DE3214942A1 - Process for the preparation of vincamic acid derivatives by oxidative rearrangement of tabersonin or dihydrotabersonin - Google Patents

Description

32U942

Judge Gedeon Vegyeszeti Gyar, Rt., Budapest, Hungary

PROCESS FOR THE PREPARATION OF VINGAMINE ACID DERIVATIVES BY OXYDATIVE REPLACEMENT OF TABERSONINE OR DI-HYDROTABERSONINE

The invention relates to a new process for the preparation of eburnan derivatives, namely of vincaminic acid and 17,13-didehydrovincaminic acid esters oxidative transfer of tabersonine or dihydrotabersonine (Vincadifformin). -o- ^ the invention ] ^ β- $ a new process for the preparation of vincamine acid derivatives of the general formula I.

R is an alkyl group with 1 to 4 carbons

2 3

R and R each represent a hydrogen atom or both together another bond between the two

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neighboring carbon atoms

, soiv / e der
mean, o corresponding 14-epivincaminic acid derivatives / f 'by jd-tij oxidative rearrangement of the corresponding tabersonine derivativesja' of general formula II

(II)

12 3
wherein R, R and R have the meanings given in the general formula ^ I, which is characterized in that acid addition salts of compounds

12th

fertilize the general formula II, in which R, R and R have the meanings given above, in aqueous organic solvents · ^ in the presence of acids ^ with at least equimolecular amounts of from two bases-e ^ en organic carboxylic acids or inorganic acids formed diacyl peroxides or with salts thereof treated.

It is known that tabersonine derivatives undergo a rearrangement under the action of certain oxidizing agents and are converted into eburnane derivatives. E. Wenkert and B. vVickberg / _ ~~ 3. At the. Chem. Soc. 87 , 1580-1589 (1965) J , when investigating the biosynthesis of indole alkaloids of the eburnamonine type, assumed this synthetic route starting from tabersonine as early as 3 years 1964, which then started from 0.P. Kutney and coworkers / D. At the. Chem. Soc. 93, 255-257 (197l _} / has also been proven experimentally. For the industrial implementation of this already known biosynthetic

Numerous attempts have been made since 1971 and several practically applicable

bare method for the preparation of vincamine derivatives described in this way. So was after the Belgian Patent specification 761 628 the dihydrotabersonine with the equimolecular amount of a peroxide to N-oxy / dihydrotabersonine ^ and this then by a 3 to 5 day treatment with another equimolecular Amount of peroxide to form 1 ^ -Dehydro-ie-carbomethoxy-16-hydroxy-N-oxy-aspidospermindine oxidized; this latter connection was then made with a Redukfioui ■ ) agents, appropriately treated with triphenylphosphine whereby a mixture of vincamine, 14-epivincamine and apovincamine was obtained as a reaction product. The peroxy compounds which can be used as oxidizing agents can according to the cited patent organic Persacids, such as peracetic acid, performic acid, perbenzoic acid or substituted derivatives of the latter, e.g. be m-chloro- or p-nitro-perbenzoic acid.

According to the Belgian patent specification 763 730 (additional patent on Belgian patent 761 628), alkyl peroxides, lead tetraacetate or oxygen can also be used in the above process in the presence of p © * 1 a / i catalyst (e.g. platinum oxide) can be used as an oxidizing agent.

According to the Belgian patent 765 795, the same Process (+) - dihydrotabersonine used as starting material, with reaction times lasting 1 to 5 days the (3/5, 16y *>) epimers of vincamine, 14-epivincamine and apovincamine can be obtained as products.

A further development of this process was described in Belgian patent 837 049, according to which the dihydrotabersonine in the form of a with an acid addition salt formed from an organic carboxylic acid with an organic peracid (with p-nitro / perbenzoic acid) is oxidized; in this case will

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during the oxidation no N-oxide is formed, but the molecular rearrangement into the corresponding vincamine compounds takes place with 1.1 mol peracid, with the corresponding carboxylic acid salt of 1, Z-dehydro-lo-hydroxy-lo-methoxycarbonyl-aspidospermindine as an intermediate is formed.

