Naltrexone CAS 16590-41-3
Introduction：Basic information about Naltrexone CAS 16590-41-3, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Naltrexone 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;(4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one;Naltrexone (controlled) HCl;Um-792;3,14-Dihydroxy-17-(cyclopropylmethyl)-4,5α-epoxymorphinan-6-one |
| CAS: | 16590-41-3 |
| MF: | C20H23NO4 |
| MW: | 341.4 |
| EINECS: | 240-649-9 |
| Product Categories: | NICLOSIDE;Isotope labelled API;Isotopically Labeled Pharmaceutical Reference Standard;16590-41-3 |
| Mol File: | 16590-41-3.mol |
Naltrexone Chemical Properties
| Melting point | 168-170° |
| Boiling point | 477.03°C (rough estimate) |
| density | 1.2064 (rough estimate) |
| refractive index | 1.5614 (estimate) |
| Fp | 9℃ |
| storage temp. | 2-8°C |
| solubility | Chloroform (Slightly), Methanol (Slightly) |
| pka | pKa 8.38/8.13(H2O,t =20/37,I<0.01) (Uncertain) |
| form | Solid |
| color | White to Light Beige |
| Major Application | forensics and toxicology |
| 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-/s3 |
| InChIKey | DQCKKXVULJGBQN-AOJBWHFRNA-N |
| SMILES | [C@@]123CCN(CC4CC4)[C@@H]4CC5=CC=C(O)C(O[C@H]1C(CC[C@]24O)=O)=C35 |&1:0,8,17,21,r| |
| EPA Substance Registry System | Naltrexone (16590-41-3) |
Safety Information
| Hazard Codes | F,T |
| Risk 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 |
| HS Code | 2939190000 |
| Storage Class | 3 - Flammable liquids |
| Hazard Classifications | Acute Tox. 3 Dermal Acute Tox. 3 Inhalation Acute Tox. 3 Oral Flam. Liq. 2 STOT SE 1 |
| Hazardous Substances Data | 16590-41-3(Hazardous Substances Data) |
| Toxicity | LD50 in mice (mg/kg): 586 s.c. (Maickel) |
| Description | This drug does not have agonistic properties. It is similar to naloxone in terms of pharmacological characteristics; however, it differs in two important ways—long-lasting actionand that its metabolite 6-β-naltrexol is also a strong antagonist. Naltrexone is potentiallyhepatotoxic. Naltrexone is used for blocking pharmacological effects of opioids upon theiroverdose. |
| Originator | Antaxone,Zambon Group,Italy |
| History | Naloxone was discovered by Drs. Jack Fischman and Mozez Lewenstein of the Memorial Sloan Kettering Institute for Cancer Research in 1961, based on a theory proposed by their colleague, Dr. Harold Blumberg at the Long Island-based Endo Laboratories. Intravenous naloxone (Envizio) was approved by the Food and Drug Administration (FDA) for opioid overdose reversal in 1971 and was shortly adopted as a standard emergency treatment at many of the nation’s premier academic medical centers. |
| History | Naltrexone was first synthesized in 1963 by Endo Laboratories, which was patented by Endo Laboratories in 1967 under the developmental code name EN-1639A. Naltrexone was later purchased in 1969 by DuPont Pharmaceuticals. It was developed by the National Institute on Drug Abuse in the 1970s and early 1980s . In 1984, it was approved by the Food and Drug Administration (FDA) for the treatment of heroin addiction . In 1995, Naltrexone was approved by the FDA for the treatment of alcoholism, when the brand name was changed by DuPont to Revia. A new extended-release formulation of naltrexone has been developed and was approved by the FDA in 2006 for use in the treatment of alcohol dependence. |
| Uses | Naltrexone is an opioid antagonist shown to reduce the occurrence of addictive behaviours such as eating, smoking and drinking excessively. in addition to curbing drug use it has recently been used in flavor avoidance studies. |
| Uses | anthelmintic, teniacide |
| Uses | Labeled Naltrexone, intended for use as an internal standard for the quantification of Naltrexone by GC- or LC-mass spectrometry. |
| Definition | ChEBI: An organic heteropentacyclic compound that is naloxone substituted in which the allyl group attached to the nitrogen is replaced by a cyclopropylmethyl group. A mu-opioid receptor antagonist, it is used to treat alcohol dependence. |
| Indications | Naltrexone, an orally active opioid receptor antagonist,restores erectile function in some patients with idiopathicED. |
