Enzymatic synthesis of chiral intermediates for Omapatrilat, an antihypertensive drug.

摘要: Biocatalytic processes were used to prepare chiral intermediates required for the synthesis of Omapatrilat 1 by three different routes. The and enzymatic conversion 2-keto-6-hydroxyhexanoic acid 3 L-6-hydroxynorleucine 2 was demonstrated reductive amination using beef liver glutamate dehydrogenase. To avoid lengthy chemical ketoacid 3, a second route developed treatment racemic 6-hydroxy norleucine [readily available from hydrolysis 5-(4-hydroxybutyl) hydantoin 4] with D-amino oxidase porcine kidney or Trigonopsis variabilis followed convert mixture completely in 98% yield 99% enantiomeric excess (e.e.). (S)-2-amino-5-(1,3-dioxolan-2-yl)-pentanoic (allysine ethylene acetal, 5) phenylalanine dehydrogenase (PDH) T. intermedius. Phenylalanine cloned overexpressed Escherichia coli Pichia pastoris. Using PDH E. P. pastoris, process scale-up kg quantity allysine acetal 5. reaction yields >94% e.e. >98% obtained An [4S-(4a,7a,10ab)]1-octahydro-5-oxo-4 [[(phenylmethoxy)carbonyl]amino]-7H-pyrido-[2,1-b] [1,3]thiazepine-7-carboxylic [BMS-199541-01]. oxidation epsilon-amino group lysine dipeptide dimer N(2)-[N[[(phenyl-methoxy)carbonyl] L-homocysteinyl] L-lysine)-1,1-disulphide [BMS-201391-01] produce BMS-199541-01 novel L-lysine epsilon-aminotransferase (LAT) Sphingomonas paucimobilis SC 16113 demonstrated. This enzyme recombinant enzyme.