JP2008044932A - Composition containing thiazolidinedione compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine containing a thiazolidinedione derivative having excellent preventing and treating action on diseases caused by insulin resistance. <P>SOLUTION: The invention provides a method for producing a compound expressed by formula (A) (R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>and R<SP>4</SP>are each independently hydrogen atom, hydroxyl group, 1-6C alkyl group, 1-6C alkoxyl group, benzyloxy group, acetoxy group, trifluoromethyl group or halogen atom; and R<SP>5</SP>is 1-6C alkyl group) or its salt, and a pharmaceutical composition containing the crystal of the compound. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a high-purity thiazolidinedione compound having an excellent preventive and therapeutic action for diseases caused by insulin resistance and a pharmaceutical composition containing the crystal thereof.

  Thiazolidinedione derivatives are known to activate PPAR (peroxisome proliferator-activated receptor) γ, and diabetes (especially type 2 diabetes), hyperglycemia, glucose intolerance, hypertension, hyperlipidemia It has preventive and therapeutic effects on diseases caused by insulin resistance such as diabetes complications, diabetes complications, polycystic ovary syndrome, and cardiovascular diseases such as atherosclerosis. (For example, see Patent Documents 1, 2, and 3).

In addition, regarding these production methods, several methods through different intermediates are disclosed (see Patent Documents 1 and 4). For example, Patent Document 4 discloses the following production method (partial modification of the compound number in the formula of JP-A-2001-72671. In the formula, R ^1B is a C1-C6 alkyl group or a C1-C6 alkoxy group. R ^2B represents a C1-C6 alkyl group, and R ^3B represents a hydrogen atom or a protecting group).

Patent Document 4 describes that the 1,2-phenylenediamine derivative represented by the general formula (2) and the compound (3) are subjected to a condensation reaction in the presence of a condensing agent. Specifically, there is a description of a production example of a compound represented by the general formula (4) in which R ^1B is a methoxy group, R ^2B is a methyl group, and R ^3B is a t-butoxycarbonyl group. The reaction yield was 85% and there was room for further improvement. In addition, in order to decompose propylphosphonic acid cyclic anhydride used excessively as a condensing agent, a complicated operation such as extraction operation after adding 5% aqueous sodium hydrogen carbonate solution to the reaction mixture after completion of the reaction is required. These operations are one of the causes of the decrease in yield and purity.

  On the other hand, {4-[(2,4-dioxo-1,3-thiazolidin-5-yl) methyl] phenoxy} acetic acid (above (3)) by condensation with a phenylenediamine compound (eg, (2) above) A production method using a halide has not been known at all. The reason is that a compound having a 1,3-thiazolidine-2,4-dione skeleton similar to {4-[(2,4-dioxo-1,3-thiazolidin-5-yl) methyl] phenoxy} acetic acid is oxidized. There is a report that a 2,4-dichlorothiazol derivative is produced when it is treated with a halogenating agent such as phosphorus chloride (for example, see Non-Patent Documents 1 and 2). That is, when the halogenating agent is reacted with {4-[(2,4-dioxo-1,3-thiazolidin-5-yl) methyl] phenoxy} acetic acid, the target acid halide This is because it was thought that a compound in which the ring portion of the thiazole ring was halogenated was mainly produced or by-produced.

  Moreover, organochlorine solvents such as dichloromethane are widely used as solvents at the laboratory level because of their ease of use. However, since there is a suspicion such as toxicity, an industrial production method using a large amount of a solvent requires a synthesis method not using dichloromethane.

Further, Japanese Patent Application No. 2006-15412 can be cited as a prior application, which is an application relating to a production method and a crystal form. On the other hand, the present application is an application relating to the pharmaceutical use of the compound and crystal obtained by the production method described in Japanese Patent Application No. 2006-15412, and the subject matter of this application is different from that of Japanese Patent Application No. 2006-15412.
JP-A-9-95970 JP 2001-39976 International Publication No. 00/71540 Pamphlet JP 2001-72671 A Journal of Chemical Society, Perkin Transaction I [J. Chem. Soc. Perkin I] (UK), 1992, pp. 973-978 Bioorganic and Medicinal Chemistry Letters [Bioorganic Med. Chem. Lett.] (UK), Volume 14, pages 235-238 (2004)

  Substances used in pharmaceuticals are required to have particularly high purity so that unexpected side effects (for example, toxicity and the like) due to the impurities do not occur. Further, in the industrial production method (mass production method), it is required to remove impurities by a simpler operation.

  In addition, it is important that the drug substance can be stored for a long time while maintaining its quality. Finding stable crystals that can be stored at room temperature or above is industrially meaningful because large refrigeration facilities are required to maintain quality when storage conditions are required to be low. is there.

  Therefore, the present inventors have developed a disease caused by insulin resistance (preferably diabetes, hyperglycemia, glucose intolerance, hypertension, hyperlipidemia, diabetic complications, gestational diabetes mellitus, polycystic ovary syndrome). Thiazolidine having an excellent preventive and therapeutic action for diabetes, hyperglycemia, glucose intolerance, particularly preferably diabetes, and most preferably type 2 diabetes) As a result of earnest research for the purpose of developing a method to produce dione derivatives with higher quality, higher yield, industrially more advantageous operation method and less environmental impact, it is a novel synthetic intermediate Reactions using {4-[(2,4-dioxo-1,3-thiazolidin-5-yl) methyl] phenoxy} acetic acid halides and decomposition of synthetic intermediate compounds with higher purity and superior stability over time High recovery rate without letting It found a novel purification method of, thereby establishing a method for producing a high-quality, high yield and industrially advantageous operation of thiazolidinedione derivatives, the present invention has been completed. In addition, a series of reactions have been established up to a method that does not use an organic chlorine-based solvent such as dichloromethane.

  Furthermore, crystals of high-purity 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride are the drug substance. As a result, the present invention was completed.

  Hereinafter, the present invention will be described in detail.

The present invention
(1) In powder X-ray diffraction obtained by irradiation of copper with Kα rays, the surface spacing d = 14.29, 7.12, 5.34, 4.97, 4.74, 3.95, 3.85, 3.75, 3.55, 3.51, 3.15, 2.84, 2.76, 2.52 and From 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride, characterized by a main peak at 2.37 A pharmaceutical composition containing the crystal as an active ingredient,
(2) 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione Hydrochloride content is 98 wt. % Or more, in the powder X-ray diffraction obtained by irradiation of copper Kα rays, the surface spacing d = 14.29, 7.12, 5.34, 4.97, 4.74, 3.95, 3.85, 3.75, 3.55, 3.51, 3.15, 2.84, 2.76, 2.52 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride, characterized by showing a main peak at 2.37 A pharmaceutical composition comprising the composition of the crystal as an active ingredient,
(3) 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione Hydrochloride content is 99 wt. % Or more, in the powder X-ray diffraction obtained by irradiation of copper Kα rays, the surface spacing d = 14.29, 7.12, 5.34, 4.97, 4.74, 3.95, 3.85, 3.75, 3.55, 3.51, 3.15, 2.84, 2.76, 2.52 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride, characterized by showing a main peak at 2.37 A pharmaceutical composition comprising the composition of the crystal as an active ingredient,
(4) 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione Hydrochloride content is 98 wt. % Of purified 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride as an active ingredient A pharmaceutical composition
(5) 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione Hydrochloride content is 99 wt. % Of purified 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride as an active ingredient A pharmaceutical composition
(6) The following general formula (III)

[Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and are a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a benzyloxy group, an acetoxy group, a trifluoromethyl group. Alternatively, it represents a halogen atom, R ⁵ represents a C1-C6 alkyl group, and R ⁶ represents an amino-protecting group. ] By adding an organic solvent (the organic solvent is selected from alcohols, ethers, nitriles or a mixed solvent thereof) to the compound represented by After purification, which is characterized by removing the substance, the purified product is treated with an acid and cyclized to an imidazole ring.

