FR2504531A1 - PROCESS FOR THE PREPARATION OF VINCAMINIC ACID DERIVATIVES BY OXIDATIVE TRANSPOSITION OF TABERSONINE OR DIHYDROTABERSONINE - Google Patents

Abstract

The invention relates to a novel process for the preparation of vincamic acid esters, specifically 17,18-didehydrovincamic acid esters, and the corresponding 14-epi compounds by oxidative rearrangement of, respectively, tabersonic acid esters and dihydrotabersonic acid esters, which is characterised in that these starting substances are treated with at least equimolar amounts of dialkyl peroxides formed from dibasic organic carboxylic acids or inorganic acids, or with salts thereof, in aqueous organic solvents in the presence of acids.

Description

dans laquelle R1 représente un groupe alkyle en C 1-C 4,
R2 et R3 représentent chacun un atome dthydrogène ou forment ensemble une autre liaison entre les deux atomes de carbone voisins, et les dérivés correspondants de l'acide 14-épivincaminique par transposition oxydative des dérivés correspondants de la tabersonine répondant à la formule générale II

dans laquelle R1, R2 et R3 ont les significations indiquées en référence à la formule générale I, ce procédé se caractérisant en ce que l'on traite des sels des composés de formule générale II, dans laquelle R1, R2 et R3 ont les significations indiquées ci-dessus, formés par addition avec des acides, dans des solvants organiques aqueux, en présence d'acides, par des qiant':tésai moins équimo séculaires de peroxydes de diacyle formés à partir d'acides carboxyliques organiques dibasiques ou d'acides minéraux, ou de sels de ces peroxydes.The invention relates to a novel process for preparing derivatives of lteburnane, namely esters of vincaminic acid and of 17,18-didehydro vincaminioue acid by oxidative transposition of tabersonine or dihydrotabersonine (vincadifformin). , the invention relates to a new process for preparing the derivatives of vincaminic acid corresponding to the general formula I

in which R1 represents a C 1 -C 4 alkyl group,
R2 and R3 each represent a hydrogen atom or together form another bond between the two neighboring carbon atoms, and the corresponding derivatives of 14-epivincaminic acid by oxidative transposition of the corresponding derivatives of tabersonine corresponding to general formula II

in which R1, R2 and R3 have the meanings indicated with reference to the general formula I, this process being characterized in that the salts of the compounds of general formula II are treated, in which R1, R2 and R3 have the meanings indicated above, formed by addition with acids, in aqueous organic solvents, in the presence of acids, by qiant ': less equimo secular tésai of diacyl peroxides formed from dibasic organic carboxylic acids or mineral acids , or salts of these peroxides.

 It is known that the tabersonine derivatives, under the action of certain oxidizing agents, undergo transposition and are converted into derivatives of eburnane.

E. Wenkert and B. Wickberg EJ. Am. Chem. Soc. 87, 1580-1589 (1965) 7, in the study of the biosynthesis of indole alkaloids of the eburnamonine type, provided for this synthetic route starting from tabersonine as early as 1964, and this hypothesis has been confirmed experimentally by JP Kutney et al. ÊJ. Am. Chem. Soc. 93, 255-257 (1971) 7.

Since 1971, numerous tests have been carried out with a view to the industrial implementation of this biosynthetic pathway known per se, and several processes applicable in practice have been described in the technical literature for preparing derivatives in this way. vincamine. Thus, according to Belgian Patent No. 761.628, the dihydrotabersonine is oxidized by the equimolecular amount of a peroxide to N-oxy-dihydrotabersonine, and the latter is oxidized by a treatment of 3 to 5 days with another equimolecular amount of the peroxide in 1,2-dehydro 1 6-carbomethoxy-1 6-hydroxy-N-oxy-aspidospermindine; the latter compound is then treated with a reducing agent, preferably triphenylphosphine, and a mixture of vincamine, 14-epivincamine and apovincamine is obtained as the reaction product. According to the aforementioned patent, the peroxide compounds which can be used as agents oxidants can consist of organic peracids such as peracetic acid, performic acid, perbenzolque acid or substituted derivatives of the latter, for example m-chloro- acid or p-nitro-perbenzoTque acid.