According to the Belgian patent 848 475, a Acid addition salt, e.g. the hydrochloride or the Tabersonine perchlorate used as a starting material; this is converted into the corresponding salt of dihydrotabersonine by hydrogenation} from the latter is then re · * by treatment with an equimolecular amount of an organic persaeu. -m-i-t response times a mixture of vincamine and 14-epivincamine was obtained immediately as a product from 1 to 3 days.

According to Belgian patent specification 856 723, the tabersonine or dihydrotabersonine is reacted with a carbanion-forming agent, for example with sodium hydride or sodium amide, then the oxidative rearrangement is carried out by treatment with oxygen and finally the intermediate product obtained is reduced. The reaction is carried out at room temperature; After acidification of the reaction mixture, vincamine and 14-epivincamine, or (if tabersonine was used as the starting material) the corresponding 17,18-dehydro compounds are obtained as products in yields of about 35%.

According to Belgian patent 870 978, acid addition salts are used of dihydrotabersonine in the presence of vanadium, chromium, molybdenum or tungsten salts with hydrogen peroxide oxidized; so the rearrangement takes place at room temperature in 4 days and it is mainly

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mainly vincamine. *, in addition to much smaller amounts obtained from 14-epivincamine.

Of the known processes described above, the older ones can be converted via the N-oxide are no longer considered economical methods because of the relatively low yields. In addition, the extremely long, 1 to 5 days f response times are common Disadvantage of most of the known methods. The aja- * "as an oxidizing agent in most known processes Recommended organic peracids can be used advantageously in the laboratory, their sensitivity to Heavy metal ions but brings in their large-scale Application with technological problems and complicates the handling of the larger Mafi-3-eft reactions carried out.

It has now been found, in a surprising way, that the aforementioned difficulties are largely eliminated and the oxidative rearrangement reaction takes place with a short reaction time (a few hours) and a high degree of conversion (SO to 90%) if the tabersonine or dihydrotabersonine (vincadifformine) takes the form of a appropriately selected acid addition saltsv. with a diacyl peroxide formed from two-base organic carboxylic acids, for example with bis-suX / rinyl peroxide or su ^ einyl-glutaryl peroxide, or with a peroxide formed from an inorganic acid or with a
delt.

a salt thereof * ifa aqueous-organic media treated

The acid addition salt to be used as the starting material of tabersonine or dihydrotabersonine can be a salt formed with an inorganic acid, e.g. Hydrochloride or sulfate, or one with an organic

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Acid formed salt, e.g. the tartrate; particularly the perchlorates can advantageously be used for this purpose. The reaction medium is appropriate a water-miscible organic solvent, e.g. a lower alkanol such as methanol or ethanol, or acetone is used in admixture with water; -ee- can but also in a two-phase system of one with Water immiscible organic solvents and water work. To ensure the desired acidity of the reaction mixture can be any mineral acid, e.g. hydrochloric acid, or optionally, especially if a salt formed with an organic acid is used as the starting material, an organic one Acid, e.g. tartaric acid.-G-tFr solution of the starting material acid addition salt used are added.

The use of organic or inorganic diacyl peroxides or salts thereof as oxidizing agents in the process according to the invention is not only advantageous because these diacyl peroxides show no sensitivity to heavy metal impurities, but above all because the oxidation with these oxidizing agents takes a much shorter time ( passes at 40 ⁰ C in 3 to 6 hours, but even at room temperature within 12 to 48 hours), which in addition to it 'following technological advantages also results in a greater selectivity of the oxidation and brings higher yields with it. The shorter reaction times that can be achieved by the process according to the invention are partly also related to a further advantage of using diacyl peroxides as oxidizing agents: during the oxidative rearrangement reaction carried out in a known manner with organic peracids at higher temperatures, for example at 40 ° C. Yield-reducing and the end product contaminating secondary reactions already strongly in the foreground

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reason occur and thus make the use of such elevated reaction temperatures questionable, when diacyl peroxides are used as oxidizing agents, side reactions only occur to a practically insignificant extent, so that the use of higher, shorter reaction times enabling temperatures (around 40 ⁰ C) also from this point of view there are no obstacles in the way.