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same meaning as described above. A thiazolidinedione compound represented by the above or a pharmacologically acceptable salt thereof as an active ingredient,
(7) The following general formula (I) obtained by reacting 4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetic acid with a halogenating agent

  [Wherein X represents a halogen atom. Or a salt thereof represented by the following general formula (II)

[Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and are a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a benzyloxy group, an acetoxy group, a trifluoromethyl group. Alternatively, it represents a halogen atom, R ⁵ represents a C1-C6 alkyl group, and R ⁶ represents an amino-protecting group. By reacting with a compound represented by the following general formula (III)

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meaning as described above. Or a salt thereof, and purify the product by refluxing a suspension or solution of the organic solvent (the organic solvent is selected from alcohols, ethers, nitriles, or a mixed solvent thereof). Then, the compound represented by the general formula (A) obtained by cyclization to an imidazole ring by treatment with an acid

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same meaning as described above. A thiazolidinedione compound represented by the above or a pharmacologically acceptable salt thereof as an active ingredient,
(8) The thiazolidinedione compound represented by the general formula (A) is 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4 -A pharmaceutical composition comprising the thiazolidinedione compound or a pharmacologically acceptable salt thereof according to (6) or (7) as an active ingredient, which is a dione,
(9) The above (1) for the prevention or treatment of diabetes, hyperglycemia, glucose intolerance, hypertension, hyperlipidemia, diabetic complications, gestational diabetes, polycystic ovary syndrome or atherosclerosis To (8) the pharmaceutical composition according to any one of (1) to (8), more preferably for the prevention or treatment of diabetes, hyperglycemia, glucose intolerance, diabetic complications or gestational diabetes (8) The pharmaceutical composition according to any one of
(10) The pharmaceutical composition according to any one of (1) to (8) above for preventing or treating diabetes,
(11) The pharmaceutical composition according to the above (10), wherein the diabetes is type 2 diabetes,
(12) The pharmaceutical composition according to any one of (1) to (8) above for improving insulin resistance,
(13) In powder X-ray diffraction obtained by irradiation with copper Kα rays for producing the pharmaceutical composition according to any one of (1) to (12) above, the interplanar spacing d = 14.29, 7.12, 5- {4-[(6-methoxy-1-methyl), characterized by showing main peaks at 5.34, 4.97, 4.74, 3.95, 3.85, 3.75, 3.55, 3.51, 3.15, 2.84, 2.76, 2.52 and 2.37 Use of crystals consisting of -1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride,
(14) In powder X-ray diffraction obtained by irradiation with copper Kα rays for producing a pharmaceutical composition for the prevention or treatment of diabetes, the interplanar spacing d = 14.29, 7.12, 5.34, 4.97, 4.74, 3.95, 3.85, 3.75, 3.55, 3.51, 3.15, 2.84, 2.76, 2.52 and 2.37 are characterized by showing main peaks, 5- {4-[(6-methoxy-1-methyl-1H-benzimidazole-2- Ir) methoxy] benzyl} thiazolidine-2,4-dione Hydrochloric acid irradiation of copper to produce a pharmaceutical composition for the prevention or treatment of type 2 diabetes In the powder X-ray diffraction obtained in the above, it is characterized by having main peaks at interplanar spacings d = 14.29, 7.12, 5.34, 4.97, 4.74, 3.95, 3.85, 3.75, 3.55, 3.51, 3.15, 2.84, 2.76, 2.52 and 2.37 A crystal comprising 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride Use of,
(15) A method for preventing or treating diabetes, and more preferably, preventing or treating type 2 diabetes, comprising administering the pharmaceutical composition according to any one of (1) to (12) above Is the method.

In the present invention, the “content” is a value (% by weight) measured by quantitative analysis (preferably, quantitative analysis shown in Example 8-2).

In the present invention, the “C1-C6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t- Butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2- Examples include dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl groups. R ¹ , R ² , R ³ , R ⁴ and R ⁵ are preferably a C1-C4 alkyl group, more preferably an ethyl or methyl group, and particularly preferably a methyl group.

In the present invention, the `` C1-C6 alkoxy group '' is a group in which the C1-C6 alkyl group is bonded to an oxygen atom. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t- Butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, 1-ethylpropoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2- Examples include dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy or 2-ethylbutoxy groups. R ¹ , R ² , R ³ and R ⁴ are preferably C1-C4 alkoxy groups, more preferably ethoxy or methoxy groups, and particularly preferably methoxy groups.

In the present invention, the “halogen atom” is a fluorine, chlorine, bromine or iodine atom. R ¹ , R ² , R ³ , R ⁴ and X are preferably fluorine, chlorine or bromine atoms, and more preferably chlorine.

In the present invention, the “amino-protecting group” is not particularly limited as long as it is usually used as an amino-protecting group. For example, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl, benzyl, methyl C1-C6 alkyl such as benzyl, methoxybenzyl, chlorobenzyl, bromobenzyl or naphthylmethyl group, arylmethyl group optionally substituted with C1-C6 alkoxy or halogen, benzyloxycarbonyl, methylbenzyloxycarbonyl, methoxybenzyl Aryl-methyloxyalkyl optionally substituted with C1-C6 alkyl, C1-C6 alkoxy or halogen such as oxycarbonyl, chlorobenzyloxycarbonyl, bromobenzyloxycarbonyl or naphthylmethyloxycarbonyl Examples thereof include an alkenyloxycarbonyl group such as a rubonyl group, allyloxycarbonyl or methallyloxycarbonyl group, or an alkyloxycarbonyl group such as t-butoxycarbonyl group. R ⁶ is preferably t-butoxycarbonyl, benzyl, p-methoxybenzyl, p-bromobenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-bromobenzyloxycarbonyl or allyloxycarbonyl group, More preferred is t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-bromobenzyloxycarbonyl or allyloxycarbonyl group, and particularly preferred is t-butoxycarbonyl group.

R ¹ is preferably a hydrogen atom or a C1-C4 alkoxy group, more preferably a hydrogen atom or a methoxy group, and particularly preferably a hydrogen atom.

R ² is preferably a hydrogen atom or a C1-C4 alkoxy group, more preferably a hydrogen atom or a methoxy group, and particularly preferably a hydrogen atom.

R ³ is preferably a hydrogen atom or a C1-C4 alkoxy group, more preferably a hydrogen atom or a methoxy group, and particularly preferably a methoxy group.