 According to Belgian patent no. 763,730 (addition patent to Belgian patent no. 761,628) it is also possible to use, in the above process, as oxidizing agents, alkyl peroxides, lead tetracetate or oxygen in the presence of a catalyst (for example platinum oxide).

 According to Belgian Patent No. 765,795, the (+) - dihydrotabersonine is used in the same process as a starting product and in a reaction lasting from 1 to 5 days, the reaction products are obtained (3 beta, 16 beta) - epimers of vincamine, 14-epivincamine and apovincamine.

Another development of this process is described in Belgian patent no. 837.049 according to which the dihydrotabersonine is oxidized in the form of a salt formed by addition with an organic carboxylic acid, by means of an organic peracid (p-nitro- perbenzolque); in this case, N-oxide does not form on oxidation, but a molecular transposition into the corresponding vincamine derivatives already takes place with 1.1 moles of peracid, and the salt is formed as an intermediate product. of the corresponding carboxylic acid of 1,2-dehydro-16-hydroxy 16-methoxycarbonyl-aspidxcermindine e
According to Belgian Patent No. 848.475, a salt of tabersonine formed by addition with an acid, for example the hydrochloride or perchlorate, is used as starting material, this salt is converted by hydrogenation to the corresponding salt of dihydrotabersonine; starting from this salt, by treatment with an equimolecular amount of an organic peracid, in reaction times of 1 to 3 days, a mixture of vincamine and 14-epivincamine is obtained directly in the reaction product .

According to Belgian Patent No. 856.723, tabersonine or dihydrotabersonine is reacted with a carbanion-forming agent, for example sodium hydride or sodium amide, then oxidative transposition is carried out using treatment of oxygen and finally the intermediate product formed is reduced. The reaction is carried out at room temperature; after acidification of the reaction mixture, vincamine and 14-epivincamine are obtained or else (when tabersonine was used as starting material) the corresponding 17,18-dehydro derivatives with yields of approximately 3596
According to Belgian Patent No. 870,978, dihydrotabersonine salts are oxidized by addition with acids, in the presence of vanadium, chromium, molybdenum or tungsten salts, ~ using hydrogen peroxide; under these conditions, the transposition is complete in 4 days at room temperature and mainly vincamine is obtained with much lower amounts of 14-epivincamine.

 Among the known methods and described above, the oldest, passing through the intermediary of N-oxide, can no longer be considered as economic methods because of the relatively low yields. In addition, the extremely long reaction times, from 1 to 5 days, constitute a common drawback for most of the known methods. The organic peracids recommended as oxidizing agents in most of the known processes are certainly usable with advantage in the laboratory but their sensitivity to heavy metal ions poses, in industrial use, technological problems and complicates the manipulations in the reactions carried out. on large quantities.

 It has now been surprisingly found that the difficulties mentioned above can be practically eliminated and that the oxidative transposition reaction takes place within short reaction times (a few hours) and with high conversion rates (80 to 90% ) when tabersonine or dihydrotabersonine (vincadifformin) was treated in the corresponding salt form formed by addition with a chosen acid, by a diacyl peroxide formed from dibasic organic carboxylic acids, for example bis- peroxide succinyl or succinyl and glutaryl peroxide, or by a peroxide formed from a mineral acid or by a salt of such a peroxide, in aqueous-organic media.

