New, efficient synthesis of oseltamivir phosphate (Tamiflu) via enzymatic desymmetrization of a meso-1,3-cyclohexanedicarboxylic acid diester.
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 S(N)2 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 approximately 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.
Zutter
Ulrich
U
F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Technical Sciences, Synthesis & Process Research and Biocatalysis, CH-4070 Basel, Switzerland. ulrich.zutter@roche.com
Iding
Hans
H
Spurr
Paul
P
Wirz
Beat
B
D000998:Antiviral Agents / Q000138:chemical synthesis*; D003998:Dicarboxylic Acids / Q000737:chemistry*; D015394:Molecular Structure; D053139:Oseltamivir / Q000138:chemical synthesis*
D000998:Antiviral Agents; D003998:Dicarboxylic Acids; D053139:Oseltamivir