Method for producing tafamidis or its salt

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

[Technical Field]

[0001] This invention relates to a method for producing tafamidis or its salts. More specifically, it relates to a method for producing tafamidis or its salts and the synthetic intermediates thereof. [Background technology]

[0002] Tafamidis meglumine is a pharmaceutical drug indicated for inhibiting the progression of peripheral neuropathy in transthyretin-type familial amyloid polyneuropathy and for transthyretin-type cardiac amyloidosis. In recent years, cardiomyopathy due to transthyretin amyloidosis has been added as an indication, and increased demand is expected.

[0003] One known method for producing tafamidismeglumine is to amidate 3,5-dichlorobenzoic acid chloride and 3-hydroxy-4-aminobenzoic acid in the presence of pyridine, and then cyclize 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 had the problem of requiring complicated purification due to the frequent occurrence of side reactions during amidation, resulting in low selectivity and yield. Furthermore, 3-hydroxy-4-aminobenzoic acid was expensive, leading to high costs. In particular, the method described in Patent Document 1 required methyl esterification of the carboxyl group derived from 3-hydroxy-4-aminobenzoic acid for purification, necessitating column purification, which is difficult to industrialize. Additionally, the method described in Patent Document 1 required a liquid volume of 187 v / w, and the method described in Patent Document 2 required 170 v / w, resulting in poor production efficiency. Moreover, the poor filterability of the intermediate N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide made 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 called iridium catalyst) as a catalyst when cyclizing N-(2-bromo-5-nitrophenyl)benzamide (CO coupling reaction) to obtain a benzoxazole derivative (Non-Patent Literature 1). Furthermore, Non-Patent Literature 1 describes that by carrying out the cyclization reaction using the iridium catalyst for 48 hours, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylate (Methyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylate) (methyl ester of tafamidis) was obtained in a yield of 52%. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Special Publication No. 2006-511612 [Patent Document 2] Japanese Patent Publication No. 2021-517118 [Non-patent literature]

[0006] [Non-Patent Document 1] Tetrahedron Letters 2019,60,151082 [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] In Non-Patent Document 1 mentioned above, the cyclization reaction of N-(2-Bromo-5-nitrophenyl)cinnamamide was carried out using the iridium catalyst (0.01 mmol) and the copper iodide catalyst ((CuI) 0.20 mmol), respectively. When the iridium catalyst was used, the benzoxazole derivative was obtained in a yield of 74% without generating any by-products (debrominated products). However, when using a copper iodide catalyst, the yield of benzoxazole derivatives was only 24%, and a large amount of by-products (debrominated products) were observed (61%). Therefore, iridium catalysts were considered more useful than copper catalysts such as copper iodide catalysts for improving the efficiency of cyclization by CO coupling reactions.

[0008] Furthermore, as a result of our investigations, we found that although the iridium catalyst efficiently cyclizes N-(2-bromo-5-nitrophenyl)benzamide, when a synthetic intermediate of tafamidis having an alkoxycarbonylphenyl group in its molecule, such as N-[2-bromo-4-(methoxycarbonyl)phenyl]-3,5-dichlorobenzamide, is used as a substrate, the yield of cyclization is insufficient. The object of the present invention is to provide a method for producing tafamidis or its salts in high yield. [Means for solving the problem]

[0009] The inventors of the present invention diligently investigated the cyclization reaction of N-[2-halo-4-(alkoxycarbonyl)phenyl]-3,5-dichlorobenzamide using various catalysts. As a result, they discovered that, surprisingly, tafamidis or its salts can be produced in high yield and at low cost by a method comprising a cyclization step in which N-[2-halo-4-(alkoxycarbonyl)phenyl]-3,5-dichlorobenzamide is 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, thus completing the present invention.

[0010] In other words, the present invention is as follows <1> ~ <14> This provides... <1> A method for producing tafamidis or a salt thereof (hereinafter also referred to as the production method of the present invention) comprising a cyclization step to obtain a compound represented by the following formula (2) by 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.

[0011] [Chemical formula]

[0012] [In formula (1), R , , ,

[0020] , , , 1 , ,

[0019] , , , , ,

[0021] , , represents a linear or branched alkyl group, X represents a halogen atom. ]

[0013] [Chemical formula]

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

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

[0016] [Chemical formula]

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

[0018] [Chemical formula]

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

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

[0021] [ka]

[0022] [In formula (5), R 1 This is synonymous with the above.

