JPH10195068A - Crystal of 2-2(2-pyridylmethylsulfinyl) benzimidazole compound and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the crystal of the subject compound essentially free from solvent and useful as a pharmaceutical agent such as an antitumor agent by recrystallizing the subject compound in a hydrated alcohol and suspending and stirring the obtained water-ethanol solvated crystal of the subject compound in hot water. SOLUTION: A compound of the formula [ring A may have substitutes; R<1> is H or an N-protecting group; R<2> , R<3> and R<4> are each H, a (halogen- substituted)alkyl, etc.], especially 2-[[3-methyl-4-(2,2,2,-trifluoroethoxy)pyridin-2- yl]methylsulfinyl]benzimidazole is recrystallized from a hydrated alcohol composed of 1pt.vol. of water and 2-30pts.vol. of an alcohol, 1pt. of the obtained solvated compound crystal is suspended in about 2-20pts. of water and stirred for 0.05-5hr while keeping the water temperature between room temperature and 90 deg.C and the obtained desolvated crystal is dried under reduced pressure or in vacuum at about 20-60 deg.C for 5-48hr to obtain the crystal of the objective compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to 2- (2-pyridylmethylsulfinyl) benzimidazole compounds (for example, JP-A-1-13)
No. 1176 (EP-0302720A), JP-A-58-192880 (EP-0005129A), JP-A-61-22079, JP-A-64-62
No. 70, U.S. Pat.No. 4,425,431, European Patent Publication No. 45200, U.S. Pat.No. 7,431,80602, U.S. Pat.
Or No. 175464, British Patent Publication No. 2134523A) or a salt thereof and a method for producing the same.

[0002]

2. Description of the Related Art Japanese Patent Laid-Open No. 1-131176 (EP-0302720A)
In Example 1, 2-[[3-methyl-4- (2,2,2-
Trifluoroethoxy) pyridin-2-yl] methylthio] benzimidazole (monohydrate) was dissolved in dichloromethane, oxidized with hydrogen peroxide in the presence of a vanadium pentoxide catalyst, and concentrated to give a residue. −
A water mixture (9: 1) was added thereto, and the precipitated crystals were collected by filtration, washed, and then added with an ethanol-water mixture (9: 1) and heated (65-65).
After dissolution, the filtrate obtained by hot filtration was cooled with ice, the crystallized crystals were collected by filtration, washed, and dried in vacuo to give 2-
There is a description that [[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole was obtained as white crystals.

[0003]

The 2- (2-pyridylmethylsulfinyl) benzimidazole-based compound has a small amount of residual solvent, especially water, in the crystal, which causes the stability to decrease and the decomposition to occur easily. It is necessary to reduce the residual solvent in the crystal as much as possible. However, the 2-[[3-methyl-
4- (2,2,2-trifluoroethoxy) pyridine-2
In the method for obtaining [-yl] methylsulfinyl] benzimidazole, it is difficult to remove water and ethanol, and it is obtained only as a crystal mixed with a considerable amount of water and ethanol. That is, the benzimidazole compound obtained by the method described in the publication,
It is a solvate holding one molecule of water and one molecule of ethanol, and it means that it is extremely difficult to remove the residual solvent to the extent that there is no problem in the stability of the compound by vacuum drying alone. However, the benzimidazole compound has low thermal stability in the form of its solvate, particularly in the form of a hydrate, so that it can be easily used in a subsequent vacuum drying treatment, particularly in a step such as a drying treatment under heating conditions. There is a serious problem that decomposition occurs and the purity of the target benzimidazole compound is reduced. Therefore, it has been desired to establish a solvent-free crystal of the benzimidazole compound and an excellent desolvation method with good operability on a large-scale industrial scale for obtaining the crystal.

[0004]

DISCLOSURE OF THE INVENTION In view of such circumstances, the inventors of the present invention have proposed a benzimidazole-based compound which is useful as a drug such as the above-mentioned anti-ulcer agent and the like, which contains substantially no solvent and a crystal thereof. In order to improve the above-mentioned problems, an intensive study has been carried out in order to establish an excellent desolvation method with good operability on an industrial large scale for obtaining the above. as a result,
The 2- (2-pyridylmethylthio) benzimidazole-based compound is oxidized to lead to a 2- (2-pyridylmethylsulfinyl) benzimidazole-based compound, and the 2- (2-pyridyl) obtained by recrystallization with a hydroalcoholic alcohol. Water of methylsulfinyl) benzimidazole compound
By suspending and stirring ethanol solvate crystals in hot water, they can be unexpectedly transformed into a crystal form substantially containing no solvent, and therefore can be easily desolvated by the subsequent drying under reduced pressure. Was found. In addition, the crystals of the benzimidazole compound substantially free of solvent obtained by this method are quite unexpectedly obtained.
It has been found that the solvate crystals of the benzimidazole compound obtained heretofore have superior stability and no decomposition during drying under reduced pressure.

