HU185720B - Process for preparing compounds with eburnane skeleton by means of the oxydation of tabersonine or dihydrotabersonine - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to a novel process for the preparation of the vincamic acid derivatives of formula (I) wherein R1 is a C1-4 alkyl group, R2 and R3 are each independently hydrogen or together with the two adjacent carbon atoms to form the corresponding 14-epivinkamic acid derivatives. by the oxidation of a Tabersonone derivative of Formula II wherein R1, R2 and R3 are as defined in Formula I, wherein the starting compound of Formula II wherein R1, R2, and R3 are as defined above. as defined above - in the presence of an acid in an organic solvent inert to the oxidizing agent, a hexavalent chromium or quaternary manganese compound soluble in this reaction medium, preferably chromium (VI) oxide, an alkali metal bichromate, an ester or complex of chromic acid as tertiary -butyl chromate or pyridinium chlorochromate or manganese (IV) dioxide or potassium permanganate. Arrow (II) -1-

Description

The present invention relates to a novel process for the preparation of eburnane backbone compounds such as vincamic acid and 17,18-dehydrovincamic acid esters by oxidative rearrangement of tabersonin or dihydrotabersonin (vincadifformin). More particularly, the present invention provides a process for the preparation of vincamic acid derivatives of formula I

R '· (C 1 -C 4) alkyl,

R ² and R ³ each independently represent a hydrogen atom or together form a double bond between two adjacent carbon atoms and to produce the corresponding 14-epivincamic acid derivatives a tabersonin derivative of formula II wherein R ¹ , R ² and R ³ are the same as As defined in formula (I) - by oxidation; The process according to the invention is characterized in that in the presence of an acid such as hydrochloric acid or acetic acid in a organic solvent inert to the oxidizing agent, the starting compound of formula III, wherein R ¹ , R ² and R ³ are as defined above hexavalent chromium or tetravalent manganese compound soluble in reaction medium, preferably chromium (VI) oxide, an alkali metal bichromate, an ester or complex of chromic acid such as tert-butyl chromate or pyridinium chlorochromate or manganese (IV) reacted.

Aspospospidine backbone compounds are known to undergo oxidative rearrangement and conversion to eburnan backbone compounds.

As early as 1964, E. Wenkert and B. Wickberg, in their study of the biosynthesis of eburnamonine-type indole alkaloids, assumed this pathway from tabersonin [J. Chem. Soc. 87, 1580-1589 (Apr. 5, 1965)], which was then. P. Kutney et al. Chem. Soc. 93, 255-257 (Jan. 13, 1971)]. Many attempts have been made to commercialize this known biosynthetic pathway since 1971, and several practically useful methods have been described in the literature for the preparation of vincamine-type compounds in this manner. Thus, U.S. Patent No. 761,628. According to a Belgian patent, dihydro-tabersonin is treated with an equimolar amount of a peroxide to N-oxydihydrotabersonone, followed by treatment with an additional 1 molar equivalent of peroxide for 3-5 days to give 1,2-dehydro-16-carbomethoxy-16-hydroxy-N-oxy-aspidospermidine. oxidized; the latter compound was converted to a mixture of vincamine, 14-epivincamine and apo vincamine by treatment with a reducing agent, preferably triphenylphosphine. Peroxides to be used as oxidizing agents as used herein include organic peracids such as peracetic acid, peracetic acid, perbenzoic acid, or substituted derivatives of the latter; as m-chloro or p-nitro-perbenzoic acid.

No. 763,730. According to Belgian Patent Specification (Belgian Patent No. 761,628), they may also be used as oxidizing agents in the presence of alkyl peroxides, lead tetraacetate or oxygen in the presence of a catalyst such as platinum oxide.

No. 765,795. According to a Belgian patent, the same procedure was carried out starting from (+) -dihydrotabersonin, yielding a form of vincamine, 14-epivincamine and apovincamine (3β, 16β) with a reaction time of 1-5 days.

It is also an improvement of the above procedure in U.S. Patent No. 837,049. Belgian patent, according to which dihydrotabersonin is oxidized in the form of an organic carboxylic acid salt with organic persaw (p-nitroperbenzoic acid) and thus the oxidation does not result in the formation of N-oxide, but rearrangement to 1,2-dehydro-16-methoxycarbonyl. 16-hydroxy-aspidospermidine was already carried out with 1.1 molar equivalents of peracid.

No. 848,475. According to Belgian Patent Application, an acid addition salt of tabersonin, such as its hydrochloride or perchlorate, was hydrogenated to give the corresponding salt of dihydrotabersonin, followed by equimolecular addition of peracid with m-chloro or pnitro-perbenzoic acid. with a reaction time, a mixture of vincamine and 14-epivincamine was obtained directly.