[0023] <4> The process further includes an esterification step in which a compound represented by formula (11) and a compound represented by formula (12) are subjected to a dehydration condensation reaction, and the compound represented by formula (4) obtained in this step is used in the amidation step. <2> The manufacturing method described above.

[0024] [ka]

[0025] [In equation (11), X is the same as described above.]

[0026] [ka]

[0027] [In formula (12), R 1 This is synonymous with the above.

[0028] <5> The process further includes a hydrolysis step of esterifying the compound represented by formula (2) obtained in the cyclization step, <1> ~ <4> A manufacturing method described in any of the following.

[0029] <6> 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. <1> ~ <5> A manufacturing method described in any of the following. <7> As the copper catalyst, one or more copper catalysts selected from copper halides, copper carboxylates, and copper sulfates are used. <1> ~ <5> A manufacturing method described in any of the following. <8> As the copper catalyst, copper halide is used. <1> ~ <5> A manufacturing method described in any of the following. <9> As the copper halide, one or more copper halides selected from copper(I) iodide, copper(I) bromide, and copper(I) chloride are used. <8> The manufacturing method described above.

[0030] <10> As the amine ligand, an amine ligand selected from monovalent amine ligands and diamine ligands is used. <1> ~ <9> A manufacturing method described in any of the following. <11> X is a chlorine atom or a bromine atom. <1> ~ <10> A manufacturing method described in any of the following.

[0031] <12> A compound represented by the following formula (1) (hereinafter also referred to as the specific compound of the present invention). [ka] [In formula (1), R 1 This represents a linear or branched alkyl group. X represents a fluorine atom, a bromine atom, or an iodine atom.

[0032] <13> R 1 However, it is an ethyl group. <12> The compounds described above. <14> X is a bromine atom or an iodine atom. <12> or <13> The compounds described above. [Effects of the Invention]

[0033] According to the present invention, tafamidis or its salts can be produced in high yield and at low cost. The specific compounds of the present invention are useful as synthesis intermediates for tafamidis or its salts. [Modes for carrying out the invention]

[0034] The production method of the present invention includes a cyclization step of cyclizing a compound represented by the following formula (1) (hereinafter also referred to as compound (1)) to obtain a compound represented by the following formula (2) (hereinafter also referred to as compound (2)) 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. The cyclization step in the production method of the present invention is less likely to cause side reactions and can quantitatively produce high-purity compound (2). Therefore, according to the production method of the present invention, it is an industrially very excellent production method. In addition, the cyclization step in the production method of the present invention has a small required liquid volume (the maximum liquid volume until the separation of the product), and it is easy to compact the production equipment required for producing tafamidis.

[0035]

Chemical formula

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

[0037]

Chemical formula

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

[0039] (Cyclization step) In formula (1), R 1 represents a linear or branched alkyl group. From the viewpoints of availability and reaction efficiency, the number of carbon atoms of the alkyl group is preferably 1 to 12, more preferably 1 to 8, still 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, a tert-butyl group, etc. Among these, a methyl group and an ethyl group are preferred, and an ethyl group is more preferred. Examples of halogen atoms represented by X include fluorine, chlorine, bromine, and iodine. Among these, chlorine, bromine, and iodine are preferred from the viewpoint of reaction efficiency and suppression of by-products, with chlorine and bromine being 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]. Examples include 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, and N-[2-iodo-4-(isopropoxycarbonyl)phenyl]-3,5-dichlorobenzamide.

[0040] The cyclization step uses one or more copper catalysts selected from copper halides, copper carboxylates, copper sulfates, and copper oxides. By using these copper catalysts, the cyclization reaction can be carried out with high efficiency. Among these, one or more copper catalysts selected from copper halides, copper carboxylates, and copper sulfates are preferred from the viewpoint of reaction efficiency and suppression of by-products. As the copper catalyst mentioned above, from the viewpoint of reaction efficiency and suppression of by-products, 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 preferred. I) More preferably one or more selected from copper(II) chloride, copper(II) acetate, copper(II) acetate, copper(II) sulfate, copper(II) sulfate, copper(II) oxide and copper(II) oxide; even more preferably one or more selected from copper(II) iodide, copper(II) bromide, copper(II) chloride, copper(II) acetate, copper(II) sulfate and copper(II) oxide; even more preferably one or more selected from copper(II) iodide, copper(II) bromide, copper(II) chloride, copper(II) acetate and copper(II) sulfate, with copper(II) iodide being particularly preferred.

