FR2534920A1 - Vincamine and 14,15-dehydro-vincamine prepn - Google Patents

Abstract

Process for the prepn. of vincamine (I) or 14,15-dehydro-vincamine (apovincamine) by oxidn. and then rearrangement of a soln. of vincadifformine or tabersonine respectively, is characterised in that a protecting agent is added to the starting soln., which is in a polar solvent at a temp. equal to or below 5 deg.C, then the oxidn. is effected with permaleic or peracetic acid, and when addn. of peracid is complete, the rearrangement is effected by heating the reaction mixt. at 20-50 deg.C. The protecting cpd. may be a copper salt, added in quantities such that the ratio of starting cpd. to copper salt is 1-10:1. The protecting agent may also be oxalic acid, which is added to the initial soln. at -5 deg.C, followed by addn. of the peracid at -2 deg.C. The polar solvent used is a lower aliphatic alcohol pref. methanol. The pH after addn. of the peracid is 6-2.5. Permaleic acid may be prepd. in situ from maleic anhydride and hydrogen peroxide. The peracid is added at -5 to 0 deg.C. At the end of the reaction the copper salt is sepd. When permaleic acid is used the precipitated copper salt is filtered off. When peracetic is used, the copper salt may be removed by chelation on a resin, such as a macroporous polystyrene polymer having amino-phosphonic, amino-diacetic or amino-oximic functional gps. The rearrangement is effected by heating at 30-50 deg.C, pref. 35-40 deg.C. Before or during this stage, a reducing agent, such as sodium metabisulphite, sulphur dioxide or sodium, may be added, which aids later purificn. Prepn. of vincamine used for the treatment of cerebrovascular troubles.

Description

 Procedure for the nincarnation of vincamine.

The present invention relates to the preparation of vincamine corresponding to the formula

Vincamine is an indolic alkaloid that was isolated from the Vinca Minor, from which it is still extracted
Vincamine is endowed with interesting therapeutic properties which make it suitable for the effective treatment of cerebrovascular disorders. Various methods of synthesis, partial or total, of vincamine are known, as well as other indole alkaloids of the same family.

 As regards the total synthesis, mention may be made of that described in US Pat. No. 3,454,583 (uehne) which provides for a fairly complex series of reactions starting from triptamine and 4-ethyl-formyl-dimethyl-pimelate.

 Partial synthesis, on the other hand, includes the preparation of vincamine from other indole alkaloids.

The semi-synthetic production of vincamine and its dorivates from alkaloids of the aspidosperma type (tabersonin and its dihydrate derivative, that is to say vincadiformin) is described, for example in Belgian patents No. 761,628 and 763,730. According to this process, the vincamine is prepared by a process which schematically provides for the following steps
a 'hydrogenation of tabersonine to 14,15-dihydro tabewsonineZ or vincadiformine
vs! two-stage oxidation by a peracid of vincadiformin to N-oxy-16-hydroxy-vineadiormin, preferably with isolation of the intermediate compounds
c) reduction and transposition of the above intermediate with triphenylphosphine and in an acid medium, obtaining a mixture of vincamine, epivincamine and apovincamine, from which the desired compound is then isolated.

 In Belgian patent No. 837.049, an improvement to the process which has just been described is described, consisting in that before the treatment with a peracid, vincadiformine is salified with an organic acid such as, for example, acetic acid, trichloroacetic acid or trifluoroacetic acid. The salt obtained is then reacted as in the general process described above, except that the reduction step by triphenylphosphine is omitted.

In this case it turns out roughly, that one uses a teaching provided in the Swiss patent nO 625.239 in the name of Buskine, which one will examine with more details in the continuation, consisting in preventing the oxidative fixing on the level of the nitrogen atom in position 4 of the initial tabersonine or vincadiformine, which prevents the formation of the derivative
N-oxy-16-hydroxy through which all the previous semi-synthetic processes passed.

 It is on the very principle of this process that is based that described in the German patent application No. 2.

745.415, in which vincadiformin, transformed into an addition salt by an acid, is subjected to oxidation by hydrogen peroxide in the presence of a water-soluble metal salt of vanadium, chromium, molybdenum or tungsten.

As already indicated, a process for the preparation of vincamine from tabersonin or vincadiformin, which provided for a unique oxidation stage with oxygen in the presence of an organic or mineral salt of
Cu, Fe or Co More particularly, according to this process, which had the undoubted industrial advantage of not comprising isolation phases of intermediate products, the reaction is carried out at a temperature between 10 and 500C and for a period varying from 5 to 15 days.

