76-42-6

Usage

Uses

Analgesic (narcotic).

Definition

oxycodone: An opioid, C18H21N2,similar in structure to codeine butwith a –OH group in codeine replacedby a carbonyl group. It is ananalgesic often used for the treatmentof chronic pain. It is also usedillegally and is a controlled substancein most countries.

Biological Functions

Oxycodone is nearly 10 times as strong as codeine, with absorption equal to that of orally administered morphine. Neither hydromorphone nor oxycodone is approved for use in children, and hydromorphone is contraindicated in obstetrical analgesia and in asthmatics.

General Description

Oxycodone is synthesized from the natural opium alkaloidthebaine. Oxycodone is the 14 beta-hydroxyl version of hydrocodone.This additional functional group gives oxycodonegreater potency (1.5 times orally) than hydrocodone presumablyby increasing receptor affinity. The oral bioavailabilityof oxycodone is 65% to 87%. The metabolism of oxycodonefollows the similar pattern of opioid metabolism withN-demethylation, O-demethylation, and their glucuronides allidentified. Per the manufacturer, the analgesic effect of oxycodonecorrelates well with oxycodone plasma concentrations,not the minimal amount of oxymorphone formed, thusoxycodone is not assumed to be a prodrug. There are no largescalestudies of oxycodone used for analgesia in CYP2D6poor metabolizers that can confirm this.Oxycodone is marketed in combination with acetaminophen(Percocet), aspirin (Percodan), and ibuprofen(Combunox). It has been available for over 50 years as animmediate-release tablet, and in 1995 an extended-releasetablet was approved by the FDA (OxyContin). OxyContin ismanufactured in eight strengths from 10 to 160 mg, and thehigh-dose preparations quickly became attractive to drugabusers. The extended-release tablets are crushed and theninjected or snorted to give an immediate high. The DrugAbuse Warning Network (DAWN) is a public health surveillancesystem that monitors drug-related emergency roomvisits and drug-related deaths. In 1995, they estimated that598,542 emergency room visits involved the nonmedical useof a pharmaceutical (e.g., antidepressant, anxiolytic, stimulant).Of these ER visits, 160,363 visits were attributed toopiates with an estimated 42,810 involving oxycodone or anoxycodone combination. Methadone and hydrocodone/combinationswere estimated to be similar to oxycodone.

Pharmacology

Oxycodone is a potent semisynthetic opioid that has been in use for many years. In addition to actions at the MOP receptor, it may also have analgesic effects mediated via the KOP receptor, resulting in incomplete crosstolerance with morphine. It has a good oral bioavailability, and its plasma concentrations are more predictable than those of morphine after oral administration. It is available in both long- and short-acting oral preparations and, more recently, in a parenteral formulation. Oral oxycodone is roughly 1.5 times more potent than oral morphine.

Safety Profile

Poison by intraperitoneal route. Moderately toxic by subcutaneous route. When heated to decomposition it emits toxic fumes of NOx.

InChI:InChI=1S/C18H21NO4/c1-19-8-7-17-14-10-3-4-12(22-2)15(14)23-16(17)11(20)5-6-18(17,21)13(19)9-10/h3-4,13,16,21H,5-9H2,1-2H3

Upstream product

• 146582-59-4 1-bromo-4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one 
• 61949-73-3 alpha-Oxycodol 
• 7183-69-9 14-hydroxydihydrocodeine 
• 19763-77-0 14β-hydroxycodeinone N-oxide 
• 76-41-5 oxymorphone 
• 18107-18-1 diazomethyl-trimethyl-silane 
• 124-90-3 oxycodone hydrochloride 
• 508-54-3 14-hydroxycodeinone 
• 865844-01-5 8α-hydroxyoxycodone 
• 71539-52-1 oxycodone N-oxide 
• 111355-33-0 oxycodone-N-oxide hydrochloride 
• 1276121-94-8 N-{(S)-4-guanidino-1-[2-(methyl-[(5R,9R,13S,14S)-4,5a-epoxy-6,7-didehydro-14-hydroxy-3-methoxy-17-methylmorphinan-6-oxy]carbonyl-amino)-ethylcarbamoyl]-butyl}-malonamic acid 
• 76-57-3 codeine 
• 1422-07-7 codeine hydrochloride 

