Tag Archives: diastereoselective aldol

Publication of the week, number 4, 13 December 2013

Friday the 13th brings a series of three ASAPs of the week  describing the process optimisation and scale-up of the RNA polymerase inhibitor Filibuvir by the Pfizer process Group. Part 1 deals with the diastereoselective preparation of a β‐Hydroxy alkynyl oxazolidinone and its conversion to a 6,6- disubstituted 2H‐pyranone. Various conditions were investigated for this key reaction:


the best being the following: LHMDS, THF, Toluene, -78°C. This gave the product which after crystallisation gave the aldol product with a diastereoselectivity of >200:1. Further progression along the route led to a Dieckmann cyclisation. Part 2 of this series discusses the problems encountered with this critical cyclisation and the reagent variability.


Solvent played a major role, THF giving 90% yield vs. toluene with 76%. The real problem was with the quality of the LiHMDS which caused problems such as elimination, incomplete conversion and so on. This quality from different suppliers was examined focusing on the method of preparation. Finally  sources were identified that delivered the required quality of LiHMDS. This is a typical development problem, one which I have encountered many times and can be extremely difficult to solve.

Part 3 of this series highlights yet another typical problem that one encounters in development research an Ames positive reagent. This requires extreme care not only in manipulation but in the acceptable levels that may be carried through to the final API in this case <5ppm. A careful optimisation of the process finally led to the required levels being actually bettered. This takes time and a lot of work.

This nice three part series is well worth a read. Congratulations to the Pfizer development team who worked on this very challenging project. They produced some excellent work and a very nice series of papers for the rest of us to enjoy.

It is a scandal how Pfizer is now going about it’s business with blatant disregard to any such success stories such as the one above. Showing absolutely no consideration to those who actually produce things for the corporate good unlike the high level managers who rest on the laurels of others while collecting immense salaries and then wielding the axe indiscriminately. The demise of the Sandwich site is terrible, not only for the work force there but the surrounding areas and businesses. I spent some time at that site a long time ago and can tell you that is is a great place to be. Pity Pfizer owned it.

264,417 total views, 2 views today