HU198294B - Process for producing butenoic acid amides and pharmaceutical compositions comprising such active ingredient - Google Patents

Description

The present invention relates to a process for the preparation of new 4- (substituted-phenyl) -4-oxobutenoylamides of the general formula (I) of the E and / or Z configuration -

R is hydrogen or halo, or (1-4C) alkyl or (1-4C) alkoxy or (2-5C) alkanoylamino,

R 1 is C 1 -C 5 straight or branched chain alkylene optionally substituted by phenyl, hydroxy-C 1-3 alkylthio, phenyl (C 1-4 alkylthio) or indolyl,

R 2 is hydrogen or C 1-4 alkyl.

The double bond in the compounds of formula (I) allows for two geometric isomers, so that the compounds of formula (I) can exist as E or Z isomers.

When the amino acid component of the compounds of formula (I) has a chiral center, the formula (I) may be any enantiomer or mixture of any of the enantiomers.

When R2 is hydrogen in the formula (I), the compounds of the formula (I) can be converted into pharmaceutically acceptable salts.

The compounds of formula I are potent cytoprotective agents.

Compounds close to the scope and structure of the compounds of the present invention are described in U.S. Patent No. 2,096,999. United Kingdom Patent No. 4,198.

Among the compounds claimed in the above patent, 4- (3,4,5-trimethoxyphenyl) -4-oxobutyric acid is one of the most potent compounds obtained by the aldol reaction of aldol with 3,4,5-trimethoxyacetophenone and glyoxylic acid. dehydration of the adduct. The aldol reaction proceeds with 28% yield and the dehydration step with 71% yield, resulting in a total yield of 20%.

It is an object of the present invention to provide novel therapeutic compounds which can be prepared from simple commercially available starting materials in good yield.

The present invention therefore relates to a process for the preparation of new compounds of general formula (I) having the E and / or Z configuration.

R is hydrogen or halogen, (C1-C4) alkyl, (C1-C4) alkoxy or (C2-C5) alkanoylamino,

R 1 is C 1 -C 5 straight or branched chain alkylene optionally substituted with phenyl, hydroxy, alkyl partially C 1-3 alkylthio, phenyl (C 1-4 alkylthio) or indolyl,

R2 is hydrogen or (C1-C4) -alkyl, such that a compound of formula (11) or an acid addition salt thereof, wherein R1 is as defined above, and R2, when it is C1-C4-alkyl, is a compound of formula (111) with a substituted butenic acid, wherein R is as defined above, or with a carboxyl-activated derivative thereof, the desired C 1 -C 4 alkyl group in R 2 is optionally removed in a manner known per se and / or optionally double-bonded to compounds of formula 1 is changed by UV irradiation.

When R 2 is hydrogen, the compounds of formula (I) may be formulated into salts with pharmaceutically acceptable organic or inorganic bases.

The starting compounds are either commercially available or prepared according to the literature. For example, the preparation of (E) -4-phenyl-4-oxo-2-butenoic acid is described in Org. Synth. Coll., Vol. 3, 109 (1955), (E) -4- (4-methylphenyl) -4-oxo-2-butenoic acid is described in Pechman, Ber. 15, 888 (1982) and (E) 4- (4-methylphenyl) -4-oxo-2-butenoic acid according to Papa et al. al., J. Am. Chem. Soc., 70, 3356 (1948). The amino acid esters of formula (II) can be prepared from Houben-Weyl: 15 / 1,316-340. G. Thieme Verlag, Stuttgart (1974).

In our experiments, it was found that the reaction of the starting compounds was carried out under average conditions in a yield of 40%.

