CS250692B2 - Method of 9- or 11- substituted apovincamine acid's racemic and optically active derivatives preparation - 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

The invention relates to a process for the preparation of racemic and optically active derivatives of the 9 or 11-substituted apovincaminic acid of the general formula I

where

R is 9- or 11-nitro, and salts thereof.

9- and 11-nitroapovincamic acid have the formulas Ia and Ib

(Ib)

The novel compounds of formula I, wherein R is as defined above, are useful intermediates for the preparation of biologically active ring substituted A-substituted oburnan derivatives, such as nitroapovincamic acid esters.

There is no known method of nitration of apovincamic acid in the prior art; 9- and 11-nitroapovincamic acid is a novel compound. On the other hand, the 9- and 11-nitroderivatives of vincamine and apovincamine are known compounds, which can, for example, be prepared as described in French Patent Application Publication No. 2,341,585; No. 2,320,302 and 2,342,980. Vincamine and apovincamine are nitrated with nitric acid in glacial acetic acid to give a mixture containing 9- and 11-nitro compounds at a given ratio. In the case of vincamine, the reaction proceeds favorably to the formation of 11-nitrovincamine [Bull. Soc. Chim. Belg. 88, 1-2 (1979)], while apovincamine nitration yields 9-nitroapovincamine in greater quantities. No effective method was found to change the ratio of the two isomers that could be separated only by a cumbersome chromatographic procedure at the cost of a large loss of material.

According to the invention, the apovincaminic acid is preferably also nitrated with nitric acid in glacial acetic acid. However, it has unexpectedly been found that by properly selecting the reaction conditions, the ratio of nitration products (compounds of formula Ia and Ib) can be influenced within a certain range.

The present invention provides a process for the preparation of compounds of formula (I), characterized in that the apovincamic acid of formula (II)

nitration and optionally obtaining a compound of formula I, wherein R is as defined above, is cleaved and / or optionally converted to a salt.

If the reaction is carried out in pure acetic acid or. glacial acetic acid containing 1 to 3 (v / v) acetonitrile or dimethylformamide to give 9- and 11-nitroapovincamic acid of the formulas Ia and Ib in equal amounts. On the other hand, if glacial acetic acid contains 10 to 50%. (v / v) chloroform, moving the reaction towards the formation of 11-nitroapovincaminic acid.

In addition, the nitration process can be influenced by changing the temperature. Although the reaction can be carried out over a wide temperature range, for example in the range of -15 to +45 ° C, it is preferable to operate in the range of 0 to +16 ^q C. In this temperature range, 11-nitroapovincaminic acid predominates at lower temperatures. below 5%. Around the upper temperature range, two nitro isomers are obtained in almost the same amount and the amount of by-products that can be difficult to identify is slightly increased.

If the reaction is carried out at a temperature in the range of 0 to 16 ° C, it is complete in about two hours. By pouring the mixture obtained by nitration into ice water, 9- and 11-nitroapovincaminic acid are precipitated together as nitrate salts. The overall yield of the products obtained is high (about 75-85%). The two compounds are preferably separated by crystallization over a nitrate salt. Recrystallization of the obtained mixture from 50% aqueous alcohol at 5olu yields 9-nitroapovincamic acid nitrate first, followed by is precipitated by concentrating the mother liquor (after precipitation of a small amount of the mixed product on standing) pure 11-nitroapovincaminate nitrate. After separation, 9a and 11-nitroapovmamic acid are liberated from the nitrate salts in a known manner, dissolved in an alkaline solution and precipitated with the calculated amount of acid. preferably, the nitrate salt is dissolved in an ethanolic solution alkalized with sodium hydroxide (50%) and the corresponding apovincamic acid derivative is then precipitated by the calculated amount of hydrochloric acid.

The compounds of formula I can optionally be converted into acid addition salts by reaction with an acid according to known methods. These acids include, but are not limited to, inorganic acids such as hydrohalic acids, for example hydrochloric and hydrobromic acids, sulfuric, phosphoric, nitric, perchloric, etc.; organic carboxylic acids such as formic, acetic, propionic, oxalic, glycolic, maleic, fumaric, hydroxymaleinic, succinic, tartaric, ascorbic, citric, malicylic, lactic, cinnamic, benzoic, phenylacetic, p-aminobenzoic, hydroxybenzoic, p-aminosalicyl, etc.; alkylsulfonic acids such as methanesulfonic acid, ethanesulfonic acid, etc., cycloaliphatic sulfonic acids such as cyclohexylsulfonic acid; arylsulfonic acids such as p-toluenesulfonic acid, naphthylsulfonic acid, sulfonilic acid, etc.; amino acids such as aspartic acid, glutamic acid, N-acetylasparaginic acid, N-acetylglutaric acid, etc.

