency and by-product suppression, one or more selected from 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 copper iodide(I), copper iodide(II), copper bromide(I), copper bromide(II), copper chloride( More preferred are at least one selected from copper(I), copper(II) chloride, copper(I), copper(II) acetate, copper(II), copper sulfate, copper(I), copper(II), oxide, and copper(II), even more preferred are at least one selected from copper(I) iodide, copper(I), bromide, copper(I), chloride, copper(I), copper acetate, copper(II), sulfate, and copper(II), even more preferred are at least one selected from copper(I), iodide, copper(I), bromide, copper(I), chloride, copper(I), acetate, and sulfate, and copper(II), with copper(I) being particularly preferred.

[0041] The amount of one or more copper catalysts selected from copper halide, copper carboxylate, copper sulfate, and copper oxide used is usually in the range of 0.1 to 500 mol per 100 mol of compound (1). From the viewpoints of reaction efficiency and production costs, it is preferably in the range of 0.5 to 100 mol, more preferably in the range of 1 to 50 mol.

[0042] The base used in the cyclization step is preferably an inorganic base. Examples of the base include alkali metal carbonates such as potassium carbonate, sodium carbonate, and lithium carbonate; alkali metal hydrogen carbonates such as potassium hydrogen carbonate, sodium hydrogen carbonate, and lithium hydrogen carbonate; and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. The base may be used alone or in combination of two or more.

[0043] The amount of the base used in the cyclization step is preferably in the range of 10 to 1,000 mol, more preferably in the range of 100 to 750 mol, and particularly preferably in the range of 200 to 500 mol, relative to 100 mol of compound (1), from the viewpoints of reaction efficiency and production costs.

[0044] Examples of the amine ligand used in the cyclization step include monovalent amine 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-propanediamine, 2,2'-bi[2-oxazoline], 1,2-cyclohexanediamine, N,N'-di-tert-butylethylenediamine, ethylenebis(diethylamine), and N,N'-diphenylethylenediamine. Among monovalent amine ligands and diamine ligands, diamine ligands are preferred from the viewpoints of reaction efficiency and production costs. Amine ligands may be used alone or in combination of two or more. Among these, from the viewpoints of reaction efficiency and production costs, 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-propanediamine, 2,2'-bi[2-oxazoline], and 1,2-cyclohexanediamine 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.

[0045] The amount of the amine ligand used in the cyclization step is preferably in the range of 0.1 to 1,000 mol, more preferably in the range of 0.5 to 200 mol, and particularly preferably in the range of 1 to 100 mol, relative to 100 mol of compound (1), from the viewpoints of reaction efficiency and production costs.

[0046] From the viewpoint of reaction efficiency and production costs, the cyclization step is preferably carried out in the presence of a solvent, and more preferably in the presence of an organic solvent. Examples of organic solvents 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 methylene chloride, ethylene chloride, 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, as well as N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide. The solvent may be used alone or in combination of two or more. The amount of solvent used is preferably in the range of 150 to 5,000 parts by mass, more preferably 300 to 3,000 parts by mass, per 100 parts by mass of compound (1).

[0047] The reaction temperature in the cyclization step is usually from room temperature to the boiling point of the solvent, preferably from 50°C to the boiling point of the solvent. The reaction time in the cyclization step is usually from 0.1 to 72 hours, preferably from 1 to 48 hours. The cyclization step can be carried out by a batch method, a semi-continuous method, or a continuous method.

[0048] Compound (1) is preferably obtained by an amidation step in which 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)) are subjected to an amidation reaction in the presence of a base. The amidation step proceeds quantitatively, making it possible to reduce the amount of liquid required (the maximum amount of liquid required until the product is separated), and post-treatment is also simple. Obtaining compound (1) in this manner through the amidation step can further increase yield and reduce costs. Compound (4) can also be obtained by, for example, a halogenation step in which a compound represented by the following formula (5) (hereinafter also referred to as compound (5)) is subjected to a halogenation reaction, or an esterification step in which a compound represented by the following formula (11) (hereinafter also referred to as compound (11)) and a compound represented by the following formula (12) (hereinafter also referred to as compound (12)) are subjected to a dehydration condensation reaction. The halogenation step proceeds quantitatively, making it possible to reduce the amount of liquid required (the maximum amount of liquid required until the product is separated), and post-treatment is simple. By obtaining compound (4) through the halogenation step, it is possible to further increase the yield and reduce costs. Furthermore, compound (3) may be a commercially available product, or may be prepared by referring to a known method.

