CS250700B2 - Method of 9 or 11- substituted apovincamine acid's racemic and optically active derivatives preparation - Google Patents

Description

The novel compounds of formula I, wherein R is as defined above, are useful intermediates for the preparation of biologically active eburnan derivatives substituted in ring A, such as the derivatives of ecylaminoapovincaminic acid, as disclosed in Hungarian Patent Application Nos. 2704/84 and 2703/82.

According to the state of the art, 9- and 11-aminincincamine are prepared from the corresponding nitro compounds by catalytic hydrogenation (see, for example, French Published Applications Nos. 2,341,585 and 2,320,302). French Patent Application No. 2,342,980 also discloses the preparation of 9- and 11-aminoapovincamine from the respective nitro compounds by zinc dust reduction in the presence of calcium chloride. According to the published data, the reaction is carried out in a low yield.

In studying reactions known from the literature, it is concluded that the reduction of the nitroapovincamine isomer by catalytic hydrogenation can only be carried out at a very low yield. The major product is the dihydroderivative obtained by saturating the 14,15-double bond.

Unexpectedly, it has been found that aminoapovincamic acid derivatives of formula Ia and Ib can be obtained by virtually quantitatively reducing the corresponding nitro compounds by catalytic hydrogenation.

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

where

R 1 is a 9- or 11-nitro group, reducing and optionally obtaining a compound of formula I, wherein R is as defined above, is cleaved and / or optionally converted to a salt. The catalytic hydrogenation can be carried out in an alkaline or acidic medium, but is preferably carried out in an aqueous-alcoholic medium under near neutral conditions. Under these conditions, saturation of the double bond between atoms 14 and 15 is not observed. Preferably, palladium on carbon or Raney nickel is used as the catalyst. After the catalytic hydrogenation is complete, the catalyst is filtered off and the desired product is isolated in a known manner, for example by evaporation of the solvent.

Because of the simplicity of the reaction and the high yields obtained, catalytic hydrogenation is preferred, the reduction can also be carried out with chemical reducing agents (Bruckner, Gy .: Organic Chemistry II / 1, 469, Trankónyvkiadó, Budapest, Hungary, 1977).

Among the reducing agents mentioned, those in which no 14,15-double bond saturation occurs can be used in the process. The amino compounds may be prepared by Béchamp reduction, but the reduction may also be performed by zinc in glacial acetic acid or by tin or zinc in hydrochloric acid. Equally suitable are variants of these processes which can be carried out in a neutral environment but reduction with eg sodium dithionite or sodium sulfide, etc.

It can be stated that also in the process according to the invention the reduction step is easy to carry out and virtually quantitatively 9- and 11-aminoapovincaminic acid is obtained.

It is particularly advantageous that the amines of formula Ia and Ib obtained by the process according to the invention, in particular by catalytic hydrogenation, can be converted to other biologically active eburnan derivatives, e.g. directly to the corresponding acylaminoapovincamic acid derivatives without isolation from the reaction mixture. This is due to the high purity and excellent process yield.

The 9- and 11-nitroderivatives of vincamine and apovincamine are known compounds which can be prepared, for example, as described in French Patent Application Publication Nos. 2,341,585, 2,320,302 and 2,342,980. 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 the nitration of apovlncamine yields 9-nitrovincamine in greater quantities. No effective method was found to change the ratio of the two isomers, which could only be separated by a cumbersome-chromatography procedure at the cost of a large loss of material.

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 such as hydrochloric and hydrobromic acids, sulfuric, phosphoric, nitric, perchloric acid, etc .; organic carboxylic acids such as formic, acetic, propionic, oxalic, glycolic, maleic, fumaric, hydroxymaleinic, succinic, tartaric, ascorbic, citric, malicylic, lactic, cinnamon, 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, sulfanilic 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 a C 1 -C 6 aliphatic alcohol 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, for example by filtration.

Due to their acidic character, the apovincamic acid derivatives according to the invention also form salts with inorganic bases 25050 mi. 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 monoquaternary salts. The quaternization is preferably carried out with an equivalent amount or a slight excess of the corresponding 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, e.g. 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-Amino-apovincamic acid

Dissolve 3.6 g (0.01 mol) of (+) 9-nitro-o-apinotartaric acid in a mixture of 10 ml of ethanol and 5 ml of water. To the solution was added 0.04 g of 10% palladium on carbon catalyst and the mixture was stirred under a hydrogen atmosphere at room temperature. When 0.03 mol of hydrogen gas was consumed, the catalyst was filtered off and washed with 3X 2 ml of 40% aqueous ethanol. The solution obtained can be used, for example, to prepare the corresponding acylamine derivative.