No. 856,723. According to a Belgian patent, tabersonin or dihydrotabersonin were reacted with a carbanion-forming agent, such as sodium hydride or sodium amide, followed by oxygen oxidative rearrangement and reduction of the resulting product. After reaction at room temperature and acidification of the reaction mixture, the product was obtained as a mixture of vincamine and epivincamine or, in the case of tabersonin, the corresponding 17,18-dehydro compounds in a yield of about 35%.

No. 870,978. according to a Belgian patent, an acid addition salt of dihydrotabersonin was oxidized with hydrogen peroxide in the presence of vanadium, chromium, molybdenum or tungsten salts; Thus, rearrangement occurred at room temperature within 4 days and predominantly vincamine was produced with much less epivincamine.

No. 0 038 619. European Patent Application Publication No. 889,119 discloses that (-) -dihydrotabersonone is oxidized with ozone in an acidic medium, and the resulting intermediate is treated with a base; According to a Belgian patent, the reaction was carried out with oxygen gas in the presence of a photosensitizing agent.

Of the above known processes, older methods based on Noxid conversion are no longer economical due to their relatively low production rates, and the common disadvantage of most known processes, the extremely long reaction time, usually 1 to 5 days, by-product formation. In addition, the use of organic peracids recommended as oxidizing agents in most known processes is advantageous only in laboratory scale, because in industrial scale, the sensitivity of the peracids to heavy metal ions causes technological problems and greatly complicates the control of larger scale reactions.

It has been found that the above drawbacks can be largely eliminated and the oxidative sham reaction can be effected in a short time without adverse side effects.

185,720 can be accomplished by using a chromium (VI) or manganese (IV) compound as an oxidizing agent in the presence of an acid. Suitable compounds for the oxidation of hexavalent chromium or tetravalent manganese include oxides such as chromium trioxide or manganese dioxide, salts such as sodium bichromate or potassium permanganate, and organic esters or complexes of chromic acid such as tert-butyl chromate or pyridinium chlorine; the oxidation reaction may be carried out at room temperature to about -70 ° C, depending on the oxidizing ability of the chromium or manganese compound used as the oxidizing agent; the use of mildly oxidizing permanganates is preferably carried out at room temperature, while the use of particularly strong oxidizing chromium trioxide and bichromates and manganese dioxide is carried out under vigorous cooling, preferably at temperatures between -50 ° C and -70 ° C. Depending on the nature and solubility of the oxidizing agent used, the reaction medium may be an organic solvent such as chloroform, tetrahydrofuran or a lower aliphatic alcohol, preferably concentrated acetic acid or a dilute mineral acid such as aqueous hydrochloric acid.

The reaction mixtures obtained by the oxidative rearrangement reaction of the chromium (VI) or manganese (IV) compounds using the chromium (VI) or manganese (IV) compounds according to the process of the invention can be worked up in the usual manner by evaporation, extraction and / or chromatography. In addition to vincamine and 17,18-dehydro-vincamine, the reaction product generally also contains a smaller amount of 14-epivincamine and 17,18-dehydro-14-epivincamine; this 14-epi compound can be epimerized to vincamine or 17,18-dehydrovincamine, if desired, without isolation from the main product vincamine or 17,18-dehydrovincamine, if desired. The starting material which is not converted in the oxidative rearrangement reaction can also be isolated during the preparation of the final product and returned to a subsequent oxidation step; In this way, the desired end product is obtained with low loss, good yield and very good purity.

Practical embodiments of the process of the invention are illustrated by the following examples.

alkaline with ammonium hydroxide solution to pH 8.5 and extracted three times with 40 ml each of dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on Brockmann's alumina 111 activity; first eluting with benzene the unconverted dihydrotabersonone (1.3 g, 65%) and then eluting the resulting vincamine and 14-epivincamine mixture with a 98: 2 mixture of benzene and ethanol from the adsorbent. From the latter eluate, 0.55 g (26.3%) of a mixture of vincamine-pivincamine is obtained, which according to the analysis of the sample of the crude product contains 81% vincamine and 19% 14-epivincamine.

To epimerize the? 4-epivincamine present in the product, 3 ml of methanol and 0.08 g of potassium tert-butylate were added to the crude product mixture and the mixture was heated under reflux for 3 hours. The reaction mixture was then cooled to 0 ° C and the product crystallized as now pure vincamine was isolated by filtration. The product has the same physical constants as the authentic sample: mp 230-232 ° C; [α] D + 41 ° (c -1, chloroform); M ⁺ = 354; IR 1756,1074,747 and 727 cm * ^1st

The unconverted dihydrotabersonin recovered by chromatographic separation can be re-oxidized, yielding a useful conversion of 70.1% based on the starting material actually consumed.

