Scalable, efficient process for the synthesis of ( R)-3,5-bistrifluoromethylphenyl ethanol via catalytic asymmetric transfer hydrogenation and isolation as a DABCO inclusion complex

Abstract

( R)-3,5-Bistrifluoromethylphenyl ethanol 2, a key building block in the synthesis of aprepitant, has been synthesized from ketone 5 via catalytic asymmetric transfer hydrogenation using a simplified catalyst generation procedure. The process uses (1 S,2 R)- cis-1-aminoindan-2-ol 10 and dichloro( p-cymene)Ru(II)dimer 9 as the chiral ligand and metal source for the reduction. While the reduction provides 2 in 90–92% ee, an isolation of 2 as a 2:1 inclusion complex with DABCO was developed to allow for the upgrade of the enantiomeric excess to >99%.