SU474983A3 - The method of obtaining vinkamina - Google Patents

Description

The invention relates to a process for the preparation of a valuable physiologically active vincamine alkaloid from 16-epivinkamine by epimerization of the latter.

A known method for the production of vincamine from vegetable raw materials is carried out by its extraction, subsequent chromatographic separation and crystallization. However, both natural and synthetic Vincamine is usually contaminated with a significant amount of Epivinkamine 16, which reduces Vincamine output and its quality.

The purpose of the proposed method is to increase the yield of the target product.

The essence of the described method of obtaining vincamine is that the solution of 16-epivinkamine or a mixture of 16-epivinkamine and vivcamine is treated with an alkali metal alcohol or an inorganic or organic salt of silver, mercury, copper, calcium, manganese, magnesium, cobalt, nickel, chromium, iron , platinum, palladium or ruthenium, or rhodium, platinum, ruthenium, cobalt or chromium oxide or a mixture of these compounds.

Pure 16-epivinkamine and a mixture of 16-epivinkamine and vincamine can be converted into Vincammine with a good yield, if the solution of 16-epivinkamine or a mixture of 16-epivinkamine and Vincamine is treated with one metal or several metals from groups IA, Ш,

IV, VB, VIB, V1IB or UI1 of the Periodic Table of the Elements and / or one or more compounds of these metals. Typically, treatment is carried out by heating said solution in the presence of a metal or its compound, but in some cases, epimerization occurs already upon prolonged incubation of the mixture at room temperature. This method can also be used to epimerize racemic and optically active 16-epivinkamine.

In accordance with the present invention, a mixture of 16-epivinkamine and vincamine (obtained by extraction from Vinca minor or formed during the synthesis of vincamine) or pure 16-epivinkamine is dissolved in a suitable solvent, preferably in xylene (the best is a solution containing 1% of the original ), and one or more of these metals or one or more compounds of these metals are added to the resulting solution. The reaction mixture is heated for an appropriate period of time, for example for

a few hours.

Solvents are selected from a variety of organic solvents capable of dissolving 16-epivinkamine, such as aliphatic, aromatic, and chlorinated hydrocarbons, namely, chloroform, tetrachloride

3

carbon, decalin, benzene, toluene, and xylene, or syrty: metaiol, ethanol, isopropanol, and n-butanol, and; other inert solvents; 1i, for example, acetonitrile, dimethylformamide, etc.

Epimerization is preferably carried out at the point jCHnenHH of the solvent. The listed metals and / or compounds of these metals can be nitrated themselves in their own combination with a carrier.

After several hours of heating, the solvent is distilled off, and the dry residue is recrystallized, pz corresponding to the solvent or their mixtures or clarified, using an adsorbent used in chromatography (Alerk P, alumina).

If the reagent is used as an EO from an alcohol, a Christmas tree, for example, sodium, potassium or lithium ethylate or ethylate, then a solvent and some alcohol, for example, methanol, ethanol, isopropanol or n-butanol is used as a solvent.

The reaction is carried out by heating the reaction mixture, preferably under reflux, for one or several hours.

Example 1. 200 mg of (±) -epivinkamine are dissolved in 20 ml of xylene. 0.75 g of silver carbonate precipitated on 1.5 g of celite is added to the solution, and the reaction mixture is boiled for about 3-4 hours. The conversion is controlled by thin layer chromatography. The catalyst is filtered off and washed with hot xylene. The xylene solutions are combined and extruded under reduced pressure to approximately 20% of the original volume. This last operation is carried out in a nitrogen atmosphere. The remainder is left standing. The next day, the separated crystals are filtered, tromped and dried. Obtain 170 mg (85%) (±) -vinkamine, so pl. 227-228 ° C.

Calculated,%: C 71.15; H 7.39; N 7.90

C21H2bOz 2 (mol. Weight 354.44)

Found,%: C 70.95; P 7.41; N 7.89

Example 2. 200 mg (±:) - epivinkamine is dissolved in 20 ml of tetrahydronaphthalene. 0.5 g of silver acetate is added to this solution and the baking suspension is vigorously stirred at 130 ° C for 5 hours. Silver acetate is removed by filtration, and the solvent is distilled off under reduced pressure. This last operation is performed under a nitrogen atmosphere. The residue is recrystallized from xylene. Obtain 150 mg (75%) (±) of Vincamine, so pl. 226-228 ° C.

Example 3. 20 mg of (±) -epivinkamine is dissolved in 2 ml of xylene. To this solution, 50 mg of a mixture of rhodium / platinum oxide is added. The reaction mixture is boiled for 8 hours with vigorous stirring. The catalyst is filtered off, the solvent is evaporated in vacuo and the residue is dissolved in methanol / methylene chloride (1: 200). This solution is treated in a chromatographic column filled with alumina of the brand Merk R. Substance having a higher value of K ,, is washed out. Receive 5 mg (25%) (±) -vinkamine, so pl. 225-228 ° C. Example 4. Il50 mg (±) -Aiivpnkamina and 50 mg (±) -vinkamine are dissolved in 20 ml of xylene. 0.75 g of silver carbonate precipitated on 1.5 g of celite is added to this solution, and the reaction mixture is heated

under reflux for about 3-4 hours. Conversion is checked by thin layer chromatography. The catalyst is filtered off and tipped off with hot xylene, the xylene solutions are combined and evaporated at a well-defined pressure and approximately to a volume of 20% of its original volume. This last operation is carried out under a nitrogen atmosphere. The residual concentrate is left to stand for a day.

