SU545263A3 - The method of obtaining ethyl ester of apovincaminic acid or its iodomethyl - Google Patents

Description

(54) METHOD FOR PRODUCING ETHYL ETHER APOVIN-KAMINIC ACID OR ITS HYDOMETHYLATE

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The invention relates to a process for the preparation of new derivatives of apovincamic acid, the ethyl ester of the latter or its iodomethyl acetate, which possess valuable pharmacological properties.

The proposed method is based on the reaction of esterification of an acid with an alcohol in the presence of an acidic catalyst. Applying the known reaction in apovincaminic or vincamic acid, new derivatives of apovincaminic acid are obtained, possessing high physiological activity.

In accordance with the invention, a process for the preparation of ethyl ester of apovincaminic acid of formula

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OR its iodomethyl acetate, which implies that apovinkamic or vincamic acid is esterified with ethanol in the presence of an acidic catalyst, followed by isolation of the desired product as the free base or its iodomethyl.

As an acidic catalyst, a mineral or aromatic sulfonic acid is preferably used and the process is carried out in a solvent, for example benzene, toluene and (or) in an excess of alcohol or in a mixture of these solvents.

Example 1. 1 g (0.0029 mol) of cincaminic acid and 0.11 g (0.0027 mol) of sodium hydroxide are dissolved in 200 ml of anhydrous ethanol. The solution is heated under reflux and after boiling 10 ml of concentrated ethanesulfonic acid is added to it.

The formation of apovincaminic acid is monitored by thin layer chromatography. After 3 hours of boiling, the solution is evaporated to about 20 ml under reduced pressure.

500 ml of distilled water is added to the concentrate and the mixture is placed in a separatory funnel. The pH of the solution is adjusted to 8 by adding a 5% aqueous solution of sodium hydroxide. The precipitate is separated. The mixture was extracted 5 times with 200 ml of methylene chloride and the organic solution was formed over anhydrous potassium carbonate.

The solution is filtered and evaporated to dryness under pressure. The dry residue is dissolved in 20 ml of ethanol and the solution is left to stand for crystallization at. Obtain 0.86 g (76.7%) of ethyl ester of apovincaminic acid. According to the analysis by thin layer chromatography, a homogeneous product is obtained. Melting point 144 ° C (Bethus).

Calculated,%: C 75.40; H 7.48; N 7.99.

Found,%: C 75.20; H 7.52; N 8.02. The structure of the product is identified by its IR spectrum (ester linkage appears at 5.75 microns).

Example 2. 0.95 g of (-) - vincaminoxy acid is dissolved in a mixture of 40 ml of anhydrous ethanol and 3 ml of concentrated (97%) sulfuric acid. The solution is heated under reflux for 8 hours. During the boiling process, the reaction is monitored by thin layer chromatography. After completion of the reaction, the solution is cooled, evaporated to 7 ml under reduced pressure, and the residue is transferred to a separatory funnel containing 100 ml of distilled water. The pH of the solution was adjusted to 8.5 with an aqueous 10% sodium hydroxide solution. The precipitate is separated. The mixture is extracted 5 times with 30 ml of dichloromethane. The organic phases are combined, dried over anhydrous potassium carbonate, the drying agent is filtered off and the filtrate is evaporated to dryness under reduced pressure. The oily residue is dissolved in 15 ml of anhydrous ethanol. The {-) - apovincaminic acid ethyl ester begins to crystallize immediately. The mixture is allowed to crystallize at O-2 ° C for 8 to 10 hours. The resulting crystalline substance is filtered off. Obtain 0.71 g (75%) of ethyl ester of (-) - apovincaminic acid. Melting point 153 ° C (Bethus); a 112.5 ° (, in pyridine).

Example 3. Methyliodide ethyl ester of apovincaminic acid.

1 g (0.0028 mol) of apovincaminic acid ethyl ester is dissolved in 25 ml of anhydrous acetone, and 0.44 g (0.003 mol) of methyl iodide is added to the resulting solution. The mixture is left to stand at room temperature for 24 hours. In this case, the reaction is monitored by thin layer chromatography. Even when standing at room temperature, needle-shaped crystals begin to precipitate out of the reaction mixture. The mixture is evaporated under reduced pressure to approximately 10 ml and the resulting concentrate is allowed to crystallize at a temperature from 0 to approximately 8-10 hours. The crystals are filtered and washed with a small amount of cold acetone. Obtain 1.29 g (92%) of methyl iodide of ethyl ester of apovincaminic acid. Melting point 204 ° C.

N 5.69;

%; C 56.12; P 5.93;

Calculated J 25.77. %: C 56.02; H 5.88; K 5.70;

Found J 25.79.

Formula

and 3 o r ete n and

Claims (2)

1. A method for preparing the apovincaminic acid ethyl ester of the formula or its iodomethyl, characterized in that apovinkamic or vincamic acid is subjected to esterification with ethanol in the presence of an acidic catalyst, followed by isolation of the desired product as a free base or its iodomethyl. 2. A method according to claim 1, characterized in that mineral or aromatic acid is used as an acid catalyst, and the process is carried out in the presence of a solvent, for example benzene, toluene and (or) in an excess of alcohol or in a mixture of these solvents. Sources of information taken into account in the examination: 1. Weigand-Hilgstag. Experimental methods in organic chemistry. M., “Himi, 1968, p. 343.