 The salt of tabersonine or dihydrotabersonine formed by addition with an acid which is used as starting material may consist of a mineral acid salt, for example the hydrochloride or the sulfate, or of an organic acid salt, for example tartrate; perchlorates are used with a particular advantage. The reaction medium used is preferably an organic solvent miscible with water, for example a lower alkanol such as methanol or methanol, or acetone, mixed with water; however, it is also possible to operate in a two-phase system consisting of an organic solvent immiscible with water and water. To ensure the desired acidity of the reaction mixture, it is possible to add salt to the solution. acid used as starting material any mineral acid, for example hydrochloric acid or optionally, especially when an organic acid salt is used as starting material, such an organic acid, for example tartaric acid.

 The use of organic or inorganic diacyl peroxides or their salts as oxidizing agents in the process according to the invention has advantages not only because these diacyl peroxides are not sensitive to impurities containing heavy metals but above all because the oxidation carried out using these oxidizing agents requires much shorter durations (3 to 6 hours at 400C but even 12 to 48 hours at room temperature) which, in addition to the resulting technological advantages, results also a better oxidation selectivity and higher yields. The shorter reaction times which cannot be achieved by the process according to the invention are also in certain cases related to another advantage of the use of diacyl peroxides. as oxidizing agents: whereas in the oxidative transposition reaction carried out in a known manner, by means of organic peracid, when hot, for example at 400C, the r secondary reactions reducing the yield and the purity of the final product already strongly come to the fore and make the use of these high reaction temperatures unfortunate, these side reactions only take place in a process which is practically completely negligible when uses diacyl peroxides as oxidizing agents, so that the observation of high temperatures allowing shorter reaction times (about 400C) does not raise objections from this point of view.

 The examples which follow illustrate the invention without however limiting its scope; in these examples, the indications of parts and of 96 are by weight unless otherwise stated.

Example 1
43.85 g (0.1 mol) of dihydrotabersonine perchlorate are dissolved in 3,000 ml of methanol and then 900 ml of water, 100 ml of a 2N hydrochloric acid solution and 25.76 g (0, 11 mol) of bis-succinyl peroxide (calculated as active peroxide, the content of which is determined by titration). The mixture is heated to 400C and stirred for 6 hours at this temperature (after the end of the reaction, a sample of the reaction mixture is taken and the conversion rate is determined by chromatography; the conversion rate is 82.296 of which 71.596 into vincamine and 10.7 / a into 14-epivincamine (after separation of the first jet of crystals from the product, the residue is subjected to epimerization, so that this epivincamine is also converted into vincamine).

 The reaction mixture obtained above is concentrated to a final volume of 1 liter, adjusted to alkaline pH of 8.5 with concentrated ammonia and then stirred once with 500 ml of benzene and 6 times with 250 ml of benzene each time. The benzene phases are combined, dried over anhydrous sodium sulfate, filtered, concentrated to a final volume of 150 ml and left to stand overnight in the refrigerator. The crystals are filtered, washed with cold benzene and dried at room temperature (21.2 g). The mother liquors obtained during crystallization are evaporated to dryness, 50 ml of methanol and 1 g of potassium tert.-butoxide are added to the residue, the mixture is boiled for 3 hours at reflux and left overnight in the refrigerator. crystals which have separated, washed with cold methanol and dried at room temperature (6.8 g). This gives a total of 28.0 g of vincamine (79.1% of theory).

Example 2
4.39 g (0.01 mole) of dihydrotabersonine perchlorate are dissolved in 300 ml of methanol and then 90 ml of water, 10 ml of a 2N hydrochloric acid solution and 2.58 g (0.011 mole) are added. ) bis-succinyl peroxide (active peroxide determined by the titration). The mixture is maintained for 16 hours at 200C and then concentrated in vacuo to a final volume of 100 ml. The pH of the solution is adjusted to 8.5 with concentrated ammonia and then stirred once with 50 ml of benzene and 6 times with 25 ml of benzene each time. The combined benzene phases are dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue is chromatographed on Brockmann alumina (activity II) and eluted with benzene. From the corresponding eluate fractions, 0.42 g of 14-epivincamine (11.9in of theory) and 2.83 g of vincamine (79.996 of theory) are obtained; the overall yield therefore stands at 91.8%.

