posted on 2020-03-05, 15:53authored byThierry Boyer, Bernie M. Choudary, Andrew J. Edwards, Erika Etridge, Steve Etridge, Amanda Giddings, Jim Harvey, Neil S. Hodnett, Sophie Druot-Houllemare, John H. Leahy, Kathryn Payne, Robert Reid, Andrew D. Roberts, Mike Sasse, Alec Simpson, Steve Smith, Neil G. Stevenson, Paul Stonestreet, Michael William Urquhart, Angela White
The development of
the synthetic process to the PPAR-α receptor
antagonist 5-((4-(tert-butoxy)-3-methylphenoxy)methyl)-3-(4-(tert-butyl)phenyl)-1,2,4-oxadiazole (GW641597X) 1 is described. The discussion ranges from the initial supply route,
used to deliver early batches for preliminary safety studies to enable
dosing in man, to an efficient manufacturing route, which delivered
35 kg of drug substance following on from a pilot plant campaign.
The process includes a key oxidative Baeyer–Villiger reaction,
where process development identified sodium perborate in acetic acid
as a safer alternative to m-chloroperoxybenzoic acid
that was used in the initial supply route. Described within is a discussion
of impurities, how they are formed, and the process modifications
incorporated to either reduce or remove them. There is also a discussion
of potential mutagenic impurities within the synthetic process and
a retrospective evaluation using ICH M7 control options. Finally,
an alternative route to GW641597X is described, which offers the advantage
that all intermediates are crystalline facilitating material handling,
offering purification opportunities through recrystallization if required,
and potentially providing greater controls for the process. This new
route was also retrospectively assessed using ICH M7 option controls
and highlighted that ICH M7 option 4 controls can be implemented even
with excess mutagenic reagents being introduced near to the drug substance
as long as the science for its purging is well understood.