CS260644B1 - Method of 2-(4-chlorbutyrylamino)-acetamide preparation - Google Patents

Abstract

The present invention relates to the preparation of 2- (4-chlorobutyrylamino) acetamide with ammonia to 2- (4-chlorobutyrylamino) alkyl acetate, obtained by acylation of glycine alkyl ester hydrochloride 4-chlorobutyryl chloride in the presence base. 2- (4-chlorobutyrylamino) acetamide is a precursor for the synthesis of 2-OXX-1-pyrrolidineacetamide, drugs with nootropic effect.

Description

The present invention relates to a process for the preparation of 2- (4-chlorobutyrylamino) acetamide of the formula I Cl (CH 2 J 3 CONHCH 2 CONH 2 (I))

The compound of formula I is a key intermediate for the synthesis of 2-oxo-1-pyrrolidineacetamide (III), which shows a nootropic effect (Giurgea C., Current Dev. Psychopharmacol 1976,3,221, CA 86, R 83 356). cyclization of 2- (chlorobutyrylamino) acetamide of formula I in an alkaline medium (Slob. Djokica inc., Craotica Chem. Acta 57 (2), 271, 1984) The preparation of the amide of formula I is described in two ways. after protection of the carboxyl group with trimethylchlorosilane in the presence of triethylamine in dichloromethane, it is reacted with 4-chlorobutyryl chloride to form 2- (4-chlorobutyrylamino) acetic acid which is converted to the corresponding acyl chloride with phosphorus pentachloride which reacts with ammonia gas to yield the desired amide I Melting point: 128 DEG-130 DEG C. After crystallization from ethyl acetate.

The second process consists in reacting 4-chlorobutyl chloride with glycinamide in the environment

Base

C1 (CH2) 3COCl + NH2CH2.COOR.HCl --- 44

Of Ν, Ν-dimethylacetamide and dioxane yields an amide yield of formula I up to 78%, mp 123-125 ° C. Only after crystallization from ethyl acetate or acetone and n-hexane melts at 128-130 ° C.

Both of these processes are protected by a number of patents of the Yugoslavian company PLIVA, on the one hand, Ger, 2,701450 (1977), CA 87, 135051, and on the other hand the Belg patent. 850,184 (1977), CA 88,23,392.

The synthesis of 2- (4-chlorobutyrylamino) acetamide of the formula I according to the invention consists in the preparation of the hitherto unwritten 2- (4-chlorobutyrylamino) acetate, wherein alkyl is C 1 -C 3, by acylation of readily accessible glycinalkylester hydrochlorides. 327, 365, 1903), in a solution of a base, preferably an aqueous solution of sodium bicarbonate, a solution of 4-chlorobutyryl chloride in an aprotic solvent, preferably benzene or toluene, with vigorous stirring at a temperature in the reaction mixture of -5 ° to + 50 ° , preferably at + 10 °, and amldating the thus-formed 2- (4-chlorobutyrylamino) acetate with ammonia in a protic and / or aprotic solvent at a temperature of -10 ° to + 80 °, preferably at 20 ° C.

The following scheme illustrates the synthesis process:

Cl (CH 2) 3 CONHCH 2 COOR II

NH3

-------> CI (CH 2) 3 CONHCH 2 CONH 2

II, R = C1-C3 alkyl

This synthesis yields 80 to 85% t of compound I with a purity of 99.28 to 99.91% mp, 129-132 ° C.

The following Examples illustrate a number of options for the preparation of amide I without departing from the scope of the invention.

Example 1

Ethyl 2- (4-chlorobutyrylamino) acetate

While stirring and cooling, 20.0 g (144 mmol) of glycine ethyl ester hydrochloride are added in portions to a solution of 30.0 g of sodium bicarbonate in 60 ml of water. To this solution was added dropwise a solution of 20.7 g (146.8 mmol) of 4-chlorobutyryl chloride in 120 mL of benzene at 10 ° C with vigorous stirring over 1 h. Then the reaction mixture is stirred so that the temperature reaches 20 ^µl within 1 h. The organic layer was separated, washed with 20 ml of 10% aqueous sodium bicarbonate solution, 20 ml of 0.2 M aqueous tartaric acid solution, 2 X 20 ml of water and dried over 10.0 g of anhydrous sodium sulfate. . Concentration in a rotary evaporator (30 ° / 3.3 kPa) resulted in 29.7 g (99.3% th.) Of a pale yellow liquid. Thin-layer chromatography on Silufol UV 254 using dichloromethane, acetone, methanol (10: 10: 2 v / v) as indicated by iodine vapor shows the product as a uniform material having a rf of 0.62. Fractional distillation in vacuo collected the t1 fraction at 40 Pa in a yield of 24.1 g (80.6% th.). The product is a clear colorless liquid with a delicate aromatic fragrance. The crystalline product melts at 35.5-38.5 ° C.

