NO852794L - 9- AND 11-SUBSTITUTED APOVINCAMIC ACID DERIVATIVES AND PROCEDURES FOR THEIR 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 present invention relates to new 9- or 11- substituted apovincamic acid derivatives and a method for producing these compounds. More specifically, the invention relates to new, racemic and optically active nitro- and amino-apovincamic acid derivatives of formula (I)

where R is a 9- or 11-nitro or -amino group,

and salts thereof.

According to another aspect of the invention, a method is provided for the preparation of the new compounds of formula (I) and salts thereof. This process comprises the nitration of apovincamic acid of formula (II)

if desired, reduction of the obtained 9- and/or 11-nitro-apovincinamic acid (possibly after separation from the reaction mixture), and if desired, dissolution of an obtained racemic compound of formula (I) where R has the same meanings as defined above, in the optically active compounds, and/or, if desired, converting the same compound into a salt thereof. 9- and 11-nitro-apovincinamic acid are illustrated by the respective formulas (Ia) and (Ib), while the corresponding amino compounds obtained by reduction of the nitro compounds are illustrated by the formulas (Ic) and (Id)

The new compounds of formula (I) (R is as defined above) are useful intermediates in the preparation of biologically active eburnane derivatives which are substituted in ring A, such as nitro-apovincaminic acid esters or acylamino-apovincaminic acid derivatives which are described respectively in NO patent application no. 852796 and no. 852795.

According to the invention, compounds of formula (I) are prepared by nitration of the apovincamic acid of formula (II), and, if desired, a subsequent reduction of the obtained nitro compounds. Apovincamic acid is a known compound that was first described in HU patent document no. 160 367

(GB patent document no. 1 252 618).

There is no known method in the field of nitration of apovincamic acid, 9- and 11-nitro-apovincamic acid are new compounds. On the other hand, the 9- and 11-nitro derivatives of vincamine and apovincamine are known compounds such as e.g. can be prepared as described in the respective FR patent documents no. 2 341 585, 2 3 20 302 and 2 34 2 980. Both vincamine and apovincamine were nitrated with nitric acid in glacial acetic acid, and as a result a mixture containing 9- and 11-nitro compounds in a given ratio. In the case of vincamine, the reaction favored the formation of 11-nitrovincamine [Bull. Soc. Chim. Bell. 88, 1-2 (1979)], while 9-nitro-apovincamine was obtained in a larger proportion by nitration of apovincamine. No effective method was found for changing the ratio between the two isomers, which could only be separated by difficult chromatographic methods at the expense of a large loss of material.

Also according to the invention, apovincamic acid is preferably nitrated with nitric acid in a medium of glacial acetic acid. However, it has surprisingly been found that by suitable choice of reaction conditions, the ratio between the nitration products (the compounds with the formulas (Ia) and (Ib)) can be influenced within certain limits. If the reaction is carried out in pure glacial acetic acid or in glacial acetic acid containing 1 to 3% (volume/volume) acetonitrile or dimethylformamide, 9- and 11-nitro-apovincamic acid with the formulas (Ia) and (Ib) are thus obtained in approximately the same amount. On the other hand, the reaction goes in the direction of 11-nitro-apovincamic acid formation if the glacial acetic acid contains 10 to 50% (volume/volume) chloroform.

In addition, the development of the nitration can be influenced by changing the temperature. Although the turnover can be carried out within wide temperature limits, e.g. between -15 and +45°C, it is preferred to work between 0 and +16°C. At lower temperatures within this temperature range, 11-nitro-apovincamic acid predominates, and the amount of the accompanying impurities remains below 5%. Around the upper temperature limit, the two nitroisomers are obtained in approximately equal amounts, and ■ the quantity of by-products, which are difficult to identify, increases slightly.

If the reaction is carried out between 0 and +16°C, the reaction is complete within approx. 2 hours. By pouring the mixture obtained by nitration into ice water, 9- and 11-nitro-apovincamic acid are precipitated together in the form of the nitrate salts. The total yield of the products obtained is high (approx.

75 to 85%). The two compounds are preferably separated by crystallization, via the nitrate salts. Recrystallization of the mixture obtained from a 50% aqueous alcohol first gives the 9-nitro-apovincamic acid nitrate, after which the pure 11-nitro-apovincamic acid nitrate is precipitated by concentration of the mother liquor (after precipitation of a small amount of a mixed product on standing). After the separation, 9- and 11^-nitro-apovincamic acid can be set free from the respective nitrate salts in a known manner by dissolution in an aqueous alkaline solution and precipitation with a calculated amount of an acid. The nitrate salt is preferably dissolved in an ethanol solution that has been made alkaline with sodium hydroxide (50%), and the corresponding apovincamic acid derivative is then precipitated with a calculated amount of hydrochloric acid.