To isolate (-) 9-amino-apovincamic acid, the solution was evaporated to dryness in vacuo. The residue is triturated with 20 ml of ethanol, the crystals obtained are filtered off, washed with 2 X 3 ml of ethanol. 2.85 g (85%) of the title compound are obtained. The product melts at 340 ^DEG C. [ _.alpha. ] _D = -25 (c = 0.4 pyridine).

Ultraviolet spectrum (ethanol containing 0,5 ml of 1 n hydrochloric acid / Anm):

210 (43), 222 (4.53), 263 (4.05), 333 (78).

1 H-NMR spectrum (DMSO-d 6) <5:

Et: 0.93 (3), about 1.8 (2), H-3: 4.44s (1),

NH 2 OH: 4.75 (3), H-15: 5.68s (1), H-10: 6.25,

H-11, H-12: 6.72 (1-1), skeletal protons

1.2.-3.4.

Mass Spectrum M (rel. Int.%):

333 (67); 308 (67); 295 (18); 293 (55); 267 (92); 264 (92); 223 (100).

Example 2

Preparation of (4) 11-Amino-apovincamic acid

3.6 g (0.01 mol) of (-) - • 11-nitro-apovincamic acid are dissolved in a mixture of 5 ml of ethanol and 10 ml of 1M aqueous sodium hydroxide solution. To the solution was added 0.04 g of 10% palladium on carbon catalyst and the mixture was stirred under a hydrogen atmosphere at room temperature. After uptake of 0.03 mol (720 ml of hydrogen gas), the catalyst is filtered off and washed with 3.times.2 ml of 50% aqueous ethanol, and the solution obtained can be used directly, e.g.

To isolate (+) 11-amino-apovincammic acid, 10 ml of a 1N aqueous hydrochloric acid solution was added to the solution, and the solution was then concentrated in vacuo to a volume. The concentrated solution was allowed to stand overnight. The precipitated crystalline product was filtered off and washed with ice water. 3.1 g (92%) of the title compound of melting point 200 DEG-202 ^DEG C. are decomposed.

[α] _D = +77.89 (c = 0.4, pyridine).

Ultraviolet spectrum (ethanol containing 0,5 ml of 1 n hydrochloric acid / Λ nm):

210 (4.32), 220 (4.43), 272 (3.98), 313 (3.77). ¹ H-NMR spectrum (DMSO-d 6) <5:

Et: 0.90t (3), about 1.80q (2), H-3: 4.29s (1),

H-15: 5.72s (1), H-9: 7.10d (1), ((= 9Hz),

H-10: 6.43dd (1), H-12: 6.64d (1), J-2 Hz).

M / C20H mass spectrum.

Mass spectrum N (C 6 H 6 N 5 Cu, rel. Int. Percent):

337 (54); 308 (85); 293 (15); 267 (100).

Example 3

Preparation of (- (-) 11-amino-apovincamic acid)

7.3 g (0.02 mole) of (- {-. Beta.-nitro-apovincamic acid) are dissolved in a mixture of 100 ml of concentrated hydrochloric acid and 50 ml of water, and 7.3 g of powdered tin are added. The solution is decanted and diluted with 50 ml of water, hydrogen sulfide gas is added until a dark brown precipitate is observed, the reaction mixture is boiled, cooled to 20 DEG C. and the precipitated stannous sulphide is filtered off. The clear solution was concentrated in vacuo to 1/3 volume and the concentrated solution was allowed to stand overnight in the refrigerator.

The crystalline product obtained is filtered off and washed with ice-water. 5.8 g (86%) of the desired compound are obtained.

When the product is mixed with the product of Example 4, there is no lowering of the melting point.

Claims (5)

A process for the preparation of racemic and optically active 9- or 11-substituted apovincarninic acid derivatives of the general formula I (11) wherein: R is 9- or 11-amino, and salts thereof, characterized in that the compound of formula II wherein R 1 is a 9- or 11-nitro group, reducing and optionally obtaining a compound of formula I, wherein R is as defined above, is cleaved and / or optionally converted to a salt. 2. Process according to claim 1, characterized in that the reduction is carried out by catalytic hydrogenation. 3. The process of claim 2, wherein the hydrogenation is carried out in the presence of palladium on carbon or Raney nickel catalyst at near neutral pH. 4. A process according to any one of claims 1-3 wherein the reduction is carried out using a chemical reducing agent. 5. The process of claim 4, wherein the chemical reducing agent is tin in a hydrochloric acid medium.