JPS6224429B2 - - Google Patents

Description

[Detailed description of the invention]

General formula: [In the formula, R ₁ represents hydrogen or a methyl group, and
is a novel 3-cyano-propionic acid amide derivative of -CH ₂ - or -O-. The 3-cyano-propionic acid amide derivatives of the general formula are useful intermediates for the preparation of medicaments since they can be easily converted into the corresponding 4-aminobutyric acid amide derivatives by catalytic hydrogenation of the cyano group. The invention therefore also relates to the use of 3-cyano-propionic acid amide derivatives of the general formula for the preparation of derivatives of 4-amino-butyric acid amide. The compounds according to the invention can be prepared by various methods. Method A: General formula: The 3-cyano-propionic acid in which R ₁ is as defined above is reacted with the corresponding primary or secondary or cyclic amine in the presence of a binder such as dicyclohexylcarbodiimide. In this case, the solvent may be a halogenated hydrocarbon such as dichloromethane, chloroform or carbon tetrachloride; an ether such as diethyl ether, diisopropyl ether, methyl t-butyl ether, dioxane or tetrahydrofuran; a nitrile such as acetonitrile; or benzene or toluene. Aromatic hydrocarbons such as can be used. The reaction takes place at a temperature of -20~
It is advantageous to carry out the reaction at +20°C, especially at -10 to +10°C. Method B: First, 3-cyano-propionic acid of the general formula is converted into its anhydride or mixed anhydride or into the corresponding acid chloride using, for example, acetic acid or with the Woodward reagent K,N- Ethoxycarbonyl-2-ethoxy-
activated using 1,2-dihydroquinoline,
Thereafter it is reacted with the corresponding primary or secondary or cyclic amine. The presence of a base, for example caustic soda or a tertiary amine such as pyridine, 4-(dimethylamino)-pyridine or triethylamine, is advantageous here. For an overview of known acylation methods that can be applied in connection with the present invention, see Hoven-Weil,
Houben-Weyl, “Methoden der
Organischen Chemie”) Volume XV, Part 1
(1974) shown below. In a preferred embodiment of process B, 3-cyano-propionic acid of the general formula V is converted into the corresponding acid chloride by reacting with thionyl chloride or oxalyl chloride, which is then reacted with an amine in the presence of caustic soda water. This reaction takes place at a temperature of -20 to +50
It is advantageous to carry out the reaction at temperatures between -20 DEG and +30 DEG. Method C: General formula: The corresponding first 3-cyano-propionic acid ester [wherein R ₁ represents the above-mentioned and R ₇ represents a linear or branched alkyl group having 1 to 6 carbon atoms] or react with a secondary or cyclic amine. The reaction is carried out hot, especially under reflux. This can be done in the absence of additional solvents or in the presence of such as benzene, toluene or xylene. Method D: General formula: Acrylic acid amide [in the formula, R ₁ and X represent the above] is reacted with hydrocyanic acid to add H--CN to the double bond of the acrylic acid residue. especially,
This addition involves a catalytic amount of alkali metal cyanide,
For example, it is carried out smoothly in the presence of sodium cyanide or potassium cyanide. For example, dimethylformamide, diethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dimethylsulfoxide, tetramethylenesulfone (sulfolane) or tetramethylurea and its homologs having up to 8 carbon atoms are used as solvents for this reaction. can do. This reaction is carried out at a temperature of 20~
It is advantageous to carry out the reaction at 150 DEG C., in particular from 70 DEG to 120 DEG C.