R ⁴ is preferably a hydrogen atom or a C1-C4 alkoxy group, more preferably a hydrogen atom or a methoxy group, and particularly preferably a hydrogen atom.

R ⁵ is preferably a C1-C4 alkyl group, more preferably a C1-C2 alkyl group, and particularly preferably a methyl group.

R ⁶ is preferably a t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl group, more preferably t-butoxycarbonyl.

  X is preferably a chlorine atom.

The method for producing the synthetic intermediate (I), synthetic intermediate (III), final target compound (A) and salt thereof of the present invention will be described in detail below.

The method of the present invention is a first step of producing an acid halide represented by compound (I) by reacting 4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetic acid with a halogenating agent. The second step of producing compound (III) by reacting compound (I) and compound (II), the third step of purifying compound (III), and compound (III) to compound (A) in the presence of an acid It consists of the 4th process to convert. Each step will be described in detail below.

(First step)
This step is a step for producing an acid halide (I), and reacting 4-[(2,4-dioxothiazolidine-5-yl) methyl] phenoxyacetic acid with a halogenating agent in an inert solvent. Is achieved.

  The halogenating agent used in this step is not particularly limited as long as it can convert a carboxylic acid into an acid halide. Examples of such a halogenating agent include thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride and the like, and preferably thionyl chloride, oxalyl chloride, phosphorus pentachloride and the like. Particularly preferred is thionyl chloride.

  The amount of the halogenating agent used in this step is not particularly limited as long as it is 1 equivalent or more with respect to 4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetic acid to be used. To 2 equivalents, more preferably 1 to 1.2 equivalents.

  In this step, the reaction is usually performed in a solvent. When using a solvent, there is no particular limitation as long as it does not inhibit the reaction. Examples of such solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin, or petroleum ether, aromatic hydrocarbons such as benzene, toluene, and xylene, acetonitrile, propionitrile, and benzonitrile. Nitriles, dichloromethane, chloroform, 1,2-dichloroethane, halogenated hydrocarbons such as carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethers such as diethylene glycol dimethyl ether, formamide, Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, sulfoxides such as dimethyl sulfoxide, sulfolane, and mixtures thereof, preferably halogenated carbon Hydrides, nitriles, ethers or amides, and mixtures thereof, more preferably acetonitrile, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide or mixtures thereof, particularly preferably dichloromethane or acetonitrile. .

  In this step, the reaction may proceed more rapidly by adding a catalyst.

  When a catalyst is added, an amine, an amine derivative or a nitrogen-containing heterocyclic compound is usually used as the catalyst. When an amine is used, a tertiary amine is usually used. Examples of such amines include trialkylamines such as trimethylamine, triethylamine, diisopropylethylamine or tributylamine, N, N-dimethylaniline, N, N-diethylaniline and the like. Or diarylalkylamines such as diphenylmethylamine. Examples of amine derivatives include N, N-dialkylamides such as dimethylformamide and dimethylacetamide. Examples of nitrogen-containing heterocyclic compounds include pyridine, N, N-dimethyl-4-aminopyridine, imidazole, and triazole. Preferred are trimethylamine, triethylamine, diisopropylethylamine, tributylamine, N, N-dimethylaniline, dimethylformamide or dimethylacetamide, pyridine, N, N-dimethyl-4-aminopyridine, more preferably triethylamine, dimethylformamide, Pyridine or N, N-dimethyl-4-aminopyridine, particularly preferably dimethylformamide.

  The amount of the catalyst used is not particularly limited, but is usually 0.01 to 20 equivalents, preferably 0.1 to 10 equivalents, more preferably 0.3 to 5 equivalents, relative to the halogenating agent used. The reaction temperature in this step varies depending on the raw material compounds, reagents and the like, but is usually −20 ° C. to 150 ° C., preferably −10 ° C. to 100 ° C., more preferably −10 to 40 ° C.

  The reaction time in this step varies depending on the raw material compound, reagent, reaction temperature, etc., but is usually 30 minutes to 80 hours, preferably 30 minutes to 48 hours, and more preferably 1 hour to 6 hours. is there.

After completion of this step, compound (I) or a salt thereof may be isolated and then the second step may be performed, or the second step may be performed without isolation, and preferably not isolated. It is better to carry out the second step.
(Second step)
This step is a step for producing compound (III), and is achieved by reacting acid halide (I) with a known phenylenediamine compound (II) in an inert solvent.

  If a base is used in this step, the reaction may proceed rapidly. When a base is used in this step, examples of the base used include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. Salts, alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium methoxide, sodium methoxide Alkali metal alkoxides such as sodium ethoxide, potassium t-butoxide, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline , N, N-diethylaniline, 1,5-diazabi Organic amines such as b [4.3.0] nano-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) And preferably organic amines, more preferably triethylamine, tributylamine or pyridine, and particularly preferably triethylamine.

  This step is usually performed in a solvent. The solvent is not particularly limited as long as it does not inhibit the reaction. Examples of such solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin, or petroleum ether, aromatic hydrocarbons such as benzene, toluene, and xylene, acetonitrile, propionitrile, and benzonitrile. Nitriles, dichloromethane, chloroform, 1,2-dichloroethane, halogenated hydrocarbons such as carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethers such as diethylene glycol dimethyl ether, formamide, Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, and mixtures thereof; Preferred are halogenated hydrocarbons, nitriles, ethers or amides, and mixtures thereof, more preferred are acetonitrile, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide or mixtures thereof, and particularly preferred are dichloromethane or Acetonitrile.

  The reaction temperature in this step varies depending on the raw material compounds, reagents and the like, but is usually −20 ° C. to 150 ° C., preferably −20 ° C. to 100 ° C.

  The reaction time in this step varies depending on the raw material compound, reagent, reaction temperature and the like, but is usually 30 minutes to 80 hours. It is preferably 1 to 48 hours.

After completion of the reaction in this step, compound (III) is isolated by an isolation operation such as natural crystallization or extraction and concentration after the usual post-treatment, and then the third step or the fourth step is performed.
(Third process)
In this step, compound (III) is heated and stirred in an organic solvent, dissolved or suspended, and then cooled to remove impurities by recrystallization or resuspension to produce compound (III) with higher purity. However, when the compound (III) is not a crystal or has a sufficiently high purity, this step can be omitted.

  This step is performed in a solvent. The solvent is not particularly limited as long as it does not react with compound (III) and dissolves to some extent. Examples of such solvents include alcohols such as methanol, ethanol, propanol, isopropyl alcohol, and butyl alcohol, nitriles such as acetonitrile, propionitrile, and benzonitrile, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane and diethylene glycol dimethyl ether, and mixtures thereof, preferably acetonitrile, methanol, ethanol, or a mixture thereof, and particularly preferably methanol.

  The heating temperature in this step varies depending on the properties of compound (III) and the solvent, but is usually room temperature to the reflux temperature of the solvent used, and preferably the reflux temperature of the solvent used.

  The time for this step varies depending on the properties of the compound (III) and the solvent, but is usually 10 minutes to 20 hours, preferably 20 minutes to 10 hours.

After the completion of this step, the compound (III) is isolated by filtration after a normal crystallization operation, and then the fourth step is performed.
(Fourth process)
This step is a step for producing the final target compound (A), and is achieved by cyclizing the compound (III) in the presence of an acid.

