Desymmetrization of a Propane-1,3-diol to Introduce the Quaternary Chiral Center of an AMG 176 Drug Substance Intermediate

This article is dedicated to Professor David A. Evans, a friend and mentor, for his outstanding contributions to the organic chemistry community, his dedication to the education of an outstanding generation of undergraduate students, graduate students and post docs, and his excellence as a teacher to the broader organic chemistry community. Professor Evans will be remembered fondly and deeply missed.

Abstract

A chiral Cu(II)-PyBOX complex was prepared and utilized to accomplish desymmetrization of a 1,3-diol en route to AMG 176. An expedient synthesis of the racemic 1,3-diol is described, in addition to efforts for rapid optimization and subsequent kilogram-scale execution of the desymmetrization process to generate material for pre-clinical activities. An overview of the kilogram-scale synthesis of the Cu(II)-PyBOX complex is provided.

Key words

AMG 176 - process development - desymmetrization - Evans­ - PyBOX ligand - 1,3-diol

Publication History

Received: 20 November 2022

Accepted: 29 November 2022

Accepted Manuscript online:
29 November 2022

Article published online:
10 January 2023

• References

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• 3 Current address: Skyhawk Therapeutics, 35 Gatehouse Drive, Waltham, MA 02451.
• 4 Current address: Sanofi, Inc., 350 Water Street, Cambridge, MA 02141.
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