MXPA99004021A - Crystals of benzimidazole derivatives and their production - Google Patents

Abstract

A substantially solvent-free and stable crystal of the compound of formula (I) wherein the ring A may optionally be substituted, R1 represents hydrogen or an N-protecting group, each of R2, R3 and R4 is (1) a hydrogen atom, (2) an alkyl group which may optionally be substituted with halogen atom(s) or (3) an alkoxy group which may optionally be substituted with halogen atoms(s) or alkoxy;or its salt, is produced by subjecting a solvate of the compound (I) or its salt to de-solvent treatment, in an industrially advantageous method.

Description

CRYSTALS OF BENZYMIDAZOLE DERIVATIVES AND THEIR PRODUCTION Technical Field The present invention provides crystals of benzimidazole derivatives, which are of importance as a medicine, such as an antiulcer agent, and a method for producing the crystals.

Background of the Technique The benzimidazole derivatives, ie the derivatives of 2- (2-pyridylmethylsulfinyl) benzimidazole, which are of importance as a medicine, such as an antiulcer agent, have been known in European Patent Application Publication No. 302720 (Application Japanese Patent Laid-Open No. 1-131176), European Patent Application Publication No. 5129 (Japanese Patent Application Laid-Open No. 58-192880), Japanese Patent Application Laid-Open No. 61-22079, Japanese Patent Application Laid-Open No. 64-6270, US Patent No. 4,255,431, European Patent Application Publication Nos. 45200, 74341, 80602, 174726, 175464, British Patent Application Publication No. 2134523.

Ref. 030003 European Application Publication No. 302720 (Japanese Patent Application Laid-open No. 1-131176) describes in Example 1 that 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy ) pyridin-2-yl] methylsulfinyl] -benzimidazole is obtained as white crystals by subjecting a solution of 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylthio] benzimidazole (monohydrate ) in dichloromethane to an oxidation reaction with hydrogen peroxide using vanadium pentoxide as a catalyst, concentrating the reaction mixture, adding a mixture of ethanol-water (9: 1) to the residue, recovering the resulting crystals by filtration, rinsing the crystals , dissolving this batch of crystals in the ethanol-water mixture (9: 1) at an elevated temperature (65 - 70 ° C), filtering the solution when it is hot, cooling the filtrate with ice, recovering the resulting crystals by filtration, rinsing the crystals, and drying the crystals in vacuum.

Any compound in the 2- (2-pyridylmethylsulfinyl) -benzimidazole derivatives tends to lose stability and is subject to decomposition when it contains traces of a solvent, particularly water, in its crystalline structure and, therefore, this residual solvent in the crystal it must be reduced to a minimum.

However, when the production process for 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] -methylsulfinyl-benzimidazole is followed as described in EP-302720, the Water and ethanol can hardly be removed from the product and the resulting crystals inevitably contain considerable amounts of water and ethanol. Therefore, the benzimidazole compound provided by the process described in the prior literature is a solvate containing one molecule, each of water and ethanol and it is very difficult to desolvate the compound by vacuum drying without decreasing the stability of the product.

There is a serious problem with the above benzimidazole compound in the form of a solvate, particularly a hydrate, because it is heat-labile, it readily decomposes in the vacuum drying step, particularly under heating, therefore decreasing the purity of the benzimidazole compound as a product. Therefore, there has been a notable demand for a supply of solvent-free crystals of the benzimidazole compound and development of a high-production, highly practicable scale, and effective desolvation technology to provide such crystals.

Description of the invention In view of the above statement of the art, the inventors of the present invention do intensive research directed to improvements in the aspects mentioned above for the purpose of providing substantially solvent-free crystals of the benzimidazole compound, which is of importance as a medicine, for example an antiulcer agent, etc., and a high production scale, highly practicable, and effective desolvation technology to provide such crystals. As a consequence, they discovered to everyone's surprise that the desired desolvation can easily be achieved by oxidizing the 2- (2-pyridylmethylthio) benzimidazole compound to the corresponding 2- (2-pyridylmethyl-sulfinyl) benzimidazole compound, recrystallizing the latter with aqueous alcohol to give solvate crystals in water and alcohol of the compound of 2- (2-pyridylmethylsulfinyl) -benzimidazole, and suspending and stirring the crystals in hot water, which procedure unexpectedly causes a transformation of the solvate crystals into crystals substantially free of solvent, followed by drying under reduced pressure. The inventors also discover to their own surprise that the substantially solvent-free crystals of the benzimidazole compound thus obtained are remarkably stable in comparison with the conventional benzimidazole solvate, and completely free from decomposition in the course of drying under vacuum.

