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Issue 6, 2017
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Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

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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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Publication details

The article was received on 11 Nov 2016, accepted on 03 Jan 2017 and first published on 03 Jan 2017


Article type: Paper
DOI: 10.1039/C6GC03123D
Citation: Green Chem., 2017,19, 1454-1461
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    Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

    M. A. Marsini, F. G. Buono, J. C. Lorenz, B. Yang, J. T. Reeves, K. Sidhu, M. Sarvestani, Z. Tan, Y. Zhang, N. Li, H. Lee, J. Brazzillo, L. J. Nummy, J. C. Chung, I. K. Luvaga, B. A. Narayanan, X. Wei, J. J. Song, F. Roschangar, N. K. Yee and C. H. Senanayake, Green Chem., 2017, 19, 1454
    DOI: 10.1039/C6GC03123D

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