CS268471B1 - Substituted 3-phenyl-2-propenoic acid amides and process for their preparation - Google Patents

Abstract

The solution relates to 3-phenyl-2-propenoic acid derivatives of the general formula I, which form important pharmaceutically usable compounds and starting materials for the synthesis of more complex organic structures. The radicals R1 denote an amino group, unsubstituted or substituted by an aliphatic residue C^ - Ο^θ, 2 R denotes hydrogen, bromine or an acetyloxy group and R·5 denotes an acetylamino or acetyloxy group. According to the invention, the substance is prepared by treating the chloride of the substituted acid with a 2 to 5-fold molar excess of an aliphatic amine, e.g. propylamine, isopropylamine, ammonia or a hydroaromatic amine in an anhydrous solvent environment in the optional presence of a reagent that binds hydrogen halide. The reaction is carried out at temperatures of -5 to 100 °C

Description

The present invention relates to 3-phenyl-2-propenoic acid amides substituted on the benzene ring at the 3- and 4-positions by acetylamino, acetoxy or bromine, which form important pharmaceutically useful compounds and starting materials for the synthesis of more complex organic structures.

The group of compounds described herein has not yet received synthetic attention, although some other prepared derivatives have different pharmacological effects, such as antibacterial, analgesic, sedative, etc., or find various technical uses.

The present invention relates to novel 3-phenyl-2-propenoic acid derivatives of the general formula I

where r! denotes an amino group substituted by propyl, isopropyl or cyclohexyl, 2 R denotes hydrogen, bromine, acetoxy, R ³ denotes acetylamino or acetoxy.

The invention further relates to a process for the preparation of acid derivatives of formula I, which comprises treating 3-phenyl-2-propenoic acid chloride with a 2 to 5-fold molar excess of propylamine, isopropylamine or cyclohexylamine in an anhydrous solvent selected from the group consisting of benzene and dioxane, optionally in the presence of a hydrogen halide scavenger such as pyridine, the reaction being carried out at temperatures of -5 to 100 ° C, preferably at 0 to 20 ° C. At temperatures higher than the boiling points of the corresponding amine, it is possible to work at elevated pressure.

The acid chlorides are prepared with chlorinating agents such as thionyl chloride, phosphorus oxychloride, chloroformates and the like. This reaction is carried out in anhydrous benzene or dioxane, optionally without the use of solvents.

After completion of the reaction, the excess solvent is distilled off. If a water-miscible solvent is used, the resulting product is diluted with the required amount of water. The crystalline compounds are purified by crystallization from a suitable solvent or mixture of solvents. The structures of the final compounds were also confirmed by NMR spectra.

The most suitable starting compounds for the preparation of chlorides are substituted 3-phenyl-2-propenoic acids, obtained from the corresponding esters by known methods.

The prepared compounds have bacteriostatic properties on gram-negative bacteria. It acts on E. coli in concentrations of 125 to 500 .mu.g. ml ^-1 . The most active compounds are: 3- (3-acetone-4-bromophenyl) propenoic acid isopropylamide, 3- (3-acetone-4-bromophenylpropenoic acid propylamide and 3- (3,4-diacetoxyphenyl) propenoic acid propylamide.

Example 1

3- (3,4-Diacetoxyphenyl) propenoic acid propylamide

To a solution of 70 g (0.25 mol) of 3- (3,4-diacetoxyphenyl) propenoic acid chloride in 200 ml of anhydrous dioxane at 13 DEG-15 DEG C. is added in 15 minutes 42 ml (0.5 mol) of propylamine in 100 ml of water. ml of anhydrous dioxane. After 30 min, the solution is filtered. The dioxane is distilled off in vacuo and the product is mixed with petroleum ether. After separating the petroleum ether, the remaining product was dissolved in chloroform and extracted in the cold with sodium bicarbonate solution. The chloroform layer was dried and chloroform was distilled off. The amide crystallizes out in a refrigerator in a yield of 53 g, m.p. 108-112 ° C (precipitated from anhydrous xylene with anhydrous petroleum ether).

For C ₁₆ H ₁₉ NO ₅ (305.3) calculated: 62.93 ° C, 6.27% H, 4.58% N; Found: 62.48% C, 5.99% H, 4.55% N.

