Codeine isolation

In 1803 the German pharmacist Seturner achieved the isolation of morphine as one of the active ingredients of opium. He named the compound after Morpheus, Ovid s god of dreams, the son of sleep. Among the other alkaloids of opium are codeine, isolated in 1832, thebaine, narceine, narcotine, and papaverine. From the isolation of pure morphine to the elucidation of its structure by first Gulland and Robinson(1,2) and later Schopf(3) took another 120 years. A total synthesis by Gates and Tschudi(4,5) confirmed the structure in the early 1950s. 

Narcotic Antitussives. Since its isolation in 1832, codeine [76-57-3] (27) has been one of the most widely used and effective compounds for the treatment of cough. Though less potent than morphine [57-27-2] (28), it has become the reference against which most antitussives are measured. 

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). 

The first scheme for the separation of the six chief alkaloids of opium, VIZ., morphine, codeine, thebaine, papaverine, narcotine and narceine, is probably that of Plugge. Much later Kljatschkina investigated for each of these six bases the properties by means of which isolation and estimation could probably be effected and, on the basis of the results, devised a plan for such analyses. More recently Anneler has published a detailed account of a scheme with the same objective. l Attention had already been given to complex, systematic analyses of this kind, in connection with examination of the mixtures of opium alkaloids, which have long been in use in medicine in these at first only morphine and other alkaloids were determined, but in the more recent schemes provision is made for the estimation of each alkaloid. ... 

Papaverine, C20H21O4N. This alkaloid, first obtained by Merck, occurs in the mixture precipitated by ammonia from the mother liquors of opium extract from which morphine and codeine have been separated in Gregory s process, and methods for its isolation from this mixture have been published by Hesse and others. The alkaloid may be purified by conversion into the acid oxalate, B. H2C2O4, m.p. 196° or 201-5-202°, which is nearly insoluble in alcohol. 

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. ... 

Morphine (10) and codeine (11), constituents of opium, are the most interesting alkaloids found in nature. Morphine is also the oldest alkaloid isolated, in 1805, by the German pharmacist Sertiimer from opium, the sun dried latex of Papaver somniferum. The structure of morphine with its so-called morphinan skeleton, once called the acrobat under the alkaloids, was finally elucidated in 1952 by the first total synthesis performed by Gates and Tschudi. Many syntheses would follow [26], but all morphine used today, whether legal or illicit, originates in the natural source P. somniferum or its extract, opium. The latex may contain up to 20% morphine. Most legal morphine is converted into the anticough medicine codeine (Table 5.1) by treatment with trimethylanilinium methoxide, whereas almost all illicit morphine is acetylated to the diacetate heroin. 

The use of natural products as medicine has invoked the isolation of active compounds the first commercial pure natural product introduced for therapeutic use is generally considered to be the narcotic morphine (1), marketed by Merck in 1826, and the first semi-synthetic pure dmg aspirin (2), based on a natural product salicin (3) isolated from Salix alba, was introduced by Bayer in 1899. This success subsequently led to the isolation of early dmgs such as cocaine, codeine, digitoxin (4), quinine (5), and pilocarpine (6), of which some are still in use. ... 

Reduction of coumarin in aqueous methanol, pH 5-6, in the presence of alkaloids yields an increased amount of dihydrocoumarin. Tliis is also the case for reduction of 4-methylcoumarin and now the 4-methyldihydrocoumarin isolated is optically active [137]. Tlie enantiomeric excess and yield of diliydrocompound both depend on the alkaloid used (Table 3.9) and Low concentrations of alkaloid are effective in achieving asynunetric induction. Concentrations of codeine above 4 mM do not further influence either the yield of dihydrocompound or the degree of induction. 

Catalytic reduction of codeine gives dihydrocodeine and Oppenauer oxidation (a ketone such as acetone and an aluminum alkoxide, the ketone being reduced to an alcohol) gives hydrocodone. Hydrocodone can also be prepared directly from codeine with a metal catalyst, which isomerizes the allylic alcohol to a ketone. Codeine is prepared by methylation of morphine, which is isolated from the opium poppy. Hydrocodone is more potent than codeine. Acetaminophen is a mild analgesic and is discussed in Section 8. 

Chapter 1). Examples include digoxin and digitoxin, originally isolated from the foxglove (a member of the genus Digitalis), as well as aspirin, codeine and taxol. 

Serturner reported the isolation of morphine in 1805 Pelletier and Magendie published on the isolation of emetine in 1817 the paper by Robiquet on the isolation of codeine was dated 1832 and that by Mein on the isolation of atropine in pure form was dated... 

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. 

Morphine and codeine are both isolated from opium. Codeine (Schedule II), less potent that morphine, is biotransformed into morphine in the body and then further metabolized. 

Meanwhile, opium had been joined by other narcotics. Back in 1805 a German pharmacist s assistant had discovered how to isolate its main ingredient, morphine. A preparation of morphine is about 10 times as potent as raw opium. In 1832, another morphine derivative called codeine was isolated. By the 1850s, a more effective way to administer these powerful narcotics was developed—the hypodermic needle. During the American Civil War, battlefield surgeons had one effective way to relieve the pain of a shattered limb or punctured lung—an injection of morphine. Soldiers who survived their wounds after this treatment often became addicted to the drug. Morphine addiction was thus sometimes referred to as the soldier s disease. ... 

The first group contains the natural products morphine, codeine and thebaine, which have been isolated from the natural product opium. In addition, the group contains various semi-synthetic derivatives of morphine, codeine and thebaine, which are prepared by chemical modifications of these natural products... 

Following the isolation of morphine by Serturner in 1805 further alkaloids were isolated from opium, for example narcotine in 1817, codeine in 1832, thebaine in 1835 and papaverine in 1848. 

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). 

Opium contains more than 20 distinct alkaloids. In 1806, Sertiirner reported the isolation of a pure substance in opium that he named morphine. The discovery of other alkaloids in opium quickly followed that of morphine (codeine by Robiquet in 1832 and papaverine by Merck in 1848). By the middle of the 19th century, the use of pure alkaloids rather than crude opium preparations began to spread throughout the medical world. 

Achieving consistent results with opium has always been difficult. Different methods of production and naturally varying concentrations of morphine and codeine produce widely varying results from one batch to the next. Once the chemical methods became available, scientists were eager to isolate the active ingredient(s), hoping to produce a pure analgesic. 

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