The present invention provides: (1) A method for producing a substantially solvent-free crystal of the compound of the formula: wherein ring A can be optionally substituted, R1 represents hydrogen or a protecting group of N, each of R2, R3 and R4 is (1) a hydrogen atom, (2) an alkyl group, which can be substituted optionally with a halogen atom (s) or (3) an alkoxy group, which may be optionally substituted with a halogen or alkoxy atom (s); or its salt, which comprises subjecting a solvate of the compound (I) or its salt to treatment with a solvent. (2) The method as in item (1), where the treatment with a solvent is to suspend the compound in water, (3) The method as in item (1), wherein the protecting group of N in the compound (I) is an alkyl group, an acyl group, a carboalkoxy group, a carbamoyl group, a group of alkylcarbamoyl, a dialkylcarbamoyl group, an alkylcarbonylmethyl group, an alkoxycarbonylmethyl group or an alkylsulfonyl group, (4) The method as in item (1), where R1 in the compound (I) is a hydrogen atom, (5) The method as in item (1), wherein the substituent on ring A of compound (I) is an alkoxy group, which may be optionally substituted by halogen, (6) The method as in item (1), wherein ring A of compound (I) is unsubstituted, (7) The method as in item (1), wherein R 2 is methyl or methoxy, R 2 is C 4 -4 alkoxy, which may be optionally substituted by fluorine (s) or C 1 -4 alkoxy-C 1 -alkoxy 8, R4 is a hydrogen or methyl atom, (8) The method as in item (1), wherein the compound (I) is 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) -pyridin-2-ylmethyl-sulfinyl] benzimidazole, (9) A substantially solvent-free crystal of the compound of the formula: wherein ring A can be optionally substituted, R1 represents hydrogen or a protecting group of N, each of R2, R3 and R4 is (1) a hydrogen atom, (2) an alkyl group, which can be substituted optionally with a halogen atom (s) or (3) an alkoxy group, which may be optionally substituted with a halogen or alkoxy atom (s); or its salt, and (10) The crystal as in item (9), wherein the compound (I) is 2 - [[3-methyl-4- (2,2, 2-trifluoroethoxy) -pyridin-2- il] methylsulfinyl] benzimidazole.

Best Way to Carry Out the Invention Now the different definitions relevant to the above chemical formula and the present invention are presented in general and preferred examples of species that meet the definitions.

Referring to formula (1), the optional substituent on ring A includes, but is not limited to halogen, alkyl, cyano, carboxy, alkoxycarbonyl, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy, hydroxyalkyl, halogenated alkyl, halogenated alkoxy , acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, and alkylsulfinyl.

The aforementioned halogen includes fluorine, chlorine, bromine, etc., with fluorine being particularly preferred.

The alkyl mentioned above is preferably alkyl of 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and heptyl.

The alkoxycarbonyl mentioned above is preferably one containing 1 to 4 carbon atoms in the carboxy moiety, including methoxycarbonyl (CH3OOC-) and ethoxycarbonyl (C2H5OOC-), among others.

The aforementioned carboalkoxyalkyl is preferably one containing 1 to 4 carbon atoms in each of its alkoxy and alkyl parts, therefore it includes carbomethoxymethyl (CH3OOCCH2-), carbomethoxyethyl (CH3OOCC2H4-), carboethoxymethyl (C2H5OOCCH2-) , and carboethoxyethyl (C2H5OOCC2H4-), among others.

The carbamoylalkyl mentioned above is preferably one containing 1 to 4 carbon atoms in its alkyl part, including carbamoylmethyl (H2NCOCH2-) and carbamoylethyl (H2NCOC2H4-), among others.

The alkoxy mentioned above is preferably one containing 1 to 5 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and pentoxy.

The above-mentioned hydroxyalkyl is preferably one containing 1 to 7 carbon atoms in its alkyl part, such as hydroxymethyl, l-hydroxy-propyl-2, l-hydroxy-ethyl-2, and l-hydroxy-2. -methyl-propyl-2, among others.

The halogenated alkyl mentioned above is preferably one containing 1 to 7 carbon atoms in its alkyl part, including difluoromethyl and trifluoromethyl, but few preferred examples are mentioned.

The halogenated alkoxy mentioned above is preferably one containing 1 to 4 carbon atoms in its alkoxy moiety, including difluoromethoxy as a typical preferred example.

The acyl mentioned above is preferably one containing 1 to 4 carbon atoms, such as formyl, acetyl, propionyl, butyryl, and isobutyryl.

The acyloxy mentioned above is preferably one containing 1 to 4 carbon atoms in its acyl moiety, including formyloxy, acetyloxy, propionyloxy, butyryloxy, and isobutyryloxy.

The aryl mentioned above includes, but is not limited to, phenyl, tolyl, and naphthyl.

The aryloxy mentioned above includes, but is not limited to, phenyloxy, tolyloxy, and naphthyloxy.

The aforementioned alkylthio is preferably one containing 1 to 6 carbon atoms in its alkyl part, including but not limited to methylthio, ethylthio, and propylthio.

The alkylsulfinyl mentioned above is preferably one containing 1 to 6 carbon atoms, including but not limited to methylsulfinyl, ethylsulfinyl, and propylsulfinyl.

Further, with reference to formula (1), ring A is preferably either unsubstituted or substituted by, among the groups of substituents mentioned above, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy (more preferably such species as methoxy, trifluoromethyl or difluoromethoxy). Particular preference is given to cases in which such a substituent occurs in position 4 or 5 of the benzimidazole ring.

R1 in the formula (1) represents a hydrogen atom or a protecting group of N.

The protecting group of N for R1 includes, but is not limited to alkyl, acyl, sarboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl and alkylsulfonyl.

The alkyl mentioned above is preferably one containing 1 to 5 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and pentyl.

The acyl includes the same species as mentioned for the substituent on ring A.

The carboalkoxy includes the same species as mentioned for the substituent on ring A.

The alkylcarbamoyl, which can be represented by the formula: alkyl-JMH-CO-, is preferably one containing 1 to 4 carbon atoms in its alkyl part, such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, etc. .

Dialkylcarbamoyl, which may be represented by the formula: (alkyl) 2N-CO-, is preferably one containing 1 to 4 carbon atoms in each of its alkyl portions, including dimethylcarbamoyl, diethylcarbamoyl, and N -methyl-N-ethylcarbamoyl, among others.

