Researchers find new routes to boost Tamiflu supply
(oseltamivir) have published two new syntheses based on cheaper
starting materials than the conventional method.
Roche is battling to meet demand for Tamiflu by increasing its external contractors and finding new methods to produce shikimic acid, as sales this year for the drug are expected to reach 1.1bn to 1.2bn Swiss francs (€7bn - €7.5bn).
The shikimic acid used in the manufacturing of Tamiflu is expensive and in limited supply, since it is obtained almost exclusively from the pods of the star anise, a fruit that is found mainly in China and whose availability has dwindled due to high demand for the flu drug.
But two new synthetic routes published in the Journal of the American Chemical Society avoid the use of shikimic acid and start with cheaper building blocks.
The most promising pathway was developed by Harvard Professor Elias Corey, who won the Nobel Prize for Chemistry in 1990 for his achievements in devising lab bench approaches to synthesising natural compounds.
Corey's starting materials - butadiene and acrylic acid - are two of the cheapest feedstocks around, used for synthetic rubber, Plexiglass, and other plastics.
Moreover, while one step in the manufacturing process, which Roche usually outsources, involves a highly explosive chemical called an azide, allowing only small batches of Tamiflu to be made at a few tens of litres at a time, Corey's route does not involve any hazardous azide intermediates.
The synthesis provides complete enantio-, regio-, and diastereo-control and an impressive yield of 30 per cent, which Corey says is still not optimised despite it being twice that of the commercial route.
Across the globe, a team at the University of Tokyo led by Corey's former student, Masakatsu Shibasaki, has came up with a longer process which also starts with an inexpensive material, 1,4-cyclohexadiene.
However, Shibaki's synthesis, for which he has applied for a patent, may prove good only as an alternative since its yield is rather poor.
Even Corey's route may not stand up to scrutiny though, as very often chemistry done in his lab is difficult to scale up, and there are several steps in the synthesis that may not work on a manufacturing scale.
In addition, assuming the new routes are feasible and commercially viable, they will have to be approved by drug authorities.
Nevertheless, Corey is optimistic, pointing out that a key catalyst in the synthesis is almost identical to one already widely used in the manufacturing of GlaxoSmithKline's asthma treatment Advair.
A Roche spokeswoman would not comment on the new routes but reiterated to In-PharmaTechnologist.com that "Roche welcomes any research and collaborations with companies that can significantly enhance efforts to expand the production of Tamiflu and welcomes being updated on any developments in this area."
