DE2203655B2 - Process for the manufacture of vincamine - Google Patents

Description

The invention relates to a method for producing vincamine.

Vincamine is an important medicine and is used in particular as a special cerebral vasodilator and peripheral vasodilators were used (cf. L. Szporny and K. Szasz: Arch. Exp. Path. Pharmac. [1959], pp. 236 to 296).

Vincamine can be isolated from Vinca minor L. (cf. Ungerian patents 146 703 and 147 282) or synthetically (cf. USA. Patent 3,454,583; Journ. Am. Chem. Soc. 86 [1964], p. 2946; Lloydia 27 [1964], p. 435; Gibson and Saxton, Chem. Commun. [1969], p. 1490).

In addition to vincamine, vinca minor also contains 16-epivincamine and this latter connection can be derived from the Drug can also be isolated (cf. Morky, Kempis: Lloydia 27 [1964], p. 428). Bu the known In addition to vincamine, a considerable amount of 16-epivincamine is also formed in syntheses. The formation of 16-epivincamine leads to significant yield losses. Another disadvantage is that vincamine only through cumbersome and difficult chromatographic processes or others costly cleaning process separated from the 16-Epivincamin accompanying it and in one for The degree of purity required for pharmaceutical purposes can be produced.

The invention now relates to a method for 5 < > Production of Vincr.min, which is characterized in that one is racemic or optically active 16-epivincamine or a mixture of racemic or optically active 16-epivincamine and vincamine in the presence of an inert organic solvent with an alkali metal alcoholate. an inorganic one or organic salt of silver, mercury, copper, calcium, manganese, magnesium, cobalt, Nickel, chromium, iron, platinum, palladium or ruthenium or an oxide of rhodium, platinum, Treated ruthenium, cobalt or chromium or their mixtures at a temperature of 40 to 150'C and separating the vincamine obtained in this way from the solution in a manner known per se.

Among the metal compounds mentioned above, the silver or mercury salts and the alkali metal alcoholates have proven to be particularly advantageous.

Silver carbonate or silver acetate is preferably used as the silver compound. from The use of mercury (I) acetate is preferred among the mercury compounds.

A preferred mixture of metal compounds for the process according to the invention is such of platinum oxide and rhodium oxide.

Examples of usable inert solvents! are aliphatic and aromatic hydrocarbons and chlorinated hydrocarbons such as chloroform. Carbon tetrachloride, tetrahydronaphthalene, decahydronaphthalene, benzene, toluene and xylene alcohols such as methanol, ethanol, isopropanol and n-butanol, or other inert solvents such as acetonitrile and dimethylformamide. Of these, aromatic hydrocarbons, in particular xylene or tetrahydro naphthalene and lower aliphatic alcohols are preferred.

According to the invention, it is expedient to proceed in such a way that a mixture of 16-epivincamine and vincamine, which was obtained, for example, by extracting vinca minor or was formed in the course of the synthesis of vincamine, or pure 16-epivincamine in a suitable solvent, preferably in xylene ( a solution containing 1% of the starting substance is preferred), is dissolved, one or more of the above metal compounds are added to the solution and the reaction mixture is heated to the temperatures indicated above for a suitable period of time, for example several hours.

According to a preferred embodiment of the invention, the epimerization is at the boiling point of the Solvent carried out. The metal compounds listed above can be used as such or in conjunction can be used with a carrier.

After heating for a few hours, the solvent can be distilled off and the dry residue be recrystallized from a suitable solvent or a suitable solvent mixture. As another option, the vincamine solution can also be used with the help of one used in chromatography Adsorbent, for example an aluminum oxide, are cleaned.

According to a further preferred embodiment of the invention, an alkali metal alcoholate is used as the epimerizing agent, for example sodium methylate, potassium methylate, lithium methylate, sodium ethylate, Potassium ethylate or lithium ethylal, and as a solvent an alcohol such as methanol, ethanol, isopropanol or n-butanol, is used and the reaction can be carried out by heating the reaction mixture, preferably by heating to the boil under reflux, for example one or several hours, be performed.