The alkylcarbonylmethyl, which can be represented by the formula: alkyl -C0-CH2-, is preferably a group in which the alkyl contains 1 to 4 carbon atoms, such as acetylmethyl and propionylmethyl, among others.

The alkoxycarbonylmethyl, which can be represented by the formula: alkyl-OCO-CH2-, is preferably a group in which the alkyl contains 1 to 4 carbon atoms, therefore includes methoxycarbonylmethyl, ethoxycarbonylmethyl, and propoxycarbonylmethyl, among others.

Alkylsulfonyl, which can be represented by the formula: alkyl-S02-, is preferably one containing 1 to 4 carbon atoms in its alkyl part, including methylsulfonyl, ethylsulfonyl, propylsulfonyl, and isopropylsulfonyl, etc.

In the formula (I), R1 preferably represents hydrogen.

In formula (I), R2, R3, and R4 are the same or different and each represents hydrogen, alkyl optionally substituted by halogen, or alkoxy optionally substituted by halogen, or alkoxy.

The alkyl of the alkyl optionally substituted by halogen as mentioned for R2, R3, and R4 is preferably an alkyl group of 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl. The halogen of the alkyl optionally substituted by halogen includes fluorine, chlorine, bromine, etc. and is preferably fluorine.

The alkyl substituted by halogen is preferably alkyl substituted by fluorine, such as trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3, 3 -tetrafluoropropyl, 2,2,3,3, 3 -pentafluoropropyl, 1- (trifluoromethyl) -2,2,2-trifluoroethyl, 2, 2, 3, 4, 4, 4, 4-heptafluorobutyl, etc., and as examples of alkyl substituted by chlorine or bromine, also, there may be mentioned species available in the substitution of fluorine with chlorine or bromine in the species mentioned above for the alkyl substituted by fluorine.

The alkyl optionally substituted by halogen as mentioned for R2, R3, and R4 is preferably an unsubstituted alkyl group of 1 to 4 carbon atoms, with methyl being particularly preferred.

The alkoxy of the alkoxy optionally substituted by halogen or alkoxy as mentioned for R2, R3, and R4 is alkoxy containing 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, including methoxy, ethoxy, propoxy, isopropoxy , butoxy, isobutoxy, pentoxy, hexyloxy, heptyloxy and octyloxy. The halogen of the alkoxy optionally substituted by halogen includes fluorine, chlorine, bromine, etc., with fluorine being particularly preferred.

The alkoxy substituted by halogen is alkoxy of 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, which is substituted by 1 to 8 (preferably 3 or 4) fluorine atoms, such as 2, 2, 2-trifluoroethoxy, 2,2,3,3, 3-pentafluoropropoxy, 1- (trifluoromethyl) -2,2, 2-trifluoroethoxy, 2,2,3, 3-tetrafluoropropoxy, 2,2,3,3, 4,4,4-heptafluorobutoxy, 2, 2, 3, 3, 4, 4, 5, 5-octafluoropentoxy, etc. Particularly 2, 2, 2-trifluoroethoxy or 2, 2, 3, 3-tetrafluoropropoxy is preferred. With respect to the alkoxy substituted by chlorine or bromine, also, the available species can be mentioned in the substitution of fluorine with chlorine or bromine in the species mentioned above for the fluorine-substituted alkoxy.

The substituted alkoxy-alkoxy includes the C 1-4 alkoxy-1,8-alkoxy (particularly the C 1-4 alkoxy-C 4 -alkoxy), such as 3-methoxypropoxy, 2-methoxyethoxy, 3-ethoxyprophoxy, 2-ethoxyethoxy , etc., 3-methoxypropoxy being particularly preferred.

In the formula (I), preferably R2 and R4 are the same or different and each represents hydrogen, methyl, or methoxy and R3 represents alkoxy containing 1 to 5 carbon atoms, preferably 2 to 4 carbon atoms , which have been replaced by 3 to 4 halogen atoms, or methoxy.

Further, with reference to the compound of the formula (I), the preferred specific compounds are such that ring A is unsubstituted or the 4 or 5 position of the benzimidazole ring is substituted by methoxy, difluoromethoxy, or trifluoromethyl, R1 is hydrogen, R2 is methyl or methoxy, R3 is C2-4 alkoxy substituted by 3 or 4 fluorine atoms, methoxy, or 3-methoxypropoxy, and R4 is hydrogen or methyl.

The salt of the compound of the formula (I) is preferably a pharmaceutically acceptable salt, which includes salts with inorganic bases, salts with organic bases, and salts with basic amino acids. Preferred salts with inorganic bases are salts with alkali metals, such as sodium and potassium, salts with alkaline earth metals, such as calcium and magnesium, and ammonium salts. Preferred salts with organic bases are salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, and N, N 1 -dibenzylethylenediamine. Preferred salts with basic amino acids are salts with arginine, lysine, ornithine, etc. The preferred salt of the compound of the formula (I) according to the present invention includes salts with alkali metal salts and alkaline earth metal salts. The sodium salt is particularly preferred.

Specifically, the compound of the formula (I) includes, but is not limited to: 2 - [[3-Methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole, 2 - . 2 - [[3,5-dimethyl-4-methoxypyridin-2-yl] methylsulfinyl] -5-methoxybenzimidazole, sodium salt of 2 - [[4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethyl-sulfinylbenzimidazole, Y -difluoromethoxy -2 - [(3,4-dimethoxypyridin-2-yl) methylsulfinyl-benzimidazole.

Particularly preferred is 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole.