| Manufacturing Process | Codeine is a component of gum opium and can also be produced bymethylation of morphine using known prior art techniques. A solution of codeine (30 g, 100.2 mmol), acetic anhydride (18.4 g, 180.2mmol), 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 12hr, added saturated aqueous sodium bicarbonate solution until no aceticanhydride detected. The organic portion was separated, washed with water (3times 120 ml), dried over anhydrous sodium sulfate, and evaporated in vacuoto 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-chloroethylchloroformate (5.51 g, 37.8 mmol), and proton sponge (1.0 g) in methylenechloride (80 ml) was heated at reflux for 80 min. The reaction mixture wasevaporated in vacuo to dryness. The residue was chromatographed on silicagel with ethyl acetate to give 6-acetyl-17-(1-chloroethoxycarbonyl)norcodeineas 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 toalmost 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-chloroethylchloroformate (5.56 g, 38.1 mmol), and proton sponge (1.0 g) in methylenechloride (50 ml) was heated at reflux for 50 min. The reaction mixture wasevaporated 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. andevaporated in vacuo to almost dryness. The residue was added hexane andfiltered 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. Theresidue (11.7 g) was chromatographed on silica gel with a eluting solventsystem 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) inmethylene chloride (20 ml) in 20 min. After stirring at -78°C for 20 min., asolution of 17-cyclopropylmethylnorcodeine (9.0 g, 26.5 mmol) in methylenechloride (40 ml) was added dropwise in 50 min. The reaction mixture wasstirred 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 withwater (10 times 50 ml), and evaporated in vacuo to dryness. The residue wasmixed 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), andtoluene (6 ml) was heated at 71°-73°C for 14 hr. The reaction mixture wascooled, added methylene chloride (250 ml), water (50 ml), and sodiumbicarbonate (73.5 g), stirred for 4 hr, and filtered. The organic portion of thefiltrate was separated, washed with water (30 ml), dried over anhydroussodium sulfate, and evaporated in vacuo to dryness. The residue (3.94 g) waschromatographed 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 of17-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%, 0.17g) was heated at 42°-43°C for 15 hr, added water (20 ml), basified withNa2CO3 (1.02g), and extracted with EtOAc (80 ml and 2 times 20 ml). Thecombined extract was washed with water, dried over anhydrous sodiumsulfate, and evaporated in vacuo to dryness to give 17-cyclopropylmethyl-14-hydroxynorcodeinone (0.10 g, 56% yield). The Rf value in TLC and the IRspectrum of the product were comparable to those obtained from an authenticsample. Preparation of 17-cyclopropylmethyl-14-hydroxynorcodeinone. A solution of 17-cyclopropylmethylnorcodeinone dienol acetate (1.00 g, 2.63mmol), formic acid (8 ml, 90%), and hydrogen peroxide (0.37 g, 30%, 3.26mmol) was heated at 44°-45°C for 6 hr, added water (20 ml) and ethylacetate (80 ml), basified with sodium bicarbonate. The organic portion wasseparated, washed with water (15 ml), dried over anhydrous sodium sulfateand evaporated in vacuo to dryness, the residue (0.9 g) was chromatographedon 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, 1.31mmol), 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 methylenechloride (100 ml). The extract was washed with water (2 times 30 ml), driedover anhydrous sodium sulfate, and evaporated in vacuo to dryness. Theresidue (0.41 g) was chromatographed on silica gel to give 17-cyclopropylmethyl-14-hydroxynorcodeinone (0.34 g, 74% yield). The Rf valuein TLC and the IR spectrum of the product were comparable to those obtainedfrom an authentic sample. Preparation of 3-methylnaltrexone. A mixture of 17-cyclopropylmethyl-14-hydroxynorcodeinone (0.30 g, 0.85mmol) and Pd/C (5%, 0.45 g) in ethanol (35 ml) was hydrogenated in a Parrhydrogenator 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 ofboron tribromide (5.4 ml, 1 M solution in methylene chloride, 5.4 mmol). Thereaction mixture was stirred at rt. for 15 hr, basified with NH4OH, andextracted with methylene chloride (60 ml). The extract was washed with water(2 times 15 ml), dried over anhydrous sodium sulfate, and evaporated invacuo to dryness to give naltrexone (0.45 g, 98% yield). |
