16590-41-3 Usage
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 action
and that its metabolite 6-β-naltrexol is also a strong antagonist. Naltrexone is potentially
hepatotoxic. Naltrexone is used for blocking pharmacological effects of opioids upon their
overdose.
Originator
Antaxone,Zambon Group,Italy
Uses
Different sources of media describe the Uses of 16590-41-3 differently. You can refer to the following data:
1. 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.
2. anthelmintic, teniacide
3. 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 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).
Brand name
Vivitrol (Alkermes).
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.
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.
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.
Check Digit Verification of cas no
The CAS Registry Mumber 16590-41-3 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 1,6,5,9 and 0 respectively; the second part has 2 digits, 4 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 16590-41:
(7*1)+(6*6)+(5*5)+(4*9)+(3*0)+(2*4)+(1*1)=113
113 % 10 = 3
So 16590-41-3 is a valid CAS Registry Number.
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
16590-41-3Relevant 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
Endoma-Arias, Mary Ann A.,Cox, D. Phillip,Hudlicky, Tomas
, p. 1869 - 1873 (2013)
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
Endoma-Arias, Mary Ann A.,Machara, Ales,Cox, D. Phillip,Hudlicky, Tomas
, p. 824 - 832 (2016)
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
MacHara, Ales,Cox, D.Phillip,Hudlicky, Tomas
, p. 2713 - 2718 (2012)
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
Dongbang, Sun,Pedersen, Blaine,Ellman, Jonathan A.
, p. 535 - 541 (2019/01/10)
(-)-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.
PROCESS FOR THE PREPARATION OF MORPHINANE COMPOUNDS
-
Page/Page column 9, (2019/01/21)
The invention describes the process of catalytic O-demethylation of 3-methoxy-morphinane compounds using boron tribromide. Addition of catalysts reduces the reaction time, improves reacting the substrate to give the product in very good purity and yield. The said approach can be used, for example, for the preparation of oxymorphone, naltrexone, naloxone and nalbuphine from their respective O-methyl derivatives.
PROCESS FOR OBTAINING 3,14-DIACETYLOXYMORPHONE FROM ORIPAVINE
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Page/Page column 48; 49, (2018/01/17)
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.