In the process of the present invention, a substituted butenoic acid of formula (111) or a carboxyl-activated derivative thereof, which may have the E or Z configuration based on the double bond geometry, is reacted with an amino acid derivative of formula (II) in an inert organic solvent. The activated derivative of the compound of the formula (111) may be an ester, an acid halide or an anhydride of a known compound of the formula (111) or an activating agent, preferably a carbodiimide such as dicyclohexylcarbodiimide. preferably anhydrous dichloromethane is used and the reaction is carried out at a temperature of 0 to 20 ° C. Diphenylphosphinic acid chloride can also be used as the activating reagent, preferably ethyl acetate as the inert organic solvent, and the reaction is carried out at -10 ° C as described in the literature (Houben-Weyl E5, 949 (1985)). preferably triethylamine or N-methylmorpholine is added to the reaction mixture.

If desired, the E or Z configuration isomers of the compounds of formula (I) may be converted into one another, for example by UV light in an inert organic solvent.

The compounds of formula (I) wherein R 2 is hydrogen are prepared by removal of the C 1-4 alkyl group attached to the carboxyl group in question in a manner known per se, such as trifluoroacetic acid.

In physiological studies, we have found that 4-phenyl-4-oxo-2 (E) -butenoyl-O-alanine ethyl ester and related compounds are dtoprotective. The experiments were carried out using the method of A. Róbert (1979) (Gastroenterology, 77, 761-767), whereby fasted rats were treated with concentrated hydrochloric acid. ethanol, which causes long-term hemorrhages in the glandular part of the stomach. Dtoprotective agents prevent this deleterious effect. The ED ₅₀ of the substances of the invention is 1-3 mg / kg orally (e.g., the compound of Example 1 has an ED 50 of 1.5 mg / kg orally,

2.7 mg / kg oral, as in Example 8 1.5 mg / kg oral), however, the toxicity values of the substances are very favorable as they do not cause toxic symptoms at a single oral dose of 1000 mg / kg.

The invention is further illustrated by the following non-limiting Examples.

Example 1

N- [4-Phenyl-4-oxo-2 (E) -butenoyl] - 3-aluminoethyl ester in ml abs. 3.0 g (17 mmol) of 4-phenyl-4-oxo-2 (E) -butenoic acid and 2.61 g (17 mmol) of 6-alanine ethyl ester hydrochloride are suspended in dichloromethane. After cooling to 0 ° C, 1.72 g (17 mmol) of N-methylmorpholine are added and, after stirring for 5 minutes, 3.50 g (17 mmol) of Ν, Ν-dicyclohexylcarbodiimide are added. The heterogeneous system was stirred for half an hour at 0 ° C and then for one hour at room temperature. The precipitated dicyclohexylurea was filtered off and the solution was extracted twice with 15 ml of 1N hydrochloric acid solution, once with 15 ml of water, twice with 15 ml of 10% aqueous sodium carbonate solution and finally with 15 ml of water. The organic phase is then dried over anhydrous magnesium sulfate and evaporated. The residue was crystallized from diethyl ether.

Yield: 2.20 g (47%) of the title compound

Mp: 69-70 ° C.

Example 2

N- [4-phenyl-4-oxo-2 (E) -butenoyl] -7-amino-butyric acid ethyl ester

3.0 g (17 mmol) of E4-phenyl-4-oxo-2-butenoic acid and 2.85 g (17 mmol) of ethyl γ-aminobutyric acid hydrochloride are suspended in 50 ml of dichloromethane. The slurry was cooled to 0 ° C, and N-methylmorpholine (1.72 g, 17 mmol) was added and, after stirring for 5 minutes, a solution of 50, Ν-didclohexylcarbodiimide (3.50 g, 17 mmol) in dichloromethane (10 mL). into the system. The mixture was stirred for half an hour at 0 ° C and then for one hour at room temperature. The precipitated dicyclohexylurea was filtered and the filtrate was extracted twice with 15 ml of IN hydrochloric acid, 15 ml of water, twice with 15 ml of aqueous sodium carbonate solution and finally with 15 ml of water. The organic phase is then dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue was crystallized from diethyl ether.

Yield: 2.05 g (42%) of the title compound.

M.p. 56-57 'C.

ANALYSIS:

Found: C, 66.56; H, 6.75; N, 5.04. Found: C, 66.42; H, 6.62; N, 4.84.