The benzimidazole compound of the formula (I) can be produced by the manners described in the literatures mentioned above, ie, European Patent Application Publication No. 302720 (Japanese Patent Application Laid-Open No. 1-131176) , European Patent Application Publication No. 5129 (Japanese Patent Application Laid-Open No. 58-192880), Japanese Patent Application Laid-Open No. 61-22079, Japanese Patent Application Laid-Open No. 64-6270 , US Patent No. 4,255,431, European Patent Application Publication Nos. 45200, 74341, 80602, 174726, 175464, British Patent Application Publication No. 2134523 or methods analogous thereto.

The benzimidazole compound has an asymmetric center in the sulfur atom. That is, it can be presented as two types of isomers, 0 0 1 -3- -s- The above benzimidazole compound can be obtained as crystals of its solvate in water and alcohol by recrystallization with the corresponding aqueous alcohol according to, for example, the purification procedure described in European Patent Application Publication No. 302720 (Application for Japanese Patent -Open to the Public No. 1-131176) or any analogous procedure thereto. The aforementioned alcohol includes C?-6 alcohols (eg, methanol, ethanol, isopropyl alcohol, etc.), with ethanol being particularly preferred. The aqueous alcohol, for example, can be one containing about 2 to about 30 parts by volume of an alcohol (especially ethanol), preferably about 5 to about 15 parts by volume of an alcohol (especially ethanol) for each part by volume of water. It is specific that, a mixture consisting of an alcohol (especially ethanol) and water in a ratio of about 9: 1, v / v can be used.

The crystals of such a solvate of the compound of the formula (I) or its salt can easily be corroborated by known analytical techniques, such as powder X-ray diffraction analysis.

According to the process of the invention, the solvate crystals mentioned above are allowed to stand suspended or are stirred in water. As a result of this procedure, the solvate crystals are desolvated due to a morphological transformation. While the conditions of this leave-in or suspension procedure, such as the amount and temperature of the water used and the agitation time, can be judiciously selected, the following conditions can typically be mentioned. As for the amount of water, the water can be used in a ratio of about 2 to about 20 parts by volume, preferably about 5 to about 10 parts by volume, relative to the solvate crystals. The temperature of the water can fluctuate from room temperature (about 15 to about 30 ° C) to about 90 ° C, preferably from about 30 ° to about 50 ° C. The stirring time may range from about 0.5 to about 5 hours, preferably from about 1 to about 2 hours.

Then the solvent-free crystals available in the morphological transformation of the solvate crystals are collected by a procedure known per se, such as filtration., and dried, if necessary, by a process known per se, thereby obtaining the substantially solvent-free crystals of the particular benzimidazole compound. The drying process referred to above is preferably dried under reduced pressure or under vacuum, where for example, the drying temperature can be about 20 ° to about 60 ° C, preferably about 30 ° to about 50 ° C, and the drying time may be about 5 to about 48 hours, preferably about 10 to about 20 hours.

It is understood that the water content of the substantially solvent-free crystals according to the present invention is not greater than about 500 ppm, preferably not more than about 300 ppm, and, for even better results, not greater than about 200. ppm, and the alcohol content (e.g., ethanol) is not greater than about 200 ppm, preferably not more than about 100 ppm, and, for even better results, no greater than about 80 ppm. The water content and the alcohol content of the crystals depends on the conditions used in the suspension process and the drying process (particularly the treatment times) and, therefore, if the degree of desolvation is found to be insufficient , the duration of the suspension process and / or the drying process can be extended to achieve a more complete desolvation.

The substantially solvent-free crystals of the compound of the formula (1) or its salt, as produced in the above manner, can easily be verified by a known technique, such as X-ray powder diffraction analysis and water content. and the alcohol (ethanol) content thereof can be determined by analytical methods known per se. Specifically, the Karl-Fischer (KF) method can be mentioned for the water content, and gas chromatography for the alcohol content.

The substantially solvent-free crystals obtained above can be processed into the dosage forms desired by routine pharmaceutical procedures and are suggested for use as medicines, for example, anti-ulcer agents. For pharmaceutical manufacture, for example, the methods described in the Reference Examples may be employed.

The present invention is explained in detail in the following practicable examples, but is not limited to that illustrated in the Examples. In the following, the water content is measured by the Karl Fischer method, and the alcohol content is measured by gas chromatography.

Reference Example 1 Production of 2,3-dimethylpyridine N-oxide: One hundred grams of 2,3-lutidine is dissolved in 200 milliliters of glacial acetic acid, followed by the addition in drops of 120 grams of 35% aqueous hydrogen peroxide solution at about 40 ° C. The mixture is allowed to react at 105 ° C for about 2 hours. After completion of the reaction, the mixture is allowed to cool to about 50 ° C, followed by the addition of 5.0 g of p-formaldehyde. The resulting mixture is heated to 105 ° C to cause the reaction to take place for about 10 minutes. The resulting mixture is cooled to about 40 ° C, followed by the addition of 150 grams of 98% sulfuric acid. The resulting mixture is subjected to distillation under reduced pressure to evaporate the glacial acetic acid to give the 2,3-dimethylpyridine N-oxide as a sulfuric acid solution.