[0041] The amount of one or more copper catalysts selected from copper halides, copper carboxylates, copper sulfates, and copper oxides used is usually in the range of 0.1 to 500 moles per 100 moles of compound (1), but from the viewpoint of reaction efficiency and manufacturing cost, it is preferably in the range of 0.5 to 100 moles, and more preferably in the range of 1 to 50 moles.

[0042] Inorganic bases are preferred as the bases used in the cyclization process. Examples of bases 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. A single base may be used, or two or more bases may be used in combination.

[0043] From the viewpoint of reaction efficiency and manufacturing cost, the amount of base used in the cyclization step is preferably in the range of 10 to 1000 moles, more preferably in the range of 100 to 750 moles, and particularly preferably in the range of 200 to 500 moles, per 100 moles of compound (1).

[0044] Examples of amine ligands used in the cyclization process 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'-ditert-butylethylenediamine, ethylenebis(diethylamine), and N,N'-diphenylethylenediamine. Among monovalent amine ligands and diamine ligands, diamine ligands are preferred from the viewpoint of reaction efficiency and manufacturing cost. Amine ligands may be used individually or in combination of two or more. Among these, 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 from the viewpoint of reaction efficiency and manufacturing cost, 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] From the viewpoint of reaction efficiency and manufacturing cost, the amount of amine ligand used in the cyclization step is preferably in the range of 0.1 to 1000 moles, more preferably in the range of 0.5 to 200 moles, and particularly preferably in the range of 1 to 100 moles, per 100 moles of compound (1).

[0046] The cyclization process is preferably carried out in the presence of a solvent, and more preferably in the presence of an organic solvent, from the viewpoint of reaction efficiency and manufacturing cost. 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; and others such as N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide. Solvents may be used individually or in combination of two or more. The amount of solvent used is preferably in the range of 150 to 5000 parts by mass, more preferably in the range of 300 to 3000 parts by mass, per 100 parts by mass of compound (1).

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

[0048] Furthermore, 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 reacted in the presence of a base. The amidation step proceeds quantitatively, the required liquid volume (the maximum liquid volume until the product is separated) can be kept low, and post-treatment is also simple. Obtaining the compound by the amidation step in this way further increases yield and reduces costs. Furthermore, compound (4) can be obtained, for example, by 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 by 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, the required liquid volume (the maximum liquid volume required for product separation) can be kept low, and post-treatment is simple. Furthermore, obtaining compound (4) in the halogenation step allows for even higher yields and lower costs. Compound (3) may be a commercially available product or one prepared by referring to known methods.

[0049] [ka]

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

[0051] [ka]

[0052] [In formula (4), R 1 And X is synonymous with the above.

[0053] [ka]

[0054] [In formula (5), R 1 This is synonymous with the above.

[0055] [ka]

[0056] [In equation (11), X is the same as described above.]

[0057] [ka]

[0058] [In formula (12), R 1 This is synonymous with the above.

[0059] Here, we will explain the halogenation process, esterification process, and amidation process in detail. (Halogenation process) Examples of compound (5) include methyl 4-aminobenzoate, ethyl 4-aminobenzoate, n-propyl 4-aminobenzoate, and isopropyl 4-aminobenzoate. Compound (5) is inexpensive and can be obtained in a halogenation step to significantly reduce costs.

[0060] The halogenation process is preferably carried out in the presence of a halogenating agent. Examples of halogenating agents include brominaters such as bromine (Br2), hydrogen bromide, N-bromosuccinimide, tetrabutylammonium tribromide, dibromoisocyanuric acid (DBI), and 1,3-dibromo-5,5-dimethylhydantoin; chlorinating agents such as chlorine (Cl2), thionyl chloride, and N-chlorosuccinimide; fluorinating agents such as fluorine (F2); and iodizing agents such as iodine (I2), iodine chloride (ICl), 1,3-diiodo-5,5-dimethylhydantoin, and N-iodosuccinimide. Halogenating agents may be used individually or in combination of two or more.