Example 3
43.85 g (0.1 mole) of dihydrotabersonine perchlorate are dissolved in 3,000 ml of methanol and then 900 ml of water, 100 ml of 2N hydrochloric acid solution and 25.76 g (0.11 mole) are added. ) bissuccinyl peroxide (active peroxide determined by the titration). The mixture is stirred for 6 hours at 400C. The conversion rate determined on a sample of the reaction mixture by high pressure liquid chromatography is 81.8% including 72.0% in vincamine and 9.8% in 14epivincamine.

 The reaction mixture is concentrated to a final volume of 1 liter, 15 ml of perchloric acid at 6096 are added and the vincamine perchlorate which has precipitated is filtered.

The crude product obtained under these conditions is added with 300 ml of water and 300 ml of dichloromethane; the mixture is adjusted to pH 9 with concentrated ammonia. After stirring, the phases are separated; the aqueous phase is extracted twice with 50 ml of dichloromethane each time; the organic phases are combined, dried over anhydrous sodium sulfate, concentrated in vacuo to a final volume of 50 ml, then 500 ml of methanol are added and again concentrated to a final volume of 50 ml. The methanolic solution obtained is cooled to OOC; the crystals which have separated are filtered, washed with cold methanol and dried at room temperature. 25.1 g of vincamine are thus obtained (70.955 of theory); the 14-epivincamine also formed in the conversion remained in the mother liquors of crystallization.

Example 4
The procedure is as described in Example 1, but for the oxidation of 43.85 g (0.1 mole) of dihydrotabersonine, the bis-succinyl peroxide is replaced by 28.84 g (0.11 mole) of peroxide bis-glutaryl. In this case, the conversion rate measured on the mixture of the oxidation reaction is 73.5% (64.096 in vincamine and 9.5% in 14-epivincamine). Upon crystallization, 19.1 g of vincamine are obtained in the first product and then after epimerization another 5.8 g of vincamine, ie a total of 24.9 g of vincamine (70.3% of theory).

Example 5
The procedure is as described in Example 1, but to oxidize 43.85 g (0.1 mole) of dihydrotabersonine, the bis-succinyl peroxide is replaced by 27.30 g (0.11 mole) of glutaryl peroxide and succinyl . In this case, the conversion rate measured on the oxidation reaction mixture is 70.2% (61.696 of vincamine and 86% of 14-epivincamine); on crystallization, 18.0 g of vincamine are obtained in the first jet and after itperimerization another 5.8 g of vincamine, ie a total of 23.8 g of vincamine (67.3% of theory).

Example 6
45.85 g (0.1 mol) of dihydrotabersonine perchlorate are dissolved in 3,000 ml of methanol and then 900 ml of water, 100 ml of a 2N hydrochloric acid solution and 25.76 g (0, 0) are added. 11 mol) of bisuccinyl peroxide (as active peroxide determined by titration). The mixture is heated to 400C and stirred for 6 hours at this temperature. The reaction mixture is then concentrated to a final volume of 1 liter, it is adjusted to pH 8.5 with concentrated ammonia then extraction is carried out once with 500 ml and 6 times with 250 ml each time with benzene. benzene phases, dried over anhydrous sodium sulfate, concentrated to a final volume of 150 ml and left overnight in the refrigerator. The crystals which have separated are filtered, washed with cold benzene and dried (20.2 g). The mother liquors are evaporated to dryness, 50 ml of methanol and 1 g of potassium tert.-butoxide are added to the residue and the mixture is boiled at reflux for 3 hours. After cooling, the reaction mixture is left in the refrigerator, the crystals which have separated are filtered, washed with cold methanol and dried (6.3 g). A total of 26.5 g of vincamine is thus obtained (74.996 of theory). The conversion rate determined in the oxidation reaction mixture by high pressure liquid chromatography is 77.896 (including 67.896 in vincamine and 10.096 in 14epivincamine ).

