FR2508037A1 - - Google Patents

Abstract

The invention relates to certain derivatives of 3-cyanopropionamide or 2-methyl-3-cyanopropionamide in which the amino group is substituted by one or two monovalent radicals or by a divalent radical, and to the use of these derivatives for preparing corresponding derivatives of 4-aminobutyramide ("gabamide") by catalytic hydrogenation of the cyano group.

Description

dans lesquelles R1 signifie un atome d'hydrogène ou un groupe méthyle, et R2 un atome d'hydrogène, un groupe alcoyle a' channe droite ou ramifiée, avec 1 à 5 atomes de carbone, un groupe alkényle à channe droite ou ramifiée avec 2 à 5 atomes de carbone, un groupe phényle de formule générale

ou un groupe benzyle de formule générale

The invention relates to 3-cyanopropionic amide derivatives, characterized in that they correspond to general formulas I or II

in which R1 signifies a hydrogen atom or a methyl group, and R2 signifies a hydrogen atom, a straight or branched chain alkyl group with 1 to 5 carbon atoms, a straight or branched chain alkenyl group with 2 with 5 carbon atoms, a phenyl group of general formula

or a benzyl group of general formula

R3 has, with the exception of hydrogen, one of the meanings indicated for R2 with this condition that R2 and R3 are identical or different, R4, R5 and R6 are identical or different and each represents a hydrogen, fluorine, chlorine, bromine, methyl group or trifluoromethyl group, n and m are the same or different and represent an enter number equal to 1, 2 or 3, and X represents one of the groups

 The 3-cyanopropionic amide derivatives of general formula (I) and (II) are advantageous intermediate products for the manufacture of pharmaceutical products, since it is easy to convert them by catalytic hydrogenation into corresponding derivatives of amide 4- amino-butyric.

 Consequently, the subject of the invention is also 3cyano-propionic corresponding to the general formulas (I) or (II) and which is used for the manufacture of derivatives of the 4-amino-butyric amide.

dans laquelle R1 a la signification indiquée précédemment, ont été soumis à une réaction avec l'amine appropriée primaire, secondaire ou cyclique, en présence d'un agent de couplage tel que le dicyclohexylcarbodiimide. On peut utiliser ici comme solvant un hydrocarbure halogéné comme le dichlorométhane, le chloroforme ou le tétrachlorure de carbone ; un éther comme le diéthyléther, le diisopropyléther, le méthyl-tertiobutyléther, le dioxane ou le tétrahydrofuranne : un nitrile, comme l'acétonitrile, ou un hydrocarbure aromatique comme le benzène ou le toluene.La réaction s'effectue de préférence à une température comprise entre -20 et +20 C, de préférence entre -10 et +lO0C. The compounds according to the invention can be obtained by various methods
Process A: 3-cyano-propionic acids of general formula

in which R1 has the meaning indicated above, have been subjected to a reaction with the appropriate primary, secondary or cyclic amine, in the presence of a coupling agent such as dicyclohexylcarbodiimide. A halogenated hydrocarbon such as dichloromethane, chloroform or carbon tetrachloride can be used here as solvent; an ether such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane or tetrahydrofuran: a nitrile, such as acetonitrile, or an aromatic hydrocarbon such as benzene or toluene. The reaction is preferably carried out at a temperature between -20 and +20 C, preferably between -10 and + 10OC.

Method B
3-cyano-propionic acids of general formula (V) are first transformed into their anhydride or into a mixed anhydride, for example with acetic acid, or into the corresponding acid chloride, or they are activated by means of the reagent Woodward, K, N-ethoxyearbonyl-2-ethoxy-1,2-dihydroquinoline, and then reacted with the appropriate amine, primary, secondary or cyclic. The presence of a base, for example caustic soda or a tertiary amine such as pyridine, 4- (dimethylamino) -pyridine or triethylamine, is recommended.

