CH657617A5 - PROCEDURE FOR THE PREPARATION OF VINCAMINA. - Google Patents

Description

The present invention relates to the preparation of vincamine having the formula:

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I HAVE.

Vincamine is an indole alkaloid that has been isolated from Vinca Minor from which it is still extracted.

Vincamine has interesting therapeutic properties that make it suitable for an effective treatment of cerebro-vascular disorders. Various methods of synthesis, both partial and total, of vincamine as well as other indole alkaloids of the same family are known.

As far as the total synthesis is concerned, the one described in the US patent No. 3,454 583 (Kuehne) can be mentioned which provides a rather complex series of reactions starting from tryptamine and 4-etiI-formyl-dimethylpimelate.

By partial synthesis is meant the preparation of vincamine from other indole alkaloids.

The semi-synthetic obtainment of vincamine and its derivatives starting from the alkaloids of the aspidosperm type (tabersonin and its dihydroderivative, ie vincadifformin) is for example described in the Belgian patents. 761 628 and 763 730.

According to this process, vincamine is prepared through a process which schematically envisages the following stages:

a) hydrogenation of tabersonin to 14,15-dihydrotabersonin, or vincadifformin;

b) oxidation in two stages with a vincadifformin peracid

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to N-oxy-16-hydroxy-vincadifformin, preferably with isolation of the intermediate compounds;

c) reduction and transposition of the previous intermediate, with triphenylphosphine and in acid medium with the obtainment of a mixture of vincamine, epivincamine and apovincamine, from which the desired compound is subsequently isolated. In the Belgian patent 837 049, an improvement is described to the process just described, consisting in the fact that vincadifformin, before treatment with a peracid, is salified with an organic acid, such as for example acetic, trichloroacetic or trifluoroacetic acid . The resulting salt is then reacted as described in the general process previously described, except that the reduction step with triphenylphosphine is omitted.

In this case, in essence, a teaching provided in the Swiss patent 625 239, in the name of Buskine, appears to be used, which will be considered in more detail later, consisting in preventing the oxidizing attack at the nitrogen atom in position 4 of the starting tabersonin or vincadifformin, thus avoiding the formation of the N-oxy-16-hydroxy derivative through which all the previous semi-synthesis processes passed.

The one described in the published German patent application n. No. 2 745 415, in which vincadifformin, transformed into an addition salt with an acid, is subjected to oxidation with hydrogen peroxide in the presence of a water-soluble metal salt of vanadium, chromium, molybdenum or wolframio.

As already mentioned, in the previous Swiss patent 625 239 a process for the preparation of vincamine starting from tabersonin or vincadifformin was described and claimed, which provided for a single oxidation step with oxygen in the presence of an organic or inorganic salt of Cu, Fe o Co. More specifically, according to this process, having the undoubted industrial advantage of not involving isolation phases of intermediate products, the reaction is carried out at a temperature ranging from 10 to 50 ° C and for a time ranging from 5 to 15 days.

One of the problems which have remained unsolved so far with the previously known processes is that of the long duration of the transformation of the starting alkaloid, regardless of the number of process stages, a duration which is on the average of the order of a few days.

This problem, which is undeniably extremely important, is accompanied by that of the yields in vincamina, so that simpler and / or shorter processes are accompanied by lower yields.

A further problem, which is also very important from an industrial point of view, is that of the need to separate intermediate compounds, since the relative operations affect the overall duration and therefore the costs of the transformation.

The main object of the present invention is to provide a process for the preparation of vincamine which is both short and simple from an industrial point of view and has good yields in the desired active principle.

This object is achieved with a process for the preparation of vincamine having formula (I) or of l4-vincamine, by oxidation and subsequent transposition starting from a solution of vincadifformin and respectively tabersonin, characterized in that said starting solution , prepared in a polar solvent and kept at a temperature not higher than + 5 ° C, a protective agent is added, after which oxidation is carried out with a peracid selected from permaleic acid and peracetic acid, and at the end of the addition of the peracid, the transposition is carried out by heating the reaction mixture at a temperature between 20 and 50 ° C.

In accordance with a first embodiment of the process according to the invention, the protection agent is constituted by a copper salt and in correspondence with said increase in temperature of the reaction mixture, the latter is added with a reducing agent, such as sodium meta-bisulfite, sulfur dioxide.