Example 7
4.88 g (0.01 mole) of dihydrotabersonine bitartrate are dissolved in 300 ml of methanol, 90 ml of water and 10 ml of 2N ~ solution of hydrochloric acid are added, the mixture is heated to 400C and stirred for 6 hours at this temperature. The reaction mixture is concentrated to a final volume of 100 ml, basified to pH 8.5 with ammonia, extracted once with 50 ml of benzene and 6 times with 25 ml of benzene each time. The benzene phases are combined, dried over anhydrous sodium sulfate, concentrated to a final volume of 15 ml and left overnight in the refrigerator. The crystals which have separated are filtered, washed with cold benzene and dried (2.02 g). The mother liquors are evaporated to dryness, 5 ml of methanol and 0.1 g of potassium tert.butylate are added to the residue and the mixture is boiled under reflux for 3 hours. After cooling, the reaction mixture is left to refrigerator, the crystals which have separated are filtered, washed with cold methanol and dried (0.63 g). A total of 2.65 g of vincamine is thus obtained (74.996 of theory). The conversion rate determined on the oxidation reaction mixture by high pressure liquid chromatography is 81.9% (including 71.2% in vincamine and 10.7% in 14-epivincamine).

The dihydrotabersonine bitartrate used as a starting material in the above example was prepared as follows
10 g of dihydrotabersonine base are dissolved in 30 ml of ethanol, a solution of 15 g of tartaric acid in 200 ml of water is added to the solution and the mixture is left in the refrigerator overnight. The crystalline precipitate is filtered and dried. This gives 6 g of dihydrotabersonine bitartrate melting at 140-1420C (dec.); solubility in ethanol: 2 g / 100 ml in water: 0.3 g / 100 ml. UV spectrum (in methanol) \ = 214, 223, 228, 700 and 330 nm.

Example 8 223, 228, 300 and 330 nm.

 21 g (0.056 mole) of tabersonin hydrochloride are dissolved in 2,000 ml of 75% methanol, 30 ml of a 2N solution of hydrochloric acid and 14.52 g (0.062 mole) of bis-succinyl peroxide are added ( active peroxide determined by titration). The solution is left at room temperature away from light for 48 hours. The yellow acid hydromethanolic solution is then diluted with 500 ml of water, made alkaline with ammonia at 2556 and then extracted once with 400 ml of benzene and 3 times with 100 ml of benzene each time. The benzene phases are combined, stirred with 200 ml of water, dried over anhydrous sodium sulphate and thrown on a column of 100 g of alumina. Eluted from the column first, with benzene, tabersonine not convex; from this eluate, 4.0 g (21) of unconverted tabersonine are recovered. Then eluted with benzene containing 2% by volume of ethanol; the evaporation residue from this eluate contains the products of the oxidative transposition reaction: a mixture of 17,18-didehydrovincamine and 17,18-di-dehydro-14-epivincamine (13.4 g).

This mixture of crude alkaloids is dissolved in 200 ml of anhydrous chloroform, 20 g of anhydrous formic acid and 11.3 g of acetyl chloride are added and the mixture is kept at rest at room temperature for 2 hours. The reaction mixture is then diluted with 200 ml of chloroform, extracted with 550 ml of solution N of sodium hydroxide cooled with ice then with 100 ml of water, dried over anhydrous sodium sulfate and evaporated to dryness . A residue is obtained 11.9 g of 17.18-didEshydro-apovincamine (80.79 (of the theoretical yield calculated from tabersonine hydrochloride used as starting material, taking into account the starting material not converted and recovered).

Example 9
0.71 g (1.77 moles) of hydrochloride of the isopropyl ester of dihydrotabersoninic acid is dissolved in a mixture of 53.1 ml of methanol and 15.9 ml of water and then 1.77 ml of 2N solution of hydrochloric acid and 0.456 g (1.95 millimoles) of bis-succinyl peroxide.

