Papaverine base

In an attempted synthesis of papaverine based on Rugheimer s preparation of 6 7-dimethoxyisoquinoline from veratrylaminoacetal (McO)2—CjHg—NH—CH2(OEt)2, Allen and Buck reduced deoxy-veratroin oxime, (MeO)2—CgHg—C(NOH)—CHj—C6H3(OMe)2, to a 3-di-(3 4-dimethoxy)-phenylethylamine,... 

To 3,65 g (0X)1 mol) of monohydrated adanosine-5 -monophosphoric acid,brought into suspension in a mixture of 45 ml of water and 5 ml of ethanol, are added 3.39 g (0.01 mol) of papaverine base (melting point, 147°C). The mixture Is gently heated until a final temperature of 40°C is reached. The solution obtained is then filtered and the filtrate is concentrated under vacuum. The remaining product quickly crystallizes. After drying to 50°C to constant weight, there are obtained 6.68 g of desired product, in the monohydrated state, as a white crystalline powder, which melts at 140°C and is very soluble in water. 

Adenosine-6 -monopho phoric acid Papaverine base... 

To 3.65 g (0X)1 moi) of monohydrated adenosine-5 -monophosphoric acid, brought into suspension in a mixture of 45 ml of water and 5 mi of ethanol, are added 3.39 g (0.01 mol) of papaverine base (meiting point, The mixture is gently heated until a final tempera-... 

At about the same time, Vogtle and Frensch reported the synthesis of a similar bis-crown based on the papaverine nucleus. This synthesis also was executed in the Williamson fashion using doubly-demethylated papaverine and tetraethylene glycol dichloride. The base, if used, was not specified but it was noted that the high dilution technique was not used. It was presumed that the major product was 10, shown below, but there was also evidence of other components, presumably 11 and 12. 

Experiments in the selection of poppies for morphine production have also been made in Germany by Kiissner. The yields from capsules of two selections, over two years, were morphine 0-257 to 0-544 per cent, and codeine 0-011 to 0-029 per cent. From seven commercial varieties grown in plots of 50 square metres, the yields in grammes per square metre were seeds 141 to 200, capsules 65 to 116, morphine 0-123 to 0-471 and non-phenolic bases (codeine, thebaine, papaverine, narcotine, etc.) 0-043 to 0-131. 

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. ... 

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 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°. ... 

Papaverine was condensed with formaldehyde to methylenepapaverine (XXII), which on successive catalytic and electrolytic hydrogenation yielded two dZ-methyltetrahydropapaverines (XXIII), which on successive demethylation, condensation with formaldehyde and re-methylation yielded a mixture of bases, from which the two optically inactive corydalines (XXIV), jwesocorydaline, m.p. 163-4° (nac.), and dZ-corydaline, m.p. 132-3°, identical with the products obtained by the hydrogenation of dehydrocorydaline were isolated. For the conversion of corycavine to corydaline, see p. 304. 

The convective diffusion approach for weak basic drugs dissolving in acidic media was previously derived by Litt and Serad [9] and, as shown by McNamara and Amidon, could be applied to dissolution of the free base of papaverine. 

In a specific instance where the organic medicinal substance is basic in nature e.g., papaverine in papaverine hydrochloride, it is primarily treated with an aqueous solution of a base and subsequently the liberated organic base is extracted with either chloroform or ether. 

Opium alkaloids such as codeine, thebaine, papaverine, and noscapine exhibit high solubility (0.09-0.9 mg/g) in supercritical fluids including CO N,0, CHF, [37]. However, in spite of their high solubilities, they were not extracted from plant material by pure CO, to the degree expected [29], possibly because these alkaloids exist as their salt forms in plant tissue. In this chapter, the examples that show the difference of the solubilities between alkaloidal free bases and salts are presented. For this comparison, the solubilities of the free bases of hyoscyamine (1), scopolamine (2), pseudoephedrine (6) were measured and compared with those of their hydrochloride salts (Figures 3 and 4). 

Narcotine was isolated by Derosne (592) and Robiquet (593) from opium. It has a mild antitussic and a relaxant effect on smooth muscles (similar to those of papaverine). The relaxant effect is about ten times smaller than that of papaverine (594-597). LaBarre and Plisnier (598, 599) found that narcotine is a better antitussic than codeine. j8-Narcotine proved to be much more effective than a-narcotine (600) the effect of the N-oxides of the two isomers was more marked than that of the base. /3-Narcotine N-oxide was much more effective than dihydrocodeine. Those substances did not increase the analgesic effect of morphine. Contrary to codeine they did not cause obstipation (601). The therapeutic dose of the hydrochloride is 25-50 mg three times daily for adults and 25 mg three times daily per os for children. For the effect of narcotine upon the cough reflex and upon the bronchial muscle, see (602-613). 

The optical resolution of pavine (I) (obtained by synthesis from papaverine) and Trdger s base (II) on a microcrystalline triacetylcellulose (MCTC) column has been demonstrated [20]. 

In 1886 Guido Goldschmiedt reduced papaverine with tin and hydrochloric acid and isolated 1,2,3.4-tetrahydropapaverine and a crystalline base now known as pavine, the structure of which was established by Battersby and Binks. ... 

For the identification of a number of opium alkaloids (morphine, codeine, thebaine, noscapine, papaverine, cryptopine, narceine) and heroin, 3-0-acetylmorphine, 6-0-acetylmorphine and acetyl codeine, Viala et al. 7 made use of three gas chromatographic columns of different polarities (SE-30 3 %, OV-1 2 % and OV-1 2 % plus Igepal 0.2 %).They obtained reliable separation and identification in this way, which was based on the difference in the retention times in the three columns. 

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