Synthesis of chiral pharmaceutical intermediates by oxidoreductases

Abstract

Chiral intermediates were prepared by enzymatic process using oxidoreductases for the chemical synthesis of pharmaceutical drug candidates. These includes: (1) the microbial reduction of 1-(4-fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]-butanone 1 to R-(+)-1-(4-fluoro-phenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]-butanol [R-(+)-BMY 14802], a antipsychotic agent; (2) the reduction of N-(4-(1-oxo-2-chloroacetyl ethyl) phenyl methane sulfonamide 3 to corresponding chiral alcohol 4, an intermediate for D-(+)-N-[4-[1-Hydroxy-2-[(-methylethyl)amino]ethyl]phenyl] methanesulfonamide [D-(+) sotalol], a β-blocker with class III antiarrhythmic properties; (3) biotransformation of Nε-carbobenzoxy (CBZ)-L-lysine 7 to CBZ-L-oxylysine 5 an intermediate needed for synthesis of (S)-1-[6-amino-2-[[hydroxy(4-phenylbutyl) phosphinyl]oxy]1-oxohexyl]-L-proline [ceronapril] , a new angiotensin converting enzyme [ACE] inhibitor 6 (4) enzymatic synthesis L-β-hydroxyvaline 9 from α-keto-β-hydroxy isovalerate 16. L-β-Hydroxy valine 9 is a key chiral intermediate needed for the synthesis of [S-(Z)]-[[[1-(2-Amino-4-thiazolyl)-2- [[2,2-dimethyl-4-oxo-1-(sulfooxy)-3-azetidinyl] amino]-2-oxoethylidene] amino]oxy]acetic acid [tigemonam] 10 , a orally active monobactam, (5) enzymatic synthesis of L-6-hydroxynorleucine 17, and (6) enzymatic synthesis of (S)-2-amino-5-(1,3-dioxolan-2-yl)-pentanoic acid (allysine ethylene acetal, 21), one of three building blocks used for an alternative synthesis of omapatrilat, a vasopeptidase inhibitor.