[0049]

[0050] [In formula (3), Y represents a halogen atom.]

[0051]

[0052] [In formula (4), R 1 and X have the same meanings as defined above.]

[0053]

[0054] [In formula (5), R 1 has the same meaning as above.]

[0055]

[0056] (In formula (11), X has the same meaning as defined above.)

[0057]

[0058] [In formula (12), R 1 has the same meaning as above.]

[0059] Here, the halogenation step, esterification step, and amidation step will be described in detail. (Halogenation Step) Examples of compound (5) include methyl 4-aminobenzoate, ethyl 4-aminobenzoate, n-propyl 4-aminobenzoate, and isopropyl 4-aminobenzoate. Compound (5) is inexpensively available, and obtaining compound (4) in the halogenation step can significantly reduce costs.

[0060] The halogenation step is preferably carried out in the presence of a halogenating agent. Examples of the halogenating agent include brominating agents such as bromine (Br), hydrogen bromide, N-bromosuccinimide, tetrabutylammonium tribromide, dibromoisocyanuric acid (DBI), and 1,3-dibromo-5,5-dimethylhydantoin; chlorinating agents such as chlorine (Cl), thionyl chloride, and N-chlorosuccinimide; fluorinating agents such as fluorine (F); and iodinating agents such as iodine (I), iodine chloride (ICl), 1,3-diiodo-5,5-dimethylhydantoin and N-iodosuccinimide. The halogenating agents may be used alone or in combination of two or more.

[0061] The amount of the halogenating agent used is preferably in the range of 80 to 120 mol, more preferably in the range of 90 to 110 mol, and particularly preferably in the range of 95 to 105 mol, per 100 mol of compound (5), from the viewpoints of reaction efficiency and production costs.

[0062] From the viewpoint of reaction efficiency and production costs, the halogenation step is preferably carried out in the presence of a solvent, and more preferably in the presence of an organic solvent. 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 methylene chloride, ethylene chloride, dichloromethane, and chloroform; nitrile solvents such as acetonitrile; and monohydric lower alcohol solvents such as methanol and ethanol. The solvent may be used alone or in combination of two or more. The amount of the solvent used is preferably in the range of 100 to 2,000 parts by mass, more preferably 250 to 1,000 parts by mass, per 100 parts by mass of compound (5).

[0063] The reaction temperature in the halogenation step is usually −15° C. to the boiling point of the solvent, preferably 0 to 50° C. The reaction time in the halogenation step is usually 0.1 to 24 hours, preferably 0.5 to 12 hours.

[0064] (Esterification Step) 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.

[0065] Examples of compound (12) include monohydric lower alcohols (specifically, monohydric alcohols having 1 to 4 carbon atoms) such as methanol, ethanol, n-propanol, and isopropanol. From the viewpoints of reaction efficiency and production costs, the amount of compound (12) used is preferably in the range of 90 to 50,000 mol, more preferably in the range of 100 to 10,000 mol, per 100 mol of compound (11).

[0066] The esterification step is preferably carried out in the presence of an esterification catalyst. 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 alcoholates. The esterification catalyst may be used alone or in combination of two or more. From the viewpoints of reaction efficiency and production costs, the amount of the esterification catalyst used in the esterification step is preferably in the range of 10 to 1,000 mol, more preferably in the range of 50 to 300 mol, per 100 mol of compound (11).

[0067] Since compound (12) functions not only as a substrate but also as a solvent, this esterification step can be carried out without using any solvent other than compound (12), but a solvent other than compound (12) may also be used together with compound (12). Examples of such solvents other than compound (12) include ether-based solvents, halogenated hydrocarbon-based solvents, and nitrile-based solvents, similar to those used in the halogenation step.

[0068] The reaction temperature in the esterification step is usually from 35° C. to the boiling point of the solvent. The reaction time in the esterification step is usually from 0.1 to 36 hours, preferably from 0.5 to 12 hours.