Pressure has no appreciable influence on the reaction rate and the composition of the reaction mixture after the end of the reaction. Advantageously, the reaction can be carried out by providing a suspension of the catalyst in part of the solvent and gradually metering in a solution of the acrylamide of the general formula and hydrocyanic acid in the remaining solvent. However, it is also possible to prepare a solution of acrylamide in which the catalyst is equally well suspended and to introduce hydrocyanic acid. The amines used in the above processes A, B and C, if not commercially available, can be prepared by conventional amine preparation methods, for example by reaction of the corresponding halogen compounds with ammonia, by reductive amination of the corresponding carbonyl compounds, by the appropriate can be prepared by reduction of nitro compounds, nitriles, oximes or acid amides, Hofmann decomposition of the corresponding acid amides, or Gabriel synthesis. The acrylamide used in method D above, if it is not a commercially available material, may be manufactured by Schotten Baumann.
-Baumann) method by reacting the corresponding amine with acrylic chloride or methacrylic chloride. Examples of compounds of the general formula according to the invention are 3-cyano-propionic acid-piperizide, 2-methyl-3
-Cyano-propionic acid-piperidide, 3-cyano-propionic acid-morpholide, 2-methyl-3
-Cyano-propionic acid-morpholide. Advantageously, 3-cyano-4-propionic acid derivatives of the general formula are reacted under reaction conditions at temperatures of 0 to 150° C. in the presence of an inert solvent, a noble metal catalyst and hydrogen chloride.
A derivative of 4-amino-butyric acid amide can be produced by hydrogenation with . In general, the hydrochloride of the 4-amino-butyric acid amide derivative is initially obtained during the hydrogenation, which can optionally be prepared in a very simple manner, for example by treatment with a basic ion exchanger or with a suitable base. It can be converted into a free 4-amino-butyric acid amide derivative. 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 having up to 6 carbon atoms, especially 1 to 3, or mixtures thereof with each other or with water. The amount of solvent used is not critical, but it is advantageous if it is determined in such a way that the 3-cyano-propionic acid amide derivative charged is completely dissolved at the selected reaction temperature. Particularly suitable solvents are water, methanol, ethanol or isopropyl alcohol. Furthermore, the hydrogenation requires the presence of noble metal catalysts, especially platinum metal catalysts.
Particularly good catalysts are metallic platinum and platinum oxide (). It is likewise possible to use mixtures of several noble metals or mixtures of noble metals and platinum oxide. The catalyst can be used in free form or as a supported catalyst (eg deposited on activated carbon). The catalyst can be recovered after the end of the hydrogenation and used repeatedly without purification, in the case of platinum oxide (), which after the first use is partially or completely converted into pt ²⁺ -compounds or metals. It doesn't matter whether it exists after being reduced to platinum. The amount of precious metal catalyst used is not absolute. However, in order to achieve a short hydrogenation time, the weight ratio of the 3-cyano-propionic acid amide derivative to the catalyst used must be adjusted.
Preferably, the noble metal catalyst is used in an amount of from 300:1 to 1:1, in particular from 100:1 to 5:1. Finally, the hydrogenation is preferably carried out in the presence of hydrogen chloride, which is used in equimolar amounts relative to the 3-cyano-propionic acid amide derivative used. It is also possible to use a small excess of hydrogen chloride. The hydrogenation is carried out at a temperature of 0 to 150°C, in particular 10 to 50°C. It can be carried out without pressure by passing hydrogen through the reaction mixture, or it can be carried out in a pressure reactor at hydrogen pressures of up to 100 bar. It is advantageous to carry out the hydrogenation at a pressure of up to 20 bar. Hydrogen pressure has a certain effect on the time required for complete hydrogenation, which decreases with increasing pressure, but has no effect on the 4-amino-butyric acid amide derivative formed. Next, the present invention will be explained in detail with reference to Examples. Example 1 3-cyano-propionic acid ethyl ester 12.7
(0.1 mol) are boiled with 30 ml of piperidine under reflux for 5 hours. Distillation under a pressure of 1.7 mbar gives 9.6 g (58% of theory) of 3-cyano-propionic acid piperidide with a boiling point of 143 DEG -145 DEG C. IR spectrum (film): ν(-C≡
N) 2260cm ^-1 ν

