Highly Enantioselective Chemoenzymatic and Kilogram-Scale Process Development of (S)-3-Bromo-2-(1-methoxyethyl)pyridine

(S)-3-Bromo-2-(1-methoxyethyl)pyridine 1 is a key intermediate of RMC-6236. In this report, we detail the development and optimization of a highly enantioselective chemoenzymatic and kilogram-scale process for 1. The developed process for intermediate (S)-1-(3-Bromopyridin-2-yl)ethanol 3 was performed on 1 kg scale with a substrate concentration of 70.0 g/L, achieving a yield of 93.0% and an ee value of >99.9%. Subsequently, a simple and effective NaHMDS/CH3I methylation system afforded the title compound 1, in 95.0% yield and with >99.9% ee, achieving 88.4% overall yield from intermediate 1-(3-bromopyridin-2-yl)ethanone 2. This represents a notable increase compared to the early stage process (overall yield 55.5%). This optimized highly efficient and sustainable process was demonstrated during kilogram-scale production of 1.