[0005] Based on these findings, the present inventors,
As a result of further intensive studies, the present invention has been completed. That is, the present invention provides the following equation (1).

Embedded image [Wherein, ring A may have a substituent, R ¹ is hydrogen or an N-protecting group, and R ² , R ³ and R ⁴ are the same or different and are (1) hydrogen, (2) It represents an alkyl group optionally substituted by a halogen atom or (3) an alkoxy group optionally substituted by a halogen atom or an alkoxy group. A method for producing a crystal substantially free of a solvent of the compound or a salt thereof, which comprises subjecting a solvate of the compound or a salt thereof to desolvation treatment,
(2) The above (1), wherein the desolvation treatment is a suspension operation in water.
(3) The method according to ( ¹ ), wherein the N-protecting group represented by R ¹ is an alkyl, acyl, carbalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl group. The method for producing a crystal according to the above (1), (4) the method for producing a crystal according to the above (1), wherein R ¹ is hydrogen, and (5) an alkoxy group optionally substituted with a halogen atom for the substituent of ring A. (6) the method for producing a crystal according to the above (1), (6) the method for producing a crystal according to the above (1), wherein ring A is unsubstituted, (7) R ² is a methyl group or a methoxy group, and R ³ is fluorinated. The method for producing a crystal according to the above (1), wherein the optionally _substituted C _1-4 alkoxy group or C _1-4 alkoxy C _1-8 alkoxy group, and R ⁴ is hydrogen or a methyl group,
(8) When the compound represented by the formula (I) is 2-[[3-methyl-4- (2,2,2-trifluoroethoxy) pyridine-
The method for producing a crystal according to the above (1), which is 2-yl] methylsulfinyl] benzimidazole, formula (9)

Embedded image [Wherein, ring A may have a substituent, R ¹ is hydrogen or an N-protecting group, and R ² , R ³ and R ⁴ are the same or different and are (1) hydrogen, (2) It represents an alkyl group optionally substituted with a halogen atom or (3) an alkoxy group optionally substituted with a halogen atom or an alkoxy group. The crystal of the compound represented by the formula (I) or a salt thereof substantially free of a solvent and (10) a compound represented by the formula (I) are formed as follows: 2-[[3-methyl-4- (2,2,2 -Trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole.

Descriptions of the definitions in the above formulas and in the present invention and preferred examples thereof are described below. In the formula (I), examples of the substituent on the ring A include a halogen atom, alkyl, cyano, carboxy, alkoxycarbonyl, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy, hydroxyalkyl, halogenated alkyl, halogenated Examples include groups such as alkoxy, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio or alkylsulfinyl. Examples of the halogen atom include fluorine, chlorine, and bromine, and among them, fluorine is preferable. As the alkyl group, an alkyl group having 1 to 7 carbon atoms is preferable, and examples thereof include groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and heptyl. Examples of the alkoxycarbonyl group, is preferably one containing 1 carbon atoms in its alkoxy 4 include groups such as methoxycarbonyl (CH ₃ OOC-), ethoxycarbonyl (C ₂ H ₅ OOC-) as an example . As the carboalkoxyalkyl group, those having 1 to 4 carbon atoms in the alkoxy and the alkyl are preferable, and examples thereof include carbomethoxymethyl (CH
₃ OOCCH ₂ -), carbomethoxy ethyl (CH ₃ OO
CC ₂ H ₄ −), carbethoxymethyl (C ₂ H ₅ OOCC)
H ₂ -), carboethoxy ethyl _{(C 2 H 5 OOCC 2 H} 4
-) And the like.

The carbamoylalkyl group is preferably one having 1 to 4 carbon atoms in the alkyl, such as carbamoylmethyl (H ₂ NCOCH ₂ —),
And a group such as carbamoylethyl (H ₂ NCOC ₂ H ₄ —). The alkoxy group is preferably one having 1 to 5 carbon atoms, and examples thereof include methoxy, ethoxy,
Examples include groups such as propoxy, isopropoxy, butoxy, isobutoxy, pentoxy and the like. The hydroxyalkyl group is preferably an alkyl group having 1 to 7 carbon atoms, such as hydroxymethyl, 1-
Hydroxy-propyl-2,1-hydroxy-ethyl-
2, 1-hydroxy-2-methyl-propyl-2 and the like. As the halogenated alkyl group, those having 1 to 7 carbon atoms in the alkyl are preferable, and examples thereof include a difluoromethyl group and a trifluoromethyl group. As the halogenated alkoxy group, those having 1 to 4 carbon atoms in the alkoxy are preferable, and examples thereof include a difluoromethoxy group.

