16590-41-3

Basic information

• Product Name: Naltrexone
• Synonyms: 17-(cyclopropylmethyl)-4,5-alpha-epoxy-3,14-dihydroxy-morphinan-6-on;17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-one;5-epoxy-3,14-dihydroxy-17-(cyclopropylmethyl)-(5-alpha)-morphinan-6-on;celupan;en1639;en1939;Naltrexone Base Monohydrate;Morphinan-6-one,17-(cyclopropylMethyl)-4,5-epoxy-3,14-dihydroxy-, (5a)-
• CAS NO: 16590-41-3
• Molecular Formula: C₂₀H₂₃NO₄
• Molecular Weight: 341.4
• EINECS: 240-649-9
• Product Categories: NICLOSIDE;Isotope labelled API;Isotopically Labeled Pharmaceutical Reference Standard
• Mol File: 16590-41-3.mol
• Article Data: 45

Chemical Properties

• Melting Point: 168-170°
• Boiling Point: 477.03°C (rough estimate)
• Flash Point: 9℃
• Appearance: /
• Density: 1.2064 (rough estimate)
• Vapor Pressure: 2.71E-13mmHg at 25°C
• Refractive Index: 1.5614 (estimate)
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: pKa 8.38/8.13(H2O,t =20/37,I<0.01) (Uncertain)
• CAS DataBase Reference: Naltrexone(CAS DataBase Reference)
• NIST Chemistry Reference: Naltrexone(16590-41-3)
• EPA Substance Registry System: Naltrexone(16590-41-3)

Safety Data

• Hazard Codes: F,T
• Statements: 11-23/24/25-39/23/24/25
• Safety Statements: 16-36/37-45
• RIDADR: UN1230 - class 3 - PG 2 - Methanol, solution
• WGK Germany: 1
• Hazardous Substances Data: 16590-41-3(Hazardous Substances Data)

Usage

Description

Naltrexone is a pure opioid antagonist that acts on all opioid receptor subtypes, with the highest affinity for the μ-receptor. It is orally bioavailable and blocks the effects of opiate agonists for approximately 24 hours after a single dose of 50 mg. Naltrexone does not produce opioid agonist effects and is devoid of any intrinsic actions other than opioid receptor blockade. It is used for blocking the pharmacological effects of opioids in cases of overdose and has been studied for treating alcohol and opioid dependence with mixed results.
Used in Pharmaceutical Industry:
Naltrexone is used as an opioid antagonist for reducing the occurrence of addictive behaviors such as eating, smoking, and drinking excessively. It is also used for curbing drug use and has been recently employed in flavor avoidance studies.
Used in Veterinary Medicine:
Naltrexone is used as an anthelmintic and teniacide, helping to treat and prevent parasitic infections in animals.
Used in Research and Analysis:
Labeled Naltrexone is intended for use as an internal standard for the quantification of Naltrexone by gas chromatography (GC) or liquid chromatography (LC) mass spectrometry, aiding in the accurate measurement of the compound in various samples.
Used in Treatment of Alcohol Dependence:
Naltrexone has been developed into an extended-release injectable microsphere formulation for intramuscular injection once a month (Vivitrol). This formulation provides steady-state plasma concentrations of naltrexone threefold to fourfold higher than the 50-mg oral dose 4 times a day. Currently, Vivitrol is only indicated for the treatment of alcohol dependence.

Originator

Antaxone,Zambon Group,Italy

Indications

Naltrexone, an orally active opioid receptor antagonist, restores erectile function in some patients with idiopathic ED.

