- A concise and practical synthesis of oseltamivir phosphate(Tamiflu) from d-mannose
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A short and practical synthesis of oseltamivir phosphate was accomplished in 11 steps from inexpensive and abundant starting material, d-mannose. This synthetic route featured an intramolecular Horner-Wadsworth-Emmons reaction as the key step to furnish the cyclohexene ring product. The hydroxyl group was converted stereo specifically into an amino group by oxidation to the ketone and reductive amination whereas the second amino group was introduced by azide substitution of a hydroxyl group. This synthesis provided an economical and practical alternative for the synthesis of Tamiflu.
- Chuanopparat, Nutthawat,Kongkathip, Ngampong,Kongkathip, Boonsong
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p. 6803 - 6809
(2012/08/28)
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- An efficient synthesis of oseltamivir phosphate (Tamiflu) via a metal-mediated domino reaction and ring-closing metathesis
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An efficient synthesis of the influenza neuraminidase inhibitor prodrug oseltamivir phosphate (Tamiflu) from cheap, commercially available d-ribose is described. The main features of this approach comprise a metal (Zn, In)-mediated domino reaction and ring-closing olefin metathesis (RCM) of the resultant functionalized dienes to produce the Tamiflu skeleton. The synthesis described in this Letter represents a new and efficient transformation of a shikimic acid derivative into a 1,2-diamino compound which involved oxidation of an alcohol followed by reductive amination, regioselective ring opening of an amino pentylidene ketal and stereospecific nucleophilic replacement of a triflate with an azide.
- Wichienukul, Pawinee,Akkarasamiyo, Sunisa,Kongkathip, Ngampong,Kongkathip, Boonsong
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supporting information; experimental part
p. 3208 - 3210
(2010/08/07)
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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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(Chemical Equation Presented) 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.
- Zutter, Ulrich,Iding, Hans,Spurr, Paul,Wirz, Beat
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p. 4895 - 4902
(2008/12/20)
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- Stereo-specific synthesis of shimikic acid derivatives with improved efficiency
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The invention provides a multistep synthesis for the preparation of 4,5-diamino shikimic acid derivatives of formula 1starting from an isophthalic acid derivative of formula 24,5-Diamino shikimic acid derivatives are potent inhibitors of viral neuraminidase.
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