Thebaine from Papaver somniferum

Opium, the sun-dried latex of the unripe fruit of Papaver somniferum, cultivated from early times for this drug, contains at least 23 alkaloids. Of the major alkaloids three—morphine, codeine, and thebaine—contain the morphinan ring system. 

The starting material for these 14-hydroxy compounds is the opium alkaloid thebaine (9). Although present in only small amounts in the alkaloid fraction from Papaver somniferum, it constitutes the major component (as much as 26% of the dried latex) from a... 

The opium is obtained from the opium poppy Papaver somniferum. It contains two type of alkaloids e.g. phenanthrene derivatives (morphine, codeine thebaine) and benzyl isoquinoline derivatives (papaverine and noscapine). 

As is often the case with complex natural products, opium, the dried sap from papaver somniferum, contains a number of structurally closely related compounds. One of these minor constituents, thebaine (6-1), although itself devoid of signihcant... 

Thebaine, codeine and morphine from poppy straw (Papaver somniferum) were extracted with carbon dioxide and various polar modifiers at 20 MPa and 40.5 °C. Kinetic extraction curves for morphine showed that 50% methanol in carbon dioxide was necessary in order to achieve quantitative yields in less than 20 min. A mixture of 25% methanol, 0.22% methylamine and 0.34% water had the same effect as 50% methanol in the catbon dioxide. However, it was also reported that, in spite of its strong extraction power, the methylamine-water mixture had a major drawback in that morphine in the presence of the amine degraded in the presence of light. Hence, carbon dioxide-methanol-water mixtures were investigated increasing the water content in the extraction fluid dramatically enhanced the extraction rate for thebaine [29]. 

The opium alkaloids, which are obtained from Papaver somniferum, contain two groups of compounds compounds with phenanthrene derivatives, consisting of morphine, codeine, and thebaine and compounds with isoquinoline derivatives, consisting of papaverine and noscapine. 

Opium is obtained from the dried juice from the seed capsule of the oriental poppy, Papaver somniferum. The dried juice contains up to 17% morphine and 4% codeine by weight, as well as other, non-additive alkaloids that lack analgesic activity such as noscapine, papaverine, and thebaine. Papaveretum is a standardized preparation of opium containing 50% morphine. 

Varieties of Papaver somniferum with varying content of morphine alkaloids have been studied, and varieties having a genetically governed low alkaloid content have been identified.143 The dynamics of the variation of amount of morphine and codeine present in P. somniferum with time of harvesting of the capsule have been studied.144 The thebaine content of P. bracteatum in relationship to plant development has been studied, and strains have been isolated from which may be obtained a dried latex that contains >55% thebaine, corresponding theoretically to a yield of 58 kg ha-1 or approximately 50 kg ha-1 from harvested capsule.145... 

Papaver Alkaloids.—Biosynthesis of morphine (36) occurs, in Papaver somniferum, through reticuline (33) by way of thebaine (35). The sequence from (35) to (36) involves, inter alia, two O-demethylations, with that at the methoxy-group at C-6 occurring first.1,2 Confirmation that the other methoxy-group is not demethylated first in this Papaver species obtains from the failure to detect oripavine (37), which is found in other Papaver species, as a natural constituent of P. somniferum. The experiment involved attempted isolation of radioactive (37), using inactive alkaloid as carrier, following a feeding experiment with radioactive reticuline (33).37... 

Isolation of the alkaloids from the latex of the opium poppy, Papaver somniferum, led to the identification of over 20 compounds (Fig. 11.1). The most abundant alkaloids were morphine (1), codeine (2), thebaine (3), noscapine (4), and papaverine (5). 

The capsules and stems of Papaver somniferum contain opiate alkaloids essential in medicine. They are classified into two groups, phenanthrene types (morphine, codeine, thebaine) and benzylisoquinoline types [papaverine and noscapine(narcotine)]. These two types of alkaloids show sharply specific pharmacological properties. It is noteworthy that morphinane alkaloids are formed from (-)-(/ )-reticuline, whereas most other alkaloids derive from (-l-)-(5)-re-ticuline 11). 

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). 

Opium poppy Papaver somniferum L., Papaveraceae) is one of the most important medicinal plants and has been cultivated since early centuries. Opium, the dried cytoplasm of a specialized internal secretory system called the laticifer, is normally collected from the unripe capsule. It is the source for the commercial production of medicinally important alkaloids, morphine, codeine, thebaine, noscapine and papaverine [130, 131], Fig. (61). Morphine, which has strong addictive property, is still the most effective analgesic for the treatment of mortal cancer patients in modem medicine. Codeine is commonly used as an antitussive. However, field cultivation of this plant has been limited since 1953 by the United Nations Opium Conference Protocol to prevent narcotic crimes. Therefore, establishing tissue culture technique for the production of morphinan alkaloids seems to be desirable not only for medicinal purpose but also for decreasing abuse of opiates. 

Opium, Gum opium crude opium. Air-dried, milky exudation from incised, unripe capsules of Papaver somniferum L., Or jP. album Mill., Papaveraceae. Habit of the plant Asia Minor, Persia, China, Africa, India cultivated in tlie Balkan States, Hungary, Southern Russia. In Japan the strain cultivated from the production of opium is called Ikkanshu Appearance and sources Chem. A Eng. News 32, 2701 (1954). Conshf, About 20 alkaloids, constituting about 25% of the opium meconic acid, some lactic and sulfuric acids, sugar, resinous and waxy-like subsrances 12 25% water. Morphine is the most important alkaloid and occurs to the extent of 10-16%, noscapine 4-8%, codeine 0 8-2.5%, papaverine 0 5 2,5%, thebaine 0,5-2%,... 

