Chemoenzymatic synthesis of calcilytic agent NPS-2143 employing a lipase-mediated resolution protocol

The kinetic resolution of chlorohydrin (±)-6 has been successfully carried out via a lipase-mediated transesterification with vinyl acetate in organic as well as ionic liquid media to yield (R)-alcohol 6 and (S)-acetate 7 in high enantioselectivity. An enantioconvergent synthesis has also been achieved by a Mitsunobu esterification of a mixture of (R)-alcohol 6 and (S)-acetate 7 in one pot to convert the (R)-alcohol 6 to (S)-acetate 7. (S)-Acetate 7 has been hydrolyzed by LiOH·H2O to give epoxide (R)-2. This enantiopure epoxide has been used as a chiral precursor for the synthesis of calcilytic agent NPS-2143.

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2-Chloro-6-{[(2R)-3-chloro-2-hydroxypropyl]oxy}benzonitrileC10H9Cl2NO2Ee = 98% [by chiral HPLC analysis][α]D25=-3.1 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: R

(1S)-2-Chloro-1-[(3-chloro-2-cyanophenoxy)methyl]ethyl acetateC12H11Cl2NO3Ee = 99% [by chiral HPLC analysis][α]D25=+33.8 (c 1.2, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: S

2-Chloro-6-[(2R)-oxiran-2-ylmethoxy]benzonitrileC10H9Cl2NO2Ee = 95% [by chiral HPLC analysis][α]D25=-11.2 (c 0.5, CHCl3)Source of chirality: (1S)-2-chloro-1-[(3-chloro-2-cyanophenoxy)methyl]ethyl acetateAbsolute configuration: R

2-Chloro-6-{3-[1.1-dimethyl-2-(2-naphthyl)ethylamino]-2-(R)-hydroxypropoxy}benzonitrileC24H26ClN2O2[α]D25=+13.3 (c 1.2, CHCl3)Source of chirality: 2-chloro-6-[(2R)-oxiran-2-ylmethoxy]benzonitrileAbsolute configuration: R