Synthesis of Chiral Pharmaceutical Intermediates by Oxidoreductases
ACS Symposium SeriesApplied Biocatalysis in Specialty Chemicals and Pharmaceuticals(2001)
摘要
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]-1-butanone 1 to R-(+)-1-(4-fluoro-phenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]-1-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 Neε-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
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关键词
chiral pharmaceutical intermediates,oxidoreductases,synthesis
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