Example 3

N- [4-phenyl-4-oxo-2 (E) -butenyl] - (S) -alanine ethyl ester

(E) 4-Phenyl-4-oxo-2-butenoic acid (3.52 g, 20 mmol) was dissolved in dichloromethane (50 mL) and (S) -alanine ethyl ester hydrochloride (3.07 g, 20 mmol) was added. The suspension is cooled to 0 ° C, N-methylmorpholine (2.02 g, 20 mmol) is added and after stirring for 5 min, 4.12 g (20 mmol) of NN-dicyclohexylcarbodiimide in 10 ml of dichloromethane are added dropwise. solution. The mixture was stirred for half an hour at 0 ° C and then for one hour at room temperature. The precipitated dicyclohexylurea was filtered off, and the filtrate was extracted twice with 15 ml of 1N hydrochloric acid solution, twice with 15 ml of water, twice with 15 ml of 10% aqueous sodium carbonate solution and finally with 15 ml of water. The organic phase is then dried over magnesium sulfate and the solvent is evaporated. The residue was crystallized from diethyl ether.

Yield: 2.20 g (40%) of the title compound.

84-85 ° C.

[α] θ ⁵ - -49.9 ° (c = 2, methanol)

ANALYSIS:

H, 6.22; N, 5.08. Found: C, 65.39; H, 6.50; N, 5.10.

Example 4

N- (4-phenyl-4-oxo-2 (E) -butenoyl] - (S) -alanine

Dissolve 2.0 g (11.3 mmol) of (E) 4-phenyl-4-oxo-2-butenoic acid in 20 mL of anhydrous dichloromethane and add 1.64 g (11.3 mmol) of (S) -alanine tert. butyl ester and the solution was cooled to 0 ° C. Then 2.34 g (11.3 mmol) of Ν, Ν-didclohexylcarbodiimide in 10 ml of abs. dichloromethane solution was added dropwise to the reaction mixture. The mixture was stirred for half an hour at 0 ° C and then for one hour at room temperature. The precipitated dicyclohexylurea was filtered off and the filtrate was extracted twice with 15 ml of 1N hydrochloric acid solution, 15 ml of water, twice with 15 ml of saturated aqueous sodium carbonate solution and finally with 15 ml of water. The organic phase is dried over anhydrous magnesium sulfate and the solvent is evaporated. The resulting oil was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (20 mL) was added to the solution under cooling, and the solution was allowed to warm to room temperature (about 2 hours). The solvent was evaporated and the residual oil was filtered off with ethyl acetate.

Yield: 1.30 g (47%) of the title compound.

165-167 ° C.

[α] D = -32 ° (c = 2, methanol).

Example 5

N- [4-Phenyl-4-oxo-2 (E) -butenoyl] - (S) -methionine methyl ester

(E) 4-Phenyl-4-oxo-2-butenoic acid (3.52 g, 20 mmol) was dissolved in anhydrous dichloromethane (40 mL) and (S) -methionine methyl ester hydrochloride (3.99 g, 20 mmol) was added. The solution was cooled to 0 ° C and N-methylmorpholine (2.02 g, 20 mmol) was added dropwise followed by a solution of N, N-didclohexylcarbodiimide (4.12 g, 20 mmol) in dichloromethane (15 mL). The mixture was stirred for half an hour at 0 ° C and then for one hour at room temperature. The precipitated didclohexylurea was filtered, and the filtrate was extracted twice with 15 ml of 1N hydrochloric acid solution, 15 ml of water, twice with 15 ml of 10% aqueous sodium carbonate solution and finally with 15 ml of water. The organic layer was dried over magnesium sulfate and the solvent was evaporated. The residual oil was crystallized from diethyl ether.

Yield: 3.60 g (56%) of the title compound.

77-79 ° C.

[α] D = -36.8 ° (c = 2, methanol).

H, 5.96; N, 4.35. Found: C, 59.81; H, 5.95; N, 4.32.