  This step is performed in a solvent. The solvent is not particularly limited as long as it does not react with compound (III) and dissolves to some extent. Examples of such solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin, or petroleum ether, aromatic hydrocarbons such as benzene, toluene, and xylene, methanol, ethanol, propanol, and isopropyl alcohol. , Alcohols like butyl alcohol, nitriles like acetonitrile, propionitrile, benzonitrile, halogenated hydrocarbons like dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, diethyl ether, diisopropyl ether Ethers such as tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and mixtures thereof, preferably halogenated hydrocarbons, nitriles, alcohols, ethers and the like More preferred are dichloromethane, chloroform, acetonitrile, methanol, ethanol, or a mixture thereof, and particularly preferred is methanol.

  As the acid used in this step, either Bronsted acid or Lewis acid may be used, but usually Bronsted acid is used. The Bronsted acid usually used in this step is not particularly limited, but examples thereof include inorganic acids such as hydrogen chloride, hydrogen bromide, hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid and boric acid, formic acid, acetic acid and propionic acid. , Oxalic acid, succinic acid, maleic acid, hydroxyacetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, salicylic acid and the like, preferably hydrochloric acid, sulfuric acid, acetic acid, citric acid, tartaric acid, and more preferably Is hydrochloric acid and sulfuric acid, and hydrochloric acid is particularly preferred.

  When the compound (A) is produced as a salt in this step, the acid of the salt to be produced can be used as it is to obtain a corresponding salt.

  Although there will be no limitation in particular if the quantity of the acid used at this process is 1 equivalent or more with respect to compound (III) to be used, it is 1-15 equivalent suitably, More preferably, it is 2-8 equivalent.

  When compound (III) is dissolved in the solvent in this step, inorganic or organic hardly soluble impurities mixed in compound (III) can be removed by performing a filtration operation before adding the acid.

  The reaction temperature in this step varies depending on the properties of the compound (III), acid and solvent, but is usually room temperature to 100 ° C, preferably 35 ° C to 80 ° C, more preferably 40 ° C to 60 ° C. is there.

  While the reaction time in this step varies depending on the properties of compound (III), acid and solvent, it is generally 30 min to 20 hr, preferably 1 hr to 10 hr.

  When the compound (A) or a salt thereof crystallizes as crystals after completion of the reaction in this step, it can be isolated by a filtration operation. When the compound (A) or a salt thereof does not become a crystal, it can be isolated by an isolation operation such as an extraction operation after usual post-treatment. The obtained compound (A) may be used as it is after drying, or may be used after carrying out usual purification operations such as recrystallization and column chromatography.

The high-purity thiazolidinedione compound of the present invention and a medicine containing the crystal thereof can be used in preparations that can be administered orally, such as tablets, capsules, pills, granules, or fine granules. , Tablets.

  The said formulation may contain a pharmaceutically acceptable additive suitably. Such additives include, for example, excipients (eg sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; corn starch, potato starch, pregelatinized starch, dextrin, carboxymethyl starch, carboxymethyl starch sodium Starch derivatives such as: pregelatinized starch; cellulose such as crystalline cellulose, methylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carmellose, carmellose calcium, croscarmellose, croscarmellose sodium Derivatives; gum arabic; dextran; pullulan; light anhydrous silicic acid, calcium silicate, silicic acid hydrate, synthetic aluminum silicate, metasilicic acid aluminate Silicate derivatives such as gnesium; phosphate derivatives such as dicalcium phosphate; chloride derivatives such as sodium chloride; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate; ), Binders (eg, compounds exemplified in the above excipients; gelatin; polyvinylpyrrolidone; macrogol; or mixtures thereof), disintegrants (eg, compounds exemplified in the above excipients; cross-linked polyvinyl Pyrrolidone; or mixtures thereof), lubricants (eg, stearic acid; metal stearates such as calcium stearate and magnesium stearate; metal benzoates such as sodium benzoate; waxes such as bee gum and gay wax) Boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium sulfate Metal sulfates such as thorium; leucine; metal lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicate derivatives exemplified by the above excipients; starch derivatives exemplified by the above excipients; hydrogen Carnauba wax; sucrose fatty acid esters; or mixtures thereof), stabilizers (eg, benzoic acid; benzoic acid metal salts such as sodium benzoate; paraoxybenzoic acid esters such as methylparaben and propylparaben; chlorobutanol; Alcohols such as benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid; or a mixture thereof], fluidizing agents (for example, the above-mentioned shaping) Silicate derivatives exemplified by the agent; Or mixtures thereof), surfactants (eg, polysorbates such as polysorbate 80; polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 60; sorbitan fatty acid esters; sucrose fatty acid esters; poly; Oxyethylene polyoxypropylene glycols; polyoxyethylene fatty acid ethers; stearic acid polyoxyls; or mixtures thereof, preferably polysorbate 80, polyoxyethylene hydrogenated castor oil 60 or mixtures thereof), colorants (eg, Yellow iron sesquioxide, iron sesquioxide, black iron oxide), antioxidants, flavoring agents (for example, commonly used sweeteners, acidulants, flavorings, etc.) or additives that can be used and diluents The type and amount depends on the tablet, capsule or other dosage form drug It is selected to a known art formulations fields.

  For example, in the case of tablets, the content of the binder is usually 1 to 10 parts by weight (preferably 2 to 5 parts by weight) in the total drug composition, and the content of the disintegrant is usually 1 To 40 parts by weight (preferably 5 to 30 parts by weight), and the lubricant content is usually 0.1 to 10 parts by weight (preferably 0.5 to 3 parts by weight). The content is 0.1 to 10 parts by weight (preferably 0.5 to 5 parts by weight).

  The pharmaceutical composition of the present invention is easily produced by a known method (for example, a kneading method using water, a wet granulation method, etc.) using a pharmaceutically acceptable additive. Examples of such production include, for example, the addition of active ingredients, stabilizers, excipients, binders, disintegrants and other types of auxiliaries as required, and mixing with a high speed agitation granulator. Then, an aqueous solution of a binder is added to the obtained mixture and kneaded to obtain a granulated product. The obtained granulated product is dried using a fluidized bed drying apparatus, and the dried granulated product is forced to pass through a screen using a crushing granulator and a lubricant, a disintegrant. If necessary, other types of auxiliaries and the like may be added and mixed in a V-type mixer, and the resulting mixture may be tableted or filled into capsules to produce tablets or capsules, respectively. it can.

  The obtained tablet can be sugar-coated or coated (preferably, coated) as necessary. For example, by spraying the obtained tablet with a coating solution consisting of hydroxypropylmethylcellulose, talc, titanium oxide, lactose, triacetin or polyethylene glycol, yellow iron or iron dioxide, and water in a pan coating machine. Film coating can be applied.

  Moreover, after mixing with the high-speed agitation granulator and adding the aqueous solution of the binder and kneading, the kneaded product is granulated with an extrusion granulator, and then with a fence dryer. Granules can be produced by forcing the dried granules to pass through a screen using a crushing and granulating machine.