The acylation processes which can find an application on this subject, are gathered in Houben-Weyl, Methoden der Organischen Chemie, volume XV, 2nd part, 1974, pages 1 and following
According to a recommended procedure of process B, the 3-cyano-propionic acid of formula (V) is transformed, by reaction with thionyl chloride or oxalyl chloride, into acid chloride and the latter then reacts with l amine in the presence of caustic soda lye, aqueous. The reaction is preferably carried out at a temperature between -20 and + 500CI or better between -20 and + 300C.

où R1 a la même signification que plus haut et R7 représente un groupe alcoyle à chaîne droite ou ramifiée, avec 1 à 6 atomes de carbone, réagissent avec les amines appropriées, primaires, secondaires ou cycliques. La réaction s'effectue à chaud, de préférence sous reflux. Elle peut se dérouler en l'absence d'un solvant additionnel, ou en présence d'un tel solvant, par exemple le benzène, le toluène ou le xylène.
Process: 3-cyano-roprioniac esters of general formula

where R1 has the same meaning as above and R7 represents a straight or branched chain alkyl group, with 1 to 6 carbon atoms, react with the appropriate amines, primary, secondary or cyclic. The reaction is carried out hot, preferably under reflux. It can take place in the absence of an additional solvent, or in the presence of such a solvent, for example benzene, toluene or xylene.

dans laquelle R1, R2, R3, n, m et X ont la meme signification que plus haut, avec l'acide cyanhydrique de façon telle que
H-CN vienne se fixer sur la double liaison du groupe acrylique. Method D
Acrylic amides of general formula are reacted

in which R1, R2, R3, n, m and X have the same meaning as above, with hydrocyanic acid so that
H-CN is fixed on the double bond of the acrylic group.

This addition takes place in a particularly regular manner in the presence of catalytic amounts of an alkali metal cyanide, for example of sodium or potassium cyanide.

 As solvent, it is possible to use for this reaction, for example, dimethylaformamide, diethylformamide, dimethylacetamide, N-methylpyprolidone, tetrahydrofuran, dimethylsulfoxide, tetramethylenesulfone (sulfolane) or tetramethylurea and its counterparts up to 8 carbon atoms.

The reaction is preferably carried out at a temperature between 20 and 1500C, or better between 70 and 1200C. The pressure has no appreciable influence on the speed of the reaction and on the composition of the reaction mixture at the end of the reaction.

The reaction can preferably be carried out by preparing a suspension of the catalyst in part of the solvent, and slowly introducing into it a solution of the acrylic amide of general formula (VII) or (VIII), and hydrocyanic acid, in the rest of the solvent. However, one can also operate by preparing an acrylic amide solution in which the catalyst is in suspension and by introducing hydrocyanic acid into it.

The amines used in the above processes A, B and C can be obtained, for their part, insofar as they are not commercially available, by the usual processes for the manufacture of amines, for example by reacting the halogenated compounds suitable with ammonia, by reduction ination of the appropriate carbonylated compounds, reduction of the appropriate nitrated compounds, nitriles oximes or amides, by reaction of Hoffmann of the corresponding amides or by a synthesis of Gabriel. As for the acrylic amides used in process D above, they can be obtained, if they are not commercially available, from the corresponding amines, by reaction with chloride of acrylic or methacrylic acids, according to Schotten
Baumann.

 Examples of compounds according to the invention, of general formula (I), are constituted by: methylamide 3-cyano-propionic, dimethylamide 3-cyano-propionic, dimethylamide 2-methyl-3-cyano-propionic, ethylamide 2-methyl -3cyano-propionique, 2-methyl-3-cyano-propionic diethylamide, 3-cyano-propionic diallylamide, 2-methyl-3cyano-propionic diallylamide, 3-cyano-propionic anilide, 2-methyl-3-cyano-propionic anilide, 3- fluoro-anilide 3-cyano-propionic, 2-fluoro-anilide 2-methyl-3-cyano-propionic, 4-chloroanilide 2-methyl-3-cyano-propionic, 4-methyl-phenyl-amide 3-cyano-propionic, 3,5-dinethylanilide 2-methyl-3-cyano-propionic, benzylamide 3-cyano-propionic, benzylamide 2-methyl3-cyano-propionic, 4-chlorobenzylamide 3-cyano-propionic, 4-trifluoromethyl-benzyl-amide-3- cyano-propionic or 3,5-bis (trifluoromethyl) -benzyl-amide 2-methyl-3-cyano-propionic.