[0061] From the viewpoint of reaction efficiency and manufacturing cost, the amount of halogenating agent used is preferably in the range of 80 to 120 moles, more preferably in the range of 90 to 110 moles, and particularly preferably in the range of 95 to 105 moles, per 100 moles of compound (5).

[0062] The halogenation process is preferably carried out in the presence of a solvent, and more preferably in the presence of an organic solvent, from the viewpoint of reaction efficiency and manufacturing cost. Examples of organic solvents include ether-based solvents such as diethyl ether, dibutyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; amide-based solvents such as N,N-dimethylformamide; halogenated hydrocarbon-based solvents such as methylene chloride, ethylene chloride, dichloromethane, and chloroform; nitrile-based solvents such as acetonitrile; and monovalent lower alcohol-based solvents such as methanol and ethanol. Solvents may be used individually or in combination of two or more. The amount of solvent used is preferably in the range of 100 to 2000 parts by mass, more preferably in the range of 250 to 1000 parts by mass, per 100 parts by mass of compound (5).

[0063] The reaction temperature for the halogenation step is typically between -15°C and the solvent boiling point, preferably between 0 and 50°C. The reaction time for the halogenation step is typically 0.1 to 24 hours, preferably 0.5 to 12 hours.

[0064] (Esterification process) Examples of 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 viewpoint of reaction efficiency and manufacturing cost, the amount of compound (12) used is preferably in the range of 90 to 50,000 moles, and more preferably in the range of 100 to 10,000 moles, per 100 moles of compound (11).

[0066] The esterification step is preferably carried out in the presence of an esterification catalyst. Examples of esterification catalysts include inorganic acids such as sulfuric acid and phosphoric acid; inorganic oxides such as tin oxide and zinc oxide; and alkoxides. Esterification catalysts may be used individually or in combination of two or more types. From the viewpoint of reaction efficiency and manufacturing cost, the amount of esterification catalyst used in the esterification process is preferably in the range of 10 to 1000 moles, more preferably in the range of 50 to 300 moles, per 100 moles of compound (11).

[0067] Since compound (12) acts 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). However, a solvent other than compound (12) may also be used in conjunction 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 for the esterification process is typically between 35°C and the boiling point of the solvent. The reaction time for the esterification step is typically 0.1 to 36 hours, preferably 0.5 to 12 hours.

[0069] (Amidation process) 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 halogen atoms represented by Y include fluorine, chlorine, bromine, and iodine. Among these, chlorine, bromine, and iodine are preferred from the viewpoint of reaction efficiency and suppression of by-products, with chlorine and bromine being more preferred. Examples of compound (3) include 3,5-dichlorobenzoate chloride, 3,5-dichlorobenzoate bromide, and 3,5-dichlorobenzoate iodide. From the viewpoint of reaction efficiency and manufacturing cost, the amount of compound (3) used is preferably in the range of 70 to 1000 moles, more preferably in the range of 90 to 500 moles, and particularly preferably in the range of 100 to 200 moles, per 100 moles of compound (4).

[0071] The bases used in the amidation process 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 individually or in combination of two or more.

[0072] From the viewpoint of reaction efficiency and manufacturing cost, the amount of base used in the amidation step is preferably in the range of 70 to 1000 moles, more preferably in the range of 90 to 500 moles, and particularly preferably in the range of 100 to 200 moles, per 100 moles of compound (4).

[0073] The amidation step is preferably carried out in the presence of a solvent, and more preferably in the presence of an organic solvent, from the viewpoint of reaction efficiency and manufacturing cost. Examples of organic solvents include ether-based 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-based solvents such as acetonitrile; ester-based solvents such as ethyl acetate; and aromatic hydrocarbon solvents such as benzene, toluene, and xylene. The solvent may be used individually or in combination of two or more. The amount of solvent used is preferably in the range of 150 to 3000 parts by mass, more preferably in the range of 300 to 1000 parts by mass, per 100 parts by mass of compound (4).

