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

Green Chemistry Pub Date: 2017-01-03 DOI: 10.1039/C6GC03123D

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.

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