The acyl group preferably has 1 to 4 carbon atoms, and examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl and the like. As the acyloxy group, those having 1 to 4 carbon atoms in the acyl are preferable, and examples thereof include groups such as formyloxy, acetyloxy, propionyloxy, butyryloxy, and isobutyryloxy. Examples of the aryl group include groups such as phenyl, tolyl, and naphthyl. As the aryloxy group,
Examples include groups such as phenyloxy, tolyloxy, and naphthyloxy. As the alkylthio group, those having 1 to 6 carbon atoms in the alkyl are preferable, and examples thereof include groups such as methylthio, ethylthio, and propylthio. As the alkylsulfinyl group,
Those having 1 to 6 carbon atoms are preferable, and examples thereof include groups such as methylsulfinyl, ethylsulfinyl, and propylsulfinyl.

In the formula (I), the ring A is unsubstituted or, among the above substituents, a halogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group or a halogenated alkoxy group (preferably methoxy group). Group, a trifluoromethyl group or a difluoromethoxy group), and is preferably a 4- or 5-position of a benzimidazole ring.
Those having substituted positions are particularly preferred. In the formula (I),
R ¹ represents a hydrogen atom or an N-protecting group. Examples of the N-protecting group represented by R ¹ include alkyl, acyl, carbalkoxy, carbamoyl, alkylcarbamoyl,
Dialkylcarbamoyl, alkylcarbonylmethyl,
Groups such as alkoxycarbonylmethyl and alkylsulfonyl. The alkyl group has 1 carbon atom.
To 5 are preferable, for example, methyl, ethyl,
Groups such as propyl, isopropyl, butyl, isobutyl and pentyl are mentioned. Examples of the acyl group include the same groups as those defined above as the substituent for ring A. Examples of the carboalkoxy group include the same as those defined as the substituent for the ring A.

The alkylcarbamoyl group is represented by the formula alkyl-NH-CO-, and the alkyl group preferably has 1 to 4 carbon atoms, and examples thereof include groups such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl and isopropylcarbamoyl. Can be The dialkylcarbamoyl group is represented the formula (alkyl) ₂ N-CO-, carbon atoms are each preferably 1 to 4 of the alkyl group, for example dimethylcarbamoyl, diethylcarbamoyl and N- methyl -N- ethyl of carbamoyl such Groups. The alkylcarbonyl methyl group, wherein alkyl -CO-CH ₂ - is represented by the number of carbon atoms in the alkyl group is preferably 4 to 1 to, for example, acetyl methyl,
And groups such as propionylmethyl. The alkoxycarbonylmethyl group has the formula alkyl-OCO-CH ₂
The alkyl group preferably has 1 to 4 carbon atoms, and examples thereof include groups such as methoxycarbonylmethyl, ethoxycarbonylmethyl and propoxycarbonylmethyl. The alkylsulfonyl group is represented by the formula alkyl-SO ₂ —, and the alkyl group has 1 carbon atom.
To 4 are preferable, and examples thereof include groups such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, and isopropylsulfonyl. In the formula (I), R ¹ is preferably a hydrogen atom.

In the formula (I), R ² , R ³ and R ⁴ are
The same or different, each represents hydrogen, an alkyl group optionally substituted by a halogen atom, or an alkoxy group optionally substituted by a halogen or an alkoxy group.
The alkyl group in the alkyl group which may be substituted with a halogen atom represented by R ² , R ³ and R ⁴ is preferably an alkyl group having 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl , Isobutyl and the like. As the halogen atom in the alkyl group which may be substituted with the halogen atom,
Examples thereof include fluorine, chlorine, and bromine, and fluorine is particularly preferable. Examples of the alkyl group substituted with the halogen atom include, for example, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3 -Pentafluoropropyl, 1-
Preferred are fluorine-substituted alkyl groups such as (trifluoromethyl) -2,2,2-trifluoroethyl, 2,2,3,3,4,4,4-heptafluorobutyl, which are substituted with chlorine or bromine. Examples of the alkyl group include the same groups as those exemplified for the fluorine-substituted alkyl group, in which fluorine is replaced by chlorine or bromine. R ² , R ³ and R
Preferably the alkyl group which may be substituted by a halogen atom represented by ⁴ unsubstituted alkyl group having 4 to C 1 -C, especially and methyl group.

