Structural Similarity and Its Surprises: Endothelin Receptor Antagonists - Process Research and Development Report

Process research and pilot plant processes are described for three endothelin (ET) receptor antagonists. The efficient synthesis of the parent compound Darusentan proceeds via a Darzens reaction from chloroacetate with benzophenone, addition of methanol to the resulting epoxide, saponification of the alkyl propionate and optical resolution of the racemic acid by crystallisation with a chiral amine. The final stage of the synthetic sequence involves the introduction of a pyrimidine moiety. Intermediates formed during this process can be used as starting materials for the synthesis of the two other ET receptor antagonists BSF 420627 and BSF 302146. An ether exchange reaction, which replaces the methoxy with a phenethyloxy substituent, enabled BSF 420627 to be prepared. The synthetic route to BSF 302146 employs trimethylaluminum to methylate the epoxide produced by the Darzens reaction.