Morphine methyl ether

Codeine (morphine methyl ether) resembles morphine in its general effect, but is less toxic and its depressant action less marked and less prolonged, whilst its stimulating action involves not only the spinal cord, but also the lower parts of the brain. In small doses in man it induces sleep, which is not so deep as that caused by morphine, and in large doses it causes restlessness and increased reflex excitability rather than sleep. The respiration is slowed less than by morphine (cf. table, p. 261). Cases of addiction for codeine can occur but according to Wolff they are rare. The best known ethers of morphine are ethylmorphine and benzyl-morphine [cf., table, p. 261), both used to replace morphine or codeine for special purposes. 

On methylation apomorphine yields apo-i/i-coDEiNE (i/i-apocodeme, anocodeine, apomorphine methyl ether), CigHigOaN. C2H5. OH, crystallising in brilliant plates, m.p. 104-5-106-5°, or 122-5-124-5 dry), — 90° (EtOH), which is also produced when codeine or i/i-codeine is heated with oxalic acid or phosphoric acid. It stands in the same relation to codeine as apomorphine to morphine. 

Codeine, C18H21O3N. This alkaloid was isolated from opium by Robiquet in 1833. It occurs in opium to the extent of 0-1 to 3 per cent., and is isolated therefrom as the hydrochloride along with morphine hydrochloride in the first stage of Gregory s process. It is a methyl ether of morphine and is usually made from the latter by methylation, for which there are numerous patents. An extensive series of ethers of morphine and its isomerides, including ethers of the alcoholic hydroxyl group (Aeterocodeines) has been prepared by Faris and SmaU. ... 

Codeine is therefore a methyl ether of morphine, whilst thebaine is a methyl ether of an enolic form of codeinone. There has been much discussion as to the function of the third or indifferent oxygen in the three alkaloids, and its nature has only been disclosed by a study of degradation products. 

The above mentioned reactions are widely used in alkaloid modification. A good example of alkaloid modifications for clinical curation purposes are opioides. Morphine and codeine are natural products of Papaver somniferum. However, the codeine is naturally produced in small amounts. This is one reason why it is produced synthetically from morphine by modification. As codeine is the 3-0-methyl ether of morphine, the mono-O-methylation occurs in the acidic phenolic hydroxyl. Pholcodine is obtained by modification of morphine through alkylation with A-(chloroethyl)morpholine. Moreover, dihydrocodeine, hydro-morphone and heroine are also obtained from morphine through modifications. 

The adventitious discovery, in prehistory, of the analgesic soporific and the euphoriant properties of the dried sap from the flower bulb of the poppy, papaver somnifemm, has been treated too often elsewhere to warrant repetition. By the nineteenth century organic chemistry had advanced far enough so that the active principle from opium had been isolated, purified, and crystallized. Increasing clinical use of this compound, morphine (1-1), and its naturally occurring methyl ether codeine (1-2) disclosed a host of side effects, the most daunting of which was, and stUl is, these compounds propensity for inducing physical dependence. 

Catalytic hydrogenation of the hydrolysis product leads to the orally active compound oxycodenone (7-1), which is used in a number of analgesic drugs. Cleavage of the methyl ether to the free phenol leads to one of the most potent close analogues of morphine, oxymorphone (7-2) [5]. Note that both of these compounds carry the hazards of classical opiate dependence liability. 

Codeine is the methyl ether of morphine and therefore is also prepared from morphine by methylating the phenolic hydroxyl group with diazomethane, dimethyl sulfate, or methyl iodide. 

Codeine is the methylic ether of morphine (3-methylmorphine) and can be isolated from opium during the extraction of morphine, but is usually prepared by the methylation of morphine. Codeine is used in medicine as an antitussive drug and furthermore it has analgesic properties. It may cause addiction, but less than morphine. 

During the total synthesis of ( )3-deoxy-7,8-dihydromorphinone (72), a morphine derivative lacking aromatic ring substitution,<166,167) two novel aromatic ring substituted analogs were isolated as intermediates, 4,5-epoxy-2-hydroxy-N-methylmorphinan-6-one (71, R = H) and a related 1-bromo derivative (70), together with their respective methyl ethers. No biological data on these were reported. 

Hydroxy-N-methylmorphinan was also found to bind to opioid receptors), but its analgesic activity in the MW assay was of doubtful significance. Related morphinan-6-ones were synthesized via 3-methoxyphenylethyl-amide(76,77) (e.g., Scheme 3.10). Resolution at the 2-benzyltetrahydroiso-quinoline stage afforded (-)-2-hydroxy-N-methylmorphinan-6-one (75a) and the corresponding methyl ether (75b). Neither compound exhibited significant MHP activity,(50) with the ether being only about i x morphine. The (+)-enantiomorphs were prepared in a similar manner.<50)... 

All derivatives reported in these series were assayed for analgesia in the RTF and MW tests. Remarkably, members of most N-Me series of isomor-phinans were substantially more active than morphine (RTF, ED50, 0.68 for 89, R = H R and R2 = Me, cf morphine 19.3 /xmol/kg sc). 3-Methyl ethers bearing an N-Me group in the isomorphinan series were inactive in the RTF test, and the introduction of 7-Me or 7-Me, 8-short alkyl did not affect analgesic... 

Use of the opium poppy (Papaver somniferum) to ameliorate pain dates back thousands of years, and the active metabolite morphine (2) was isolated first from its extracts in 1806 followed by codeine (53) in 1832 (27, 28). Morphine and its derivatives are agonists of opiate receptors in the central nervous system and are some of the most effective pain relievers known and prescribed for postoperative pain. Morphine and codeine differ by substitution by methyl ether. Unfortunately, addictive properties of these compounds limit their use. Efforts have been made to reduce the addictive properties of morphine, which resulted in a semisynthetic derivative buprenorphine (54) (29). This compound is 25 to 50 times more potent than morphine with lower addictive potential and has been indicated for use by morphine addicts. 

Semi-Synthetic Transformations of the Morphine Alkaloids Although it has been synthesised (ref 61), (now by four distinct routes) morphine (63), a powerful analgesic is readily available from the natural source, opium obtained from Papaver somniferum as the major alkaloid present (approx. 10%) and indeed the first to be isolated by Serturner in 1803, while the methyl ether, codeine (64) which comprises only 0.5% is relatively weakly active. Thebaine (65) a third component of opium is non-analgesic but is important as an intermediate for the formation of codeine, a somewhat scarce commodity (ref. 62) but a valuable mild analgesic and anti-tussive in great demand. It is best prepared from morphine by methylation with phenyl trimethylammonium ethoxide the by-product consisting of dimethylaniline (ref.63). 

The medical uses of morphine alkaloids have been known at least since the seventeenth century, when crude extracts of the opium poppy, Pojoauer somniferum, were used for the relief of pain. Morphine was the first pure alkaloid to be isolated from the poppy, but its close relative, codeine, also occurs naturally. Codeine, which is simply the methyl ether of morphine and is converted to morphine in the body, is used in prescription cough medicines and as an analgesic. Heroin, another close relative of moiTphine, does not occur naturally but is synthesized by diacetylation of morphine. 

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