Second Generation Process Development

Many pharmaceutical companies do little process development after a drug is launched partly because of the fear of regulatory issues such as new impurities arising.  Roche (and prior to the merger Syntex) have for many years taken the view that “second generation” process development, which includes synthetic route change is some cases, can lead to large cost savings, and really does pay for itself.

At Scientific Update’s Organic Process R & D conference in New Orleans in March 2003, Peter Harrington from Roche spoke about several examples including the drug bosentan.

The last step in the synthesis involved a replacement of a chlorine by the 2-hydroxy ethoxy group, but a number of by-products arose.  By the use of ethyleneglycol t-butyl ether (ETB), a new sequence was introduced which had a crystalline intermediate suitable for cleaning up impurities, which allowed further improvements and economies to be made earlier in the sequence.  The new route is shown below.

The effect on the overall efficiency of the process is shown from the table below comparing the old and new processes.

Second generation processes are often patentable and can usefully extend the product lifetime of successful products by limiting the options for generic competition.
 
In a similar manner, the process for orlistat involved a late stage resolution without the opportunity to recycle the unwanted isomer.  However as shown on the right hand side of the Scheme    , a resolved “raw material” would allow a shorter synthesis of orlistat.  The “raw material” was synthesised from a simpler precursor by the route shown below.
 
A late stage resolution has a much lower space-time-yield and therefore involves more capital expenditure (larger equipment) than a route involving an early resolution, an asymmetric synthesis or synthesis from a readily available chiral precursor.