DD236094A5 - PROCESS FOR THE PREPARATION OF NEW 9- OR 11-SUBSTITUTED APOVINCAMINE SAE DERIVATIVES - Google Patents

Abstract

1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, NL, SE Racemic or optically active 9- and/or 11-substituted apovincamic acid derivatives having the general formula see diagramm : EP0173824,P11,F1 wherein R is a nitro or amino group in position 9 or 11, and the salts thereof. 1. Claims for the Contracting State : AT A process of producing racemic or optically active 9- and/or 11-substituted apovincamic acid derivatives having the general formula see diagramm : EP0173824,P11,F3 wherein R is a nitro or amino group in position 9 or 11, and salts thereof, characterized in that apovincamic acid having the formula see diagramm : EP0173824,P11,F4 is nitrated and the resulting 9- and/or 11-(nitro)- apovincamic acid(s) is or are optionally reduced, optionally after it has or they have been isolated from the reaction mixture and, optionally the resulting 9- and/or 11-substituted apovincamic acid derivatives having the general formula I are transformed to acid addition salts or quaternary salts and/or metal salts and/or ammonium salts and/or the resulting salts of 9- and/or 11-substituted apovincamid acid derivatives having the general formula I are transformed to the free 9- and/or 11-substituted apovincamic acid derivatives having the general formula I or to other acid addition salts and/or quaternary salts and/or metal salts and/or ammonium salts and/or the resulting racemic 9- and/or 11-substituted apovincamic acid derivatives having the general formula I and/or the acid addition salts and/or quaternary and/or metal salts and/or ammonium salts are dissociated to its or their optical antipodes and/or the corresponding optically active compounds are racemized to form stereo-isomers.

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a process for the preparation of novel 9- or 11-substituted Apovincaminsäurederivaten. The novel compounds correspond to the general formula (I) wherein

R is nitro or an amino group in the 9 or 11 position.

The invention also extends to the preparation of the salts of the compounds of general formula (I). The novel compounds of the general formula (I) are valuable intermediates in the preparation of ring-A-substituted, biologically active Eburnanderivaten, for example in the preparation of the described in HU-PA 2704/84 and 2703/84 Nitroapovincaminsäureester or Acylaminoapovincaminsäure derivatives ,

Characteristic of the known technical solutions

The compounds of general formula I are new. Only aporincamic acid is known. Further known are the 9- and 11-nitro derivatives of vincamine and of apovincamine, the preparation of which is described, for example, in FR Pat. Nos. 2431 585, 2320302 and 2342980. Both in the case of the vincamine and the apovincamine nitriding is carried out in nitric acid in acetic acid medium. This produces mixtures of 9- and 11-nitroverbndungen. In the case of vincamin, the reaction favors the formation of 11-nitrovincamine (Bull. Soc. Chim. BeIg. 88, 1-2 / 1979 /), while in the case of apovincamine, the amount of 9-nitro derivative formed outweighs it.

To influence the ratio of the two isomers no method has been found, and the separation of the product mixture obtained is possible only with difficulty by chromatographic means and is associated with considerable loss of substance.

Object of the invention

With the invention, the shortcomings of the prior art are to be eliminated.

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Explanation of the essence of the invention

The invention has for its object to provide a process for the preparation of the compounds of formula (I) and their salts.

The compounds of the general formula (I) and their salts are prepared according to the invention by nitration of the apovinic acid of the formula (I!), If desired, the resulting 9-and / or 11-nitroapovincamic acid - optionally after its isolation from the reaction mixture - reduced and, if desired the compounds of general formula (I), wherein -R has the same meaning as above, decomposed into their optical antipodes and / or, if desired, to salts.

The 9- or 11-nitroapovincamic acid is shown in the formulas (Ia) and (Ib), the amino compounds obtainable from them by reduction correspond to the formulas (Ic) or (Id).

The apovincamic acid is a known compound which was described for the first time in HU-PS 160367.

Nitration of apovincaminic acid has hitherto not been described in the literature. The 9- and 11-nitroapovincamic acid are new compounds.