[Formula] 1645 cm ^-1 Example 2 17 g (0.2 mol) of piperidine are dissolved in 100 ml of toluene. While stirring and cooling on ice, 11.7 g (0.1 mol) of 3-cyano-propionyl chloride was added over 10 minutes. After reaction for 30 minutes at 20° C., the crystallized piperidine hydrochloride is sucked off and the liquid is fractionated at low pressure. Yield: 3-cyano-propionic acid-piperizide
10.3g (62% of theory) Boiling point: 132-135℃/0.5mbar Example 3 (Reference example) 3-cyano-propionic acid-piperidide 16.6g
(0.1 mol) is dissolved in 150 ml of ethanol containing 0.1 mol of hydrogen chloride and hydrogenated at normal pressure and 30-35 DEG C. in the presence of 0.8 g of platinum oxide ().
After 11/2 hours, the theoretical amount of hydrogen has been aspirated. Separate the catalyst. The liquid is concentrated to dryness and recrystallized from acetone. In this way, 10.7 g of 4-amino-butyric acid-piperidide-hydrochloride
(51.8% of theory) is obtained as colorless crystals. Melting point: 140-141°C Thin layer chromatogram ( _SiO2 : developer = n-butanol: glacial acetic acid: water = 4:1:1):
R _F =0.35 This substance reacts positively with ninhydrin. Example 4 (Reference Example) Example 3 is repeated, except that the hydrogenation is carried out in a shaking autoclave at a hydrogen pressure of 15 bar. Yield: 12.1 g (58.6% of theoretical amount) Melting point: 139-141°C This substance reacts positively with ninhydrin Example 5 (Reference example) 30 g (0.2 mol) of acrylic acid diallylamide and 8 ml of hydrogen cyanide are mixed with 25 ml of dimethylformamide.
A mixture of 15 ml of dimethylformamide and 0.4 g of potassium cyanide, heated to 90 DEG C., is stirred for 30 minutes. 2 ₁ 1/2 hours 100~
After reaction at 110° C. and subsequent distillation at 0.5 mbar, 25.2 g (72% of theory) of 3-cyanopropionic acid diallylamide are obtained as a colorless liquid. Boiling point: 126-127℃ IR spectrum (film): ν (-C≡N)
2260cm ^-1 elemental analysis: C ₁₀ H ₁₁ N ₂ O C H N Actual value 67.42% 7.99% 14.70% Calculated value 67.38% 7.92% 14.72% Example 6 (Reference example) Using the same volume of dimethyl sulfoxide instead of dimethylformamide and repeat Example 5. Yield: 26.0 g of 3-cyano-propionic acid diallylamide (74% of theory) Boiling point: 125-127°C/0.5 mbar Example 7 (Reference example) Sodium cyanide instead of potassium cyanide
Example 5 is repeated using 1.0 g as catalyst. Yield: 26.1 g of 3-cyano-propionic acid-diallylamide (74% of theory) Boiling point: 126-128°C/0.5 mbar Example 8 (Reference example) 3-cyano-propionic acid-diallylamide
17.8 g (0.1 mol) are hydrogenated at normal pressure in the presence of 3.8 g hydrogen chloride and 0.8 g platinum oxide in 150 ml ethanol. Reaction temperature 30-35℃. Hydrogen absorption ceases after 2 hours and 45 minutes. After separating the catalyst, the solvent is distilled off. The residue is obtained in crystals. Yield: 6.9 g of 4-amino-butyric acid-di-n-propylamide hydrochloride (theoretical amount
31.4%) Melting point: 63-65°C This substance is hygroscopic and reacts positively with ninhydrin. Example 9 (Reference example) Example 8 is repeated, except that the hydrogenation is carried out at 25-35° C. and a hydrogen pressure of 16 bar. Yield: 12.9 g (56% of theory) Melting point: 64-66°C The substance reacts positively with ninhydrin. Example 10 (Reference Example) Example 5 is repeated, except that 26.3 g (0.15 mol) of acrylic acid-(3,5-dimethyl)-anilide is used instead of acrylic acid diallylamide. The reaction mixture is worked up by distilling off the solvent and recrystallizing the residue from toluene. 18.6 g (61% of theory) of 3-cyano-propionic acid-(3.5-dimethyl)-anilide are obtained. Melting point: 164-165℃ IR spectrum (film): ν(-C≡
N) 22.50cm ^-1 Elemental analysis: C ₁₂ H ₁₄ N ₂ O C H N Actual value 71.10% 6.89% 13.99% Calculated value 71.26% 6.98% 13.85% Example 11 (Reference example) 1 g of sodium cyanide and Example 10 except using the same amount of dimethyl sulfoxide instead of dimethylformamide
Repeat. Yield: 3-cyano-propionic acid-(3,5-
dimethyl)-anilide 27 g (theoretical amount of 89
%) Example 12 (Reference example) Proceed in the same manner as Example 3. 20.4 g (0.4 mol) of 3-cyano-propionic acid-(3.5-dimethyl)-anilide is used instead of 3-cyano-propionic acid-piperidide. During hydrogenation, 4-amino-butyric acid-(3.5-dimethyl)-anilide hydrochloride crystallizes. The precipitate is dissolved in hot ethanol and the catalyst is separated. After cooling, 16.6 g (68.5% of theory) of 4-amino-butyric acid-(3.5-dimethyl)-anilide hydrochloride are obtained. Melting point: 190-192℃ This substance reacts positively with ninhydrin. Example 13 2-methyl-3-cyano-propionic acid 22.6g
(0.2 mol) and 17.1 g (0.2 mol) of morpholine are dissolved in 200 ml of dichloromethane and at 0-5 DEG C. 41.2 g (0.2 mol) of N,N'-dichlorohexylcarbodiimide in 100 ml of dichloromethane are added.
Dicyclohexylurea begins to crystallize immediately. 20
Stir for 2 hours at ˜25° C., remove the solid and wash the liquid sequentially with 2N hydrochloric acid, NaHCO ₃ solution and water.
After drying over sodium sulfate, it is filtered and the solvent is distilled off under reduced pressure. 29.3 g (81% of theory) of 2-methyl-3-cyano-propionic acid morpholide remain as a residue. Elemental analysis: _C9H14N2O2CHN Actual value _59.17 % 7.85% 15.01 _% Calculated value 59.32% 7.74 _% 15.37%

Claims (1)

[Claims] 1. General formula: [In the formula, R ₁ represents hydrogen or a methyl group, and
represents -CH ₂ - or -O-] is a novel 3-cyano-propionic acid amide derivative.