Improved Synthesis of Buprenorphine from Thebaine and/or Oripavine <i>via</i> Palladium‐Catalyzed N‐Demethylation/Acylation and/or Concomitant O‐Demethylation

Abstract

Abstract An improved preparation of buprenorphine via palladium‐catalyzed N‐demethylation/acylation is reported. Three routes were investigated and compared in overall yield. The first involved N‐demethylation/acylation of an advanced intermediate obtained from thebaine followed by hydrolysis of the N ‐acetamide and alkylation with cyclopropylmethyl bromide and/or reduction of the N ‐acetyl group with the Schwartz reagent followed by N‐alkylation. The second route employed cyclopropylcarboxylic acid anhydride in the N‐demethylation/acylation protocol and subsequent reduction of the cyclopropylcarboxamide by either lithium aluminum hydride or under hydrosilylation conditions. Both of these routes originated in thebaine and therefore required O‐demethylation as a final step. The third route employed an N‐demethylation/acylation sequence starting from oripavine rather than thebaine, thus avoiding the O‐demethylation. The routes are compared for overall efficiency and experimental and spectral data are provided for all new compounds.