The method of the present invention is carried out by the following Examples illustrated in more detail; the invention is in no way limited to the content of this specific examples.

Example 1:

43.85 g (0.1 mol) of dihydrotabersonine perchlorate were dissolved in 3000 ml of methanol and then with 900 ml of water, 100 ml of 2 η hydrochloric acid solution and 25.76 g (0.11 mol) of bis-succinyl peroxide ( calculated on the active peroxide content determined by titration). The mixture was heated to 40 ⁰ C and stirred at this temperature for 6 hours. (After completing the

Y *

The reaction was taken in a ^ from the reaction mixture - the degree of conversion determined by chromatography; the conversion was 82.2%, of which 71.5 % was accounted for by vincamine and 10.7% by 14-epivincamine. After the first crystal generation of the product had been separated off, the residue was subjected to an epimeris ^ -fe-ie-tjJ, whereby this epivincamine was also converted into vincamine.)

The reaction mixture obtained in the above manner was concentrated to 1 liter with concentrated ammonium hydroxide solution Made alkaline to pH = 8.5 and then

•. ·· .: - .. · ■ 32U942

Shaken once with 500 ml of benzene and six times with 250 ml of benzene each time. The benzene phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated to 150 ml and left to stand in the refrigerator overnight. The obtained crystals were filtered off, washed with cold benzene and dried at room temperature (21.2 g). The mother liquor obtained during crystallization was evaporated to dryness, the residue was treated with 50 ml of methanol and 1 g of potassium tert-butoxide, refluxed for 3 hours and left to stand in the refrigerator overnight. The precipitated crystals were filtered off, washed with cold methanol and dried at room temperature (6.8 g). A total of 28.0 g of vincamine (79.1 % of theory ) were obtained in this way.

Example 2:

4.39 g (0.01 mol) of hydrotabersonine perchlorate were dissolved in 300 ml of methanol and then with 90 ml of water, 10 ml of 2 η hydrochloric acid solution and 2.58 g (0.011 mol) of bis- / 'suj ^ zinyl peroxide (calculated on the active peroxide content determined by titration). The mixture was stirred at 20 ⁰ C for 16 hours ge / ^ carried AAnn under reduced pressure to 100 ml concentrated. The pH of the solution was ^{adjusted to 8.5 e} with concentrated ammonium hydroxide solution, then extracted once with 50 ml of benzene and six times with 25 ml of benzene each time. The combined benzene phases were dried with anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was chromatographed using Brockmann's aluminum oxide (activity II) and eluted with benzene. 0.42 g of 14-epivincamine (11.9% of theory) and 2.83 g of vincamine (79.9 % of theory ) were obtained from the corresponding eluate fractions; the total yield is

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So carries 91.8 %.
Example 3:

43.85 g (0.1 mol) of dihydrotabersonine perchlorate were dissolved in 3000 ml of methanol and then with 900 ml of water, 100 ml of 2 η hydrochloric acid solution and 25.76 g (0.11 mol) of bis / sujinyl peroxide (calculated on the active peroxide content determined by titration) added. The mixture was ^{stirred at 40 °} C. for 6 hours. The degree of conversion determined by high pressure liquid chromatography in a sample taken from the reaction mixture was 81.8%, 72.0% of which was accounted for by vincamine and 9.8% by 14-epivincamine.

The reaction mixture was then concentrated to 1 liter, 15 ml of 60% perchloric acid were added and the vincamine perchlorate which had separated out was filtered off. The crude product obtained in this way was mixed with 300 ml of water and 300 ml of dichloromethane and the pH of the mixture was adjusted to 9 with concentrated ammonium hydroxide solution. After shaking, the phases were separated; the aqueous phase was extracted twice with 50 ml of dichloromethane each time; the organic phases were combined, dried with anhydrous sodium sulfate, concentrated to 50 ml under reduced pressure, then treated with 500 ml of methanol and concentrated again to 50 ml. The methanol solution obtained in this way was cooled to 0 C, the precipitated crystals were filtered off, washed with cold methanol and dried at room temperature. In this way, 25.1 g of vincamine (70.9 % of theory ) were obtained; the 14-epivincamine, which was also formed during the conversion, remained in the mother liquor of the crystals.