In this case, the addition of copper salt to the starting solution is carried out in the ratio between the starting compound and the copper salt comprised between 1; 1 and 10: 1 by weight, preferably 5: 1.

The total duration of the transformation of the starting alkaloid is drastically reduced, taking into account the fact that the duration from the peracid addition phase depends only on the need to control the temperature below + 5 ° C as the reaction has an exothermic course .

Since the transposition and therefore maintenance phase at a temperature of 30-50 ° C has an average duration of 2-3 hours, the whole reaction requires a time of the order of 5-6 hours.

As regards the yields in vincamina, or of the analogous derivative having a double bond in 14.15 when starting from tabersonin, it is higher than 70% referred to the starting compound.

The preferred reaction solvent is methanol and the temperature during the addition of the oxidizing medium is preferably controlled at values between -5 ° C and 0 ° C.

When the oxidizing medium is permalic acid, this can be prepared directly and promptly from malleic anhydride and hydrogen peroxide in a per se known manner (possibly also formed in the reactor itself).

Preferably, at the end of the addition of peracid, when permaleic acid is used, a filtration is carried out with the sole purpose of removing the copper salt which in the meantime has re-precipitated and is reusable.

On the other hand, in the case of peracetic diacid as an oxidizing medium, the reaction mixture, before the aforementioned increase in temperature, is treated with a chelating resin, preferably of the polystyrene type with aminophosphonic, amino-diacetic or aminoxic functional groups with the aim of eliminating the salt. copper.

Alternatively, this elimination can be carried out by extraction of the reaction mixture with an apolar solvent, such as chloroform, toluene or methylene chloride, and washing with ammonia solution.

However, it must be specified that the elimination of the copper salt is not indispensable for the purposes of the following reaction stage, but only advisable with regard to the yields of the active principle.

The temperature of the subsequent transposition step is, as already mentioned, between 30 and 50 ° C, preferably between 35 and 40 ° C.

In conjunction with the increase in temperature, it is convenient to check that the pH of the reaction mixture is acidic and between 6 and 2.5.

The exact value depends on the starting compound and the desired composition (relationship between vincamine and epivincamine) in the final mixture obtained.

The possible adjustment is done in an obvious way.

The addition of reducing agent in this step, although not indispensable, appears preferable for the purposes of subsequent purification, which can be carried out with traditional methods well known in the art.

In the final reaction mixture when starting from vincadifformin and operating at pH 3, the predominant presence of vincamine is observed, whose ratio with the epi-vincamine, also present, is greater than 4: 1.

If, on the other hand, the starting compound is tabersonin, a stage known per se of catalytic hydrogenation is provided for the saturation of the double bond in position 14-15.

In the second embodiment, the solution kept under stirring in a nitrogen atmosphere, is added with

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oxalic acid, in excess of the stoichiometric ratio with the starting alkaloid which constitutes the protective agent, the acid being added to the methanolic solution in solid form.

Upon complete dissolution of the acid, the reaction mixture is preferably cooled to -5 ° C and oxidized by dropwise addition of a maleic anhydride solution in hydrogen peroxide.

During the addition of the oxidizing solution (30-40 minutes) the reaction mixture is cooled to a temperature preferably lower than -2 ° C.

Peracetic acid can be used in place of permaleic acid.

At the same temperature, an aqueous sodium metabisulphite solution is subsequently added, having the purpose of both bleaching the reaction mixture and eliminating any residual oxidizing medium therefrom, the presence of which during the transposition would cause the formation of unwanted by-products.

After filtration, the resulting solution is heated to 30-35 ° C and kept at this temperature for 3-4 hours; the inorganic precipitate is separated, and an alkaline solution (preferably an aqueous solution of ammonia) is added to the clear filtrate to bring the reaction mixture to pH = 9.

The insulation of the desired compound is then passed, respectively vincamine or A I4-vincamine, according to the starting compound. The transposition phase can also be carried out at a temperature lower than 30 ° C, without however falling below 20 ° C, provided that the duration of the phase is correspondingly increased. Thus the concept of the net change in temperature between the oxidation and transposition phases remains unchanged.

The following examples illustrate the method according to the invention as a non-limiting example.

Example 1

A solution of vincadifformin (20 g) in methanol (600 ml) cooled to 0-5 ° C was added with Cu SO4 • 5 H2O (4 g) giving rise to a practically complete solution.