Reference Example 2 Production of 2,3-dimethyl-4-nitropyridine N-oxide: To the total sulfuric acid solution of 2,3-dimethylpyridine N-oxide as obtained in Example 1 of Reference, 130 grams of 98% sulfuric acid and 130 g of 98% nitric acid are added dropwise at approximately 80 ° C for 4 hours. The resulting mixture is allowed to react at the same temperature for 5 hours. The resulting mixture is cooled to about 40 ° C and poured into 1 liter of cold water at a temperature below 5 ° C, followed by the dropwise addition of 0.6 liters of sodium hydroxide solution at a temperature below 30 ° C. C. The resulting mixture is extracted three times, each with 1 liter of methylene chloride. The methylene chloride layers are combined and concentrated under reduced pressure to give the 2,3-dimethyl-4-nitropyridine N-oxide as a pale yellow crystalline residue. Yield: 141 grams (90% based on 2,3-lutidine).

Reference Example 3 Production of 2,3-dimethyl-4- (2,2,2-trifluoroethoxy) pyridine N-oxide To the whole amount of 2,3-dimethyl-4-nitropyridine N-oxide, which is obtained in Reference Example 2, 0.4 liters of 70% aqueous acetonitrile solution are added to make a solution, followed by the addition of 280 grams of trifluoroethanol, 9 grams of a 50% aqueous benzyltributylammonium chloride solution and 225 grams of potassium carbonate. The mixture is allowed to react at a reflux temperature for about 25 hours. The resulting mixture is cooled to about 60 ° C, followed by the addition of 0.2 liters of water. The resulting mixture is stirred and allowed to stand. The resulting organic layer is collected by decantation and concentrated under reduced pressure. 0.5 Liters of water are added to the concentrate to turn it into a solution, followed by three extractions with 0.5 liters of methylene chloride. The methylene chloride layer is combined and concentrated to give 2,3-dimethyl-4- (2,2,2-trifluoroethoxy) pyridine N-oxide as a pale yellow crystalline residue. Yield: 144 grams (70% based on 2, 3-lutidine).

Reference Example 4 Production of 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) iridine (HYD) In 0.3 liters of glacial acetic acid the entire amount of 2,3-dimethyl-4- (2,2,2-trifluoroethoxy) iridine N-oxide, which is obtained in Reference Example 3, is dissolved, followed by the addition of 0.3 liters of acetic anhydride. The resulting mixture is allowed to react at about 115 ° C for about 6 hours. After completion of the reaction, the resulting mixture is cooled to about 60 ° C, followed by the addition of 0.3 liters of water. The resulting mixture is concentrated under reduced pressure, followed by the addition of 25 milliliters of methanol and 0.2 liters of water. To the resulting mixture is added dropwise 0.2 liters of 30% aqueous sodium hydroxide solution at about 30 ° C to adjust its pH to 13, followed by stirring at about 35 ° C for 12 hours.

The resulting mixture is allowed to stand, and the supernatant is removed. To the resulting residue, 100 milliliters of methanol are added, followed by stirring at about 45 ° C for about 30 minutes to solubilize the precipitated crystals. While the resulting solution is maintained at about 20 ° C, 0.5 liter is added. of water to precipitate the crystals. The resulting mixture is cooled to about 5 ° C and maintained at rest. The precipitated crystals are collected by filtration, washed with water and dissolved in a mixed solution of 75 milliliters of 35% hydrochloric acid, 0.4 liters of water and 2.5 grams of diatomaceous earth. The resulting solution is adjusted to a pH of about 3 with a 30% aqueous sodium hydroxide solution, and insoluble compounds are filtered. The filtrate is washed three times, each with 200 milliliters of methylene chloride. After the addition of 5.0 grams of activated charcoal, the mixture is stirred at about 40 ° C for about 12 hours. The activated charcoal is filtered, and 80 milliliters of ethanol are added to the filtrate. The resulting mixture is neutralized to pH 7 with 30% aqueous sodium hydroxide solution to precipitate the crystals. The mixture is cooled to a temperature below 5 ° C, and the precipitated crystals are collected by filtration and washed with water. The obtained crystals are dried at about 37 ° C under reduced pressure for about 24 hours to give the 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) iridine as white crystals. Yield: 95 grams (46% based on 2, 3-lutidine).

Reference Example 5 Production of 2 - [[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] -methyl] thio] benzimidazole monohydrate 49. 9 Grams of 2-hydroxymethyl-3-methyl-4- (2, 2, 2-trifluoroethoxy) pyridine are dissolved in 0.4 liters of methylene chloride, followed by the dropwise addition of 24 milliliters of thionyl chloride for about 30 minutes. The mixture is allowed to react at a temperature greater than about 30 ° C for about 1 hour. After the completion of the reaction, 0.1 liter of water is added, and the methylene chloride is evaporated under reduced pressure. The residue is dissolved in 0.4 liters of methanol, followed by the addition of 34.2 grams of 2-benzimidazole thiol. To the mixture, 60 milliliters of a 30% aqueous sodium hydroxide solution are added dropwise at about 25 ° C for about 1 hour. The mixture is allowed to react at room temperature for approximately 0.5 hours. 0.3 liters of water are added to the resulting mixture, followed by stirring at a temperature below 10 ° C for about 30 minutes. The resulting mixture is adjusted to a pH of about 9 with 35% hydrochloric acid to precipitate the crystals. The resulting crystals are collected by filtration and washed with, in turn, 0.1 liters of 50% methanol and 0.2 liters of water. The obtained crystals are dried with hot air at a temperature lower than 50 ° C to give 2 - [[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] -methyl] thio] benzimidazole like white crystals. Yield: 81.0 grams (96.7% based on the HYD).

Reference Example 6 Production of 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) -pyridin-2-yl] -methylsulfinyl] benzimidazole monohydrate, monoethanol solvate.

