Potential Genotoxic Impurities (PGIs): A Topical Tip from OPRD Barcelona

A particularly topical subject of the last 18 months’ or so.  Stefan Abele from Actelion in conjunction with Thomas Dax from DSM described a route which employed a benzylic tosylate in the final step of an API synthesis (below).

Clearly the tosylate is a structural alert so they calculated that using the principles of TTC (threshold of toxicological concern) the limit for the tosylate in the API should be 7.5ppm.  The process involved alkylation in MIBK followed by aqueous extraction then salt formation and crystallization.  The team used a pragmatic approach and modified the process such that the aqueous extraction was conducted for a fixed period at 80ºC wherein the tosylate was largely hydrolysed and the resultant process yielded the API in which the tosylate was less than the level of quantitation of 3ppm, so comfortably below the TTC limit.

The message:  You should not immediately undertake (radical) modifications of synthetic routes to mitigate the risk of PGI contamination, as there may well be more pragmatic solutions available.