According to the invention, amino compounds with the formulas (Ic) and (Id) are prepared by reduction of the corresponding nitro compounds with the formulas (Ia) and (Ib).

Among the methods known from before, the production of 9- and 11-aminovincamine from the corresponding nitro compounds by catalytic hydrogenation can be considered analogous to this reaction step (see e.g. FR patent document no. 2 341 585 and 2 320 302). FR patent document no. 2 342 980 also describes the preparation of 9- and 11-amino-apovincamine from the corresponding nitro compounds by reduction with zinc powder in the presence of calcium chloride. According to the published data, the turnover was carried out with the achievement of a medium dividend.

Studies of the previously known reactions have led us to the conclusion that the reduction of the nitro-apovincamine isomers to the corresponding amino-apovincamine isomers by catalytic hydrogenation can only be carried out with a very low yield. The main product is a dihydro derivative obtained by saturation of the 14,15-double bond.

Surprisingly, we have found that the nitro-apovincamic acid derivatives of the formulas (Ia) and (Ib) can be reduced practically quantitatively to the corresponding amino derivatives of the formulas (Ic) and (Id) by catalytic hydrogenation. Catalytic hydrogenation can be carried out in an alkaline or as well

in an acidic medium, but is preferably carried out in an aqueous alcohol medium under approximately neutral conditions. Under such conditions, no saturation of the double bond between the carbon atoms in the 14- and 15-positions can be observed. Palladium-on-charcoal or Raney nickel is preferably used as a catalyst. When the catalytic hydrogenation is complete, the catalyst is filtered off, and the

desired product is isolated in a known manner, e.g. by evaporation of the solvent.

Although catalytic hydrogenation is preferred because of the simplicity of the reaction and the high yields obtained, the reduction can also be carried out with chemical reducing agents (Bruckner, Gy.: Organic Chemistry II/l, 469, TankSnyvkiad6, Budapest, Hungary, 1977). Of the reducing agents described, those which do not saturate the 14,15-double bond can be used in the present method. The amino compounds can thus be prepared by Béchamp reduction, but the reduction can also be carried out with zinc in glacial acetic acid, or with tin or zinc in hydrochloric acid. Variants of these methods which can be carried out in a neutral medium are equally suitable, but the reduction can also be carried out in an alkaline medium, e.g. with sodium dithionite or sodium sulphide, etc.

It can be concluded that with the method according to the invention the reduction step is also easy to carry out and gives the 9- and 11-amino-apovincamic acid in practically quantitative yield. It is particularly advantageous that the amines with the formulas (Ic) and (Id) which are obtained by the process according to the invention, especially by catalytic hydrogenation, can be converted into other, biologically active eburnane derivatives, e.g. to the corresponding acylamino-apovincinamic acid derivatives, directly without isolation from the reaction mixt. This is due to the high purity and excellent yield of the process.

The compounds of formula (I) can, if desired, be converted into the acid addition salts thereof by reaction with an acid according to methods which are known per se. Such acids include, among others, inorganic acids such as e.g. hydrohalic acids, e.g. hydrochloric acid and hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perhalogenic acids, e.g. perchloric acid, etc, organic carboxylic acids such as e.g. formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, maleic acid, fumaric acid, hydroxymaleic acid, succinic acid, tartaric acid, ascorbic acid, citric acid, malic acid, salicylic acid, lactic acid, cinnamic acid, benzoic acid, phenylacetic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, p-aminosalicylic acid, etc, alkylsulfonic acids such as e.g. methanesulfonic acid, ethanesulfonic acid, etc., cycloaliphatic sulfonic acids such as e.g. cyclohexylsulfonic acid, arylsulfonic acids such as e.g. p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, etc., amino acids such as aspartic acid, glutamic acid, N-acetyl-aspartic acid, N-acetyl-glutaric acid, etc.

Salt formation can be carried out e.g. in an inert organic solvent such as a C1, — b, aliphatic alcohol, so that the racemic or optically active compound of formula (I) is dissolved in the solvent and the selected acid or a solution thereof formed with the same solvent is added to the first solution until it becomes weak acidic (pH 5 to 6). The acid addition salt is then separated out and can be removed from the reaction mixture, e.g. by filtering.