The pharmaceutical composition of the present invention can be administered to warm-blooded animals (particularly humans) and is an active ingredient, 5- {4- (6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy) benzyl } The dose of thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof can vary depending on various conditions such as patient's symptoms, age, body weight, etc. / body to 20 mg / body (preferably 0.5 mg / body to 3 mg / body) can be administered to humans 1 to 6 times per day (preferably 1 or 2 times) depending on symptoms. .

The present invention provides crystals of thiazolidinedione derivatives having an excellent preventive and therapeutic action for diseases caused by known insulin resistance, and a production method suitable for mass synthesis thereof. By using the production method of the present invention, a target compound can be produced by a simple operation using a low-priced reagent with high yield and high purity even in a large-scale synthesis, and with a small environmental load.

  Examples and the like of the present invention will be described below in more detail, but the scope of the present invention is not limited thereto.

(Example 1)
4-[(2,4-Dioxothiazolidine-5-yl) methyl] phenoxyacetic acid chloride
4-[(2,4-Dioxothiazolidine-5-yl) methyl] phenoxyacetic acid (220 mg, 0.78 mmol) in dichloromethane (10 ml) at room temperature at thionyl chloride (170 mg, 1.34 mmol), then pyridine (1 drop) was added and refluxed for 3.5 hours. The resulting solution was concentrated under reduced pressure to obtain about 250 mg of the gummy target compound.
Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ) δ (ppm): 3.05 (1H, dd, J = 9.0 Hz, J = 14.1 Hz, CH ₂ CH), 3.31 (1H, dd, J = 4.1 Hz, J = 14.1 Hz, CH ₂ CH), 4.64 (2H, s, CH ₂ O), 4.87 (1H, dd, J = 4.1 Hz, J = 9.0 Hz, CH ₂ CH), 6.85 (2H, d, J = 8.6 Hz, aromatic), 7.16 (2H, J = 8.6 Hz, aromatic), 12.02 (1H, s, NH).
(Example 2)
N- {2- {4-[(2,4-Dioxothiazolidine-5-yl) methyl] phenoxyacetylamino} -5-methoxyphenyl} -N-methylcarbamate tert-butyl
To a suspension of 4-[(2,4-dioxothiazolidine-5-yl) methyl] phenoxyacetic acid (60.0 g, 213.3 mmol) in dichloromethane (390 ml) was added thionyl chloride (27.66 g, 232.5 mmol), dimethylformamide ( 12 ml) was added and warmed to reflux (up to 39 ° C). After complete dissolution, the mixture was stirred for 30 minutes and cooled to 0-5 ° C. A solution of tert-butyl N- (2-amino-5-methoxyphenyl) -N-methylcarbamate (53.84 g, 213.4 mmol) and triethylamine (25.92 g, 256.2 mmol) in dichloromethane (624 ml) while maintaining the internal temperature at 5 ° C. or lower. Was dripped. The reaction was stirred at 5 ° C. for 1 hour, then dichloromethane (300 ml) was added, then a solution prepared from sodium bicarbonate (24 g) and water (480 ml) was added and stirred at 20 ° C. for 20 minutes, After standing, liquid separation was performed, and the aqueous layer was discarded. Water (480 ml) was added to the organic layer, and the mixture was stirred at 20 ° C. for 20 minutes, allowed to stand and separated, and the aqueous layer was discarded. A solution of 38% hydrochloric acid (19.8 ml) and water (480 ml) was poured into the organic layer and stirred at 20 ° C. for 20 minutes. The aqueous layer was discarded, and activated carbon (1.8 g) and dichloromethane (18 ml) were added to the organic layer. After stirring for 30 minutes, the activated carbon was filtered. The residue was washed with dichloromethane (90 ml), and the filtrate and washings were combined and concentrated under reduced pressure to an amount of 300 ml at an internal temperature of 25 ° C. After stirring at normal pressure for 10 minutes, methanol (300 ml) was added, and the mixture was concentrated under reduced pressure to an amount of 300 ml at an internal temperature of 25 ° C. Further, methanol (300 ml) was added, and the mixture was concentrated under reduced pressure at an internal temperature of 30 ° C. to a liquid volume of 300 ml. Methanol (198 ml) was added thereto, cooled to 0-5 ° C., and further stirred for 1 hour. The obtained crystals were filtered off, washed with cold methanol (240 ml), dried under reduced pressure at 50 ° C., and N- {2- {4-[(2,4-dioxothiazolidine-5-yl) methyl] phenoxy Acetylamino} -5-methoxyphenyl} -N-methylcarbamate tert-butyl was obtained (97.09 g, 188.3 mmol) (yield 89%).
(Example 3)
N- {2- {4-[(2,4-Dioxothiazolidine-5-yl) methyl] phenoxyacetylamino} -5-methoxyphenyl} -N-methylcarbamate tert-butyl
Acetonitrile (400 ml) was added to 4-[(2,4-dioxothiazolidine-5-yl) methyl] phenoxyacetic acid (40.0 g, 142.2 mmol), and the mixture was cooled to an internal temperature of 7 ° C., and then thionyl chloride (18.4 g, 155.0 mmol) was added. Dimethylformamide (32 ml) was further added, and the mixture was stirred at the same temperature to 11.4 ° C. for 3 hours.

