1. Introduction of the C-14 hydroxyl group into a 4,5-epoxymorphinan nucleus may be accomplished from thebaine by hydrogen peroxide or peracid treatment resulting in 14-hydroxycodeinone (17). Catalytic reduction of the double bond yields oxycodone (14-hydroxydihydrocodeinone, 19) which can be converted to oxymorphone (20) by means of O-demethylation. Both compounds are more potent analgesics than morphine. However, oxymorphone is an important starting material for the synthesis of pure opioid antagonists such as naloxone (21) and naltrexone (22). First oxymorphone is subjected to N-demethylation reaction yielding noroxymorphone and N-alkylation of this secondary amine will furnish naloxone and naltrexone. Therefore noroxymorphone is also a key intermediate in the synthesis of 14-hydroxy-substituted opioid antagonists.Diels-Alder reaction of thebaine with dienophiles resulted in 6,14-endoethenotetrahydro-oripavines which possess outstanding pharmacological properties. Etorphine (23) is ca. 8000 times more potent analgesic than morphine. It is used to immobilize large wild game animals due to its margin of safety. Buprenorphine (24) is also a potent analgesic (partial opioid agonist) and it is used to treat heroin addiction, whereas diprenorphine (25) is a strong opioid antagonist. It is reasonable that the above-mentioned pharmaceuticals can be prepared from oripavine which is available from poppy straw. Oripavine may be useful as a starting material to avoid the difficult C-3 methyl ether cleavage in the preparation of 6,14-endoeheno-tetrahydrooripavines.
4.1. N-Demethylation of Thebaine and OripavineN-Demethylation of thebaine was studied with cyanogen bromide or various chloroformates but these reactions led to the scission of C-9-N bond. Diethyl azodicarboxylate has been reported to be an effective reagent for the N-demethylation of thebaine to northebaine.
Sipos and coworkers [49] reported the synthesis of nororipavine (28) in which thebaine was treated with diethyl azodicarboxylate to afford the corresponding N-nor-N-{[1,2-bis(ethoxycarbony)-hydrazinyl]methyl} derivative. Subsequent treatment of this intermediate with L-Selectride effected simultaneous O- and N-dealkyla- tions, giving N-nororipavine (28) in an overall yield of 43%.
Scammells et al. [50] employed a modified nonclassical Polonovski reaction for the N-demethylation of morphine alkaloids and this method was suitable for the preparation of northebaine (29) and nororipavine (28). This approach involved the conversion of the tertiary N-methyl amine to the corresponding N-oxide (by treatment with hydrogen peroxide or m-chloroperbenzoic acid) followed by treatment with iron sulfate. Morphine derivatives with various structures were successfully N-demethylated using this procedure in moderate to high yield. In all cases, the major by-product formed during the iron sulfate step was the parent N-methyl compound. It was found that isolation of the corresponding N-oxide as its hydrochloride (26 and 27) salt prior to iron treatment afforded superior yields of the desired ‘N-nor’ product. One of the limitations of the iron salt-mediated variant of the Polonovski reaction is the difficulty in separating the product from the iron salts. The use of EDTA as an iron-chelating agent in the reaction work-up proved to be effective in removing iron salts in a number of cases.
It was found the reaction of the N-oxide of morphine alkaloids (hydrochloride salt) with sulfonated tetraphenylporphyrin-iron (II) complex [51] took place readily yielding the corresponding N-nor derivatives in high yields. The catalyst was readily removed and recycled. Northebaine (27 ® 29) was prepared in 69% yield.
Later on, Kok and Scammells [52] reported that under Polonovski-type conditions, ferrocene has been found to be a convenient and efficient catalyst for the N-demethylation of a number of morphine alkaloids, including key pharmaceutical intermediates such as oxycodone and oxymorphone. Thus, the tertiary N-methylamine is first converted into the corresponding N-oxide hydrochloride which, following subsequent treatment with the ferrous reagent, has provided the N-nor compound in moderate to good yields. In most cases, the only by-prod- uct obtained is the parent tertiary amine. This method offers a number of advantages with the ferrocene catalyst being inexpensive and readily available, as well as being air and thermally stable. If desired, most of the catalyst could readily be recovered from the reaction via a simple extraction with hexane or column chromatography. The reaction is mild and, as demonstrated for substrates such as oripavine, morphine, and oxymorphone, does not require protection of functional groups such as hydroxyl.
Further development of the Polonovski-type N-demethylation has been reported by Kok and Scammells, and they found that the Polonovski reaction took place in the presence of iron powder catalyst [53] . The tertiary N-methylamine was first oxidized to the corresponding N-oxide, which was isolated as the hydrochloride salt. Subsequent treatment of the N-oxide hydrochloride with iron powder readily provided the N-demethylated amine. Iron powder, using iso-propanol as solvent, was effective in the N-demethylation of morphine, thebaine and oxycodone resulting in high yields after column chromatography. N-demethylation of oripavine was performed in low yield.
Kok and Scammells [54] achieved detailed investigations into the direct synthesis of N-nororipavine (28) from oripavine using iron powder under nonclassical Polonovski conditions. The stoichiometry, solvents and iron oxidation rates were found to have a dramatic effect on the rate of N-demethylation as well as product yield. The authors described a high-yield procedure to the N-demethylated product simply by employing stainless steel rather than iron powder as redox catalyst.
