降钙素基因相关肽
哌嗪
对映选择合成
哌啶
化学
组合化学
立体化学
盐酸盐
敌手
立体选择性
受体
药理学
催化作用
有机化学
生物化学
神经肽
医学
作者
Reginald O. Cann,Chung-Pin H. Chen,Qi Gao,Ronald L. Hanson,Daniel Hsieh,Jun Li,Lin Dong,Rodney L. Parsons,Yadagiri Pendri,Rita Nielsen,William A. Nugent,W. Parker,S. L. Quinlan,Nathan P. Reising,Brenda Remy,Justin B. Sausker,Xuebao Wang
摘要
(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.
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