Oseltamivir-phosphate

Figure 4.18 The structure of Tamiflu (oseltamivir phosphate), an antiviral agent active against type A influenza, and a molecular model of its minimum-energy conformation, as calculated by molecular mechanics.

Ives JA, Carr JA, Mendel DB, Tai CY, Lambkin R, Kelly L, Oxford JS, Hayden FG, Roberts NA (2002) The H274Y mutation in the influenza A/HINI neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo. Antiviral Res 55 307-317... 

A highly useful and important regioselective reduction of substrate 84 leads to a mixture of 3-hydroxy ethers 85 and 86 in a 32 1 ratio (Eq. 306). Compound 85 is further converted to the anti-influenza drug oseltamivir phosphate, better known as Tamiflu .498... 

The neuramidase inhibitor oseltamivir phosphate was discovered by Gilead Sciences and developed by Roche Pharmaceuticals under the name of Tamiflu (Scheme 5.13) to be used as an orally active antiviral compound for prevention and treatment of influenza infections. Because of the recent emergence of the avian flu, the demand for Tamiflu has gained momentum. Two industrially feasible syntheses are known, starting from (—)-shikimic acid and (—)-quinic acid, respectively (Scheme 5.13) [45]. 

NEURAMINIDASE INHIBITORS FOR INFLUENZA OSELTAMIVIR PHOSPHATE (TAMIFLU ) AND ZANAMIVIR (RELENZA )... 

USAN Oseltamivir phosphate Trade name Tamiflii Company Gilead, Roche Launched 1999 M.W. 312.4 (parent)... 

Scheme 7.3. Gilead s first process route to oseltamivir phosphate (1).

Approaches to oseltamivir phosphate (1) that were independent of ( )-shikimic acid as the raw material were also evaluated. The furan-ethyl acrylate Diels-Alder approach is shown in Scheme 7.8 (Abrecht et al., 2001, 2004). The zinc-catalyzed Diels-Alder reaction between furan and ethyl acrylate was heated at 50°C for 72 h to provide a 9 1 mixture favoring exo-isomer rac-43 over the enJo-isomer. The enJo-isomer was kinetically preferred, but with increased reaction times an equilibrium ratio of 9 1 was achieved favoring the thermodynamically preferred exo-isomer rac-43. The optical resolution of rac-43 was achieved via enantioselective ester hydrolysis using Chirazyme L-2 to give (—)-43 in 97%... 

Scheme 7.9. Synthesis of oseltamivir phosphate (1) employing an enzymatic monohydrolysis desymmetrization.

The unprotected amine was acetylated with acetic anhydride and the nitrile was converted to the ethyl ester in acidic ethanol with concomitant removal of the Boc group to provide oseltamivir. Finally, salt formation with 85% phosphoric acid in ethanol afforded oseltamivir phosphate (1). 

Orally administered oseltamivir phosphate is rapidly absorbed and converted by hepatic esterases to oseltamivir carboxylate. Approximately 80% of an oral dose reaches the systemic circulation as oseltamivir carboxylate, with peak plasma concentrations achieved within 2.5 to 5 hours. The plasma elimination half-life of oseltamivir carboxylate is 7 to 9 hours. Elimination of the parent drug and its active metabolite occurs primarily by active tubular secretion and glomerular filtration. 

Ghosh, G.C., Nakada, N., Yamashita, N. and Tanaka, H. (2010) Oseltamivir carboxylate, the active metabolite of oseltamivir phosphate (Tamiflu), detected in sewage discharge and river water in Japan. Environ. Health Perspect., 118 (1), 103-107. 

S. Abrecht, P. Harrington, H. Iding, M. Karpf, R. Trussardi, B. Wirz, and U. Zutter, The synthetic development of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu) A challenge for synthesis process research, Chimia, 58 (2004) 621-929. 

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