For example, salt formation can be carried out in an inert organic solvent such as C 1 -C 6 aliphatic alcohols by dissolving the racemic or optically active compound of formula I in a solvent and adding the selected acid or a solution thereof with the same solvent to the first solution until weakly acidic (pH 5 to 6). Then the acid addition salt is separated and can be removed from the reaction mixture by e.g. filtration.

Due to their acidic character, the apovincamic acid derivatives according to the invention also form salts with inorganic bases. The metal salts are prepared by known methods. As inorganic bases, alkali metal or alkaline earth metal hydroxides such as sodium, potassium or calcium hydroxides are preferably used.

Compounds of formula I wherein R is as defined above may also be converted to mono-quaternary salts. The quaternization is preferably carried out with an equivalent amount or a slight excess of the appropriate alkyl halide, preferably bromide or iodide, in an inert solvent at elevated temperature.

The compounds of the formula I and their salts obtained in the form of the racemate can be cleaved, for example, in a known manner.

The racemic or optically active compounds of the formula I and their salts can optionally be further purified, for example by recrystallization. The solvents used for recrystallization are selected with respect to the crystallization properties and solubility of the compounds to be recrystallized.

The invention will be further elucidated in the following examples without limiting the scope of the invention.

Example 1

Preparation of (+) 9-nitro-apovincamic acid

32.2 g (0.1 mol) of (+) apovincamic acid ((| <α] η ²⁰ = +220.48, c = 2, pyridine) are dissolved in 180 ml of glacial acetic acid. 16 ° C and a mixture of 52 ml of glacial acetic acid and 52 ml of fuming nitric acid (specific gravity: · 1.52) is added with stirring for 5 to 15 minutes, keeping the temperature at 16 ° C. The mixture was stirred at the same temperature for a further 50 minutes and then poured into one liter of ice water, and the precipitated crystals were filtered off and washed three times with 100 ml of ice water and then with 50 ml of ether each. g (75%) The crude nitrate salt was dissolved in 800 ml of a warm 50% aqueous ethanol solution, decolorized with charcoal and left to stand overnight The precipitated crystals were filtered off and washed 3 times with 20 ml of 50% aqueous ethanol solution. 12.8 g (29%) of nitrate (+) 9-nitrate is obtained o-apovincaminic acid, m.p. 232-234 ° C.

The obtained crystalline substance was dissolved in 160 ml of 50% ethanol at 60-70 ° C while adjusting the pH of the solution to 7.5 with 1 N sodium hydroxide. A 10% aqueous hydrochloric acid solution is then added to the solution to pH 6.5 and the yellow crystals precipitated upon cooling are filtered off and washed 3 times with 20 ml of water. 7.4 g (20 percent) of (+) 9-nitroapovincamic acid are obtained. After recrystallization from pyridine / ethanol (1: 1), the product melts at 260-262 ° C.

(.alpha.) = +317.32 (c = 0.4 pyridine);

ultraviolet spectrum (ethanol containing 0.5 ml of 1N hydrochloric acid)

210 (4.46),

287 (4.01);

Щ-NMR Spectrum · (DMSO-d 6) <5:

Et 0.96 (t) 3.1, 90 (q) 2, η - 3 4.52 (s) 1,

Η - 15 '6.26 (s) 1,

Η - 10 7.90 (dd) 1, (J = 8 and 1Hz),

H-11 7.80 (4) 1 (J = 8Hz)

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

Analysis:

for C20H21N3O4 (367.39):

calculated:

H, 5.76; H, 11.43.

% C, 65.30;% H, 6.00;

After separation of the pure (+) 9-nitro-apovincaminic acid nitrate from the mother liquor left aside, (+) 11-nitro-apovincaminic acid can be isolated as described in Example 2.