[0069] (Amidation Step) 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.

[0070] Examples of the halogen atom represented by Y include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among these, from the viewpoints 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. Examples of compound (3) include 3,5-dichlorobenzoic acid chloride, 3,5-dichlorobenzoic acid bromide, and 3,5-dichlorobenzoic acid iodide. From the viewpoints of reaction efficiency and production costs, the amount of compound (3) used is preferably in the range of 70 to 1,000 mol, more preferably in the range of 90 to 500 mol, and particularly preferably in the range of 100 to 200 mol, per 100 mol of compound (4).

[0071] Examples of the base used in the amidation step include tertiary amine bases, alkali metal carbonates such as potassium carbonate and sodium carbonate, and alkali metal hydroxides such as potassium hydroxide and sodium hydroxide. Among these, tertiary amine bases are preferred. Examples of such bases include pyridine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, and N-methylmorpholine. The bases may be used alone or in combination of two or more.

[0072] The amount of the base used in the amidation step is preferably in the range of 70 to 1,000 mol, more preferably in the range of 90 to 500 mol, and particularly preferably in the range of 100 to 200 mol, relative to 100 mol of compound (4), from the viewpoints of reaction efficiency and production costs.

[0073] From the viewpoints of reaction efficiency and production costs, the amidation step is preferably carried out in the presence of a solvent, and more preferably in the presence of an organic solvent. 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 methylene chloride, ethylene chloride, 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 solvent may be used alone or in combination of two or more. The amount of the solvent used is preferably in the range of 150 to 3,000 parts by mass, more preferably 300 to 1,000 parts by mass, per 100 parts by mass of compound (4).

[0074] The reaction temperature in the amidation step is usually 3° C. to the boiling point of the solvent, preferably 10 to 30° C. The reaction time in the amidation step is usually 0.1 to 36 hours, preferably 0.5 to 12 hours.

[0075] Furthermore, among the compounds (1) obtained in this amidation step, those in which X represents a fluorine atom, a bromine atom, or an iodine atom (preferably a bromine atom or an iodine atom) are novel compounds. These compounds are useful as synthetic intermediates for tafamidis or a salt thereof. 1 has the same meaning as defined above, and is preferably a methyl group or an ethyl group, more preferably an ethyl group.

[0076] Preferably, the production method of the present invention further comprises a hydrolysis step of ester hydrolysis of compound (2) obtained in the cyclization step, which produces tafamidis represented by the following formula (6):

[0077]

[0078] (Hydrolysis Step) Hydrolysis is preferably carried out in the presence of a base. The base used in the hydrolysis step is preferably an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, or cesium hydroxide. The base may be used alone or in combination of two or more. From the viewpoints of reaction efficiency and production costs, the amount of the base used in the hydrolysis 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 200 mol, relative to 100 mol of compound (2).

[0079] The amount of water used in the hydrolysis step is preferably in the range of 75 to 2000 parts by mass, more preferably in the range of 100 to 800 parts by mass, relative to 100 parts by mass of compound (2), from the viewpoints of reaction efficiency and production costs. A water-miscible organic solvent 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 lower alcohol solvents such as methanol and ethanol. The solvent may be used alone or in combination of two or more. The reaction temperature in the hydrolysis step is usually 10°C to the boiling point of the solvent, preferably 20 to 70°C. The reaction time in the hydrolysis step is usually 1 to 96 hours, preferably 3 to 48 hours.

[0080] Salts of tafamidis can be obtained by conventional methods. For example, they can be obtained by a salt formation step in which tafamidis (6) is contacted with an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, or cesium hydroxide; or an organic base such as methylamine, ethylamine, meglumine, ethanolamine, diethanolamine, dicyclohexylamine, or benzylamine. From the viewpoints of reaction efficiency and production cost, the amount of base used in the salt formation step is preferably in the range of 70 to 750 mol, more preferably 90 to 500 mol, and particularly preferably 100 to 300 mol, per 100 mol of tafamidis (6). The salt formation step 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 lower alcohol solvents such as methanol and ethanol; and water. The solvent may be used alone or in combination of two or more. The reaction temperature in the salt formation step is usually −10° C. to the boiling point of the solvent, preferably 0 to 30° C. The reaction time in the salt formation step is usually 0.1 to 96 hours, preferably 1 to 48 hours. Furthermore, tafamidis (6) obtained in the hydrolysis step described above can be subjected to the salt formation step after isolation and purification, or the solution of tafamidis (6) obtained in the hydrolysis step can be subjected to the salt formation step as it is.

