Crystals of benzimidazole derivatives and their production

ES 2 199 356 T3

DESCRIPTION

Benzimidazole derivative crystals and their production.

Technical field

The present invention provides crystals of benzimidazole derivatives, which are of value as a medicine as well as an anti-ulcer agent, and a method of producing the crystals.

Background technique

Benzimidazole derivatives, that is, 2- (2-pyridylmethylsulfinyl) benzimidazole derivatives that are valuable as a medicine as well as an anti-ulcer agent, have been known from the publication of European patent application No. 302720 (application for Japanese Patent Laid-open No. 1-131176), European Patent Application Publication No. 5129 (Japanese Patent Application Laid-Open No. 58192880), 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 Publications n^you 45200, 74341, 80602, 174726, 175464 and British Patent Application Publication No. 2134523.

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 was obtained in the form of 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 ethanol: water (9: 1) to the residue, recovering the resulting crystals by filtration, rinsing them, dissolving this crystalline culture in ethanol: water (9: 1) at an elevated temperature (65-70 ° C), filtering the solution hot, cooling the filtrate with ice, recovering the resulting crystals by filtration, rinsing and drying them in vacuo.

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

However, when the 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] -methyl-sulfinyl] benzimidazole production process is followed as described in said EP-302720, the Water and ethanol can hardly be removed from the product and the resulting crystals inevitably contain permissible amounts of water and ethanol. Thus, the benzimidazole compound provided by the procedure described in the above documentation is a solvate containing a molecule of water and ethanol, and it is very difficult to desolvate the compound by drying under vacuum without diminishing the stability of the product.

There is a serious problem with the above benzimidazole compound in the form of a solvate, particularly a hydrate, being heat unstable, it easily decomposes in the vacuum drying stage, particularly under heating, thus lowering the purity of the benzimidazole product compound. Therefore, there has been an unresolved demand for a supply of solvent-free crystals of such a benzimidazole compound and for the development of highly workable, large-scale production and efficient desolvation technology to provide such crystals.

Description of the invention

Considering the prior state of the art, the inventors of the present invention made an intense investigation directed to the improvements in the aforementioned aspects with the purpose of providing crystals of said imidazole compound substantially free of solvent that is valuable as a medicine, for example as an anti-ulcer agent and so on, and a large-scale production, very workable, and an efficient desolvation technology to provide crystals of this type. As a consequence, they discovered, to everyone's surprise, that the desired desolvation can be easily achieved by oxidizing said 2- (2-pyridylmethylthio) benzimidazole compound to the corresponding 2- (2-pyridylmethylsulfinyl) benzimidazole compound, recrystallizing the latter from within aqueous alcohol giving crystals solvated with water and alcohol of said compound 2- (2-pyridylmethylsulfinyl) benzimidazole, and suspending and stirring the crystals in warm water, the procedure of which causes, unexpectedly, a transformation of said solvate crystals into substantially solvent-free crystals, followed by drying under reduced pressure. The inventors further discovered to their own surprise that the crystals of said substantially solvent-free benzimidazole compound thus obtained are remarkably stable compared to conventional benzimidazole solvate, and completely free of decomposition in the course of vacuum drying.

The present invention provides:

(1) A method for producing a crystal of the compound of formula (I):

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wherein ring A may optionally be substituted with a substituent selected from halogen, C 1-7 alkyl, cyano, carboxy, C 1-4 alkoxycarbonyl in its alkoxy moiety, C 1-4 alkoxycarbonylalkyl in each one of its alkoxy and alkyl moieties, carbamoyl, carbamoylalkyl with 1 to 4 carbon atoms in its moiety alkyl, hydroxy, C1-5 alkoxy, C1-7 hydroxyalkyl, halogenated C1-7 alkyl, halogenated C1-4 alkoxy, C1- acyl 4, carbamoyloxy, nitro, (C 1-4 acyl) oxy, aryl, aryloxy, (C 1-6 alkyl) thio and (C 1-6 alkyl) sulfinyl;

R¹ represents hydrogen or an N-protecting group selected from a C1-5 alkyl group, a C1-4 acyl group, an alkoxycarbonyl group with 1 to 4 carbon atoms in its alkoxy residue, a carbamoyl group, an alkylcarbamoyl group with 1 to 4 carbon atoms in its alkyl moiety, a dialkylcarbamoyl group with 1 to 4 carbon atoms in each of its alkyl moieties, and an alkylcarbonylmethyl group with 1 to 4 carbon atoms in its alkyl moiety, and an alkoxycarbonylmethyl group with 1 to 4 carbon atoms in its alkoxy moiety;

each of the R² , R³ and R⁴ is (1) a hydrogen atom, (2) a C1-4 alkyl group which may optionally be substituted with a halogen atom or atoms, or (3) a C1-8 alkoxy group which may optionally be substituted with a halogen or C1-4 alkoxy atom or atoms;

wherein the crystal has a water content not greater than 500 ppm and a C1-6 alcohol content not greater than 200 ppm, which method comprises subjecting a solvate of compound (I) with water and C1-6 alcohol, the solvate of which is It is obtained by recrystallization with the use of water and C1-6 alcohol, to a solvent elimination treatment when suspended, allowed to stand or stirred in water, and then dried.

