Process Development of LCAT Activator: A Novel Optical Resolution Method for Chiral Alcohols

This study presents the initial process development for manufacturing a lecithin-cholesterol acyltransferase (LCAT) activator 1, a potential anti-atherosclerotic agent discovered at Daiichi Sankyo. The major challenge was constructing a chiral bicyclic core structure bearing cis-substituted trifluoromethyl and hydroxyl groups at the 4- and 5-positions. To address this challenge, a novel synthetic route from 2,5-dichloropyrimidine was developed. After introducing the pyrimidine moiety at an early stage, the key bicyclic pyrazole framework was constructed via a Friedel-Crafts-type reaction with trifluoroacetaldehyde ethyl hemiacetal and subsequent cyclization with diethyl malonate. Notably, the α-hydroxylation proceeded efficiently under controlled pH using Oxone/DBU. A new sulfonylcarbamate-based optical resolution method was then developed to obtain the enantiomerically pure alcohol intermediate. The resulting diastereomeric salt was crystallized in 44% yield with high diastereomeric excess and readily converted to the desired LCAT activator 1 upon deprotection. This new 15-step process (overall yield 12.6%) avoids expensive reagents, cryogenic conditions, and chiral column chromatography optical resolution required in the medicinal synthetic route. Furthermore, the sulfonylcarbamate approach provides a broadly applicable optical resolution strategy for chiral alcohols without acidic or basic functionalities.