| Brand name | Vivitrol (Alkermes). |
| Therapeutic Function | Narcotic analgesic |
| Biological Functions | Naltrexone (Trexan) is three to five times as potent asnaloxone and has a duration of action of 24 to 72 hours,depending on the dose. It is used orally in the treatmentof opioid abstinence. Naltrexone exhibits a large firstpasseffect in the liver. However, the major metabolite,6-β-naltrexol, is also a pure opioid antagonist and contributesto the potency and duration of action of naltrexone.Administration of naltrexone orally blocks thesubjective effects of abused opioids and is used to decreasethe craving for opioids in highly motivated recoveringaddicts. However, high doses of the opioidscan overcome the naltrexone blockade and lead toseizures or respiratory depression and death. In addition,it has been reported recently that naltrexone canreduce the craving for alcohol in alcoholic patients.Naltrexone also has been used with success in treatingapneic episodes in children, an effect hypothesized tobe due to blockade of β-endorphin–induced respiratorydepression. Naltrexone can induce hepatotoxicity at doses onlyfive times the therapeutic dose and should be used withcare in patients with poor hepatic function or liver damage.Side effects of the use of naltrexone are more frequentlyobserved than following naloxone administration.Such side effects include headache, difficultysleeping, lethargy, increased blood pressure, nausea,sneezing, delayed ejaculation, blurred vision, and increasedappetite. |
| General Description | Naltrexone is a pure opioid antagonist at allopioid receptor subtypes with the highest affinity for theμ-receptor. Naltrexone is orally bioavailable and blocksthe effects of opiate agonists for approximately 24 hoursafter a single dose of 50 mg. It produces no opioid agonisteffects and is devoid of any intrinsic actions other thanopioid receptor blockade. Theoretically, it should workwell to treat opioid dependence but in clinical practice,patients have shown poor compliance and high relapserates. Naltrexone has also been studied to treat alcohol dependencewith mixed results. To address the complianceissues and effectively remove the “choice” of taking theantagonist, naltrexone was developed into an extendedreleaseinjectable microsphere formulation for IM injectiononce a month (Vivitrol). This formulation providessteady-state plasma concentrations of naltrexone threefoldto fourfold higher than the 50-mg oral dose 4 times aday. Currently, Vivitrol is only indicated for the treatmentof alcohol dependence. A Cochrane review found insufficientevidence from randomized controlled trials toevaluate its effectiveness for treating opioid dependence. Currently, phase II and phase III clinical trials ofan implantable pellet form of naltrexone are being conductedfor treating opioid dependence. The CYP450 system is not involved in naltrexonemetabolism. Naltrexone is reduced to the active antagonist6-β-naltrexol by dihydrodiol dehydrogenase, a cytosolicenzyme. Naltrexone has a black box warning, because ithas the potential to cause hepatocellular injury when givenin excessive doses. |
| 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. |
| Clinical Use | Naltrexone is a pure opioid antagonist and has noanalgesic activity. Naltrexone has a higher intravenouspotency and longer duration of actionthan naloxone. It has a higher oral bioavailabilityand is given by mouth to treat opioid dependenceand to maintain abstinence during opioid detoxification. In opioid-dependent persons, naltrexoneinduces an acute withdrawal reaction. |
| 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 ofthe methods of synthesis is analogous to the synthesis of naloxone, which consists of usingcyclopropylmethylbromide instead of allylbromide. |
Naltrexone Preparation Products And Raw materials
| Raw materials | 4-Dimethylaminopyridine-->Bromoform-->Oxalyl chloride-->1-Chloroethyl chloroformate-->Formic acid-->3-Chloroperoxybenzoic acid-->CODEINE-->Acetic anhydride-->Cylopropylmethyl chloride |
| Preparation Products | Naltrexone 3-Methyl Ether-->17-(CYCLOPROPYLMETHYL)-6,7-DEHYDRO-4,5-EPOXY-3-BENZYLOXY-14-HYDROXY-6,7,2',3'-INDOLOMORPHINAN |
