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Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

By Marsini, Maurice A.; Buono, Frederic G.; Lorenz, Jon C.; Yang, Bing-Shiou; Reeves, Jonathan T.; Sidhu, Kanwar; Sarvestani, Max; Tan, Zhulin; Zhang, Yongda; Li, Ning; Lee, Heewon; Brazzillo, Jason; Nummy, Laurence J.; Chung, J. C.; Luvaga, Irungu K.; Narayanan, Bikshandarkoil A.; Wei, Xudong; Song, Jinhua J.; Roschangar, Frank; Yee, Nathan K.; Senanayake, Chris H.

Published on

Abstract

A convergent, robust, and concise synthesis of a developmental CCR1 antagonist is described using continuous flow technology. In the first approach, following an expeditious SNAr sequence for cyclopropane introduction, a safe, continuous flow Curtius rearrangement was developed for the synthesis of a p-methoxybenzyl (PMB) carbamate. Based on kinetic studies, a highly efficient and green process comprising three chemical transformations (azide formation, rearrangement, and isocyanate trapping) was developed with a relatively short residence time and high material throughput (0.8 kg h−1, complete E-factor = ∼9) and was successfully executed on 40 kg scale. Moreover, mechanistic studies enabled the execution of a semi-continuous, tandem Curtius rearrangement and acid–isocyanate coupling to directly afford the final drug candidate in a single, protecting group-free operation. The resulting API synthesis is further determined to be extremely green (RPG = 166%) relative to the industrial average for molecules of similar complexity.

Journal

Green Chemistry. Volume 19, 2017, 1454-1461

DOI

10.1039/C6GC03123D

Type of publication

Peer-reviewed journal

Affiliations

  • Boehringer Ingelheim Pharmaceuticals, Inc.

Article Classification

Research article

Classification Areas

  • API

Tags