Regio- and diastereoselective ring-opening of (S)-(−)-2-(trifluoromethyl)oxirane with chiral 2,5-disubstituted tetrahydroquinolines in hexafluoro-2-propanol

Abstract

Multi-hundred grams of (S)-1,1,1-trifluoro-3-{(R)-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}propan-2-ol, a potent cholesteryl ester transfer protein (CETP) inhibitor, was prepared in quantitative isolated yield (>99%) with excellent chemical (>99% HPLC area%) and optical (>99% de) purities. The cornerstone to these results were achieved by regiospecific and diastereoselective ring-opening of optically pure (S)-(−)-2-(trifluoromethyl)oxirane (>99% ee) with (R)-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroquinoline (>99% ee) in hexafluoro-2-propanol at 22 °C for 24 h. This reaction did not require a rare earth metal salt (Yb(OTf)₃) as the catalyst nor a column chromatography for the purification. The excess (S)-(−)-2-(trifluoromethyl)oxirane and the solvent hexafluoro-2-propanol were recovered by distillation from the reaction and reused.