To the mixture, kept under stirring, a solution of maleic anhydride (11.7 g) was added dropwise, for 30 minutes, in 40% H2O2 (10 ml). After filtration of the reprecipitated copper salt, using celite (2.5 g) as an adjuvant, the solution was added with a 10% aqueous solution of Na2S2C> 5 (150 ml) and heated to 35-40 ° C for 2.5 hours.

The reaction mixture was then diluted with a 5% aqueous solution of NaCl (1 lt) and, under stirring, brought to pH 8.5 by adding 30% aqueous ammonia solution.

The precipitate, filtered, washed with water, then with a little cold methanol and dried at 70 ° C provided a mixture (about 9: 1) of vincamine and epi-vincamine.

From this material, taken up in methanol (200 ml), boiled under reflux for 15 minutes, cooled to room temperature and filtered, vincamine (10.1 g) was obtained.

The filtering mother liquors of the crude product were extracted with chloroform (3 x 250 ml).

The chloroform extract was washed in succession with 2% NaOH and 10% aqueous solution of NaCI; dried on Na2S04, filtered and evaporated to dryness, under reduced pressure. The residue was combined with the methanol mother liquors of the first vincamine crop and methylated sodium (I g) added. The reaction mixture was boiled under reflux for 30 minutes and then concentrated by distillation to a residue of about 50 ml. The crystalline precipitate, after cooling to room temperature, was filtered, washed with a little methanol, then with water and dried at 70 ° C to give a second vincamine crop (2.4 g).

Example 2

A solution of vincadifformin (20 g) in methanol (600 ml) was treated with Cu SO4 • 5H20 (4 g) and cooled to 0 ° C; then under stirring, 17 ml of 34% peracetic acid were added dropwise for 30 minutes and keeping the temperature below 4 ° C.

After addition of acetic acid (250 ml), the reaction mixture was added with chelating resin Duolite ES 466 (20 ml) and kept under stirring for 60 minutes by heating at 40-45 ° C. After filtering the resin, the reaction mixture was diluted with H2O (500 ml), brought to pH 9 with 30% ammonia, and extracted with chloroform (3 x 250 ml).

The chloroform extracts, washed with 1% NaOH solution and 5% NaCI solution, and dried on Na2S04, were concentrated under reduced pressure and taken up with methanol. The solution was then concentrated by distillation until incipient crystallization (250 ml) with the addition of methylated sodium (3 g) and heated under reflux for 30 minutes.

After concentration at half volume, and cooling to room temperature, the reaction product was recovered by filtration, washed with water and, subsequently, with little methanol, and dried at 70 ° C to give vincamine (11.6 g).

Example 3

a) A solution of tabersonin (40 g) in methanol (1 lt) kept under stirring, was added with CUSO4 • 5 H2O (4 g) and cooled to 0 ° C.

34% peracetic acid (34 ml) was then added dropwise for 75 minutes and the temperature maintained between 2 and 4 ° C. The reaction mixture was then left overnight at room temperature diluted with H2O brought to pH 9 with 30% ammonia and extracted with chloroform (3 x 400 ml). The extracts were combined, washed with 2% NaOH, then with water, dried over Na2SO4 and concentrated to about 200 ml. After precipitation with n.hexane, filtration and drying at 70 ° C, a product (26.5 g) consisting of A 14-epivincamine to A 14-vincamine was obtained in a ratio of about 13: 1.

The further concentration of the mother liquors provided other product (5.6 g) consisting of A 14-epivincamine and A 14-vincami-na in a 2: 1 ratio.

b) In a repeat of the experiment, at the end of the addition of peracid, the reaction mixture was treated with chelating Duolite ES-467 resins (50 ml) and kept under stirring for 30 minutes at 35-40 ° C.

At the end of this period an examination by thin-layer chromaghage showed the practically complete transformation into A 14-epivincamine and A l4-vincamine.

After separation of the resin by filtration, the processing carried out as described above resulted in comparable results.

c) In a further repetition of the experiment [conducted as in_b)] the chloroform extract, dried on NaiS04, was evaporated to dryness under vacuum. The solid residue obtained was taken up with methanol (800 ml), added with methylated sodium (5 g) and boiled under reflux for 2.5 hours and then concentrated in the full up to 500 ml.

After cooling to room temperature, the separated crystalline product was filtered, washed with methanol, then with water, and dried at 70 ° C to give A4-vincamine (17 g).

