Enzyme-catalyzed preparation of methyl (R)-N-(2,6-dimethylphenyl)alaninate: a key intermediate for (R)-metalaxyl |
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| Institution: | 1. LG Chem, Ltd/Research Park, 104-1 Moonji-dong, Yusung-gu, Daejon 305-380, Republic of Korea;2. LG Life Sciences Ltd/Research Park, 104-1, Moonji-dong, Yusung-gu, Daejon 305-380, Republic of Korea;1. Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy;2. Molecular Medicine, Katholieke Universiteit Leuven and IRC KULAK, Kapucijnenvoer 33, B-3000 Leuven, Flanders, Belgium;1. Bioprojet-Biotech, 4 rue du Chesnay Beauregard, BP 96205, 35762 Saint-Grégoire, France;2. Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany |
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| Abstract: | A biocatalytic approach for the production of (R)-metalaxyl, mefenoxam, has been developed. A practical synthesis of methyl (R)-N-(2,6-dimethylphenyl)alaninate, a key intermediate for (R)-metalaxyl, has been developed by the use of lipase-catalyzed hydrolytic kinetic resolution and chemical racemization of the remaining ester. At high concentrations in aqueous media (300 g/L) lipases were stable and gave moderate to good conversions and excellent enantioselectivities (>98% ee). A simple extraction procedure was used to separate the acid product from the remaining ester and the acid was esterified with methanol to give methyl (R)-N-(2,6-dimethylphenyl)alaninate without any reduction in enantiomeric excess (>98% ee). Subsequent chemical coupling with methoxyacetyl chloride provided enantiomerically pure (R)-metalaxyl (>98% ee) without racemization. |
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