The alkoxy group in the alkoxy group which may be substituted with a halogen atom or an alkoxy group represented by R ² , R ³ and R ⁴ has 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms. Alkoxy groups are preferred and include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, hexyloxy, heptyloxy, octyloxy and the like. Examples of the halogen atom in the alkoxy group which may be substituted with a halogen atom include fluorine, chlorine, and bromine, and fluorine is particularly preferable. Examples of the alkoxy group substituted with the halogen atom include, for example, 2,2,2-trifluoroethoxy, 2,2,
3,3,3-pentafluoropropoxy, 1- (trifluoromethyl) -2,2,2-trifluoroethoxy,
2,3,3-tetrafluoropropoxy, 2,2,3,3,
4,4,4-heptafluorobutoxy, 2,2,3,3,4,
1 to 8 such as 4,5,5-octafluoropentoxy group
(Preferably 3 to 4) fluorine atoms have 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms.
The alkoxy group is preferably mentioned, and in particular, 2,2,2
-Trifluoroethoxy or 2,2,3,3-tetrafluoropropoxy is more preferred. Examples of the alkoxy group substituted with chlorine or bromine include the same groups as those exemplified for the fluorine-substituted alkoxy group except that fluorine is replaced with chlorine or bromine.

Examples of the alkoxy substituted with the alkoxy group include C _1-4 alkoxy C _1-8 alkoxy groups such as 3-methoxypropoxy, 2-methoxyethoxy, 3-ethoxypropoxy and 2-ethoxyethoxy ( Particularly, a C _1-4 alkoxy C _1-4 alkoxy group) is preferable, and a 3-methoxypropoxy group is particularly preferable. In the formula (I), preferably, R ² and R ⁴ are the same or different and each represents a hydrogen atom, a methyl group or a methoxy group, and R ³ has 1 to 5 carbon atoms substituted with 3 to 4 halogen atoms. And preferably an alkoxy group having 2 to 4 carbon atoms or a methoxy group. In the compound represented by the formula (I), more preferably, ring A is unsubstituted or the 4- or 5-position of the benzimidazole ring is substituted by a methoxy group, a difluoromethoxy group or a trifluoromethyl group, and R ¹ is Hydrogen, R ² is a methyl group or a methoxy group, and R ³ is an alkoxy group having 2 to 4 carbon atoms substituted with 3 to 4 fluorine atoms;
A methoxy group or a 3-methoxypropoxy group;
⁴ is a hydrogen atom or a methyl group.

The salt of the compound represented by the formula (I) includes
Pharmaceutically acceptable salts are preferred and include, for example, salts with inorganic bases, salts with organic bases, salts with basic amino acids and the like. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and ammonium salt. Preferred examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine and the like. The salt of the compound represented by the formula (I) in the present invention is preferably an alkali metal salt or an alkaline earth metal salt, particularly preferably a sodium salt.

Specific examples of the compound represented by the formula (I) include 2-[[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benz Imidazole, 2-[[3,5-dimethyl-4
-Methoxypyridin-2-yl] methylsulfinyl]-
5-methoxybenzimidazole, 2-[[4- (3-methoxypropoxy) -3-methylpyridin-2-yl]
Methylsulfinyl] benzimidazole sodium salt, 5-difluoromethoxy-2-[(3,4-dimethoxypyridin-2-yl) methylsulfinyl] benzimidazole, and the like, particularly 2-[[3-methyl-4- (2,2,2-trifluoroethoxy) pyridine-
2-yl] methylsulfinyl] benzimidazole is preferred.

In the production method of the present invention, the benzimidazole compound represented by the formula (I) can
No. 1176 (EP-0302720A), JP-A-58-192880 (EP-0005129A), JP-A-61-22079, JP-A-64-62
No. 70, U.S. Pat.No. 4,425,431, European Patent Publication No. 45200, U.S. Pat.No. 7,431,80602, U.S. Pat.
, No. 175464, British Patent Publication No. 2134523A, or the like, or a method analogous thereto. The benzimidazole-based compound has an asymmetric center at a sulfur atom. That is, two kinds of enantiomers

Embedded image Can exist as The benzimidazole-based compound is disclosed, for example, in the aforementioned JP-A-1-131176 (EP-030
According to the method described in 2720A) or a method analogous thereto, the product is purified by recrystallization from aqueous alcohol to obtain water-alcohol solvate crystals. As the alcohol, a C _1-6 alcohol (eg, methanol, ethanol, isopropanol, etc.), among which ethanol is more preferably used. As the hydrous alcohol, about 2 to about 30 volumes of alcohol (particularly ethanol) per 1 volume of water,
An alcohol (particularly ethanol) water mixture, which is preferably about 5 to about 15 volumes, may be mentioned. Specifically, for example, a mixed solution of alcohol (particularly ethanol) and water (about 9 volumes: 1 volume) and the like can be mentioned.

