Nitrilase-Catalysed Desymmetrisation of 3-Hydroxyglutaronitrile: Preparation of a Statin Side-Chain Intermediate

Autor:	Graham Ruecroft, Sophie Bergeron, Brian S. W. Ellis, Thomas Mahoney, Jonathan R. Knight, Karen Holt-Tiffin, David A. Chaplin, and Andrew P. Osborne, Catherine Hill, John H. Edwards
Rok vydání:	2006
Předmět:	chemistry.chemical_classification Cyanide Organic Chemistry Substrate concentration Nitrilase Kinetic resolution chemistry.chemical_compound Enzyme chemistry Biocatalysis Side chain Organic chemistry Epichlorohydrin Physical and Theoretical Chemistry
Zdroj:	Organic Process Research & Development. 10:661-665
ISSN:	1520-586X 1083-6160
DOI:	10.1021/op050257n
Popis:	An efficient, scaleable synthesis of ethyl (R)-4-cyano-3-hydroxybutyrate, a potential intermediate in the synthesis of Atorvastatin (Lipitor), has been developed. The three-stage process starts with reaction of low-cost epichlorohydrin with cyanide to give 3-hydroxyglutaronitrile (3-HGN). The second stage utilises a nitrilase-catalysed desymmetrisation of 3-HGN. The nitrilase reaction has been optimized to work at 3 M (330 g/L) substrate concentration, pH 7.5, 27 °C. Under these conditions, with an enzyme loading of 6 wt %, 100% conversion and 99% ee product is obtained in 16 h. This material is then esterified to give the target compound, ethyl (R)-4-cyano-3-hydroxybutyrate. The cost-effectiveness of the process is determined by three factors: use of a low-cost starting material, the introduction of the chiral centre by desymmetrisation as opposed to kinetic resolution, and the use of Pfēnex Expression Technology to allow a lower-cost supply of biocatalyst.
Databáze:	OpenAIRE
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