Manufacturing Process

Codeine is a component of gum opium and can also be produced by methylation of morphine using known prior art techniques.A solution of codeine (30 g, 100.2 mmol), acetic anhydride (18.4 g, 180.2 mmol), triethylamine (18.25 g, 180.2 mmol) and 4-dimethylaminopyridine (0.5 g) in dry ethyl acetate (620 ml) was stirred at rt. under nitrogen for 12 hr, added saturated aqueous sodium bicarbonate solution until no acetic anhydride detected. The organic portion was separated, washed with water (3times 120 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness to give 6-acetylcodeine as white solids (34.0 g, 99% yield).Preparation of 6-acetylnorcodeine hydrochloride.A solution of 6-acetylcodeine (10.0 g, 29.3 mmol), 1-chloroethyl chloroformate (5.51 g, 37.8 mmol), and proton sponge (1.0 g) in methylene chloride (80 ml) was heated at reflux for 80 min. The reaction mixture was evaporated in vacuo to dryness. The residue was chromatographed on silica gel with ethyl acetate to give 6-acetyl-17-(1-chloroethoxycarbonyl)norcodeine as an oil (12.13 g), which was dissolved in methanol with a few drops of conc. HCl. The solution was heated at reflux for 1 hr and evaporated in vacuo to almost dryness. The residue was added hexane and filtered to give 6- acetylnorcodeine hydrochloride (10.7 g, 100% yield).Preparation of norcodeine hydrochloride.A solution of 6-acetylcodeine (10.0 g, 29.3 mmol), 1-chloroethyl chloroformate (5.56 g, 38.1 mmol), and proton sponge (1.0 g) in methylene chloride (50 ml) was heated at reflux for 50 min. The reaction mixture was evaporated in vacuo to about 30 ml. Methanol (25 ml) and concentrated HCl (2 ml) were added. The solution was heated at reflux for 40 min. and evaporated in vacuo to almost dryness. The residue was added hexane and filtered to give norcodeine hydrochloride (8.8 g, 93% yield).Preparation of 17-cyclopropylmethylnorcodeine.A mixture of norcodeine hydrochloride (11.48 g, 27.8 mmol), (chloromethyl)cyclopropane (5.14 g, 55.6 mmol), sodium carbonate (14.73 g, 139.0 mmol), and potassium iodide (4.61 g, 27.8 mmol) in ethanol (250 ml) was heated at reflux for 20 hr, cooled, and evaporated in vacuo to dryness. The residue was basified with NH4OH, and extracted with methylene chloride. The extract was washed with water and evaporated in vacuo to dryness. The residue (11.7 g) was chromatographed on silica gel with a eluting solvent system of methanol/ethyl acetate (10/90) to give 17- cyclopropylmethylnorcodeine (10.68 g, 91% yield).Preparation of 17-cyclopropylmethylnorcodeinone.To a solution of DMSO (14.50 g, 185.6 mmol) in methylene chloride (80 ml) at -78°C, was added a solution of oxalyl chloride (11.78 g, 92.8 mmol) in methylene chloride (20 ml) in 20 min. After stirring at -78°C for 20 min., a solution of 17-cyclopropylmethylnorcodeine (9.0 g, 26.5 mmol) in methylene chloride (40 ml) was added dropwise in 50 min. The reaction mixture was stirred at -74° to -76°C for 3 hr, added triethylamine (9.39 g, 92.8 mmol), allowed to warm up to rt., added methylene chloride (200 ml), washed with water (10 times 50 ml), and evaporated in vacuo to dryness. The residue was mixed with hexane and filtered to give 17-cyclopropylmethylnorcodeinone (8.85 g, 99% yield).Preparation of 17-cyclopropylmethylnorcodeinone dienol acetate.A mixture of 17-cyclopropylmethylnorcodeinone (3.55 g, 10.5 mmol), acetic anhydride (20 ml, 210.4 mmol), sodium acetate (1.3 g, 15.8 mmol), and toluene (6 ml) was heated at 71°-73°C for 14 hr. The reaction mixture was cooled, added methylene chloride (250 ml), water (50 ml), and sodium bicarbonate (73.5 g), stirred for 4 hr, and filtered. The organic portion of the filtrate was separated, washed with water (30 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness. The residue (3.94 g) was chromatographed on silica gel with 100% ethyl acetate to give 17- cyclopropylmethylnorcodeinone dienol acetate (2.87 g, 72% yield).Preparation of 17-cyclopropylmethyl-14-hydroxynorcodeinone. A solution of 17-cyclopropylmethylnorcodeinone (0.20 g, 0.59 mmol), formic acid (90%, 0.304 g), water (0.504 g), EtOAc (0.27 g), and hydrogen peroxide (30%, 0.17 g) was heated at 42°-43°C for 15 hr, added water (20 ml), basified with Na2CO3 (1.02g), and extracted with EtOAc (80 ml and 2 times 20 ml). The combined extract was washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness to give 17-cyclopropylmethyl-14- hydroxynorcodeinone (0.10 g, 56% yield). The Rf value in TLC and the IR spectrum of the product were comparable to those obtained from an authentic sample.Preparation of 17-cyclopropylmethyl-14-hydroxynorcodeinone.A solution of 17-cyclopropylmethylnorcodeinone dienol acetate (1.00 g, 2.63 mmol), formic acid (8 ml, 90%), and hydrogen peroxide (0.37 g, 30%, 3.26 mmol) was heated at 44°-45°C for 6 hr, added water (20 ml) and ethyl acetate (80 ml), basified with sodium bicarbonate. The organic portion was separated, washed with water (15 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to dryness, the residue (0.9 g) was chromatographed on silica gel with methanol/methylene chloride (2.5/97.5) to give 17- cyclopropylmethyl-14-hydroxynorcodeinone (0.72 g, 78% yield).Preparation of 17-cyclopropylmethyl-14-hydroxynorcodeinone.A solution of 17-cyclopropylmethylnorcodeinone dienol acetate (0.5 g, 1.31 mmol), 3-chloroperbenzoic acid (0.36 g, 2.10 mmol) and oxalic acid (0.27 g, 2.90 mmol) in acetic acid (7 ml) was stirred at rt. overnight, added cold water (35 ml), basified with sodium carbonate, and extracted with methylene chloride (100 ml). The extract was washed with water (2 times 30 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness. The residue (0.41 g) was chromatographed on silica gel to give 17- cyclopropylmethyl-14-hydroxynorcodeinone (0.34 g, 74% yield). The Rf value in TLC and the IR spectrum of the product were comparable to those obtained from an authentic sample.Preparation of 3-methylnaltrexone.A mixture of 17-cyclopropylmethyl-14-hydroxynorcodeinone (0.30 g, 0.85 mmol) and Pd/C (5%, 0.45 g) in ethanol (35 ml) was hydrogenated in a Parr hydrogenator at rt. under 28 psi of hydrogen gas. The mixture was filtered. The filtrate was evaporated in vacuo to dryness to give 3-methylnaltrexone (0.30 g, 99% yield).Preparation of naltrexone from 3-methylnaltrexone.A solution of 3-methylnaltrexone (0.48 g, 1.35 mmol) in methylene chloride (30 ml) was cooled with an ice-water bath, and then added a solution of boron tribromide (5.4 ml, 1 M solution in methylene chloride, 5.4 mmol). The reaction mixture was stirred at rt. for 15 hr, basified with NH4OH, and extracted with methylene chloride (60 ml). The extract was washed with water (2 times 15 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness to give naltrexone (0.45 g, 98% yield).