The next day, the separated crystals are filtered, tromped and dried. Get 177 mg (Chg) -vinkamine, t. square 227-228 ° C. Example 5. The process described in Procedure 1 is repeated, but the optically active (+) -16 epivinkamin is used as the starting material. Obtain 170 mg (85%) (- f) Vincamine, so pl. 227-228 ° C; ajg 41 ° (C 1, niridine). Calculated,%: C 71.15; H 7.39; L 7.90

C21H2b1 2Oz (mol. Weight. 354.44)

Found,%: C 70.95; H 7.41; N 7.89

Example 6 200 mg of epivinkamine are dissolved in 20 ml of isopropanol. 200 mg of mercury acetate was added to the solution and the mixture was heated under reflux for 20 minutes. Conversion of the starting material to viikamine is a quantitative reaction (as shown by chromatography). The crystalline product is separated. Yield 198 mg (99.08%) of chromatographically pure vincamine.

Example 7. 200 mg dissolved in 20 ml of acetonitrile. 200 mg of mercury acetate (I) was added to the solution and the mixture was heated under reflux for 1 hour. The yield is 190 mg (95%) chromatographically pure vincamna.

Example 8. The process is carried out analogously to example 7, but instead of acetonitrile, 20 ml of dimethylformamide is used. Yield 100 mg (50%) of pure content.

Example 9. 300 mg of epivinkamine and 60 mg of mercury (I) acetate in 20 ml of xylene are heated

under reflux for 1 hour.

After cooling the crystalline product

separate yut. Yield-240 mg (80%) pure

vinkam1in.

Example 10. The process is carried out analogously to Example 9, but instead of mercury (I) acetate, the following compounds are used as epnmerization reagents: palladium chloride, copper acetate, copper chloride, ruthenium oxide, iron chloride, manganese acetate,

cobalt oxide, nickel sulfate, chromium oxide

or silver nitrate. Yield within 30-90 mg (10-90%) pure Vincamia.

Example 11. The process is carried out analogously to Example 9, but instead of copper (I) acetate, 80 mg of magnesium perchlorate are used as an epimerization reagent. Yield-60 mg (20%) of pure vin.kampa.

Example 12. The process is carried out analogously to example 9, but instead of mercury (I) acetate, 80 mg of "alci chloride" is taken as a whole. The yield is 45 mg (15%) pure Vincamia.

Example 13. 200 mg of epivinkamine are dissolved in 20 ml of methanol. 50 mg of sodium methoxide is added to this solution and the mixture is heated under reflux for 1 hour. After cooling, the crystalline product is separated. Yield -195 mg (97.4%) chromatographically pure wincamp.

Example 14. The process is carried out analogously to example 13, "o instead of epiviicamnum" as the starting product, and the same amount of the epivinkamin / vincamnp mixture is used. Yield -178 mg (98.5%) chromatograph of pure white wine.

Example 15. The process is carried out analogously to example 13, but instead of sodium methoxide, an equivalent amount of potassium methylate is used as the epimerisadium reagent. The yield is 198 mg (99.0%) of pure vincampus.

Example 16. The process is carried out analogously to example 13, but instead of sodium methoxide, epimers are used: an equivalent amount of lithium lnatlat is used. The yield is -191 mg (95.5%) of pure winking.

Example 17. The process is carried out analogously to example 13, but instead of metaiol 1, the same amount of isopropanol is used to dissolve the starting epivinkamia, and sodium isopropylate is used instead of sodium methoxide. Yield -198 mg (99.0%) pure vinca.

Example 18. The process is carried out in analogy to Example 13, but instead of patriathoxide, 60 mg of sodium acetate are used as an epimerizing agent. Exit -190 rg

(95.0%) purity of the vincamine.

Subject ai C o b e e i u

Claims (3)

1. The method of i Vinch.min is distinguished by HUI and so that, in order to increase the yield of the target product, a solution of 16-epivipkamia or a mixture of U-epinvampia and vpnkamina is treated with an alkali metal or inorganic or organic alcohol salt of silver, mercury, copper, calcium, manganese, magnesium, cobalt, nickel, chromium, iron, platinum, palladium or ruthenium, or rhodium, platinum, ruthenium, cobalt oxide or chromium oxide, or a mixture of these compounds. 2. Sioosob pop. 1, of those who have used 16-epivinkamine in racemic or optically active form. 3. A method according to claim 1, characterized in that an aromatic hydrocarbon is used as a solvent, i.e. xylene.