Downstream Products

• 70509-92-1 14-Hydroxy-dihydrocodeinon-acetat 
• 114126-20-4 4,5-epoxy-14-hydroxy-3-methoxy-17-methyl-morphinan-6-one-phenylhydrazone 
• 7240-06-4 4,5-epoxy-14-hydroxy-3-methoxy-17,17-dimethyl-6-oxo-morphinanium; iodide 
• 3205-46-7 3-methoxy-17-methyl-morphinane-6,14-diol 
• 6199-38-8 14-Hydroxy-dihydrothebainon 
• 76-41-5 oxymorphone 
• 145301-08-2 (E)-(5R,9R,13S,14S)-(+)-4,5α-Epoxy-14-hydroxy-3-methoxy-17-methyl-7-(4-nitrobenzyliden)-morphinan-6-on 
• 145301-02-6 (R/S,5R,7R,9R,13S,14S)-(4,5α-Epoxy-14-hydroxy-3-methoxy-17-methyl-6-oxo-7α-morphinanyl)-(4-nitrophenyl)-methanol 
• 145301-30-0 (6R,6aS,8S,8aR,9aS,10R,15bS,16R,16aR,18R,18aS)-(-)-1,18;15,16-Diepoxy-5,6,6a,7,8a,9,9a,10,11,16a-decahydro-6,18a;10,15b-bis-(iminoethano)-2,14-dimethoxy-21,24-dimethyl-8-(4-nitrophenyl)-(8H,16H,18H)-dinaphtho<2,1-b:1',2'-i>xanthen-6a,9a,16a-triol 
• 145301-33-3 (6R,6aS,9aS,10R,15bS,16R,18R,18aS)-(-)-1,18;15,16-Diepoxy-5,6,6a,7,8,9,9a,10,11,17-decahydro-2,14-dimethoxy-21,24-dimethyl-8-(2-nitrophenyl)-6,18a;10,15b-bis(iminoethano)-(16H,18H)-dinaphth<2,1-b:1',2'-i>acridin-6a,9a-diol 
• 145301-29-7 (6R,6aS,8S,8aR,9aS,10R,15bS,16R,16aR,18R,18aS)-(-)-1,18;15,16-Diepoxy-5,6,6a,7,8a,9,9a,10,11,16a-decahydro-6,18a;10,15b-bis-(iminoethano)-2,14-dimethoxy-21,24-dimethyl-8-(3-nitrophenyl)-(8H,16H,18H)-dinaphtho<2,1-b:1',2'-i>xanthen-6a,9a,16a-triol 
• 70509-92-1 14-acetoxy-4,5α-epoxy-3-methoxy-17-methylmorphinan-6-one 
• 71539-52-1 oxycodone N-oxide 
• 75659-91-5 14-acetoxy-7,8-dihydronorcodeinone 

Relevant academic research and scientific papers

Synthesis of (-)-Oxycodone

Our novel synthetic route to (-)-oxycodone, a semisynthetic opioid analgesic, features a palladium-catalyzed direct intramolecular arylation of an aryl bromide, oxidative dearomatization of a dihydrophenanthrenol, formation of a benzylic quaternary carbon by an intramolecular Michael addition of a malonate moiety, and construction of the morphinan skeleton via a Hofmann rearrangement/lactamization cascade.

Synthesis and opiate receptor binding properties of 17-methyl-6,7- dehydro-3,14-dihydroxy-4,5α-epoxy-6,7:4',5'-pyrimidinomorphinans

A class of opioid receptor active derivatives of oxymorphone has been synthesized using a common enaminone intermediate. The derivatives have heterocyclic groups fused to the 6,7-positions of the morphinan system and all were synthesized in high yield. A pyrazolo derivative is an agonist for the μ and δ receptors and an antagonist for the κ receptor.

Structural elucidation and synthesis of a dimeric degradation impurity during long-term stability studies of oxycodone hydrochloride injection

Oxycodone is one of the most prescribed narcotic medications for the treatment of moderate to severe pain in clinical practice. During long-term stability studies of oxycodone hydrochloride for injection performed as per ICH Q1A (R2) guidelines, an unknown degradation product, impurity-I, increased over time and reached a level of 0.21% after 24 months, based on the results of HPLC analysis. The observed impurity was preliminarily characterized as an oxycodone aldol dimer by using two-dimensional (2D) liquid chromatography (LC) coupled with quadrupole time-of-flight mass spectrometry (QTOF MS/MS) analysis. Impurity-I was synthesized and its molecular structure confirmed based on detailed analysis of 1D-NMR (1H, 13C, and DEPT) and 2D-NMR (1H-1H COSY, HSQC, and HMBC) spectroscopy data. The plausible mechanism for the formation of impurity-I was an aldol condensation reaction under weakly acidic conditions. In addition, the potential toxicity of impurity-I was assessed by in silico toxicity predictions using the TOPKAT software.