The formation of the crystal of the solvate of the compound represented by the formula (I) or a salt thereof can be easily confirmed by a known powder X-ray crystal analysis method or the like. In the production method of the present invention, the solvate crystals may be allowed to stand in water or may be stirred in a suspended state. By this operation,
The solvate crystals are desolvated by crystal form transition.
The amount of water, water temperature, stirring time, and the like used in this operation, ie, standing or suspension operation in water, can be appropriately selected, and specific examples include the following conditions. The amount of water is about 2 to about 20 times the volume of the solvate crystals,
Preferably, a volume of about 5 to about 10 times may be used. In this case, the water temperature is from room temperature (about 15 to about 30 ° C.) to about 90 ° C.
° C, preferably about 30 to about 50 ° C. The stirring time is about 0.5 to about 5 hours, preferably about 1 to about 5 hours.
About 2 hours. The crystals thus desolvated from the solvate crystals by the transformation of the crystal form are then separated by a method known per se such as filtration and, if necessary, dried by a method known per se to obtain the desired compound. A substantially desolvated crystal of the benzimidazole compound can be obtained. As the drying operation, for example, about 20 to about 60 ° C,
The reduced pressure or vacuum drying operation is preferably performed at about 30 to about 50 ° C. for about 5 to about 48 hours, preferably for about 10 to about 20 hours.

The substantially desolvated crystals in the present invention are those having a water content of about 500 ppm or less, preferably about 30 ppm or less.
It is 0 ppm or less, more preferably about 200 ppm or less, and means those having an alcohol content such as ethanol of about 200 ppm or less, preferably about 100 ppm or less, more preferably about 80 ppm or less. The water content and the alcohol content are
It is affected by the conditions (especially the processing time, etc.) in the suspension operation in water and the next drying operation. Should be lengthened and sufficient processing should be performed. The thus-obtained crystal of the compound represented by the formula (I) or a salt thereof substantially containing no solvent can be easily confirmed to be produced by a known powder X-ray crystallography method or the like, The water content and the alcohol content such as ethanol in the crystal can be determined by an analytical method known per se. Specifically, the KF (Karl Fischer) method is used for the water content, and the gas chromatography method is used for the alcohol content. The crystals substantially containing no solvent can be formed into a desired preparation by a usual preparation method and used as a drug such as an anti-ulcer agent. Examples of the formulation method include the methods shown below as Reference Examples.

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail with reference to the following Examples, which, of course, are not intended to limit the scope of the present invention. In the following examples, the water content was measured by the KF (Karl Fischer) method, and the alcohol content was measured by the gas chromatography method.

[0020]

【Example】

Reference Example 1. Production of 2,3-dimethylpyridine N-oxide After dissolving 100 g of 2,3-lutidine in 200 ml of glacial acetic acid, 120 g of 35% hydrogen peroxide solution was added dropwise at about 40 ° C.
The reaction was further performed at 105 ° C. for about 2 hours. After completion of the reaction, the mixture was cooled to about 50 ° C., and 5.0 g of paraformaldehyde was added. The mixture was heated again to 105 ° C. and reacted for about 10 minutes. The reaction solution was cooled to about 40 ° C., and
After addition of glacial acetic acid under reduced pressure, 2,3-dimethylpyridine N-oxide was obtained as a sulfuric acid solution.

Reference Example 2 Production of 2,3-dimethyl-4-nitropyridine N-oxide To a total amount of the sulfuric acid solution of 2,3-dimethylpyridine N-oxide obtained in Reference Example 1 was added 130 g of 98% sulfuric acid and 130 g of 98% nitric acid at about 80 ° C. After dropping over about 4 hours, the reaction was carried out at the same temperature for 5 hours. After cooling the reaction mixture to about 40 ° C, it was poured into 1L of cold water of 5 ° C or lower, and 0.6L of 30% sodium hydroxide was further added.
At 30 ° C. or lower. 1L of methylene chloride from processing solution
After extraction three times, the methylene chloride layers were combined and concentrated under reduced pressure to obtain 2,3-dimethyl-4-nitropyridine N-oxide as a pale yellow crystalline residue. Yield 141 g (apparent yield 9 from 2,3-lutidine 9)
0%)

Reference Example 3 2,3-dimethyl-4- (2,
Production of 2,2-trifluoroethoxy) pyridine N-oxide 70% acetonitrile water was added to the total amount of 2,3-dimethyl-4-nitropyridine N-oxide obtained in Reference Example 2.
After adding 4 L and dissolving, 280 g of trifluoroethanol, 9 g of a 50% aqueous benzyltributylammonium chloride solution and 225 g of potassium carbonate were added, and the mixture was reacted at a reflux temperature for about 25 hours. Approximately 60
After cooling to 0 ° C, 0.2 L of water was added, and the mixture was stirred and allowed to stand. Then, the organic layer was separated and concentrated under reduced pressure. The concentrated residue was dissolved by adding 0.5 L of water, and extracted three times with 0.5 L of methylene chloride. The methylene chloride layers were combined and concentrated to give 2,3-dimethyl-4- (2,2,2-trifluoroethoxy) pyridine N-oxide as a pale yellow crystalline residue. Yield 144 g (7, apparent yield from 2,3-lutidine)
0%)

