Lipase-catalyzed hydrolytic resolution of trans-2-(3,4-difluorophenyl)cyclopropyl azolides, a key building block for Ticagrelor synthesis

Ticagrelor as a platelet aggregation antagonist can be prepared from (1R,2S)-2-(3,4-diflurophenyl)cyclopropan-1-amine that is converted from (1R,2R)-2-(3,4-diflurophenyl)cyclopropane-1-carboxylic acid ((1R,2R)-DFPCPCA)) via Curtius or Hofmann rearrangement. In this work, an efficient hydrolytic resolution process for the preparation of (1R,2R)-DFPCPCA from trans-2-(3,4-diflurophenyl)cyclopropyl 1,2,4-azolide via an immobilized Candida antarctica lipase B (CALB) in methyl tert‑butyl ether was developed. Quantitative improvements of the enzyme activity and enantioselectivity, i.e., k _2RR K _mRR ^{− 1} = 5.512 L/h g and E _trans = 197, at 45 °C were obtained. Insights into CALB performances via kinetic and thermodynamic analysis were then addressed and compared with those by using trans-2-phenylcyclopropyl 1,2,4-azolide as the substrate, and demonstrated the prospect of present resolution process for synthesizing other optically pure 2-phenylcyclopropane-1-carboxylic acids containing derivatives in the phenyl subunit in the future.