Cinchonidin

With the introduction of improved analytical techniques, starting around 1817, the evaluation of dmgs began and, over a span of about 10 years, strychnine (13, R = H), emetine (14), bmcine (13, R = OCH3), piperine (15), caffeine (16), quinine (17, R = OCH3), colchicine (4), cinchonidine (17,... 

The cinchona alkaloids of practical importance are quinine, quinidine, cinchonine and cinchonidine, but, in addition, over twenty others have been isolated from cinchona and cuprea species. Their names and formulae are as follows ... 

Cinchonine, cinchonicine, cinchonidine. Cinchotine, cinchamidine, cinchonamine. Cupreine. 

Analyses of Cinchona Barks. For galenical preparations, pharmacopoeia recognition is usually restricted to barks of cultivated cinchona species known to yield total alkaloids satisfactory in composition thus, the British Pharmacopoeia 1932 prescribes the varieties to be used, and specifies not less than 6 per cent, of total alkaloids, of which at least half must be quinine and cinchonidine, determined by the process prescribed. Numerous other processes have been published and references to the more important of these are given under the following headings —identifica-... 

For the separate determination of the four principal components in the total alkaloids, the method in general use is based on the isolation of quinine and cinchonidine as d-tartrates, of cinchonine as the base in virtue of its sparing solubility in ether, and of quinidine as the hydriodide. Types of this method have been described by Chick, and special modifications designed for use in the analysis of totaquina are given in the British Pharmacopoeia 1932 and in a special report by the Malaria Commission of the League of Nations. Goodson and Henry have critically examined this process and shown that, with care, it gives satisfactory... 

Cmchonine, C19H22ON2. This alkaloid is usually present in cinchona and cuprea barks. One of the best sources is Cinchona micrantha bark. It occurs in the crude quinine sulphate mother liquors. The mixed alkaloids recovered from these may be extracted with ether to remove quinidine and cinchonidine and the insoluble residue boiled with successive small quantities of alcohol, from which cinchonine crystallises on cooling. The crude alkaloid is neutralised with dilute sulphuric acid and the sulphate recrystallised from boiling water. Cinchonine so prepared contains quinidine, from which it may be freed by crystallisation from boiling alcohol until it ceases to exhibit fluorescence in dilute sulphuric acid. It will then still contain 10 to 15 per cent, of dihydrocinchonine, which may be removed by reprecipitation as the cuprichloride, B. 2HC1. CuClj, or by the simpler mercuric acetate process of Thron and Dirscherl. ... 

Detection. Cinchonine is sparingly soluble in all ordinary solvents, is not fluorescent in dilute sulphuric acid, is dextrorotatory, forms a soluble tartrate and hydriodide and does not give the thalleioquin reaction. Hesse s homocinchonine has been shown to be impure cinchonine. Cinchonidine, C49H22ON2. This alkaloid occurs in most varieties of cinchona bark, but especially in C. succiruhra. 

The ethereal solution of crude quinidine and cinchonidine, obtained as described under cinchonine, is shaken with dilute hydrochloric acid, the excess acid neutralised with ammonia and sodium potassium tartrate added. The base is recovered from the precipitated tartrate by dissolving the latter in dilute acid and pouring the filtered solution in a thin stream, slowly and with constant stirring, into excess of ammonia solution. The crude alkaloid is converted into the neutral sulphate, and this recrystallised... 

Cinchonidine crystallises in large trimetric prisms, m.p. 204-5°, and when purified as described has [a] /° — 178° (c = Mj40, N/10 HjSO ). The following figures also on record probably relate to cinchonidine containing dihydrocinchonidine — 107-9° (alcohol-chloroform 1 2,... 

Detection. Cinchonidine is distinguished from quinine and quinidine by not being fluorescent in dilute sulphuric acid, and by not giving the thalleioquin reaction and from cinchonine in being laevorotatory and more soluble in ether, and in the sparing solubility of its tartrate. 

Hesse s homocinchonidine was probably, according to Skraup, merely an unusually pure cinchonidine. 

Hydrodnchonidinc Dihydrocinchonidine, Cinchamidine), Cj This alkaloid was isolated by Forst and Bohringer from commercial cinchonidine, from which it may be obtained by the mereurie acetate process, but is more conveniently prepared by the hydrogenation of pure cinehonidine. It crystallises in six-sided leaflets, m.p. 232°,... 

The isomeric substance, cinchotenidine, similarly obtained from cinchonidine, crystallises in needles, m.p. 256°, [ajo — 201-4° or — 207° (iV-H2S04), and, like cinchotenine, gives by further oxidation cinchoninic and cincholoiponic acids. 

Cinchoninone, CigHaaONj, produced by the oxidation of either cinchonine or cinchonidine by chromic acid in presence of sulphuric acid forms pale yellow prisms, m.p. 126-7°, [a]j) -(-71° to -(-76°, is sparingly soluble in light petroleum, easily in ether or chloroform and insoluble in water. The hydrochloride forms minute colourless needles, m.p. 245-7°, [a]r) -(-175-9°. By further oxidation with chromic acid, cinchoninone yields cinchoninic acid and meroquinenine (meroquinene). 

The directions of rotation at C and C have been arrived at from the following considerations. The deoxy-bases (II p. 443 Q = quinoline residue) obtained from cinchonine and cinchonidine are structurally identical, i but optically different, and since they must be optically identical at C and C, and C is no longer asymmetric, the difference between them (see table, p. 446) must be due to difference in direction of rotation at C , which must therefore be dextrorotatory in cinchonine and laevorotatory in cinchonidine, and this must also be true of quinidine and quinine respectively and of the corresponding dihydro-bases. The keto-bases, cinchoninone and quininone, might be expected to exist each in two pairs, since carbon atom 8 is, according to the formula (p. 442), asymmetric, but it is better represented by the tautomeric grouping —... 

A similar mixture results from the reduction of quininone, and an analogous mixture of cinchonine and cinchonidine, each accompanied by its epimeride, results from alkali treatment of cinchonine or cinchonidine or from the reduction of cinchoninone. The characters of the whole series... 

One result of all these reactions is the change of the vinyl group to an ethylidene group (CHj CH. -A-CH3. CH ) with the formation of the opo-bases, e.g., opocinchonidine and 3-cinchonidine, which are the two geometrical isomerides required by the formula (E Q = quinolyl residue). 

In addition to this change, the elements of a molecule of water may be added to the vinyl group with the formation of hydroxydihydro-bases represented by formula (B). This change also appears to occur with all the vinyl-containing alkaloids though neither of the pair of stereoiso-merides so produced has been described for cinchonidine. 

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