The invention is explained in more detail with reference to the following examples.

example 1

200 mg (+) - 16-epivincamine were dissolved in 20 cm ^{3 of} xylene. 0.75 g of silver carbonate deposited on 1.5 g of kieselguhr was added to the solution and the reaction mixture was heated to the boil for about 3 to 4 hours. The conversion could be followed by thin layer chromatography. The catalyst was filtered off and washed with hot xylene and the xylene solutions were combined and reduced under reduced pressure to about 20 % of the original

See volume constricted. This last operation was carried out in a nitrogen atmosphere. The remaining as residue concentrate was left standing t inen day. The next day, the deposited crystals were filtered off, washed and dried. 170 mg (85% of theory) of (±) -vincamine were obtained; Melting point: 227 to 228 "C.

Example 2

200 mg of (±) -16-epivincamine were dissolved in 20 cm ^{3 of} tetrahydronaphthalene, 90.5 g of silver acetate were added to the solution and the resulting suspension was stirred vigorously at 130.degree. C. for 5 hours. The silver acetate was filtered off and the solvent was distilled off under reduced pressure. This latter operation was carried out in a nitrogen atmosphere. The residue was recrystallized from xylene. 150 mg (75% of theory) <±) -vincamine were obtained in this way; Melting point: 226 to 228 ⁰ C.

Example 3

20 mg of (±) -16-epivincamine were dissolved in 2 cm ^{3 of} xylene and 50 mg of a mixture of rhodium oxide and platinum oxide were added to the solution. The reaction mixture was heated to boiling with vigorous stirring for 8 hours. The catalyst was filtered off, the solvent was evaporated off in vacuo and the residue was dissolved in 40 cm ^{3 of} a mixture of methanol and methylene chloride in a ratio of 1: 200. This solution was chromatographed on an aluminum oxide column with 50 g of aluminum oxide. The substance with the higher R / value was eluted. Benzene containing 0.5% methanol was used as the eluent; the first two fractions (10 cm ³ ) were collected, combined and evaporated and the residue was recrystallized from xylene. In this way 5 mg (25% of theory) ( ± ) -vincamine were obtained; Melting point: 225 to 228 ⁰ C.

Example 4

150 mg (; i) -16-Epi vincamin and 50 mg (: t) -Vinctmin were dissolved in 20 cm ^{3 of} xylene. 0.75 g of silver carbonate deposited on 1.5 g of kieselguhr were added to this solution, and the reaction mixture was refluxed for about 3 to 4 hours. The conversion could be followed by thin layer chromatography. The catalyst was filtered off and washed with hot xylene and the xylene solutions were combined and concentrated under reduced pressure to about 20% of the original volume. This latter operation was carried out in a nitrogen atmosphere. The concentrate remaining as residue was left to stand for a day. The next day, the deposited crystals were filtered off, washed and dried. 177 mg (84.7% of theory) of (±) -vincamine were thus obtained; Melting point: 227 to 228 ⁰ C.

Example 5

The procedure given in Example 1 was repeated with the difference that as a starting material optically active (+) -16-epi vincamin was used. So 170 mg (85% of theory) optically active (+) - vincamine obtained; Melting point: 232 to 233 ° C.

Example 6

200 mg of (±) -16-epi vincamin were dissolved in 20 cm ^{3 of} isopropanol, 200 mg of mercury (l) acetate were added to the solution and the mixture was refluxed for 20 minutes. The conversion of the starting material to {±) -Vineamine was quantitative, as it was indicated by the chromatography. The crystalline product was removed. Yield: 198 mg (99.0% of theory) chromatographically pure (χ) -vincamine; Melting point: 227 ^C C.

Example 7

200 mg (±) -16-epivincamine were dissolved in 20 cm ^{3 of} acetonitrile, 200 mg of mercury (I) acetate were added to the solution and the mixture was refluxed for 1 hour. After cooling, the crystalline product was separated Yield: 190 mg (95.0% of theory) chromatographically pure (±) -vincamine; Melting point: 227 to 228 ° C.

Example 8

The procedure of Example 7 was repeated with the difference that 20 cm ^{3 of} dimethylformamide were used in place of the acetonitrile. Yield: 100 mg (50% of theory) of pure (±) -vincamine; Melting point: 227 to 228 ^C C.