The apovincamic acid derivatives according to the invention, due to their acidic character, also form salts with inorganic bases. The metal salts are produced by methods which are known per se. Alkali metal or alkaline earth metal hydroxides such as e.g. sodium, potassium or calcium hydroxide.

Compounds of formula (I) (R is as defined above) can also be converted to monoquaternary salts. Quaternization is preferably carried out with an equivalent amount or a small excess of a corresponding alkyl halide, preferably bromide or iodide, in an inert solvent at elevated temperature.

The compounds of formula (I) and their salts can,

when they are obtained in the form of a racemate, if desired, dissolve in the optically active compounds in a manner known per se.

The racemic or optically active compounds of formula (I) and their salts can, if desired, be further purified, e.g. by recrystallization. The solvents used for recrystallization are selected on the basis of the crystallization properties and solubility of the compounds to be recrystallized.

The invention is explained in more detail using the examples below.

Example 1

Preparation of (+)-9-nitro-apovincamic acid

32.2 g (0.1 mol) of (+)-apovincinamic acid ([a1D +220.48, c = 2, pyridine) was dissolved in 180 ml of glacial acetic acid. The solution was cooled to 16°C, and a mixture of 52 ml of glacial acetic acid and 52 ml of fuming nitric acid (specific gravity: 1.52) was added with stirring over 5 to 15 minutes, taking care that the temperature should kept at 16°C. The reaction mixture was stirred at the same temperature for a further 50 minutes and then poured into 1 liter of ice water. The precipitated crystals were filtered off and washed three times, each time with 100 ml of ice water and then 50 ml of ether. The nitrate salt of the intended compound was obtained as crude product in an amount of 32.2 g (75%). The impure nitrate salt was dissolved in 800 ml of a warm 50% aqueous ethanol solution, decolorized with charcoal, and the solution was allowed to stand overnight. The precipitated crystals were filtered off and washed three times, each time with 20 ml of a 50% aqueous ethanol solution. 12.8 g (29%) of (+)-9-nitro-apovincaminic acid nitrate with melting point 232 to 234°C were obtained.

The obtained crystalline substance was dissolved in 160 ml of 50% ethanol at 60 to 70°C while the pH of the solution was adjusted to 7.5 with 1 N sodium hydroxide. Then 10% aqueous hydrochloric acid was added to the solution until pH 6.5, and the yellow crystals which separated during cooling were filtered off and washed with three 20 ml portions of water. 7.4 g (20%) of (+)-9-nitro-apovincamic acid was obtained. After recrystallization from a 1:1 mixture of pyridine and ethanol, the product melted at 260 to 262°C.

[α]D = +317.32 (c = 0.4, pyridine);

UV spectrum (ethanol containing 0.5 ml 1 N hydrochloric acid)

Notes: 210 (4.46), 287 (4.01),

<1>H-NMR spectrum (DMSO-dg) S: Et 0.96(t)3, 1.90(q)2,

H-3 4.52(s)l, H-15 6.26(s)l, H-10 7.90(dd)l, (J=8 and 1Hz), H-ll 7.80(t) l (J=8Hz), H-12 7.74(dd)1 (J=8 and 1Hz).

Analysis for C20H21N3<0>4 (<3>67.39):

calculated: C 65.38%, H = 5.76%, N = 11.43%,

found: C 65.30%, H = 6.00%, N = 11.44%.

From the mother liquor that remained after the separation of pure (+)-9-nitro-apovincamic acid nitrate, (+)-11-nitro-apovincamic acid could be isolated by the method described in example 2.

Example 2

Preparation of (+)-11-nitrb-apovincamic acid

32.2 g (0.1 mol) of (+)-apovincinamic acid was dissolved in 180 ml of glacial acetic acid. To the solution was added 77 ml of chloroform. The mixture was cooled to 0°C, and a mixture of 52 ml of glacial acetic acid and 52 ml of fuming nitric acid (specific gravity: 1.52) was added with stirring over 10 to 20 minutes, taking care that the temperature should remain at 0°C. The reaction mixture was stirred at the same temperature for a further 1 hour and was then poured into 1 liter of ice water. Water was decanted from the resulting thick, sticky material and the residue was triturated with 200 to 300 ml of ice water. The aqueous phase was discarded. The crystalline mass was triturated with 200 to 300 ml of ether, filtered, washed three times, each time with 100 ml of ice water and then 50 ml of ether, (on filter) and dried. 37.8 g (85%) of impure 9-nitro-apovincaminic acid nitrate was obtained. The impure salt was dissolved in 900 ml of hot 50% aqueous ethanol, the solution was decolored with charcoal and allowed to stand at room temperature overnight. The precipitated crystals were filtered off and washed three times, each time with 20 ml of 50% ethanol. 7.9 g of 9-nitro-apovincinamic acid nitrate were obtained. After standing overnight, some additional crystalline 9-nitro-apovincaminic acid nitrate precipitated from the mother liquor which was filtered off and washed with 3 10 ml portions of 50% aqueous ethanol. Weight: 1 g.