Forty milligrams of vanadium (IV) acetylacetone are dissolved in 150 milliliters of ethanol, followed by the addition of 20.0 grams of 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) -pyridin-2 monohydride. -yl] -methylthio] benzimidazole and also dropwise addition of 6.14 grams of 35% aqueous hydrogen peroxide solution at 20 to 25 ° C. The mixture is allowed to react at the same temperature for about 5 hours. After the completion of the reaction, the aqueous solution of sodium thiosulfate (2.7 grams / 16 milliliters) is added, followed by vigorous stirring for about 10 minutes. The precipitated crystals are collected by filtration and washed with ice-water ethanol-water (8: 2) mixture. To the resulting crystals are added 90 milliliters of ethanol-water mixture (9: 1), and the mixture is heated to 60 to 70 ° C under stirring to dissolve the crystals. The insoluble compounds are filtered while the mixture is hot. The filtrate is cooled with ice to precipitate the crystals. The precipitated crystals are collected by filtration, washed with ice-cold ethanol-water (8: 2) mixture and dried under reduced pressure at room temperature to give the monohydrate of 2 - [[3-methyl4- (2.2 , 2-trifluoroethoxy) -pyridin-2-yl] -methylsulfinyl] benzimidazole, monoethanolate solvate as white needles. Yield: 21.2 grams (91.0%).

Example 1 Production of 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) -pyridin-2-yl] -methylsulfinyl-benzimidazole substantially free of solvent (hereinafter sometimes abbreviated as Compound A).

To 75 milliliters of ethanol-water mixture (9: 1) is added 70 μl. of 25% aqueous ammonium solution. While the solution is heated to about 60 ° C, 13.0 grams of j2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) -pyridin-2-yl] -methylsulfinyl] benzimidazole monohydrate, solvate of monoethanolate which is obtained in Reference Example 6, are added to the solution to dissolve them. The insoluble compounds are removed by filtration while the solution is hot. The filtrate is cooled with ice to precipitate the crystals. The precipitated crystals are collected by filtration to give wet crystals of 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) -pyridin-2-yl] -methylsulfinyl] benzimidazole monohydrate, monoethanolate solvate. Therefore, the obtained wet crystals are suspended in 53 milliliters of water and the suspension is stirred for 1 hour, while maintaining the temperature at 30 ° C. The crystals that appear are recovered by filtration, washed with 10 milliliters of water, and then dried at 40 ° C in vacuo for 10 hours to give 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy ) -pyridin-2-yl] -methylsulfinyl] benzimidazole as white needles. Yield: 9.72 grams (87.7%). P.f. 177-178 ° C (decomposition). Water content: 0.01%. Ethanol content: 63 ppm.

Comparative Example 1 Production of 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) -pyridin-2-yl] -methylsulfinyl] benzimidazole by a known method.

To 58 milliliters of ethanol-water mixture (9: 1) are added 54 μl. of 25% aqueous ammonium solution. The mixture is heated to about 60 ° C, followed by the addition of 10.0 grams of 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) -pyridin-2-yl] -methylsulfinyl] benzimidazole monohydrate. , monoethanolate solvate, which dissolve. The insoluble compounds are removed by filtration while the mixture is hot. The filtrate is cooled with ice to precipitate the crystals. The precipitated crystals are collected by filtration to give the monohydrate of 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) -pyridin-2-yl] -methylsulfinyl] benzimidazole, monoethanolate solvate as wet crystals. The crystals are dried at 40 ° C for 20 hours under vacuum to give 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) -pyridin-2-yl] -methylsulfinyl] -benzimidazole as white needles . Yield: 7.58 grams (89.0%). P.f. 177-178 ° C (decomposition). Water content: 0.12%. Ethanol content: 360 ppm.

Reference Example 7 Preparation (1) of an injection containing Compound A.

An aqueous solution of sodium hydroxide is added to 15 grams of Compound A, and the mixture is prepared in a solution. To the solution are added 30 grams of mannitol and 5 grams of meglumine, and the mixture is prepared in a solution of 1000 milliliters having a pH of 11.2. The solution is sterilized by filtration by a conventional method. The resulting solution is sealed in ampoules, each in an amount of 1 milliliter and dried by freezing by a conventional method to prepare the freeze-dried product containing Compound A.

Meanwhile, 750 grams of macrogol 400 is diluted with water for injection, followed by the addition of hydrochloric acid to prepare 2500 milliliters of an aqueous solution with a pH of 4.5. The resulting solution is sterilized by filtration by a conventional method and filled into ampoules, each in an amount of 2.5 milliliters. The vials are sealed and sterilized with high pressure steam. For administration, an injection is prepared by adding 2.5 milliliters of the macrogol solution to the freeze-dried product containing Compound A and dissolving it.

Reference Example 8 Preparation (2) of an injection containing Compound A.

Three hundred grams of Compound A, 600 grams of mannitol, 100 grams of meglumine and an aqueous solution of sodium hydroxide are mixed by a homomixer and solubilized to prepare 20 liters of a solution containing Compound A having a pH of 11.2. The resulting solution is sterilized by filtration by a conventional method, filled into vials, each in an amount of 2 milliliters, and dried by freezing in a conventional method to prepare the freeze-dried product containing Compound A.

Meanwhile, 15 kilograms of macrogol 400 are diluted with water for injection, followed by the addition of hydrochloric acid to prepare 50 liters of an aqueous solution of pH 4.5. The resulting solution is sterilized by filtration in a conventional manner and filled in ampoules, each in an amount of 5 milliliters. The ampoules are sealed and sterilized with high pressure steam. Concerning use, 5 milliliters of the above solution is added to the freeze-dried product containing Compound A, and the resulting mixture is prepared in a solution and used.

