76-57-3

Basic information

• Product Name: CODEINE
• Synonyms: CODEINE HYDROCHLORIDE-HYDRATE;CODEINE;CODEINE BASE;MORPHINAN-6-OL,7,8-DIDEHYDRO-4,5-EPOXY-3-METHOXY-17-METHYL-, (5A,6A)-;7,8-Didehydro-4,5alpha-epoxy-3-methoxy-17-methyl morphinan-6alpha-ol;7,8-didehydro-4,5-alpha-epoxy-3-methoxy-17-methyl-morphinan-6-alpha-o;7,8-didehydro-4,5alpha-epoxy-3-methoxy-17-methyl-morphinan-6alpha-o;7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-,(5alpha,6alpha)-morphinan-6-o
• CAS NO: 76-57-3
• Molecular Formula: C18H21NO3
• Molecular Weight: 299.36
• EINECS: 200-969-1
• Product Categories: Chiral Reagents;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 76-57-3.mol

Chemical Properties

• Melting Point: 156-158?C
• Boiling Point: 440.69°C (rough estimate)
• Flash Point: 9℃
• Appearance: white crystalline powder
• Density: 1.3200
• Vapor Pressure: 2.47E-09mmHg at 25°C
• Refractive Index: 1.5500 (estimate)
• Storage Temp.: 2-8°C
• Solubility: Soluble in boiling water, freely soluble in ethanol (96 per cent).
• PKA: 8.21(at 25℃)
• Water Solubility: 47.62g/L(25 oC)
• Stability: Stable, but light sensitive. Combustible. Incompatible with strong oxidizing agents, bromides, iodides, heavy metal salts.
• CAS DataBase Reference: CODEINE(CAS DataBase Reference)
• NIST Chemistry Reference: CODEINE(76-57-3)
• EPA Substance Registry System: CODEINE(76-57-3)

Safety Data

• Hazard Codes: F,T
• Statements: 11-23/24/25-39/23/24/25
• Safety Statements: 7-16-36/37-45
• RIDADR: UN 1230 3/PG 2
• WGK Germany: 1
• Hazardous Substances Data: 76-57-3(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
CODEINE is used as an analgesic for the relief of aches and pains, as well as a sedative in cough mixtures to suppress coughing. It is incorporated into numerous prescription medicines for headache, heartburn, fatigue, coughing, and other conditions.
Used in Medical Treatments:
CODEINE is used as a medication for its narcotic analgesic action, and it is sometimes used in cases of acute pericarditis to relieve severe chest pains in the early phases of the disease. Additionally, it is sometimes used in drug therapy for renal (kidney) diseases.
Note: CODEINE can cause contact dermatitis in some individuals, as seen in workers involved in the production of opium alkaloids and concentrated poppy straw. It is important for people with a history of urticaria (hives) to inform their physician about the presence of CODEINE in prescription medicines.

World Health Organization (WHO)

Codeine, which has antitussive, opioid analgesic and antidianhoeal activity, was first extracted from opium in 1832 and has since been widely used in medicine. The development of dependence and its potential for abuse resulted in the control af the substance under Schedule II of the 1961 Single Convention on Narcotic Drugs. Preparations containing codeine remain widely available and are included in the WHO Model List of Essential Drugs.(Reference: (WHTAC1) The Use of Essential Drugs, 2nd Report of the WHO Expert Committee, 722, , 1985)

Biological Functions

Like morphine, codeine is a naturally occurring opioid found in the poppy plant. Codeine is indicated for the treatment of mild to moderate pain and for its antitussive effects. It is widely used as an opioid antitussive because at antitussive doses it has few side effects and has excellent oral bioavailability. Codeine is metabolized in part to morphine, which is believed to account for its analgesic effect. It is one of the most commonly used opioids in combination with nonopioids for the relief of pain. The administration of 30 mg of codeine in combination with aspirin is equivalent in analgesic effect to the administration of 65 mg of codeine. The combination of the drugs has the advantage of reducing the amount of opioid required for pain relief and abolition of the pain via two distinct mechanisms, inhibition of prostanoid synthesis and opioid inhibition of nociceptive transmission. When given alone, orally administered codeine has about one-tenth to one-fifth the potency of morphine for the relief of pain. In addition, IV codeine has a greater tendency to release histamine and produce vasodilation and hypotension than does morphine. Thus, the use of IV codeine is rare. Codeine is rarely addictive and produces little euphoria.