The mixture is stirred for 6 hours at 400C and then concentrated in vacuo to a final volume of 20 ml. The solution is adjusted to pH 8.5 with concentrated ammonia and the solution is extracted once with 15 ml and 6 times with 8 ml of benzene each time. The benzene phases are combined, dried over anhydrous sodium sulfate and evaporated to dryness. The residue is chromatographed on 20 g of Brockmann alumina (activity II) and elution is carried out with benzene. From the corresponding eluate fractions, 0.38 g of isopropyl ester of vincaminic acid and 0.03 g of isopropyl ester of 14-epifincaminic acid are obtained (overall yield: 65.4% of the theory).

The hydrochloride of the isopropyl ester of dihydrotabersonine used as starting material in example above was prepared in the following manner
0.1 g of metallic sodium is dissolved in 50 ml of anhydrous isopropanol, 1.0 g of tabersonin base is added to the solution and the mixture is heated for 5 hours at 800C with nitrogen injection. The progress of the transesterification reaction is monitored by thin layer chromatography (on an alumina layer, eluent: benzene, tabersonine
Rf w û, 60; isopropyl ester of tabersonine
Rf = 0.71). When the reaction is complete, the reaction mixture is evaporated in vacuo, the residue is diluted with 30 ml of water and extracted three times with 25 ml of benzene each time. The benzene phases are combined, washed with 10 ml of water, dried over anhydrous sodium sulfate and evaporated to dryness. A residue is obtained 1.0 g of crude product colored yellow, which is dissolved in benzene; the solution is clarified with 10 g of alumina, filtered and the adsorbent remaining on the filter is rinsed with benzene. The combined filtrates are evaporated; a residue of 0.92 g of isopropyl ester of tabersoninic acid is obtained (84% of theory) in the form of a pure oily product on chromatography: [α] D20 = 308 (c = 1 in methanol ).

 0.782 g (2 millimoles) of the isopropyl ester of tabersoninized acid obtained as described above is dissolved in 60 ml of ethanol and after the addition of 0.14 g of catalyst containing 10% palladium on active carbon, hydrogen until saturation. The catalyst is then filtered and the filtrate is evaporated to dryness. A residue of 0.73 g of isopropyl dihydrotabersoninate is obtained; '720 = -540 (c = 1 in methanol). This product is dissolved in 5 ml of ethanol, 25 ml of hydrochloric acid solution N are added and the mixture is left in the refrigerator for crystallization. The crystals which have separated are filtered, washed with cold methanol and washed. dried. 0.71 g of crystallized (-) - dihydrotabersoninic acid hydrochloride are obtained in this way (1.77 millimoles; 8856 of theory); this compound melts at 144-146 "C; Q / D20 = -3880 (c = 1 in methanol).

Example 10
4.39 g (0.01 mol) of dihydrotabersonine perchlorate are dissolved in 300 ml of methanol, 90 ml of water and 10 ml of a 2N solution of chlororyrihydrate are added to the solution, then 2 are added, 5 g (0.011 mole) of ammonium peroxydisulfate and the mixture is stirred for 4 hours at 400C. The reaction mixture is concentrated to a final volume of 100 ml and 15 ml of 60% per chiriou acid solution are added. The precipitated vincamine perchlorate is filtered, 300 ml of water and 300 ml of dichloromethane are added and the two-phase mixture is made alkaline at pH 9 with ammonia at 2556. After stirring, the aqueous phase is separated and extract it twice more with 50 ml of dichloromethane each time. The organic phases are combined, dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated in vacuo to a final volume of 50 ml, 500 ml of methanol are added and again concentrated to a final volume of 50 ml. The solution obtained is left at OOC for 2 hours and then the crystals formed are separated by filtration. 2.63 g of vincamine are obtained in this way (74.356 of theory); the 14-epivincamine formed in the smallest amount remains in the mother liquors. The conversion rate determined in the reaction mixture by high pressure liquid chromatography is 86.2% of which 78.2 in vincamine and 8.0% in 14epivincamine .

