Alkaloids papaverine

CgHjoO,. A compound of largely historical interest for its role in establishing the structure of many natural products. Methylation of vanillin gives veratraldehyde which may be oxidized to veratric acid. Veratric acid was identified as a degradation product of the alkaloid papaverine. 

Review Problem 4 This compound (TM 78) is an important intermediate in the synthesis of alkaloids Treatment with POCI3 gives the poppy alkaloid papaverine. How would you make TM 78 from simple starting materials ... 

Opium is the dried, powdered sap of the unripe seed pod of Papaver somniferum, a poppy plant indigenous to Asia minor. Theophrastus described its medical properties in the third century BC, but the Sumerians, ca BC 4000, probably perceived its utility. Arab physicians knew of the dmg, and Arab traders carried it to the Orient where it was used as a treatment for dysentery. Paracelsus is credited with repopularizing the dmg in western Europe in the early sixteenth century by formulating opium into "laudanum", which is still in use. More than 20 different alkaloids (qv) of two different classes comprise 25% of the weight of dry opium. The benzylisoquinolines, characterized by papaverine [58-74-2] (1.0%), a smooth muscle relaxant, and noscapine [128-62-1] (6.0%), an antitussive agent, do not have any analgesic effects. The phenanthrenes, the second group, are the more common and include 10% morphine (1, = R = H), 0.5% codeine [76-57-3], C gH2 N03, (1, R = H, R = CH3), and 0.2 thebaine [115-37-7], C 2H2 N03, (2). 

Estimation of Other Alkaloids in Opium. Of the other alkaloids the most important is codeine, and processes for its estimation in opium have been described by Cespari, Andrews,and Annett and co-workers methods for its assay in admixture with other drugs in tablets and other products are also available. The estimation of papaverine has been described by Issekutz,i and of narcotine by Snesarov. As to methods for the separation and estimation of two or more of these subsidiary alkaloids, codeine and narcotine have been dealt with by van der Widen,narcotine and papaverine by Annett and Bose, ( and the bromination of codeine and narceine has been studied by Vaisberg et al. with a view to estimation by this means. 

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. ... 

Xanthaline has been shown to be papaveraldine (p. 182). The alkaloid tritopine is identical with laudanidine, now known to be Z-laudanine. Gnoscopine is dZ-narcotine. Merck s pseudopapaverine is papaverine. 

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. ... 

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. 

Papaverine crystallises in rhombic prisms or needles, m.p. 147°, [a]n 0°, is insoluble in water, soluble in hot alcohol or chloroform, and slightly so in cold alcohol or ether. It is a weak base for which, according to Wales, there is no satisfactory indicator, though bromophenol-blue has its colour change at the right point for this alkaloid. The hydrochloride, B. HCl, forms monoclinic plates, m.p. 225-6°, sparingly soluble in water (1 in 37 at 18°). The picrate forms quadratic plates, m.p. 186°. ... 

In this, the first serious and successful work on the structure of a complex alkaloid, there was naturally at first some confusion between Moquinoline and the better-known quinoline. The 6 7-dimethoxy-woquinolinecarboxylic acid was thought to be a dimethoxycinchoninic acid. It known, however, that quinoline benzylchloride on oxidation furnished formylbenzylanthranilic acid, CjH4(COOH)—N(C,H,)—CHO, whereas various papaverine alkyl halides gave what were presumed to be... 

Special Reactions of Papaverine. Papaverine undergoes a number of reactions, which are of interest as providing methods of synthesis for other alkaloids, of which examples will be found under laudanosine, laudanine, laudanidine, codamine (pp. 187-195), berberine (p. 331), corydaline (p. 284), and glaucine (p. 311). 

Papaverine, CjiHgiO N. Hesse s alkaloid of this name and formula was re-examined by Spath and Polgar and shown to be papaverine. 

A characteristic feature of the action of the opium alkaloids is their simultaneous depressing and exciting action on the central nervous system. In this respect there is no clear line of demarcation between the morphine group—morphine, codeine and thebaine—and the papaverine-narcotine group, and as the series is ascended in the order, morphine, papaverine, codeine, narcotine, thebaine, narcotic action diminishes and power of rellex stimulation increases until in thebaine a strychnine-like effect is exhibited. 

Minor Corydalis Alkaloids. The following four alkaloids have been isolated by Manske from various Corydalis species but have not yet been assigned to chemical groups. Cularine has been compared pharmacologically with papaverine and hydrastine, and may prove to be related to one of these alkaloids. 

Pharmacological Action. As already pointed out, cularine shows some resemblance to papaverine and hydrastine in action (p. 196). The M.L.D. (mgm./kilo.) for mice by intravenous injection of ochotensine is 10-6 i 0-54 so that it seems to be the most toxic of the fifteen corydalis alkaloids examined by Anderson and Chen, who also state that it stimulates isolated guinea-pig or rabbit uterus, inhibits isolated rabbit-intestine and induces a fall in blood pressure on intravenous injection in etherised cats. 

Other examples of syntheses under physiological conditions will be found under arecaidine, lobelia, papaverine, cusparia bark alkaloids, harmala alkaloids, rutascarpine and yohimbine. 

Burn has pointed out that the grouping together of many properties as fundamentally the same, brings into some sort of order the long list of apparently pharmacologically unrelated alkaloids, and that the similarity in many properties of atropine, papaverine and quinine, and of conessine and quinine, suggests points of biochemical similarity. 

On treatment of N-methylpapaverine, formed by the lithium aluminum hydride reduction of papaverine methiodide with phosphoric acid, N-methylpavine is formed which is identical with the racemic alkaloid argemonine. This reaction was used for the synthesis of the alkaloid (-h)-coreximine (268) (174) and similar compounds containing the proto-berberine grouping in the molecule (269,270). 

Papaverine (107) is among the host of minor alkaloids that have been isolated from opium. The compound is distinct in its biologic activity from many of the other opium constituents in that it does not exhibit any analgesic activity. Instead, papaverine acts as a nonspecific spasmolytic agent. As such, it has found... 

Opium is an extract of the juice of the poppy Papaver somnifemm, which contains more than 20 distinct alkaloids, including morphine, codeine and papaverine. 

This procedure yielded a colorless background, on which the colors of the alkaloid zones became pale brown (narceine), blue (morphine) or violet (codeine, papaverine, narcotine) (Fig. 2B). 

The opiate alkaloid, papaverine, from Papaver somniferum is an anti-spasmodic, vasodilator, and smooth muscle relaxant. Its total synthesis has been studied since Pictet and Gams early work in 1909 and has since been followed up by various industrial syntheses up till the early 1950s using important industrial commodities as vanillin, acetovanillone, veratraldehyde (methylvanillin), and homoveratric acid as starting materials (see Figure 4.50). Table 4.23 summarizes the results of the five synthetic plans for this natural product. All are convergent... 

Papaveraceae, alkaloids in, 2 75 Papaverine, 2 87-88 from vanillin, 25 554 Paper, 18 89-132. See also Papermaking analysis of moisture and fluid resistance for, 18 101... 

More than 30 alkaloids have been identified in opium (Robbers et al. 1996). The most relevant are morphine (4-21%), codeine (0.8-2.5%), noscapine (4-8%), papaverine (0.5-2.5%), and thebaine (0.5-2%) (figure 8.4). Other opium alkaloids include narceine, protopine, laudanine, codamine, cytopine, lanthopine, and meconidine. Numerous other opioids have been synthesized from opium alkaloids. Among them is heroin, or diacetylmorphine. 

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