According to the invention is also preferably nitrated in nitric acid with acetic acid medium. Surprisingly, it has been found that by appropriate choice of the reaction conditions, the product ratio (the ratio between [Ia]) and (I b) can be influenced within certain limits. If the reaction is carried out in pure glacial acetic acid or in glacial acetic acid containing 1-3% by volume of acetonitrile or dimethylformamide, 9- and 11-nitroapovincamic acid are formed in approximately equal amounts. On the other hand, if the glacial acetic acid contains 10-50% by volume of chloroform, the reaction shifts towards the formation of 11-nitroapovincamine. In addition, the direction of nitriding can also be influenced by the temperature. It has been found that - although the reaction within a wide temperature range are made (from-15 ° to + 45 ⁰ C) may be-particularly derTemperaturbereich suitably between ⁰ ° C and + 16 ° C. Working within this range at the lower limit produces predominantly 11-nitroapovincamic acid and the amount of other impurities contaminating the product remains below 5%. Near the upper limit of the specified temperature range, the two isomers are formed in approximately equal amounts, and the amount of difficult to identify byproducts increases slightly.

If the reaction is carried out at temperatures between 0 ^c C and 16 ^C C, the reaction takes about 2 hours. The mixture obtained by nitriding is poured into ice-water, the 9-and 11-nitroapovincamic acid precipitating in the form of their nitrates. The overall yield of product is 75-85% high. The two isomers are most easily separated by crystallizing their nitrates; when the mixture is recrystallized from 50% aqueous alcohol, the 9-nitroapovincamine acid nitrate precipitates first. If the mother liquor is allowed to stand, first a small amount of mixture and then, on concentration, the pure 11-nitroapovincamine acid nitrate precipitates. From the thus separated nitrates, the 9- or 11-nitroapovincamic acid can then be released by dissolving in an aqueous liquor and precipitating with the calculated amount of acid. The nitrates are preferably dissolved in ethanol which has been rendered alkaline with aqueous 50% strength sodium hydroxide solution, and the corresponding apovincamic acid derivatives are precipitated by addition of the calculated amount of hydrochloric acid.

According to the invention, the amino compounds of the formulas (Ic) and (Id) are prepared from the nitro compounds (Ia) and (Ib) by reduction. This step of the process according to the invention is to be regarded as an analogy process for the preparation of the corresponding 9- and 11-amino derivatives of vincamine (FR-PS 2341 585 and 2320302). The reduction is carried out by catalytic hydrogenation. FR-PS 2342980 describes the reduction of the corresponding nitro compounds with zinc dust in the presence of calcium chloride for the preparation of 9- and 11-amino-capovincamin, but this reaction gives only average yields.

The study of the reactions described in the literature showed that the reduction of the nitroapovincamin isomers by means of catalytic hydrogenation leads to the corresponding aminoapovincamine isomers only with low yield, because the main product produced by saturation of the 14,15-double bond is the dihydro derivative.

It has only been found, surprisingly, that the nitroapovincamic acids of the formulas (Ia) and (Ib) can be reduced quantitatively by catalytic hydrogenation to the amino derivatives of the formulas (Ic) or (Id). The catalytic hydrogenation can be carried out both in alkaline and in acidic medium, it is expedient to work in aqueous-alcoholic medium in the vicinity of the neutral point. Under these circumstances, not even traces of the 14.15-saturated product are formed. The catalyst used is suitably palladium activated carbon or Raney nickel.

After completion of the catalytic hydrogenation, the catalyst is filtered off and the product isolated in a conventional manner, for example by evaporation.

Although the catalytic hydrogenation is most advantageous for the preparation of 9- or 11-amino-apovincaminsäure because of their simplicity and good yield, the reduction can also be made with a chemical reducing agent (Bruckner Gy .: Szerves Kemia, 11/1, p.469 Tankönyvkiado Budapest 1977). Of the reducing agents listed in the said reference, those which do not saturate the double bond in the 14, 15-position are suitable.