Therapeutic Function

Narcotic analgesic

Biological Functions

Naltrexone (Trexan) is three to five times as potent as naloxone and has a duration of action of 24 to 72 hours, depending on the dose. It is used orally in the treatment of opioid abstinence. Naltrexone exhibits a large firstpass effect in the liver. However, the major metabolite, 6-β-naltrexol, is also a pure opioid antagonist and contributes to the potency and duration of action of naltrexone. Administration of naltrexone orally blocks the subjective effects of abused opioids and is used to decrease the craving for opioids in highly motivated recovering addicts. However, high doses of the opioids can overcome the naltrexone blockade and lead to seizures or respiratory depression and death. In addition, it has been reported recently that naltrexone can reduce the craving for alcohol in alcoholic patients. Naltrexone also has been used with success in treating apneic episodes in children, an effect hypothesized to be due to blockade of β-endorphin–induced respiratory depression. Naltrexone can induce hepatotoxicity at doses only five times the therapeutic dose and should be used with care in patients with poor hepatic function or liver damage. Side effects of the use of naltrexone are more frequently observed than following naloxone administration. Such side effects include headache, difficulty sleeping, lethargy, increased blood pressure, nausea, sneezing, delayed ejaculation, blurred vision, and increased appetite.

Biological Activity

Naltrexone is derived from oxymorphone and exhibit agonist activity only at doses that are of little clinical significance. In the absence of opioid drugs, naloxone does not cause analgesia, respiratory depression, or sedation. However, when administered with an opioid analgesic, the effects produced by the opioid agonist are promptly reversed. The ability to antagonize opioids at all of the different opioid receptors makes naloxone useful for the treatment of opioid overdose. Naltrexone has a similar profile, but it is orally active and has a significantly longer half-life.

Synthesis

Naltrexone, (-)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-one (3.1.93), is an N-cyclopropylmethyl derivative of oxymorphone (3.1.82). One of the methods of synthesis is analogous to the synthesis of naloxone, which consists of using cyclopropylmethylbromide instead of allylbromide.