Air & Water Reactions

CODEINE is light sensitive and sensitive to prolonged exposure to air. Insoluble in water.

Reactivity Profile

CODEINE is incompatible with bromides, iodides and salts of heavy metals. . CODEINE is an amine. Amines are chemical bases. They neutralize acids to form salts plus water. These acid-base reactions are exothermic. The amount of heat that is evolved per mole of amine in a neutralization is largely independent of the strength of the amine as a base. Amines may be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated by amines in combination with strong reducing agents, such as hydrides.

Hazard

Habit-forming narcotic, sale legally restricted.

Health Hazard

The toxic effects due to codeine are similarbut less toxic than those of morphineand other opium alkaloids. An overdosecan cause respiratory failure. It is a weakdepressant of the central nervous system.It also exhibits stimulant action. Toxicsymptoms from high dosages may includedrowsiness, sleep, tremors, excitement, andhallucinations. It may also produce gastricpains and constipation. An oral LD50 value in rats is 427 mg/kg. The habit-forming effectsof codeine are lower than those associatedwith morphine.Nagamatsu and coworkers (1985) havereported in vitro formation of codeinonefrom codeine by rat or guinea pig liverhomogenate. Codeinone may be a metabolicintermediate in the presence of nicotinamideadenine dinucleotide (NAD). Its acute toxicityin mice was determined to be 30 timeshigher than that of codeine.

Fire Hazard

CODEINE is combustible.

Pharmacology

Codeine is a constituent of opium. Up to 10% of a dose of codeine is metabolised by the hepatic microsomal enzyme CYP2D6 to morphine, which contributes significantly to its analgesic effect. The rest is metabolised in the liver to norcodeine and then conjugated to produce glucuronide conjugates of codeine, norcodeine and morphine. Codeine is considerably less potent than morphine. A round 8% of Western Europeans are deficient in the CYP2D6 enzyme and may not experience adequate analgesia with codeine. S imilarly, with super-metabolisers, there may be problems with opioid toxicity; particular care is needed in the breastfeeding mother as morphine is transferred in milk. Codeine can cause significant histamine release, and intravenous administration should be avoided. It has marked antitussive effects and also causes significant constipation. It is often combined with paracetamol.

Purification Methods

Codeine crystallises from water or aqueous EtOH. Dry it at 80o. Evaporation of a CHCl3 extract gives a colourless glass which crystallises on scratching. It crystallises from H2O as the monohydrate, m 157-158.5o, and has [] D -136o (c 2.8, EtOH). The hydrobromide crystallises in needles from H2O, and effervesces at 151-160o, solidifies and remelts with extensive decomposition at 273-278o. It sublimes at 100o/0.03mm. [Gates J Am Chem Soc 75 4340 1953, Dauben et al. J Org Chem 44 1567 1979, Beilstein 27 II 136, 27 III/IV 2228.]

InChI:InChI=1/C18H21NO3/c1-19-8-7-18-11-4-5-13(20)17(18)22-16-14(21-2)6-3-10(15(16)18)9-12(11)19/h3-6,11-13,17,20H,7-9H2,1-2H3/t11-,12+,13-,17-,18-/m0/s1

Upstream product

• 467-13-0 codeinone 
• 470465-32-8 C₂₀H₂₃NO₅ 
• 87-59-2 2,3-Dimethylaniline 
• 57-27-2 MORPHIN 
• 467-08-3 6β-chloro-4,5α-epoxy-3-methoxy-17-methyl-morphin-7-ene 
• 7647-01-0 hydrogenchloride 
• 467-13-0 4,5-epoxy-3-methoxy-17-methyl-morphin-7-en-6-one 
• 312920-40-4 (S)-(-)-methyl 6-(2-bromo-3-formyl-6-methoxyphenoxy)-cyclohex-1-enecarboxylate 
• 312920-36-8 methyl 6-(2,2,2-trichloroethoxycarbonyloxy)cyclohex-1-enoate 
• 865780-25-2 methyl 6-hydroxy-cyclohex-1-enecarboxylate 
• 481634-93-9 5-methoxy-9b-(2-methylaminoethyl)-3,3a,9a,9b-tetrahydrophenanthro[4,5-bcd]furan-3-ol 
• 18871-66-4 N,N-dimethylacetamide dimethyl acetal 
• 5140-28-3 3-O-Acetylmorphin 
• 466-96-6 allopseudocodeine 