[0081] The reaction products obtained in each of the above steps may be purified by separation means such as distillation, extraction, crystallization, washing, etc.

[0082] According to the production method of the present invention, tafamidis or a salt thereof can be produced in high yield and at low cost. Furthermore, the amount of liquid required in the cyclization step (the maximum amount of liquid required until the product is separated) is small, making it easy to compact the production equipment required to produce tafamidis. Furthermore, the amount of liquid required in the amidation step and the halogenation step (the maximum amount of liquid required until the product is separated) is also small, making it easy to compact the production equipment required to produce tafamidis even when the production method of the present invention includes the amidation step and / or the halogenation step.

[0083] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0084] Example 1 (Synthesis of Tafamidis) (1) Synthesis of Ethyl 4-amino-3-bromobenzoate 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. 218 g (1.22 mol) of N-bromosuccinimide was then added and stirred for 1 hour. 1000 mL of water and 1000 mL of ethyl acetate were added to this reaction solution, and the layers were separated. The organic layer was washed with 1000 mL of saturated brine, dehydrated over anhydrous sodium sulfate, and concentrated under reduced pressure. 460 mL of ethyl acetate and 1500 mL of n-heptane were added to the concentrate, and the mixture was stirred at an external temperature of 0°C for 1 hour. The precipitated solid was collected by filtration. The collected solid was dried under reduced pressure at an external temperature of 40°C to obtain 297 g (1.22 mol, 100% yield) of ethyl 4-amino-3-bromobenzoate as a pale yellow-white solid.

[0085] 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)

[0086] (2) Synthesis of N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide 290 g (1.19 mol) of the ethyl 4-amino-3-bromobenzoate obtained above was dissolved in 2900 mL of tetrahydrofuran, and 141 g (1.79 mol) of pyridine was added. Next, 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 the mixture was stirred at an external temperature of 0°C for 1 hour, and the precipitated solid was collected by filtration. The solid collected by filtration 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.

[0087] 1 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)

[0088] (3) Synthesis of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate To 50 mL of toluene were added 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 the N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide obtained above, and 4.97 g (36.0 mmol) of potassium carbonate, and the mixture was stirred at an external temperature of 110°C for 5 hours. To this reaction liquid were added 25 mL of a 10% aqueous ammonium chloride solution and 60 mL of tetrahydrofuran, and the layers were separated. The organic layer was washed with a 10% aqueous ammonium chloride solution and saturated brine, then dehydrated over 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 pale yellow solid.

[0089] 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), 7.80 (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)

[0090] (4) Synthesis of Tafamidis To a mixture of 64 mL of tetrahydrofuran and 16 mL of water, 3.99 g (11.9 mmol) of the ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate obtained above and 0.70 g (16.6 mmol) of lithium hydroxide monohydrate were added, and the mixture was 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 collected by filtration. The collected 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 Tafamidis as a pale yellowish white solid.

[0091] 1 H-NMR(DMSO):δ / ppm= 7.91 (d, 1H, J=8.4Hz), 7.94 (t, 1H, J=2.0Hz), 8.03 (dd, 1H, 1.2,8.0Hz), 8.13 (d, 2H, J=2.0Hz), 8.26 (d, 1H, J=0.8Hz), 13.28 (br-s, 1H)

[0092] To 50 mL of toluene were added 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 procedures as in (1) and (2) of Example 1, and 4.97 g (36.0 mmol) of potassium carbonate, and the mixture was stirred overnight at an external temperature of 110°C. To this reaction solution were added 25 mL of a 10% aqueous ammonium chloride solution and 60 mL of tetrahydrofuran, followed by separation of the layers. The organic layer was washed with a 10% aqueous ammonium chloride solution and saturated brine, then dehydrated 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 pale yellow solid. The obtained spectral data was consistent with the spectral data described in Example 1(3). Subsequently, the same procedure as in Example 1(4) was carried out to obtain tafamidis as a pale yellowish white solid in a yield of 87% (total yield from ethyl 4-aminobenzoate: 78%). The obtained spectral data was consistent with the spectral data described in Example 1(4).

