DE3214942C2 - - Google Patents

Description

The invention relates to a new method of manufacture of eburnan derivatives, namely vincamic acid and 17,18-didehydrovincamic acid esters oxidative rearrangement of tabersonin or dihydrotabersonin (Vincadifformin). In particular, the invention relates a new process for the production of vincamic acid derivatives of the general formula I

wherein
R¹ is an alkyl group with 1 to 4 carbon atoms and R² and R³ each represent a hydrogen atom or both together represent a further bond between the two adjacent carbon atoms, and the corresponding 14-epivaminamic acid derivatives by oxidative rearrangement of the corresponding tabersonine derivatives of the general formula II

wherein R¹, R² and R³ those in the general formula I have indicated meanings, which is characterized is that you add acid addition salts of compounds of general formula II, wherein R¹, R² and R³ have the meanings given above, in aqueous organic solvents in the presence of acids with at least equimolecular amounts of Ammonium peroxydisulfate, bis-succinyl peroxide, bis-glutaryl peroxide or succinyl-glutaryl peroxide or with a salt thereof treated.

It is known that tabersonin derivatives act rearrangement of certain oxidizing agents suffer and be converted into Eburnan derivatives. E. Wenkert and B. Wickberg [J. At the. Chem. Soc. 87, 1580-1589 (1965)] have examined the Biosynthesis of the indurn alkaloids of the eburnamonin type Already in 1964, this one from Tabersonin Provided synthesis route, which then by J. P. Kutney and employees [J. At the. Chem. Soc. 93, 255-257 (1971)] has also been demonstrated experimentally. For industrial Realization of this already known biosynthetic pathway numerous attempts have been made since 1971, and there have been several practical ones in the literature  Process for the preparation of vincamine derivatives described in this way. So after the Belgian Patent 7 61 628 with the dihydrotabersonin the equimolecular amount of a peroxide to N-oxy dihydrotabersonin and this by a 3 to 5 Days of treatment with another equimolecular Amount of peroxide to 1,2-dehydro-16-carbomethoxy 16-hydroxy-N-oxy-aspidospermindin oxidized; this latter compound was then treated with a reducing agent, appropriately treated with triphenylphosphine, being a mixture of vincamine, 14-epivamin and apovincamine was obtained as a reaction product. The peroxy compounds that can be used as oxidizing agents can organic according to the cited patent Peracids such as peracetic acid, performic acid, perbenzoic acid or substituted derivatives of the latter, e.g. B. m-chloro or p-nitro-perbenzoic acid.

According to Belgian patent 7 63 730 (additional patent to Belgian patent 7 61 628) can use the above method also alkyl peroxides, lead tetraacetate or oxygen in the presence of a catalyst (e.g. platinum oxide) can be used as an oxidizing agent.

According to Belgian patent specification 7 65 795, the same Process (+) - Dihydrotabersonin as starting material used, with reaction times lasting from 1 to 5 days the (3β, 16β) epimers of Vincamin, 14-Epivincamin and apovincamine can be obtained as products.

A further development of this procedure was in the Belgian patent specification 8 37 049 described after which the dihydrotabersonin in the form of a an organic carboxylic acid formed acid addition salt with an organic peracid (with p-nitroperbenzoic acid) is oxidized; in this case  no N-oxide formed during the oxidation, but the molecular rearrangement into the corresponding vincamine compounds takes place with 1.1 moles of peracid, the corresponding carboxylic acid salt as an intermediate of 1,2-dehydro-16-hydroxy-16-methoxycarbonyl aspidospermindin is formed.

According to the Belgian patent 8 48 475 a Acid addition salt, e.g. B. the hydrochloride or Perchlorate from tabersonin, used as starting material; this is hydrogenated into the corresponding salt transferred from dihydrotabersonin; from the latter is then treated with an equimolecular Amount of an organic peracid at reaction times a mixture of vincamine for 1 to 3 days and 14-Epivaminamin obtained as a product.

