Chemo-Enzymatic Synthesis of Enantiopure β-Blocker (S)-Metoprolol and Derivatives

Abstract

Abstract(S)-Metoprolol, ((2 S)-1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol has been synthesised in 99% ee with high yield by a four step chemoenzymatic protocol. Several preparations of Candida antarctica lipase B have been screened in a kinetic resolution of the secondary chlorohydrin 1-chloro-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol. We here report specific rotation values of the enantiopure chlorohydrins from the enzyme catalysed kinetic resolution, in addition to a specific rotation value for (S)-metoprolol, which determines the absolute configuration of the drug, and also the absolute configuration of the chlorohydrin enantiomers.

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

“…For a similar reason, it is also possible to use less acetic acid than previously reported in the syntheses of other beta-blockers. We have previously used between five and ten equivalents of acetic acid and two to five equivalents of lithium chloride [ 20 ]. By addition of excess lithium chloride relative to 2b in the reaction mixture and approximately five equivalents of acetic acid relative to 2b , a 52% yield of 2a was achieved.…”