For example, the Bechamp reduction is suitable for the preparation of the amino compounds, but it can also be reduced in glacial acetic acid with zinc or in hydrochloric acid with tin or zinc. The variants of these reductions which can be carried out in a neutral medium are also suitable, and finally the reduction can also be carried out in an alkaline medium, for example with sodium dithionite or sodium sulphide.

Accordingly, in the process according to the invention, the reduction step can also be carried out easily and leads to the 9- or 11-aminoapovincamic acid of the formula (Ic) or (Id) in virtually quantitative yield. It is particularly advantageous that the amino compounds of the formula (Ic) or (Id) prepared according to the invention (in particular those prepared by catalytic hydrogenation) react without intermediate isolation to form biologically active Eburnan compounds, for example to the corresponding acylamino-apovincamic acid derivatives. This possibility is given primarily by the fact that the inventive method provides a very pure product in high yield.

By reacting the compounds of the general formula (I) with suitable acids, acid addition salts can be prepared.

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For salt formation, for example, the following acids can be used:

inorganic acids, such as hydrohalic acids, for example hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perhalogenic acids, for example perchloric acid etc., furthermore organic acids, for example formic acid, acetic acid, propionic acid, glycolic acid, maleic acid, hydroxymaleic acid, fumaric acid, succinic acid, tartaric acid, Ascorbic acid, citric acid, malic acid, salicylic acid, lactic acid, cinnamic acid, benzoic acid, phenylacetic acid, p-aminobenzic acid, p-hydroxybenzoic acid, p-aminosalicylic acid, also alkylsulfonic acid such as methanesulfonic acid and ethanesulfonic acid, cycloaliphatic sulfonic acid such as cyclohexylsulfonic acid, arylsulfonic acids, for example p-toluenesulfonic acid, naphthylsulfonic acid, Sulfenilic acid, and finally amino acids, for example aspartic acid, glutamic acid, N-acetylaspartic acid, N-acetylglutaric acid, etc.

The salt formation can be carried out in an inert solvent, for example an aliphatic alcohol having 1-6 carbon atoms, by dissolving the optically active compound of the general formula (I) or its racemate in the solvent and the corresponding acid or its with the same solvent prepared solution, the mixture is slightly acidic (about pH 5-6). Then, the precipitated acid addition salt is separated in a suitable manner, for example by filtration.

Due to their acid character, the apovincamic acid derivatives according to the invention also form salts with inorganic bases. The preparation of these metal salts is carried out using the known methods of salt formation. As the inorganic base, the hydroxides of the alkali and alkaline earth metals, for example, sodium, potassium or calcium hydroxide are preferably used. From the compounds of the general formula (I) it is also possible to prepare monoquaternary salts. For quaternization, the appropriate alkyl halide, preferably bromide or iodide, is used in an equivalent amount or slight excess. The formation of the quaternary salts is carried out in an inert organic solvent with heating. The racemate mixtures of the compounds of the general formula (I) can be decomposed in a manner known per se into the optically active antipodes.

If desired, the optically active compounds of the general formula (I) prepared according to the invention or their racemates or salts can be further purified, for example recrystallized. The solvent used for recrystallization is selected in consideration of the dissolution and crystallization properties of the respective substance.

embodiments

The invention will be explained in more detail with reference to the following examples, but is not limited to the examples.

Example 1 (+) - 9-nitroapovincamic acid

The solution of 32.2 g (0.1 mol) of (+) - apovincamic acid (Wd ⁰ = +220.48, c = 2, pyridine) in 180 ml of glacial acetic acid is cooled to 16 ° C and stirred with stirring within 5 to 15 minutes Mixture of 52 ml of glacial acetic acid and 52 ml of fuming nitric acid (specific gravity: 1.52), care being taken that the temperature of the mixture does not rise above 16 ° C. At the same temperature, the mixture is stirred for a further 50 minutes and then poured into 1 liter of ice-water. The precipitated crystals are filtered off and washed on the filter three times with 100 ml of ice water and then with 50 ml of ether. The crude product obtained is the nitrate of the title compound (32.2 g = 75%). The crude nitrate is dissolved warm in 800 ml of 50% ethanol, the solution clarified with charcoal and then allowed to stand overnight. The precipitated crystals are filtered off and washed three times with 20 ml of 50% ethanol. This gives 12.8 g (29%) of (+ JS-nitroapovincamine acid nitrate, which melts at 232 to 234 ° C.

