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Noroxymorphone was prepared from thebaine in seven operations. The key steps involved the successive N- and O-demethylations of an iron tricarbonyl complex of thebaine followed by the unusual ceric ammonium nitrate oxidation of the methoxydiene moiety to the corresponding enone-γ-nitrate during the decomplexation of the iron tricarbonyl functionality.

Hydrocodone, a high value active pharmaceutical ingredient (API), is usually produced in a semisynthetic pathway from morphine, codeine or thebaine. The latter alkaloid is an attractive precursor as it is not used as a remedy itself. The key step in this production route is a selective olefin reduction forming 8,14-dihydrothebaine which can be subsequently hydrolyzed to yield hydrocodone. Unfortunately, standard hydrogenation procedures cannot be applied due to severe selectivity problems. A transfer hydrogenation using in situ generated diimide is the only known alternative to achieve a selective transformation. The most (atom) economic generation of this highly unstable reducing agent is by oxidizing hydrazine hydrate (N2H4·H2O) with O2. In the past, this route was “forbidden” on an industrial scale due to its enormous explosion potential in batch. A continuous high-temperature/high-pressure methodology allows an efficient, safe, and scalable processing of the hazardous reaction mixture. The industriall...

The N-oxide of O-acyloxymorphone, when treated with the Burgess reagent, provides the corresponding oxazolidine in a one-pot sequence and in excellent yield. The oxazolidine derived from oxymorphone, temporarily protected at O-3 and C-6, reacts with Grignard reagents to provide directly N-allyl, N-cyclopropylmethyl, and N-cyclobutylmethyl derivatives that are further converted to the title compounds, namely naltrexone, naloxone, nalbuphone, and nalbuphine in excellent yields. Each of these medicinal agents is obtained from the oxazolidine in a one-pot sequence. Complete spectral and experimental data are provided for all compounds.

Heteroatom analogues of hydrocodone, in which the N-methyl functionality was replaced with oxygen, sulfur, sulfoxide, and sulfone, were prepared by a short sequence from the ethylene glycol ketal of hydrocodone; a carbocyclic analogue of bisnorhydrocodone was also prepared. The compounds were tested for receptor binding and revealed moderate levels of activity for the sulfone analogue of hydrocodone.

Oxymorphone was converted to naltrexone in three steps by palladium-catalyzed oxidative N-demethylation and intramolecular acyl transfer from C-14 hydroxy to N-17. Vitride™ reduction of N-acylamide to N-alkylamine proceeded with concomitant reductive deprotection of C-6 and O-3 functionalities.

N-Oxides derived from oxycodone and O-acyloxymorphone were treated with the Burgess reagent to provide the corresponding oxazolidines in excellent yields. Oxazolidines derived from O-acyloxymorphone were further hydrolyzed to noroxymorphone, whose alkylation furnished naltrexone, naloxone, and nalbuphone, which can be converted to nalbuphine, the mixed agonist-antagonist analgesic. The entire sequence from oxymorphone to the various antagonists was reduced to three one-pot operations, proceeding in excellent overall yields. In addition, quaternary salts of the oxazolidines with allyl or cyclopropylmethyl groups in fixed equatorial configurations were synthesized. Complete spectral and experimental data are provided for all compounds.

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.

Morphine alkaloids and some of its derivatives (morphine, codeine, thebaine, oripavine, hydrocodone, and oxycodone) were subjected to fermentations with six fungal strains. The alkaloids were transformed to a variety of products via biological oxidations, reductions, and oxidative demethylations. The strain Cunninghamella echinulata proved to be the most effective for demethylations of all of the above compounds, except for morphine. The time profile of the conversion of 3-[14CH3]thebaine to 3-[14CH3]northebaine by C. echinulata cultures was also determined.

The ethylene glycol ketal of neopinone was prepared in a one-pot procedure by the reaction of thebaine with ethylene glyocol in the presence of p-toluenesulfonic acid. The ketal is also an intermediate in the conversion of thebaine to hydrocodone with ethylene glycol and Pd(OAc)(2), followed by hydrogenation. Additionally, a one-pot procedure for the conversion of thebaine to hydrocodone was achieved by employing palladium catalysis in aqueous medium. Palladium serves a dual purpose in this transformation, first for the activation of the dienol ether of thebaine and second as a hydrogenation catalyst. This procedure was found to be comparable to the two-step protocol which employs diimide reduction of thebaine followed by acid-catalyzed hydrolysis of the resulting 8,14-dihydrothebaine to hydrocodone. Experimental and spectral data are provided for all compounds.

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

Thebaine was subjected to catalytic hydrogenation under a variety of conditions in order to determine the regioselectivity for C-6/C-7 versus C-8/C-14 olefin saturation.

Thebaine was converted into its iron tricarbonyl complex, which underwent successive N- and O-demethylation with BrCN and BBr 3 , respectively. Decomplexation of the iron tricarbonyl moiety was accomplished with ammonium cerium(IV) nitrate (CAN) and base-catalyzed hydrolysis furnished nororipavine. When excess CAN was used the methoxydiene unit was converted into its C-14 nitrate that on hydrogenation and further hydrolysis furnished noroxymorphone. Full experimental and spectral data are provided for all key compounds.

The synthesis of nalbuphine (VI) from oripavine (I) requires only five chemical transformations and is conducted with an overall yield of 45%, in contrast to current methods requiring seven to ten steps.

As a first step in our search for new opiates, we have established cellular assays to monitor opioid receptor activation and study the activities of a set of morphine derivatives. Intracellular calcium changes were monitored in human embryonic kidney-293 T cells expressing individual opioid receptors upon cotransfection with a chimeric G protein. This assay was validated by comparing the potencies of the endogenous peptides to reported values. All of the opiates were found to interact with the three opioid receptor subtypes but with a range of differences in efficacies and potencies. Most of the opiates preferentially acted at the μ receptor. None of the opiates showed a preference for the δ receptor. Only oripavine and its precursor thebaine showed a preference for the κ over the μ receptor. The results indicate that the opiates with a C-3 hydroxyl group or C-6 ketone group but in the presence of a 7, 8-single bond exhibit higher activity. It is noteworthy that the 6-O-methyl group seems to improve the selectivity for κ receptor. This is the first comparative and comprehensive report on the activation of the three different opioid receptors by a set of morphine derivatives in a well-defined assay system. These data can serve as a basis for the characterization of novel opiates.

Buprenorphine was synthesized from oripavine by a sequence involving the conversion of oripavine into its cyclopropylmethyl quaternary salt, N-demethylation with thiolate to N-cyclopropylmethyl nororipavine, and conversion of this material to the title compound by previously available methods. The new synthesis avoids toxic reagents used previously, is shorter, and proceeds in comparable yields. Experimental and spectral data are provided for all new compounds.