 One of the problems still insoluble by the previously known methods is that of the long duration of the transformation of the initial alkaloid, regardless of the number of treatment steps, which duration is on average of the order of a few days.

 To this problem of undeniable importance is added that of the yields of vincamine, because of which simpler processes and / or of shorter duration were accompanied by lower yields.

 Another problem, also very important from the industrial point of view, is that of the need to separate intermediate compounds, since the different operations have an impact on the overall duration and therefore on the cost of the transformation.

 The main object of the invention is a process for the preparation of vincamine, of short duration and simple from an industrial point of view, while exhibiting good yields of the desired active principle.

 This result is achieved by a process for the preparation of vincamine corresponding to formula (I) or of 14 -vincamine, by oxidation followed by transposition from a solution of vincadiformine and respectively of tabersonine, characterized in that one adds in the initial solution, prepared in a polar solvent and maintained at a temperature not higher than 50C, a protective agent, then the oxidation is carried out by means of a peracid chosen from permaleic acid and peracetic acid, and at the end of the addition of the peracid, the reaction mixture is transposed by heating to a temperature between 20 and 500C.

 According to a first embodiment of the method according to the invention, the protective agent consists of a copper salt and, at the time of said increase in temperature of the reaction mixture, the latter is added with a reducing agent, like for example sodium metabisulfite, sulfur dioxide.

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

 The total transformation time of the starting alkaloid is extremely reduced, taking into account that the duration of the peracid addition phase depends solely on the need to keep the temperature below + 50C, since the reaction has an exothermic appearance.

 Because the phase of transposition and therefore of maintaining at a temperature of 30 to 500 ° C. has on average a duration of 2 to 3 hours, the entire reaction requires a duration of the order of 5 to 6 hours.

 As regards the yields of vincamine, or of the analogous derivative exhibiting a double bond at 14.15 when starting from tabersonine, the yield is greater than 70%, relative to the initial compound.

 The preferred reaction solvent is methanol and the temperature during the addition of the oxidant is preferably set to values between -50C and OOC.

 When the oxidant is permaleic acid, it can be prepared directly and quickly from maleic anhydride and hydrogen peroxide, in a manner known per se (it can also optionally be formed in the reactor itself).

 Preferably, to add peracid, when permaleic acid is used, filtering is carried out with the sole purpose of separating the copper salt which is meanwhile reprecipitated and therefore reusable.

 On the other hand, in the case where peracetic acid is used as oxidant, the reaction mixture is treated, before the abovementioned temperature increase, with a chelating resin, preferably of the polystyrenic type with aminophosphonic functional groups. , amino-diacetic or amino-oxymic, having the role of separating the copper salt.

 Alternatively, this separation can be carried out by extracting the reaction mixture with a nonpolar solvent, such as chloroform, toluene or methylene chloride, and washing with an ammoniacal solution.

 It should however be pointed out that the elimination of the copper salt is not essential for the subsequent reaction stage, but only recommended for the yields of active principle.

 The temperature of the subsequent transposition phase is, as already mentioned, between 30 and 50 ° C., preferably between 35 and 400 ° C.

 In connection with the increase in temperature, care should be taken to ensure that the pH of the reaction mixture is acidic and between 6 and 2.5.

 The exact value depends on the initial composition and the desired composition (relationships between vincamine and ltepivincamine) in the final mixture obtained.

 This possible adjustment is carried out in itself obvious.

 Although not essential, the addition of a reducing agent during this phase turns out to be preferable for the subsequent purification which can be carried out by ceramic processes and well known in the art of this branch.

 In the final reaction mixture, when starting from vincadiformin and operating at pH 3, the preponderant presence of vincamine is observed, the ratio of which to eivivincarmine, also pulsating, is greater than S i.

 If, on the other hand, the initial compound is taberso ne, provision is made for a stage known per se of catalytic hydrogenation for the saturation of the double bond in position 14.15.

 In the second embodiment, the solution maintained under agitation is added in an atmosphere of nitrogen oxalic acid, in excess relative to the stoichiometric proportions with the initial alkaloid which constitutes the protective agent, the acid being added to the solution. in methanol in solid form.

 Once the acid has completely dissolved, the reaction mixture is cooled, preferably to -50 ° C., and it is oxidized by the dropwise addition of a solution of maleic anhydride in hydrogen peroxide.

 During the addition of the oxidizing solution (30 to 40 minutes), the reaction mixture is cooled to a temperature preferably below -20C.