[0093] To 50 mL of toluene were added 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 procedures as in (1) and (2) of Example 1, and 4.97 g (36.0 mmol) of potassium carbonate, and the mixture was stirred for 5 hours at an external temperature of 110°C. To this reaction solution were added 25 mL of 10% aqueous ammonium chloride solution and 60 mL of tetrahydrofuran, followed by phase separation. The organic layer was washed with 10% aqueous ammonium chloride solution and saturated brine, then dehydrated 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 was consistent with the spectral data described in Example 1(3). Subsequently, the same procedure as in Example 1(4) was carried out to obtain tafamidis as a gray-white solid in a yield of 87% (total yield from ethyl 4-aminobenzoate: 78%). The obtained spectral data was consistent with the spectral data described in Example 1(4).

[0094] To 50 mL of toluene were added 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 procedures as in (1) and (2) of Example 1, and 4.97 g (36.0 mmol) of potassium carbonate, and the mixture was stirred for 5 hours at an external temperature of 110°C. To this reaction solution were added 25 mL of 10% aqueous ammonium chloride solution and 60 mL of tetrahydrofuran, followed by phase separation. The organic layer was washed with 10% aqueous ammonium chloride solution and saturated brine, then dehydrated 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 pale yellow solid. The obtained spectral data was consistent with the spectral data described in Example 1(3). Subsequently, the same procedure as in Example 1(4) was carried out to obtain tafamidis as a pale yellowish-white solid in a yield of 90% (total yield from ethyl 4-aminobenzoate: 80%). The obtained spectral data was consistent with the spectral data described in Example 1(4).

[0095] Example 5 (Synthesis of Tafamidis) 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 procedures 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 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, followed by separation. The organic layer was washed with 10% aqueous ammonium chloride solution and saturated brine, dehydrated over anhydrous sodium sulfate, and concentrated under reduced pressure. 100 mL of ethyl acetate was added to the concentrate, and the mixture was dissolved at an external temperature of 80°C. The mixture was then cooled to room temperature, and the precipitated crystals were collected by filtration. 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. Subsequently, the same procedure as in Example 1(4) was carried out to obtain tafamidis as a pale yellowish-white solid in a yield of 97% (total yield from ethyl 4-aminobenzoate 64%). The obtained spectral data were consistent with the spectral data described in Example 1(4).

[0096] Example 6 (Synthesis of Tafamidis) N-[2-chloro-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide was obtained by performing the same operations as in (1) and (2) of Example 1, except that N-bromosuccinimide was changed to N-chlorosuccinimide. 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 the 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 the mixture was stirred at an external temperature of 110°C for 22 hours. To this reaction solution, 5 mL of 10% aqueous ammonium chloride solution and 12 mL of tetrahydrofuran were added, and the mixture was separated. The organic layer was washed with 10% aqueous ammonium chloride solution and saturated brine, then dehydrated over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 0.91 g (2.7 mmol, 100% yield) of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate as a pale yellow solid. The spectral data obtained were consistent with the spectral data described in Example 1(3). Subsequently, the same procedure as in Example 1(4) was performed to obtain tafamidis as a pale yellow-white solid in a 93% yield (86% overall yield from ethyl 4-aminobenzoate). The spectral data obtained were consistent with the spectral data described in Example 1(4).

[0097] Example 7 (Synthesis of Tafamidis) (1) Synthesis of Ethyl 4-amino-3-iodobenzoate 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 under reflux for 5 hours and concentrated under reduced pressure. 10 mL of saturated aqueous sodium bicarbonate was added to the concentrate, and the solid was collected by filtration. The collected 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 pale yellowish white solid.

