Selection of an Enantioselective Process for the Preparation of a CGRP Receptor Inhibitor
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- 作者：Reginald O. Cann ; Chung-Pin H. Chen ; Qi Gao ; Ronald L. Hanson ; Daniel Hsieh ; Jun Li ; Dong Lin ; Rodney L. Parsons ; Yadagiri Pendri ; R. Brent Nielsen ; William A. Nugent ; William L. Parker ; Sandra Quinlan ; Nathan P. Reising ; Brenda Remy ; Justin Sausker ; Xuebao Wang
- 刊名：Organic Process Research & Development
- 出版年：2012
- 出版时间：December 21, 2012
- 年：2012
- 卷：16
- 期：12
- 页码：1953-1966
- 全文大小：556K
- 年卷期：v.16,no.12(December 21, 2012)
- ISSN：1520-586X
文摘
(R)-N-(3-(7-Methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazine-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (1) is a potent calcitonin gene-related peptide (CGRP) receptor antagonist. We have developed a convergent, stereoselective, and economical synthesis of the hydrochloride salt of 1 and demonstrated the synthesis on a multikilogram scale. Two different routes to the chiral indazolyl amino ester subunit were developed utilizing either a Rh-catalyzed asymmetric hydrogenation or a biocatalytic process to install the single chiral center. The advantages and disadvantages of each of these process routes are discussed, as are challenges addressed in the assembly of the final drug substance.