Example 6

N- [4-phenyl-4-oxo-2 (E) -butenoyl] -S-benzyl- (R) -cysteine ethyl ester

1.97 g (11.2 mmol) of (E) -4-phenyl-4-oxo-2-butenoic acid and 3.08 g (11.2 mmol) of S-benzyl- (R) -cysteine ethyl ester hydrochloride 50 After slurrying in anhydrous dichloromethane (1 ml), N-methylmorpholine (1.13 g, 11.2 mmol) was added at 0 ° C followed by Ν, Ν-didclohexylcarbodiimide (2.31 g, 11.2 mmol). After stirring for half an hour at 0 ° C and for one hour at room temperature, the precipitated didclohexylurea was filtered off, the filtrate was washed twice with 15 ml of 1N hydrochloric acid solution, 15 ml of water, twice with 15 ml of saturated aqueous sodium carbonate solution. and finally extracted with 15 ml of water. The organic phase is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue was crystallized from diethyl ether.

Yield: 2.00 g (45%) of the title compound.

M.p. 86-88 ° C.

(α] θ ⁵ = -81.3 ° (c = 2, methanol).

ANALYSIS:

Found: C, 66.47; H, 5.83; N, 3.52. Found: C, 66.01; H, 5.88; N, 3.73.

Example 7

N- [4- (4-Methylphenyl) -4-oxo-2 (E) -butenoyl] - (S) -alanine ethyl ester in dichloromethane (3.80 g, 20 mmol) (E) -4 - (4-Methylphenyl) -4-oxo-2-butenoic acid and 3.07 g (20 mmol) of (S) -alanine ethyl ester hydrochloride. The suspension was cooled to 0 ° C and N-methylmorpholine (2.02 g, 20 mmol) was added followed by

4.12 g (20 mmol) of Ν, Ν-didclohexylcarbodiimide. The reaction mixture was stirred for half an hour at 0 ° C and then for one hour at room temperature. The precipitated didclohexylurea was filtered off and the filtrate was extracted twice with 15 ml of 1 1 hydrochloric acid, 15 ml of water, twice with 15 ml of saturated aqueous sodium carbonate solution and finally with 15 ml of water. The organic phase is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue was crystallized from diethyl ether.

Yield: 2.30 g (40%) of the title compound.

106-108 ° C.

[Α] D = -54 ° (c = 1, methanol).

ANALYSIS:

Found: C, 66.42; H, 6.62; N, 4.84. Found: C, 65.98; H, 6.56; N, 4.65.

Example 8

N- (4- (4-methoxyphenyl) 4-oxo-2 (E) -butenoyl] - (S) -alanine ethyl ester

4.12 g (20 mmol) of (E) -4- (4-methoxyphenyl) -4-oxo-2-butenoic acid are dissolved in 40 ml of anhydrous dichloromethane and 3.07 g (20 mmol) of S / alanine are added. -etilíszter hydrogen chloride. The solution was cooled to 0 ° C and N-methylmorpholine (2.02 g, 20 mmol) was added followed by N, N-didclohexylcarbodiimide (4.12 g, 20 mmol) in anhydrous dichloromethane (15 mL). The reaction mixture was stirred for half an hour at 0 ° C and then stirred at room temperature for one hour. The precipitated didclohexylurea was filtered off and the filtrate was extracted twice with 15 ml of saturated aqueous sodium carbonate solution and finally with 15 ml of water. The organic phase is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue is crystallized from diethyl ether.

Yield: 2.56 g (42%) of the title compound.

103-106 ° C.

-56.6 ° (c = 2, methanol).

ANALYSIS:

Found: C, 62.94; H, 6.27; N, 4.58; C, 62.47; H, 6.11; N, 4.78.