 Examples of compounds according to the invention of general formula (I) consist of: piperidy 3cyano-propionique, pipéridide 2-methyl-3 -cyano-propionique, morpholide 3 -cyano-propionique, morpholide-2-methyl-3- cyanopropionic, 3-cyano-propionic thiomorpholide, 2-methyl-3-cyano-propionic thiomorpholide, 3-cyano-propionic piperazide, 2-methyl-3-cyano-propionic piperazide N-phenyl-piperazide 3-cyano-propionic, N- phenyl-piperazide 2-methyl-3-cyano-propionic, N- (2-ethylphenyl) -piperazide 2-methyl-3-cyano-propionic, N- (2-chlorophenyl) -piperazide 2-methyl-3-cyano -propionic, N- (3,4-dimethylphenyl) -piperazide 2-methyl-3-cyano-propionic, N- (3,5-dimethylphenyl) -piperazide 3-cyano-propionic, N-2 (phenyl) -ethyl- piperazine 2-methyl-3-cyano-propionic, carbonic N-ethylate-piperazide 2-methyl-3-cyano-propionic, or 4-phenylpiperidide 2-methyl-3-cyano-propionic.

 From the derivatives of 3-cyano-propionic amides of general formula (I) or (II), derivatives of 4-amino-butyric amides can be obtained by hydrogenation in the presence of an inert solvent under the reaction conditions of a precious metal and hydrochloric acid catalyst, at a temperature between 0 and 1500C, Insofar as in the general formula (I), the groups R2 and / or R3 signify an alkenyl group, during hydrogenation, the defined double bond is hydrogen also normally, so that the corresponding saturated products are obtained.

 In general, the hydrochloride of the 4-amino-butyric amide is obtained during the hydrogenation, which can be easily transformed, for example by means of a basic ion exchanger, or a suitable base, in free 4-aminobutyric amide. The hydrogenation is carried out in the presence of an inert solvent under the conditions of the hydrogenation reaction. Suitable solvents are water, primary or secondary alcohols which may contain up to 6, and preferably 1 to 3 carbon atoms, or mixtures thereof with each other or with water. The amount of solvent used is not critical, but it should preferably be determined so that the 3-cyanopropionic amide used is completely dissolved at the chosen reaction temperature. The solvents which are particularly recommended are water, methanol, ethanol, or isopropyl alcohol. The hydrogenation also requires the presence of a precious metal catalyst, in particular a platinum catalyst. Particularly recommended catalysts are metallic platinum or platinum oxide IV.

It is also possible to use mixtures of several precious metals or a mixture of precious metals with platinum oxide IV. The catalysts can be used in the free state or as supported catalysts (for example precipitated on activated carbon). After the end of the hydrogenation, they can be recovered and used again without further purification, since in the case of platinum oxide
IV, it is immaterial that it is reduced, after the first use, partially or completely to Pt2 + compounds or to metallic platinum. The quantity of precious metal catalyst to be used is not critical. For obtaining short hydrogenation times, it is however recommended to use the precious metal catalyst in such quantity that the weight ratio between the 3cyano-propionic amide used and the catalyst is from 300: 1 to 1: 1, preferably from 100 -: 1 to 5: 1.

 The hydrogenation is finally carried out in the presence of hydrochloric acid, preferably used in equimolecular proportion relative to the 3-cyanopropionic amide. But a small excess of hydrochloric acid is also possible.

 The hydrogenation takes place at a temperature between 0 and 1500CI, preferably between 10 and 500C. It can take place at atmospheric pressure, and in this case the hydrogen is passed through the reaction mixture, or else into a closed reaction vessel, under a hydrogen pressure of up to 100 bars. The hydrogenation is preferably carried out under a pressure of up to 20 bars. If the hydrogen pressure exerts a certain influence on the time necessary for complete hydrogenation, which is somewhat shortened by raising the pressure, it has no influence on the purity of the 4-amino-butyric amide formed. .

The invention will be better understood using the examples below
Example 1
12.7 g (0.1 mole) of 3-cyano-propionic ethylate were brought to the boil under reflux with 30 ml of piperidine for 5 hours. By distillation under a pressure of 1R7 mbar, there was obtained, with a boiling point of 143-1450C? 9.6 g (58% of theoretical yield) of 3-cyanopropionic piperidide.

