Cotarnine

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. 

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. ... 

When the alkaloid is heated with water at 150°, or boiled with dilute acids, it is hydrolysed into hydrocotarnine, and opianic acid. Similar decompositions are induced by acid oxidation or acid reduction, thus (1) dilute nitric acid furnishes opianic acid, CjoHioOj, and cotarnine, C12H15O4N (2) zinc and hydrochloric acid produce meconin, C10H10O4, and hydrocotarnine, C12H15O3N. 

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. 

Cotarnine, This base, first obtained by Wohler, is... 

Cotarnine with methyl iodide furnishes cotarnine hydriodide and cotarnine methine methiodide, CiiHu04NMe3l (IX), which is decomposed by alkalis into trimethylamine and cotarnone (X), CuHioO, rhombic plates, m.p. 78°. The latter yields an oxime, m.p. 130-2°, and is oxidised by potassium permanganate to a mixture of cotarnic acid (VI) and cotamlactone, CuHjqOj (XI), brilliant leaflets, m.p. 154°, which is convertible into the corresponding acid, cotarnonelactone acid, leaflets, m.p. 90-100° dec.). The lactone on further oxjdiltion yields cotarnic aeid. ... 

The formation of cotar none from cotar nine methine methiodide by the action of potash (IX—X) led Roser to represent cotarnine and its salts by the following formulae, the loss of a molecule of water in the formation of cotarnine salts being explained by the production of a partially reduced pyridine ring, which is fully hydrogenated in the reduction of cotarnine to hydrocotarnine. In the reverse process, oxidation of liydrocotarnine to cotarnine, Roser assumed the scission of the ring at the point indicated, with the formation of a hydration product, and oxidation of the latter to cotarnine thus —... 

On this basis the formation of 1-alkylhydrocotarnines by the action of Grignard reagents on cotarnine, investigated by Freund and collaborators, is represented as taking place in the following way —... 

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. ... 

The synthesis of meconin has been referred to already (p. 201). Cotarnine has been synthesised by Salway from myristicin (I) as a starting-point. This was transformed into jS-3-methoxy-4 5-methylenedioxy-phenylpropionic acid (II), the amide of which was converted by Hofmann s reaction into )S-3-methoxy-4 5-methylenedioxyphenylethylamine, and the phenylacetyl derivative (HI) of this condensed, by heating it in xylene solution with phosphoric oxide, giving rise to the two possible dihydroiso-quinoline derivatives. The first of these substances, 8-methoxy-6 7-methylenedipxy-1-benzyl-3 4-dihydroiioquinoline (IV), on conversion into the methochloride and reduction with tin and hydrochloric acid, gave... 

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. ... 

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. 

Cotarnine resembles hydrastinine (p. 167) in its pharmacological effects, but Its action on the uterus is less marked. It does not constrict the arterioles and appears to have a depressant action on the heart. Magidson and Gorbovizki have shown 1 that the Schiff s bases formed by the condensation of aldehydes with 1-aminomethylanhydrocotarnine have a marked local anaesthetic action but are irritant. 

Compound 74 belongs to a special group which forms cyclic aldehyde ammonia 75 (cotarnine) by interaction of the secondary amine group with the aldehyde group. This aldehyde ammonia can be considered to be a pseudo base. 

Treatment of cotarnine and similar compounds with hydrogen cyanide, alkoxides, mercaptides, hydroxylamine, hydrazine, and amines has been reported to give 1-substituted derivatives of 1,2,3-tetrahydroisoquinoline (171, R = CN, OR, SP, NHOH, NHNH, NHR) (262-265). 

From the foregoing considerations it follows that the problems of threefold tautomerism postulated by Gadamer can only be solved by the simultaneous use of various physical and chemical methods. This is well demonstrated by using cotarnine as an example. 

The aqueous solution of cotarnine reacts strongly alkaline. Accord-... 