[0098] 1H-NMR(CDCl3):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)

[0099] (2) Synthesis of N-[2-iodo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide 0.7 g (2.4 mmol) of ethyl 4-amino-3-iodobenzoate obtained above was dissolved in 7 mL of tetrahydrofuran, and 0.29 g (3.6 mmol) of pyridine was added. Next, 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 layers were separated. The organic layer was washed with saturated brine, dehydrated over 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 the solid was collected by filtration. The solid collected by filtration 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.

[0100] 1 H-NMR(CDCl3):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)

[0101] (3) Synthesis of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate To 6 mL of toluene were added 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 the N-[2-iodo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide obtained above, and 536 mg (3.88 mmol) of potassium carbonate, and the mixture was stirred at an external temperature of 110°C for 30 hours. To this reaction solution, 3 mL of 10% aqueous ammonium chloride solution and 7.2 mL of tetrahydrofuran were added, and the layers were separated. The organic layer was washed with 10% aqueous ammonium chloride solution and saturated brine, then dehydrated over anhydrous sodium sulfate and concentrated under reduced pressure to give 360 ​​mg (1.07 mmol, yield 83%) of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate as a pale yellow solid. The spectral data obtained were consistent with the spectral data described in Example 1(3). Subsequently, the same procedure as in Example 1(4) was carried out to give tafamidis as a pale yellowish-white solid in a yield of 93% (total yield from 4-amino-3-iodobenzoic acid: 34%). The spectral data obtained were consistent with the spectral data described in Example 1(4).

[0102] Example 8 (Synthesis of tafamidis meglumine) To 1.00 g (3.25 mmol) of tafamidis obtained in Example 1, 20 mL of 2-propanol, 5.5 mL of water, and 0.63 g (3.25 mmol) of N-methyl-D-glucamine were added, and the mixture was stirred at an external temperature of 80°C for 1 hour. Thereafter, the mixture was cooled to an internal temperature of 10°C, and the precipitated solid was collected by filtration. The collected solid was dried under reduced pressure at an external temperature of 50°C, yielding 1.26 g (2.50 mmol, yield 77%) of tafamidis meglumine as a white solid.

[0103] 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, 4.8Hz), 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)

[0104] Comparative Example 1 (Synthesis of Tafamidis) Tafamidis was synthesized according to the method described in JP-A-2006-511612. (1) Specifically, 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, refluxed for 1 hour, and the reaction mixture was concentrated under reduced pressure. The resulting N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide was used in the next step without purification.

[0105] (2) To the concentrate of N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide obtained above, 330 mL of xylene and 24.9 g (131 mmol) of p-toluenesulfonic acid monohydrate were added, and the mixture was stirred at an external temperature of 140°C for 14 hours. After cooling the reaction solution, 131 mL (131 mmol) of 1 mol / L aqueous sodium hydroxide solution was added, and the organic layer was separated. 1 mol / L hydrochloric acid was added to the aqueous layer to adjust the pH to 2, and the mixture was extracted four times with 200 mL of ethyl acetate. The organic layers were combined, dehydrated over anhydrous sulfuric acid, and concentrated under reduced pressure to obtain 2.31 g (7.5 mmol, yield 57.2%) of tafamidis as a reddish-white solid. The method of Comparative Example 1 produced an insufficient yield.

[0106] Test Example 1 The maximum liquid volume (mL) required to obtain 1 g of tafamidis in each step of the methods of Examples 1 to 7 and Comparative Example 1 was estimated by rough calculation. In the halogenation step and cyclization step, the liquid volume reached its maximum immediately before separation, so the liquid volume immediately before separation was estimated as the maximum liquid volume. In the esterification step, amidation step, and hydrolysis step, the liquid volume reached its maximum immediately before filtration, so the liquid volume immediately before filtration was estimated as the maximum liquid volume. The specific gravity of the liquid was assumed to be 1 g / mL, and the solid was assumed to be a liquid with a specific gravity of 1 g / mL. Furthermore, the largest liquid volume among the maximum liquid volumes required to obtain 1 g of tafamidis in each step was recorded as the "maximum value." It can be said that the smaller the maximum liquid volume required to obtain 1 g of tafamidis in each step or the "maximum value," the easier it is to compact the manufacturing equipment required to produce tafamidis. The results are shown in Table 1.

