Process Development for ABT-472, a Benzimidazole PARP Inhibitor

Abstract

A nine-step convergent process was developed for the synthesis of ABT-472, a benzimidazole PARP inhibitor. The identity and origin of several impurities were determined, and the process was modified to reduce or eliminate these impurities. A number of safety and control issues were investigated. The original synthesis was shortened to 9 steps and streamlined while maintaining a convergent strategy. A stable salt was selected, and control of the API solid form was established. The process was successfully scaled up to provide 8.5 kg of final product of >99% purity in 33% yield over 9 steps.

Benzimidazole derivatives as potential dual inhibitors for PARP-1 and DHODH

“…Numerous reports on benzimidazole ring system construction have been published (Barkalow et al, 2007;Penning et al, 2009;Penning et al, 2008). We started off with the preparation of methyl ester 1 with different functional groups placed at the ortho (R 3 ), meta (R 4 ) and para (R 5 ) positions of the phenyl ring moiety to be connected at position 2 of the benzimidazole core as shown in Scheme 1.…”

Discovery of 2-(1-(3-(4-Chloroxyphenyl)-3-oxo- propyl)pyrrolidine-3-yl)-1H-benzo[d]imidazole-4-carboxamide: A Potent Poly(ADP-ribose) Polymerase (PARP) Inhibitor for Treatment of Cancer

“…The benzimidazole ring was constructed by a ten-step large scale synthesis procedure as described previously (Scheme 1) [17,22]. Cbz-protected cyclic amine carboxylic ester B1_6 was hydrolyzed to give acid B1 .…”

Design, synthesis, and antiviral properties of 2-aryl-1H-benzimidazole-4-carboxamide derivatives

“…Compound 3 was converted into 2-amino-3-nitro-benzoic acid 4 by Hofmann rearrangement. Then, the nitro group was reduced by Ranney nickel in hydrazine hydrate/methanol, and the resulting diamine was isolated as the bis-hydrochloride salt 5 [1,8].…”