According to Belgian patent 8 56 723, the tabersonin or dihydrotabersonin with a carbanion-forming Means, e.g. B. with sodium hydride or sodium amide then implemented by treatment with oxygen carried out the oxidative rearrangement and finally the intermediate product obtained is reduced. The reaction is carried out at room temperature; to acidifying the reaction mixture becomes vincamine and 14-epivamine, or (if tabersonin as a starting material was used) the corresponding 17,18-dehydro compounds in yields of about 35% as products receive.

According to the Belgian patent specification 8 70 978, acid addition salts of dihydrotabersonin in the presence of Vanadium, chromium, molybdenum or tungsten salts with hydrogen peroxide oxidized; this is how the rearrangement takes place at room temperature in 4 days and it will mainly  Vincamin in addition to much smaller amounts obtained from 14-epivamin.

Of the known methods described above can the older conversions that take place over the N-oxide because of the relatively low yields are no longer considered economic methods. In addition, the extremely long, 1 to 5 days reaction times a common Disadvantage of most known methods. The two most known processes as oxidants Recommended organic peracids are in the laboratory advantageously applicable, their sensitivity to Heavy metal ions, however, bring in their large-scale Applying technological problems with itself and complicates the handling of on a larger scale executed reactions.

It has now surprisingly been found that the difficulties mentioned are largely eliminated and the oxidative rearrangement reaction with short Response time (a few hours) and high conversion rate (80 to 90%) expires when you see the tabersonin or dihydrotabersonin (vincadifformin) in the form a correspondingly chosen acid addition salt Ammonium peroxydisulfate, bis-succinyl peroxide, bis-glutaryl peroxide or succinyl-glutaryl peroxide or with a salt thereof treated in aqueous organic media.

The acid addition salt to be used as the starting material of tabersonin or dihydrotabersonin can be with an inorganic acid salt, e.g. B. that Hydrochloride or sulfate, or one with an organic  Acid formed salt, e.g. B. be the tartrate; especially the perchlorates can advantageously be used for this purpose will. It is useful as the reaction medium an organic solvent miscible with water, e.g. B. a lower alkanol such as methanol or ethanol or acetone mixed with water; one can but also in a two-phase system with one Water immiscible organic solvents and Water work. To ensure the desired acidity the reaction mixture can be any mineral acid, e.g. B. hydrochloric acid, or optionally, especially if you have one formed with an organic acid Salt used as a raw material, an organic Acid, e.g. B. tartaric acid, the solution of the starting material acid addition salt used are added.

The use of the organic or inorganic diacyl peroxides mentioned or of salts thereof as an oxidizing agent is not only in the process according to the invention therefore advantageous because these diacyl peroxides have no sensitivity towards heavy metal contaminants, but mainly because the oxidation with these Oxidizing agents in a much shorter time (at 40 ° C in 3 to 6 hours, but also at room temperature within from 12 to 48 hours), which runs alongside the resulting technological advantages to one greater selectivity of the oxidation leads and higher Yields. The by the invention Process achievable shorter response times are also partly with another advantage of the application related to diacyl peroxides as oxidants: while in the known way with organic Peracids carried out oxidative rearrangement reaction at higher temperatures, e.g. B. at 40 ° C, those which reduce the yield and contaminate the end product Side reactions are already very much in the foreground  occur and thus the use of such increased Make reaction temperatures questionable when using diacyl peroxides as an oxidizing agent Side reactions only in practically completely insignificant Measure on so that the application of higher, shorter reaction times allow temperatures (about 40 ° C) none from this point of view Obstacles stand in the way.

The method according to the invention is illustrated by the following Examples illustrated in more detail; The invention but is in no way dependent on the content of this limited to concrete examples.