Example 2

Preparation of (+) 11-nitro-apovincamic acid

Dissolve 32.2 g (0.1 mol) of (+) apovincamic acid in 180 ml of glacial acetic acid. 77 ml of chloroform are added to the solution. The mixture is cooled to 0 ° C and a mixture of 52 ml of glacial acetic acid and 52 ml of fuming nitric acid (specific weight: 1.52) is added with stirring over 10-20 minutes and the temperature is maintained at 0 ° C. The reaction mixture was stirred for another hour at the same temperature and then poured into 1 L of ice water. Water is decanted from the thick, sticky material and the residue is triturated with 200-300 ml of ice water. The aqueous phase was discarded. The crystalline slurry was triturated with 200 to 300 ml of ether, filtered, washed 3 times with 100 ml of ice water and then with 50 ml of ether (on a filter) and dried. 37.8 g (85%) of crude 9-nitroapovincamic acid nitrate are obtained. The crude salt was dissolved in 900 ml of warm 50% aqueous ethanol, the solution was decolorized with activated carbon and allowed to stand overnight at room temperature. The precipitated crystals were filtered off and washed 3 times with 20 ml of 50% ethanol. 7.9 g of 9-nitroapovincamic acid nitrate are obtained. After standing overnight, additional crystalline 9-nitroapovincaminate nitrate precipitates from the mother liquor, which is filtered off and washed with 3 times 10 ml of 50% aqueous ethanol. Weight: 1 g.

The mother liquor and the combined washings were concentrated to half the volume, the precipitated crystals were filtered off and washed 3 times with water. 24.9 g (Э8%) of (+) 11-nitroapovincaminic acid nitrate melts at 211-214 ° C.

The salt obtained is dissolved in 500 ml of 50% aqueous ethanol at 60-70 ° C with the addition of 60 ml of 1 N sodium hydroxide solution. If necessary, adjust the pH of the solution to 7. The yellow crystals precipitated upon cooling are filtered off and washed 3 times with 40 ml of water. 15 g (40%) of 11-nitto-apovincamic acid are obtained. The melting point after recrystallization from pyridine / ethanol (1: 1) is 250 to 254 ° C.

[α] D = +187.43 (c = 0.4, pyridine).

Ultraviolet spectrum (ethanol containing 0,5 ml of 1 N hydrochloric acid) λ nm:

212 (4.32),

254 (413),

316 (3.98).

* H-NMR (DMSO-d6) [delta]:

Et 0.93 (t) 3,

1.9 (overlapping with solvent peak),

H - 3 4,2O0s),

H - 15 6.20s),

H - 9 7.6Od)

J = 9Hz),

H - 10 7.93 (dd) 1, (J = 9 and 2 Hz),

H - 12 8.38 (d) 1,

J = 2Hz).

Analysis:

for C20H21N3O4 (367.39):

calculated:

% C, 65.38;% H, 5.76;% N, 11.43;

found:

H, 5.84; N, 11.40.

Example 3

Preparation of (+) - 11-nitro-apovincamic acid potassium salt

3.6 g (0.01 mol) of (+) - 11-nitro-apincincanlinic acid are dissolved in 200 ml of ethanol containing 0.56 g of potassium hydroxide. The solution was evaporated and the residue was recrystallized from a mixture of 100 ml of acetone and 5 ml of ethanol. 3.2 g of the desired potassium salt are obtained as a yellow crystalline solid. It does not melt to 340 degrees Celsius.

Example 4

Preparation of (+) - 11-methyl-apovmamino acid oxalate for the first time

A solution of 0.36 g (0.001 mol) of (- | - 11-nitrocapvincaminic acid in 30 ml of hot water) was basified with concentrated ammonium hydroxide to pH 7.8.

0.35 g (78%) of the desired oxalate salt is obtained. Melting point: 278-280 ° C.

The mixture was cooled to pH 3 and cooled to room temperature. The crystals obtained are filtered off and washed with cold water.

Claims (6)

A process for the preparation of racemic and optically active derivatives of a 9- or 11-substituted apovincamic acid of the formula I wherein R is a 9- or 11-nitro group, and salts thereof, characterized in that the apovincamic acid of the general formula II OF THE INVENTION is nitrated and optionally the obtained compound of formula I, wherein R is as defined above, is cleaved and / or optionally converted to a salt. 2. Process according to claim 3, characterized in that the nitration is carried out with concentrated nitric acid in a glacial acetic acid medium. 3. A process according to claim 4 wherein the nitration is carried out in glacial acetic acid containing 1 to 3% (v / v) acetonitrile or dimethylformamide. 4. The process of claim 4 wherein the nitration is carried out in glacial acetic acid containing 10 to 50% (v / v) chloroform. 5. A process according to any one of claims 3 to 4, wherein the nitration is carried out at a temperature in the range of 0 to 4-16 ° C. 6. A process as claimed in claim 3, wherein the 9- and / or 11-nitro-apovincamic acid is separated by means of a nitrate salt. (II)