Codeine ethers

The processes used in the manufacture of morphine are believed to be still based on that described by the Scottish chemist Gregory,in 1833, with improvements devised by Anderson. A description has been published by Schwyzer, who also deals with the manufactme of codeine, narcotine, cotarnine, and the commercially important morphine derivatives, diamorphine (diacetylmorphine), and ethylmorphine (morphine ethyl ether). More recently Barbier has given an account of processes, based on long experience in the preparation of alkaloids from opium. Kanewskaja has described a process for morphine, narcotine, codeine, thebaine and papaverine, and the same bases are dealt with by Chemnitius, with the addition of narceine, by Busse and Busse, and by Dott. It is of interest to note that a number of processes for the extraction and separation of opium alkaloids have been protected by patent in Soviet Russia. ... 

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. 

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. 

Singer and Scammells have investigated the y-Mn02 oxidation of codeine methyl ether (CME) to thebaine in the ionic liquid [BMIM][BF4] [63]. The ionic liquid was used in different ways and with mixed results (Scheme 5.1-35). For example, the oxidation of CME in the ionic liquid gave 38 % yield after 120 hours. A similar reaction under biphasic conditions (with diethyl ether) gave a 36 % yield of thebaine. This reaction gave a 25 % yield of thebaine when carried out in tetrahydrofuran... 

Finally, it should be mentioned that ionic liquids have successfully been used in classical, stoichiometric oxidation reactions as well. Singer et al., for example, described the application of [BMIM][Bp4] in the oxidation of codeine methyl ether to thebaine [64]. The ionic liquid was used here as a very convenient solvent to extract excess Mn02 and associated impurities from the reaction mixture. 

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. 

Very simple liquid-liquid partitioning systems have been employed to isolate many drugs from biological media. Alkaloids, antihistamines, barbiturates, and tranquilizers from blood, can be extracted from urine, stomach juices, and tissue, using acetone diethyl ether, 1 1, and aqueous phases of varying pH (3-6). Typical drugs include caffeine, cocaine, atropine, codeine, heroin, morphine, quinine, doxylamine, chlorpheniramine, diphenyl-pyraline, amobarbital, pentobarbitol, secobarbitol, and pheno-barbitol (2-5). 

Dextromethorphan (Romilar) is the dextroisomer of the methyl ether of levorphanol. Unlike its levorotatory congener, it possesses no significant analgesic property, exerts no depressant effects on respiration, and lacks addiction liability. It is an antitussive agent with a potency approximately one half that of codeine. 

W. R. Agyangar, S. R. Bhide, and U. R. Kalhote, Assay of semisynthetic codeine base with simultaneous determination of codei-methine and 06-codeine methyl ether as by-product impurities by HPLC, J. Chromatogr., 579 250 (1990). 

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. 

A new method for the demethylation of codeine to morphine, previously a capricious reaction, has been reported, the product being obtained in good yield. Demethylation by boron tribromide in chloroform gives 90—91%150 and by potassium t-butoxide in propanethiol gives 80% morphine.151 A patent describes an improved method for the preparation of codeinone from thebaine, by adding the alkaloid to anhydrous hydrogen bromide in solution in methylene chloride and dibutyl ether at -20 °C, in the presence of small quantities of iodine, followed by hydrolysis with aqueous sodium bicarbonate. The claimed yields of codeinone are 95% crude and 90% after purification.152 Codeinohe is an intermediate in the conversion of thebaine into codeine. An overall yield of 85% of codeine from thebaine, without purification of any of the intermediates, has been claimed for an... 

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