The crystalline substance is dissolved at 60-70 ⁰ C in 160 ml of 50% ethanol, and during the dissolution process, the pH of the solution is adjusted to 7.5 with sodium hydroxide solution in. Then the solution is added to a pH of 6.5 with 10% hydrochloric acid. The solution is cooled, depositing yellow crystals. These are filtered off and washed three times with 20 ml of water each time. This gives 7.4 g (20%) of (+ 1-i-nitroapovincamic acid, and after recrystallization from a ratio of 1: 1, the mixture of pyridine and ethanol melts the product at 260-262 ° C. Ia] ₀ = +317.32 ( c = 0.4, pyridine)

 UV spectrum (in hydrochloric acid ethanol):

λ (nm): 210 (4,461,287 (4.01); ¹ H NMR spectrum (DMSO-d ₆ ): δ EtO, 96 (t) 3, l, 9 (q) 2, H-3, 4.52 ( s) l, H-15 6.26 (s) l, H-10 7.90 (dd) l, (J = 8 and 1 Hz), H-11 7.30 (t) l

(J = 8Hz), H-12 7.74 (dd) l (J = 8 and 1 Hz)

Elemental analysis calculated for C ₂ OH ₂ IN ₃ O ₄ (M = 367.39); %: C65.38 H5.76 N 11.43

found; %: C65.30 H6.00 N 11.44.

From the mother liquor remaining after the separation of the pure (+) - 9-nitroapovincamine acid nitrate, (+) - 11-nitroapovincamic acid is prepared in the manner described in Example 2.

Example 2

(+) - 11-Nitroapovincaminsäure

The solution of 32.2 g (0.1 mol) of (+) - apovincaminic acid in 180 ml of glacial acetic acid is mixed with 77 ml of chloroform and then cooled to ⁰ ° C. With stirring, the mixture of 52 ml of glacial acetic acid and 52 ml of fuming nitric acid (specific gravity 1.52) are added to the solution, care being taken that the temperature of the mixture remains at 0 ° C. At this temperature, the mixture is stirred for a further hour and then poured into 1 liter of ice-water. From the obtained thick, sticky mass, the water is decanted, and the residue is triturated with 200-30OmI ice water. The water is discarded. The crystal slurry is triturated with 200-300 ml of ether, filtered off, washed on the filter three times with 100 ml of ice water and then with 50 ml of ether and finally dried. 37.8 g (85%) of crude 9-nitroapovincamine acid nitrate are obtained. The substance is dissolved warm in 900 ml of 50% aqueous ethanol, the solution is clarified and then overnight at room temperature

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tehengelassen. The precipitated crystals are filtered off, washed three times with 20 ml of 50% ethanol and then left to dry. 7.9 g of S-nitroapovincamine acid nitrate are obtained. From the mother liquor separates until the next day further: ristallines9-Nitroapovincaminsäurenitratabab. This is filtered off, washed three times with 10 ml of 50% aqueous ethanol and then dried. Weight: 1 g. ·

) The mother liquor and the combined washing liquids are concentrated to half their volume, the precipitated crystals are filtered off and washed three times with 50 ml of water. This gives 24.9 g (58%) of (+) - 11-litroapovincaminsäuritrate, which melts at 211-214 ° C.

) The resulting salt is dissolved at 60-70 ° C with the addition of about 60 ml of sodium hydroxide in 500 ml of 50% ethanol. If necessary, the pH is adjusted to 7. The solution is cooled to precipitate yellow crystals. These are filtered and washed three times with 40 ml of water each time. This gives 15 g (40%) of 11-nitroapovincamic acid, which, after recrystallization, melts at 250-254 ° ^C. from a mixture of pyridine and ethanol prepared in a ratio of 1: 1.

a] ₀ = +187.43 (c = 0.4, pyridine).

