17-Methyl morphine

The quaternary salts of codeine and its isomers can be degraded to unsaturated bases to which the general term methylmorphimethine has hitherto been applied, but here the less cumbersome and more systematic term codeimethine [1] will be used, the term methylmorphimethine being reserved for the derivatives obtained from nuclear methylated morphines. The term dihydromethine will be applied to bases in which the double bond introduced by degradation has been saturated. In this way a convenient and unambiguous system of nomenclature is available. 

As a classical pre-medicine before operations morphine+scopolamine 10 mg+0.4 mg is used. Morphine is used to make diacetyl-morphine (heroin) and codeine (methyl morphine). 

Codeine (methyl-morphine),C H NO(OH)O.CH,.— On the electrolysis of the neutral sulphate hydrogen is evolved, codeine is precipitated, and the solution turns brown. The acid sulphate undergoes more complete decomposition, and carbon dioxide, carbon monoxide, oxygen, and nitrogen are split off. 

Louis fidouard Grimaux (Rochefort-sur-Mer, Charant-Infer., 3 July 1835-Paris, 3 May 1900), at first a pharmacist in a small town of Vendee, left to study in Paris with Wurtz. He lectured in the ficole de Medecine and became professor in the Institut agronomique national and (1876) in the ficole Polytechnique. He signed a protest in the famous affaire Dreyfuss and in consequence was deprived of his post in 1898. He was the biographer of Lavoisier (see Vol. Ill) and contributed to the Life of Gerhardt (see p. 407). He synthesised parabanic acid, allantoin, barbituric acid, and with P. Adam citric acid from glycerol. He showed that codeine is methyl-morphine. 

Codeiae (2, R = CH3) occurs ia the opium poppy along with morphine (2, R = H) but usually ia much lower concentration. Because it is less toxic than morphine and because its side effects (including depression, etc) are less marked, it has found widespread use ia the treatment of minor pain and much of the morphine found ia cmde opium is converted to codeiae. The commercial coaversioa of morphine to codeiae makes use of a variety of methylating ageats, amoag which the most common are trimethylphenylammonium salts. Ia excess of two huadred toas of codeiae are coasumed anauaHy from productioa faciUties scattered arouad the world. 

The replacement of the /V-methyl group on the nitrogen atom of the piperidine ring of morphine and analogues by aHyl, isopropyl, or methyl cyclopropyl, an isopropyl isostere, results in compounds which antagonize opioid responses, especially respiratory depression. Naloxone [465-65-6] C22H2 N04 (10... 

Codeine, like morphine, is isolated from the opium poppy. However, the low yield of 0.7—2.5% does not provide sufficient material to meet commercial demands. The majority of marketed codeine is prepared by methylating the phenolic hydroxyl group of morphine. Morphine yields from opium poppy are 4—21%. When prescribed for cough, the usual oral dose is 10—20 mg, three to four times daily. At these doses, adverse side effects are very few. Although the abuse potential for codeine is relatively low, the compound can substitute for morphine in addicts (47). 

Dibenz[h,e]azepine-6,11-diones ent-Morphinan nomenclature, 1, 29 Morphinan, 1,2,3,4-tetrahydro-nomenclature, 1, 29 14-a-Morphinan, N-methyl-synthesis, 1, 480 Morphinans nomenclature, 1, 29 as pharmaceuticals, 1, 148 synthesis, 2, 377 Morphine, 2, 512 as analgesic, 1, 167 as metabolite of normorphine, 1, 235 as pharmaceutical, 1, 146, 147, 148 synthesis, 1, 480 Morphine alkaloids structure, 4, 534 Morphin-7-en nomenclature, 1, 29 Morphinone, dihydro-as pharmaceutical, 1, 147 Morpholine — see also 1,4-Oxazine, tetrahydrocarcinogenicity, 1, 229 corrosion inhibitor, 1, 409 metabolism, 1, 226 nomenclature, 3, 996 structure, 2, 5 synthesis, 2, 89 Morpholine, 4-aciyloyl-polymers, 1, 291 Morpholine, alkenyl-polymers, 1, 291... 

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. ... 

The three alkaloids concerned, morphine, codeine and thebaine, all behave as tertiary bases. Morphine contains two hydroxyl groups of which one is phenolic and the other a secondary alcohol group. On methylation of the phenolic hydroxyl codeine results. On oxidation, codeine is transformed into codeinone by conversion of the secondary alcohol group into a carbonyl group, and when thebaine is boiled with A-sulphuric acid for a few minutes, it is hydrolysed into codeinone and methyl sulphate, and in other ways thebaine has been shown to contain two methoxyl groups. That the relationship between the three alkaloids is close may be illustrated by the following slightly extended formula —... 

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. 

Dihydromorphinone, Cj,Hjg03N, and derivatives. Dihydromorphinone (LIII MeO HO) is formed when morphine in solution is treated with relatively large quantities of platinum or palladium catalyst under various conditions.It melts at 262-3° and yields an oxime, m.p. > 234°. The hydrochloride is the drug known as dilaudid. On 0-methyla-tion dihydromorphinone yields dihydrocodeinone (see above), and when dissolved in ether and treated with methyllithium the corresponding tertiary alcohol, 6-methyldihydromorphine, CigHggOgN, m.p. 209-211°, Wd ° 14i7° (EtOH), is formed. This on methylation with diazomethane gives 6-methyldihydrocodeine as described above (Small and Rapoport... 

Methylmospiiimethines. The principal characters of these derivatives of the four known morphines have been given already (p. 218). Below are shown formulae for the two stereoisomeric pairs of morphines and the three stereoisomeric pairs of methylmorphimethines. -Methyl-morphimethine is also neopinemethine (p. 219), and for that reason the formula of neopine is added. 

The stereoisomeric pair, morphine and a-womorphine, on methylation of the phenolic hydroxyl at C, give rise to codeine and isocodeine respectively, and similarly and y-i omorphines produce [Pg.250]

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