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Example 4:

The procedure described in Example 1 was followed, with the difference that in addition to the oxidation of 43.85 g (0.1 mol) of dihydrotabersonine instead of \ r & f ^ bis-suj ^ inyl-peroxide, 28.84 g (0.11 Mol) bis-glutaryl / peroxide were used. In this case, the degree of conversion measured in the oxidation reaction mixture was 73.5% (64.0 vincamine and 9.5% 14-epivincamine); In the case of the Kristallislbe-rHJ-R-ij, 19.1 g of vincamine were obtained as the primary product and, after the epimeric phase, a further 5.8 g of vincamine, so that a total of 24.9 vincamine (70.3 % of theory ) were obtained.

Example 5:

The procedure described in Example 1 was used, with the difference that the oxidation of 43.85 g (0.1 mol) of dihydrotabersonine instead of (s ^ ecf

ClC C-

Bis-su ^ inyl-peroxide 27.30 g (0.11 mol) of glutaryl-suX- ^ inyl-peroxide were used. In this case, the degree of conversion measured in the oxidation reaction mixture was 70.2% (61.6% vincamine and 8.6 % 14-epivincamine); in the case of crystallization -) = 4 = H ^: t- £ $, 18.0 g of vincamine were obtained as the primary product, and after the epimerization a further 5.8 g of vincamine were obtained, so that the total yield was 23.8 g of vincamine ( 67.3 % of theory ).

Example 6:

43.85 g (0.1 mole) of dihydrotabersonine perchlorate were dissolved in 3000 ml of methanol and then with 900 ml of water, 100 ml of 2 η hydrochloric acid solution and 25.76 g (0.11 mol) of bis / suJ9? inyl peroxide (based on the active peroxide content calculated). The mixture was heated to 40 ° C. and at this temperature

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Stirred for 6 hours. The reaction mixture was then concentrated to a volume of 1 liter, made alkaline with concentrated ammonium hydroxide solution to pH = 8.5 and then extracted once with 500 ml and six times with 250 ml of benzene each time. The benzene phases were combined, dried with anhydrous sodium sulfate, then concentrated to a volume of 150 ml and left to stand in the refrigerator overnight. The precipitated crystals were filtered off, washed with cold benzene and dried (20 _r 2 g). The mother liquor was evaporated to dryness, 50 ml of methanol and 1 g of potassium tert-butoxide were added to the residue and the mixture was refluxed for 3 hours. After cooling, the reaction mixture was left to stand in the refrigerator; the precipitated crystals were filtered off, washed with cold methanol and dried (6.3 g). A total of 26.5 g of vincamine (74.9 % of theory ) were thus obtained. The degree of conversion determined in the oxidation reaction mixture by high pressure liquid chromatography was 77.8 % (of which vincamine: 67.8 %; 14-epivincamine: 10.0 %) .

Example 7:

4.88 g (0.01 mol) of dihydrotabersonine hydrogen tartrate were dissolved in 300 ml of methanol *, 90 ml of water and 10 ml of 2 η hydrochloric acid solution were added? The mixture was heated to 40 ⁰ C and stirred for 6 hours at this temperature. The reaction mixture was concentrated to 100 ml of Uiumen, made alkaline to pH = 8.5 with ammonium hydroxide solution, extracted once with 50 ml of benzene and six times with 25 ml of benzene each time. The benzene phases were combined, dried with anhydrous sodium sulfate, concentrated to 15 ml volume and left to stand in the refrigerator overnight. The precipitated crystals were filtered off with cold benzene

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washed and dried (2.02 g). The mother liquor was evaporated to dryness, 5 ml of methanol and 0.1 g of potassium tert-butoxide were added to the residue and the mixture was refluxed for 3 hours. After cooling, the reaction mixture was left to stand in the refrigerator; the precipitated crystals were filtered off, washed with cold methanol and dried (0.63 g). In this way, a total of 2.65 g of vincamine (74.9 % of theory ) were obtained. The concentration determined in the oxidation reaction mixture by high pressure liquid chromatography

hf / -vu.g

version grade -we-r 81.9 % (of which vincamin: 71.2%; 14- / epivincamin: 10.7%).

