New synthetic strategies towards oseltamivir phosphate

Abstract

Oseltamivir phosphate or Tamiflu(R), the inhibitor neuraminidase enzyme of influenza virus, is currently in use widely for acute influenza treatment. This research aimed to synthesize oseltamivir phosphate 10 and its derivatives to survey potentially improved process and enhance the possibility to discover new drugs in this family that could lead to future treatment of the emerging resistant strain. The synthesis started from naturally available (-)-shikimic acid 32, through 11 steps yielding epoxide intermediate, followed by additional 6 steps in the azide route to provide oseltamivir phosphate 10 in overall yield of 10% from (-)-shikimic acid 32. Five derivatives in the group of 4R,5S diastereomers, 56, 124 and 130-132, could be obtained via SN2 substitution or Mitsunobu reaction as the key step in overall yields of 18%, 18%, 40%, 40%, and 29%, respectively from (-)-shikimic acid 32. Another four derivatives in the group of 4S,5R diastereomers, 121-123 and 125a could be obtained in 41%, 35%, 37% and 62%, respectively from (-)-shikimic acid 32 via substitution on epoxide 28 or none.