Here, tert-butyl N- (2-amino-5-methoxyphenyl) -N-methylcarbamate (38.4 g, 137.9 mmol) and triethylamine (18.7 g, 184.9 mmol) in acetonitrile ( 240 ml) The solution was added dropwise over 65 minutes while cooling so that the reaction temperature was maintained at 0 to 5 ° C., and the mixture was further stirred at the same temperature for 2 hours. Next, water (320 ml) was added over 15 minutes, and the mixture was stirred at an internal temperature of 0 to 5 ° C. for 2.5 hours. The obtained crystals were washed with acetonitrile: water = 2: 1 solution (160 ml), dried under reduced pressure at 50 ° C. for 19 hours, and N- {2- {4-[(2,4-dioxothiazolidine-5 Crystals of tert-butyl (-yl) methyl] phenoxyacetylamino} -5-methoxyphenyl} -N-methylcarbamate (63.6 g, 123.4 mmol) were obtained (yield 89%).
Example 4
N- {2- {4-[(2,4-Dioxothiazolidin-5-yl) methyl] phenoxyacetylamino} -5-methoxyphenyl} -N-methylcarbamate tert-butyl (4-1)
(In this example, 4-[(2,4-dioxothiazolidine-5-yl) methyl] phenoxyacetic acid and N- (2-amino-5-methoxyphenyl) of the same lot used in Example 3 were used. ) -N-methylcarbamate tert-butyl was used.)
Acetonitrile (400 ml) was added to 4-[(2,4-dioxothiazolidine-5-yl) methyl] phenoxyacetic acid (40.0 g, 142.2 mmol), and the mixture was cooled to an internal temperature of 8 ° C., and then thionyl chloride (18.4 g, 155.0 mmol) was added. Dimethylformamide (32 ml) was further added, and the mixture was stirred at the same temperature to 12 ° C. for 3 hours. Here, tert-butyl N- (2-amino-5-methoxyphenyl) -N-methylcarbamate (38.4 g, 137.9 mmol) and triethylamine (18.7 g, 184.9 mmol) in acetonitrile ( 240 ml) The solution was added dropwise over 65 minutes while cooling so that the reaction temperature was maintained at 0 to 3 ° C., and the mixture was further stirred at the same temperature for 3.5 hours. Next, water (320 ml) was added over 27 minutes, and the mixture was stirred at 0-5 ° C. for 2.5 hours, and then the precipitated crystals were separated by filtration. The obtained crystals were washed with acetonitrile: water = 2: 1 solution (160 ml) and dried under reduced pressure at 50 ° C. for 15 hours to give N- {2- {4-[(2,4-dioxothiazolidine-5 Crystals of tert-butyl- (yl) methyl] phenoxyacetylamino} -5-methoxyphenyl} -N-methylcarbamate (67.6 g, 131.0 mmol) were obtained (yield 92%).
(4-2)
N- {2- {4-[(2,4-Dioxothiazolidin-5-yl) methyl] phenoxyacetylamino} -5-methoxyphenyl} -N-methylcarbamic acid tert-obtained in (4-1) A suspension of butyl crystals (56.1 g, 108.6 mmol) in methanol (1680 ml) was heated with stirring (dissolved completely when the internal temperature reached 65.5 ° C.). The reaction solution was cooled to 0-5 ° C. over 2 hours and further stirred at the same temperature for 95 minutes, and then the precipitated crystals were separated by filtration. The obtained crystals were washed with methanol (224 ml) and dried under reduced pressure at 50 ° C. for 15 hours to give N- {2- {4-[(2,4-dioxothiazolidine-5-yl) methyl] phenoxyacetylamino. A purified crystal (51.6 g, 100.0 mmol) of tert-butyl} -5-methoxyphenyl} -N-methylcarbamate was obtained (yield 92%, total yield 85%).
(Example 5)
5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride (5-1)
To a suspension of 4-[(2,4-dioxothiazolidine-5-yl) methyl] phenoxyacetic acid (61.0 kg, 216.9 mol) in dichloromethane (398 L), thionyl chloride (28.15 kg, 236.6 mol), dimethylformamide ( 6.1 L) was added and refluxed for 6 hours. After cooling the resulting solution to 0-5 ° C, tert-butyl N- (2-amino-5-methoxyphenyl) -N-methylcarbamate (54.72kg, 216.9mol) while maintaining the internal temperature below 5 ° C A solution of triethylamine (26.35 kg, 260.4 mol) in dichloromethane (562 L) was added dropwise over 1 hour, and the mixture was stirred at 0 to 5 ° C. for 15 minutes. Pour water (488L) with stirring, add sodium bicarbonate (24.4kg) (internal temperature rose to about 20 ° C), pour dichloromethane (305L), stir for 20 minutes with cooling, It was 0-3 degreeC. Water (488L) was poured here, and after stirring for 5 minutes at 10-20 degreeC, it was left still for 30 minutes and the water layer was discarded. Water (488 L) and 38% hydrochloric acid (23.8 kg) were poured into this, and the mixture was stirred for 5 minutes and then allowed to stand for 10 minutes, and the aqueous layer was discarded. Water (488 L) was poured into this, stirred for 5 minutes, and then allowed to stand for 12 hours, and the aqueous layer was discarded. To this was added a suspension of activated carbon (1.83 kg) in dichloromethane (18 L), stirred for 30 minutes, and then the activated carbon was filtered off. Activated charcoal was washed with dichloromethane (92 L), and the filtrate and the washing solution were combined, and concentrated to about 300 L under reduced pressure at an internal temperature of 20 to 30 ° C. Methanol (305 L) was poured here, and the mixture was concentrated to about 300 L under reduced pressure at an internal temperature of 20-30 ° C. Furthermore, methanol (305L) was poured here, and it concentrated until it became about 300L under pressure reduction at internal temperature 20-30 degreeC. Methanol (201 L) was poured into this and stirred at 5 ° C for 1 hour. The obtained crystals were filtered off, washed with methanol (244 L), dried at 50 ° C under reduced pressure, and N- {2- {4 -[(2,4-Dioxothiazolidine-5-yl) methyl] phenoxyacetylamino} -5-methoxyphenyl} -N-methylcarbamate tert-butyl (103.9 kg, 201.5 mol) was obtained (yield 93% ).
(5-2)
N- {2- {4-[(2,4-Dioxothiazolidin-5-yl) methyl] phenoxyacetylamino} -5-methoxyphenyl} -N-methylcarbamic acid tert-obtained in (5-1) Butyl (97.0 kg, 188.1 mol) was suspended in a solution consisting of methanol (2803 L), water (43 L) and 38% hydrochloric acid (72.8 kg), and then refluxed with stirring for 5 hours. The reaction solution was cooled to 0-5 ° C., stirred for 1 hour, and allowed to stand at the same temperature for 12 hours. The obtained crystals were filtered off, washed with methanol (291 L), dried at 50 ° C. under reduced pressure, and 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy ] Benzyl} thiazolidine-2,4-dione hydrochloride (74.9 kg, 172.5 mol) was obtained (yield 92%, total yield of Example 5 86%).

Table 1 shows a peak pattern having a relative intensity of 9 or more in powder X-ray diffraction (Cu Kα, λ = 1.54 Å).
(Table 1)

(Example 6)
5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride (6-1)
Acetonitrile (140.9 kg) was added to 4-[(2,4-dioxothiazolidine-5-yl) methyl] phenoxyacetic acid (18.0 kg, 64.0 mol), and the mixture was cooled to an internal temperature of 8 ° C., and then thionyl chloride (8.3 kg) 69.8 mol). Dimethylformamide (14.4 L) was further added, and the mixture was stirred at the same temperature to 15 ° C. for 3.5 hours. Here, tert-butyl N- (2-amino-5-methoxyphenyl) -N-methylcarbamate (15.7 kg, 62.2 mol) and triethylamine (8.4 kg, 83.0 mol) in acetonitrile (kept at 0 to 10 ° C.) 84.6 kg) The solution was added dropwise over 1 hour while cooling so that the reaction temperature was maintained at 0 to 5 ° C., and the mixture was further stirred at the same temperature for 2 hours. Next, water (144 L) was added over 22 minutes, and the mixture was stirred for 30 minutes while maintaining the internal temperature of 0 to 6 ° C., and then allowed to stand for 12 hours. The obtained crystals are filtered, washed with water (54 L), and N- {2- {4-[(2,4-dioxothiazolidine-5-yl) methyl] phenoxyacetylamino} -5-methoxyphenyl } Wet crystals of tert-butyl N-methylcarbamate were obtained.
(6-2)
N- {2- {4-[(2,4-Dioxothiazolidin-5-yl) methyl] phenoxyacetylamino} -5-methoxyphenyl} -N-methylcarbamic acid tert-obtained in (6-1) The suspension was refluxed in methanol (450 L) of wet butyl crystals for 25 minutes with stirring. The suspension was cooled to 0 to 5 ° C. and stirred at the same temperature for 1 hour, and then the precipitated crystals were separated by filtration. The obtained crystals were washed with methanol (54 L), and N- {2- {4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetylamino} -5-methoxyphenyl} -N- Wet purified crystals of tert-butyl methylcarbamate were obtained.
(6-3)
N- {2- {4-[(2,4-Dioxothiazolidin-5-yl) methyl] phenoxyacetylamino} -5-methoxyphenyl} -N-methylcarbamic acid tert-obtained in (6-2) The purified butyl wet crystals were suspended in methanol (1080 L) and then refluxed to obtain a solution. The solution was cooled to 50 ° C. and filtered over 45 minutes. The residue was washed with 50 ° C. methanol (37 L). The filtrate and the washing solution were combined, 38% hydrochloric acid (20.9 kg) and then water (11.2 L) were poured at 48 ° C., and the mixture was stirred at the same temperature for 6 hours. The reaction solution was cooled to 0-5 ° C., stirred at the same temperature for 30 minutes, and allowed to stand for 12 hours. The obtained crystals were filtered off, washed with methanol (91 L), dried at 50 ° C. under reduced pressure, and 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy. ] Benzyl} thiazolidine-2,4-dione hydrochloride (19.5 kg, 44.9 mol) was obtained (70% overall yield of Example 6).
(Example 7)
(N- {2- {4-[(2,4-Dioxothiazolidine-5-yl) methyl] phenoxyacetylamino} -5-methoxyphenyl} -N-methylcarbamate tert-butyl (compound (III ¹ ) Quality and stability over time)
The crystals obtained in Example 3, the crystals obtained in Example 3 were stored at 40 ° C. for 40 days, the purified crystals obtained in Example 4 and the purified crystals obtained in Example 4 were obtained at 40 ° C. The quality of 4 samples of crystals stored for 42 days was analyzed. The quality analysis method is as follows.