[0074] The reaction temperature for the amidation step is typically between 3°C and the solvent boiling point, preferably 10 to 30°C. The reaction time for the amidation step is typically 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 is 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 its salts. Note that R in equation (1) 1 This is the same as described above, and is preferably a methyl group, an ethyl group, and more preferably an ethyl group.

[0076] Furthermore, the manufacturing method of the present invention preferably further includes a hydrolysis step in which compound (2) obtained in the cyclization step is esterified hydrolyzed. By performing such a hydrolysis step, tafamidis represented by the following formula (6) can be obtained.

[0077] [ka]

[0078] (Hydrolysis process) Hydrolysis is preferably carried out in the presence of a base. Inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, and cesium hydroxide are preferred as bases to be used in the hydrolysis process. A single base may be used, or two or more bases may be used in combination. From the viewpoint of reaction efficiency and manufacturing cost, the amount of base used in the hydrolysis step is preferably in the range of 70 to 750 moles, more preferably in the range of 90 to 500 moles, and particularly preferably in the range of 100 to 200 moles per 100 moles of compound (2).

[0079] From the viewpoint of reaction efficiency and manufacturing cost, the amount of water used in the hydrolysis process is preferably in the range of 75 to 2000 parts by mass, more preferably in the range of 100 to 800 parts by mass, per 100 parts by mass of compound (2). Furthermore, organic solvents that are miscible with water may be used along with water. Examples of such organic solvents include ether-based solvents such as diethyl ether, dibutyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; nitrile-based solvents such as acetonitrile; and monovalent lower alcohol-based solvents such as methanol and ethanol. The solvent may be used alone or in combination of two or more types. The reaction temperature for the hydrolysis step is typically between 10°C and the solvent boiling point, preferably between 20°C and 70°C. The reaction time for the hydrolysis step is usually 1 to 96 hours, preferably 3 to 48 hours.

[0080] Furthermore, salts of tafamidis can be obtained by conventional methods. For example, they can be obtained by a salt-making process in which tafamidis (6) is contacted with inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, and cesium hydroxide; or with organic bases such as methylamine, ethylamine, meglumine, ethanolamine, diethanolamine, dicyclohexylamine, and benzylamine. From the viewpoint of reaction efficiency and manufacturing cost, the amount of base used in the salt production process is preferably in the range of 70 to 750 moles, more preferably in the range of 90 to 500 moles, and particularly preferably in the range of 100 to 300 moles, per 100 moles of tafamidis(6). The salt formation process is preferably carried out in the presence of a solvent. Examples of solvents include ether-based solvents such as diethyl ether, dibutyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; nitrile-based solvents such as acetonitrile; ester-based solvents such as ethyl acetate; monovalent lower alcohol-based 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 production process is typically between -10°C and the solvent boiling point, preferably between 0 and 30°C. The reaction time for the salt production process is typically 0.1 to 96 hours, preferably 1 to 48 hours. Furthermore, the tafamidis (6) obtained in the aforementioned hydrolysis step can be isolated and purified before being subjected to the salt production step, or the tafamidis (6) solution obtained in the hydrolysis step can be subjected to the salt production step immediately afterward.

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

[0082] Furthermore, the manufacturing method of the present invention allows for the production of tafamidis or its salts in high yield and at low cost. In addition, the required liquid volume in the cyclization process (the maximum liquid volume required until the product is separated) is small, making it easier to compact the manufacturing equipment necessary for producing tafamidis. Furthermore, since the required liquid volume (maximum liquid volume until product separation) in the amidation step and the halogenation step is small, the manufacturing method of the present invention makes it easy to compact the manufacturing equipment necessary to produce tafamidis, even when it includes the amidation step and / or the halogenation step. [Examples]

[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 ambient temperature of 0°C. Then, 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 this reaction mixture and separated. The organic layer was washed with 1000 mL of saturated brine, 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 and stirred at an ambient temperature of 0°C for 1 hour. The precipitated solid was filtered off. The filtered solid was dried under reduced pressure at an ambient 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.