[0107] The method for estimating the maximum liquid volume (mL) required to obtain 1 g of tafamidis in each step is explained below using Example 1 as an example. In Example 1, the hydrolysis step had the largest liquid volume of the halogenation step, amidation step, cyclization step, and hydrolysis step, at 52 mL, and therefore the "maximum value" of the maximum liquid volumes in each step was recorded as 52 mL.

[0108] The total liquid volume in the hydrolysis step of Example 1 was approximately 164.49 mL. Breakdown: tetrahydrofuran (64 mL) + water (16 mL) + ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate (approximately 3.99 mL) + lithium hydroxide monohydrate (approximately 0.70 mL) + water (48 mL) + 1 mol / L hydrochloric acid (32 mL). The amount of tafamidis obtained by this hydrolysis step was 3.17 g, and the maximum liquid volume required to obtain 1 g of tafamidis in the hydrolysis step of Example 1 is 164.49 ÷ 3.17 ≈ 52 mL.

[0109] The total volume of the liquid in the cyclization step in Example 1 was approximately 145.48 mL. Breakdown: toluene (50 mL) + N,N,N',N'-tetramethylethylenediamine (approximately 0.28 mL) + copper(I) iodide (approximately 0.23 mL) + N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide (approximately 5.00 mL) + potassium carbonate (approximately 4.97 mL) + 10% aqueous ammonium chloride solution (25 mL) + tetrahydrofuran (60 mL). The amount of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate obtained by this 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 tafamidis is 3.99 ÷ 3.17 ≈ 1.26 g. Therefore, the maximum liquid volume required to obtain 1 g of tafamidis in the cyclization step of Example 1 is 145.48 ÷ 3.99 × 1.26 ≈ 46 mL.

[0110] The total liquid volume in the amidation step in Example 1 was approximately 7,690 mL. Breakdown: ethyl 4-amino-3-bromobenzoate (approximately 290 mL) + tetrahydrofuran (2,900 mL) + pyridine (approximately 141 mL) + tetrahydrofuran (580 mL) + 3,5-dichlorobenzoyl chloride (approximately 299 mL) + water (3,480 mL). The amount of N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide obtained by this amidation step was 460 g, and the amount of N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide required to obtain 1 g of tafamidis is 5.00 ÷ 3.99 × 1.26 ≒ 1.58 g. Therefore, the maximum liquid volume required to obtain 1 g of tafamidis in the amidation step of Example 1 is 7690 ÷ 460 × 1.58 ≈ 26 mL.

[0111] The total liquid volume in the halogenation step of Example 1 is approximately 3,418 mL. Breakdown: ethyl 4-aminobenzoate (approximately 200 mL) + tetrahydrofuran (1,000 mL) + N-bromosuccinimide (approximately 218 mL) + water (1,000 mL) + ethyl acetate (1,000 mL). The amount of ethyl 4-amino-3-bromobenzoate obtained in this halogenation step was 297 g, and the amount of ethyl 4-amino-3-bromobenzoate required to obtain 1 g of tafamidis is 290 ÷ 460 × 1.58 ≒ 0.99 g. Therefore, the maximum liquid volume required to obtain 1 g of tafamidis in the halogenation step of Example 1 is 3,418 ÷ 297 × 0.99 ≒ 11 mL.

[0112]

[0113] As shown in Table 1, by producing Tafamidis using the methods of Examples 1 to 7, the production facilities required for producing Tafamidis can be made compact.

[0114] Comparative Example 2 (Synthesis of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate) 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 to 12 mL of dimethyl sulfoxide, 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 this reaction solution, and the mixture was extracted with a mixture of 60 mL of ethyl acetate and 20 mL of tetrahydrofuran. The organic layer was washed with saturated brine, dehydrated over 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 pale yellow solid. The yield was insufficient in the method of Comparative Example 2.