In these methods the utilized reagents are cheap, but the drawback that the N-nor derivative always contains the parent N-methyl compound as a by-product and the separation can be performed by means of column chromatography.
4.2. Syntheses of 14-Hydroxymorphinans from OripavineKok and Scammells [55] elaborated a new procedure for the syntheses of oxymorphone and noroxymorphone directly from oripavine and nororipavine respectively.
Oxidation of thebaine (2) hydrochloride was performed with m-chloroperbenzoic acid in 10% acetic acid at ambient temperature. 14-hydroxycodeinone (17) hydrochloride was obtained in a 98% yield. In the same way, 14-hydroxymorphinone (16) hydrochloride was prepared from oripavine (1) hydrochloride, again in an excellent yield (99%). Both compounds had purities of 95% and 94% respectively, according to HPLC analysis. Similar results were obtained for the reduction of 14-hydroxymorphinone (16) hydrochloride, with the reduction in methanol over 5% Pd/BaSO4 resulting in oxymorphone (20) hydrochloride in a 98% yield and a purity of 94% by HPLC.
The improved oxidation–reduction protocol was also investigated for the direct synthesis of noroxymorphone (31) from nororipavine (28). Oxidation of nororipavine (28) hydrochloride using with m-chloroperbenzoic acid in 10% acetic acid at ambient temperature afforded 14-hydroxy-normorphinone (30) hydrochloride in a 99% yield (purity 96% via HPLC). The latter was hydrogenated in methanol using 5% Pd/BaSO4 catalyst and furnished noroxymorphone (31) hydrochloride in a 97% yield with a purity of 95% via HPLC. Noroxymorphone was alkylated with cyclopropylmethyl bromide to furnish naltrexone (22) in 95% yield.
Hudlicky et al. [56] reported a quaternization/N-demethylation protocol for the synthesis of nalbuphine (34) from oripavine. Quaternization of oripavine with cyclobutylmethyl bromide resulted in a mixture of diastereomer quaternary ammonium salts (32) (S:R = 3:1) in excellent yield. The N-demethylation of the quaternary salts was achieved with sodium thiolate derived from 1-dodecanethiol in dimethyl sulfoxide at elevated temperature providing the desired N-cyclobutylmethylnororipavine (33) in consistent yields of 60%. The latter compound was oxidized with peracetic acid yielding the 14-hydroxy-morphinone derivative, which was subjected to catalytic hydrogenation (H2/Pd-C) to obtain nalbuphone. Nalbuphone was reduced (H2/PtO2) to nalbuphine (34).
4.3. Synthesis of Buprenorphine from OripavineHudlicky et al. [57] reported a novel synthetic sequence for the preparation of buprenorphine (24) utilizing oripavine as starting material. The major improvement over the previous synthesis is the elimination of cyanogen bromide as the reagent of N-demethylation and avoidance of O-demethylation required in the route from thebaine.
Oripavine was converted to a mixture of diastereomeric quaternary salts (35) by heating with cyclopropylmethyl bromide in dimethyl formamide. The N-demethylation of the quaternary ammonium salts of oripavine was accomplished with tert-dodecanethiol as the nucleophilic reagent and sodium ethoxide as the base to give N-cyclopropylmethylnororipavine (36). The conversion of N-yclopropylmethylnororipavine to buprenorphine involves several steps which were elaborated previously. It was found that it is neccessary to protect the phenolic hydroxyl of N-cyclopropylmethylnororipavine by ethoxycarbonyl group. Subsequently the Diels-Alder reaction with methyl vinyl ketone (37), hydrogenation of the orvinone derivative and the Grignard reaction yielded the C-3 protected buprenorphine. Finally the ester protecting group was removed by hydrolysis with sodium hydroxide.
Hudlicky et al. [58] elaborated another synthesis of buprenorphine from oripavine. Oripavine was converted to dihydroorvinone and its phenolic hydroxyl was protected with ethoxycarbonyl group (38). Grignard reaction with tert.-butylmagnesium chloride afforded the N-methyl-tertiary alcohol derivative (39). The latter compound was treated with cyclopropanecarboxylic acid anhydride in the presence palladium and copper catalysts yielding the acyl amide of norbuprenorphine (40). This amide was reduced with lithium aluminium hydride or Red-Al resulting in the target compound buprenorphine (24).
The research team of Mallincrodt Inc. took out a patent [59] for the preparation of norbuprenorphine, and ultimately buprenorphine, utilizing oripavine as the starting material. It was claimed that the use of oripavine does not require an O-demethylation step, since this reaction takes place in low to moderate yields. On the contrary, before N-demethylation of dihydroorvinone they used benzyl group to protect the phenolic hydroxyl. The protecting group was then removed by an additional step by means of catalytic hydrogenation.
It is mentionable that numerous patents [60] -[63] have been published covering the preparations of oxymorphone and buprenorphine from oripavine. Unfortunately, in these procedures the prepared new compounds have not been characterized, for example melting points, chromatographic properties and spectral data were not reported.