Exemple 2:
17 g (0,2 mole) de pipéridine ont été dissous dans 100 ml de toluène. Sous agitation et refroidissement avec de la glace, 11,7 g (0,1 mole) de chlorure d'acide 3-cyano-propionique ont été ajoutés goutte-à-goutte en l'espace de 10 minutes. On a laissé la réaction se poursuivre durant encore 30 minutes à 200C, on a filtré sous pression réduite le chlorhydrate de pipéridine cristallisé, et l'on a soumis le filtrat à une distillation fractionnée sous pression réduite ; rendement 10,3 g (62 % de la théorie) de pipéridide 3-cyano-propionique.IR SPeCre (film)

Example 2:
17 g (0.2 mole) of piperidine was dissolved in 100 ml of toluene. With stirring and cooling with ice, 11.7 g (0.1 mole) of 3-cyanopropionic acid chloride was added dropwise over 10 minutes. The reaction was allowed to continue for a further 30 minutes at 200C, the crystallized piperidine hydrochloride was filtered under reduced pressure, and the filtrate was subjected to fractional distillation under reduced pressure; yield 10.3 g (62% of theory) of piperidide 3-cyano-propionique.

Boiling point below 0.5 mbar; 132 - 1350C.

temple 3:
16.6 g (0.1 mole) of piperidide 3-cyano-propionic were dissolved in 150 ml of ethanol containing 0.1 mole of hydrochloric acid, and they were hydrogenated in the presence of 0.8 g platinum oxide IV at atmospheric pressure, between 30 and 350C. 1 hour and a half later, the theoretical quantity of hydrogen has been consumed. The catalyst was then filtered. The filtrate was concentrated to the dry state by evaporation, and then recrystallized from acetone. 10.7 g (51.8% of theory) of 4-amino-butyric piperidide hydrochloride were thus obtained in the form of colorless crystals. Melting point: 140 - 1410C.

 Thin layer chromatography: (Si02; eluent = n-butanol: anhydrous acetic acid: water = 4: 1: 1) = = = 0.35.

 The substance reacts ninhydrinpositive.

EXAMPLE 4
The operation was carried out according to Example 3 with the difference that the hydrogenation was carried out in a shaking autoclave under a hydrogen pressure of 15 bars. Yield: 12.1 g (58.6% of theory): Melting point: 139 - 1410C.

 The substance reacts ninhydrinpositive.

EXAMPLE 5
30 g (0.2 mole) of acrylic diallylamide and 8 ml of hydrocyanic acid were dissolved in 25 ml of dimethylformamide and introduced, with stirring over 30 minutes, into a hot mixture at 90C of 15 ml of dimethylformamide and 0.4 g of potassium cyanide. The reaction was allowed to continue for 2 hours at a temperature of 100 to 1100CI and 25.2 g (72% of theory) of 3-cyano- diallylamide were obtained by consecutive distillation under 0.5 mbar. propionic, as a colorless liquid. Boiling point: 126-1270C.

SPectre IR (film): t (- C = N) 2260 cml
Elementary analysis: C10 H11 N2 0
CHN
Found: 67.42% 7.99% 14.70%
Calculated: 67.38% 7.92% 14.72%
EXAMPLE 6
The procedure was as in Example 5 with this difference, that instead of dimethylformamide, an identical volume of dimethylsulfoxide was used.

Yield: 26 g (74% of theory) of 3-cyanopropionic diallylamide: Boiling point: 125 - 1270C (0.5 mbar).

EXAMPLE 7
The procedure was as in Example 5 with the only difference, that instead of potassium cyanide, 1 g of sodium cyanide was used as catalyst.

Yield: 26.1 g (74% of theory) of 3-cyanopropionic diallylamide. Boiling point: 126 - 1280C (0.5 mbar).

EXAMPLE 8
17.8 g (0.1 mole) of 3-cyanopropionic diallylamide were hydrogenated in the presence of 3.8 g of hydrochloric acid and 0.8 g of platinum oxide in 150 ml of ethanol at pressure atmospheric. Reaction temperature: 30 to 350C.

