Journal
ADVANCED SYNTHESIS & CATALYSIS
Volume 354, Issue 4, Pages 613-626Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adsc.201100807
Keywords
buprenorphine synthesis; hydrosilylation; morphine alkaloids; N-demethylation; O-demethylation; palladium-catalyzed N-demethylation; acylation; Schwartz reagent
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Funding
- Noramco, Inc.
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Canada Research Chair Program
- Canada Foundation for Innovation (CFI)
- Research Corporation
- TDC Research, Inc.
- TDC Research Foundation
- Brock University
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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.
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