Synthesis of Oseltamivir Phosphate Tamiflu

Deallylation of 29 was achieved using 10% Pd/C in the presence of ethanolamine in refluxing ethanol to afford 30 in 77% yield (with 4% of the regioisomer). The reaction 

The 4-amino group of 31 was selectively acetylated under acidic conditions using acetic anhydride (1 equiv.) and methanesulfonic acid (1 equiv.) in acetic acid and f-butylmethyl ether to give 32. Deallylation of 32 using 10% Pd/C in the presence of ethanolamine in refluxing ethanol proceeded as before to afford 1, which was converted to the phosphate salt in 70% yield with high purity (99.7%). The overall yield of 1 from epoxide 23 was 35-38%. 

Acetylation of the stericaUy hindered amine in 40 required treatment with acetic anhydride and sodium acetate at 116°C. The resulting r-butyl acetamide was treated with one equivalent of hydrogen chloride in ethanol followed by filtration of the precipitate to give clean hydrochloride salt 41 in 87% yield. This was the only purification step in the entire 

In May 2006, E. J. Corey at Harvard University and two of his co-workers published a short enantioselective pathway for the synthesis of oseltamivir. Corey came up with the idea after reading a New York Times article on the shortage of Tamiflu supply, after 

Good overall yield ( 30%, still not completely optimized). 

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Osato H, Jones IL, Chen A, Chai CLL. Efficient formal synthesis of oseltamivir phosphate (Tamiflu) with inexpensive d-ribose as the starting material. Org. Lett. 2010 12(1) ... 

Wichienukul P, Akkarasamiyo S, Kongkathip N, Kongka-thip B. An efficient synthesis of oseltamivir phosphate (Tamiflu) via a metal-mediated domino reaction and ringclosing metathesis. Tetrahedron Lett. 2010 51(24) 3208-3210. 

A short and practical synthesis of oseltamivir phosphate (Tamiflu) (391), an effective neuraminidase inhibitor, has been accomplished in 11 steps in 2.9% overall yield, from inexpensive and abundant D-mannose (389). The key step of the synthesis include formation of the cyclohexene ring (390) by an intramolecular Horner-Wadsworth-Emmons reaction (Scheme 137). °... 

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. 

Karpf, M. et al. New, Azide-Free Transformation of Epoxides into 1,2-Diamino Compounds Synthesis of the Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu). 3.4.4 2001 [135]... 

The heterogeneous, catalytic hydrogenation of substituted aromatic rings is a powerful means for the preparation of cis-substituted cycloalkanes in a highly stereoselective fashion [16]. An elegant example has been reported by researchers at Roche in a synthesis of the anti-influenza drug oseltamivir phosphate (Tamiflu, 20, Scheme 8.4) [35]. Diester 18 was reduced at elevated pressure, exclusively affording the all-cis-substituted meso-cyclohexane 19. 

In pursuit of a rapid and cost-effective synthesis of the anti-influenza drug (—)-oseltamivir (83) (Tamiflu , as phosphate), Hayashi and coworkers have developed an innovative synthesis involving three one-pot processes (Scheme 7.15) [56]. A large-scale synthesis of Tamiflu is considered so profoundly important today with... 

Oseltamivir phosphate (24, Tamiflu ), a neuraminidase inhibitor, is administered orally for the treatment and prevention of influenza A and B virus infections, and stockpiling of this drug has been proposed to counter the threat of a pandemic such as avian flu [63,64]. One synthesis... 

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