Example 2

3- (3,4-Diacetoxyphenyl) propenoic acid isopropylamide

Melting point: 93-96 ° C (precipitated from anhydrous xylene with anhydrous petroleum ether).

The preparation is carried out according to Example 1, except that isopropylamine is used as the amidating agent.

For (305.3) calculated: 62.93% 0, 6.27% H, 4.58% N; found: 62.44% C,

6.03% H, 4.40 * N.

Example 3

3- (3,4-Diacetoxyphenyl) propenoic acid cyclohexylamide

Melting point 120-122.5 ° C (precipitated from anhydrous xylene with anhydrous petroleum ether).

The procedure of Example 1 is followed, except that cyclohexylamine is used as the amidating agent.

For X ₁₉ H ₂₃ NO ₅ (345.3) calculated: 66.07% C, 6.7% H, 4.05% N; Found: 65.81% C, 6.78% H, 4.37% N.

Example 4

3- (4-Acetylaminophenyl) propenoic acid cyclohexylamide g (0.34 mol) of 3- (4-acetylaminophenyl) propenoic acid chloride in 600 ml of anhydrous benzene are mixed successively at 5-7 ° C with 67.4 g (0 68 mol) of cyclohexylamine dissolved in 100 ml of anhydrous benzene. After 15 min, the temperature was raised to 25 ° C for 30 min, then heated to 60 ° C for 30 min. The solvent is distilled off. Yield 59 g. Melting point 258-259 ° C (ethanol).

For C ₁₇ H ₂₂ N ₂ O ₂ (268.33) calculated: 71.30% C, 7.73 h H, 9.78% N; found: 71.7% C,

7.8 * H, 9.8% N.

Example 5

3- (4-Acetylaminophenyl) propenoic acid propylamide

Melting point 232-235 ° C (aqueous ethanol).

The preparation is carried out according to Example 4, except that propylamine is used as amidating agent.

For C ₁₄ H ₁₀ N ₂ O ₂ (246.28) calculated: 68.27% C, 7.35 H, 11.37% N; Found: 67.88% C, 7.38% H, 11.59% N.

Example 6

3- (4-Acetylaminophenyl) propenoic acid isopropylamide

Melting point 228-230.5 ° C (aqueous ethanol)

The preparation is carried out according to Example 4, except that isopropylamine is used as the amidating agent. The reaction is carried out in an autoclave at a temperature of 70 to 90 ° C.

For C ₁₄ H ₁₀ H ₂ O ₂ (246.28) calculated: 68.27 ° C, 7.35 Η H, 11.37 ° C; found: 67.95% C,

7.34% H, 11.52% N.

Example 7

3- (4-Acetoxy-3-bromophenyl) propenoic acid isopropylamide

Melting point 153.5-155.5 ° C (ethanol).

The preparation is carried out according to Example 4, except that isopropylamine is used as the amidating agent. ’

For C ₁₄ H ₁₆ BrNO ₃ (326.1 *) calculated: 51.55 VC, 4.94% N, 4.29% N, 24.5% Br;

Found: 51.4 ° C, 4.9% H, 4.3% N, 24.22% Br.

Example 8

3- (4-Acetoxy-3-bromophenyl-propenoic acid propylamide

Melting point 105.5-107 ° C (aqueous ethanol)

The preparation is carried out according to Example 4, except that propylamine is used as amidating agent.

For C ₁₄ H ₁₆ BrNO ₃ (326.15) calculated: 51.55% C, 4.94% H, 4.29% N, 24.5% Br;

found: 51.22% C, 5.05% H, 4.47 h N, 24.57% Br.

Example 9

3- (4-Acetoxy-3-bromophenyl) propenoic acid cyclohexylamide

Melting point 169-172 ° C (aqueous ethanol)

The procedure is as in Example 4, except that cyclohexylamine is used as the amidating agent.

For C ₁₇ H _{2 O} BrNO ₃ (289.19) calculated: 43.97% C, 6.96% H, 4.84% N, 27.62% Br; Found: 44.16% C, 7.15% H, 4.52% N, 27.87 Br.