Instead of permaleic acid, peracetal acid can be used
At the same temperature, an aqueous solution of sodium metabisulphate is then added, both to discolor the reaction mixture and to remove any oxidant residue therefrom, the presence of which in the transposition phase would determine the formation of non-by-products. - desired.

 After filtering, the solution obtained is heated to 30-350C, and maintained at this temperature for 3 to 4 hours; the mineral precipitate is separated and to the clear filtrate an alkaline solution (preferably an aqueous ammonia solution) is added, to bring the reaction mixture to pH = 9.

 Is then carried out the isolation of the desired compound, respectively vincamine or t14 -vincamine, depending on the initial compound. We could also carry out the transposition phase at a temperature below 30 C, without however going below 20oC, although the duration of the said phase is correlatively increased. The idea of the net temperature variation between the phases oxidation and transposition thus remains unchanged.

 The nonlimiting examples which follow serve to illustrate the invention.

EXAMPLE - 1
A solution of vincadiformin (20g) in methanol (600mol), cooled to 0-5 C, of CuSO4, 5H20 (4g) is added, which produces a practically complete solution.

 To the mixture, kept under stirring, a solution of maleic anhydride (11.7 g) in 40% H 2 O 2 (10 mol) is added dropwise over 30 minutes. After filtration of the reprecipitated copper salt using celite (2.5 g) as an adjuvant, the solution is added to a 10% aqueous solution of Na2Sg05 (150 ml) and it is heated to 35-400C during 2 ,5 hours.

 The reaction mixture is then diluted with a 5% aqueous NaCl solution (1 L) and, while stirring, it is brought to pH 8.5 by adding a 30% aqueous ammonia solution.

 The precipitate, filtered, washed with water, then with a little cold methanol and dried at 700C, provides a mixture (approximately 9: 1) of vincamine and epivincamine. From this material, taken up in methanol (200 ml), boiled under reflux for 15 minutes5, cooled to room temperature and filtered, we obtain vincamine (10, lg).

 The filtration water from the crude product is extracted with chloroform (3 × 250 ml).

 The extract is washed with chloroform, successively with 2% NaOH and a 10% aqueous NaCl solution; it is dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The residue is combined with the methyl mother liquors from the first vincamine crop and added with sodium methylate (1 g). The reaction mixture is boiled in the reflex for 30 minutes, then concentrated by distillation, until a residue of approximately 50 ml is obtained.

 The crystalline precipitate is filtered, after having cooled it to room temperature, it is washed with a little methanol, then with water, and it is dried at 700C, to obtain a second crop of vincamine (2.4 g ).

EXAMPLE 2
A solution of vincadiformin (20 g) in methanol (600 ml) is treated with CuSO4, 5H20 (4 g), and it is cooled to 0 C, then, while stirring, 17 ml of acid are added dropwise. peracetic at 34% over 30 minutes, keeping the temperature below 40C.

 After adding acetic acid (250 ml), add the reaction mixture of chelating resin "Duolite ES 466" (20 ml) and keep stirring for 60 minutes, heating it to 40-450C. After filtration of the resin, the reaction mixture is diluted with H2O (500 ml), it is brought to pH 9 with 30% ammonia, and it is extracted with chloroform (3 x 250 ml).

 The chloroform extracts are concentrated under reduced pressure, washed with a 1% NaOH solution and a 5% NaCl solution, and they are dried over Na2SO4, they are concentrated under reduced pressure and they are taken up in methanol. The solution is then concentrated by distillation until the start of crystallization (250 ml), sodium methoxide (3 g) is added and the mixture is refluxed for 30 minutes.

 After concentration to mid-volume and cooling to room temperature, the reaction product is recovered by filtration, washed with water and then, with a little methanol, and dried at 70 ° C. to obtain vincamine ( 11.6 g).

EXAMPLE - 3
a) adding to a tabersonin solution (40 g) in methanol (1 1) maintained with stirring, CuSO 4, 5H 2 O (4 g) and it is cooled to 00C.

 34% peracetic acid (34 ml) is then added dropwise over 75 minutes, keeping the temperature between 2 and 40C. The reaction mixture is then left to stand overnight at room temperature, diluted with H2O, brought to pH 9 with 30% ammonia and extracted with chloroform (3 x 400 ml). The extracts are 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 700C, a product (26.5 g) is obtained consisting of 814-epivincamine and t14-vincamine, in a proportion of approximately 13: 1.

 The concentration of mother liquors which follows provides another product (5.6 g) consisting of kal $ -epivinea- mine and A14-vincamine in a proportion of 2: 1.

 b) By repeating the experiment, at the end of the addition of peracid, the reaction mixture is treated with "Duolite ES-467" chelating resin (50 ml) and kept stirring for 30 minutes at 35 -40 C.