The mother liquor and the mixed washing liquors were concentrated to half the volume, the precipitated crystals were filtered off and washed three times with 50 ml of water each time. 24.9 g (58%) of (+)-11-nitro-apovincaminic acid nitrate was obtained with melting point 211 to 214°C.

The salt obtained was dissolved in 500 ml of 50% aqueous ethanol at 60 to 70°C with the addition of approx. 60 ml of 1 N sodium hydroxide solution. If desired, the pH of the solution was adjusted to 7. The yellow crystals that precipitated after cooling were filtered off and washed three times with 40 ml of water each time. 15 g (40%) of 11-nitro-apovincamic acid was obtained. Melting point after recrystallization from a 1:1 mixture of pyridine and ethanol: 250 to 254°C.

[α]D = +187.43 (c = 0.4, pyridine).

UV spectrum (ethanol containing 0.5 ml 1 N hydrochloric acid)

Notes: 212 (4.32), 254 (4.13), 316 (3.98).

<1>H-NMR spectrum (DMSO-db,) 6 : Et 0.93(t)3, 1.9 (overlap with solvent peak), 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)1 (J = 2 Hz).

Analysis for C2o<H>21N3°4 (<3>67'39):

calculated: C = 65.38%, H = 5.76%, N = 11.43%,

found: C = 65.42%, H = 5.84%, N = 11.40%.

Example 3

Preparation of (-)-9-amino-apovincamic acid

3.6 g (0.01 mol) of (+)-9-nitro-apovincinamic acid prepared according to example 1 was dissolved in a mixture of 10 ml of ethanol and 5 ml of water. To the solution was added 0.04 g of a 10% palladium-on-charcoal catalyst, and the mixture was stirred in a hydrogen atmosphere at room temperature. After 0.03 mol of hydrogen gas had been used up, the catalyst was filtered off and washed three times with 2 ml of 50% aqueous ethanol each time. The solution obtained could be used directly, e.g. for the production of the corresponding acylamino derivatives.

To isolate (-)-9-aminoapovincinamic acid, the solution was evaporated to dryness under vacuum. The residue was triturated with 20 ml of ethanol, the crystals obtained were filtered off and washed twice with 3 ml of ethanol each time.

In this way, 2.85 g (85%) of the intended compound was obtained. The product did not melt below 340°C.

[α]D = -25 (c = 0.4, pyridine).

UV spectrum (ethanol containing 0.5 ml 1 N hydrochloric acid)

Note: 210 (4.43), 222 (4.53), 263 (4.05), 333 (3.78).<1>H-NMR spectrum (DMSO-dg) 5 : Et: 0.93 (3), approx. 1.8(2),

H-3: 4.44s(l), Nr^OH: 4.75(3), H-15: 5.68s(l), H-10: 6.25, H-ll, H-12: 6.72(1-1), molecular skeleton 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 4

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

3.6 g (0.01 mol) of (+)-11-nitro-apovincinamic acid was dissolved in a mixture of 5 ml of ethanol and 10 ml of 1 N aqueous sodium hydroxide solution. To the solution was added 0.04 g of a 10% palladium-on-charcoal catalyst, and the mixture was stirred in a hydrogen atmosphere at room temperature.

After 0.03 mol (720 ml) of hydrogen gas had been used up, the catalyst was filtered off and washed three times with 2 ml of 50% aqueous ethanol each time. The obtained resolution could, if desired, be used directly, e.g. for the production of various acylamino derivatives.

To isolate (+)-11-amino-apovincinamic acid, 10 ml

of a 1N aqueous hydrochloric acid solution added to the solution which was then concentrated to half its volume in vacuo. 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 was obtained which melted at 200 to 202°C with decomposition.

[α]D = +77.89 (c = 0.4, pyridine).

