A Short and Practical Synthesis of Oseltamivir Phosphate (Tamiflu) from (−)-Shikimic Acid

Abstract

Oseltamivir phosphate (1) was synthesized from (-)-shikimic acid through a short and practical synthetic route via eight steps in 47% overall yield. In addition, the highly regioselective and stereoselective nucleophilic replacement of OMs by the N(3) group in the third and seventh steps has been studied in detail, and the reaction conditions were optimized.

Current perspectives on applications of shikimic and aminoshikimic acids in pharmaceutical chemistry

“…49 To protect people from pandemic human or H5N1 avian influenza, OSP should be manufactured and stocked in every country worldwide. 50 Topics of current research are the relatively new techniques for SA isolation from known and novel sources. According to the WHO Pandemic influenza preparedness and response guidance, threats of influenza pandemics will continue to emerge.…”

“…19 Different major chemical routes for the synthesis of OSP include 17-, 13-, ten-, and nine-step synthesis starting from SA. 19,50 The ten-step route includes three explosive and/or toxic azide derivatives; the 17-step route is an azidefree process, 19 but it is a long synthetic route, which significantly retards its use in the large-scale production of OSP. 50 In the 17-and ten-step routes, approximately four of the steps are performed to add an amino group substituent at the 5-position of SA ring.…”

“…19,50 The ten-step route includes three explosive and/or toxic azide derivatives; the 17-step route is an azidefree process, 19 but it is a long synthetic route, which significantly retards its use in the large-scale production of OSP. 50 In the 17-and ten-step routes, approximately four of the steps are performed to add an amino group substituent at the 5-position of SA ring. ASA as a substrate for the synthesis of OSP might eliminate the requirement for those first four steps, which could significantly improve the speed and cost of the production of OSP and other oseltamivir carboxylates.…”

Reactions of 4,5-bis(morpholin-4-yl)cyclopent-2-en-1-one with sodium salts derived from methyl dichloroacetate and ethyl (dimethyl-λ4-sulfanylidene)acetate

“…Compound I is a derivative of cyclohexenecarboxylic acid. Several syntheses of Tamiflu have recently been reported [1][2][3][4][5][6][7][8][9][10]; however, they include a number of steps and require the use of expensive reagents, as well as of sodium azide, to introduce the amine and acetamide moieties. Therefore, the described procedures cannot be regarded as practical from the viewpoint of largescale synthesis.…”

Selective functionalization of alicyclic beta-amino acids by 1,3-dipolar cycloaddition of nitrile oxides

“…As a consequence of their ability to undergo reductive ring opening, isoxazolines are of interest as precursors for the synthesis of highly functionalized molecules such as β-hydroxyketones [7][8][9][10], amino alcohols or amino acids [11][12][13][14][15][16][17], etc. The multifunctionalized cyclic amino acids -e.g., the antibiotic Oryzoxymycin [18][19][20][21], the antiviral agents Tamiflu [22][23][24][25][26][27][28][29][30][31][32][33], Zanamivir and 2,3-didehydro-2-deoxy-N-acetylneuraminic acid (DANA) [34][35][36][37][38] -are bioactive derivatives of great significance for medicinal chemistry. A promising neuraminidase inhibitor, BCX-1812 (Peramivir), is currently under evaluation in clinical trials [39][40][41][42][43][44][45] (Figure 1).…”