Reference Example 4 2-hydroxymethyl-3-
Methyl-4- (2,2,2-trifluoroethoxy) pyridine (HYD) 2,3-dimethyl-4- (2,2,2) obtained in Reference Example 3
-Trifluoroethoxy) pyridine N-oxide was dissolved in 0.3 L of glacial acetic acid, 0.3 L of acetic anhydride was added, and the mixture was reacted at about 115 ° C for about 6 hours. After the completion of the reaction, about 60 ° C
And 0.3 L of water was added. After the reaction mixture was concentrated under reduced pressure, 25 mL of methanol and 0.2 L of water were added, and about 0.2 L of a 30% aqueous sodium hydroxide solution was added dropwise while maintaining the temperature at about 30 ° C., and the pH was adjusted to 13; Stirred. The reaction solution was allowed to stand, the supernatant was removed, 100 ml of methanol was added, and the mixture was stirred at about 45 ° C. for about 30 minutes to dissolve the precipitated crystals. While maintaining the solution at about 20 ° C., 0.5 L of water was added to crystallize the crystals, and then cooled to about 5 ° C. for ripening. The precipitated crystals were collected by filtration, washed with water, and dissolved in a mixture of 75 ml of 35% hydrochloric acid, 0.4 l of water and diatomaceous earth (2.5 g). Dissolve the solution with 30% caustic soda, pH
After adjusting to about 3, insolubles were removed by filtration. The filtrate was washed three times with 200 ml of methylene chloride, and 5.0 g of activated carbon was added to the filtrate.
Stirred at 0 ° C. for about 12 hours. The activated carbon was removed by filtration, 80 ml of ethanol was added to the filtrate, and the pH was adjusted with 30% sodium hydroxide.
The solution was neutralized to 7 to precipitate crystals. After cooling the crystallized solution to 5 ° C. or lower, the crystals were collected by filtration and washed with water. The obtained crystal is about 3
Dry under reduced pressure at 7 ° C. for about 24 hours.
3-methyl-4- (2,2,2-trifluoroethoxy)
Pyridine (95 g) was obtained as white crystals. (46% yield from 2,3-lutidine)

Reference Example 5 2-[[[3-methyl-4-
(2,2,2-trifluoroethoxy) -2-pyridyl]
Preparation of -methyl] thio] benzimidazole monohydrate 2-hydroxymethyl-3-methyl-4- (2,2,2-
After dissolving 49.9 g of (trifluoroethoxy) pyridine in 0.4 L of methylene chloride, 24 ml of thionyl chloride was added dropwise in about 30 minutes, and the mixture was reacted at about 30 ° C. or more for about 1 hour. After the reaction was completed, 0.1 L of water was added, and then methylene chloride was distilled off under reduced pressure. After dissolving the residue in 0.4 L of methanol, 34.2 g of 2-benzimidazole thiol was added.
About 60 ml of a 30% aqueous sodium hydroxide solution was added dropwise at about 25 ° C. over about 1 hour, and the reaction was continued at the same temperature for about 0.5 hours.
0.3 L of water was added to the reaction solution, and the mixture was stirred at 10 ° C. or lower for about 30 minutes or more, and then adjusted to a pH of about 9 with 35% hydrochloric acid to precipitate crystals. The crystals were collected by filtration, and 50% aqueous methanol (0.5%) was added.
Washed sequentially with 1 L and 0.2 L of water. The obtained crystals were dried with warm air of 50 ° C. or lower to give 2-[[[3-methyl-4-
(2,2,2-trifluoroethoxy) -2-pyridyl]
[-Methyl] thio] benzimidazole (81.0 g) was obtained as white crystals. (96.7% yield from HYD)

Reference Example 6 2-[[3-methyl-4-
Preparation of (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole monohydrate, monoethanolate crystal Dissolve acetylacetone vanadium (IV) (40 mg) in ethanol (150 ml), 2-[[3-methyl-
4- (2,2,2-trifluoroethoxy) pyridine-2
-Yl] methylthio] benzimidazole (monohydrate)
(20.0 g), 35% aqueous hydrogen peroxide (6.14 g) was added dropwise thereto at 20 to 25 ° C, and 20 to 25 ° C.
For about 5 hours. After completion of the reaction, an aqueous solution of sodium thiosulfate (2.7 g / 16 ml) was added to the reaction solution, and about 10
Stir vigorously for minutes. The precipitated crystals were collected by filtration and washed with an ice-cooled ethanol-water mixture (8: 2). A mixed solution of ethanol and water (9: 1, 90 ml) was added to the obtained crystals, and the mixture was stirred by heating (60 to 70 ° C.) to dissolve the crystals. Insolubles were removed by hot filtration, and the filtrate was cooled with ice. Thus, crystals were crystallized. The crystallized crystals are collected by filtration, washed with an ice-cooled ethanol-water mixture (8: 2), dried at room temperature in vacuo,
[[3-Methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole monohydrate, monoethanolate crystal (21.2
g) was obtained as white needles. (Yield 91.0%)