Example 9

300 mg (±) -16-epivincamine and 60 mg mercury (I) acetate were refluxed for 1 hour ^{in 20 cm 3 of xylene.} After cooling, the crystalline product was separated off. Yield: 240 mg (80% of theory) of pure (±) -vincamine; Melting point: 227 to 228 ° C.

Example 10

The procedure of Example 9 was repeated with the difference that instead of the mercury (I) acetate the following compounds were used as epimerizing agents: palladium chloride, Copper (II) acetate, copper (I) chloride, ruthenium oxide, iron (III) chloride, manganese (II) acetate, cobalt (II) oxide, Nickel sulfate, chromium (III) oxide or silver nitrate. the Yields were 30 to 90 mg (10 to 30% of the

Theory) pure (±) -vincamine; Melting point: 225 to 227 ^C C.

Example 11

The procedure of Example 9 was repeated with the difference that 80 mg of magnesium perchlorate were used as an epimerizing agent instead of the mercury I) acetate. Yield: 60 mg (20% of theory) of pure (±) -vincamine; Melting point: 226 to 228 ⁰ C.
6o

Example 12

The procedure of Example 9 was repeated with the difference that instead of the mercury (I) acetate, 80 mg calcium chloride was used as an epimerizing agent. Yield: 45 mg (15% of theory) of pure (±) -vincamine; Melting point: 226 to 227 ⁰ C.

Example 13 Example 16

200 mg (±) -16-Epivincamin were in 20 cm ³ The procedure of Example 13 was with the

Dissolved methanol The solution was repeated with 50 mg of sodium difference that instead of sodium methylate added and the mixture was 1 hour 5 methylate the equivalent amount of lithium methylate as

heated to boiling under reflux. After cooling, epimerizing agent was used. Yield:

the crystalline product was separated off. Yield: 191 mg (95.5% of theory) of pure (±) vineamine;

195 mg (97.5% of theory) chromatographically pure melting point: 227 to 228 ° C.

(±) -Vincamine; Melting point: 227 to 228 ° C. . . ,,.,

_lo example 17

Example 14 The procedure of Example 13 was followed with the rv ,, _. . · J η · ι 11 jj difference repeatedly that in place of the methanol The procedure of Example 13 was mt the _{same M isopropanol 2um solvents} n of as off difference repeats that of S ^ _smateria f used <=) - 6 -Epivincamins vervincamins the same amount of a preparation of (±) -16- ^^ _{and an} ^ _{des Natrujmmethy} i _{ats dic aqui} _ Epivincamin and (±) -16-yincamm as starting _{valents M} sodium isopropylate was used as epimerisiematenal Yield: 178 mg (98.5% _Announcement | _in set yield: 198 mg of Theone.) of chromatographically pure (^ J-Vincamm; _{(99% def} ^ ^^ _{pure (=) V} i _nC amine; melting-melting point: 226 to. 228 C. _point . _{M bjs m} -. _Q

2O

Example 15 Example 18

The procedure of Example 13 was followed by The procedure of Example 13 was followed by the

Difference repeats that instead of the sodium difference repeats that instead of the sodium

methylate the equivalent amount of potassium methylate as methylate 60 mg of sodium ethylate as epimerization

Epimerizing agent was used. Yield: 25 medium were used. Yield: 190 mg (95.0%

198 mg (99.0% of theory) of pure (±) -vincamine: of theory) of pure ( ₌ ) -vincamine; Melting point:

Melting point: 226 to 228 ⁰ C. 226 to 228 "C.

Claims (1)

Claim: Process for the production of vincamine, characterized in that one race- mixed or optically active 16-epivincamine or a mixture of racemic or optically active 16-epivincamine and vincamine in the presence an inert organic solvent with an alkali metal alcoholate an inorganic or organic salt of silver, mercury, copper, calcium, manganese, magnesium, cobalt, nickel, chromium, iron, platinum, palladium or ruthenium or an oxide of rhodium, platinum, ruthenium, cobalt or chromium or their mixtures at a temperature of 40 to Treated 150 ⁰ C and the vincamine thus obtained is separated from the solution in a manner known per se.