Development of a Multikilogram Synthesis of a Chiral Epoxide Precursor to a CCR1 Antagonist. Use of in Situ Monitoring for Informed Optimisation via Fragile Intermediates

The optimisation and scale up of a manufacturing route to a key intermediate, acetic acid 4-acetylamino-3-(2-methyl-oxiranylmethoxy)phenyl ester (2), utilising a SNAr coupling, the hydrogenation of a nitro moiety and the conversion of a chiral acetonide into a chiral epoxide is described along with other routes to access intermediate 2 including the chemoselective reduction of a nitro moiety in the presence of an epoxide.