Embodiment 1 FIG. 2- containing substantially no solvent
Production of [[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole (hereinafter sometimes abbreviated as compound A) Ethanol-water mixture (9 : 75 ml), 25% aqueous ammonia (70 µl) was added, and the mixture was heated to about 60 ° C in advance, and the 2-[[3-methyl-4- (2,
2,2-Trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole monohydrate, monoethanolate crystal (13.0 g) was added and dissolved. After removing the insolubles by hot filtration, the filtrate was ice-cooled to precipitate crystals. The crystallized crystals are collected by filtration, and 2-[[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole monohydrate, monoethanol solvate wet Crystals were obtained. Next, the wet crystals were suspended in 53 ml of water and stirred for 1 hour while maintaining the temperature at 30 ° C. The crystals were filtered, washed with water (10 ml) and dried in vacuo at 40 ° C. for 10 hours to give 2-[[3-methyl-
4- (2,2,2-trifluoroethoxy) pyridine-2
-Yl] methylsulfinyl] benzimidazole (9.
72 g) were obtained as white needles. (Yield 87.7
%) Melting point 177-178 ° C (decomposition) Water content 0.01% Ethanol content 63ppm

Comparative Example 1 Preparation of 2-[[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole by a conventional method 25 to an ethanol-water mixture (9: 1, 58 ml). 54% of aqueous ammonia was added, and the mixture was heated to about 60 ° C. in advance, and the 2-[[3-methyl-4- (2,2) obtained in Reference Example 6 was added thereto.
2,2-Trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole monohydrate, monoethanolate crystal (10.0 g) is added and dissolved. After removing the insolubles by hot filtration, the filtrate was ice-cooled to precipitate crystals. The crystallized crystals are collected by filtration, and 2-[[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole monohydrate, monoethanol solvate wet Crystals were obtained. At 40 ° C
And dried under vacuum for 20 hours, and 2-[[3-methyl-4- (2,
2,2-Trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole (7.58 g) was obtained as white needles. (Yield: 89.0%) Melting point: 177-178 ° C (decomposition) Water content: 0.12% Ethanol content: 360 ppm

Reference Example 7 Preparation of Injection Containing Compound A (1) To 15 g of Compound A was added and dissolved an aqueous sodium hydroxide solution, and then 30 g of mannitol and 5 g of meglumine were added and dissolved to make 1000 mL of a drug-containing solution having a pH of 11.2. This was sterilized and filtered by a conventional method, and the obtained liquid was dispensed into vials in an amount of 1 mL each, and then freeze-dried by a conventional method to obtain a freeze-dried product containing Compound A. On the other hand, 750 g of Macrogol 400 was diluted with water for injection, hydrochloric acid was added, and p
The aqueous solution of H4.5 was made 2500 mL. This was sterilized and filtered by a conventional method, filled into ampoules in 2.5 mL portions, sealed, and then subjected to high-pressure steam sterilization. When used, add 2.5 mL of this solution to the freeze-dried product containing Compound A, dissolve and use.

Reference Example 8 Preparation of injection containing compound A (2) 300 g of compound A, 600 g of mannitol, 100 g of meglumine, and an aqueous solution of sodium hydroxide were mixed and dissolved with a homomixer to obtain 20 L of a drug-containing liquid having a pH of 11.2. This was sterilized and filtered by a conventional method, and the obtained liquid was dispensed into vials in an amount of 2 mL each, and then lyophilized by a conventional method to obtain a lyophilized product containing Compound A. On the other hand, 15 kg of Macrogol 400 was diluted with water for injection, and hydrochloric acid was added thereto.
The aqueous solution of 4.5 was made 50 L. This was sterilized and filtered by a conventional method, filled into ampoules of 5 mL each, sealed, and then subjected to high-pressure steam sterilization. At the time of use, 5 mL of the present solution is added to a freeze-dried product containing Compound A and dissolved.