Elemental Analysis for C8H14ClNO3 (207.66)

Calculated:

C 46.27%,

H 6.79%,

N 6.74%,

Cl, 17.08

Found:

C 46.67%,

H 6.79%,

N 6.57%,

Cl 16,99%

IC spectra (cm ^-1 )

R — COOR — NH — CO— — NH—

030, 1 200, 1 743 1 540, 1 655 3 305

Example 2

Ethyl 2- (4-chlorobutyrylamino) acetate

While stirring and cooling, 20.0 g (144 mmol) of glycine pentyl ester hydrochloride are added to a solution of 36.35 g (300 mmol) of Ν, dim-dimethylaniline in 100 ml of benzene. After stirring at 20 ° C for 1 h, a solution of 20.7 g (146.8 mmol) of 4-chlorobutyryl chloride in 100 mL of benzene at 10 ° C was added dropwise over 1 h. The mixture is then stirred for 10 hours at 15 ^and 25 ° ^C! C. The reaction mixture was washed with 3 X 30 millimeters of water, 3 X 30 mL of 2 N hydrochloric acid, 2 X 30 mL of water, and 3 X 30 mL of 10% aqueous sodium bicarbonate. The organic layer was dried over 10 grams of anhydrous sodium sulfate. Thereafter, this organic layer was either concentrated in vacuo (5070.3 kPa) to a residue of 23.5 g (78.6% thj) or used directly for the subsequent amidation according to Example 4.

Example 1 -a d 3

2- (4-chlorobutyrylamino) acetamide (I)

To a solution of 27.4 g (132 mmol) of 2- (4-chlorobutyrylamino) ethyl acetate (II) in 270 ml of methanol was stirred and cooled at 20 ° C to ammonia gas for 4 h. The reaction mixture was stirred at room temperature for 2 h. The solution is then concentrated under vacuum (4073.3 kPa). The solid product is obtained in a quantitative yield of 120 ° -128 ° C. Dissolving the crude product in 500 ml of acetone hot, filtering with 1 g of activated carbon and pouring 100 ml of n-hexane into the clear filtrate upon cooling to room temperature, crystallized 14.84 g (64% th. 129 DEG-132 DEG C. The mother liquors are filtered at 30 DEG C. with 1 g of activated carbon over a 2 centimeter-high layer of aluminum c-xide (Brockmann®-III), concentrated in a vacuum of 3.3 kP-a. from a water bath to a temperature of 40 ° to a volume of 150 ml and diluted with 50 ml of n-hexane, after 12 hours of crystallization at +4 ° C, 4.65 g of the product was obtained. mp 129-131 ° C. m.p.

Elemental Analysis for C6H11ClN2O2 (178.62)

Calculated:

C 40.34%,

H 6.21%,

N 15.68%,

Gl 19,85%

Found:

C, 40.16%.

H 6.02%,

N 15.84%,

Cl 19.71%

IC spectra (cm ¹ )

1,320, 1,548 R — NH— ₍ COR ') 1,526, 1,644 —CONH2 1 660 —CONH— 3,190, 3- 3-80 —NH2 3 328 —NH— Example 4 2- (4-chlorobutyrylamino) acetamide (1) To a solution of 20.0 g (143 m-mol) glycine

thylester hydrochloride in 60 ml of water and 19.8 g (180 mimoles) of sodium carbonate are added dropwise at 10 ° to 15 ° C with vigorous stirring over a period of 1 h. The reaction mixture was stirred at 15 to 17 ° C for 1 hour and at 20 to 24 ° C for 3 hours. The organic layer was washed successively with 20 mL of 10% aqueous sodium carbonate, 20 mL of 0.2 M aqueous tartaric acid, 2 X 20 mL of water. It is then diluted with 200 ml of methanol and ammonia gas is introduced under stirring and cooling at 20 to 23 ° C for 4 hours. The ammonia solution is allowed to stand at room temperature overnight. At 30 ° C, 2 g of activated carbon is filtered through a 5 cm high alumina column (Brockmann II-III). PO- concentrating the clear filtrate to a 100 ml-volume under reduced tl-batteries (3.3 kPa) of the water bath temperature db 30 C 0chl-shifting C to 20 ^{° C} the product crystallized in a yield of 20.7 g (81%) m.p. at 126 to 131 degrees Celsius. Crystallization from ethyl acetate (1:60) gave an analytical pure product, mp 132.5 ° C.

Claims (6)

Subject A process for the preparation of 2- (4-chlorobutyrylamino) acetamide, characterized in that 4-chlorobutyryl chloride and glycinalkyl ester hydrochloride, wherein alkyl is C 1 -C 3, are reacted in the presence of a base and the resulting alkynyl 2- (4-chlorobutyrylamino) acetate is treated with ammonia. 2. The process of claim 1 wherein the solution of glycine ethyl ester hydrochloride in the presence of a strong organic base such as Ν, Ν-dimethylaniline is acylated with a solution of 4-chlorobutyryl chloride in an aprotic solvent such as benzene or toluene. Process according to Claim 1, characterized in that a solution of glycine ethyl ester hydrochloride in the presence of an inorganic base is OF THE INVENTION sodium bicarbonate, acylated with a solution of 4-chlorobutyryl chloride in a protic solvent such as water. 4. The method of claim 1, wherein ammonia is treated with a solution of 2- (4-chlorobutyrylamino) ethyl acetate in a protic solvent such as methanol or ethanol. 5. The method of claim 1, wherein ammonia is treated with a solution of 2- (4-chlorobutyrylamino) ethyl acetate in an aprotic solvent such as dichloromethane, benzene, toluene. 6. The process of claim 1 wherein the reaction is carried out without isolation of the intermediate.