That used as the starting compound in the above examples Dihydrotabersonine hydrogen tartrate was on manufactured in the following way:

10 g of dihydrotabersonine base were dissolved in 30 ml, the solution of 15 g of tartaric acid in 200 ml of water was added and the solution was left to stand in the refrigerator overnight. The separated crystalline precipitate was filtered off and dried. In this way 6 g of dihydrotabersonine hydrogen tartrate were obtained; F. 140-142 ⁰ C (dec.); Solubility in ethanol: 2 g / 100 ml, in water: 0.3 g / 100 ml. UV spectrum (in

Methanol): I _v = 214, 223, 228, 300 and 330 nm. Max

Example 8:

21 g (0.056 mol) of tabersonine hydrochloride were in 2000 ml of 75% methanol dissolved, with 30 ml of 2 η acidic acid solution and 14.52 g (0.062 moles) of bis-sujrinyl / peroxide (calculated on the active peroxide content determined by titration) added. The solution obtained was at room temperature ^, with exclusion of light

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48 hours «left. The pale yellow, acidic, aqueous-methanolic solution was then diluted with 500 ml of water, made alkaline with 25% aqueous ammonium hydroxide solution and then extracted once with 400 ml of benzene and three times with 100 ml of benzene each time. The benzene phases were combined, extracted with 200 ml of water, then dried with anhydrous sodium sulfate and placed on a column containing 100 g of aluminum oxide. The unreacted tabersonine was first eluted from the column with benzene; 4.0 g (21 %) of fc§- ΐ-θ-el tabersonine were recovered from this eluate. It was then eluted with benzene containing 2% by volume of ethanol; the evaporation residue of this eluate contained the products of the oxidative rearrangement reaction: a mixture of 17,18-didehydro-vincamine and 17,18-didehydro-14-epivincamine (13.4 g). This crude alkaloid mixture was dissolved in 200 ml of anhydrous chloroform, 20 g of anhydrous formic acid and 11.3 g of acetyl chloride were added, and the mixture was left to stand at room temperature for 2 hours. The reaction mixture was then diluted with 200 ml of chloroform, extracted with 550 ml of ice-cold η sodium hydroxide solution and then with 100 ml of water, dried with anhydrous sodium sulfate and evaporated to dryness. The residue was 11.9 g of 17,18-didehydro-apovincamine (80.7 % of the calculated theoretical yield of the tabersonine hydrochloride used as the starting compound, taking into account the recovered -a * - • töflj starting compound ) obtain.

Example 9:

0.71 g (1.77 mol) of dihydrotabersonic acid isopropyl ester hydrochloride were dissolved in a mixture of 53.1 ml of methanol and 15.9 ml of water, and then

... ..... .... 32U942

1.77 ml of 2 η hydrochloric acid solution and 0.456 g (1.95

cc

mmol) bis-sulfyl peroxide added. The mixture was stirred at 40 ° C. for 6 hours and then concentrated to a volume of 20 ml under reduced pressure. The pH of the solution was adjusted to 8.5 with concentrated ammonium hydroxide solution and the solution was extracted once with 15 ml and six times with 8 ml of benzene each time. The benzene phases were combined, dried with anhydrous sodium sulfate and evaporated to dryness. The residue was chromatographed in 20 g of Brockmann's aluminum oxide (activity II) and eluted with benzene. 0.38 g of isopropyl vincaminate and 0.03 g of xisopropyl 14-epivincaminate were obtained from the corresponding eluate fractions (total yield: 65.4 % of theory ).

