Oseltamivir – Yet Another Academic Synthesis Reported

Oseltamivir – Yet Another Academic Synthesis Reported

J-M Fang and collegues at the National Taiwan University have recently reported a synthesis of oseltamivir and a related drug, tamiphosphor (Shie J-J et al, Angew Chem Int Ed, 2008, 47, 5788).  The synthesis, described in the title as concise and efficient, is one of many that have been reported in the last year from academic groups (Corey, Fukaiyama, Shibasaki, Trost etc).  Many of these try to get around the use of shikimic acid as starting material in the Roche commercial process, citing that, being a natural product, this may be in short supply.  However, biotechnology approaches to shikimic acid mean that this is not now the case, so these syntheses need to be very efficient to compete.

The raw material used in the Angew Chem paper is commercially available diol, easily made by microbial oxidation of bromobenzene, and this is transformed in 12 linear steps with 9 isolated intermediates to oseltamivir as shown in the Scheme.  A key feature is the selective ring opening of the aziridine to introduce the pentyloxy and acetamide groups early on in the desired positions and in the required stereochemistry.  The bromo (from the bromobenzene originally) is elaborated, using a nickel catalysed ethoxycarbonylation to the desired ester functionality.  Some of the negative process chemistry aspects are the conversion of one of the OH groups in the starting material to Br then to H using stoichiometric and expensive reagents, such as LiBHEt₃, and the conversion of the other OH to NH₂ via an azide, as in the current industrial synthesis.  A tin catalyst is also used in the early stages.  Yields are in the range 21-26% overall.  A second synthesis, this one azide-free was also reported, wherein the OH is converted to a NHBoc group using DDQ, PPh₃, and BuN⁺OCN^-, and the Br is converted to I then CO₂Et using first CuI, then palladium catalysed ethoxycarbonylation.

It remains to be seen whether this gram scale synthesis will be modified further for scale up, reducing the costs by the use of less expensive reagents and catalysts.

The article is very well referenced and contains all the useful syntheses, including the Harrington process from Roche (Org Process Res Dev, 2004, 8, 86-91) which I understand is not used commercially.