JV spectrum (in hydrochloric ethanol):

λ (nm): 212 (4.32.254 (4.13), 316 (3.98) ¹ H-NMR spectrum (DMSO-d ₆ ) a: Et 0.93 (t) 3.1.9 (overlaid from the signal of the solvent), H-3 4.20 (s) l, H-15 6.20 (s) l, H-9

7.60 (d) ℓ (J = 9 Hz), H-10 7.93 (dd) ℓ (J = 9 and 2 Hz), H-12 8.38 (d) ℓ (J = 2 Hz). Elemental analysis calculated for C ₂₀ H ₂ IN ₃ O ₄ (M = 367.39),%: C 65.38 H 5.76 N 11.43

found; %: C 65.42 H 5.84 N 11.40.

Example 3 [-J-S-Aminoapovincamic acid

3.6 g (0.01 mol) of the (+) - 9-nitroapovincamic acid prepared according to Example 1 are dissolved in a mixture of 10 ml of ethanol and 5 ml of water. The solution is mixed with 0.04 g of 10% Pd activated carbon and stirred at room temperature under a hydrogen atmosphere. After 0.03 mol of hydrogen was taken up, the catalyst is filtered off and washed three times with 2 ml of 50% aqueous ethanol. Filtrate and washing are combined. If desired, the resulting solution can be used directly for the preparation of the corresponding acylamino derivative.

To isolate the (-) - 9-Aminoapovincaminsäure the solution is evaporated in vacuo. The residue is triturated with 20 ml of ethanol, the crystals are filtered off, washed twice with 3 ml of ethanol and then dried. This gives 2.85 g (85%) of the title compound, which does not melt up to 340 ⁰ C.

Ia] ₀ = -25 ° (c = 0.4, pyridine),

UV spectrum (in hydrochloric acid ethanol) λ (nm):

210 (4.43), 222 (4.53), 263 (4.05), 33 (3.78)

¹ H-NMR spectrum (DMSO-d ₆ ) 8: Et 0.93 (3), approx. 1.8 (2), H-3-4.44 (s) 1, NH ₂ OH 4.75 (3), H-15 5.68 (s) 1, H-10 6.25, H-11 , H-12 6,72s (1-1),

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 Mass spectrum M: (rel intensity,%): 337 (67), 308 (67), 295 (18), 293 (55), 267 (92), 264 (92), 223 (100).

Example 4 (+ J-H-Apovincaminic acid

To the solution of 3.6 g (0.01 mol) of (+) - 11-nitroapovincamic acid in a mixture of 5 ml of ethanol and 10 ml of 1 N aqueous sodium hydroxide solution 0.04 g of 10% Pd activated carbon catalyst are added. The solution is stirred at room temperature under a hydrogen atmosphere. After 0.03 mol (720 ml) of hydrogen were taken up, the catalyst is filtered off and washed three times with 2 ml of 50% aqueous ethanol. Filtrate and washing are combined. If desired, the solution can be used directly for the preparation of the corresponding acylamino derivatives.

Before isolation of the (+) - 11-Aminoapovincaminsäure the solution is mixed with 10 ml of 1 η aqueous hydrochloric acid and eigeengt in vacuo to half its volume. The concentrated solution is allowed to stand overnight. The crystallized product is filtered off and washed with ice-water. This gives 3.1 g (92%) of the title compound, which melts at 200-202 ⁰ C with decomposition.

[a] ₀ = + 77.89 ° (c = 0.4, pyridine).

UV spectrum (in hydrochloric acid ethanol):

λ (nm): 210 (4.32), 220 (4.43), 272 (3.98), 313 (3.77)

NMR spectrum (DMSO-d ₆ ) δ: Et 0.90t (3), about 1.80q (2), H-3,4,29s (l), H-15 5,72s (1), H -97.1 Od (I) (J = 9Hz), H-10 6.43dd (1), H-12

6.64d (l) (J = 2Hz)

Mass spectrum M (C ₂₀ H ₂₃ N ₃ O ₂ rel% int.): 337 (54), 308 (85), 292 (15), 267 (100).