Reference Example 9.

Product (3) of an injection containing Compound A. 150 grams of Compound A are mixed with 300 grams of mannitol, followed by the addition of an aqueous solution of sodium hydroxide and dissolved. To the resulting solution 50 grams of meglumine are added, which is dissolved to prepare 10 liters of a solution of pH 11.3 containing Compound A. The resulting solution is sterilized by filtration by a conventional method, filled in flasks, each in an amount of 4 milliliters and dried by freezing by a conventional method to prepare the freeze-dried product containing Compound A.

Meanwhile, 7.5 kilograms of macrogol 400 are diluted with water for injection, followed by the addition of hydrochloric acid to prepare 25 liters of an aqueous solution of pH 4.5. The resulting solution is sterilized by filtration by a conventional method, filled in ampoules, each in an amount of 10 milliliters, sealed and sterilized with high pressure steam. Concerning administration, the injection is prepared by adding 10 milliliters of the macrogol solution to the freeze-dried product and dissolving it.

Reference Example 10 Preparation of capsules containing Compound A.

The capsules of the formula as indicated in Table 3 are prepared by the following method with the feed amount (1) or (2) as shown in Table 1 or Table 2, respectively. (1) Compound A and ingredients of item (3) through (6) are mixed well to prepare the powders. (2) The unspecified granules are placed in a centrifugally fluidized coating granulator (made by Freunt Industry Co. Ltd., CF-1000 in the case of the feed of Table 2 and CF-1300 in the case of feed of Table 3) and coated with the spray powder prepared above under spraying with an aqueous solution (7) of hydroxypropyl cellulose dissolved in purified water.

The resulting spherical granules are dried in vacuum at 40 ° C for 16 to 18 hours and sieved (500 μm and 1190 μm) to give granules of an active ingredient. Two batches of the granules are placed in a Flow Coater (made by Powrex Corp.) and coated with a suspension of (8) LD copolymer of methacrylic acid - (12) polysorbate 80 in purified water. To the coated granules (13) talc is added, and the mixture is screened (600 μm and 1420 μm and dried under vacuum at 42 ° C for 16 to 18 hours to give enteric granules.

The (14) talc and (15) light anhydride silicic acid are added to a batch of the enteric granules (in the amount processed in table 2, mixing is possible up to 5 batches, and in the amount processed in Table 3 , mixing is possible up to 3 batches). The mixture is prepared in granules mixed by a drum mixer (made by Showa Chemical Machinery Co.).