 At the end of this period, an examination by thin layer chromatography shows the almost complete transformation into Q14 ~ epivincamine and L 14-vincamine.

 After separation of the resin by filtration, the treatment carried out as described above gives comparable results.

 c) During a subsequent repetition of the experiment (carried out as in b), the extract with dried chloroform is evaporated on Na2 S04 asept vacuum. The solid residue obtained is taken up in methanol (80 ml), sodium methoxide (5 g) is added and it is boiled under reflux for 2.5 hours, then it is concentrated to 500 ml.

 After cooling to room temperature, the crystalline product which has separated is filtered, washed with methanol, then with water, and dried at 700C to obtain t vincamine 117 g).

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

EXAMPLE-4
Is added to a solution of tabersonin (20 g) in methanol v600 mi) cooled to 0-5 C, kept stirring, CuSO4, 5H90 (2 g). To the mixture, a solution of maleic anhydride (11.7 g) in 40% H 2 O 2 (10 ml) is then added dropwise over 20 minutes. At the end of the addition, the mixture is saturated reaction with gas
S02 over the course of about 10 minutes, while increasing the temperature to 35-400C.

 After maintaining for 90 minutes at this temperature, the reaction mixture is treated according to Example 3.

 Analysis by high pressure liquid chromatography of the content of the chloroform extract shows that A14 4-epivincamine and 214-vincamine were obtained in a ratio of about 1: 1 to 16 , 4 g in total.

EXAMPLE - 5
To a solution of vincadiformin (50 g) in methanol (1,500 ml) cooled to -50C in a nitrogen atmosphere, oxalic acid dihydrate (27 g) is added
Then, while continuing to stir in a nitrogen atmosphere, a solution prepared separately and constituted by maleic anhydride (23.2 g) in hydrogen peroxide is added dropwise over 30 minutes. 130 volumes (20.2 ml) while keeping the temperature below -20C,
Finally, at the same temperature, a 20% w / v aqueous solution of sodium metabisulfite (75 ml) is added dropwise over 20 minutes.

 After having stirred for 30 minutes, the precipitated mineral salts are filtered through celite and the clear solution is stirred for 4 hours at 350C. The reaction mixture is then brought to pH 9 by adding a 30% aqueous ammonia solution (120 ml).

 The precipitate obtained, filtered, washed with methanol (50-ml), then thoroughly with water, and dried at 700C, provides a first jet of vincamine (31.5 g).

 The mother liquors are concentrated in vacuo until most of the methanol is removed, diluted with water (600 ml) and extracted with chloroform (2 x 200 ml).

 The chloroform extracts, washed successively with a 2% w / v aqueous solution of sodium hydroxide (120 ml) and with a 5% w / v aqueous solution of sodium chloride (2 x 120 ml), and dried over anhydrous sulfate, are then evaporated to dryness under reduced pressure, and are taken up in methanol (200 ml). The solution is boiled, supplemented with sodium methylate (1.5 g) at reflux for 30 minutes, then concentrated by distillation, until a residue of about 80 ml is obtained.

 After cooling to room temperature, the crystalline precipitate is filtered, washed with cold methanol (15 ml), then with water until neutral, and dried at 700C, to obtain a second jet of vincamine ( 9.8g).

EXAMPLE E-- 6
To a solution of tabersonine (50 g) in methanol (1,500 ml), maintained with stirring in a nitrogen atmosphere, oxalic acid dihydrate (27 g) is added and, after having cooled to -5 ° C., drop is added dropwise over 40 minutes a solution prepared separately and consisting of maleic anhySride (27.5 g) in hydrogen peroxide at 130 volumes (23.7 ml). The temperature is kept below -2 "C.

 At the same temperature, a 20% w / v aqueous solution of sodium metabisulfite (75 ml) is then added dropwise over 20 minutes. After 30 minutes of stirring, the mixture is filtered through precipitated mineral salts and the clear solution is stirred for 3 hours at 30-350C.

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

 The extracts are combined, washed successively with a 2% sodium hydroxide solution (300 ml) and with an aqueous solution at 5% weight / volume of sodium chloride (2 x 300 ml), they are dried: e over anhydrous sodium sulfate and evaporated under reduced pressure until a volume of 300 ml is obtained. Methanol (800 ml) is added and distilled until the chloroform is completely eliminated.

 After cooling to room temperature, the crystalline product is filtered, washed with a little methanol and dried at 700C to obtain a first jet of l \ 14-vincamine (22 g).

