Synthesis of Enantiopure (<i>S</i>)-Atenolol by Utilization of Lipase-Catalyzed Kinetic Resolution of a Key Intermediate

Abstract

(S)-Atenolol ((S)-2-(4-(2-Hydroxy-3-(isopropylamino)propoxy)phenyl)acetamide) has been synthesized in >99% enantiomeric excess (ee) with the use of Candida antarctica lipase B from Syncozymes (Shanghai, China), in a kinetic resolution of the corresponding racemic chlorohydrin. A catalytic amount of base was used in deprotonation of the phenol building block. The enantiopurity of the chlorohydrin building block remained unchanged upon subsequent amination to yield the final drug. All four steps in the synthesis protocol have been optimized compared to previously reported methods, which makes this new protocol more sustainable and in accordance with green chemistry principles. The overall yield of (S)-atenolol was 9.9%, which will be further optimized.

Keywords

• enantiopure (<i>S</i>)-atenolol
• <i>Candida antarctica</i> lipase B
• base catalysis
• Chiralcel OD-H column