Feasible Column Chromatography-Free, Multi-Gram Scale Synthetic Process of VH032 Amine, Which Could Enable Rapid PROTAC Library Construction

Wei Yan; Bo-Syong Pan; Jingwei Shao; Hui-Kuan Lin; Hong-Yu Li

doi:10.1021/acsomega.2c00245

Feasible Column Chromatography-Free, Multi-Gram Scale Synthetic Process of VH032 Amine, Which Could Enable Rapid PROTAC Library Construction

ACS Omega. 2022 Jul 19;7(30):26015-26020. doi: 10.1021/acsomega.2c00245. eCollection 2022 Aug 2.

Authors

Wei Yan^{1

2}, Bo-Syong Pan³, Jingwei Shao¹, Hui-Kuan Lin³, Hong-Yu Li¹

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas72205, United States.
² Department of Internal Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas72205, United States.
³ Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston-Salem, North Carolina27157, United States.

Abstract

PROTACs represent a promising modality that has gained significant attention for the treatment of cancer, Alzheimer's disease, and so forth. Due to limited structural information of the POI-PROTAC-E3 ligase ternary complex, the discovery of active PROTACs relies on the screening of diversity-oriented PROTAC libraries. VH032 amine is a key building block for the synthesis of VHL E3 ligase-based PROTACs. To construct VHL PROTAC libraries rapidly, the availability of VH032 amine is crucial. In this paper, we report a column chromatography-free process which enables the production of 42.5 g of VH032 amine hydrochloride in 65% overall yield with 97% purity in a week.