Downstream Products

• 57-27-2 (+/-)-morphine 
• 120094-77-1 isocodeine benzyl dithiocarbonate 
• 466-95-5 8β-chloro-4,5α-epoxy-3-methoxy-17-methyl-morphin-6-ene 
• 3688-66-2 4,5α-epoxy-3-methoxy-17-methyl-6α-nicotinoyloxy-morphin-7-ene 
• 467-15-2 norcodeine 
• 120203-83-0 C₂₄H₂₅NO₃ 
• 72707-00-7 8β-phenyldihydrocodeinone 
• 119461-14-2 C₂₅H₂₇NO₄ 
• 119461-14-2 C₂₅H₂₇NO₄ 
• 119461-13-1 C₂₅H₂₇NO₄ 
• 119461-13-1 C₂₅H₂₇NO₄ 
• 119461-11-9 C₂₅H₂₇NO₄ 
• 119461-11-9 C₂₅H₂₇NO₄ 
• 120094-72-6 C₂₆H₂₇NO₃S₂ 

Relevant articles and documents

Enantioselective synthesis of (-)-codeine and (-)-morphine

A new synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges employing a Pd-catalyzed asymmetric allylic alkylation to set the stereochemistry. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate, the latter available from glutaraldehyde and the Emmons-Wadsworth-Horner phosphate reagent. This intermediate requires only two steps to convert to (-)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine is formed. The final ring formation involves a novel visible light-promoted hydroamination. Thus, six steps are required to convert the pivotal tricyclic intermediate into codeine, which has been demethylated in high yield to morphine. Copyright

BIOTRANSFORMATION OF CODEINONE TO CODEINE BY IMMOBILIZED CELLS OF PAPAVER SOMNIFERUM

Papaver somniferum (opium poppy) cells were immobilized in calcium alginate, where they continued to live with their biological activity for 6 months.The immobilized living cells performed the biotransformation of (-)-codeinone to (-)-codeine in both a shake flask and a column bioreactor.The biotransformation ratio in the shake flask (70.4percent) was higher than that in the cell suspension (60.8percent).Furthermore, 88percent of the codeine converted was extracted in the medium.The column bioreactor was functional for 30 days under optimal conditions (20 deg C, 3,75 vvm in aeration), whereas the ratio was 41.7percent.Key Word Index - Papaver somniferum; Papaveraceae; immobilized cell; biotransformation; bioreactor; codeinone; codeine; GC/MS; SIM.

Total Synthesis of Codeine

In this paper, a new strategy towards the synthesis of codeine and morphine is reported. This new approach features a cascade cyclization to construct the dihydrofuran ring, and an intramolecular palladium catalyzed C-H olefination of unactivated aliphatic alkene to install the morphinan ring system.

On the selection of an opioid for local skin analgesia: Structure-skin permeability relationships

Recent studies demonstrated that post-herpetical and inflammatory pain can be locally managed by morphine gels, empirically chosen. Aiming to rationalize the selection of the most suitable opioid for the cutaneous delivery, we studied the in vitro penetration through human epidermis of eight opioids, evidencing the critical modifications of the morphinan core. Log P, log D, solid-state features and solubility were determined. Docking simulations were performed using supramolecular assembly made of ceramide VI. The modifications on position 3 of the morphinan core resulted the most relevant in determining both physicochemical characteristics and diffusion pattern. The 3-methoxy group weakened the cohesiveness of the crystal lattice structure and increased the permeation flux (J). Computational studies emphasized that, while permeation is essentially controlled by molecule apolarity, skin retention depends on a fine balance of polar and apolar molecular features. Moreover, ChemPLP scoring the interactions between the opioids and ceramide, correlated with both the amount retained into the epidermis (Qret) and J. The balance of the skin penetration properties and the affinity potency for μ-receptors evidenced hydromorphone as the most suitable compound for the induction of local analgesia.