Example 9

N- [4- (4-methoxyphenyl) -4-oxo-2 (E) -butenoyl] -5S-alanine ethyl ester

3.50 g (17 mmol) of (E) -4- (4-methoxyphenyl) -4-oxo-2-butenoic acid and 2.6 g (17 mmol) of 0-alanine ethyl ester hydrochloride in 40 ml of anhydrous slurried in methane, cooled to 0 ° C, treated with N-methylmorpholine (1.72 g, 17 mmol) followed by Ν, Ν-didclohexylcarbodiimide (3.5 g, 17 mmol). The reaction mixture was stirred for half an hour at 0 ° C and then for one hour at room temperature, and after filtration of didclohexylurea, the filtrate was washed with 1N hydrochloric acid (2 x 15 ml), water (2 x 15 ml), of water. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated. The residue was crystallized from diethyl ether.

Yield: 3.30 g (64%) of the title compound

M.p. 86-88 ° C.

Analysis: Calculated: C, 62.94; H, 6.27; N, 4.58.

Found: C, 62.45; H, 6.24; N, 4.66.

Example 10

N- [4- (4-Chloro-phenyl) -4-oxo-2 (E) -butenoyl] -O-alanine ethyl ester in anhydrous dichloromethane (4.21 g, 20 mmol) (E) -4- ( 4-Chlorophenyl) -4-oxo-2-butenoic acid and 3.07 g (20 mmol) of β-alanine ethyl ester hydrochloride were dissolved. The suspension was cooled to 0 ° C and N-methylmorpholine (2.02 g, 20 mmol) was added followed by N, N-dicydohexylcarbodiimide (4.12 g, 20 mmol) after a few minutes. The reaction mixture was stirred for half an hour at 0 ° C and then for one hour at room temperature. The precipitated dicyclohexylurea was filtered off, and the filtrate was extracted twice with 1 ml of 1N hydrochloric acid, 15 ml of water, twice with 15 ml of 10% aqueous sodium carbonate solution and finally with 15 ml of water. The organic phase is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residual oil was crystallized with diethyl ether.

Yield: 3.10 g (50%) of the title compound.

Mp: 112-114 ° C.

Flpman η1ίτί δ Calculated: 58.16, H: 5.20, N: 4.52, 0: 11.44%, found. C: 58.05; H: 5.35; N: 4.69; Cl: 11.10%.

Preparation of starting material

4- (4-chlorophenyl) -4-oxo-2 (E) -butenoic acid

Dissolve 17.0 g (0.172 mol) of maleic anhydride in 100 ml of chlorobenzene and add 50.45 g (0.378 mol) of anhydrous aluminum chloride in five equal portions. The suspension was heated at 80 ° C for 8 hours. Then 200 g ice and 25 ml cc. The reaction mixture was poured into a mixture of hydrochloric acid and the final product was extracted with dichloromethane (4 x 50 mL). The organic layer was extracted with water (50 mL), filtered through a pad of celite, and the solvent was evaporated in vacuo. The residue was crystallized from toluene.

Yield: 21.70 g (60%) of the title compound.

159-161 ° C.

Found: C, 57.03; H, 3.34; Cl, 16.83. C: 56.97; H: 3.45; Cl: 16.55%.

Example 11

N- [4- (4-Methoxyphenyl) -4-oxo-2- (Z) -butenoyl] - (S) -alanine ethyl ester

4.12 g (20 mmol) of 4- (4-methoxyphenyl) 4-oxo-2 (7) -butenoic acid in 50 ml of abs. Dissolve in dichloromethane and add 3.07 g (20 mmol) of S-alanine ethyl ester hydrochloride. The solution was cooled to 0 ^6, after (20 mmol) was added 2.02 g of N-methylmorpholine and the mixture is added dropwise 4.12 g (20 mmol) of N, N-cyclohexylamino dlcikl carbodiimide in 20 ml abs. dichloromethane. The reaction mixture was stirred at 0 ° C for two hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was extracted twice with 20 ml of 1N hydrochloric acid solution, 20 ml of water, twice with 20 ml of saturated aqueous sodium carbonate solution and finally with 20 ml of water. The organic phase is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residual oil was crystallized from a mixture of diethyl ether and n-hexane.

Yield: 3.12 g (52%) of the title compound.

74-75 ° C.