 Boil the methyl mother liquors, supplemented with sodium methylate (2 g) at reflux for 30 minutes, then concentrate them to approximately 80 ml. The crystalline product which has separated after cooling to room temperature is filtered, washed with methanol, then with water until neutral, and dried at 700C to obtain a second jet of vincamine (17, 3 g).

 The above examples clearly show the advantages of the process according to the invention.

 Of course, in the examples relating to the use of tabersonin, it is possible, in a manner known per se 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 in all probability constitutes one of the characteristic aspects of the present invention that at the end of the addition of the peracid, the oxidation of the initial compound is complete in fact, the analysis of the reaction mixture at this point confirms the significant formation of the 16-hydroxy derivative of vincadiformin, which was then simply assumed in the aforementioned Swiss patent.

 This derivative undergoes directly itself, by simple increase in temperature and in acidic medium, the transposition into vincamine and epivincamine (or into the corresponding A 14 derivatives, if the initial compound is tabersonine). At the same time, the same analysis shows the presence of traces only of the intermediate compounds (-) - N-oxy-vincadiformine and (-) - 1,2-dehydro-N-16-carbometoxy-16-hydroxy-N-oxy- aspidospermidine, described and claimed in Belgian patents Nos 761,628 and 736,730, as obligatory intermediates in the preparation of vincamine.

 This confirms the explanation of a protective action, by oxalic acid and copper salt respectively, by inhibiting or reducing to the level of traces the formation of N-oxides (mentioned above) responsible for the complexity and the duration notably. higher than previously known methods.

Claims (18)

CLAIMS 1. - Process for the preparation of vincamine corresponding to formula (I) or t14 Vlncamlne, by oxidation, then transposition from a solution of vincadiformine and tabersonine respectively, characterized in that one adds to said initial solution prepare in a polar solvent and maintained at a temperature not higher than + 50C, a protective agent, then the oxidation is carried out with a peracid chosen from permaleic acid and peracetic acid, and at at the end of the addition of the peracid, the reaction mixture is transposed by heating to a temperature between 20 and 50 ° C.  2. - Method according to claim 1, characterized in that said protective agent is a copper salt, added in an amount such that the ratio between the starting compound and the copper salt is between 1: 1 and 10: 1.  3. - Method according to claim 1, characterized in that said protective agent is oxalic acid  4. - Method according to claim 3, characterized in that said oxalic acid is added to said initial solution maintained at SOC.  5. - Method according to claim 4, characterized in that one carries out the addition of peracid to the solution after complete dissolution of oxalic acid, maintaining it at -20C.  6. - Method according to claim 1, characterized in that said peracid is permaleic acid prepared at the time from maleic anhydride and hydrogen peroxide.  7. - Method according to claim 1, characterized in that said polar solvent is a lower aliphatic alcohol.  8. - Method according to claim 7, characterized in that said polar solvent is methanol.  9. - Method according to claim 2, characterized in that the said temperature of the mixture is adjusted during the addition of the peracid to a value between -50C and 0 C.  10. - Method according to claim 2, characterized in that the reaction mixture is treated at the end of the addition of the peracid, so as to separate the copper salt which is contained therein.  11. - Method according to claim 1O, characterized in that said treatment for separating the copper salt consists, when the peracid is permaleic acid, in a filtration of the precipitated copper salt.  I2, - Method according to claim 10, characterized in that said treatment for separating the copper salt consists, when the peracid is peracetic acid, in the treatment with a chelating resin.  13. - Method according to claim 12, characterized in that the chelating resin is a polystyrenic macroporous polymer with aminophosphonic, amino-diacetic or amino-oximic functional groups.  14. - Method according to claim 2, characterized in that the phase is carried out at increased temperature at a temperature between 35 and 40 OC.  15. - Method according to claim 1, characterized in that before or during the stage at increased temperature, the reaction mixture of a reducing agent is added.  16. - Method according to claim 15, characterized in that one chooses said reducing agent from sodium metabisulfite and sulfur dioxide, sodium hydroboride.  17. - Method according to claim 1, characterized in that the pH of the reaction mixture is adjusted at the end of the addition of peracid to a value between 6 and 2.5,  18. - Method according to claim 3, characterized in that at the end of the oxidation phase, the reaction mixture of sodium metabisulfite is added.  19. - Method according to claim 3, characterized in that the transposition is carried out at a temperature of 20 to 35OC.  20. - Method according to claim 3, characterized in that the transposition is carried out at a temperature of 30 to 35OC.