A second crop (3.5 g) of A4-vincamine was obtained by concentration of the mother liquors.

Example 4

A solution of tabersonin (20 g) in methanol (600 ml) cooled to 0-5 ° C kept under stirring, was added with Cu SO4 • 5H2O (2 g). A maleic anhydride solution (11.7 g) in 40% H2O2 (10 ml) was added dropwise, during 20 minutes, to the mixture. At the end of ag5

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once the reaction mixture was reached, it was saturated with gaseous SO2 for about 10 minutes, while the temperature was raised to 35-40 ° C.

After holding for 90 minutes at this temperature the processing of the reaction mixture was carried out as in example 3.

An analysis by high pressure liquid chromatography of the chloroform extract content showed the obtainment of A 14-epivincamine at A 14-vincamine in a ratio of about 1: 1 for a total of 16.4 g.

Example 5

Oxalic acid dihydrate (27 g) is added to a solution of vincadifformin (50 g) in methanol (1500 ml) cooled to -5 ° C in a nitrogen atmosphere.

Then, under stirring always in a nitrogen atmosphere, a separately prepared solution consisting of maleic anhydride (23.2 g) in hydrogen peroxide 130 volumes (20.2 ml) is added drop by drop, over a period of 30 minutes, keeping the temperature below -2 ° C.

Finally, at the same temperature, a 20% w / v aqueous solution of sodium metabisulphite (75 ml) is added drop by drop in 20 minutes.

After 30 minutes of stirring, the precipitated inorganic salts are filtered on Celite and the clear solution is stirred at 35 ° C for 4 hours. The reaction mixture is then brought to pH 9 by addition of 30% aqueous ammonia solution (120 ml).

The precipitate obtained, filtered, washed with methanol (50 ml) then thoroughly with water and dried at 70 ° C provides a first jet of vincamine (31.5 g).

The mother liquors are concentrated in vacuo to eliminate most of the methanol, diluted with water (600 ml) and extracted with chloroform (2 x 200 ml). Chlor-formic extracts, washed in succession with 2% w / v aqueous solution of sodium hydrate (120 ml), and with 5% w / v aqueous solution of sodium chloride (2 x 120 ml) and dried on sodium sulphate anhydrous, they are then evaporated to dryness under reduced pressure and taken up with methanol (200 ml). The solution, added with sodium methylate (1.5 g) is boiled under reflux for 30 minutes and then concentrated by distillation to a residue of about 80 ml.

After cooling to room temperature, the crystalline precipitate is filtered, washed with cold methanol (15 ml), then with water to neutrality and dried at 70 ° C to give a second jet of vincamine (9.8 g).

Example 6

To a solution of tabersonin (50 g) in methanol (1500 ml), kept under stirring in a nitrogen atmosphere, oxalic acid dihydrate (27 g) is added and, after having cooled to -5 ° C, is added drop by drop in the time of 40 minutes a separately prepared solution consisting of maleic anhydride (27.5 g) in hydrogen peroxide 130 volumes (23.7 ml). The temperature is kept below -2 ° C.

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At the same temperature, a 20% w / v aqueous solution of sodium metabisulphite (75 ml) is then added drop by drop in 20 minutes. After 30 minutes of stirring, the precipitated inorganic salts are filtered on Celite and the clear solution is stirred at 30-35 ° C for 3 hours.

The reaction mixture is diluted with water, brought to pH 9 by addition of 30% ammonia aqueous solution (130 ml) and extracted with chloroform (4 x 300 ml).

The extracts are combined, washed in succession with a 2% aqueous solution of sodium hydrate (300 ml), and with 5% w / v aqueous solution of sodium chloride (2 x 300 ml), dried on anhydrous sodium sulphate and evaporated at reduced pressure up to a volume of 300 ml. Methanol (800 ml) is added and distilled in the full until total elimination of the chloroform.

After cooling to room temperature, the crystalline product is filtered, washed with a little methanol and dried at 70 ° C to give a first jet of A 14-vincamine (22 g).

The methanolic mother liquors, added with methylated sodium (2 g) are boiled under reflux for 30 minutes and then concentrated in the tank up to about 80 ml. The crystalline product which separated after cooling to room temperature is filtered, washed with methanol, then with water until neutral and dried at 70 ° C to give a second jet of A 14-vincamine (17.3 g).