Example 2

A solution of 2.0 g (5.9 mmol) of dihydrotabersonin in 420 ml of chloroform and 150 ml of glacial acetic acid was cooled to 0 ° C, followed by a solution of 4 g of chromium (VII) oxide and 8 g of tert-butanol in 160 ml of n-hexane. a solution of tert-butyl chromate is added. After stirring at 0 ° C for 30 minutes, work up as in Example 1. The crude product obtained was a 82:18 mixture of vincamine and epivincamine (1.1 g; 52.7% of theory); unreacted dihydrotabersonone is not present.

Example 1

A solution of dihydrotabersonone (2.0 g, 5.90 mmol) in glacial acetic acid (150 mL) and chloroform (420 mL) was cooled to -55 ° C and a solution of chromium (VI) oxide (1.0 g, 10 mmol) in acetic anhydride (372 mL) was added dropwise. and the mixture was stirred at the same temperature for 30 minutes, then poured into ice water and basified to pH 8.5 with 25% ammonium hydroxide. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is dissolved in 150 ml of methanol, 45 ml of water and 5 ml of 2N hydrochloric acid are added and the mixture is left at room temperature for 2 hours. The solution was then concentrated in vacuo to a volume of 50 ml and the residue was 25%

Example 3

To a solution of dihydrotabersonin (1.01 g, 3 mmol) in chloroform (50 mL) was added glacial acetic acid (1 mL) and acetic anhydride (0.2 mL), and the mixture was cooled to -55 ° C and 5.2 g (60 mmol) of -dioxide was added and the mixture was stirred at the same temperature for a further 2 hours. The reaction mixture was poured into ice water, basified to pH 8 to 9 with 25% aqueous ammonium hydroxide solution, the organic solvent layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was dissolved in 80 ml of methanol, 20 ml of water and 2.5 ml of 2N hydrochloric acid were added and

The mixture was allowed to stand at room temperature 185 729 for 2 hours. The solution was then concentrated to a volume of 25 mL, the residue was basified to pH 8-9 with 25% aqueous ammonium hydroxide solution and extracted with dichloromethane (3 x 20 mL). The organic solvent layers were combined, dried over anhydrous sodium sulfate, filtered, and chromatographed on Brockmann activity III alumina. The unconverted dihydrotabersonone (0.56 g, 55.4%) was first eluted with benzene, then eluted with a 98: 2 mixture of benzene and ethanol to give 0.24 g of vincamine-pivincamine mixture (24.7%).

To epimerize the 14-epivincamine present in the product, 1.3 ml of methanol and 0.03 g of potassium tert-butylate were added to the crude product, and the mixture was refluxed for 3 hours. The reaction mixture was then cooled to 0 ° C and the product which had crystallized to form pure vincamine was isolated by filtration. The resulting vincamine melts at 230-232 ° C; [.alpha.] D @ 20 = + 41 DEG (c = - 1, chloroform).

The unreacted dihydrotabersonin recovered by chromatographic separation can be re-oxidized, resulting in a useful conversion of 54.5% based on the starting material actually consumed.

It is dried over um sulfate, filtered and the filtrate is chromatographed on Brockmann activity III alumina. The adsorbent was first eluted with benzene to give the unconverted dihydrotabersonone (0.07 g, 70%), then benzene: ethanol (98: 2) to give 0.15 g (15%) of the vincamine-epivincamine mixture. can be converted to pure vincamine as described in the previous examples.

The useful conversion rate, calculated on the basis of recovered and reusable dihydrotabersonin, is 50%.

Example 6

The procedure described in Example 1 was followed except that 2 g of tabersonin base were used as starting material instead of dihydrotabersonin. After working up the reaction mixture as described, 0.34 g of the product (80% of a mixture of 17,18-dehydro-vincamine and 20% of 17,18-dehydro-4-epivincamine; 16.4% of theory) is obtained. The amount of recovered unconverted starting material was 1.28 g (64%); so the useful conversion is 45.2%.

Example 4

To a solution of 1.0 g (3 mmol) of tabersonin base in 50 mL of chloroform was added 1 mL of glacial acetic acid and 0.2 mL of acetic anhydride, followed by cooling to -55 ° C and 5.2 g (60 mmol) of active manganese (60 mL). IV) oxide is added and the reaction mixture is further treated as described in Example 3 and the resulting crude reaction product is chromatographed as described therein. Elution with benzene yielded first 0.38 g (38%) of the non-converted tabersonin, followed by 0.17 g (17%) of 17,18-dehydro-vincamine and 17,18-dehydro-14-epivincamine in a 98: 2 mixture of benzene and ethanol. yielding a reaction product of the mixture which can also be converted to pure 17,18-dehydrovincamine as described in Example 3; mp 218-220 ° C; [α] D = + 115 ° (c = 1, chloroform).

Useful conversion rate calculated from unreacted starting material recovered

27.5%.

