Fosinopril – Synthesis and Separation of Isomers

Fosinopril is a drug which came off patent in 2002, although several process patents have extended the protection to 2007.  For the generic drug companies, one challenge is either a stereoselective synthesis or a novel strategy for separation of the isomers.  At the recent Scientific Update conference on Organic Process R & D, Dr. Girij Pal Singh of Lupin Laboratories, India described the separation of the SRSS from the RRSS, RSSS and SSSS isomers by making the cesium salt dihydrate which crystallised easily, leaving the other isomers behind.  The process is operated on 100 kg scale – all the unwanted isomers are recycled back into the system.  Fosinopril sodium crystallises in 2 forms depending on the water content of the solvent.  From a keto or hydroxylic solvents with > 2% water form A is produced, whereas form B is produced when the water is < 0.2%.  However Lupin have developed a slow crystallisation process which gives the desired form A but in a low water content solvent.  Lupin have also an improved process for preparing phosphorous acids under mild conditions.