Example 1

43.85 g (0.1 mol) of dihydrotabersonine perchlorate were added dissolved in 3000 ml of methanol and then with 900 ml of water, 100 ml of 2N hydrochloric acid solution and 25.76 g (0.11 mol) Bis-succinyl-peroxide (on those determined by titration active peroxide content calculated) added. The mixture was heated to 40 ° C and at this temperature Stirred for 6 hours. (After completing the Reaction was taken out of the reaction mixture Sample the degree of conversion chromatographically determined; the conversion was 82.2%, of which it did not apply 71.5% on vincamine and 10.7% on 14-epivamine. After the first generation of crystals of the The residue was subjected to epimerization, which also causes this epivamin in Vincamin was transferred.)

The reaction mixture obtained as above was concentrated to 1 liter with concentrated ammonium hydroxide solution alkalized to pH = 8.5 and then  with 500 ml of benzene once and with 250 ml of benzene each shaken six times. The gasoline phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated to 150 ml and overnight in Refrigerator left. The crystals obtained were filtered off, washed with cold benzene and dried at room temperature (21.2 g). The at Crystallized mother liquor obtained became Evaporated to dryness and the residue was washed with 50 ml Methanol and 1 g of potassium tert-butoxide were added, 3 hours boiled under reflux and refrigerated overnight ditched. The deposited crystals were filtered off, washed with cold methanol and dried at room temperature (6.8 g). It was on this way a total of 28.0 g vincamine (79.1% of theory) receive.

Example 2

4.39 g (0.01 mol) of dihydrotabersonine perchlorate were added dissolved in 300 ml of methanol and then with 90 ml of water, 10 ml of 2N hydrochloric acid solution and 2.58 g (0.011 mol) of bis- succinyl peroxide (on those determined by titration active peroxide content calculated) added. The mixture was stirred at 20 ° C for 16 hours and then under reduced pressure Concentrated to 100 ml. The pH of the solution was with concentrated ammonium hydroxide solution set to 8.5, then with 50 ml of benzene once and shaken six times with 25 ml of benzene. The United Benzene phases were treated with anhydrous sodium sulfate dried, filtered and evaporated to dryness. The residue was on Brockmann's aluminum oxide (Activity II) chromatographed and eluted with benzene. From the corresponding eluate fractions 0.42 g of 14-epivamine (11.9% of theory) and 2.83 g of vincamine (79.9% of theory); the total yield is  so 91.8%.

Example 3

43.85 g (0.1 mol) of dihydrotabersonine perchlorate were added dissolved in 3000 ml of methanol and then with 900 ml of water, 100 ml of 2N hydrochloric acid solution and 25.76 g (0.11 mol) of bis- succinyl peroxide (on those determined by titration active peroxide content calculated) added. The mixture was stirred at 40 ° C for 6 hours. The one in the Sample taken from the reaction mixture by high pressure Liquid chromatography determined degree of conversion was 81.8%, of which 72.0% was vincamine and 9.8% on 14-epivamin.

The reaction mixture was then concentrated to 1 liter, with 15 ml of 60% perchloric acid, and that excreted vincamine perchlorate was filtered off. The crude product obtained in this way was with 300 ml of water and 300 ml of dichloromethane are added, and the pH of the mixture was adjusted with concentrated ammonium hydroxide solution set to 9. After shaking the phases were separated; the watery Phase was extracted twice with 50 ml dichloromethane; the organic phases were combined with dried anhydrous sodium sulfate, under reduced pressure Concentrated pressure to 50 ml, then with 500 ml of methanol added and again concentrated to 50 ml. The on this The methanol solution obtained in this way was cooled to 0 ° C. the crystals which separated out were filtered off with washed cold methanol and dried at room temperature. In this way, 25.1 g of vincamine 70.9% of theory Th.) Received; the same with the conversion 14-Epivincamin is in the mother liquor remained of crystallization.  