Colchicum cornigerum on the basis of an X-ray analysis of its methiodide. A review on the opium poppy Papaver somniferum describing its diverse uses and effects has appeared.Apparently the positive identification of morphine, codeine, thebaine, papaverine, and narcotine in unknown resins and powders may be taken as evidence that they are derived from P. somniferum. The yield and alkaloid content of P. somniferum capsules upon fertilization has been determined. ... 

The Juice opium in Greek) or latex from the unripe seed pods of the poppy Papaver somniferum is among the oldest recorded medications used by humans. The writings of Theophrastus around 200 BC describe the use of opium in medicine however, evidence suggests that opium was used in the Sumerian culture as early as 3500 BC. The initial use of opium was as a tonic, or it was smoked. The pharmacist Surturner first isolated an alkaloid from opium in 1803. He named the alkaloid morphine, after Morpheus, the Greek god of dreams. Codeine, thebaine, and papaverine are other medically important alkaloids that were later isolated from the latex of opium poppies. 

Opioids are those substances that can activate localized opioid receptors in the pain-controlling system of the body. Their action can therefore be antagonized by naloxone. From a clinical point of view, morphine is the most important substance of this group. It is obtained from opium, which is the brownish latex obtained from cuts made in the unripe but fully grown fruits of Papaver somniferum, the opium poppy. Opium contains not only morphine but also over thirty other alkaloids (Fig. 8-13) including the isoquinoline alkaloids codeine, papaverine, noscapine, thebaine and others, which make up ca. 25% of the opium. The alkaloids in opium are sometimes present as salts of meconic acid. The opiates form a separate subgroup within the opioids whose member... 

Morphinan Alkaloids.—Extensive research on the biosynthesis of morphine (51) and related alkaloids in Papaver somniferum has allowed a detailed description of the pathway from the amino-acid tyrosine through reticuline (44), thebaine (46), and codeine (50) to morphine (51) (Scheme The incorporation of (R)-... 

An example of this are the concentrations of the isoquinoline alkaloids morphine, codeine, and thebaine (D 22.1.2) in the latex of Papaver somniferum. Morphine concentrations peak in the morning codeine, at noon and thebaine gradually increases from 6 am until the late evening... 

Alkaloids of the morphinane group. If the tetrahydroisoquinoline alkaloid norlaudanosoline is written in such a way that part of the molecule is rotated around the dotted line (Fig. 280), the relationship to the morphinane-type alkaloids becomes obviously. The actual precursor of these compounds, however, is (R)-reticuline. It is probably attacked by a phenol oxidase (C 2.3.1) yielding a biradical which is stabilized by the formation of the dienone (- -)-salutaridine. After reduction of (-j-)-salutaridine closure of a new 0-heterocyclic ring results in the formation of thebaine. The alkaloids codeine and morphine are synthesized from thebaine in Papaver somniferum,... 

The opiate alkaloids are a mix of semisynthetic and synthetic compounds derived from or related to the extract of the unripe seed pods of the opium poppy Papaver somniferum. Specifically, the alkaloids are obtained from the latex, or milky, exudates of the seed pod that appear when it is cut or sliced. The liquid contains about 10% morphine and about 1.5% codeine, with various amoimts ( 0.2-8%) of papaverine, thebaine, and noscapine (Table 8.3). The... 

In conclusion, it appears that the impressive experiments on minor alkaloids in Papaver somniferum confirmed only the minor value of these compounds for genetic investigations (Table 2.4). On the other hand, crosses involving major alkaloids are important for such investigation. This kind of cross was performed between the morphine-bearing Papaver somniferum and the thebaine-accumulating P, bracteatum (Bdhm, 1965). As was expected from the biosynthetic experiments of Stermitz and Rapoport... 

In a discussion of the nonspecific character of nicotine demethylation, it is appropriate to mention a curious finding of Gruetzmann and Schroeter (1966). They were looking for a system to accomplish the biological production of codeine and morphine from thebaine, which does not have as much pharmacological use. They succeeded with a tissue culture of Papaver somniferum and surprisingly also with a tissue culture from Nicotiana allata, which also O-demethylated and reduced thebaine to yield codeine and morphine (Figure 6.13). No details have been published, probably because of the practical value of the procedure. 

Figure 6.28. N-oxides of Papaver alkaloids. Thebaine N-oxide, major isomer (1) minor isomer (2) codeine A -oxide. major isomer (3) minor isomer (4) morphine N-oxide, major isomer (5). 1 and 2 were isolated from P. bracteatum (thebaine-rich strain), 3, 4, and 5 were isolated from P. somniferum (Halle strain), courtesy of J. D. Phillipson and Pergamon Press, Ltd., copyright 1976.

Even synthetic chemists are involved in the war against illegal drug production, as shown by a recent example. As you probably know, the restrictions imposed on the cultivation of morphine-producing Papaver somniferum has led to a shortage of codeine for medical purposes. Since codeine can also be made from thebaine, an alkaloid biologically synthesized by the species Papaver bracteatum, and since illicit heroin production from thebaine seems unlikely (Table I), it has been suggested (1) to substitute the cultivation of somniferum for bracteatum. 

Reticuline (25) is also the key precursor for isoboldine (33), which is a minor alkaloid of Papaver somniferum (Brochmann-Hanssen et al. 1973) (the hydrophenan-threne alkaloids of this plant, e.g. thebaine (35) also derive from reticuline). Orienta-line (36) with a methylation pattern different to that in reticuline (25) was not incorporated into (33). Coupling of the two rings in reticuline (25) is thus ortho to a hydroxy-group on one ring and para on the other. 

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