(2) The method of point (1), in which R¹ is a hydrogen atom, (3) The method of point (1), in which the substituent on ring A of compound (1) is a C1-4 alkoxy group which, optionally, may be substituted with halogen, (4 ) The method of point (1), in which ring A of compound (I) is unsubstituted, (5) The method of point (1), in which R² is methyl or methoxy, R³ is C1-4 alkoxy which, optionally, may be substituted with one or more fluorine atoms or (C1-4 alkoxy) - (C1-8 alkoxy), and R⁴ is a hydrogen or methyl atom, and (6) The method of item (1), wherein the compound (I) is 2 [[3-methyl-4- (2,2,2-trifluoroethoxy) -pyridine- 2-yl] methylsulfinyl] -benzimidazole.

Best way to carry out the invention

The various definitions related to the above chemical formula and the present invention, in general, and preferred examples of species meeting the definitions are now presented.

With regard to formula (I), the halogen mentioned above includes fluorine, chlorine, bromine, etc., with fluorine being particularly preferred.

The aforementioned alkyl is C 1-7 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and heptyl.

The alkoxycarbonyl mentioned above is one containing 1 to 4 carbon atoms in the alkoxy moiety, including methoxycarbonyl (CH3 OOC-) and ethoxycarbonyl (C2 H5 OOC-), among others.

The carboalkoxyalkyl mentioned above is one that contains 1 to 4 carbon atoms in each of its alkoxy and alkyl moieties, thus including carbomethoxymethyl (CH3 OOCCH2 -), carbomethoxyethyl (CH3 OOCC2 H4 -), carboethoxymethyl (C2H5 OOCCH2-), and carboethoxyethyl (C2H5OOCC2H4-), among others.

The aforementioned carbamoylalkyl is one containing 1 to 4 carbon atoms in its alkyl moiety, including carbamoylmethyl (H2 NCOCH2 -) and carbamoylethyl (H2 NCOC2 H4 -), among others.

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

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

The halogenated alkyl mentioned above is one containing 1 to 7 carbon atoms in its alkyl moiety, including difluoromethyl and trifluoromethyl, to name just a few preferred examples.

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

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

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

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

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

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

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

With regard, furthermore, to formula (1), ring A is preferably unsubstituted or substituted, among the aforementioned substituent groups, with halogen, alkyl, alkoxy, haloalkyl or halogenoalkoxy (more preferably, species such as methoxy, trifluoromethyl or difluoromethoxy). Particularly preferred are cases where such a substituent is present at the 4- or 5-position of the benzimidazole ring.

R¹ in formula (1) it represents a hydrogen atom or an N-protecting group.

The N-protecting group for R¹ includes alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, and alkylsulfonyl.

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

Acyl includes the same species mentioned for the substituent on ring A.

Carboalkoxy includes the same species mentioned for the substituent on ring A.

Alkylcarbamoyl, which can be represented by the formula: alkyl-NH-CO-, is one containing 1 to 4 carbon atoms in its alkyl moiety, such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, etc.

Dialkylcarbamoyl, which can be represented by the formula: (alkyl) 2N-CO-, is one that contains 1 to 4 carbon atoms in each of its alkyl moieties, including dimethylcarbamoyl, diethylcarbamoyl, and N-methyl-Netylcarbamoyl, among others.

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

Alkoxycarbonylmethyl, which can be represented by the formula: alkyl-OCO-CH2 -, is a group in which said alkyl contains 1 to 4 carbon atoms, thus including methoxycarbonylmethyl, ethoxycarbonylmethyl and propoxycarbonylmethyl, among others.

Alkylsulfonyl, which can be represented by the formula: alkyl-SO2 -, is one containing 1 to 4 carbon atoms in its alkyl moiety, including methylsulfonyl, ethylsulfonyl, propylsulfonyl, and isopropylsulfonyl, etc.

