Synthesis, Structure Elucidation, and Pharmacological Evaluation of 5‐Methyl‐oxymorphone (= 4,5α‐epoxy‐3,14‐dihydroxy‐5,17‐dimethylmorphinan‐6‐one)

Abstract

Synthesis of 5-methyl-oxymorphone (3) was accomplished by oxidation of 5-methylthebaine (4) with performic acid, followed by catalytic hydrogenation and cleavage of the 3-Me0 group. X-Ray analysis confirmed that the 14-OH group has, like the one in oxymorphone (l), 8-orientation. Pharmacological studies in uiuo and in vitro showed 3 to possess slightly less opioid agonistic properties than 1.In our pursuit of structure-activity relationships in the N-methylmorphinan-6-one series, we have found that 14-0-methylation of oxymorphone ( = 4,5a -epoxy-3,14-dihydroxy-17-methylmorphinan-6-one; 1) results in a compound (2) which possesses much higher antinociceptive potency and opioid receptor binding affinity than the parent compound of the series, oxymorphone (1). It was of interest to determine if a 5-Me group on 1 would enhance the opioid agonistic properties to a similar extent as the 14-0-Me group. In addition, the up to now unknown structure of 5-methyl-oxymorphone (3) would be a starting point for further synthetic and pharmacologic investigations in the class of 14-hydroxy-morphinan-6-ones.Chemistry. -The oxidation of 5-methylthebaine (4) [2] [3] with rn-chloroperbenzoic acid in AcOH/CF,COOH, carried out as described for the oxidation of thebaine (5) to 14-hydroxycodeinone (7) [4], was unsuccessful; and likewise, the oxidation with performic acid employing the conditions of a published procedure [5]. However, we found that the oxidation of 5-methylthebaine (4) with performic acid proceeded smoothly at lower temperatures and prolonged reaction time (4" and 66 h instead at 40" and 6.5 h [5])

Investigation of structure, vibrational and NMR spectra of oxycodone and naltrexone: A combined experimental and theoretical study

“…a X-ray crystal data of naltrexone were obtained from Ref. [53]. b All bond lengths are reported in angstroms and angles are reported in degrees.…”

“…Following optimization of structures, important molecular parameters were extracted from the outputs of calculations and compared with available X-ray data for naltrexone [52] and oxycodone [53], respectively in Tables 1 and 2.…”

Development of 5-SubstitutedN-Methylmorphinan-6-ones as Potent Opioid Analgesics with Improved Side-Effect Profile

“…Introduction of an alkyl substituent in position 5 of thebaine ( 2 ) can be accomplished by formation of the thebaine anion using n -butyllithium in THF at low temperature [ 18 ], followed by alkylation with the respective alkylating agent (methyl fluorosulfonate, dimethyl sulfate, or benzyl chloride), yielding 5-methylthebaine ( 3 ) and 5-benzylthebaine ( 4 ), respectively [ 18 – 21 ]. Treatment with performic acid afforded 14-hydroxy-5-methylcodeinone ( 5 ) [ 19 , 20 ] and its 5-benzyl analogue 6 ( Scheme 1 ) [ 14 ]. The β -orientation of the 14-hydoxy group was proved by X-ray analysis [ 20 ].…”

Synthesis and Biological Evaluation of 14‐Alkoxymorphinans. Part 9. 14‐O‐ethyl‐5‐methylnaltrexone, and opioid antagonist with unusual selectivity

“…opioid-agonist properties [4], whereas a 14-0-alkyl group enhanced opioid-agonist effects significantly [5] [6]. In 14-methoxymetopon (3), where a 5-Me group exists in addition to a 14-0-Me group, the opioid-agonist effects were further increased, producing a compound that had ca.…”

“…-Starting material for the synthesis of compounds 7 and 8 was 14-0-ethyl-5-methyloxycodone ( = 4,5a -epoxy-14-ethoxy-3-methoxy-w, 17-dimethylmorphinan-6-one; 9) which is available from thebaine via 5-methylthebaine [7] [S] in four steps [l] [4]. N-Demethylation using 1-chloroethyl chloroformate [9] afforded carbamate 10 which was refluxed in MeOH to yield N-normorphinan 11.…”