Narceine

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... 

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. ... 

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. ... 

Narceine, C23H2,OjN. aHjO. This alkaloid was obtained by Pelhtier in 1832, and was subsequently eharaeterised by Couerbe and by Anderson, The latter assigned to it the formula, C23H29O9N, whieh was aeeepted until Freund observed that the base erystallised with 3 mols of water, of whieh only two are lost at 100°. Anderson s base therefore was C23H2,OgN. HjO. 

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. 

Narceine has been used as a sedative and hypnotic but is believed to... 

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. 

Fig. 1 Reflectance scan of a chromatogram track with 1 pg of each substance per chromatogram zone (excqttion papaverine 5 pg). Chromatogram (A) before and (B) after reagent treatment (registration of B with double sensitivity) 1 = narceine, 2 = morphine, 3 = codeine, 4 = thebaine, 5 = papaverine, 6 = narcotine.

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). 

In situ quantitation The absorption photometric evaluation in reflectance was carried out at the wavelength k = 540 nm (Fig. 3). The detection limits in substance per chromatogram zone were 20 ng for thebaine and papaverine, 200 ng for codeine, 300 ng for morphine and 500 ng for narceine. 

Fig 3 Reflectance scan of a chromatogram track with 1 ug each per chromatogram zone of narceine (1), morphine (2), codeine (3), thebaine (4), papaverine (5) and narcotine (6). 

From a historical standpoint, the first secoisoquinoline alkaloid was narceine, isolated from opium by Pelletier as early as 1832 (/). Up to 1986, over 70 secoisoquinoline alkaloids had been discovered. Most of them were found... 

The first secoisoquinoline alkaloid discovered was the secophthalideisoquinoline, narceine (106), isolated from opium by J. Pelletier in 1832 (7). Up til now 19 natural bases belonging to this group have been isolated, and 6 others have been synthesized. Secophthalideisoquinoline alkaloids have been described in several reviews papers by Shamma et al. 2,4,5), by Santavy (7), and most recently, in 1985, by MacLean (5). 

Narcotine (95) Threo ( )-Narceine enol E Nomarceine — ( )-Narceine ... 

In this chapter the proposed (5) division of secophthalideisoquinolines into the four subgroups and the nomenclature have been preserved. Since the publication of the most recent review (5), information about the synthesis of the missing ( )-narceine enol lactone (102) (87), the isolation of ( )-fumaramine (112) from Fumaria vailanti (88), and the discovery of a new seco alkaloid, coryrutine (118), from Corydalis rutifolia (89) has appeared. In the former plant fumaramine (111) (55) and in the latter N-methylhydrasteine... 

The secophthalideisoquinoline enol lactones may exist as Z or geometric isomers. Three pairs of such isomers are known aobamidine (96) (Z) and adlumidiceine enol lactone (97) ( ), /V-methylhydrastine (98) (Z) and (E)-N-methylhydrastine (99) ( ), (Z)-narceine enol lactone (101) and ( )-narceine enol lactone (102). Three of these enol lactones (99, 101, 102) are synthetic products. Lists of these alkaloids, the plant species in which they occur, as well as their spectral data and other references are provided in the review papers (4,5,8). Narceine enol lactones (101 and 102) are described in Refs. 87 and 90. 

The enol lactones were synthesized by Hofmann degradation of metho salts of classic phthalideisoquinoline alkaloids. The biogenetically relevant transformations were highly stereospecific. In this way aobamidine (96) was obtained from the methiodide of (erythro) bicuculline (88) (2), and ad-lumidiceine enol lactone (97) was produced from both (threo) isomeric adlumidiceine (89) and capnoidine (90) methiodides (14,15,91-93). (Z)- (98) and ( )-N-methylhydrastine (99) were obtained from / - (91, erythro) and a-N-methylhydrastinium (92, threo) iodides (5,87,91,96-98), respectively, as were (Z)- (101) and (JE)-narceine enol lactones (102) synthesized from a- (94, erythro) and /J-narcotine (95, threo) quaternary N-metho salts (87,90), respectively. In a similar process /J-hydrastine (91) JV-oxide heated in chloroform yielded enol lactone 124 of Z configuration (99) however, a-narcotine (94) N-oxide was transformed to benzoxazocine 125 (99). ... 

Enol lactones can also be obtained from keto acids by enolization-dehydration. Adlumidiceine (103) as well as N-methylhydrasteine (104) when heated in toluene with acetic anhydride or p-toluenosulfonic acid were transformed to enol lactones 97 (97) and 98 (5,102), respectively. Narceine (106) under the influence of PC13 yielded 101 (87,100). 

Both Z and E isomeric enol lactones undergo photoisomerization to yield mixtures of isomers (5,14,87) in which the thermodynamically more stable one prevails. It is the Z form in hydrastine series (5) and the E isomer in the more hindered narcotine series (87). Relative stabilities of isomeric enol lactones (98 versus 99 and 101 versus 102) were determined by comparing their rates of methanolysis. Keto esters of type 126 were formed (87). It turned out that both ( )-N-methylhydrastine enol lactone (99) and (Z)-narceine enol lactone (101) solvolyzed faster than their geometric partners. 

A series of N-substituted narceine amides (Section III,D,1) was prepared from 101 under the action of primary amines (100). Acid-catalyzed dehydration transformed these amides to corresponding imides (ene lactams) of the ( )-narceine imide (117) type (100). Similar transformations were performed in the hydrastine series (101). JV-Methylhydrastine (98) when treated with dilute ammonium hydroxide gave hydroxy lactam 127, which was dehydrated to (Z)-fumaridine (113) (5). Sodium borohydride was able to reduce the stilbene double bond in 98 to produce saturated lactone 132 (5). 

The hydroxy lactams are postulated to be intermediates in transformations of enol lactones to ene lactams. This hypothesis was proved by synthesis. For example, treatment of N-methylhydrastine (98) with dilute ammonium hydroxide resulted in hydroxy lactam 148, which by the action of hydrochloric acid underwent dehydration to produce fumaridine (113) (5). Similarily, fumschleicherine (120) in reaction with trifluoroacetic acid gave fumaramine (111) 121). Narceine amide (149) was prepared from (Z)-narceine enol lactone (101) in likewise fashion 100,122) and dehydrated to narceine imide (116). A large number of N-alkylated narceine amides was synthesized from (Z)-narceine enol lactone (101) and primary amines by Czech investigators for... 

Ene lactams can be obtained directly from quaternary phthalideisoquino-linium salts by treating them with concentrated ammonium hydroxide. In this way fumaramine (111) was synthesized from bicuculline (88) methiodide (121,124), fumaridine (113) from methiodides of both diastereomeric / - (91) and a-hydrastines (92) (5,124-126), and narceine imide (116) from narcotine (94) methiodide (122,127,128). In the case of the hydrastines (91 and 92) the Hofmann degradation of their methiodides in ammonia was not stereospecific but yielded the thermodynamically more stable Z isomer (113) (5). It seems, however, that from narcotine (94) a mixture of the Z and E forms was produced rather than a single isomer (123,127). 

The less stable isomers were obtained from the more stable ones by photoisomerization. (Z)-Fumaridine (113) when exposed to sunlight was isomerized to a separable 3 2 mixture of geometric isomers (5). The Z form of narceine imide (116) is unstable and in daylight equilibrates easily to a mixture of Z and E forms (123). 

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