The blended granules are filled by a capsule filling machine (MG2 Co. or Zanasi Co.) in (16) No. 1 gelatin capsules, each in an amount of 30 milligrams and in (17) gelatin capsules. .3, each in an amount of milligrams Table 1 Amount Processed - 1 Common Composition 15 mg and 30 mg Capsules Active ingredient granules: (1) Compound A 4.481 kg * 1 (2) Spherical granules of sucrose Starch (unspecified) 15.950 (3) Magnesium carbonate 3.345 * 1 (4) Purified sucrose 8.931 * 1 (5) Corn starch 5.436 * 1 (6) Substituted hydroxypropyl cellulose low 5.974 * 1 (7) Hydroxypropylcellulose 0.203 Purified water (10.297L) Subtotal 43,500 kg oo Enteric granules: Granules of active ingredient 87,000 kg (8) Copolymer LD of methacrylic acid 13.5807 * 2, (Eudragit L30D-55 R) (45.269 kg) * 3, * 4 (9) Talc 4.0808 * 4 (10) Macrogol 6000 1.3398 * 4 (11) Titanium oxide 1.3398 * 4 (12) Polysorbate 80 0.690 * 4 Purified water (95.004L) * 4 (13) Talc 0.116 Subtotal 107,068 kg Mixed granules: * 5 Enteric granules 107.068 kg 214.136 kg 321.204 kg 428.272 kg 535.340 kg (14) Talc 0.058 0.116 0.174 0.232 0.290 (15) Light anhydride silicic acid 0.174 0.348 0.522 0.696 0.870 Subtotal 107,300 kg 214,600 kg 321,900 kg 429,200 kg 536,500 kg Capsules: Mixed granules 107,300 kg 214,600 kg 321,900 kg 429,200 kg 536,500 kg (16) Gelatin Capsule No. 1 * 6 290,000 580,000 870,000 1,160,000 1, 450,000 Capsules 00 (17) Gelatin capsule No. 3 * 7 580,000 1, 160,000 1,740,000 2,320,000 2,900,000 Capsules. * 1: More than 3% is processed * 2: Quantity of solid * 3: Quantity of solution (processed a solution) * 4: Processed more than 5% * 5: Mixing can be possible from 1 to 5 batches of enteric granules * 6: Number of capsules when filled as a 30 mg capsule * 7: Number of capsules when filled as a 15 mg capsule Table 2 Processed Amount - 2 Common Composition to Capsules of 15 mg and 30 mg Granules of active ingredient: (1) Compound A 6.953kg * 1 (2) Spherical granules of sucrose Dalmidon (unspecified) 24.750 (3) Magnesium carbonate 5.191 * 1 (4) Purified sucrose 13.860 * 1 (5) Corn starch 8.436 * 1 (6) Substituted hydroxypropyl cellulose low 9.270 * 1 (7) Hydroxypropylcellulose 0.315 Purified water (15.435L) -F- »O Subtotal 67,500 kg Enteric granules: Granules of active ingredient 135,000 kg (8) DL copolymer of methacrylic acid 21,0757 * 2, * 4 (Eudragit L30D-55 R) (70,250 kg) * 3, * 4 (9) Talc 6.332 * 4 ( 10) Macrogol 6000 2.079 * 4 (11) Titanium oxide 2.079 * 4 (12) Polysorbate 80 0.945 * 4 Purified water (98.910L) * 4 (13) Talc 0.180 Subtotal 166,140 kg Mixed granules: * 5 Enteric granules 166.140 kg 332.280 kg 498.420 kg (14) Talc 0.090 0.180 0.270 (15) Light anhydride silicic acid 0.270 0.540 0.810 Subtotal 166,500 kg 333,000 kg 499,500 kg Capsules: Mixed Granules 166,500 kg 333,000 kg 499,500 kg (16) Gelatin Capsule No. 1 * 6 450,000 900,000 1, 350,000 Capsules. -P » (17) Gelatin Capsule No. 3 * 7 900,000 1, 800,000 2,700,000 Capsules. * 1: More than 3% is processed * 2: Quantity of solid * 3: Quantity of solution (processed a solution) * 4: Processed more than 5% * 5: Mixing can be possible from 1 to 3 batches of enteric granules * 6: Number of capsules when filled as a 30 mg capsule * 7: Number of capsules when filled as a 15 mg capsule Table 3 Prescription per one capsule Composition 15 mg Capsule 30 mg Capsule (1) Compound A 15.0 mg 30.0 mg (2) Spherical granules of sucrose Starch (unspecified) 55.0 110.0 (3) Magnesium carbonate 11.2 22.4 (4) Purified sucrose 29.9 59.8 (5) Corn Starch 18.2 36.4 (6) Substituted Hydroxypropyl Cellulose Low 20.0 40.0 (7) Hydroxypropyl Cellulose 07 1.4 Subtotal 150.0 mg 300.0 mg ro Enteric granules: Granules of active ingredient 150.0 mg 300.0 mg (8) Methacrylic acid copolymer 22.3 44.6 (Eudragit L30D-55R) (9) Talc 6.7 13.4 (10) Macrogol 6000 2.2 4.4 (11) Titanium oxide 2.2 4.4 (12) Polisorbate 80 1.0 2.0 (13) Talc 0.2 0.4 Subtotal 184.6 mg 369.2 mg Mixed granules: Stranded granules 184.6 mg 369.2 mg (14) Talc 0.1 0.2 (15) Silicic acid of light anhydride 0.3 0.6 Subtotal 185.0 mg 370.0 mg Capsules: Mixed granules 185.0 mg 370.0 mg (16) Gelatin capsule No. 1 79.0 (17) Gelatin capsule No. 3 50.0 Subtotal 235.0 mg 449.0 mg Industrial Applicability The present invention provides a method for producing crystals of benzimidazole compounds substantially free of solvent and of uniform purity, which are of importance for medicines such as, for example, antiulcer agents, and which is an industrially advantageous method for a production on a large scale.

The substantially solvent-free crystals, which can be produced by the present method are more stable than those solvate crystals known to date, and the degree of decomposition of the compound is extremely low in the course of the production and storage step.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (10)

1. A method for producing a substantially solvent-free crystal of the compound of the formula: wherein ring A can be optionally substituted, R-1 represents hydrogen or a protecting group of N, each of R2, R3 and R4 is (1) a hydrogen atom, (2) an alkyl group, which is it may optionally be substituted with a halogen atom (s) or (3) an alkoxy group, which may be optionally substituted with a halogen or alkoxy atom (s); or its salt, which is characterized in that it comprises subjecting a solvate of the compound (I) or its salt to the treatment with a solvent.

2. The method according to claim 1, characterized in that the treatment with the solvent is to suspend the compound in water.

3. The method according to claim 1, characterized in that the protecting group of N in the compound (I) is an alkyl group, an acyl group, a carboalkoxy group, a carbamoyl group, an alkylcarbamoyl group, a group of dialkylcarbamoyl, an alkylcarbonylmethyl group, an alkoxycarbonylmethyl group or an alkylsulfonyl group.

4. The method according to claim 1, characterized in that R1 is a hydrogen atom.

5. The method according to claim 1, characterized in that the substituent on the A ring of the compound (I) is an alkoxy group, which can be optionally substituted by halogen.

6. The method according to claim 1, characterized in that ring A of compound (I) is unsubstituted.

7. The method according to claim 1, characterized in that R 2 is methyl or methoxy, R 2 is (1) C 1-4 alkoxy, which can be optionally substituted by fluorine (s) or (2) C 4 alkoxy-alkoxy C ? -8, R4 is a hydrogen or methyl atom.

8. The method according to claim 1, characterized in that compound (I) is 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) -pyridin-2-yl] methylsulfinyl-benzimidazole or its salt.

9. A substantially solvent-free crystal of the compound of the formula: characterized in that the ring A can be optionally substituted, R1 represents hydrogen or a protecting group of N, each of R2, R3 and R4 is (1) a hydrogen atom, (2) an alkyl group, which can be substituted optionally with a halogen atom (s) or (3) an alkoxy group, which may be optionally substituted with a halogen or alkoxy atom (s); or its salt.

10. The crystal according to claim 9, characterized in that the compound (I) is 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) -pyridin-2-yl] methylsulfinyl-benzimidazole.