According to Dobbie et the ultraviolet spectrum of cotarnine in dilute aqueous or alcoholic solution is identical with that of cotarnine chloride [(1), Ch instead of OH"], but in nonpolar solvents it is identical with that of hydrocotarnine (10a), 1-ethoxy-hydrocotarnine (10b), and cotarnine pseudocyanide (10c). This is in agreement with Decker s view of the structure of cotarnine and with the conclusions of Hantzsch and Kalb. Measurement of electrical conductivity in-... 

I) derived from this by dissociation, or in a mobile equilibrium mixture of both these forms. Dobbie et reproduced the spectra of cotarnine solutions containing varying amounts of potassium hydroxide by using cotarnine chloride and hydrocotamine and by dissolving mixtures of the latter two compounds or by placing the separate solutions of these compounds in the apparatus in series. Thus no evidence could be obtained for the occurrence of the amino-aldehyde (3) postulated by Roser. Steiner, Kitasato, and Skinner came to similar conclusions. The band at 285 m/x in alkaline solutions is not due to an aromatic aldehyde. This band also occurs in the spectrum of hydrocotamine (10a) and in the carbinolamine... 

The R band characteristic for aromatic aldehyde groups (aldehyde n TT bands) occurs in the spectrum of A -methylcotarnine (9a) and that of JV-benzoylcotarnine (9c), which are real aldehydes, at 330 m/i in the form of an inflection. Even in alkaline solution the hypothetical amino-aldehyde form of cotarnine can only occur in amounts not detectable by spectroscopic methods. 

Comparative polarographic investigations show a significant difference in the polarographic behavior of cotarnine and that of N-methylcotarnine. The polarographically active form of cotarnine is the cotarninium ion, even in strongly alkaline solution,... 

The determination of the degree of dissociation of cotarnine ° and the good agreement with the values derived from measurements of electrical conductivity with those from the spectrophotometric methods is indirect evidence that no significant part of the undissociated cotarnine is in the amino-aldehyde form. In the conductance calculation, the undissociated part was neglected. If this included a significant amount of amino-aldehyde (i.e., a secondary base), there would be a noticeable discrepancy in the degree of dissociation obtained by the two methods. 

Kinetic investigation of the reaction of cotarnine and a few aromatic aldehydes (iV-methylcotarnine, m-nitrobenzaldehyde) with hydrogen eyanide in anhydrous tetrahydrofuran showed such differences in the kinetic and thermodynamic parameters for cotarnine compared to those for the aldehydes, and also in the effect of catalysts, so that the possibility that cotarnine was reacting in the hypothetical amino-aldehyde form could be completely eliminated. Even if the amino-aldehyde form is present in concentrations under the limit of spectroscopic detection, then it still certainly plays no pfi,rt in the chemical reactions. This is also expected by Kabachnik s conclusions for the reactions of tautomeric systems where the equilibrium is very predominantly on one side. 

Ultraviolet and infrared spectroscopic investigations and also chemical behavior show unambiguously that the compounds which result from the last-rnentioned type of nucleophilic reagent and cotarnine possess the cyclic form. " Examples of these are cotar-nine anil (20a), cotarnine oxime (20b), cotarnine phenylhydra-zone (20c), anhydrocotarnine carbamide (20d), hydrocotarnyl-acetic acid (20e), anhydrocotarnine acetone (20f), and also the compound (21) obtained from two molecules of cotarnine and one molecule of acetone by the elimination of two molecules of water. The cyclic form had ben demonstrated earlier for anhydrocotarnine-nitromethane (20g) and anhydrocotarnine-acetophenone (20h). ... 

However, the cyclic structure of "hydrocotarnine acetic acid (20e) and the two condensation products of cotarnine with acetone (20f, 21) were even unambiguously determined by chemical methods alone. These compounds were not reduced either catalytically nor by sodium amalgam, although acetylhydrocotarnine acetic acid (22b) is easily reduced by both these methods. If even a small pro-... 

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