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

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

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

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

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

The alkoxy of said alkoxy optionally substituted with halogen or alkoxy as mentioned for R² , R³ and R⁴is 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 said optionally halogen-substituted alkoxy includes fluorine, chlorine, bromine, etc., with fluorine being particularly preferred.

Halogen-substituted alkoxy is alkoxy of 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, which are substituted by 1 to 8 (preferably 3 or 4) fluorine atoms, such as 2,2,2-trifluoroethoxy, 2 , 2,3,3,3-pentafluoropropoxy, 1- (tri-fluoromethyl) -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-octafluoro-pentoxy, etc. Particularly preferred is 2,2,2-trifluoroethoxy or 2,2,3,3-tetrafluoropropoxy. With regard to chlorine or bromine substituted alkoxy, the species available after replacement of fluorine with chlorine or bromine in the aforementioned species for fluorine substituted alkoxy may also be mentioned.

Alkoxy-substituted alkoxy includes (C1-4 alkoxy) - (C1-8 alkoxy) (particularly, (C1-4 alkoxy) - (C1-4 alkoxy)), such as 3-methoxypropoxy, 2-methoxyethoxy, 3-ethoxypropoxy, 2-ethoxyethoxy, etc., with 3-methoxypropoxy being particularly preferred.

In formula (I), R² and R⁴ are preferably 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 has been substituted with 3 to 4 halogen atoms, or methoxy.

With regard, furthermore, to the compound of formula (I), the specific preferred 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 with 3 or 4 fluorine atoms, methoxy, or 3-methoxypropoxy, and R⁴ it is hydrogen or methyl.

Specifically, the compound of formula (I) includes but is not limited to:

2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] -benzimidazole,

2 - [[3,5-dimethyl-4-methoxypyridin-2-yl] methylsulfinyl] -5-methoxy-benzimidazole,

2 - [[4- (3-methoxypropoxy) -3-methylpyridin-2-yl] methylsulfinyl] benzimidazole sodium salt, and

5-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 ways described in the documents mentioned above, that is, European Patent Application Publication No. 302720 (Japanese Patent Application Laid-open No. ), European Patent Application Publication No. 5129 (Japanese Patent Application Open for Public Consultation No. 58-192880), Japanese Patent Application Open for Public Consultation No. 61-22079, Japanese Patent Application Laid-Open No. 64-6270, U.S. Patent No. No. 4,255,431, European Patent Application Publication No.^you 45200, 74341, 80602, 174726, 175464 and British Patent Application Publication No. 2134523, or methods analogous thereto.

The benzimidazole compound has an asymmetric center at the sulfur atom. Namely, it can be present as either two kinds of isomers, or ·.

s ~ * ~~ s—

The above benzimidazole compound can be obtained in the form of crystals of its solvate with water and alcohol by recrystallization in the corresponding aqueous alcohol according, for example, with the purification procedure described in European patent application publication No. 302720 (Japanese patent application opened

ES 2 199 356 T3 for consultation by the public n ° 1-131176) or any procedure analogous to it. The aforementioned alcohol includes C1-6 alcohols (eg, methanol, ethanol, isopropyl alcohol, etc.), with ethanol being particularly preferred. The aqueous alcohol can be, for example, one containing about 2 to about 30 parts by volume of an alcohol (especially ethanol), preferably about 5 to about 15 parts by volume (especially ethanol) for each part by volume of water. To be specific, a mixture consisting of an alcohol (especially ethanol) and water in a ratio of about 9: 1 volume / volume can be used.

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

According to the process of the invention, the above-mentioned solvate crystals are suspended, allowed to stand or stirred in water. As a result of this procedure, the solvate crystals are desolvated due to a morphological transformation. Although the conditions of this standing or suspending procedure, such as the amount and temperature of the water used and the stirring time, can be sensibly selected, the following conditions can typically be mentioned. Regarding the amount of water, 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 range from room temperature (about 15 to about 30 ° C) to about 90 ° C, preferably from about 30 ° C to about 50 ° C. The stirring time can range from about 0.5 to about 5 hours, preferably from about 1 to about 2 hours.

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

It will be understood that the water content according to the present invention is not more than 500 ppm, preferably not more than about 300 ppm, and, for even better results, not more than 200 ppm, and the alcohol content (eg ethanol) it is not more than about 200 ppm, preferably not more than about 100 ppm, and, for still better results, not more than about 80 ppm. The water content and the alcohol content of the crystals depend on the conditions used in said suspension procedure and in said drying procedure (particularly the treatment times) and, therefore, if the degree of desolvation is found to be insufficient. , the duration of said suspension process and / or said drying process can be extended to achieve a more complete desolvation.

