Synthesis of Akt Inhibitor Ipatasertib. Part 2. Total Synthesis and First Kilogram Scale-up

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• 作者：Travis Remarchuk ; Frederic St-Jean ; Diane Carrera ; Scott Savage ; Herbert Yajima ; Brian Wong ; Srinivasan Babu ; Alan Deese ; Jeffrey Stults ; Michael W. Dong ; David Askin ; Jonathan W. Lane ; Keith L. Spencer
• 刊名：Organic Process Research & Development
• 出版年：2014
• 出版时间：December 19, 2014
• 年：2014
• 卷：18
• 期：12
• 页码：1652-1666
• 全文大小：533K
• ISSN：1520-586X

文摘

Herein, the first-generation process to manufacture Akt inhibitor Ipatasertib through a late-stage convergent coupling of two challenging chiral components on multikilogram scale is described. The first of the two key components is a trans-substituted cyclopentylpyrimidine compound that contains both a methyl stereocenter, which is ultimately derived from the enzymatic resolution of a simple triester starting material, and an adjacent hydroxyl group, which is installed through an asymmetric reduction of the corresponding cyclopentylpyrimidine ketone substrate. A carbonylative esterification and subsequent Dieckmann cyclization sequence was developed to forge the cyclopentane ring in the target. The second key chiral component, a 尾²-amino acid, is produced using an asymmetric aminomethylation (Mannich) reaction. The two chiral intermediates are then coupled in a three-stage endgame process to complete the assembly of Ipatasertib, which is isolated as a stable mono-HCl salt.