The hydrogen absorption ended after 2 hours and 45 minutes. After filtration of the catalyst, the solvent was removed by distillation. The residue was obtained in crystalline form.

Yield of di-n-propylamide 4-amino-butyric hydrochloride 6.9 g (31.4% of theory).

Melting point: 63 - 650C.

 The substance is hygroscopic and reacts ninhydrinpositive.

Example 9
The procedure was as in Example 8 with the difference that the hydrogenation was carried out at 25-35 C, under a hydrogen pressure of 16 bars. Yield: 12.9 g (56% of theory): Melting point: 64 - 660C.

 The substance reacts ninhydrinpositive.

Example 10
The procedure was as in Example 5, with the difference that, in place of the acrylic diallylamide, 26.3 g (0.15 mol) of 3,5-dimethyl-anilide acrylic were used. The solvent was removed from the reaction mixture by distillation and the residue was recrystallized from toluene. 18.6 g (61 X of theory) were obtained of 3,5-dimethyl-anilide 3-cyanopropionic.

Melting point: 164 - 1650C.

IR spectrum (film): t (- C = N) 2250 cm
Elementary analysis: C12 H14 N2 O
CHN
Found: 71.10% 6.89% 13.99%
Calculated: 71.26% 6.98% 13.85%
EXAMPLE 11
The procedure was as in Example 10 with this difference, that instead of potassium cyanide, 1 g of sodium cyanide was used and that instead of dimethylformamide, an equal amount of dimethylsulfoxide was used.

Yield: 27 g (89% of theory). of 3,5-dimethyl-anilide3-cyano-propionic.

EXAMPLE 12
The procedure was as in Example 3. In place of piperidide 3-cyano-propionic, 20.4 g (0.1 mol) of 3,5-dimethyl-anilide 3-cyano-propionic was used. During the hydrogenation, it crystallized from 3,5-dimethylanilide 4-amino-butyric hydrochloride. The precipitate was dissolved in hot ethyl alcohol and the catalyst was separated. After cooling, 16.6 g (68.5% of theory) of 3,5-dinlethyl-anilide 4-amino-butyric hydrochloride were obtained.

Melting point: 190 - 1920C.

 The substance reacts ninhydrinpositive.

Example 13
22.6 g (0.2 mole) of 2-methyl-3-cyano-propionic acid and 17.1 g (0.2 mole) of morpholine were dissolved in 200 ml of dichloromethane and added thereto at a temperature of 0 to 50C, a solution of 41.2 g (0.2 mole) of N, N'dicyclohexyl-carbodiimide in 100 ml of dichloromethane. The dicyclohexylurea immediately begins to crystallize. The mixture is stirred for 2 hours at 20-250 ° C., the solid product is filtered and the filtrate is washed successively with 2N1 hydrochloric acid, a solution of
NaHC03 and water. After drying over sodium sulfate, it is filtered and the solvent is removed by distillation under reduced pressure.

 As residue, 29.3 g (81% of theory) of 2-methyl-3-cyanopropionic morpholide are obtained.

Elementary analysis: C9 H14 N2 02
CHN
Found: 59.17% 7.85% 15.01%
Calculated: 59.32% 7.74% 15.37%

Claims (2)

 or a benzyl group of general formula

 in which R1 signifies a hydrogen atom or a methyl group, and R2 signifies a hydrogen atom, a straight or branched chain alkyl group with 1 to 5 carbon atoms, a straight or branched chain alkenyl group with 2 to 5 carbon atoms, a phenyl group of general formula

 10) 3-Cyanopropionic amide derivatives, characterized in that they correspond to general formulas (I) or (II)

 3 indicated for R2 with this condition that R2 and R3 are identical or different, R4, R5 and R6 are identical or different and each represents a hydrogen, fluorine, chlorine, bromine atom, a methyl group or a trifluoromethyl group , n and m are the same or different and represent an integer of 1, 2 or 3, and X represents one of the groups R a, with the exception of hydrogen, one of the meanings  2) 3-cyanopropionic amide derivatives according to claim 1, characterized in that they correspond to general formulas (I) or (II), and that they are used for the manufacture of derivatives of amide 4 -amino-butyric.