Example 7

The procedure described in Example 2 was followed except that 2 g of tabersonin base were used as starting material instead of dihydrotabersonin. After working up the reaction mixture, 0.72 g (79.8% of a mixture of 17,18-dehydro-vincamine and 20.2% of 17,18-dehydro-14-epivincamine; 34.7% of theory) is obtained. .

Example 8

The same procedure as in Example 2 was followed except that 3.8 g (17-7 moles) of pyridinium chlorochromate was used as the oxidizing agent. 0.94 g of a mixture of vincamine-epivincamine (45.3% of theory) was obtained, containing 81% of vincamine and 19% of 14-epivincamine.

Example 9

Example 5

Dihydrotabersonone (0.1 g, 0.295 mmol) in methanol (7.5 mL) was added followed by water (2.25 mL), 2N hydrochloric acid (0.25 mL) and potassium permanganate (0.05 g, 0.32 mol). After stirring at room temperature for 10 hours, the mixture was concentrated under reduced pressure to a volume of 2.5 ml, basified to pH 8 with 25% aqueous ammonium hydroxide solution and extracted three times with 2 ml of dichloromethane. The organic layers were combined, anhydrous sodium

Dihydrotabersonin (0.1 g) was dissolved in tetrahydrofuran (25 mL), glacial acetic acid (0.75 mL) was added and the mixture was cooled to -65 ° C, followed by stirring at this temperature with 0.3 g sodium bicromate dihydrate in 1.5 mL water and 0.2 mL. A solution of 1 ml of concentrated sulfuric acid was added dropwise so that the temperature of the reaction mixture did not rise above -50 ° C. The reaction mixture was then cooled again to -65 ° C and stirred at this temperature for 3 hours under a nitrogen atmosphere and then poured into ice-water (20 ml).

It was basified to pH 8 with 185 720% ammonium hydroxide solution. The basic mixture was extracted with dichloromethane (3 x 25 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness. The dry residue was added in methanol (7.5 mL), water (2.5 mL) and 2N hydrochloric acid (0.25 mL) were added and the mixture was allowed to stand at room temperature for 3 hours and then under reduced pressure (3 m). to volume. Water (10 mL) was added to the residue, adjusted to pH 8, and extracted with dichloromethane (3 x 5 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and chromatographed on a Brockmann alumina column III activity column. Elution with a 98: 2 (v / v) mixture of benzene and ethanol afforded 0.078 g of a vincamine-epivincamine mixture, which corresponds to a 78% conversion.

Example 10

0.8 g of tert-butyl alcohol and 16 ml of n-hexane are added and the solution is cooled to 0 ° C. To this solution was added, while stirring, 0.4 g of chromium trioxide, which was dried over 1 g of solid anhydrous magnesium sulfate, filtered, and the filtrate was the oxidizing agent.

Dissolve 0.5 g of dihydrotabersonin base in 50 ml of dichloromethane, add 5 ml of glacial acetic acid and cool to 0 ° C and add. previously prepared t-butyl chromate solution. After stirring for half an hour, 12.5 ml of concentrated aqueous ammonium hydroxide solution was added. The organic phase was separated from the aqueous phase, the aqueous phase was extracted with dichloromethane (2 x 20 mL), and the combined organic phases were dried over solid anhydrous sodium sulfate and filtered.

The filtrate is chromatographed as in Example 3 below.

The amount of non-converted dihydrotabersonin was 0.29 g (58%) and the weight of the vincamine-epivincamine mixture was 0.14 g (26.8%).

Claims (5)

Patent claims A process for the preparation of a vincamic acid derivative of the Formula I wherein R ^{1 is C} 1 -C 4 alkyl, R ² and R ³ each independently represent a hydrogen atom or a double bond between two adjacent carbon atoms - and a tabersonin derivative of formula II for the preparation of the corresponding 14-epivincamic acid derivatives - in which R ¹ , R ² and R ³ the meanings given under the general formula (I) defined as in - the oxidation and, if desired the 14-epimers separately, and / or by the 14-epi derivatives epimerisation, characterized in that in (II) of the formula starting compound - wherein R ¹ , R ² and R ³ are as defined above, in the presence of an acid, with a hexavalent chromium or tetravalent manganese compound soluble in the reaction medium in an inert organic solvent. 2. The process of claim 1 wherein the hexavalent chromium compound is chromium (VI) oxide or a salt, ester or complex of chromic acid. 3. The process of claim 1 wherein the hexavalent chromium compound is an alkali metal bichromate, tert-butyl chromate or pyridinium chlorochromate. 4. A process according to claim I wherein the tetravalent manganese compound is manganese (IV) dioxide or potassium permanganate. 5. The process of claim 1 wherein the acid is hydrochloric acid or acetic acid.