Process Research and Development of an Enantiomerically Enriched Allyic Amine, One of the Key Intermediates for the Manufacture of Synthetic Tetracyclines

Abstract

A robust, cost-effective, and high yielding manufacturing process for enantiomerically enriched (S)-allylic amine 3, a key intermediate for fully synthetic tetracyclines have been developed. Two novel and scalable asymmetric vinylations resulting in high-to-excellent stereoselectivity have been developed for the key step. The final product is purified by an efficient crystallization of a l-tartaric salt. The process described has been used to manufacture ∼350 kg of the tartaric salt of 3 with 99.0% ee in 8 steps (35% overall yield) from cheap and readily available dimethyl maleate.