Codeine, synthesis

During total synthesis studies on ( )-3-deoxy-7,8-dihydromorphine and ( )-4-methoxy- N-methylmorphinan-6-one, a series of racemic mixtures with both 2- and 4-oxygen substituents (76) was isolated and characterized.(69) 2,4-Dihydroxy-3-methoxymorphinan-6-ones were isolated in an investigation of the Grewe codeine synthesis/78 ... 

Identification and determination of by-products of the codeine synthesis Proksa, B. Cemy, J. 

In a study of the Grewe method of codeine synthesis, the p-bromophenol (98) and its N-methoxycarbonyl derivative failed to undergo acid-catalysed cyclization to a morphinan. Also, although 2-hydroxydihydronorthebainone (99) was readily obtained by cyclization of (100), removal of the 2-hydroxy-group could not be... 

Partial synthesis is relatively unimportant in the field of alkaloid synthesis, since only a few compounds are available at low price (see table 23). An exception is the derivatization of the morphine base, which leads to codeine, heroin, and other important compounds. These trivial reactions, however, are covered in elementary text books. 

Oxolamine [959-14-8] (57) is sold in Europe. It is an oxadiazole, and its general pharmacological profile is described (81). The compound possesses analgesic, antiinflammatory, local anesthetic, and antispasmodic properties, in addition to its antitussive activity. Although a central mechanism may account for some of the activity, peripheral inhibition of the cough reflex may be the dominant effect. The compound has been shown to be clinically effective, although it is less active than codeine (82,83). The synthesis of oxolamine is described (84). 

Scheme 14. Tandem radical bicyclization-f rag mentation in Parker s synthesis of intermediate 76 en route to codeine (77) and morphine (78).

Rice, K.C. (1980) Synthetic Opium Alkaloids and Derivatives. A Short Total Synthesis of (ib)-Dihydrothebainone, ( )-Dihydrocodeinone, and ( )-Nordihydrocodemone as an Approach to a Practical Synthesis of Morphine, Codeine, and Congeners. Journal of Organic Chemistry, 45, 3135-3137. 

Weller, D.D. 8c Rapoport, H. (1976) A Practical Synthesis of Codeine from Dihydrothebainone. Journal of Medicinal Chemistry, 19, 1171-1175. 

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. 

Opium is a cmde exudate obtained from the opium poppy Papaver somniferum, and it provides several medicinally useful alkaloids. One of these is codeine, which is widely used as a moderate analgesic. Opium contains only relatively small amounts of codeine (1-2%), however, and most of the codeine for dmg use is obtained by semi-synthesis from morphine, which is the major component (12-20%) in opium. Conversion of morphine into... 

Both morphine and codeine are valuable analgesics. Morphine is extracted from opium, the dried latex of the opium poppy, and codeine is usually obtained from morphine by semi-synthesis (see Box 6.2), since the amounts in opium are rather small. Thebaine is a valuable raw material for semi-synthesis of a wide range of morphine-like drugs. 

Hydrocodone is an opium analgesic (pain reliever) and antitussive (cough suppressant). It is related in structure to other alkaloids used as drugs, such as morphine and codeine (see Section 8). It increased 20% in number of prescriptions for one year. Its synthesis from codeine is by simple reactions. 

Oxycodone The synthesis of oxycodone, 4,5-epoxy-3-methoxy-14-hydroxy-iV-methyl-6-oxomorphinane (3.1.25), from 14-hydroxycodeinone (3.1.24) was described above. It can also be synthesized in other ways for example, by the oxidation of codeine using sodium dichromate in acetic acid [17], and is also a stractural analog of morphine and codeine. 

Codeine (3.1.20) Synthesis of this drug is described in Chapter 3. 

The asymmetric synthesis of (+)-Codeine 432 devised by White and colleagues included a Beckmann rearrangement to introduce the nitrogen atom in the carbocyclic structure (equation 182). Even though two isomeric lactams 430 and 431 were obtained as a result of the rearrangement, the preferential migration of the bridgehead carbon atom produced 430 as the predominant isomer. The synthesis of the non-natural enantiomer of Codeine was completed after oxidation, olefin formation and reduction. 

Summation - different mechanisms of action are involved with the same effects for each. Analgesia can be achieved by stimulating opiate receptors (codeine) and blocking prostaglandin synthesis (aspirin). 

Synthesis (Stein, 1955, Ehrhart and Ruschig, 1972 Kleemann et al., 1999) Hydrogenation of codeine yields Dihydrocodeine (Kleemann et al., 1999). 

Synthesis (Krauli (E. Merck), 1925, Juby et al., 1968, Ehrhart and Ruschig 1972) Thebaine is oxidized with hydrogene peroxide to 14-hydroxycodeinone (Bentley 1954, Hauser 1974), which is hydrogenated directly or via its oxime, or its bromination products to oxycodone. The reduction of 14-hydroxycodeinone can also be carried out with sodium hydrosulfite. Alternatively 14-hydroxycodeinone is prepared by oxidation of codeine. 

SCHEME 23. Synthesis of morphine, codeine, and other opiates. 

Omori AT, Finn KJ, Leisch H, Carroll RJ, Hudlicky T (2007) Chemoenzymatic Total Synthesis of (+)-Codeine by Sequential Intramolecular Heck Cyclizations via C-B-D Ring Construction. Synlett 2859... 

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