Process for production of sulfoxide derivatives or salts thereof in the amorphous state

Abstract

A process for producing sulfoxide derivatives or salts thereof in the amorphous state, characterized by heat-drying solvated crystals of a sulfoxide derivative or a salt thereof represented by the general formula (I): wherein R 1 represents a hydrogen atom, a methoxy group, or a difluoromethoxy group; R 2 represents a methyl group or a methoxy group; R 3 represents a 3-methoxypropoxy group, a methoxy group, or a 2,2,2-trifluoroethoxy group; R 4 represents a hydrogen atom or a methoxy group; and B represents a hydrogen atom, an alkali metal or ½ alkaline earth metal.

1 . A method of preparing an amorphous substance of sulfoxide derivative (I) or the salt thereof, which comprises heat-drying an solvated crystal of sulfoxide derivative represented by the following formula (I) or the salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a hydrogen atom, a methoxy group or a difluoromethoxy group; R 2  represents a methyl group or a methoxy group; R 3  represents a 3-methoxypropoxy group, a methoxy group or a 2,2,2-trifluoroethoxy group; R 4  represents a hydrogen atom or a methyl group; respectively, and B represents a hydrogen atom, an alkaline metal or ½ alkaline earth metal.  
     
     
         2 . The method according to  claim 1 , wherein the solvated crystal of sulfoxide derivative (I) or the salt thereof is heat-dried under reduced pressure.  
     
     
         3 . The method according to  claim 1 , wherein the solvated crystal of sulfoxide derivative (I) or the salt thereof is heat-dried with moist gas.  
     
     
         4 . The method according to  claim 1 , wherein the solvated crystal of sulfoxide derivative (I) or the salt thereof is heat-dried in an inert medium.  
     
     
         5 . The method according to  claim 1 , wherein the sulfoxide derivative is 2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-benzimidazole, 2-[[4-(2,2,2-trifluoroethoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1 H-benzimidazole, 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole or 5-difluoromethoxy-2-[(4,5-dimethoxy-2-pyridyl)methylsulfinyl]-1 H-benzimidazole.  
     
     
         6 . A method of preparing an amorphous substance of 2-[[4-(3-methoxypropoxy)-3 -methylpyridine-2-yl]methylsulfinyl]-1H-benzimidazole sodium salt, comprising heat-drying an acetone complex of 2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimidazole sodium salt or an acetonitrile complex of 2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimidazole sodium salt under reduced pressure.  
     
     
         7 . A method of preparing an amorphous substance of 2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimidazole sodium salt, which comprises heat-drying an acetone complex of 2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimidazole sodium salt under reduced pressure.  
     
     
         8 . The method according to  claim 1 , wherein the heating temperature ranges from 30 to 130° C.  
     
     
         9 . The method according to  claim 1 , wherein the heating temperature ranges from 100 to 110° C.  
     
     
         10 . The method according to  claim 1 , wherein the amorphous substance of sulfoxide derivative (I) or the salt thereof has 50 μm or less of average particle diameter and 80 μm or less of 90% cumulative diameter, measured by laser diffractometry.  
     
     
         11 . The method according to  claim 1 , wherein the amorphous substance of sulfoxide derivative (I) or the salt thereof has 30 μm or less of average particle diameter and 50 μm or less of 90% cumulative diameter, measured by laser diffractometry.  
     
     
         12 . The method according to  claim 1 , wherein the amorphous substance of sulfoxide derivative (I) or the salt thereof has from 1 to 75 μm of particle diameter, from 5 to 30 μm of average particle diameter and from 10 to 50 μm of 90% cumulative diameter, measured by laser diffractometry.  
     
     
         13 . The method according to  claim 1 , wherein the amorphous substance of sulfoxide derivative (I) or the salt thereof has from 1 to 50 μm of particle diameter, from 5 to 15 μm of average particle diameter and from 10 to 25 μm of 90% cumulative diameter, measured by laser diffractometry.  
     
     
         14 . An amorphous substance of 2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimidazole sodium salt, which is obtainable by heat-drying an acetone complex of 2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimidazole sodium salt or an acetonitrile complex of 2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-benzimidazole sodium salt under reduced pressure.  
     
     
         15 . An amorphous substance of 2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimidazole sodium salt, which is obtainable by heat-drying an acetone complex of 2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimidazole sodium salt under reduced pressure.  
     
     
         16 . The amorphous substance according to  claim 14 , which has from 1 to 75 μm of particle diameter, from 5 to 30 μm of average particle diameter and from 10 to 50 μm of 90% cumulative diameter, measured by laser diffractometry.  
     
     
         17 . The amorphous substance according to  claim 14 , which has from 1 to 50 μm of particle diameter, from 5 to 15 μm of average particle diameter and from 10 to 25 μm of 90% cumulative diameter, measured by laser diffractometry.  
     
     
         18 . An acetonitrile complex of 2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimidazole sodium salt.