[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 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 ambient temperature of 15°C for 19.5 hours. 3480 mL of water was added to the reaction mixture, and the mixture was stirred at an ambient temperature of 0°C for 1 hour, after which the precipitated solid was filtered off. The filtered solid was dried under reduced pressure at an ambient 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] 1H-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 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate ethyl To 50 mL of toluene, 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 above-mentioned N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide, and 4.97 g (36.0 mmol) of potassium carbonate were added, and the mixture was stirred at an ambient temperature of 110°C for 5 hours. To this reaction solution, 25 mL of 10% aqueous ammonium chloride solution and 60 mL of tetrahydrofuran were added and 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 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 ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate and 0.70 g (16.6 mmol) of lithium hydroxide monohydrate were added, and the mixture was stirred overnight at an ambient temperature of 40°C. After cooling the reaction mixture, 48 mL of water and 32 mL of 1 mol / L hydrochloric acid were added, and the precipitated solid was filtered off. The filtered solid was dried under reduced pressure at an ambient 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 slightly 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] Example 2 (Synthesis of Tafamidis) To 50 mL of toluene, 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 procedure as in (1) and (2) of Example 1, and 4.97 g (36.0 mmol) of potassium carbonate were added and stirred overnight at an ambient temperature of 110°C. To this reaction solution, 25 mL of 10% aqueous ammonium chloride solution and 60 mL of tetrahydrofuran were added and 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 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). Next, the same procedure as in Example 1(4) was carried out to obtain tafamidis as a slightly yellowish-white solid in a yield of 87% (78% total yield from ethyl 4-aminobenzoate). The obtained spectral data was consistent with the spectral data described in Example 1(4).

[0093] Example 3 (Synthesis of Tafamidis) To 50 mL of toluene, 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 procedure 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 ambient temperature of 110°C for 5 hours. To this reaction solution, 25 mL of 10% aqueous ammonium chloride solution and 60 mL of tetrahydrofuran were added and 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 to obtain 3.89 g (11.6 mmol, yield 96%) of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate as a gray-yellow solid. The obtained spectral data matched the spectral data described in Example 1(3). Next, the same procedure as in Example 1(4) was carried out to obtain tafamidis as a grayish-white solid in a yield of 87% (78% total yield from ethyl 4-aminobenzoate). The obtained spectral data was consistent with the spectral data described in Example 1(4).

[0094] Example 4 (Synthesis of Tafamidis) To 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 procedure 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 ambient temperature of 110°C for 5 hours. To this reaction solution, 25 mL of 10% aqueous ammonium chloride solution and 60 mL of tetrahydrofuran were added and 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 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 matched the spectral data described in Example 1(3). Next, the same procedure as in Example 1(4) was carried out to obtain tafamidis as a slightly yellowish-white solid in a yield of 90% (80% total yield from ethyl 4-aminobenzoate). The obtained spectral data was consistent with the spectral data described in Example 1(4).

[0095] Example 5 (Synthesis of Tafamidis) To 50 mL of toluene, 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 procedure 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 ambient temperature of 110°C for 24 hours. The reaction conversion rate at this time was 93%. To this reaction solution, 25 mL of 10% aqueous ammonium chloride solution and 60 mL of tetrahydrofuran were added and 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, dissolved at an ambient temperature of 80°C, cooled to room temperature, and the precipitated crystals were filtered off. The crystals were dried under reduced pressure at an ambient 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. Next, the same procedure as in Example 1(4) was carried out to obtain tafamidis as a slightly yellowish-white solid in a yield of 97% (64% total yield from ethyl 4-aminobenzoate). The obtained spectral data was 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 procedure as in Example 1 (1) and (2), except that N-bromosuccinimide was replaced with N-chlorosuccinimide. To 10 mL of toluene, 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 above-prepared N-[2-chloro-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide, and 1.11 g (8.1 mmol) of potassium carbonate were added, and the mixture was stirred at an ambient 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 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 pale yellow solid. The obtained spectral data matched the spectral data described in Example 1(3). Next, the same procedure as in Example 1(4) was carried out to obtain tafamidis as a slightly yellowish-white solid in a yield of 93% (86% total yield from ethyl 4-aminobenzoate). The obtained spectral data was 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 sodium bicarbonate solution was added to this concentrate, and the solid was filtered off. The filtered solid was dried under reduced pressure at an ambient 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.