Example 4

The procedure was as described in Example 1, with the difference that to the oxidation of 43.85 g (0.1 mole) of dihydrotabersonin instead Bis-succinyl peroxide 28.84 g (0.11 mol) of bis-glutaryl peroxide were used. In this case the Degree of conversion measured in the reaction mixture of the oxidation 73.5% (64.0 vincamine and 9.5% 14-epivamine); in the crystallization were considered the primary product 19.1 g vincamine and another 5.8 g after epimerization Vincinc obtained, so that a total of 24.9 g of vincamine (70.3% of theory) were obtained.

Example 5

The procedure was as described in Example 1, with the difference that to the oxidation of 43.85 g (0.1 mole) of dihydrotabersonin instead Bis-succinyl peroxide 27.30 g (0.11 mol) glutaryl succinyl peroxide were used. In this case it was the degree of conversion measured in the reaction mixture of the oxidation 70.2% (61.6% vincamine and 8.6% 14-epivamine); in the crystallization were considered primary Product 18.0 g vincamine, and after epimerization receive another 5.8 g of vincamine, so that the total yield 23.8 g vincamine (67.3% of theory) was.

Example 6

43.85 g (0.1 mol) of dihydrotabersonine perchlorate were added dissolved in 3000 ml of methanol and then with 900 ml of water, 100 ml of 2N hydrochloric acid solution and 25.76 g (0.11 mol) of bis- succinyl peroxide (on those determined by titration active peroxide content calculated) added. The mixture was heated to 40 ° C and at this temperature  Stirred for 6 hours. The reaction mixture was then concentrated to 1 liter volume, with concentrated ammonium hydroxide solution made alkaline up to pH = 8.5 and then once with 500 ml and six times with extracted 250 ml of benzene. The gasoline phases were combined, dried with anhydrous sodium sulfate, then concentrated to 150 ml volume and overnight in Refrigerator left. The deposited crystals were filtered off, washed with cold benzene and dried (20.2 g). The mother liquor became Evaporated to dryness, the residue with 50 ml of methanol and 1 g of potassium tert-butoxide and the mixture Boiled under reflux for 3 hours. After cooling the reaction mixture was left in the refrigerator; the crystals which separated out 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 obtained. The in the reaction mixture of the oxidation by High pressure liquid chromatography determined degree of conversion was 77.8% (of which vincamine: 67.8%; 14-epivamine: 10.0%).  

Example 7

21 g (0.056 mol) of tabersonin hydrochloride were added 2000 ml of 75% methanol dissolved, with 30 ml of 2N hydrochloric acid solution and 14.52 g (0.062 mol) bis-succinyl- peroxide (on the active ones determined by titration Peroxide content calculated) added. The solution obtained was at room temperature with the exclusion of light  Left for 48 hours. The pale yellow, sour, aqueous methanol solution was then with 500 ml Diluted water with 25% aqueous ammonium hydroxide solution made alkaline and then with 400 ml of benzene once and with 100 ml of benzene each extracted three times. The benzene phases were merged, shaken with 200 ml of water, then with anhydrous Dried sodium sulfate and on a 100 g alumina column included. From the pillar first eluting the unreacted tabersonin with benzene; 4.0 g (21%) were obtained from this eluate Tabersonin regained. Then was with Benzene containing 2% by volume of ethanol eluted; the evaporation residue this eluate contained the products the oxidative rearrangement reaction: a mixture of 17,18-didehydro-vincamin and 17,18-didehydro-14-epivincamine (13.4 g). This crude alkaloid mixture was developed in 200 ml of anhydrous chloroform dissolved and with 20 g of anhydrous Formic acid and 11.3 g of acetyl chloride, and the mixture was allowed to stand at room temperature for 2 hours. Then the reaction mixture with 200 ml Diluted chloroform with 550 ml ice-cold sodium hydroxide solution and then shaken out with 100 ml of water, dried with anhydrous sodium sulfate and evaporated to dryness. The residue was 11.9 g 17,18-Didehydro-apovincamin (80.7% of that on the as Starting compound used tabersonin hydrochloride taking into account the recovered Starting compound calculated theoretical yield) receive.