[0115] As described above, when compound (1) was cyclized in the presence of bis(1,5-cyclooctadiene)diiridium(I) dichloride (Comparative Example 2), the yield of the cyclization step was 34%. In contrast, when compound (1) was cyclized in the presence of one or more copper catalysts selected from copper halides, copper carboxylates, copper sulfates, and copper oxides, a base, and an amine ligand (Examples 1 to 7), the yield of the cyclization step was 71 to 100%. Here, in terms of improving the efficiency of cyclization by such a C—O coupling reaction, iridium catalysts have been considered more useful than copper catalysts such as copper iodide catalysts (Tetrahedron Letters 2019, 60, 151082). However, it is surprising that a significant improvement in yield was observed as described above when one or more copper catalysts selected from copper halides, copper carboxylates, copper sulfates, and copper oxides, a base, and an amine ligand were used.

[0116] Reference Example 1 (Synthesis of N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide) N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide was synthesized with reference to the amidation reaction described in JP 2021-517118 A. 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 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, and the precipitate was collected by filtration and dried under reduced pressure at an external temperature of 50 ° C. To the obtained solid, 98 mL of a 0.5 mol / L aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature. Insoluble matter was filtered off. 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 2-3. The precipitate was collected by filtration and 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, then stirred overnight at an external temperature of 70°C, and the solid was collected by filtration. The obtained solid was dried under reduced pressure at an external temperature of 50°C, yielding 2.64 g (8.1 mmol, yield 61.8%) of N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide as a pale yellow solid.

[0117] Reference Example 2 (Synthesis of N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide) N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide was synthesized with reference to the amidation reaction described in JP 2021-517118 A. 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, and 3.28 g (15.7 mmol) of 3,5-dichlorobenzoyl chloride was added and stirred at room temperature for 1 hour. To this mixture, 1.59 g (15.7 mmol) of triethylamine was added, 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 collected by filtration. A 0.5 mol / L aqueous sodium hydroxide solution was added to the obtained solid, and the mixture was stirred at room temperature, and insoluble matter was filtered off 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 aqueous layer, and the precipitate was collected by filtration and dried under reduced pressure at an external temperature of 50 ° C. to obtain N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide as a gray-white solid. The yield was about 65%, similar to that described in JP 2021-517118 A.

Claims

1. A method for producing tafamidis or a salt thereof, comprising a cyclization 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 carboxylates, copper sulfates, and copper oxides, a base, and an amine ligand to obtain a compound represented by the following formula (2): 【Chemistry 1】 [In formula (1), R 1 represents a linear or branched alkyl group, X represents a halogen atom. 【Chemistry 2】 [In formula (2), R 1 has the same meaning as above.]

2. 2. The production method according to claim 1, further comprising an amidation step of amidating a compound represented by the following formula (3) with a compound represented by the following formula (4) in the presence of a base, and using the compound represented by formula (1) obtained in said amidation step in the cyclization step: 【Transformation 3】 [In formula (3), Y represents a halogen atom.] 【Chemistry 4】 [In formula (4), R 1 and X have the same meanings as defined above.]

3. The method according to claim 2, further comprising a halogenation step of halogenating a compound represented by the following formula (5), and using the compound represented by formula (4) obtained in the halogenation step in the amidation step: 【Transformation 5】 [In formula (5), R 1 has the same meaning as above.]

4. The production method according to claim 2, further comprising an esterification step of carrying out a dehydration condensation reaction between a compound represented by the following formula (11) and a compound represented by the following formula (12), and the compound represented by formula (4) obtained in this step is used in the amidation step: 【Transformation 6】 (In formula (11), X has the same meaning as defined above.) 【Transformation 7】 [In formula (12), R 1 has the same meaning as above.]

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

6. The method according to any one of claims 1 to 4, wherein the copper catalyst is at least one selected from the group consisting 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).

7. The method according to any one of claims 1 to 4, wherein the copper catalyst is one or more copper catalysts selected from copper halides, copper carboxylates, and copper sulfates.

8. The method according to any one of claims 1 to 4, wherein a copper halide is used as the copper catalyst.

9. 9. The method according to claim 8, wherein the copper halide is one or more copper halides selected from the group consisting of copper iodide (I), copper bromide (I), and copper chloride (I).

10. The method according to any one of claims 1 to 4, wherein the amine ligand is an amine ligand selected from a monovalent amine ligand and a diamine ligand.

11. The method according to any one of claims 1 to 4, wherein X is a chlorine atom or a bromine atom.

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