Example 11
4.39 g (0.01 mole) of dihydrotabersonine perchlorate are dissolved in 300 ml of methanol, 90 ml of water, 10 ml of 2N hydrochloric acid solution are added and finally 2.5 g (0.011 mole) ) of ammonium peroxydisulfate. The mixture is stirred for 4 hours at 400C, concentrated to a final volume of 100 ml, basified to pH 8.5 with ammonia at 259G and the alkaline solution is extracted once with 50 ml of benzene and 6 times with 25 ml each time of benzene. The benzene phases are combined, dried over anhydrous sodium sulfate and concentrated to a final volume of 15 ml. The solution is left standing for 6 hours at + 100C for crystallization and then the crystals are separated by filtration. 2.2 g of vincamine (62.1% of theory) are thus obtained. The mother liquors are evaporated, 5 ml of methanol and 0.1 g of potassium tert.-butoxide are added to the residue and the mixture is heated to reflux for 3 hours. The mixture is left standing for 2 hours at OOC. The separation of the crystals which have formed gives another 0.78 g of vincamine (22.056 of theory) so that the overall yield amounts to 84.19d of theory. The conversion rate determined in the reaction mixture by high pressure liquid chromatography is 86.2, of which 78.256 in vincamine and 8.0% in epivincamine; the epivincamine originally formed is converted to vincamine by epimerization.

Example 12
4.39 g (0.01 mole) of dihydrotabersonine perchlorate are treated as described in Example 2 but using acetone as the solvent, instead of methanol. 2.0 g (56.596 of theory) are obtained on the first jet and 0.71 g (20.0% of theory) of crystallized vincamine on the second jet (overall yield: 76.556 of theory). The conversion rate determined in the reaction mixture by high pressure liquid chromatography is 79.196, of which 70.4% in vincamine and 8.7% in 14-epivincamine.

The 14-epivincamine originally formed is entirely epimerized into vincamine.

Example 13
4.39 g (0.01 mole) of dihydrotabersonine perchlorate are treated as described in Example 2, but reacting at room temperature (250C) with a reaction time of 8 hours. 2.25 g of crystallized vincamine (63.69; of theory) are obtained in the first jet in this way and 0.74 g of crystallized vincamine (20.955 in theory) in the second jet, which corresponds to an overall yield of 84.504. of theory. The conversion rate determined in the reaction mixture by high pressure liquid chromatography is 87.0% including 79.0% into vincamine and 8.056 into 14-epivincamine. The originally formed 14epivincamine was fully converted to vincamine by epimerization.

Claims (4)

 1 - Process for the preparation of vincaminic acid derivatives corresponding to general formula I

 in which R1 represents a C 1 -C 4 alkyl group, R2 and R3 each represent a hydrogen atom or, together, another bond between the two neighboring carbon atoms, and corresponding derivatives of 14-epivincaminic acid, by oxidative transposition of the corresponding derivatives of tabersonine corresponding to the formula general II

 in which R1, RZ and R3 have the meanings indicated with reference to the general formula I, characterized in that the salts of the compounds of general formula II are treated, in which R1, R2 and R3 have the meanings indicated above , formed by addition with acids, in aqueous organic solvents, in the presence of acids, by at least equimolecular amounts of diacyl peroxides formed from dibasic organic carboxylic acids or mineral acids, or using salts of tis peroxides.  2 - Method according to claim 1, characterized in that one uses as diacyl peroxide ammonium peroxydisulfate, bissuccinyl peroxide, bis-glutaryl peroxide or succinyl and glutaryl peroxide.  3 - Process according to claim 1, characterized in that an aqueous lower alkanol or aqueous acetone is used as the reaction medium.  4 - Process according to any one of claims 1 to 3, for the preparation of vincamine, characterized in that lton uses as starting material dihydrotabersonine perchlorate or dihydrotabersonine hydrochloride.