[0098] 1 H-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 ambient temperature of 20°C for 5 hours. 11.9 mL of ethyl acetate was added to the reaction mixture and separated. The organic layer was washed with saturated brine, 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, after which the solid was filtered off. The filtered solid was dried under reduced pressure at an ambient 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 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate ethyl To 6 mL of toluene, 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 above-mentioned N-[2-iodo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide, and 536 mg (3.88 mmol) of potassium carbonate were added, and the mixture was stirred at an ambient 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 mixture 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 to obtain 360 mg (1.07 mmol, yield 83%) 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). Next, the same procedure as in Example 1(4) was carried out to obtain tafamidis as a slightly yellowish-white solid in a yield of 93% (total yield from 4-amino-3-iodobenzoic acid: 34%). The obtained spectral data was consistent with the spectral data described in Example 1(4).

[0102] Example 8 (Synthesis of Tafamidismeglumine) 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 ambient temperature of 80°C for 1 hour. The mixture was then cooled to an ambient temperature of 10°C, and the precipitated solid was filtered off. The filtered solid was dried under reduced pressure at an ambient temperature of 50°C to obtain 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 Japanese Patent Publication No. 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 ambient temperature of 140°C for 14 hours. After cooling the reaction mixture, 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 with 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 yield was insufficient in the method of Comparative Example 1.

[0106] Test Example 1 The maximum liquid volume (mL) required to obtain 1 g of tafamidis in each step of the methods in Examples 1-7 and Comparative Example 1 was estimated by estimation. In the halogenation and cyclization steps, the liquid volume is maximum immediately before liquid-liquid extraction, so the liquid volume immediately before extraction was used as the maximum liquid volume for estimation. In the esterification, amidation, and hydrolysis steps, the liquid volume is maximum immediately before filtration, so the liquid volume immediately before filtration was used as the maximum liquid volume for estimation. 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 for estimation. Furthermore, among the maximum liquid volumes required to obtain 1 g of tafamidis in each process, the largest volume was recorded as the "maximum value." The smaller the maximum liquid volume required to obtain 1 g of tafamidis in each process, and the smaller the "maximum value" mentioned above, the easier it is to make the manufacturing equipment necessary for producing tafamidis more compact. The results are shown in Table 1.

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

[0108] The total volume of liquid in the hydrolysis step of Example 1 was approximately 164.49 mL. Breakdown: Tetrahydrofuran (64 mL) + Water (16 mL) + 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate ethyl (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 volume of liquid 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 liquid in the cyclization step of Example 1 was approximately 145.48 mL. Breakdown: Toluene (50 mL) + N,N,N',N'-tetramethylethylenediamine (approx. 0.28 mL) + copper(I) iodide (approx. 0.23 mL) + N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide (approx. 5.00 mL) + potassium carbonate (approx. 4.97 mL) + 10% ammonium chloride aqueous solution (25 mL) + tetrahydrofuran (60 mL) The amount of ethyl 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate obtained by this cyclization process is 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 volume of liquid 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 volume of liquid in the amidation step of Example 1 is approximately 7690 mL. Breakdown: 4-amino-3-bromobenzoate ethyl (approx. 290 mL) + tetrahydrofuran (2900 mL) + pyridine (approx. 141 mL) + tetrahydrofuran (580 mL) + 3,5-dichlorobenzoyl chloride (approx. 299 mL) + water (3480 mL) The amount of N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide obtained by this amidation process is 460g, and the amount of N-[2-bromo-4-(ethoxycarbonyl)phenyl]-3,5-dichlorobenzamide required to obtain 1g of tafamidis is 5.00 ÷ 3.99 × 1.26 ≈ 1.58g. Therefore, the maximum volume of liquid required to obtain 1 g of tafamidis in the amidation step of Example 1 is 7690 ÷ 460 × 1.58 ≈ 26 mL.

[0111] The total volume of liquid in the halogenation step of Example 1 is approximately 3418 mL. Breakdown: Ethyl 4-aminobenzoate (approx. 200 mL) + Tetrahydrofuran (1000 mL) + N-bromosuccinimide (approx. 218 mL) + Water (1000 mL) + Ethyl acetate (1000 mL) The amount of ethyl 4-amino-3-bromobenzoate obtained by this halogenation process is 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 volume of liquid required to obtain 1 g of tafamidis in the halogenation step of Example 1 is 3418 ÷ 297 × 0.99 ≈ 11 mL.

