D. Cinchonidine
Synonyms Cinchovatine; α-Quinidine;
Biological Sources It is obtained in most varieties of the cinchona bark as described under quinine (section ‘A’). It is, however, observed to be present especially in the bark of Cinchona pubescens Vahl. (C. succirubra Pav.) and Cinchona pitayensis Wedd., (Rubiaceae).
Chemical Structure
(8a, 9R)-Cinchonan-9-ol; (C19H22N2O).
Isolation Cinchonidine can be conveniently isolated from the bark of various species of cinchona as described explicitely under quinine (section ‘A’). However, it may also be isolated by the method suggested by Leers.*
Characteristic Features
1. It is obtained as orthorhombic prisms or plates from ethanol having mp 210°C.
2. It has specific optical rotation [α]20D - 109.2° (in ethanol).
3. Solubility Profile: It is found to be freely soluble in chloroform and ethanol; moderately soluble in ether; and practically insoluble in water.
4. It has two dissociation constants: pK1 5.80 and pK2 10.03.
Identification Tests Cinchonidine may be identified by preparing its specific derivatives that possess characteristic features, such as:
1. Cinchonidine Dihydrochloride (C19H22H2O.2HCl): It is obtained as white or slightly yellow crystals or powder. It is freely soluble in ethanol and water.
2. Cinchonidine Hydrochloride Dihydrate (C19H22N2O.HCl.2H2O): It is obtained as a crystalline powder. It losses all of its water of crystallization at 120°C. It has [α]20D - 117.5° (in water). It is soluble in 25 parts of cold water, more soluble in boiling water; soluble in chloroform and ethanol; and slightly soluble in ether. The aqueous solution is almost neutral in nature.
3. Cinchonidine Sulphate Trihydrate [(C19H22N2O)2.H2SO4.3H2O]: It is obtained as silky, acicular crystals which effloresce on being exposed to air and get darkened in light. The mp of anhydrous salt is nearly 240°C with decomposition. 1g dissolves in 70 ml water, 20 ml hot water, 90 ml ethanol, 40 ml hot ethanol, 620 ml chloroform; practically insoluble in ether. The aqueous solution is more or less neutral.
4. Epicinchonidine [Synonyms: (8α, 9S)-Cinchonan-9-ol)]: It has mp 104°C; and [α]20D + 63°(C = 0.804 in ethanol).
Uses It is mostly used as an antimalarial agent.
Totaquine Totaquine is nothing but a mixture of the total alkaloids of the well-known cinchona bark. It is invariably exploited as a ‘cheap substitute’ for quinine in an unethecal practice in trade. It is found to contain not less than 7% and not more than 12% of quinine units anhydrous form; and not more than 80% of the total anhydrous crystallizable cinchona alkaloids.
The following table summarizes the characteristic features and specific tests for the four major cinchona alkaloids, namely: Quinine, Quinidine, Cinchonine and Cinchonidine.
Differences Among Four Major Cinchona Alkaloids
Biosynthesis of Cinchonine, Quinidine and Cinchonidine The various sequential steps involved in the biosynthesis of Cinchonine, Quinidine and Cinchonidine are stated as under:
1. Strictosidine is obtained by the interaction of L-tryptophan and secologanin as already shown in the Biosynthesis of Quinine.
2. Strietosidine undergoes a molecular rearrangement to form an aldehyde which upon hydrolysis and decarboxylation yields coryantheal.
3. Coryantheal generates cinchoninone by virtue of two transformations; first: an intermediate formed due to the cleavage of C-N bond (via iminium) then formation of a new C-N bond (again via iminium); and secondly: cleavage of the indole C-N bond. The resulting product loses a molecule of water to yield cinchonionone.
4. Cinchoninone undergoes epimerization at C-8 via enol to form the stereoisomer, which upon interaction with NADPH gives rise to chnchonine and quindine respectively.
5. Cinchonione with direct interaction with NADPH gives rise to cinchonidine and quinine respectively.
The outline of the biosynthesis elaborated above from (1) through (5) may be summarized as depicted below:
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** Leers, Ann., 82, 147 (1952)