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

The crystals obtained above can be processed into desired dosage forms by routine pharmaceutical procedures, and presented for use as medicaments, eg, anti-ulcer agents. For pharmaceutical manufacture, for example, the procedures described in the Reference Examples may be employed.

The present invention is explained in detail in the following working examples, but is not limited to what is 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 was dissolved in 200 ml of glacial acetic acid, followed by dropwise addition of 120 g of 35% aqueous hydrogen peroxide solution at about 40 ° C. The mixture was allowed to react at 105 ° C for about 2 hours. After completion of the reaction, the mixture was cooled to about 50 ° C, followed by the addition of 5.0 g of p-formaldehyde. The resulting mixture was heated to 105 ° C to cause the reaction to take place for about 10 minutes. The resulting mixture was cooled to about 40 ° C, followed by the addition of 150 g of 98% sulfuric acid. The resulting mixture was subjected to distillation under reduced pressure to evaporate the glacial acetic acid to give 2,3-dimethylpyridine N-oxide as a sulfuric acid solution.

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Reference example 2

Production of 2,3-dimethyl-4-nitropyridine N-oxide

To all the sulfuric acid solution of 2,3-dimethylpyridine N-oxide obtained in Reference Example 1, 130 g of 98% sulfuric acid and 130 g of 98% nitric acid were added dropwise. to approximately

80 ° C for 4 hours. The resulting mixture was allowed to react at the same temperature for 5 hours. The resulting mixture was cooled to about 40 ° C and poured into cold water below 5 ° C, followed by dropwise addition of 0.6 L of 30% sodium hydroxide solution to less than 30 ° C. The resulting mixture was extracted three times, each with 1 L. of methylene chloride. The obtained methylene chloride layers were combined and concentrated under reduced pressure to give 2,3-dimethyl-4-nitropyridine N-oxide as a pale yellow crystalline residue. Yield: 141 g (90% based on 2,3-lutidine).

Reference example 3

Production of 2,3-dimethyl-4- (2,2,2-trifluoroethoxy) -pyridine N-oxide

To the entire amount of 2,3-dimethyl-4-nitropyridine N-oxide obtained in Reference Example 2, 0.4 L of 70% acetonitrile aqueous solution was added to make a solution, followed by addition of 280 g of trifluoroethanol, 9 g of 50% benzyltributylammonium chloride aqueous solution and 225 g of potassium carbonate. The mixture was allowed to react at reflux temperature for about 25 hours. The resulting mixture was cooled to approximately 60 ° C, followed by the addition of 0.21 of water. The resulting mixture was stirred and allowed to settle. The resulting organic layer was collected by decantation and concentrated under reduced pressure. 0.5 L of water was added to the concentrate to make it a solution, followed by three extractions with 0.5 L of methylene chloride. The methylene chloride layer was combined and concentrated to give 2,3-dimethyl-4- (2,2,2-trifluoroethoxy) pyridine N-oxide as a pale yellow residue. Yield: 144 g (70% based on 2,3-lutidine).

Reference example 4

Production of 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) -pyridine (HYD)

In 0.3 l of glacial acetic acid, the entire amount of 2,3-dimethyl-4- (2,2,2-trifluoroethoxy) pyridine N-oxide that had been obtained in Reference Example 3 was dissolved, followed by addition of 0.3 l of acetic anhydride. The resulting mixture was allowed to react at about 115 ° C for about 6 hours. After completion of the reaction, the resulting mixture was cooled to about 60 ° C, followed by the addition of 0.3 L of water. The resulting mixture was concentrated under reduced pressure, followed by the addition of 25 ml of methanol and 0.2 L of water. To the resulting mixture, 0.2 L of 30% aqueous sodium hydroxide solution was added dropwise at about 30 ° C to adjust upHa13, followed by stirring at about 35 ° C for 12 hours.

