Cinchonin

This is an example of the Doebner synthesis of quinoline-4-carboxylic acids (cinchoninic acids) the reaction consists in the condensation of an aromatic amine with pyruvic acid and an aldehj de. The mechanism is probably similar to that given for the Doebner-Miller sj nthesis of quinaldiiie (Section V,2), involving the intermediate formation of a dihydroquinoline derivative, which is subsequently dehydrogenated by the Schiff s base derived from the aromatic amine and aldehyde. 

Supplement (combined with Volumes XXIV and 1936 3458-3793 methane, 25. Pyrimidine, 89. Pyrazine, 91. Nicotine, 110. Dipyridyl, 199. Phenanthroline, 227. Hydroxy compounds, 348 Cinchonine, 424. Quinine, 511. Indigo white, i... 

The optical activity of malic acid changes with dilution (8). The naturally occurring, levorotatory acid shows a most peculiar behavior in this respect a 34% solution at 20°C is optically inactive. Dilution results in increasing levo rotation, whereas more concentrated solutions show dextro rotation. The effects of dilution are explained by the postulation that an additional form, the epoxide (3), occurs in solution and that the direction of rotation of the normal (open-chain) and epoxide forms is reversed (8). Synthetic (racemic) R,.9-ma1ic acid can be resolved into the two enantiomers by crystallisation of its cinchonine salts. 

Cinchoninic acid—see Quinoline-4-carboxylic acid Cinenic acid... 

Methyl-l-butanol [137-32-6 RS 34713-94-5 S(-)- 1565-80-6] M 88.2, b 130°(/ S), 128.6°(S), [a]p -5.8° (neat), d 0.809, n 1.4082. Refluxed with CaO, distd, refluxed with magnesium and again fractionally distd. A small sample of highly purified material was obtained by fractional crystn after conversion into a suitable ester such as the trinitrophthalate or the 3-nitrophthalate. The latter was converted to the cinchonine salt in acetone and recrystd from CHCI3 by adding pentane. The salt was saponified, extracted with ether, and fractionally distd. [Terry et al. J Chem Eng Data 5 403 7960.]... 

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. 

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... 

Numerous new salts and additive compounds of cinchona alkaloids, and especially of quinine, have been described, of which only a few can be mentioned as examples quinine additive compounds with sulph-anilamide, t quinine salts of (+) and (—)-pantothenic acid, °( > quinine sulphamate and disulphamate, °( organo-mercury compounds of quinine and cinchonine such as quinine-monomercuric chloride. Various salts and combinations of quinine have also been protected by patent, e.g., ascorbates and nicotinates. 

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... 

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. 

Cinchotine (Hydrocinohonine, more correctly dihydrocinchonine, Cinchonifine, >fs-Cinchonine), C19H24ON2. This alkaloid occurs in commercial cinchonine to the extent of about 14 per cent. and may be prepared from this source by the mercuric acetate process, or more conveniently by the hydrogenation of commercial cinchonine previously freed from quinidine. ... 

The two alkaloids which have been most completely investigated are quinine and cinchonine. The scission products of both fall into two classes, viz., derivatives of quinoline and derivatives of a second heterocyclic ring system, formerly referred to as the second half of the... 

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). 

When cinchonine and quinine are oxidised energetically by chromic... 

Quinine gives in place of (1) quininone, C20H22O2N2 in place of (2) quitenine, C19H22O4N2 and instead of (3) quininic acid, C44H9O3N, the other products being the same. Cinchoninic and quininic acids are quinoline-4-carboxylic and 6-methoxyquinoline-4-carboxylic acids respectively. 

These results indicate that quinine and quinidine differ in structure from cinchonine and cinehonidine in containing a methoxyl group in position 6 in a quinoline nucleus. The identity of the other oxidation products, meroquinenine, cincboloiponic and loiponic acids, in all foiu" cases indicates that the second half of the molecule has the same structure in all four alkaloids. Further, this second half must be joined to the quinoline nucleus at position 4 by a group capable of conversion into carboxyl. 

These hydrolyses afford further evidence of the existence in the four alkaloids of a quinoline nucleus and of a second ring system containing a nitrogen atom. The formulae of the two alkaloids may, therefore, be extended thus Cinchonine, CgHjN. CiqHj5(OH)N Quinine,... 

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