Example 5 (+ 1-H-aminoapovincamic acid

7.3 g (0.02 mol) (+) - 11-nitroapovincamic acid are dissolved in a mixture of 100 ml of concentrated hydrochloric acid and 50 ml of water. To the solution is added 7.3g of tin dust and allowed to cook for a quarter of an hour. The solution is decanted from the remaining tin and diluted with 50 ml of water. Hydrogen sulfide is then bubbled into the solution until a dark brown precipitate separates. The mixture is boiled, then cooled to 20 ° C and freed by filtration from the tin sulfide. The clear solution is evaporated in vacuo to one third of its volume. The concentrated solution is left in the refrigerator overnight. The crystallized product is filtered off and washed with ice-water. This gives 5.8 g (86%) of the title compound, which does not cause melting point depression on mixing with the product of Example 4.

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Example 6

(+ 1-11-Nitroapovincaminsäure-K

3.6 g (0.01 mol) (+ 1H-nitroapovincamic acid are dissolved in 200 ml of ethanol containing 0.56 g of potassium hydroxide The solution is evaporated and the residue recrystallized from a mixture of 100 ml of acetone and 5 ml of ethanol, 3.2 g of im The title potassium salt is obtained in the form of a yellow crystalline substance Melting point: does not melt to 340 ^° C.

Example 7 (+ 1-H-nitroapovincamic acid oxalate

A solution of 0.36 g (0.001 mol) of (+) - 11-nitroapovincamic acid in 30 ml of hot water is adjusted to pH 7.8 with concentrated ammonia. The hot solution is acidified to pH 3 with a concentrated aqueous solution of oxalic acid and then cooled to room temperature. The precipitated crystals are filtered off and washed with cold water. 0.35 g (78%) of the oxalate is obtained

 Melting point: 278-280 ° C.

Claims (11)

-1- 785 15 claims: 1. A process for the preparation of racemene or optically active 9- or 11-substituted Apovincaminsäurederivaten the general formula (I) wherein R is nitro or an amino group in the 9- or 11-position, and their salts, characterized in that the apovincamic acid of the formula (II) is nitrated, if desired, the. obtained 9- and / or 11-nitroapovincamic acid - optionally after its isolation from the reaction mixture - reduced and, if desired, the compounds of general formula (I) wherein R has the same meaning as above, decomposed into their optical antipodes and / or, if desired, to salts implements. 2. The method according to claim 1, characterized in that nitrated in glacial acetic acid medium with concentrated nitric acid. 3. The method according to claim 2, characterized in that nitrated in 1-3 vol .-% acetonitrile or dimethylformamide containing glacial acetic acid. 4. The method according to claim 2, characterized in that nitrated in 10-50 vol .-% chloroform containing glacial acetic acid. 5. The method according to any one of claims 1-4, characterized in that one carries out the nitration at temperatures between ^{0 0} C and + 16 ° C. 6. The method according to any one of claims 1-4, characterized in that the 9- and / or 11-nitroapovincamic acid is separated in the form of their nitrates. 7. The method according to any one of claims 1-5, characterized in that one carries out the reduction as a catalytic hydrogenation. 8. The method according to claim 7, characterized in that one carries out the catalytic hydrogenation in the presence of Pd activated carbon or Raney nickel at approximately neutral pH. 9. The method according to any one of claims 1-6, characterized in that the reduction is carried out with a chemical reducing agent. 10. The method according to claim 9, characterized in that one uses as a chemical reducing agent tin in hydrochloric acid medium. 11. The method according to claim 1-10, characterized in that one (+) - 9-Nitroapovincaminsäure,
(+) - 11-Nitroapovincaminsäure,
(-) - 9-aminoapovincamic acid or
(+) - 11-Aminoapovincaminsäure
and their salts.