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■ New Synthesis of Apabetalone

Pengfei Wu, Han Wang,* Wenxin Chen, Cong Sun, Lei Gao, and Yongjun Mao

*College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Rd., Songjiang, Shanghai, 201620, China

Abstract

A new and convergent synthesis of apabetalone (RVX-208) is developed. The key step is to build the 2-phenylquinazolin-4(3H)-one main ring from 2-bromo-4,6-dimethoxybenzoic acid (10) and 4-(2-hydroxyethoxy)-3,5- dimethylbenzamidine hydrochloride (15) in 73% yield. 1-Bromo-3,5- dimethoxybenzene (8) and 4-hydroxy-3,5-dimethylbenzonitrile (13) are used as the starting materials, 1 was obtained in 49% yield from 8 over 3 steps, or 48% yield from 13 over 3 steps, including Vilsmeier-Haack formylation, oxidation, amination, Pinner amidine synthesis methods. Purification methods of the intermediates and the final product involved in the route were developed, which make it as a process of cost effective, environmental friendly, and feasible for scale-up operation.