Improved Continuous Flow Processing: Benzimidazole Ring Formation via Catalytic Hydrogenation of an Aromatic Nitro Compound

Jian Chen *, Katrin Przyuski , Renee Roemmele , and Roger P. Bakale

Chemical Process Research and Development, Teva Pharmaceuticals, 383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States

Org. Process Res. Dev., Article ASAP

Publication Date (Web): August 6, 2013 (Article)

DOI: 10.1021/op400179f

http://pubs.acs.org/doi/abs/10.1021/op400179f

 In the development of a new route to bendamustine hydrochloride, the API in Treanda, the key benzimidazole intermediate 5 was generated via catalytic heterogeneous hydrogenation of an aromatic nitro compound using a batch reactor. Because of safety concerns and a site limitation on hydrogenation at scale, a continuous flow hydrogenation for the reaction was investigated at lab scale using the commercially available H-Cube. The process was then scaled successfully, generating kilogram quantities on the H-Cube Midi. This flow process eliminated the safety concerns about the use of hydrogen gas and pyrophoric catalysts and also showed 1200-fold increase in space–time yield versus the batch processing.