Example 8

0.71 g (1.77 mol) isopropyl dihydrotabersonic acid hydrochloride were mixed in a mixture of 53.1 ml Dissolved methanol and 15.9 ml of water, and then  1.77 ml of 2N hydrochloric acid solution and 0.456 g (1.95 mol) Bis-succinyl peroxide added. The mixture became Stirred at 40 ° C for 6 hours and then under reduced pressure Pressure reduced to 20 ml volume. The pH the solution was concentrated ammonium hydroxide solution adjusted to 8.5 and the solution once with 15 ml and extracted six times with 8 ml of benzene each. The gasoline phases were combined with anhydrous sodium sulfate dried and evaporated to dryness. The residue was added to 20 g of Brockmann aluminum oxide (activity II) chromatographed and eluted with benzene. From the corresponding eluate fractions, 0.38 g of vincamic acid isopropyl ester and 0.03 g 14-epivaminic acid Isopropyl ester obtained (overall yield: 65.4% of theory).

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

0.1 g of sodium metal was dissolved in 50 ml of anhydrous isopropanol, 1.0 g of tabersonine base was added to the solution and the mixture was heated at 80 ° C. for 5 hours while introducing nitrogen gas. The progress of the transesterification reaction was monitored by thin layer chromatography (on an aluminum oxide layer, eluent: benzene; tabersonin: R _f = 0.60; tabersonin isopropyl ester: R _f = 0.71). After the reaction had ended, the reaction mixture was evaporated in vacuo and the residue was diluted with 30 ml of water and extracted three times with in each case 25 ml of benzene. 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 and the solution clarified with 10 g of aluminum oxide and filtered off, and the adsorbent remaining on the filter was washed out with benzene. The combined filtrate was evaporated; 0.92 g of tabersonic acid isopropyl ester (84% of theory) were obtained as the residue in the form of a chromatographically pure, oily product; [α] = -308 ° [c = 1, in methanol].

0.782 g (2 mmol) of the tabersonic acid Isopropyl ester was dissolved in 60 ml of ethanol dissolved and after the addition of 0.14 g of 10% palladium / Activated carbon catalyst hydrogenated to saturation. The catalyst was then filtered off and the filtrate evaporated to dryness. 0.73 g of [-] - dihydrotabersonic acid obtained isopropyl ester as a residue; [α] = -540 ° C [c = 1, in methanol]. This product was dissolved in 5 ml of ethanol and with 25 ml of n hydrochloric acid solution was added and the mixture was allowed to crystallize left in the fridge. The eliminated Crystals were filtered off, washed with cold ethanol and dried. In this way, 0.71 g crystalline [-] - dihydrotabersonic acid hydrochloride (1.77 mmol; 88% of theory); Mp 144-146 ° C; [α] = -388 ° [c = 1, in methanol].

Example 9

4.39 g (0.01 mol) of dihydrotabersonine perchlorate were added dissolved in 300 ml of methanol and the solution with 90 ml of water and 10 ml of 2N hydrochloric acid solution are added; 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 100 ml volume and mixed with 15 ml of 60% perchloric acid solution. The excreted vincamine perchlorate was filtered off, mixed with 300 ml of water and 300 ml of dichloromethane and the two-phase mixture with 25% ammonia solution made alkaline up to pH = 9. After shaking  the aqueous phase was separated off and each with 50 ml Extracted dichloromethane twice more. The organic Phases were combined with anhydrous sodium sulfate dried and filtered. The filtrate was in vacuo concentrated to 50 ml volume, then with 500 ml of methanol added and again concentrated to 50 ml. The on this The solution obtained in this way was left to stand at 0 ° C. for 2 hours, and then the deposited crystals separated by filtration. It was this way 2.63 g of vincamine (74.3% of theory) were obtained; that in smaller The amount of 14-epivamine formed is in the mother liquor remained. The in the reaction mixture by high pressure Liquid chromatography determined degree of conversion was 86.2%, of which 78.2% on vincamine and 8.0% 14-Epivaminamin accounted for.