The resulting mixture was allowed to stand, and the supernatant was removed. To the resulting residue, 100 ml of methanol was added, followed by stirring at about 45 ° C for about 30 minutes to solubilize the precipitated crystals. Although the resulting solution was kept at about 20 ° C, 0.5 L of water was added to precipitate the crystals. The resulting mixture was cooled to approximately 5 ° C and allowed to settle. The precipitated crystals were collected by filtration, washed with water and dissolved in a mixed solution of 75 ml of 35% hydrochloric acid, 0.4 l of water and 2.5 g of diatomaceous earth. The resulting solution was adjusted to a pH of about 3 with 30% aqueous sodium hydroxide solution and the insolubles were filtered. The filtrate was washed three times, each with 200 ml of methylene chloride. After the addition of 5.0 g of activated charcoal, the mixture was stirred at about 40 ° C for about 12 hours. The activated charcoal was filtered, and 80 ml of ethanol was added to the filtrate. The resulting mixture was neutralized to pH 7 with 30% aqueous sodium hydroxide solution to precipitate crystals. The mixture was cooled to less than 5 ° C and the precipitated crystals were collected by filtration and washed with water. The obtained crystals were dried at about 37 ° C under reduced pressure for about 24 hours to give 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine as white crystals. Yield: 95 g (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 g of 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) -pyridine were dissolved in 0.4 l of methylene chloride, followed by dropwise addition of 24 ml of chloride thionyl for approximately 30 minutes. The mixture was allowed to react at greater than about 30 ° C for about 1 hour. After completion of the reaction, 0.1 L of water was added and the methylene chloride was evaporated under reduced pressure. The residue was dissolved in 0.4 L of methanol, followed by the addition of 34.2 g of 2-benzimidazolthiol. To the mixture, 60 ml of a 30% aqueous sodium hydroxide solution was added dropwise at about 25 ° C over about 1 hour. The mixture was allowed to react at room temperature for about 0.5 hours. To the resulting mixture, 0.3 l of water was added, followed by stirring at less than 10 ° C for about 30 minutes. The resulting mixture was adjusted to a pH of about 9 with 35% hydrochloric acid to precipitate crystals. The resulting crystals

ES 2 199 356 T3 were collected by filtration and washed with, alternatively, 0.1 l of 50% methanol and 0.2 l of water. The crystals obtained were dried with hot air at less than 50 ° C giving 2 - [[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] -methyl] thio] benzimidazole in the form of crystals. white. Yield: 81.0 g (96.7% based on HYD).

Reference example 6

Production of solvate monoethanolate and 2 - [[[3-methyl-4- (2,2,2-trifluoroethoxy) -pyridin] -2-yl] methylsulfinyl] -benzimidazole monohydrate

Forty mg of acetylacetone-vanadium (IV) was dissolved in 150 ml of ethanol, followed by addition of 20.0 g of 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) -pyridine- monohydride 2-yl] methylthio] -benzimidazole and additional dropwise addition of 6.14 g of aqueous hydrogen peroxide solution between 20 and 25 ° C. The mixture was allowed to react at the same temperature for about 5 hours. After completion of the reaction, aqueous sodium thiosulfate solution (2.7 g / 16 ml) was added, followed by vigorous stirring for about 10 minutes. The precipitated crystals were collected by filtration and washed with ice cold ethanol: water (8: 2). To the resulting crystals, 90 ml of ethanol: water mixture (9: 1) was added, and the mixture was heated to 60-70 ° C under stirring to dissolve the crystals. Insolubles were filtered while the mixture was hot. The filtrate was ice-cooled to precipitate the crystals. The precipitated crystals were collected by filtration, washed with ice-cold ethanol: water (8: 2) and dried under reduced pressure at room temperature to give 2 [[3-methyl-4- (2,2 , 2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] -benzimidazole in the form of white needles. Yield: 21.2 g (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 ml of ethanol: water (9: 1) mixture was added 70 µl of 25% aqueous ammonia solution. While the solution was heated to about 60 ° C, 13.0 g of the 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) pyridine monoethanolate solvate was added to the solution to be dissolved. 2-yl] methylsulfinyl] -benzimidazole obtained in Reference Example 6. Insolubles were filtered off while the solution was hot. The filtrate was ice-cooled to precipitate crystals. The precipitated crystals were collected by filtration to give wet crystals of solvate monohydrate and monoethanolate of 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole. The wet crystals thus obtained were suspended in 53 ml of water and the suspension was stirred for 1 hour while maintaining the temperature at 30 ° C. The emerged crystals were recovered by filtration, washed with 10 ml of water, and then dried at 40 ° C in vacuo for 10 hours to give 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin2 -yl] methylsulfinyl] benzimidazole in the form of white needles. Yield: 9.72 g (87.7%). Melting point 177-178 (decomposes). 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 ml of ethanol: water mixture (9: 1) was added 54 µl of 25% aqueous ammonia solution. The mixture was heated to approximately 60 ° C, followed by the addition of 10.0 g of 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] -methylsulfinyl solvate monohydrate and monoethanolate. benzimidazole, which dissolved. Insolubles were filtered off while the mixture was hot. The filtrate was ice-cooled to precipitate the crystals. The precipitated crystals were collected by filtration to give 2 [[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole monohydrate and monoethanolate solvate as wet crystals. The crystals were dried at 40 ° C for 20 hours in vacuo to give 2 - [[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] -benzimidazole as white needles. . Yield: 7.58 g (89.0%). Melting point 177-178 (decomposes)

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 was added to 15 g of Compound A, and the mixture was made into a solution. To the solution, 30 g of mannitol and 5 g of meglumine were added, and the mixture was prepared in a 1000 ml solution having pH 11.2. The solution was sterilized by filtration by a conventional method. The resulting solution was sealed in ampoules each in an amount of 1 ml and lyophilized by a conventional method to prepare lyophilized product containing Compound A.

