Continuous-Flow Synthesis of (–)-Oseltamivir Phosphate (Tamiflu)

Published as part of the Cluster Integrated Synthesis Using Continuous-Flow Technologies

Abstract

Herein the anti-influenza drug (–)-oseltamivir phosphate is prepared in continuous flow from ethyl shikimate with 54% overall yield over nine steps and total residence time of 3.5 min from the individual steps. Although the procedure involved intermediate isolation, the dangerous azide chemistry and intermediates involved were elegantly handled in situ. It is the first continuous-flow process for (–)-oseltamivir phosphate involving azide chemistry and (–)-shikimic acid as precursor.

Key words

azide chemistry - continuous flow - influenza - (–)-oseltamivir phosphate - total synthesis

• References

• 1 Magano J. Chem. Rev. 2009; 109: 4398
• 2 Magano J. Tetrahedron 2011; 67: 7875
• 3 Abrecht S, Harrington P, Iding H, Karpf M, Wirz B, Zutter U. Chim. Int. J. Chem. 2004; 58: 621
• 4 Moscona A. N. Engl. J. Med. 2005; 353: 1363
• 5 Ishikawa H, Suzuki T, Orita H, Uchimaru T. Chem. Eur. J. 2010; 16: 12616
• 6 WHO Report Standard Guidelines for the Clinical Management of Severe Influenza Virus Infections, 2017.
• 7 Nie L, Shi X. Tetrahedron: Asymmetry 2009; 20: 124
• 8 Nie L, Ding W, Shi X, Quan N, Lu X. Tetrahedron: Asymmetry 2012; 23: 742
• 9 Nie L, Shi X, Ko KH, Lu W. J. Org. Chem. 2009; 74: 3970
• 10 Ogasawara S, Hayashi Y. Synthesis 2017; 49: 424
• 11 Sagandira CR, Watts P. Eur. J. Org. Chem. 2017; 44: 6554
• 12 Brandt JC, Wirth T. Beilstein J. Org. Chem. 2009; 5: 1
• 13 Delville ME, Nieuwland PJ, Janssen P, Koch K, van Hest JC. M, Rutjes FP. J. T. Chem. Eng. J. 2011; 167: 556
• 14 Baumann M, Baxendale IR, Ley SV, Nikbin N, Smith CD. Org. Biomol. Chem. 2008; 6: 1587
• 15 Stevens CV. Chem. Soc. Rev. 2016; 45: 4892
• 16 Gutmann B, Roduit JP, Kappe CO, Roberge D. Angew. Chem. Int. Ed. 2010; 49: 7101
• 17 Ötvös SB, Hatoss G, Georgiádes A, Kovács S, Mándity I, Nováket Z. RSC Adv. 2014; 4: 46666
• 18 Smith CJ, Smith CD, Nikbin N, Ley SV, Baxendale IR. Org. Biomol. Chem. 2011; 9: 1927
• 19 Sprecher H, Payán MN. P, Weber M, Yilmaz G, Wille G. J. Flow Chem. 2011; 2: 20
• 20 Kalashnikov IA, Sysolyatin SV, Sakovich GV, Sonina EG. Russ. Chem. Bull. Int. Ed. 2013; 62: 163
• 21 Karpf M, Trussardi R. Angew. Chem. Int. Ed. 2009; 48: 5760
• 22 Sagandira CR, Watts P. J. Flow Chem. 2019; 9: 79
• 23 Sagandira CR, Watts P. Beilstein J. Org. Chem. 2019; 15: 2577
• 24 Hsueh N, Clarkson GJ, Shipman M. Org. Lett. 2015; 17: 3632
• 25 Hsueh N, Clarkson GJ, Shipman M. Org. Lett. 2016; 18: 4908
• 26 Penkova M, Nikolova S. Bulg. Chem. Commun. 2017; 44: 105
• 27 Sweeney JB. Chem. Soc. Rev. 2002; 31: 247
• 28 Fringuelli F, Pizzo F, Vaccaro L. Synthesis 2000; 646