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New, Efficient Synthesis of Oseltamivir Phosphate (Tamiflu) via Enzymatic Desymmetrization of a meso-1,3-Cyclohexanedicarboxylic Acid Diester

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F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Technical Sciences, Synthesis & Process Research and Biocatalysis, CH-4070 Basel, Switzerland
Cite this: J. Org. Chem. 2008, 73, 13, 4895–4902
Publication Date (Web):June 3, 2008
https://doi.org/10.1021/jo800264d
Copyright © 2008 American Chemical Society

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    Abstract

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    A new, enantioselective synthesis of the influenza neuraminidase inhibitor prodrug oseltamivir phosphate 1 (Tamiflu) and its enantiomer ent-1 starting from cheap, commercially available 2,6-dimethoxyphenol 10 is described. The main features of this approach comprise the cis-hydrogenation of 5-(1-ethyl-propoxy)-4,6-dimethoxy-isophthalic acid diethyl ester (6a) and the desymmetrization of the resultant all-cis meso-diesters 7a and 7b, respectively. Enzymatic hydrolysis of the meso-diester 7b with pig liver esterase afforded the (S)-monoacid 8b, which was converted into cyclohexenol 17 via a Curtius degradation and a base-catalyzed decarboxylative elimination of the Boc-protected oxazolidinone 14. Introduction of the second amino function via SN2 substitution of the corresponding triflate 18 with NaN3 followed by azide reduction, N-acetylation, and Boc-deprotection gave oseltamivir phosphate 1 in a total of 10 steps and an overall yield of ∼30%. The enantiomer ent-1 was similarly obtained via an enzymatic desymmetrization of meso-diester 7a with Aspergillus oryzae lipase, providing the (R)-monoacid ent-8a.

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    General remarks and copies of 1H NMR spectra for compounds 11, 12, 6a, 7a, 7b, 8b, 13, 14, 17, 18, 20, 21, 1, ent-8a, ent-8b, and 19 and the 13C NMR spectrum for compound 19. This material is available free of charge via Internet at http://pubs.acs.org.

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