Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement. Issue 6 (16th January 2017)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Green chemistry. Volume 19:Issue 6(2017)
• Page Start: 1454
• Page End: 1461
• Publication Date: 2017-01-16
• Subjects: Environmental chemistry -- Industrial applications -- Periodicals; Environmental management -- Periodicals; 660
• DOI: 10.1039/c6gc03123d
• Languages: English
• ISSNs: 1463-9262

Abstract

Abstract : A convergent and robust synthesis of a developmental CCR1 antagonist is described using continuous flow technology. 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 SN Ar 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.