PROCESSES FOR PREPARING NOR-OPIOID COMPOUNDS AND OPIOID ANTAGONISTS BY ELECTROCHEMICAL N-DEMETHYLATION

The present invention relates to a process for preparing a nor-opioid compound wherein an opioid precursor compound is electrochemically N-demethylated. The present invention further relates to a process for preparing an opioid antagonist compound, wherein an opioid precursor compound is electrochemically N-demethylated and the thus obtained nor-opioid compound is alkylated again at its secondary amine functional group.

Electrochemical N-Demethylation of 14-Hydroxy Morphinans: Sustainable Access to Opioid Antagonists

The most challenging step in the preparation of many opioid antagonists is the selective N-demethylation of a 14-hydroxymorphinan precursor. This process is carried out on a large scale using stoichiometric amounts of hazardous chemicals like cyanogen bromide or chloroformates. We have developed a mild reagent- and catalyst-free procedure for the N-demethylation step based on the anodic oxidation of the tertiary amine. The ensuing intermediates can be readily hydrolyzed to the target nor-opioids in very good yields.

Total Synthesis of (-)-Oxycodone via Anodic Aryl-Aryl Coupling

A fully regio- and diastereoselective electrochemical 4a-2′-coupling of a 3′,4′,5′-trioxygenated laudanosine derivative enables the synthesis of the corresponding morphinandienone. This key intermediate is further transformed into (-)-oxycodone through conjugate nucleophilic substitution for E-ring closure and [4 + 2] cycloaddition with photogenerated singlet oxygen to accomplish diastereoselective hydroxylation at C-14. The anodic transformation provides high yields and can be performed under constant current conditions both in a simple undivided cell or in continuous flow.

NOVEL OPIOID COMPOUNDS AND USES THEREOF

This invention relates to novel opioid derivatives of Formula I: or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R3, R4 and Z are as defined herein in the disclosure. The invention also relates to the use of such compounds for the treatment or prevention of, for example, pain.

HYDROGENATION PROCESS FOR PREPARING OXYCODONE HYDROCHLORIDE FROM 14-HYDROXYCODEINONE

A process for preparing oxycodone hydrochloride, said process comprising hydrogenating 14- hydroxycodeinone in an alcoholic solvent and hydrochloric acid to form oxycodone hydrochloride, wherein (a) the hydrogenation is carried out in the presence of a heterogeneous platinum group metal (PGM) catalyst and hydrogen gas, (b) the hydrogenation is carried out at one or more temperatures greater than ambient temperature in the presence of a hydrogenation catalyst and hydrogen gas, wherein the solution of 14- hydroxycodeinone and hydrochloric acid is heated to temperature before it is exposed to the hydrogen gas, (c) the oxycodone hydrochloride comprises 6a-oxycodol in an amount about 0.300 area % as determined by HPLC, characterized in that (d) the pH of the solution of 14-hydroxycodeinone and hydrochloric acid is in the range of about ≥ 2.5 to about ≤ 4.5; (e) the process is carried out in one pot, and (f) the oxycodone hydrochloride precipitates out of the solution.

PROCESS FOR IMPROVED OXYCODONE SYNTHESIS

Processes for preparing oxycodone are provided. Said processes encompass a step which is a hydrogenation of an 14-hydroxycodeinone salt in the presence of trifluoroacetic acid and/or a glycol.

An Integrated Continuous-Flow Synthesis of a Key Oxazolidine Intermediate to Noroxymorphone from Naturally Occurring Opioids

A telescoped procedure for the direct preparation of an advanced intermediate towards noroxymorphone from the naturally occurring alkaloids oripavine and thebaine is presented. The reaction procedure involves an intensified continuous-flow hydroxylation, followed by a continuous solvent switch and hydrogenation in a packed-bed hydrogenator (H-Cube). The obtained reaction mixture, containing oxymorphone as intermediate in excellent yield and purity, can be then directly converted into the desired noroxymorphone oxazolidine intermediate through palladium catalyzed N-methyl oxidation.