Reference Example 9 Production of injection containing compound A (3) 150 g of compound A and 300 g of mannitol were mixed,
An aqueous solution of sodium hydroxide was added and dissolved therein. After dissolution, 50 g of meglumine was added and dissolved, and pH11.3 was added.
And 10 L of the drug-containing liquid. This was sterilized and filtered by a conventional method, and the obtained liquid was dispensed into vials in a volume of 4 mL each, and then lyophilized by a conventional method to obtain a lyophilized product containing Compound A. On the other hand, 7.5 kg of Macrogol 400 was diluted with water for injection, and hydrochloric acid was added to make 25 L of an aqueous solution having a pH of 4.5. This was sterilized and filtered by a conventional method, filled into ampoules in 10 mL portions, sealed, and then subjected to high-pressure steam sterilization. At the time of use, 10 mL of the present solution is added to the lyophilized product containing Compound A, dissolved and used.

Reference Example 10 Production of Capsules Containing Compound A With the charged amount -1 of [Table 1] or the charged amount -2 of [Table 2],
The capsule was prepared according to the following method to obtain a capsule having the formulation shown in Table 3. (1) Compound A and the components (3) to (6) were mixed well to prepare a spray. Centrifugal flow type coating granulator (manufactured by Freund Industrial Co., Ltd., CF-1000 for the charged amount of [Table 2] and CF-13 for the charged amount of [Table 3]
(00)), (2) non-pareil was put therein, and (7) an aqueous solution of hydroxypropylcellulose dissolved in purified water was sprayed thereon to coat the above-mentioned spraying agent. The spherical granules are vacuum-dried at 40 ° C. for 16 to 18 hours, and sieved (50
(0 μm, 1190 μm) to obtain main drug particles. Two patches of the main drug particles were put into a flow coater (manufactured by Powrex), and a suspension of (8) methacrylic acid copolymer LD to (12) polysorbate 80 in purified water was coated. (13) Talc is added to the coated granules, and sieved with a sieve (600 μm, 1420 μm).
Vacuum drying at 2 ° C. for 16-18 hours gave enteric granules. 1 patch of enteric grain (up to 5 patches can be mixed with the amount of [Table 2], up to 3 patches can be mixed with the amount of [Table 3])
Talc and (15) light anhydrous silicic acid were added to the mixture, and a tumbler mixer (manufactured by Showa Kagaku Kikai Kosakusho) was used.
Mixed grains were obtained. Using a capsule filling machine (manufactured by MG2 or Xanasea), the mixed grains were filled into (16) gelatin capsule No. 1 and 30 mg capsules, and (17) gelatin capsule No. 3 to fill 15 mg capsules.

[0032]

[Table 1]

[0033]

[Table 2]

[0034]

[Table 3]

[0035]

According to the production method of the present invention, a substantially solvent-free crystal of a benzimidazole compound useful as a medicament such as an anti-ulcer agent can be converted into a uniform crystal by a simple operation on an industrial scale. Can be manufactured in large quantities. Further, the benzimidazole-based compound substantially free of a solvent obtained by the production method of the present invention is more stable than the conventionally obtained crystal of the compound, and is excellent in the production process and the storage process. Decomposition is extremely low.

Claims (10)

[Claims] (1) Formula (1) [Wherein, ring A may have a substituent, R ¹ is hydrogen or an N-protecting group, and R ² , R ³ and R ⁴ are the same or different and are (1) hydrogen, (2) It represents an alkyl group optionally substituted by a halogen atom or (3) an alkoxy group optionally substituted by a halogen atom or an alkoxy group. And subjecting the solvate of the compound or a salt thereof to a desolvation treatment, wherein the compound or a salt thereof is substantially free of a solvent. 2. The method according to claim 1, wherein the desolvation treatment is a suspension operation in water. 3. The N-protecting group represented by R ¹ is an alkyl,
The method for producing a crystal according to claim 1, which is an acyl, carbalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl or alkylsulfonyl group. 4. The method according to claim ¹ , wherein R ¹ is hydrogen. 5. The method according to claim 1, wherein the substituent on ring A is an alkoxy group optionally substituted with a halogen atom. 6. The method according to claim 1, wherein ring A is unsubstituted. 7. R ² is a methyl group or a methoxy group, and R ³ is an optionally fluorinated C _1-4 alkoxy group or C _1-4.
The method for producing a crystal according to claim 1, wherein the alkoxy C _1-8 alkoxy group and R ⁴ are hydrogen or a methyl group. 8. The compound represented by the formula (I) is 2-[[3-
The method for producing crystals according to claim 1, which is methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole. 9. A compound of the formula [Wherein, ring A may have a substituent, R ¹ is hydrogen or an N-protecting group, and R ² , R ³ and R ⁴ are the same or different and are (1) hydrogen, (2) It represents an alkyl group optionally substituted by a halogen atom or (3) an alkoxy group optionally substituted by a halogen atom or an alkoxy group. And a salt thereof substantially free of a solvent. 10. The compound represented by the formula (I) is 2-[[3
The crystal according to claim 9, which is -methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole.