CH664569A5 - PROCEDURE FOR THE PREPARATION OF EBURNAMONINE BY ELECTROCHEMISTRY. - Google Patents

Description

DESCRIPTION The present invention relates to a new process for the preparation of eburnamonins, substances with a pentacyclic skeleton derived from indole, having general formula I.

Eburnamonins are used as active ingredients in the pharmaceutical field.

The (+) -eburnamonin of formula II,

characterized by an eis junction between the D and E rings and a ß orientation of C-3H and of the ethyl chain at C-16, it is a natural product isolated for the first time by Hunteria eburnea Pichon.

Its enantiomer (-) eburnamonin of formula III,

more commonly known as vincamone, equally of natural origin, it is instead characterized by an eis junction of anel5

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li D and E and an orientation a of C-3H and of the ethyl chain to C-16.

Transis junction stereoisomers between rings D and E are also known: they are of synthetic origin and are referred to as isoeburnamonins or frwìs-eburnamonins.

The pharmacological activity of eburnamonins has been widely studied: their action is mainly expressed in the treatment of cardiovascular insufficiencies and cerebrovascular disorders.

Vincamone, for example, causes an increase in arterial and venous flow, a decrease in capillary resistance and a reduction in cardiac effort. These actions are accompanied by a spasmolytic effect on smooth muscle.

Vincamone is the active principle of some medicinal specialties on the European pharmaceutical market.

Similar activities are also shown by (+) -eburnamonin 2, isoeburnamonins and a series of derivatives of vincamone such as A (14.15) vincamone (Illa), 3-ketovincamone (Illb), 3-keto-A (14, 15) vincamone (IIIc), 9-nitro-vincamone (Illd), 11-nitro-vincamone (Ille), 10-chlorine-vincamone (Illg), and 10-bromo-vincamone (Uli).

The known methods for the preparation of eburnamonins can be traced back to three general schemes:

a) transformation of a suitable precursor having the same eburnanic skeleton,

b) rearrangement of a suitable precursor having a different skeleton,

c) total summary.

According to the first scheme, eburnamonins are obtained by oxidative decarboxylation of vincamine, pentacyclic eburnanic skeleton compounds having general formula IVa and IVb wherein R is OH, R 'represents -COOCH3 or -COOH.

In particular, vincamone is formed by oxidative decarboxylation of (+) - vincamine, a natural alkaloid isolated from Vinca minor L., endowed with pharmacological activity as a cerebral vasodilator, of formula IVd where R is COOH3.

The vincamine is hydrolyzed to vincaminic acid (R = -COOH) and this oxidized in solution of alipolent aromatic solvents, for example xylene, in a nitrogen atmosphere, with metal salts such as Pb (OAc) 4, AgC03, AgîO, Mn02, to give the vincamone with yields varying from 63 to 93%.

This technique, described in patent applications Ger. Offen. 2 323 423, U.S. 3 888 865, while providing good yields, has the disadvantage of using expensive, polluting and toxic reagents, therefore requiring the complete elimination of metal residues in the final product and the recovery of metals in the waste water of the processing.

Alternatively, according to French patent applications n. 2 268 016, 2 428 646, 2 428 643, 2 339 618, the (+) - vincami-na or its derivatives are decarboxylated by heating in benzene solution in the presence of MeONa or t-BuOK. On a laboratory scale, the yields are excellent (80-90%), however the reaction conditions must be strictly controlled with the absolute exclusion of humidity and oxygen.

The presence of water in fact causes the hydrolysis of vincamine to a salt of vincaminic acid which is removed from the reaction, while oxygen in the presence of strong bases causes autooxidation.

Other methods for the transformation of vincamine into vincamone include reduction with LÌAIH4 to vincaminol and oxidation with periodic acid or lead tetraacetate, or dehydration with apovincamine and the formation of hydrazide which, by treatment with nitrous acid, gives vincamone III according to a Curtius-Schmidt reaction.

The second general scheme of synthesis of eburnamonins follows the mechanism proposed by E. Wenkert for the biosynthesis of eburnanic alkaloids starting from the aspi-dospermidine alkaloid precursors. The Belgian patent no. 802 387 and Hugel et al. (Tetrah. Lett. 1974, (17) 1597-1600) describe the synthesis of (-) vincamone starting from the natural aspidosperminic alkaloid (-) - vincadifformin and through a long series of passages.

Even if (-) - vincadifformin is readily available, the long sequence of reactions, the modest final yields and the contamination by by-products that must be eliminated through column chromatography processes, make this synthesis scheme of little preparation interest.

Numerous total syntheses of eburnamonins are also known (Hungarian Patent No. 157 688, Chem. Abstr. 74, 3765s; Tetrah. Lett. 1976, 801-4; J. Am. Chem. Soc. 1978, 100 (15), 4893 -4; Heterocycles 1981, 15 (1), 201-6; Chem. Ber. 1979, 112 (5), 1902-12; Angew. Chem. 1977, 89 (12), 916-17; Patent applications Ger. Offen. 2 200 259 and 2 338 838, French patent application No. 2 213 276).

All of them start from tryptamine, require numerous passages with modest overall yield, but above all lead to raceme mixtures of eis- and frwzs-eburnamonine. For this reason, no total synthesis has found practical application. A very recent enantiospecific and stereospecific total synthesis of vincamone requires the preparation of a chiral synton in complex passages and has only scientific significance (J. Am. Chem. Soc. 1979, 101 (6), 1540-4).

The process according to the present invention consists in the conversion by electrochemical way of the vincaminic alkaloids in the corresponding eburnamonins in high yields; according to this procedure an electrolysis, in the presence of electrolytes and alkaline bases, is subjected to an alcoholic or hydroalcoholic solution of a vincaminic acid, obtained by preventive hydrolysis from the corresponding vincamine according to one of the known methods, or by hydrolysis in a single step of the vincamine in Yes you.

The procedure is applicable to all vincaminic alkaloids: it is thus possible, among other things, to prepare (-) - eburnamonin (vincamone), (-t -) - eburnamonin and (+) - eburnamonin, A- (14.15) vincamone, 10-bromovincamone, 10-bromine-A (14.15) vincamone, 9-nitro and Pll-nitrovincamone, 10-chlorine-A- (14.15) -vincamone starting from the corresponding derivatives of vincaminic acids.

The (-) - ebumamonin, or vincamone, can be conveniently prepared indifferently from the natural (-l -) - vincamine (IVd) or from the epivincamine of formula IVb where R is -COOCH3 and R 'is OH.

Electrolysis is carried out in a three-compartment cell with a graphite or Pt electrode, at a potential between 1.5 and 2.2 V. The concentration of the vincaminic alkaloid in the solution

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alcoholic or hydroalcoholic, preferably methanolic or ethanolic, is between 5 and 15 g / l.

The transport electrolyte is preferably LÌCIO4 or NaC104, although other electrolytes can be used while the alkaline base, which can be sodium, lithium or potassium hydroxide or a sodium alcoholate in alcoholic solution, for example sodium methoxide, is in concentration such as to salify vincaminic acid for a percentage between 5 and 40%, preferably for about 20%. The temperature is normally the ambient temperature (18-25 ° C), but it can be between + 10 ° C and + 50 ° C. The potential is maintained until the starting product disappears; the reaction product is isolated with yields of 75-85% according to known techniques, normally by simple evaporation of the solvent and subsequent crystallization.

If the reaction is carried out in a single step without isolating the vincaminic acid, a vincamine solution is heated in ethanol or methanol containing an alkaline base until the starting product disappears, the pH is then brought to about 7.0 with HCIO4 and the resulting solution is electrolyzed as described above.

The process described provides high yields of eburnamonins, comparable to those of some already known processes. However, compared to these, it offers numerous advantages, consisting of a very simple practical embodiment, which can be easily transported on an industrial scale, in not requiring particularly controlled reaction conditions or elaborate reaction sequences. Furthermore, no expensive or polluting chemical reagents are used and, consequently, no purification of the final product or recovery of excess or exhausted reagents are required.

The following examples further illustrate the process of the invention, without however limiting it in any way.

Example 1 (-) - Eburnamonin (vincamone)

In an electrolytic cell with three compartments, since the anodic and cathode compartments are separated by a sintered glass septum, an anolyte consisting of 125 ml of a 0.5 M solution of LYCIO4 in MeOH is introduced, containing 0.70 g (0 , 0020 moles) of acid (-) - vincaminic and 25.6 mg of MeONa. The catholyte instead consists of 125 ml of a 0.5 M solution of LYCIO4 in MeOH containing 25.6 mg of MeONa. The Pt anode has a surface of 10.5 cm2 and the cathode, also of Pt, of 6.0 cm2. The reference electrode consists of a saturated calomel solution (SCE) and is connected to the anodic compartment by means of a capillary. With the use of a potentiostat and a function generator, the electrode potential is kept for 0 sec at 0 (zero) V. It electrolyzes (100 mA circulating current) until it disappears (after 3.1 F / mole of current) of the starting product (determined by tic; CHCI3 - Me0H-H20, 80: 20: 2). The electrolyzed anolyte is evaporated under vacuum until complete elimination of the methanol. The residual crystalline mass is suspended in 100 ml of water containing 1 ml of conc. NH4OH. and extracted with 100 ml of ethyl acetate. The organic phase is dried over Na2SÛ4 and evaporated under vacuum. By crystallization of the residue thus obtained from methanol 0.515 g (0.00175 moles) of (-) - eburnamonin (vincamone) are obtained, having the following characteristics:

mp 182 ° C

[a] 20-102 ° (c 1, CHCI3)

Elemental analysis: (C19H22N2O; P.M. 294,40)

calculated: C 77.52; H 7.53; N 9.52%

found: C 77.36; H 7.50; N 9.53%

I.R. (CHC13): 1702, 1693, 1630 cm "1

Ultraviolet (EtOH): 241 (log s 4.30), 268 (4.01), 296 (3.68), 302

3.68).

1H-RMN (CDCI3): 0.86 (3H, t, J 7Hz, CH3), 1.56-3.10 (12H,

m), 3.30 (2H, t), 3.96 (IH, s), 8.44 (IH, m).

Chemical yield: 84%.

Example 2 (-) - Eburnamonin (vincamone)

0.90 grams (0.0025 moles) of (+) -vincamine [a] {=, ° +41 (c 1, pyridine) are dissolved in 120 ml of MeOH containing 2.4 g of NaOH and refluxed for 4 hours until disappearance of the starting product (tic chromatography; benzene-ethanol-NHjOH conc., 89: 10: 1). The solution is cooled and added with 4 ml of 70% HCIO4 (1.66 g) and then transferred to the anodic space (125 ml) of an electrolytic cell with three compartments. A 0.4 M solution of NaC104 is introduced into the anodic space (125 ml). The reference electrode consists of a saturated calomel solution (SCE). The Pt anode has a surface of 28.2 cm2 and the cathode (Pt) of 7.0 cm2. It is electrified with the impulse technique maintaining the electrode potential for 20 sec at 2.0 V and for 1 sec at 1.0 V (50 mA circulating current).

It is electrolyzed up to the passage of 3.3 F / mole, then the solvent is evaporated under vacuum. The residual mass is suspended in 150 ml of ethyl acetate. The organic phase after anhydrification on Na2So4 is evaporated under vacuum. By crystallization of the residue from methanol 0.570 g (0.00193 moles) of (-) - eburnamonin (vincamone), m.p. 181 ° C, [a] or ° -100 ° (c 1, CHCI3).

Chemical yield 76%.

Example 3

According to the conditions of Example 1, (-) - eburnamonin was obtained starting from epivincaminic acid (IVb, R '= COOH) with a chemical yield equal to 80%; mp 181 ° C. [a] ^ -101 ° (c 1, CHCI3).

Example 4 (+) - Eburnamonin

With the same methods reported for the preparation of (-) - eburnamonin in example 1, and starting from (+) - vincaminic acid obtained from (+) -vincadifformin, (+) -eburnamonin, m.p. 180 ° C (MeOH); [ci] d0 + 103 ° (c 1, CHCI3).

Chemical yield of 81%.

Example 5

Starting from (+) -vincamine, obtained from (+) -vincadifformin, and electrolyzing the solution obtained from basic hydrolysis at 2.1 V according to the methods reported for (-) - eburnamonin in Example 2, after the passage of 2.5 F / mole of current (+) -eburnamonin was isolated with yields of 71%.

Example 6

(±) -eburnamonin (racemic cis-eburnamonin)

With the same modalities reported in example 1, and starting from (±) -vincaminic acid obtained by hydrolysis of (±) -vincamine racema from total synthesis (mp 223-225 ° C), (±) -eburnamonine was obtained , pf 199-202 ° C.

Chemical yield 80%.

Example 7

Starting from the racemic synthetic (±) -vincamine and electrolysing at 2.1 V the solution obtained from the basic hydrolysis according to

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the modalities shown in example 1, after the passage of 2.7 F / mole of current, (±) -eburnamonin was isolated with a yield of 73%.

Example 8

A (14,15) -Vincamone

Electrolyzing a solution of (+) -A (14.15) -vincamine obtained by hydrolysis of (+) - A (14.15) -vincamine [m.p. 221-223 ° C (benzene)] at 1.8 V according to the methods reported in example 1, the A (14.15) -vincamone was obtained with yields of 79%.

mp 130 ° C (MeOH).

Elementary analysis: (C19H20N2O, P.M. 292.38)

calculated: C 78.05; H 6.89; N 9.58%

found: C 77.96; H 6.88; N 9.59%

1H-RMN (CDCU) 5: 1.03 (3H, t, J 7Hz, CH3), 2.77 (2H, q, J 7Hz, ÇH2-CH3), 4.08 (IH, s, H-21) , 5.53 (2H, s all., H-14 and H-15), 8.32 (IH, dd, J 8 and 3Hz, H-12).

Example 9

9-Nitrovincamone

Starting from 9-nitrovincamine [m.p. 197-198 ° C, [a] £ ° + 190 ° (c 0.3, CHCI3)] and electrolyzing the solution obtained from basic hydrolysis at 2.2 V according to the methods described in example 2, after the passage of 2.8 F / mole of current 9-nitrovincamone was isolated with yields of 78%.

mp 165 ° C (MeOH); [a] g> + 10 ° (C 0.1, pyridine).

Elementary analysis: (C19H21N3O3, P.M. 339,40)

calculated: C 67.24; H 6.24; N 12.38%

found: C 67.34; H 6.23; N 12.40%

Ultraviolet (MeOH): 269 (log and 3.90), 310 (3.71), 358 (3.58.

1H-RMN (CDCI3): 7.39 (IH, t, J 8Hz, H-ll), 8.06 (IH, dd, J 8 and 2Hz, H-10), 8.80 (IH, dd, J 8 and 2Hz, H-12).

Example 10 11-Nitrovincamone By electrolyzing an 11-nitrovincaminic acid solution,

obtained by hydrolyzing 11-nitrovincamine m.p. 196-199 ° C, Md ° + 28 ° (c 0.35, CHCI3), according to the methods shown in example 1, operating at 2.2 V and after the passage of 2.9 F / mole, it was obtained il-nitrovincamone with 71% yields.

s m.p. 185 ° C (MeOH); [a] g> -120 ° (c 0.2, pyridine).

Elementary analysis: (C19H21N3O3, P.M. 339,40)

calculated: C 67.24; H 6.24; N 12.38%

found: C 67.13; H 6.22; N 12.41%

10 U.V. (MeOH) 225 (log and 4.30), 318 (4.00), 355 (4.10)

1H-RMN (CDCU) S: 7.48 (IH, d, J 8Hz, H-9), 8.19 (IH, dd, J 8 and 2Hz, H-10), 9.17 (IH, d, J 2Hz, H-12).

Example 11 10-Bromo-h. (14,15) -vincamone

Electrolyzing a methanolic solution of 10-bro-20 mo-A- (14,15) -vincamin acid, obtained by hydrolysis of the

10-bromo-A (14.15) -vincamine at 2.1 V according to Example 1, after the passage of 3.1 F / mole of current, the 10-bromo-A- (14.15) -vincamone amorphous, with yields of 81%.

Elementary analysis: (Ci9Hi9BrN20, P.M. 371.27) 25 calculated: C 61.46; H 5.16; N 7.54%

found: C 61.30; H 5.11; N 7.51%

Ultraviolet (MeOH) 146 (log s 4.30); 276 (4.02); 296 (3.70), 306 nm (3.70).

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Example 12 10-Chlorine-0. (14.15) -vincamone

Electrolyzing a solution of 10-chloro-A (14.15) -35 vincaminic acid, obtained by hydrolysis of (+) -10-chloro-A (14.15) -vincamine [m.p. 196-198 ° C (MeOH)], operating according to the methods given in Example 1 at 2.0 V, after the passage of 2.8 F / mole of current, 10-chlorine-A (14, 15) -vinca-mone with yields of 78%.

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Elementary analysis: (C19H19CIN2O, P.M. 326,828)

calculated: C 69.82; H 5.85; N 8.57%

found: C 69.75; H 5.81; N 8.54%

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Claims (10)

664 569 2. Process according to claim 1, characterized in that vincaminic acids of general formula IVa or IVb wherein R 'is -COOH, prepared by hydrolysis from the corresponding vincamine, are used as starting products. 2 CLAIMS 1. Procedure for the preparation of eburnamonins of general formulas II or III starting from vincamine or vincaminic acids of general formula IVa or IVb wherein R is OH and R 'is -COOCH3 or -COOH, characterized in that the vincamine of formula IVa and IVb are subjected to an electrolysis process in alcoholic or hydroalcoholic solution. 3. Process according to claim 1, characterized in that vincamine of general formula IVa or IVb in which R 'is -COOCH3 and which are hydrolysed in situ by hot alkaline bases are used as starting products, finally bringing the pH at the value of 7 with strong acids. 4. Process according to claims 1 to 3, characterized in that it is carried out in methanolic or ethanolic solution in the presence of alkaline bases such as sodium, lithium, potassium hydroxides or sodium alcoholates in alcoholic solution such as sodium and an electrolyte such as LÌCIO4 or NaC104. 5. Process according to claim 4, characterized in that the alkaline base is in a concentration such as to salify about 20% of the vincaminic acid. 6. Process according to claims 1-5, characterized in that the electrolysis is carried out in cells with 3 sectors, at a temperature between + 10 ° C and + 50 ° C, with a potential between 1.5 and 2 , 2V, and with an amount of current between 2.5 and 4.5 F / mole. Method according to claims 1-6 for the preparation of (-) - eburnamonin (vincamone), (+) -eburnamonin and (+) -eburnamonin. Method according to claims 1-6 for the preparation of À (14-15) -vincamone, 10-halogen (À14.15) -vincamone. Method according to claims 1-6 for the preparation of 9 or 11 nitrovincamone, 10-halogen-vincamone. 10. (-) - Eburnamonin produced according to one of the processes of claims 1-6.