CS260644B1 - Process for preparing 2- (4-chlorobutyrylamino) acetamide - Google Patents

Abstract

The solution concerns the preparation of 2-(4-chlorobutyrylaminoacetamide by the action of ammonia on 2-(4-chlorobutyrylamino)alkylacetate, obtained by acylation of glycine alkyl ester hydrochloride with 4-chlorobutyryl chloride in the presence of a base. ;2-(4-chlorobutyrylamino)acetamide is a precursor for the synthesis of 2-O’Xo-1-pyrrolidineacetamide, a drug with nootropic effect.

Description

The invention relates to a process for the preparation of 2-(4-chlorobutyrylaminoacetamide of formula I Cl(CH2j3CONHCH2CONH2 (I)

The compound of formula I is a key intermediate for the synthesis of 2-oxo-1-pyrrolidineacetamide (III), which exhibits nootropic effects [Giurgea C., Current Dev.. Psychopharmacol 1976,3,221, CA 86,R 83 356], Compound III can be prepared by cyclization of 2-(chlorobutyrylamino)acetamide of formula I in alkaline medium (Slob. Djokica spal., Craotica Chem. Acta 57(2), 271, 1984). The preparation of the amide of formula I is described in two ways. The first of them starts from glycine, which, after protection of the carboxyl group with trimethylchlorosilane in the presence of triethylamine in dichloromethane, reacts with 4-chlorobutyryl chloride to form 2-(4-chlorobutyrylamino)acetic acid. This is converted by the action of phosphorus pentachloride to the corresponding acyl chloride, which reacts with gaseous ammonia to form the desired amide of formula I in yield 63 to 74% by weight. After crystallization from ethyl acetate, it melts at 128 to 130 °C.

The second procedure involves the reaction of 4-chloro-3-butyl chloride with glycinamide in an aqueous medium.

Base

C1(CH2)3COC1 + NH2CH2.COOR.HCl ---44

N,N-dimethylacetamide and dioxane provides a yield of amide of formula I of up to 78% with a melting point of 123 to 125 °C. Only after crystallization from ethyl acetate or acetone and n-hexane does it melt at 128 to 130 °C.

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

The synthesis of 2-(4-chlorobutyrylamino)acetamide of formula I according to the invention consists in the preparation of previously undescribed alkyl 2-(4-chlorobutyrylamino)acetates, where alkyl is C1 to C3, by acylation of easily accessible glycine alkyl ester hydrochlorides, (Harries C., Weiss M., Ann. 327, 365, 1903), in a solution of a base, preferably an aqueous solution of sodium bicarbonate, with a solution of 4-chlorobutyryl chloride in an aprotic solvent, preferably in benzene or toluene, with intensive stirring at a temperature in the reaction mixture from -5° to +50°, preferably at +10°, and the amylation of the thus formed alkyl 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 synthesis procedure is illustrated in the following diagram:

Cl(CH2)3CONHCH2COOR II

NH3

-------> CI(CH2)3CONHCH2CONH2

II, R = alkyl C1—C3

This synthesis achieves a yield of 80 to 85% by weight of compound I with a purity of 99.28 to 99.91% by weight, melting point 129 to 132 °C.

The following examples show several possible methods for preparing amide I, without, however, exhausting all possible applications 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. A solution of 20.7 g (146.8 mmol) of 4-chlorobutyryl chloride in 120 ml of benzene at 10 °C is added dropwise to this solution with vigorous stirring over 1 h. The reaction mixture is then stirred so that its temperature reaches 20 ^°C within 1 h. Stirring is continued at this temperature for another 2 h. The organic layer is 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. After concentration in a rotary vacuum evaporator (30°/3.3 kPa) 29.7 g (99.3% th.) of a light yellow liquid results. Thin-layer chromatography on Silufol UV 254 in the system dichloromethane, acetone, methanol (10:10:2 vol.) with iodine vapor indication shows the product as a uniform substance with rf 0.62. Fractional distillation in vacuum collects a fraction with a melting point of 131° at 40 Pa in a yield of 24.1 g (80.6% th.). The product is a clear colorless liquid with a mild aromatic odor. The crystalline product melts at 35.5 to 38.5 °C.

Elemental analysis for C8H14CINO3 (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 ethyl ester hydrochloride are added to a solution of 36.35 g (300 mmol) of N,N-dimethylaniline in 100 ml of benzene. After stirring for 1 h at 20 °C, a solution of 20.7 g (146.8 mmol) of 4-chlorobutyryl chloride in 100 ml of benzene at 10 °C is added dropwise to this mixture over 1 h. The reaction mixture is then stirred for 10 h at 15 ^° C to 25 ^° C. The reaction mixture is washed with 3 X 30 ml 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 solution. The organic layer is dried over 10 g of anhydrous sodium sulfate. Then this organic layer is either concentrated in vacuo (5070.3 kPa) to a residue of 23.5 g (78.6% th.j), or is 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 ethyl 2-(4-chlorobutyrylamino) acetate (II) in 270 ml of methanol, ammonia gas is introduced with stirring and cooling at 20 °C for 4 h. After the cooling bath is removed, the reaction mixture is stirred for another 2 h at room temperature. The solution is then concentrated in vacuo (4073.3 kPa). A solid product is obtained in quantitative yield, melting at 120° to 128 °C. By dissolving the crude product in 500 ml of acetone under heat, filtering with 1 g of activated carbon and adding 100 ml of n-hexane to the clear filtrate after cooling to room temperature, 14.84 g (64% of the yield) of amide I with a melting point of 129 to 132 °C crystallizes. The mother liquors are filtered at 30 °C with 1 g of activated carbon through a 2-centimeter-high layer of alumina (Brockmann ΓΙ—III), concentrated in a vacuum of 3.3 kPa from a water bath to a temperature of 40 ° to a volume of 150 ml and diluted with 50 ml of n-hexane. Twelve hours of crystallization at +4 °C yields another 4.65 g of product with a melting point of 129 to 131 °C. The total yield of amide I is 19.49 g (84% th.) with -m.p. 129 -to 132 °C. Crystallization from ethyl acetate (1:60) gives -analytically pure sample with m.p. 132.5 °C.

Elemental analysis for C6H11CIN2O2 (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 jacetamide (1} To solution 20.0 g (143 m-mol) glycine

thioester hydrochloride in 60 ml of water and 19.8 grams (180 mmol) of sodium carbonate are added dropwise at 10° to 15°C with vigorous stirring over 1 h, a solution of 20.7 g (147 mmol) of 4-chlorobutyryl chloride in 100 ml of toluene. This reaction mixture is stirred at 15° to 17°C for 1 h and then for a further 3 h at 20° to 24°C. The organic layer is washed successively with 20 ml of 10% aqueous sodium carbonate solution, 20 ml of 0.2 M aqueous tartaric acid solution, 2 x 20 ml of water. Then it is diluted with 200 ml of methanol and gaseous ammonia is introduced for 4 h at 20° to 23°C with stirring and cooling. The ammonia solution is left to stand at room temperature overnight. At 30 °C, 2 g of activated carbon is filtered through a 5 cm high column of alumina (Brockmann II-III). After concentration of the clear filtrate to a volume of 100 ml under reduced pressure (3.3 kPa) from a water bath at 30 °C and cooling to 20 ^° C, the product crystallizes in a yield of 20.7 g (81%), melting at 126 to 131 degrees Celsius. Crystallization from ethyl acetate (1:60) gives an analytically pure product, melting at 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.