Palladium‐Catalyzed N‐Demethylation/N‐Acylation of Some Morphine and Tropane Alkaloids

Abstract

Hydrocodone was converted to various Nacyl derivatives via a one-pot N-demethylation/Nacylation protocol catalyzed by palladium(II). The procedure has also been successfully applied to several N-methyltropane alkaloids. A plausible mechanism is suggested.

Probes for narcotic receptor mediated phenomena. Part 42: Synthesis and in vitro pharmacological characterization of the N-methyl and N-phenethyl analogues of the racemic ortho-c and para-c oxide-bridged phenylmorphans

“…Cu(OAc) 2 (69 mg, 0.38 mmol) and (NH 4 ) 2 S 2 O 8 (176.97 mg, 0.76 mmol ) were added to the solution. 14 The mixture was stirred overnight at room temperature and the reaction was quenched with aqueous 10% Na 2 S 2 O 3 . The reaction mixture was basified to pH ~9 with concentrated aqueous NH 4 OH, extracted with a CHCl 3 :MeOH (3:1) mixture.…”

“…To remove the phenolic hydroxy group a tetrazoyl ether 14 was prepared by reaction of 10 with phenylchlorotetrazole in DMF at room temperature. 14 Column chromatography gave the pure compound, in 89% yield. Both the tetrazoyloxy moiety and the N-benzyl group were concomitantly cleaved by reduction with 10% Pd/C and hydrogen in acidic solution, in 45% yield after chromatography, to give the intermediate 15 that could be used to prepare the desired N-substituted para -c oxide-bridged phenylmorphans; the oxide-bridge was undisturbed during this series of reactions.…”

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

“…During our research on general methods of N‐demethylation that would be more environmentally benign we have reported on the N‐demethylation of several morphine alkaloids by utilizing biotransformations with fungal enzymes 3. The N‐demethylation/acylation of hydrocodone and tropane alkaloids was also accomplished via palladium catalysis that provided N ‐acetylhydrocodone and other acyl derivatives in excellent yields 4. These methods increase the number of protocols for N‐demethylation, such as those available in the recent literature and based on N ‐oxides 5…”

Recent advances in process development for opiate-derived pharmaceutical agents

“…This process was discovered in 2008 in conjunction with the palladium-catalyzed N-demethylation/acylation of hydrocodone. 6 Treatment of amide 22 with Schwartz reagent provided the secondary amine 23, whose alkylation and O-demethylation led to buprenorphine in good yields. 7 The O-demethylation also occurred under basic condition during the hydrolysis of the acetamide in 22.…”