The advantages of the process according to the invention clearly appear from the previous examples.

Obviously in the examples relating to the use of tabersonin it is possible in a known way and at any stage of the process, to carry out a hydrogenation of the double bond in position 14-15.

It is also important to observe, and this most likely constitutes one of the characterizing aspects of the present invention, that at the end of the addition of the peracid the oxidation of the starting compound is completed: in fact the analysis of the reaction mixture at this point confirms the substantial formation of 16-hydroxy derivative of vincadifformin, at the time only hypothesized in the previously cited Swiss patent.

This derivative, in turn due to a simple increase in temperature and in an acid medium, undergoes direct transposition to vincamine and epi-vincamine (or to the corresponding A 14-derivatives if the starting compound was tabersonin). At the same time the same analysis shows the presence only in traces of the intermediate compounds (-) - N-oxy-vincadifformin and (-) - 1,2-of-dro-N-16-carbomethoxy-16-hydroxy-N-oxy aspidopermidine, described as well as claimed in the Belgian patents. 761 628 and 763 730 as obligatory intermediates in the preparation of vincamine.

This confirms the application of a protective action, by oxalic acid and copper salt respectively, in the sense of inhibiting or reducing to the level of traces the formation of N-oxides (indicated above) responsible for the complexity and duration significantly major of the previously known methods.

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Claims (20)

657 617 2. Process according to claim 1, characterized in that said protective agent is a copper salt, added in such an amount that the ratio between the starting compound and the copper salt is between 1: 1 and 10: 1. 2 CLAIMS 1. Procedure for the preparation of vincamine having formula (I) 20 I HAVE, MeOOC or A14-vincamine, by oxidation and subsequent transposition starting from a solution of vincadifformin and respectively tabersonin, characterized in that said starting solution, prepared in a polar solvent and kept at a temperature not higher than + 5 ° C, is added with a protection agent, after which oxidation is carried out with a peracid selected from permaleic acid and peracetic acid, and at the end of the addition of the peracid the transposition is carried out by heating the reaction mixture at a temperature between 20 and 50 ° C. 3. Process according to claim 1, characterized in that said protective agent is oxalic acid. 4. Process according to claim 3, characterized in that said oxalic acid is added to said starting solution maintained at -5 ° C in excess of the stoichiometric ratio with the starting alkaloid. 5. Process according to claim 4, characterized in that the addition of peracid is carried out to said solution, after all the oxalic acid is dissolved, maintained at -2 ° C. 6. Process according to claim 1, characterized in that said peracid is permalic acid prepared at the moment from maleic anhydride and hydrogen peroxide. 7. Process according to claim 1, characterized in that said polar solvent is a lower aliphatic alcohol. 8. Process according to claim 7, characterized in that said polar solvent is methanol. 9. Process according to claim 2, characterized in that said temperature of the mixture during the addition of said peracid is controlled at a temperature comprised between -5 ° C and 0 ° C. 10. Process according to claim 2, characterized in that said reaction mixture at the end of the addition of said peracid is treated so as to eliminate the copper salt contained therein. 11. Process according to claim 10, characterized in that said copper salt removal treatment when said peracid is permalic acid, consists of a filtration of the precipitated copper salt. 12. Process according to claim 10, characterized in that said copper salt removal treatment, when said peracid is peracetic acid, consists in the treatment with a chelating resin. 13. Process according to claim 12, characterized in that said chelating resin is a polystyrene macroporous polymer with aminophosphonic, amino-diacetic or amidoxymic functional groups. 14. Process according to claim 2, characterized in that said step at increased temperature is carried out at a temperature comprised between 35 and 40 ° C. 15. Process according to claim 1, characterized in that before or during said step at increased temperature the reaction mixture is added with a reducing agent. 16. Process according to claim 15, characterized in that said reducing agent is selected from sodium metho-sulphite and sulfur dioxide, sodium borohydride. 17. Process according to claim 1, characterized in that the pH of the reaction mixture at the end of the addition of peracid is controlled at a value between 6 and 2.5. 18. Process according to claim 3, characterized in that at the end of the oxidation phase the reaction mixture is added with sodium metabisulfite. 19. Process according to claim 3, characterized in that the transposition is carried out at a temperature of 20-35 ° C. 20. Process according to claim 3, characterized in that the transposition is carried out at a temperature of 30-35 ° C.