Efficient preparation of an N-aryl β-amino acid via asymmetric hydrogenation and direct asymmetric reductive amination en route to Ezetimibe

Two routes for the preparation of an N-aryl β-amino acid, an important precursor for the cholesterol-lowering drug Ezetimibe, were investigated. The first pathway proceeds via an Rh- or Ir-catalyzed asymmetric hydrogenation of N-aryl enamine giving the desired product with up to 82% ee. The other pathway involves a direct asymmetric reductive amination (DARA) of the β-keto ester which yielded the β-amino ester in high yield and 97% ee. Subsequent copper-catalyzed N-arylation gave the target compound.

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Ethyl 3-amino-3-(4-(benzyloxy)phenyl)propanoateC20H25NO5[α]D20=+8.4 (c 1.08, EtOH)Ee = 99.7%Absolute configuration unknown

Ethyl 3-(4-(benzyloxy)phenyl)-3-(4-fluorophenylamino)propanoateC24H24FNO3[α]D20=+6.35 (c 0.36, CH2Cl2)Ee = 96.6%Absolute configuration unknown