Structural similarity and its surprises: Endothelin receptor antagonists process research and development report

Process research and pilot plant processes are described for three endothel in (ET) receptor antagonists, The efficient synthesis of the parent compoun d Darusentan proceeds via a Darzens reaction from chloroacetate with benzop henone, addition of methanol to the resulting epoxide, saponification of th e alkyl propionate and optical resolution of the racemic acid by crystallis ation with a chiral amine, The final stage of the synthetic sequence involv es the introduction of a pyrimidine moiety. Intermediates formed during thi s process can be used as starting materials for the synthesis of the two ot her ET receptor antagonists BSF 420627 and BSF 302146. An ether exchange re action, which replaces the methoxy with a phenethyloxy substituent, enabled BSF 420627 to be prepared. The synthetic route to BSF 302146 employs trime thylaluminum to methylate the epoxide produced by the Darzens reaction.