Crystal of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid and process for producing the same

Abstract

A process for producing crystals of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (compound (I)), characterized by dissolving or suspending the compound (I) or a salt thereof in a solvent comprising an aprotic polar solvent and crystallizing it. By the process, the contaminants which are contained in the compound (I) or its salt and are difficult to remove, such as tin compounds, analogues of the compound (I), and a residual organic solvent, can be easily removed. Crystals of the compound (I) can be efficiently and easily mass-produced in high yield on an industrial scale.

1 . A process for producing a crystal of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid, comprising
 (i) reacting methyl 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate or a salt thereof with a compound represented by the formula (R) 3 SnN 3 ,   wherein R represents alkyl having a carbon number of 4 to 18;   (ii) subjecting the resulting methyl 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate or a salt thereof to a hydrolysis reaction; and   (iii) dissolving or suspending the resulting 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid or a salt thereof in a solvent containing an aprotic polar solvent to crystallize.   
     
     
         2 . The process according to  claim 1 , wherein said crystal of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid does not substantially contain a tin compound. 
     
     
         3 . The process according to  claim 1 , wherein said crystal of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid has a tin content of approximately 1000 ppm or less. 
     
     
         4 . The process according to  claim 1 , wherein said crystal of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid has a tin content of approximately 10 ppm or less. 
     
     
         5 . The process according to  claim 1 , wherein said crystal of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid does not substantially contain an analogue of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid. 
     
     
         6 . The process according to  claim 1 , wherein said crystal of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid has a content of an analogue of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid of less than approximately 1% or less. 
     
     
         7 . The process according to  claim 1 , wherein said crystal of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid does not substantially contain a residual organic solvent. 
     
     
         8 . The process according to  claim 1 , wherein said crystal of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid has a total residual organic solvents content of approximately 5000 ppm or less. 
     
     
         9 . The process according to  claim 1 , wherein said crystal of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid has a residual dichloromethane content of less than approximately 50 ppm. 
     
     
         10 . The process according to  claim 1 , wherein said crystal of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid has a total residual organic solvents content of approximately 5000 ppm or less and a residual dichloromethane content of less than approximately 50 ppm. 
     
     
         11 . The process according to  claim 1 , wherein said polar aprotic solvent is at least one of tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide and combinations thereof. 
     
     
         12 . The process according to  claim 1 , wherein said compound represented by the formula (R) 3 SnN 3  is trioctyltin azide.