The one used as the starting compound in the above example Dihydrotabersonine isopropyl ester hydrochloride was made in the following way:

In 50 ml of anhydrous isopropanol, 0.1 g of sodium metal was dissolved, the solution was added 1.0 g tabersonine base and for 5 hours while introducing nitrogen gas heated at 80 ⁰ C. The progress of the transesterification reaction was followed by thin layer chromatography (on aluminum oxide layer, mobile phase: benzene → tabersonine: Rr ¹ = 0.60; tabersonine isopropyl ester: Rr = 0.71). After the end of the reaction, the reaction mixture was evaporated in vacuo, the residue diluted with 30 ml of water and extracted three times with 25 ml of benzene each time. The benzene phases were combined, washed with 10 ml of water, dried with anhydrous sodium sulfate and evaporated to dryness. 1.0 g of crude product of yellow color was obtained as a residue; this was dissolved in benzene, the solution was filtered off with 10 g of aluminum oxide, and that on the filter

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r CLM4 i & tviv-iCAen.

Remaining adsorbent was flushed with benzene / r mcnge ^. The combined filtrate was evaporated; as a residue
0.92 g of isopropyl tabersonate (84% of theory)

Th.) Obtained in jb-Hj form of a chromatographically pure _/ oily product; / jkj q ° = - 308 ° (c = 1, in
Methanol /.

0.782 g (2 mmol) of the tabersonic acid isopropyl ester obtained in the above manner were dissolved in 60 ml of ethanol
dissolved and hydrogenated to saturation after the addition of 0.14 g of 10 % -xqem palladium / activated carbon catalyst. The catalyst was then filtered off and the filtrate evaporated to dryness. 0.73 g of isopropyl dihydrotabersonic acid were obtained as a residue; / _ "ö <_7 = -540 ⁰ Zc = I, in methanol /. This product
was dissolved in 5 ml of ethanol · *. ^m it was added 25 ml Salzsaeurelösung η, and the mixture was left to crystallize in the refrigerator. The precipitated crystals were filtered off, washed with cold ethanol and dried. In this way 0.71 g of crystalline fJ -dihydrotabersonic acid hydrochloride were obtained
(1.77 mmol; 88 % of theory ) obtained; F. 144-146 ⁰ C;
Z / X_ / ² D ⁼ "388 ° / Jc = 1, in methanol /.

Example 10:

4.39 g (0.01 mole) of dihydrotabersonine perchlorate was
dissolved in 300 ml of methanol ^ 90 ml of water and 10 ml of 2 η hydrochloric acid solution are added to the solution; then were
2.5 g (0.011 mol) of ammonium peroxydisulfate were added
and the mixture was ^{stirred at 40 °} C. for 4 hours. The reaction mixture was concentrated to a volume of 100 ml and
mixed with 15 ml of 60% perchloric acid solution.
The excreted vincamine perchlorate was filtered off, 300 ml of water and 300 ml of dichloromethane were added and the two-phase mixture was made alkaline to pH 9 with 25% ammonia solution. After shaking out

... ...., .. .. 32H942

the aqueous phase was separated off and extracted twice more with 50 ml of dichloromethane each time. The organic phases were combined, dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated to a volume of 50 ml in vacuo, then 500 ml of methanol were added and the mixture was concentrated again to 50 ml. The solution obtained in this way was left to stand at 0 ^° C. for 2 hours, and then the precipitated crystals were separated off by filtration. In this way, 2.63 g of vincamine (74.3 % of theory ) were obtained; the 14-epivincamine formed in smaller quantities remained in the mother liquor. The degree of conversion determined in the reaction mixture by high pressure liquid chromatography was 86.2 %, of which 78.2% was accounted for by vincamine and 8.0% by 14-epivincamine.