Meanwhile, 750 g of macrogol 400 is diluted with water for injection, followed by addition of hydrochloric acid to prepare 2500 ml of an aqueous solution with pH 4.5. The resulting solution was sterilized by filtration

ES 2 199 356 T3 by a conventional method and was filled into ampoules each in an amount of 2.5 ml. The ampoules were sealed and sterilized with high pressure steam. For administration, an injection is prepared by adding 2.5 ml of the macrogol solution to the lyophilized 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 g of mannitol, 100 g of meglumine and an aqueous solution of sodium hydroxide were mixed by a homomixer and solubilized to prepare 20 L of a solution containing Compound A with pH 11.2. The resulting solution was sterilized by filtration by a conventional method, filled into vials in an amount of 2 ml, and lyophilized by a conventional method to prepare lyophilized product containing Compound A.

Meanwhile, 15 kg of macrogol 400 was diluted with water for injection, followed by addition of hydrochloric acid to prepare 50 µl of an aqueous solution of pH 4.5. The resulting solution was sterilized by filtration in a conventional manner and filled into ampoules each with an amount of 5 ml. The ampoules were sealed and sterilized with high pressure steam. After use, 5 ml of the latter solution was added to the lyophilized product containing Compound A, and the resulting mixture was made into a solution and used.

Reference example 9

Production (3) of an injection containing Compound A

150 g of Compound A was mixed with 300 g of mannitol, followed by addition of an aqueous sodium hydroxide solution and dissolved. To the resulting solution, 50 g of meglumine was added, which was dissolved to prepare 10 L of a pH 11.3 solution containing Compound A. The resulting solution was sterilized by filtration by a conventional method, filled into vials each in an amount of 4 ml, and lyophilized by a conventional method to prepare lyophilized product containing Compound A.

Meanwhile, 7.5 kg of macrogol 400 was diluted with water for injection, followed by addition of hydrochloric acid to prepare 25 L of an aqueous solution of pH 4.5. The resulting solution was sterilized by filtration by a conventional method, filled into ampoules each with a quantity of 10 ml, sealed and sterilized with high pressure steam. In administration, the injection is prepared by adding 10 ml of the macrogol solution to the lyophilized product and dissolving it.

Reference Example 10

Preparation of capsules containing Compound A

Capsules of the formula as indicated in Table 3 were 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 from (3) to (6) were mixed well to prepare powders. (2) No equals were put into centrifugally fluidized coating granulator (manufactured by Freunt Industry Co. Ltd., CF-1000 in the case of the feed of Table 2 and CF-1300 in the case of the feed of Table 3) and was coated with medicinal powders for external use previously prepared by spraying with an aqueous solution (7 ) of hydroxypropyl cellulose dissolved in purified water.

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

(14) Talc and (15) light anhydride silicic acid were added to 1 batch of enteric granules (in the processed quantity in Table 2, it is possible to mix up to 5 batches, and in the processed quantity in Table 3 it is possible to mix up to 3 batches). The mixture was prepared into mixed granules by a drum mixer (manufactured by Showa Chemical Machinery Co.).

The mixed granules were filled by a capsule filling machine (MG2 Co. or Zanasi Co.) into (16) # 1 gelatin capsules each in an amount of 30 mg and into (17) # 3 gelatin capsules each. one in an amount of 15 mg.

ES 2 199 356 T3

TABLE 1

Quantity-1 processed

Composition

Common for 15mg and 30mg capsules

Active ingredient granules:

<td> (1)</td><td>Compound A</td><td>4.481 kg</td><td> *1</td>

<td> (2)</td><td>Spherical (non-equal) granules of sucrose-starch</td><td> 15,950</td><td></td>

<td> (3)</td><td>Magnesium carbonate</td><td> 3,345</td><td> *1</td>

<td> (4)</td><td>Purified sucrose</td><td> 8,931</td><td> *1</td>

<td> (5)</td><td>Cornstarch</td><td> 5,436</td><td> *1</td>

<td> (6)</td><td>Low substituted hydroxypropyl cellulose</td><td> 5,974</td><td> *1</td>

