Methyl chloroformate → N-[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-oxo-2H-1-benzopyran-3-carboxamide (E)-2-butenedioate

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To a stirred and cooled (below 10° C.) mixture of 3.8 parts of 2-oxo-2H-1-benzopyran-3-carboxylic acid, 2.2 parts of N,N-diethylethanamine and 225 parts of trichloromethane was added dropwise a solution of 1.9 parts of methyl carbonochloridate in 75 parts of trichloromethane. Upon completion, stirring was continued for 30 minutes at room temperature. This solution was added dropwise to a stirred and cooled solution of 6.6 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine in 75 parts of trichloromethane at 5° C. The whole was stirred for 1 hour while the mixture was allowed to reach room temperature. The reaction mixture was washed successively with water, a sodium hydroxide solution 10% and again with water. The organic phase was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the (E)-2-butenedioate salt in methanol. The salt was filtered off and dried, yielding 6.6 parts (47.5%) of N-[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-oxo-2H-1-benzopyran-3-carboxamide (E)-2-butenedioate(1:2); mp. 216.8° C. (compound 44).

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