Process for the preparation of bendamustine

摘要

The present invention relates to a method for preparation of alkyl 4-[5-[bis(2 -hydroxyethyl)amino]-1-methyl-1H-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-1H-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-l-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).

主权项

1. A method for the preparation of 4-(1-methyl-5-nitro-1H-benzimidazol-2-yl)butanoic acid (4), from 2-fluoro-5-nitroaniline, comprising the steps:
a) conversion of 2-fluoro-5-nitroaniline to 5-(2-fluoro-5-nitroanilino)-5-oxopentanoic acid (1) using glutaric anhydride: b) conversion of the reaction product (1) of step a) to methyl ammonium 5-[2-(methylamino)-5-nitroanilino]-5-oxopentanoic (2) using methylamine: c) conversion of the reaction product (2) of step b) to 5-[2-(methylamino)-5-nitroanilino]-5-oxopentanoic acid (3):  and d) condensation of the reaction product (3) of step c) to 4-(1-methyl-5-nitro-1H-benzimidazol-2-yl)butanoic acid (4):