<td> (7)</td><td>Hydroxypropyl cellulose</td><td> 0,203</td><td></td>

Purified water (10,297 l)

Subtotal 43,500 kg

Enteric granules:

<td> (8)</td><td>Active ingredient granules LD (low density) copolymer of methacrylic acid</td><td>87,000 kg 13,5807</td><td> *2, *4</td>

<td> (9)</td><td>(Eudragit L30D-55^R) talcum powder</td><td>(45.269 kg)</td><td> *3, *4</td>

<td> (10)</td><td>Macrogol 6000</td><td> 4,0808</td><td> *4</td>

<td> (11)</td><td>Titanium oxide</td><td> 1,3398</td><td> *4</td>

<td> (12)</td><td>Polysorbate 80</td><td> 1,3398</td><td> *4</td>

<td></td><td>Purified water</td><td> 0,690</td><td> *4</td>

<td> (13)</td><td>talcum powder</td><td>(95.004 l)</td><td> *4</td>

<td></td><td></td><td> 0,116</td><td></td>

Subtotal 107,068 kg

Mixed granules: * 5

<td>Enteric granules</td><td>107.068 kg</td><td>214,136 kg</td><td>321.204 kg</td><td>428,272 kg</td><td>535,340 kg</td>

<td>(14) Talc</td><td> 0,058</td><td> 0,116</td><td> 0,174</td><td> 0,232</td><td> 0,290</td>

<td>(15) Silicic acid from</td><td> 0,174</td><td> 0,348</td><td> 0,522</td><td> 0,696</td><td> 0,870</td>

light anhydride

<td>Subtotal</td><td>107,300 kg</td><td>214,600 kg</td><td>321,900 kg</td><td>429,200 kg</td><td>536,500 kg</td>

<td>Capsules: Mixed granules</td><td>107,300 kg</td><td>214,600 kg</td><td>321,900 kg</td><td>429,200 kg</td><td>536,500 kg</td>

<td>(16) Capsule n ° 1</td><td> 290,000</td><td> 580,000</td><td> 870,000</td><td> 1.160,000</td><td>1,450,000 Cap.</td>

<td>gelatin * 6</td><td></td><td></td><td></td><td></td><td></td>

<td>(17) Capsule # 3</td><td> 580,000</td><td> 1.160,000</td><td> 1.740,000</td><td> 2.320,000</td><td>2,900,000 Cap.</td>

<td>gelatin * 7</td><td></td><td></td><td></td><td></td><td></td>

* 1: More than 3% processed * 2: Amount of solid * 3: Amount of solution (one solution was processed) * 4: More than 5% processed * 5: It may be possible to mix 1 to 5 batches of granules enteric * 6: Number of capsules when filled as 30 mg capsules * 7: Number of capsules when filled as 15 mg capsules

ES 2 199 356 T3

TABLE 2

Quantity-2 processed

Composition

Common for 15mg and 30mg capsules

Active ingredient granules:

<td> (1)</td><td>Compound A</td><td>6,953 kg</td><td> *1</td>

<td> (2)</td><td>Spherical (non-equal) granules of sucrose-starch</td><td> 24,750</td><td></td>

<td> (3)</td><td>Magnesium carbonate</td><td> 5,191</td><td> *1</td>

<td> (4)</td><td>Purified sucrose</td><td> 13,360</td><td> *1</td>

<td> (5)</td><td>Cornstarch</td><td> 8,436</td><td> *1</td>

<td> (6)</td><td>Low substituted hydroxypropyl cellulose</td><td> 9,270</td><td></td>

<td> (7)</td><td>Hydroxypropyl cellulose</td><td> 0,315</td><td></td>

<td></td><td>Purified water</td><td>(15,435 l)</td><td></td>

<td></td><td>Subtotal</td><td>67,500 kg</td><td></td>

<td colspan="2">Enteric granules:</td><td></td><td></td>

<td></td><td>Active ingredient granules</td><td>135,000 kg</td><td></td>

<td> (8)</td><td>LD (low density) copolymer of methacrylic acid</td><td> 21,0757</td><td> *2, *4</td>