An approximately 10 mg / L acetonitrile-water (4: 1) solution of compound (III ¹ ) is prepared.

About 20 μL of this sample solution was used and analyzed by high performance liquid chromatography under the following conditions. (The test substance shows a retention time of about 12 minutes under these conditions.)
Column: L-column ODS 4.6 x 250 mm (Chemicals Evaluation and Research Institute)
Mobile phase: 0.02M ammonium acetate aqueous solution / acetonitrile mixture (55:45)
Flow rate: 1ml / min
Detection wavelength: 220nm
Measurement temperature: 40 degree Each peak area was calculated | required from the chromatogram, and it was set as the content (%) of each component = 100x (peak area of each component) / (total peak area of all components). The results are shown in Table 2.

(Table 2)

Each test substance has a difference in production method as described in the above examples. In the following scheme (the definitions of symbols in the scheme are the same as those described above), the crystal of Example 4 was produced by a synthesis method according to the scheme. On the other hand, the crystal of Example 3 was produced without performing the purification in the third step in the following scheme.

It can be seen from Table 2 that the amount of impurities is remarkably reduced by adding the purification operation in the third step. Furthermore, the high-purity crystal obtained by the purification operation in the third step has also been shown to be extremely excellent in stability over time, and this crystal has particularly suitable properties as an intermediate for pharmaceutical products. I understand that.
(Example 8)
Impurities of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride (hereinafter referred to as compound (A ¹ )) Analysis (8-1) Qualitative Analysis of Impurities in Crystals of Compound (A ¹ ) Obtained in Example 5 and Example 6 About 0.02 g of the compound (A ¹ ) to be analyzed was weighed and 0.5% phosphoric acid aqueous solution -Dissolve in acetonitrile (65:35) to make 100 ml, and use this as the sample solution.

(Test substance 1: compound of Example 5, test substance 2: compound of Example 6)
The sample solution is diluted exactly 100 times with 0.5% phosphoric acid aqueous solution-acetonitrile (65:35), and this is used as a standard solution.

The sample solution and the standard solution were used exactly 10 μl each and analyzed by high performance liquid chromatography under the following conditions. (The test substance shows a retention time of about 10 minutes under these conditions.)
Column: L-column ODS 4.6 x 150 mm (Chemicals Evaluation and Research Institute)
Mobile phase: 0.01M sodium acetate buffer (pH = 5) / acetonitrile mixture (13: 7)
Flow rate: 1ml / min
Detection wavelength: 225nm
Each peak area was determined from the chromatogram, and the content of each component (%) = [(peak area of each component of the sample solution) / (peak area of the test substance in the standard solution)].

(8-2) Quantitative analysis of the crystals of the compound (A ¹ ) obtained in Example 5 and Example 6.
Sample solution: acetonitrile-0.5% phosphoric acid aqueous solution (35:65)
Internal standard solution: Dissolve about 1 ml of methyl salicylate in the sample solution to make 200 ml.

  A standard solution was prepared as follows.

About 0.04 g of the standard compound (A ¹ ) was accurately weighed into a 200 ml volumetric flask, dissolved by adding about 160 ml of the sample solution, and then added with 10 ml of the internal standard solution and the sample solution to make 200 ml. After 10 ml of this solution was accurately placed in a 25 ml volumetric flask, a sample solution was added to make 25 ml.

  The measurement sample solution was prepared as follows.

About 0.04 g of the sample was weighed into a 200-ml volumetric flask, about 160 ml of the sample solution was added and dissolved, and then 10 ml of the internal standard solution and the sample solution were added to make 200 ml. After 10 ml of this solution was accurately placed in a 25 ml volumetric flask, a sample solution was added to make 25 ml.
The HPLC conditions are as follows.

Detection wavelength: 290nm
Column: L-column ODS 4.6 x 150 mm (Chemicals Evaluation and Research Institute)
Mobile phase: 0.01M sodium acetate buffer (pH = 5) / acetonitrile mixture (13: 7)
Flow rate: 1ml / min (Adjust so that the internal standard retention time is about 17 minutes)
Column temperature: 40 ° C
Each peak area was determined from the chromatogram, and the content of the compound (A ¹ ) was calculated according to the following formula.
Content (%) of compound (A ¹ ) = W ₁ × F ₁ × (Q _T / Q _S ) × [1 / {W ₂ × (100−F ₂ ) / 100}] × 100
W ₁ : Weighed amount of standard compound (A ¹ ) (g)
W ₂ : Weighed sample (g)
F ₁ : Purity factor of compound (A ¹ ) standard product
F ₂ : Moisture in the sample measured with a Karl Fischer moisture meter
Q _T : Peak area ratio between sample and internal standard
Q _S : Peak area ratio between the compound (A ¹ ) standard and the internal standard

The above analysis results of Example 8 are shown in Tables 3 and 4.

(Table 3)

(Table 4)

*) The result of quantitative analysis of the quality of the compound (A ¹ ) (comparative compound) produced by the method described in WO 00/71540 by the method of Reference Example was 76%.

  Each test substance has a difference in production method as described in the above examples. In the following scheme (the definitions of symbols in the scheme are the same as those described above), the crystal of Example 6 was produced by a synthesis method according to the scheme. On the other hand, the crystal of Example 5 was purified without performing the purification in the third step in the following scheme. In addition, the method described in International Publication No. 00/71540 is produced by a route that does not use the intermediate acid halide (I) and that does not perform the purification in the third step.

  From Table 3, a significant reduction in the amount of impurities was observed by adding the third step of purification, indicating that this purification method is particularly superior in removing impurities. Further, since the effect of removing impurities in the third step largely reflects the purity of the final product, the purification operation in the third step is an important operation in the production of the high-quality compound (A). It can be seen that it is.