UV spectrum (ethanol containing 0.5 ml 1 N hydrochloric acid)

Note; 210 (4.32), 220 (4.43), 272 (3.98), 313 (3.77).<1>H-NMR spectrum (DMS0-dg) S : Et: 0.90t(3 ), about. l.80q(2), H-3: 4.29s(l), H-15: 5.72s(l), H-9: 7.10d(l), (J = 9 Hz), H-10 : 6.43dd(l), H-12: 6.64d(l) (J=2 Hz).

Mass spectrum M (C20H23N3°2'rel'int'%): 337 (54)'308 (85)'293 (15), 267 (100).

Example 5

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

7.3 g (0.02 mol) of (+)-11-nitro-apovincinamic acid was dissolved in a mixture of 100 ml of concentrated hydrochloric acid and 50 ml of water, and 7.3 g of tin powder was added to the solution. The mixture was boiled for fifteen minutes, after which the solution was decanted from the remaining tin and diluted with 50 ml of water. Hydrogen sulphide gas was then introduced into the solution until the separation of a dark brown precipitate was observed. The reaction mixture was brought to the boiling point, cooled to 20°C, and the stannous sulphide precipitate was filtered off. The clear solution was concentrated to one third of the volume in vacuo. The concentrated solution was allowed to stand in a refrigerator overnight. The crystalline product obtained was filtered off and washed with ice water. 5.8 g (86%) of the intended compound was obtained.

The product produced no melting point depression when mixed with the product of Example 4.

Example 6

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

3.6 g (0.01 mol) of (+)-11-nitro-apovincinamic acid was 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 acetone and 5 ml ethanol. 3.2 g of the intended potassium salt was obtained as a yellow crystalline substance. Melting point: no melting up to 340°C.

Example 7

Preparation of the oxalate of (+)-11-nitro-apovincamic acid

A solution of 0.36 g (0.001 mol) of (+)-11-nitro-apovincinamic acid in 30 ml of hot water was alkalized to pH 7.8 with a concentrated ammonium hydroxide solution. The hot solution was acidified to pH 3 with a concentrated aqueous solution of oxalic acid, and the mixture was cooled to room temperature. The crystals obtained were filtered off and washed with cold water. 0.35 g (78%) of the intended oxalate salt was obtained. Melting point: 278 to 280°C.

Claims (12)

1. Racemic and optically active 9- or 11-substituted apovincamic acid derivatives of formula (I) where R is a 9- or 11-nitro or -amino group, and salts thereof. 2. Compound according to claim 1, characterized in that it is selected from the following group: (+)-9-nitro-apovincamic acid, (+)-11-nitro-apovincamic acid, (-)-9-amino-apovincamic acid, (+)-11-amino-apovincamic acid, and salts of these compounds. 3. Process for the preparation of racemic and optically active 9- or 11-substituted apovincamic acid derivatives of formula (I) where R is a 9- or 11-nitro- or -amino group, and salts thereof, characterized by nitration of apovincamic acid with formula (II) and, if desired, reduction of the obtained 9- and/or 11- nitro-apovincamic acid, optionally after separation from the reaction mixture, and, if desired, dissolving an obtained racemic compound of formula (I) where R is as defined above, in the optical active compounds, and/or, if desired, converting an obtained compound into a salt thereof. 4. Method according to claim 3, characterized in that the nitration is carried out with concentrated nitric acid in a medium of glacial acetic acid. 5.. Method according to claim 4, characterized in that the nitration is carried out in glacial acetic acid containing 1 to 3% (volume/volume) acetonitrile or dimethylformamide. 6. Method according to claim 4, characterized in that the nitration is carried out in glacial acetic acid containing 10 to 50% (volume/volume) chloroform. 7. Method according to claims 3 to 6, characterized in that the nitriding is carried out at a temperature between 0 and +16°C. 8. Process according to claims 3 to 7, characterized in that 9- and/or 11-nitro-apovincamic acid is separated via the nitrate salts thereof. 9. Method according to claims 3 to 8, characterized in that the reduction is carried out by catalytic hydrogenation. 10. Method according to claim 9, characterized in that the hydrogenation is carried out in the presence of a palladium-on-charcoal or Raney-nickel catalyst at approximately neutral pH. 11. Method according to claims 3 to 8, characterized in that the reduction is carried out with a chemical reducing agent. 12. Method according to claim 11, characterized in that tin is used as a chemical reducing agent in a medium of hydrochloric acid.