InChI:InChI=1/C20H23NO4/c22-13-4-3-12-9-15-20(24)6-5-14(23)18-19(20,16(12)17(13)25-18)7-8-21(15)10-11-1-2-11/h3-4,11,15,18,22,24H,1-2,5-10H2/t15-,18+,19?,20-/m1/s1

Upstream product

• 33522-95-1 noroxymorphone 
• 1489-69-6 Cyclopropanecarboxaldehyde 
• 913728-80-0 C₃₅H₃₇ClN₂O₈ 
• 16617-07-5 naltrexone methyl ether 

Downstream Products

• 127227-10-5 C₂₈H₃₂N₂O₄ 
• 16617-07-5 naltrexone methyl ether 
• 959215-76-0 3-O-(p-nitrophenyloxycarbonyl)naltrexone 
• 153567-11-4 2,2,2-trichloroethyl (4'R,7a'R,12b'S)-9'-(benzyloxy)-1',2',4',6'-tetrahydro-3'H,7a'Hspiro[[1,3]dioxolane-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinoline]-3'-carboxylate 
• 111555-53-4 naltrindole 
• 796876-15-8 C₂₇H₃₀N₂O₃ 
• 100678-48-6 6β-naltrexol 

Relevant articles and documents

General method of synthesis for naloxone, naltrexone, nalbuphone, and nalbuphine by the reaction of grignard reagents with an oxazolidine derived from oxymorphone

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. Copyright

Synthesis of noroxymorphone by n-demethylation/ intramolecular acylation of oxymorphone catalyzed by iron(II) chloride

Oxymorphone was converted to its 3,14-diacetate and subjected to Fe(II)/t-BuOOH-catalyzed N-demethylation that occurred with concomitant acyl migration from the C-14 hydroxyl to the N-17 nitrogen. The resulting diacetyl compound was hydrolyzed in dilute s

Direct synthesis of naltrexone by palladium-catalyzed N-demethylation/ acylation of oxymorphone: The benefit of C-H activation and the intramolecular acyl transfer from C-14 hydroxy

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. VitrideTM reduction of N-acylamide to N-alkylamine proceeded with concomitant re

Asymmetric synthesis of (-)-naltrexone

(-)-Naltrexone, an opioid antagonist used extensively for the management of drug abuse, is derived from naturally occurring opioids. Herein, we report the first asymmetric synthesis of (-)-naltrexone that does not proceed through thebaine. The synthesis starts with simple, achiral precursors with catalytic enantioselective Sharpless dihydroxylation employed to introduce the stereogenic centers. A Rh(i)-catalyzed C-H alkenylation and torquoselective electrocyclization cascade provides the hexahydro isoquinoline bicyclic framework that serves as the precursor to the morphinan core. The acidic conditions used for Grewe cyclization not only provide the morphinan framework, but also cause a hydride shift resulting in the introduction of the C-6 oxo functionality present in (-)-naltrexone. The C-14 hydroxyl group is installed by an efficient two-step sequence of Pd-mediated ketone to enone dehydrogenation followed by C-H allylic oxidation using Cu(ii) and O2, a method that has not previously been reported either for the synthesis or semi-synthesis of opioids. The longest linear sequence is 17 steps, and because the stereogenic centers in the product rely on Sharpless asymmetric dihydroxylation, the route could be used to access either enantiomer of the natural product, which have disparate biological activities. The route also may be applicable to the preparation of opioid derivatives that could not be easily prepared from the more fully elaborated and densely functionalized opioid natural products that have traditionally served as the starting inputs.

Discovery of naldemedine: A potent and orally available opioid receptor antagonist for treatment of opioid-induced adverse effects

Structure-activity relationship studies of several morphinan derivatives were conducted to obtain dual antagonists for μ- and δ-opioid receptors. We discovered peripherally restricted dual antagonists for μ/δ-opioid receptors as a new chemotype with a morphinan scaffold, which are orally available and do not easily pass the blood–brain barrier. As we expected, some of these compounds inhibit opioid-induced constipation and emesis/vomiting with limited potential to interfere the analgesic effects of morphine. Among them, naldemedine was selected as a potential drug candidate.

PROCESS FOR OBTAINING 3,14-DIACETYLOXYMORPHONE FROM ORIPAVINE

The present invention relates to a new process for obtaining 3,14-diacetyloxymorphone from oripavine, a process to transform the obtained 3,14-diacetyloxymorphone into a noroxymorphone and a process to transform said noroxymorphone into naloxone, naltrexone, nalbuphine, nalfurafine or nalmefene.