  Further, from the results of Table 4, when the quantitative value of the crystals produced according to the method described in International Publication No. WO 00/71540, which is a known production method, was 76%, the production method of the present invention was compared. It can be seen that, with regard to the production method of the compound (A), an efficient and high-purity crystal can be obtained while being an industrial production method using a simpler operation.

(Reference Example 1)
5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione Quantitative analysis of hydrochloride Column: L-column ODS 4.6 x 150 mm (Research Organization for Chemical Evaluation)
Mobile phase: 0.01M sodium acetate buffer (pH = 5) / acetonitrile mixture (13: 7)
Flow rate: 1ml / min
Detection wavelength: 290nm
Column temperature: 40 degrees Under these conditions, 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride is about 10 Elution was performed in minutes, and quantitative calculation was performed from the obtained chromatogram.

(Formulation example)
(Formulation example 1)
Tablets Tablets were obtained by the following method using the components of the types and amounts shown in Table 5. In addition, about the dose of an active ingredient, the content of each additive, and a kind, it is not limited to Table 5.

  An excipient (lactose) and a disintegrant (croscarmellose sodium (Ac-Di-Sol)) were added to the crystals of Example 5, mixed by a high-speed agitation granulator, and a binder (hydroxyl) was added to the resulting mixture. Propylcellulose) aqueous solution was added and kneaded to obtain a granulated product, which was dried using a fluid bed dryer, and the dried granulated product was crushed and granulated using a granulator The screen was forcibly passed through, and a lubricant (magnesium stearate) was added and mixed with a V-type mixer, and the resulting mixture was molded using a 7 mm diameter punch and dyed (yellow ferric oxide) The aqueous coating (Opadry WHITE YS-1-18202A) solution was dispersed using a coating machine to obtain the desired tablet.

(Table 5)

FIG. 1 shows the copper Kα ray (5-α) for a crystal of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride ( It is a powder X-ray diffraction pattern obtained by irradiation with a wavelength λ = 1.54 Å. The vertical axis of the powder X-ray diffraction pattern indicates the diffraction intensity in units of count / second (cps), and the horizontal axis indicates the value of 2θ.

Claims (15)

  In powder X-ray diffraction obtained by irradiation of copper with Kα rays, the interplanar spacing d = 14.29, 7.12, 5.34, 4.97, 4.74, 3.95, 3.85, 3.75, 3.55, 3.51, 3.15, 2.84, 2.76, 2.52 and 2.37 A crystal consisting of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride, characterized by a peak. A pharmaceutical composition containing as an active ingredient.   5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione The content of hydrochloride is 98% by weight or more excluding water. In the powder X-ray diffraction obtained by irradiation with copper Kα rays, the surface spacing d = 14.29, 7.12, 5.34, 4.97, 4.74, 3.95, 3.85, 3.75, 3.55, 3.51, 3.15, 2.84, 2.76, 2.52 and 2.37 Of crystals of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride, characterized by a main peak A pharmaceutical composition comprising the composition as an active ingredient.   5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione The content of hydrochloride is 99% by weight or more excluding water. In the powder X-ray diffraction obtained by irradiation with copper Kα rays, the surface spacing d = 14.29, 7.12, 5.34, 4.97, 4.74, 3.95, 3.85, 3.75, 3.55, 3.51, 3.15, 2.84, 2.76, 2.52 and 2.37 Of crystals of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride, characterized by a main peak A pharmaceutical composition comprising the composition as an active ingredient.   5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione The content of hydrochloride is 98% by weight or more excluding water. A pharmaceutical composition comprising a purified 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride as an active ingredient object.   5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione The content of hydrochloride is 99% by weight or more excluding water. A pharmaceutical composition comprising a purified 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride as an active ingredient object. The following general formula (III)

[Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and are a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a benzyloxy group, an acetoxy group, a trifluoromethyl group. Alternatively, it represents a halogen atom, R ⁵ represents a C1-C6 alkyl group, and R ⁶ represents an amino-protecting group. ] By adding an organic solvent (the organic solvent is selected from alcohols, ethers, nitriles or a mixed solvent thereof) to the compound represented by After purification, which is characterized by removing the substance, the purified product is treated with an acid and cyclized to an imidazole ring.

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same meaning as described above. ] The pharmaceutical composition which contains the thiazolidinedione compound represented by these, or its pharmacologically acceptable salt as an active ingredient. The following general formula (I) obtained by reacting 4-[(2,4-dioxothiazolidine-5-yl) methyl] phenoxyacetic acid with a halogenating agent

[Wherein X represents a halogen atom. Or a salt thereof represented by the following general formula (II)

[Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and are a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a benzyloxy group, an acetoxy group, a trifluoromethyl group. Alternatively, it represents a halogen atom, R ⁵ represents a C1-C6 alkyl group, and R ⁶ represents an amino-protecting group. By reacting with a compound represented by the following general formula (III)

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meaning as described above. Or a salt thereof, and purify the product by refluxing a suspension or solution of the organic solvent (the organic solvent is selected from alcohols, ethers, nitriles, or a mixed solvent thereof). Then, the compound represented by the general formula (A) obtained by cyclization to an imidazole ring by treatment with an acid

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same meaning as described above. ] The pharmaceutical composition which contains the thiazolidinedione compound represented by these, or its pharmacologically acceptable salt as an active ingredient.   The thiazolidinedione compound represented by the general formula (A) is 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione. A pharmaceutical composition comprising the thiazolidinedione compound according to claim 6 or 7 or a pharmacologically acceptable salt thereof as an active ingredient.   Any one of claims 1 to 8 for the prevention or treatment of diabetes, hyperglycemia, glucose intolerance, hypertension, hyperlipidemia, diabetic complications, gestational diabetes, polycystic ovary syndrome or atherosclerosis A pharmaceutical composition according to any one of the above.   The pharmaceutical composition according to any one of claims 1 to 8, for the prevention or treatment of diabetes.   The pharmaceutical composition according to claim 10, wherein the diabetes is type 2 diabetes.   The pharmaceutical composition according to any one of claims 1 to 8, for improving insulin resistance.   In powder X-ray diffraction obtained by irradiation with copper Kα rays for producing the pharmaceutical composition according to any one of claims 1 to 12, the interplanar spacing d = 14.29, 7.12, 5.34, 4.97, 4.74 , 3.95, 3.85, 3.75, 3.55, 3.51, 3.15, 2.84, 2.76, 2.52 and 2.37, showing a main peak, 5- {4-[(6-methoxy-1-methyl-1H-benzimidazole Use of crystals consisting of -2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride.   In powder X-ray diffraction obtained by irradiation of copper Kα rays to produce a pharmaceutical composition for the prevention or treatment of diabetes, the interplanar spacing d = 14.29, 7.12, 5.34, 4.97, 4.74, 3.95, 3.85, 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl), characterized by showing main peaks at 3.75, 3.55, 3.51, 3.15, 2.84, 2.76, 2.52 and 2.37 Use of crystals consisting of methoxy] benzyl} thiazolidine-2,4-dione hydrochloride. A method for preventing or treating diabetes, comprising administering the pharmaceutical composition according to any one of claims 1 to 12.