反应详情

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).

1. temperaturecooled
2. stirringUpon completion, stirring
3. additionThis solution was added dropwise to
4. stirringa stirred
5. stirringThe whole was stirred for 1 hour while the mixture
6. customto reach room temperature
7. washThe reaction mixture was washed successively with water
8. customThe organic phase was dried
9. filtrationfiltered
10. customevaporated
11. customThe residue was purified by column chromatography over silica gel using
12. additiona mixture of trichloromethane and methanol (95:5 by volume) as eluent
13. customThe pure fractions were collected
14. customthe eluent was evaporated
15. filtrationThe salt was filtered off
16. customdried