Example 11:

4.39 g (0.01 mol) of dihydrotabersonine perchlorate were dissolved in 300 ml of methanol, 90 ml of water, 10 ml of 2 η hydrochloric acid solution and finally 2.5 g (0.011 mol) of ammonium peroxydisulfate were added. The mixture was stirred at 40 ° C. for 4 hours, then concentrated to 100 ml volume- *, made alkaline with 25% ammonium hydroxide solution to pH = 8.5, and the alkaline solution with 50 ml of benzene once and with 25 ml of benzene each time extracted six times. The benzene phases were combined, dried with anhydrous sodium sulfate and concentrated to a volume of 15 ml. The solution was left to stand for ^{6 hours at + 10 °} C. to crystallize, then the precipitated crystals were separated off by filtration. 2.2 g of vincamine (62.1 % of theory ) were obtained in this way. The mother liquor was evaporated to the residue with 5 ml of methanol and 0.1 g of potassium tert-butoxide and refluxed for 3 hours. The mixture was left to stand at 0 C for 2 hours. By separating the

precipitated crystals, a further 0.78 g of vincamine (22.0 % of theory ) were obtained, so that the overall yield was 84.1 % of theory . Th. The degree of conversion determined in the reaction mixture by high pressure liquid chromatography was 86.2 %, of which 78.2 % was accounted for by vincamine and 8.0 % by epivincamine; the originally formed epivincamine was converted into vincamine by epimerization.

Example 12:

4.39 g (0.01 mol) of dihydrotabersonine perchlorate were worked up in the manner described in Example 2, with the difference that _{acetone was used as solvent instead of 1} ^ e-RJ methanol. The primary product was 2.0 g (56.5% of theory) and the secondary product 0.71 g (20.0 % of theory ) of crystalline vincamine (total yield 76.5 % of theory ) . The degree of conversion determined in the reaction mixture by high pressure liquid chromatography was 79.1 %, of which vincamine 70.4 % and 14-epivincamine 8.7 %. The originally formed 14- • ffEpivincamin was completely epimerized to Vincamin.

Example 13:

4.39 g (0.01 mol) of dihydrotabersonine perchlorate were worked up in the manner described in Example 2, with the difference that the reaction was carried out at room temperature (25) with a reaction time of 8 hours. In this way, 2.25 g of crystalline vincamine (63.6% of theory) were obtained as the primary product and 0.74 g of crystalline vincamine (20.9 % of theory ) as the secondary product, so that a total yield of 84.5 % d. Th. Was reached. The degree of conversion determined by high pressure liquid chromatography in the reaction mixture fttÄ-rp87.0 %, of which to vincamine

79.0% and 14-epivincamine accounted for 8.0%. That originally The resulting 14-epivincamine was completely converted into vincamine by epimerization.

Claims (4)

32U942 DipL-Chem. DR. PETER V / AGER Patent Attorney MOUCRSN S, Morasaietr. 8 / Π Telephone 22 3752 Richter Gedeon Vegyeszeti Gyär Rt., Budapest, Hungary PROCESS FOR THE PRODUCTION OF VINCAMIC ACID DERIVATIVES BY OXYDATIVE RELOCATION OF TABERSONIN OR DI- HYDROTABERSONiN (zil-ΊΊ ~ patent claims 1. J Process for the preparation of vincamine acid derivatives of the general formula I. (I) wherein R is an alkyl group having 1 to 4 carbon atoms.,. v \ .hu [ 2 3 R and R each represent a hydrogen atom or both together mean another bond between the two adjacent carbon atoms, As well as dff d -o {corresponding 14-Epivincaminsaeurederi- 32H942 by jö-i ^ oxidative rearrangement of the corresponding Tabersonine derivatives of the general formula II (II) wherein R ", R" and R ^{J have} the meanings given for the general formula I, characterized in that acid addition salts of compounds of the all- 12 3 general formula II, wherein R, R and R are as given above Have meanings in aqueous organic solvents * in the presence of acids ^, with at least ^ - At least equimolecular amounts of organic dibasic ions Carboxylic acids or inorganic acids formed Diacyl peroxides or treated with salts thereof. 2. The method according to claim 1, characterized in that ammonium peroxydisulfate, bis-suJ ^ zfinyl-pe roxyd, Bis-glutaryl-peroxide or Su ^ inyl-glutaryl-peroxide used as diacyl peroxide. 3. The method according to claim 1, characterized in that that an aqueous lower alkanol or aqueous acetone is used as the reaction medium. 4. Process according to Claims 1 to 3 for the preparation of vincamine, characterized in that dihydrotabersonine perchlorate is used or dihydrotabersonine hydrochloride is used as the starting compound.