[α] D = -58.6 ° (c = 1, methanol).

Example 12

N- [4- (4-methoxyphenyl) -4-oxo-2 (Z) -butenoyl] - (S) -alanine eülészter

Ethyl 4- (4-methoxyphenyl) -4-oxo-2 (E) -butenofl- (S) -alanine ethyl ester (1.0 g, 3.2 mmol) was dissolved in acetone (100 mL) and irradiated with UV light. The solution was stirred for 3 hours at room temperature. The solvent was evaporated and the residue was crystallized from a mixture of diethyl ether and n-hexane.

Yield: 0.82 g (82%) of the title compound.

74-76 ° C.

[α] D = 58.6 ° (c = 1, methanol).

Example 13

N- [4- (4-Acetamido-phenyl) -4-oxo-2 (E) -butenoyl] - (S) -alanine-ethyl ester

4- (4-Acetamidophenyl) 4-oxo-2 (E) -butenoic acid (2.33 g, 0.01 mol) and (S) -alanine ethyl ester hydrochloride (1.53 g, 0.01 mol) were dissolved in water. of anhydrous dichloromethane and 10 ml of dimethylformamide. The solution was cooled to 0 ° C, then N-methylmorpholine (1.01 g, 0.01 mol) was added and N, N-dicyclohexyl (2.06 g, 0.01 mol) was added at 0 ° C. of a solution of carbodiimide in 10 ml of anhydrous dichloromethane was added dropwise. The reaction mixture was stirred at 0 ° C for 1.5 hours and then at room temperature for 1 hour. The precipitated dicyclohexylurea was filtered off and the filtrate was evaporated. The residue was dissolved in dichloromethane (30 ml), extracted with 1N hydrochloric acid (2 x 15 ml), water (15 ml), saturated sodium carbonate solution (2 x 15 ml), and saturated sodium chloride solution (15 ml) and dried over magnesium sulphate.

Yield: 1.72 g (52%) of the title compound.

114-115 ° C.

[α] 25 D = -30.1 ° (c = 1, dimethylformamide).

The starting material 4- (4-acetamidophenyl) -4-oxo-2 (E) -butenoic acid was prepared according to Papa et al. J. Am. Chem. Soc., 70, 3356-60 (1948).

Example 14

N- [4-Phenyl-4-oxo-2 (E) -butenoyl] - (S) -phenylalanine methyl ester

4-Phenyl-4-oxo-2 (E) -butenoic acid (2.64 g, 0.015 mol) was dissolved in anhydrous dichloromethane (35 ml) and (S) -phenylalanine methyl ester hydrochloride (3.23 g, 0.015 mol) was added. The solution was cooled to 0 ° C and at this temperature 1.51 g (0.015 mol) of N-methylmorpholine followed by dropwise addition of 3.1 g (0.015 mol) of didclohexylcarbodiimide. The solution was stirred for two hours at 0 ° C and then for one hour at room temperature. The precipitated dicyclohexylurea was removed by filtration and the filtrate was extracted with 20 ml of 1N hydrochloric acid solution, 20 ml of water, twice 20 ml of saturated sodium carbonate solution and finally 20 ml of saturated sodium chloride solution. It is dried over anhydrous magnesium sulfate and then evaporated. The residue was crystallized from dichloroethane diisopropyl ether.

mining; 2.4 g (48%) of the title compound.

113-115 ° C.

[α] D = -25 ° (c = 1, methanol).

It IS. example

N- [4-methyl-4-oxo-2 (E) -butenoyl] - (R) -phenylalanine methyl ester

The method of preparation is the same as in Example 14 except that (R) -phenylalanine methyl ester hydrochloride is used as starting material.

We have 198.294 glazes. The physical constants of the product are the same as those described in Example 14, except: (ajg = + 25 * (c = 1, methanol)).