<td></td><td>(Eudragit L30D-55^R)</td><td></td><td></td>

<td> (9)</td><td>talcum powder</td><td>(70,250 kg)</td><td> *3, *4</td>

<td> (10)</td><td>Macrogol 6000</td><td> 6,332</td><td> *4</td>

<td> (11)</td><td>Titanium oxide</td><td> 2,079</td><td> *4</td>

<td> (12)</td><td>Polysorbate 80</td><td> 2,079</td><td> *4</td>

<td></td><td>Purified water</td><td> 0,945</td><td> *4</td>

<td> (13)</td><td>talcum powder</td><td>(98,910 l)</td><td> *4</td>

<td></td><td></td><td> 0,180</td><td></td>

<td></td><td>Subtotal</td><td>166,140 kg</td><td></td>

<td>Mixed granules: * 5</td><td></td><td></td><td></td>

<td>Enteric granules</td><td>166,140 kg</td><td>332,280 kg</td><td>498,420 kg</td>

<td>(14) Talc</td><td> 0,090</td><td> 0,180</td><td> 0,270</td>

<td>(15) Silicic acid light anhydride</td><td> 0,270</td><td> 0,540</td><td> 0,810</td>

<td>Subtotal</td><td>166,500 kg</td><td>333,000 kg</td><td>499,500 kg</td>

<td>Capsules:</td><td></td><td></td><td></td>

<td>Mixed granules</td><td>166,500 kg</td><td>333,000 kg</td><td>499,500 kg</td>

<td>(16) # 1 Gelatin Capsule * 6</td><td> 450,000</td><td> 900,000</td><td>1,350,000 Cap.</td>

<td>(17) # 3 Gelatin Capsule * 7</td><td> 900,000</td><td> 1.800,000</td><td>2,700,000 Cap.</td>

* 1: More than 3% processed * 2: Amount of solid * 3: Amount of solution (one solution was processed) * 4: Processed more than 5% * 5: It may be possible to mix 1 to 5 batches of enteric granules * 6: Number of capsules when filled as 30 mg capsules * 7: Number of capsules when filled as 15 mg capsules

ES 2 199 356 T3

TABLE 3

Prescription per capsule

<td>Composition</td><td>15 mg capsule</td><td>30 mg capsule</td>

<td>(1) Compound A</td><td>15.0 mg</td><td>30.0 mg</td>

<td>(2) Spherical sucrose-starch granules (not equal)</td><td> 55,0</td><td> 110,0</td>

<td>(3) Magnesium carbonate</td><td> 11,2</td><td> 22,4</td>

<td>(4) Purified sucrose</td><td> 29,9</td><td> 59,8</td>

<td>(5) Corn starch</td><td> 18,2</td><td> 36,4</td>

<td>(6) Low substituted hydroxypropyl cellulose</td><td> 20,0</td><td> 40,0</td>

<td>(7) Hydroxypropylcellulose</td><td> 0,7</td><td> 1,4</td>

<td>Subtotal</td><td>150.0 mg</td><td>300.0 mg</td>

<td>Enteric granules:</td><td></td><td></td>

<td>Active ingredient granules</td><td>150.0 mg</td><td>300.0 mg</td>

<td>(8) Methacrylic acid copolymer (Eudragit L30D-55^R)</td><td> 22,3</td><td> 44,6</td>

<td>(9) Talc</td><td> 6,7</td><td> 13,4</td>

<td>(10) Macrogol 6000</td><td> 2,2</td><td> 4,4</td>

<td>(11) Titanium oxide</td><td> 2,2</td><td> 4,4</td>

<td>(12) Polysorbate 80</td><td> 1,0</td><td> 2,0</td>

<td>(13) Talc</td><td> 0,2</td><td> 0,4</td>

<td>Subtotal</td><td>184.6 mg</td><td>369.2 mg</td>

<td>Mixed granules:</td><td></td><td></td>

<td>Enteric granules</td><td>184.6 mg</td><td>369.2 mg</td>

<td>(14) Talc</td><td> 0,1</td><td> 0,2</td>

<td>(15) Silicic acid light anhydride</td><td> 0,3</td><td> 0,6</td>

<td>Subtotal</td><td>185.0 mg</td><td>370.0 mg</td>

<td>Capsules:</td><td></td><td></td>

<td>Mixed granules</td><td>185.0 mg</td><td>370.0 mg</td>

<td>(16) N ° 1 Gelatin Capsule</td><td></td><td> 79,0</td>

<td>(17) N ° 3 gelatin capsule</td><td> 50,0</td><td></td>

<td>Subtotal</td><td>235.0 mg</td><td>449.0 mg</td>

Industrial applicability

The present invention provides a method for producing crystals of benzimidazole compounds of uniform purity, which are valuable for medicaments such as anti-ulcer agents, and which is an industrially advantageous method for large-scale production.

The crystals that can be produced by the present method are more stable than hitherto known solvate crystals, and the degree of decomposition of the compound is extremely low in the course of the production and storage stage.