All four isomers of 2-chloro-1-(6-fluorochroman-2-yl)ethan-1-ol, as building blocks for the two enantiomers of beta-blocker nebivolol, have been synthesized in high yield. Due to the similar physicochemical properties of these four diastereomeric halohydrins, to date, the only successful method for separation of the isomers has been preparative HPLC. To avoid this, the four halohydrins were transformed into epoxides with subsequent separation of the enantiomeric pairs by column chromatography. The enantiomeric pairs of epoxides were subsequently converted back to their corresponding halohydrins before performing kinetic resolution of the racemates catalyzed by Lipase B from Candida antarctica. (R)-2-Chloro-1-((R)-6-fluorochroman-2-yl)ethanol was isolated in 71% yield, and >99% enantiomeric excess (ee). (R)-2-Chloro-1-((S)-6-fluorochroman-2-yl)ethanol was isolated in 77% yield and >99% ee. Hydrolysis of 2-chloro-1-(6-fluorochroman-2-yl)ethyl butanoate with the same lipase yielded halohydrins (S)-2-chloro-1-((S)-6-fluorochroman-2-yl)ethanol and (S)-2-chloro-1-((R)-6-fluorochroman-2-yl)ethanol. Amination of (R)-6-fluoro-2-((S)-oxiran-2-yl)chromane with ammonia afforded (S)-2-amino-1-((R)-6-fluorochroman-2-yl)ethanol in 79% yield and >99% ee. (S)-2-Amino-1-((R)-6-fluorochroman-2-yl)ethanol was then reacted with (R)-2-chloro-1-((S)-6-fluorochroman-2-yl)ethanol to produce the desired product (R,S,S,S)-nebivolol ((−)-nebivolol) in 81% yield and >99% ee.
Hoem et al. (2026) studied this question.