Narcotines

The actions of the naturally occurring materials now known as alkaloids were probably utilized by the early Egyptians and/or Sumarians (1). However, the beginnings of recorded, reproducible isolation from plants of substances with certain composition first took place in the early nineteenth century. Then in close succession, narcotine [128-62-1] (1, now called noscopine, C22H23NOy) (2) and morphine (2, R = H) (3) (both from the opium poppy, Papaver somnijerum E.) were obtained. 

Constitution. Hydrastine contains two methoxyl groups and a methylenedioxy-group, and behaves as a tertiary base. The first insight into the inner structure of the base was obtained when Freund and Will showed that with dilute nitric acid it undergoes hydrolytic oxidation, yielding opianic acid and a new base hydrastinine, CiiHigOgN. This reaction is analogous with the similar hydrolytic oxidation of narcotine (p. 201) to opianic acid and cotarnine and hydrastinine is allied to cotarnine and can be prepared from it. 

This represents hydrastine as a seeondary amine and a free acid, though the alkaloid reacts with alkyl iodides on the whole as a tertiary amine and forms salts with alkalis rather as a lactone than as a free acid. These and other considerations led Freund and Rosenberg to suggest the alternative formula (IV), based on Roser s formula for narcotine (p. 204). 

The new /-hydrastine is considered to be /-a-hydrastine and natural hydrastine to be /- -hydrastine, which implies (1) that the latter differs from natural narcotine (/-a-narcotine) in stereochemical configuration (2) that since a-gnoscopine, but not -gnoscopine, can be resolved, the synthesis of natural hydrastine will involve the deracemisation of hydra-stine-b, to /-a-hydrastine, which can be epimerised to natural hydrastine (/- -hydrastine) by boiling with methyl-alcoholic potassium hydroxide. 

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. 

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. ... 

Narcotoline, C2iH2iO,N Z-Narcotine, C22H230,N Gnoscopine, C22H230,N Oxynarcotine, C22H230aN Narceine, C22H2,OaN... 

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. ... 

Constitution. Narcotine is a weak, monoacidic, tertiary base. It contains a methylimino-group and three methoxyl groups, and, when heated in closed tubes with dilute hydrochloric acid, furnishes a series of demethylated derivatives dimethylnornarcotine, C19HJ4O4N. OH(OCH3)2, methyl-... 

Hydrocotarnine, C12HJ5O3N. HjO. This basic hydrolytic product of narcotine occurs in opium. It crystallises from light petroleum in colourless plates, m.p. 55-5-56-5°, and yields well-crystallised salts of which the hydrobromide, B. HBr, m.p. 236-7°, is sparingly soluble in water. On oxidation, hydrocotarnine is converted into cotarnine, and on reduction by sodium in alcohol it yields hydrohydrastinine (p. 164) by loss of a mcthoxyl group. 

Utilising the formulae assigned to the two products of hydrolysis of narcotine, viz., hydrocotarnine and opianic acid, Roser constructed a formula for the alkaloid which has been confirmed by Perkin and Robinson s synthesis of narcotine from meconin and cotarnine. ... 

It is considered that in these new forms racemisation or reversible inversion has occurred at the centre of asymmetry in the phthalide group, and that the centre of asymmetry in the isoquinoline nucleus is unaffected. The melting-point, 176°, of each new isomeride is depressed by addition of the corresponding a-narcotine and the specific rotation of l-j3-narcotine, W548 is 101° (CHCI3) or — 59-2° (N. HCl), that of i-a-narcotine, under the same conditions being — 246° and -f 50-4° respectively. 

Among interesting transition products of narcotine may be mentioned narceine (described p. 207) and the tarconines. The latter are derivatives of 6 7-methylenedioxy-8-hydroxyfsoquinoline betaine, and have played some part in the discussion of the constitution of cotarnine. ... 

The alkaloid ean be prepared by blowing steam through narcotine methoehloride previously mixed with the equivalent quantity of sodium hydroxide. The identity of the produet, at first ealled i/i-nareeine, with nareeine was established by Roser, and has been eonfirmed by Addinall and Major. /iomoNareeine, C24H29O8N. SHaO, m.p. 173° (dec.) is similarly made from nareotine ethoehloride. 

Oxynarcotine, CjjHjaOgN. This alkaloid was separated by Mayer, and later by Beckett and Wright, from crude narceine. It crystallises from hot alcohol in small needles. Its close relationship to narcotine is shown by the formation of cotarnine, C12H15O4N (p. 201), and hemipinic acid when it is oxidised by ferric chloride narcotine under these circumstances furnishing cotarnine and opianic acid. Rabe and McMillan regard oxynarcotine and nomarceine as identical. 

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. 

The papaver alkaloid Narcotoline (265) can be converted into the yellow colored Cotarnoline (267) on hydrolysis which adopts a zwitterionic ground state (56MI1, 57MI1) (Scheme 87). The corresponding dihydro derivative was also identified in nature. The UV spectrum of the zwitterionic Tarkonine (268), which forms red crystals from acetone, is shifted bathochromically in comparison to the chloride. Tarkonine is a very weak base (pA b = 9.58), which is well in accord with the formation of an inner salt, and Cotarnoline (267) is a stronger base than Tarkonine (268) (pA b = 9.15). The pK values are larger than 13 (66MI3). The methylated derivative of Narcotoline is Narcotine (266). 

Mohn-saft, OT. poppy juice, opium, -samen, ot. poppyseed, -saure,/. meconic acid, -stoff, m. narcotine, -stroh, n. lit., poppy straw (residue from extraction of poppy heads and stems). 

Narceine (h/ f 1-5) yielded red-brown, morphine (h/ f 5-10), codeine (h/Jf 15-20) and thebaine (h/ j 35-40) brown-violet, papaverine (h/ f 60-65) light brown and narcotine red chromatogram zones on a colorless background. Since the colors fade in the air it is recommended that the chromatogram be covered with a glass plate. 

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