Process for preparation of Bendamustine

摘要

The present invention relates to a method for preparation of alkyl 4-[5-[bis(2-hydroxyethyl)amino]-1-methyl-1 H -benzimidazol-2-yl]butanoate (7) from 2-fluoro-5-nitroaniline, comprising the steps of:
a) conversion of 2-fluoro-5-nitroaniline to 5-(2-fluoro-5-nitroanilino)-5-oxopentanoic acid (1) using glutaric anhydride, conversion of compound (1) to methylammonium 5-[2-(methylamino)-5-nitroanilino]-5-oxopentanoate (2) using methylamine; conversion of compound (2) to 5-[2-(methylamino)-5-nitroanilino]-5-oxopentanoic acid (3) and condensation of compound (3) to 4-(1-methyl-5-nitro-1 H -benzimidazol-2-yl)butanoic acid (4),
b) esterification of the product (4) of step a) to alkyl 4-(1-methyl-5-nitro 1H- benzimidazol-2-yl)butanoate (5),
c) reduction of the product of step b) to alkyl 4-(5-amino-1-methyl- 1H -benzimidazol-2-yl)butanoate (6), and
d) conversion of the product of step c) to alkyl 4-[5-[bis(2-hydroxyethyl)amino]-1-methyl- 1H -benzimidazol-2-yl]butanoate (7).