Example 16

N- [4-Phenyl-4-oxo-2 (E) -butenoyl] - (S) • serine ethyl ester r θ

7.004 g (0.04 mole) of 4-phenyl-4-oxo-2 (E) -butenoic acid and 7.46 g (0.04 mole) of (S) -Sert-ethyl ester hydrochloride are dissolved in 60 ml of anhydrous dichloromethane. Is the solution 0 ^? After cooling to C, N-methylmorpholine (4.4 g, 0.04 mol) was added. After a few minutes, a solution of 9 g (0.04 mol) of NN-didclohexylcarbodiimide in 40 ml of anhydrous dichloromethane was added dropwise. The mixture was stirred at 0 T for 2 hours and then at room temperature for 1 hour. The precipitated Ν, did-didclohexylurea was filtered and the filtrate was extracted twice with 20 ml of 1N hydrochloric acid solution, once with 20 ml of water, twice with 20 ml of saturated sodium carbonate solution and once with 20 ml of saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and evaporated. The residue was crystallized from dichloromethane: hexane (1: 1).

mining; 4.87 g (42%) of the title compound. 25

102-106 ° C (Id ³ ( ^{c = methane} 0 ·

Example 17

N- [4-Phenyl-4-oxo-2 (E) -butenyl] - (S) -triptophan methyl ester

4-Phenyl-4-oxo-2 (E) -butenoic acid (3.52 g, 0.02 mol) was dissolved in ethyl acetate (40 mL). Triethylamine (2.02 g, 0.02 mol) was added. The solution was cooled to -10 ° C and 2.73 g (0.02 mol) of butyric acid chloroformate was added dropwise at this temperature.

After 10 minutes, a solution of 5.0 g (0.02 mol) of (S) -triptyhan methyl ester hydrochloride in 25 ml of dimethylformamide was added, followed by 2.02 g (0.02 mol) of triethylamine. The mixture was cooled to -10 to 40 ° C and stirred at this temperature for two hours. The precipitated triethylamine hydrochloride is then filtered off, the filtrate is poured into 100 ml of water and the phases are separated. The organic layer was extracted with 0.1 N hydrochloric acid, water and brine, dried over magnesium sulfate and evaporated.

The residue was crystallized from diethyl ether.

Yield: 4.1 g of dm.

M.p. 133-135 ° C.

[α] D = -19 ° (c = 2, methanol).

Claims (4)

PATENT CLAIMS A process for the preparation of 4-substituted-phenyl-4-oxobutenoylamides of formula (I) of configuration E and / or Z - wherein R is hydrogen or halo or (C 1 -C 4) -alkyl or (C 1 -C 4) -alkyl; C 4 -C 4 alkoxy or C 2 -C 5 alkanoylamino, R 1 is a linear or branched alkylene group containing from 1 to 5 carbon atoms optionally substituted by phenyl, hydroxy, alkyl in the alkyl moiety of 1 to 3 carbon atoms, phenyl (C 1 -C 4 alkylthio) or indolyl, R 2 is hydrogen or C 1-4 alkyl, wherein a compound of formula (11) or an acid addition salt thereof, wherein R 1 is as defined herein, and R 2 'is (C 1 -C 4) alkyl is represented by (111). with a substituted butenic acid of the formula wherein R is as defined herein or with a carboxyl-activated derivative thereof. they may optionally remove a C 1 -C 4 alkyl group at R 2 and / or, if desired, alter the configuration of the compounds of formula (I) as determined by their double bond by irradiation with UV light. Process according to claim 1, characterized in that the substituted butenic acid of formula (III) in which R is as defined in the preamble is used in the form activated by a carbodiimide, preferably didclohexylcarbodiimide. 3. A process according to claim 1, wherein the substituted butenoic acid of formula (III) wherein R is as defined in the foregoing is used as an activated derivative of an ester, an acid halide or an anhydride. A process for the preparation of a pharmaceutical composition comprising the compound of formula (I), wherein R, R 1 and R 2 in the formula (I) are as defined in claim 1, wherein the active ingredient of claim 1 is a pharmaceutical composition. mixed with excipients and / or excipients used in the preparation of the active ingredient.