Transformation of codeine and codeine-6-glucuronide to opioid analogues by urine adulteration with pyridinium chlorochromate: Potential issue for urine drug testing

Rationale: Pyridinium chlorochromate (PCC) is the active ingredient of 'Urine Luck', a commercially available in vitro adulterating agent used to conceal the presence of drugs in a urine specimen. The exposure of codeine and its major glucuronide metabolite codeine-6-glucuronide (C6G) to PCC was investigated to determine whether PCC is an effective masking agent for these opiate compounds. Methods: Following the addition of PCC to both spiked and authentic codeine and C6G-positive urine specimens, the samples were monitored using liquid chromatography/mass spectrometry (LC/MS). Stable reaction products were identified and characterized using high-resolution MS analysis and, where possible, nuclear magnetic resonance (NMR) analysis. Results: It was determined that PCC effectively oxidizes codeine and C6G, thus altering the original codeine-to-C6G ratio in the urine specimen. Four reaction products were identified for codeine: codeinone, 14-hydroxycodeinone, 6-O-methylcodeine and 8-hydroxy-7,8-dihydrocodeinone. Similarly, three reaction products were identified for C6G: codeinone, codeine and a lactone of C6G (tentative assignment). Conclusions: Besides addressing the complications added to interpretation, more investigation is warranted to further determine their potential for use as markers for monitoring the presence of codeine and C6G in urine specimens adulterated with PCC. Copyright

Polonovski-type N-demethylation of N-methyl alkaloids using substituted ferrocene redox catalysts

Various substituted ferrocenes have been trialed as catalysts in the nonclassical Polonovski reaction for N-demethylation of N-methyl alkaloids. Earlier studies suggest that conditions facilitating a higher ferrocenium ion concentration lead to superior outcomes. In this regard, the bifunctional ferrocene FcCH2CO2H, with electron donor and acceptor moieties in the same molecule, has been shown to be advantageous for use as a catalyst in the N-demethylation of a number of tertiary N-methylamines such as codeine, thebaine, and oripavine. These substrates are readily N-demethylated under mild conditions, employing sub-stoichiometric amounts of the substituted ferrocene at ambient temperature. These reactions are equally efficient in air and may also be carried out in one pot. Georg Thieme Verlag Stuttgart · New York.

A total synthesis of (±)-codeine by 1,3-dipolar cycloaddition

Nitrone cycloaddition on a dearomatized bicyclic phenol enabled the facile construction of the correctly configured phenanthrene skeleton of codeine. Further steps yielded allopseudocodeine in a completely diastereoselective manner and finally (±)-codeine by allylic transposition through the hydrolysis of chlorocodides.

Total synthesis of (-)-morphine

We have developed an efficient total synthesis of (-)-morphine in 5% overall yield with the longest linear sequence consisting of 17 steps from 2-cyclohexen-1-one. The cyclohexenol unit was prepared by means of an enzymatic resolution and a Suzuki-Miyaura coupling as key steps. Construction of the morphinan core features an intramolecular aldol reaction and an intramolecular 1,6-addition. Furthermore, mild deprotection conditions to remove the 2,4-dinitrobenzenesulfonyl (DNs) group enabled the facile construction of the morphinan skeleton. We have also established an efficient synthetic route to a cyclohexenol unit containing an N-methyl-DNsamide moiety.

SYNTHESIS OF MORPHINE AND RELATED DERIVATIVES

The present invention relates to methods for the synthesis of galanthamine, morphine, intermediates, salts and derivatives thereof, wherein the starting compound is biphenyl.

Further investigation of the N-demethylation of tertiary amine alkaloids using the non-classical Polonovski reaction

The iron salt-mediated Polonovski reaction efficiently N-demethylates certain opiate alkaloids. In this process, the use of the hydrochloride salt of the tertiary N-methyl amine oxide was reported to give better yields of the desired N-demethylated product. Herein, we report further investigation into the use of N-oxide salts in the iron salt-mediated Polonovski reaction. An efficient approach for the removal of iron salts that greatly facilitates isolation and purification of the N-nor product is also described.