Example 10

3- (4-Acetylamino-3-bromophenyl) propenoic acid isopropylamide g (0.2 mol) of 3- (4-acetylamino-3-bromophenyl) propenoic acid chloride are dissolved in 70 ml of anhydrous dioxane and at a temperature of 0 to 5 ° C. 23.6 g (0.4 mol) of isopropylamine in 20 ml of anhydrous dioxane are added dropwise. After 30 min, the temperature was raised to 20 ° C for 30 min. The reaction mixture is poured into 200 ml of ice water and the product is filtered off with suction. Yield 52 g, mp 219-220 ° C (ethanol). For C ₁₄ H ₁₇ BrN ₂ O ₂ (325.17) calculated: 51.71% C, 5.26% H, 8.61% N, 24.57% Br; Found: 51.9% C, 5.2% H, 8.6% N, 24.23% Br.

Example 11

3- (4-Acetylamino-3-bromophenyl-propenoic acid propylamide mp 191.5-193 ° C (washed with xylene-petroleum ether)

The procedure of Example 10 was followed except that propylamine was used as the amidating agent.

For C ₁₄ H ₁₇ BrN ₂ O ₂ (325.17) calculated: 51.71% C, 5.26% H, 8.61% N, 24.57% Br; Found: 51.3% C, 5.32% H, 8.4'-N, 24.35% Br.

Example 12

3- (4-Acetylamino-3-bromophenyl) propenoic acid cyclohexylamide

M.p. 263-265 ° C (ethanol)

The procedure of Example 10 was followed except that cyclohexylamine was used as the amidating agent.

For ^ ΐ7 ^Η 2ΐθ ^Γ ^ ₂ θ2 ^ ³⁶⁵ > ²² ) calculated: 55.90% C, 5.79% Η, 7.67% N, 21.88% Br; Found: 56.18% C, 5.7% H, 7.7% N, 22.12% Br.

Example 13

3- (4-Acetoxyphenyl) propenoic acid cyclohexylamide

56.7 g (0.3 mol) of 3- (4-acetoxyphenyl) propeonic acid chloride are dissolved! in 250 ml of anhydrous dioxane, 25 g of pyridine are added and 30 g (0.3 mol) of cyclohexylamine in 50 ml of anhydrous are added dropwise over 30 minutes at 10-15 [deg.] C. dioxane. After 30 minutes, the solution is filtered and poured into 500 ml of water. Yield 68 g.

M.p. 194-195 ° C (ethanol).

For C ₁₇ H ₂₁ NO ₃ (287.3) calculated: 71.06% C, 7.35% H, 4.86% N; Found: 70.7% C, 7.6% H, 5.1% N.

Example 14

3- (4-Acetoxyphenyl) propenoic acid propylamide

M.p. 149-151.5 ° C (90% aqueous ethanol)

The procedure of Example 13 was followed except that propylamine was used as the amidating agent.

For C 1 H 4 ₇ NO 2 (247.3) calculated: 68.0% C, 6.93% H, 5.66% N; Found: 68.25% C, 6.84% H, 5.8% N.

Example 15 '.

3- (4-Acetoxyphenyl) propenoic acid isopropylamide

M.p. 169-173 ° C (ethanol)

The procedure of Example 13 was followed except that isopropylamine was used as the amidating agent.

For C ₁₄ H ₁₇ NO ₃ (247.25) calculated: 68.0% C, 6.93% H, 5.66% N; Found: 68.35% C, 7.0 * H, 5.67% N.

Claims (2)

OBJECT OF THE INVENTION Amides of substituted 3-phenyl-2-propenoic acids of the general formula I _H 3 -Z 1 -CH = CHCOR ¹ . \ OF . '(D .'λ · ^r2' where R ³ is amino substituted propyl, isopropyl or cyclohexyl, R is hydrogen, bromo is acetoxy R ³ represents an acetylamino or acetoxy group. 2. A process for the preparation of 3-phenyl-2-propenoic acid amides of the general formula I according to item 1, characterized in that the 3-phenyl-2-propenoic acid chloride is treated with a 2 to 5-fold malate excess of an aliphatic amine selected from the group consisting of propylamine, isopropylamine or cyclohexylamine in an anhydrous solvent selected from the group consisting of benzene and dioxane, optionally in the presence of a hydrogen halide scavenger such as pyridine, the reaction being carried out at temperatures of -5 to 100 ° C.