Ethyl apovincaminate

Solti F, Iskum M and Czako E (1976). Effect of ethyl apovincaminate on the cerebral circulation Studies in patients with obliterative cerebral arterial disease. Arzneimittelforschung, 26, 1945-1947. 

Vincamine is an alkaloid extracted from the plant Vinca minor. Ethyl apovincaminate is a related synthetic ethyl ester of vincaminic acid. These drugs have spasmolytic effects similar to those of reserpine, but also have metabolic effects, including, in high doses, inhibition of phosphodiesterase. Although increased cerebral blood flow has been reported after the intravenous administration of vincamine, there have been no reliable studies of blood flow after oral medication. Improvement in scores on some psychometric tests have been obtained in some patients with cerebrovascular disease, but no clear-cut practical benefit has been demonstrated. 

Vincamine is extracted from the leaves of Vinca minor belonging to Apocynaceae family, known as lesser periwinkle native to central and southern Europe. A closely related semisynthetic derivative of vincamine most widely used as medicine is known as ethyl-apovincaminate or vinpocetine [16-19] (Fig. 20.5f). 

Ethanolamine phosphate, 1270 Ethephon, 1699, 4CM4 Ethical committee, 2412 Ethnic origin, 2399 Ethnobotanic studies, 1295 Ethnopharmacology, 2667 Ethyl acetate, 691, 3371 Ethyl alcohol-flavan-3-ol adduct, 2269 Ethylamine (EA), 2885 Ethyl-apovincaminate, 580 Ethyl-bridged flavan-3-ols, 2264 Ethylene (ET), 1690, 1695-1697, 1699,... 

Apovincaminic acid ethylester was supplied by Richter Gedeon Co., (-)-dihydroapovincaminic acid ethyl ester was prepared according to the procedure described in (11). fSj-a, -diphcnyl-2-py rro 1 idincmethanol was synthesised as described (12). 2-benzylidene-l-benzosuberone was prepared as described in (13). Isophorone was supplied by Merck. Cinchonidine was purchased from Fluka. 

L-Asparagine was used for the synthesis of chiral pipecolates, building blocks for the alkaloid apovincamine. The iodo compound, formed in a multistep transformation from L-asparagine, was cyclized with LDA and ethyl iodide to give the pyridine derivative with a defined configuration (Scheme 36) (85JOC1239). 

In the laboratory of A.G. Schultz during the asymmetric total synthesis of two vincane type alkaloids, (+)-apovincamine and (+)-vincamine, it was necessary to construct a crucial c/s-fused pentacyclic diene intermediate. The synthesis began by the Birch reduction-alkylation of a chiral benzamide to give 6-ethyl-1-methoxy-4-methyl-1,4-cyclohexadiene in a >100 1 diastereomeric purity. This cyclohexadiene was first converted to an enantiopure butyrolactone which after several steps was converted to (+)-apovincamine. 

Column pBondapak C18 (300x3.9 mm ID), mobile phase acetonitrile - 0.01 H ammonium carbonate (6 4), flow rate 1 ml/min, detection UV 280 nm. Peaks 1, (+)-cis-apovincamine 2, (+)-cis--dehydroepivincamine 3, (+)-cis-dehydrovincamine 4, (+)-trans-vincaminic acid ethyl ester 5, (+)-cis-epivincamine 6, (-)-cis-epivincamine 7, (+)-cis-vincamine 8, (-)-cis-vincamine 9, (+)-cis-epivincaminic acid ethyl ester 10, (+)-trans-epivincaminic acid ethyl ester 11, (+)-cis-vincamone 12, (+)-cis-vincanole 13, (+)-cis-vincaminic acid ethyl ester 14, (+)--cis-isovincanole 15, (+)-cis-apovincamine 16, (+)-trans-apovincaminic acid ethyl ester ... 

Stereoselective Birch reduction is possible and a number of examples have been reported, particularly for selective alkylation of the intermediate enolate anion. For example, reduction of the chiral benzamide 69 with potassium in ammonia, followed by alkylation with ethyl iodide gave essentially a single diastereomer of the cyclohexadiene 70, which was used in a synthesis of (-l-)-apovincamine (7.50). 

Tungler, A., Mathe, T., Tamai, T., Fodor, K., Toth, G., Kajtar, J., Kolos-svary, 1., Herenyi, B., Sheldon, R.A. (1995) (-)-Dihydro-apovincaminic acid ethyl ester, preparation and use as a chiral modifier in enantioselective heterogeneous catal5dic hydrogenations. Tetrahedron Asymm. 6, 2395-2402. 

Vincamine, an alkaloid first isolated from Vinca minor has gained wide application in recent years as a specific cerebral vasodilator. Another alkaloid from the same species, (-)-ebur-namonine is marketed with a similar indication. A semisynthetic derivative of vincamine, the (+)-apovincaminic acid ethyl ester is produced under the trade name CAVINTON by the Hungarian Pharmaceutical Company Gedeon Richter. The latter compound has the trade name CALAN in Japan with a substantial share of the market. 

Direct Quantification of Apovincaminic Acid Ethyl Ester (Cavinton) in Human Plasma and Urine by Mass Fragmentography... 

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