[0112] [Table 1]

[0113] As shown in Table 1, by manufacturing using the methods of Examples 1 to 7, the manufacturing equipment required to produce Tafamidis can be made more compact.

[0114] Comparative Example 2 (Synthesis of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylate ethyl) To 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 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 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 pale yellow solid. The yield was insufficient in the method of Comparative Example 2.

[0115] As described above, the yield of the cyclization step in the case of compound (1) cyclization in the presence of bis(1,5-cyclooctadiene)diiridium(I) dichloride (Comparative Example 2) 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, along with a base and an amine ligand (Examples 1-7), the yield of the cyclization step was 71-100%. Here, it was thought that iridium catalysts were more useful than copper catalysts such as copper iodide catalysts for improving the efficiency of such CO coupling cyclization (Tetrahedron Letters 2019, 60, 151082), so it was surprising that such a significant improvement in yield was observed when using one or more copper catalysts selected from copper halides, copper carboxylates, copper sulfates, and copper oxides, along with a base and an amine ligand, as described above.

[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 Japanese Patent Publication No. 2021-517118. Specifically, 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, and the mixture was stirred for 40 minutes at room temperature. 258 mL of 0.2 mol / L hydrochloric acid was added to the reaction mixture, the precipitate was filtered off, and the mixture was dried under reduced pressure at an ambient temperature of 50°C. 98 mL of 0.5 mol / L aqueous sodium hydroxide solution was added to the obtained solid and the mixture was stirred at room temperature, and the insoluble matter was filtered off 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 2-3. The precipitate was filtered off and dried under reduced pressure at an ambient temperature of 50°C. 122 mL of 1-butanol was added to the obtained solid, and the mixture was refluxed at 120°C for 7 hours. After stirring overnight at 70°C, the solid was filtered off. The obtained solid was dried under reduced pressure at 50°C to obtain 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 Japanese Patent Publication No. 2021-517118. Specifically, 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. The mixture was stirred at room temperature for 1 hour. 1.59 g (15.7 mmol) of triethylamine was added to this 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 off. A 0.5 mol / L aqueous sodium hydroxide solution was added to the obtained solid, and the mixture was stirred at room temperature. Insoluble matter was filtered off by filtration. The solution was washed with 100 mL of dichloromethane, and 30 mL of 1 mol / L hydrochloric acid and 130 mL of acetonitrile were added to the aqueous layer. The precipitate was filtered off, and the mixture was dried under reduced pressure at an ambient temperature of 50°C to obtain N-[2-hydroxy-4-carboxyphenyl]-3,5-dichlorobenzamide as a grayish-white solid. The yield was approximately 65%, similar to the description in Japanese Patent Publication No. 2021-517118.

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) to obtain a compound represented by the following formula (2) 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. 【Chemistry 1】 [In formula (1), R 1 This represents a linear or branched alkyl group. X represents a halogen atom. 【Chemistry 2】 [In formula (2), R 1 This is synonymous with the above.

2. The manufacturing method according to claim 1, further comprising an amidation step of reacting a compound represented by the following formula (3) with a compound represented by the following formula (4) in the presence of a base, wherein the compound represented by formula (1) obtained in the step is used in the cyclization step. 【Transformation 3】 [In formula (3), Y represents a halogen atom.] 【Chemistry 4】 [In formula (4), R 1 And X is synonymous with the above.

3. The manufacturing method according to claim 2, further comprising a halogenation step of halogenating a compound represented by the following formula (5), wherein the compound represented by formula (4) obtained in the step is used in the amidation step. 【Transformation 5】 [In formula (5), R 1 This is synonymous with the above.

4. The manufacturing method according to claim 2, further comprising an esterification step of dehydrating and condensing a compound represented by the following formula (11) and a compound represented by the following formula (12), wherein the compound represented by formula (4) obtained in the step is used in the amidation step. 【Transformation 6】 [In equation (11), X is the same as described above.] 【Transformation 7】 [In formula (12), R 1 This is synonymous with the above.

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

6. The manufacturing method according to any one of claims 1 to 4, 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 are used as the copper catalyst.

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

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

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

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

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

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