Example 10

4.39 g (0.01 mol) of dihydrotabersonine perchlorate were added dissolved in 300 ml of methanol, with 90 ml of water, 10 ml of 2N Hydrochloric acid solution and finally with 2.5 g (0.011 mol) ammonium peroxydisulfate added. The mixture was at Stirred at 40 ° C for 4 hours, then to 100 ml volume concentrated and with 25% ammonium hydroxide solution until pH = 8.5 made alkaline, and the alkaline solution was mixed with 50 ml of benzene once and with 25 ml of benzene six times extracted. The benzene phases were combined with anhydrous Dried sodium sulfate and to 15 ml volume constricted. The solution contributed to crystallization Let stand at + 10 ° C for 6 hours, then the separated crystals separated by filtration. 2.2 g of vincamine (62.1% of theory) were obtained in this way. The mother liquor was evaporated and the residue with 5 ml of methanol and 0.1 g of potassium tert-butoxide are added and refluxed for 3 hours. The mixture became Let stand at 0 ° C for 2 hours. By separating the  deposited crystals were a further 0.78 g vincamine (22.0% of theory), so that the overall yield 84.1% of theory Th. The in the reaction mixture High pressure liquid chromatography determined degree of conversion was 86.2%, of which 78.2% on vincamine and 8.0% was accounted for by epivamine; the original one Epivincamine was epimerized into vincamine transferred.

Example 11

4.39 g (0.01 mol) of dihydrotabersonine perchlorate were added worked up in the manner described in Example 2, with the difference that instead of methanol acetone was used as a solvent. As the primary product were 2.0 g (56.5% of theory) and as a secondary product 0.71 g (20.0% of theory) of crystalline vincamine (overall yield 76.5% of theory Th.) Received. The one in the reaction mixture determined by high pressure liquid chromatography Conversion rate was 79.1%, of which Vincamin 70.4% and 14-Epivaminamine 8.7%. The originally created 14- Epivincamine was completely epimerized to vincamine.

Example 12

4.39 g (0.01 mol) of dihydrotabersonine perchlorate were added worked up in the manner described in Example 2, with the difference that the reaction at room temperature (25 ° C) with a reaction time of 8 hours has been. The primary product was on this 2.25 g of crystalline vincamine (63.6% of theory) and as a secondary product 0.74 g of crystalline vincamine (20.9% of theory), so that an overall yield of 84.5% of theory Th. Was reached. The one in the reaction mixture determined by high pressure liquid chromatography Conversion rate was 87.0%, of which on vincamine  79.0% and 14-epivaminamine accounted for 8.0%. That originally 14-Epivaminamine was generated by epimerization completely converted into Vincamin.

Claims (3)

1. Process for the preparation of vincamic acid derivatives of the general formula I wherein
R¹ is an alkyl group with 1 to 4 carbon atoms and R² and R³ each represent a hydrogen atom or both together represent a further bond between the two adjacent carbon atoms, and the corresponding 14-epivaminamic acid derivatives by oxidative rearrangement of the corresponding tabersonine derivatives of the general formula II wherein R¹, R² and R³ have the meanings given in the general formula I, characterized in that acid addition salts of compounds of the general formula II, wherein R¹, R² and R³ have the meanings given above, in aqueous organic solvents in the presence of acids with treated at least equimolecular amounts of ammonium peroxydisulfate, bis-succinyl peroxide, bis-glutaryl peroxide or succinyl-glutaryl peroxide or with a salt thereof. 2. The method according to claim 1, characterized in that one aqueous low molecular weight alkanol or aqueous acetone as Reaction medium used. 3. The method according to claim 1 or 2 for the preparation of vincamine, characterized in that dihydrotabersonine perchlorate or Dihydrotabersonin hydrochloride is used as the starting compound.