A kind of synthetic method of 2 aminobutanamide

Abstract

The invention discloses a method for synthesizing 2-aminobutyramide, which belongs to the field of organic chemistry. The invention uses 2-chlorobutyric acid as a raw material and a reaction solvent, uses phosphorus trichloride or phosphorus pentachloride as a catalyst, and chlorinated The sulfoxide is reacted at 50-80°C to obtain 2-chlorobutyryl chloride, and 2-chlorobutyryl chloride is passed through ammonia gas in an alcohol solvent, and the ammoniation reaction obtains 2-aminobutyramide. The total product yield of the method of the invention is as high as 80%, the process is simple, the cost is low, environmental protection is safe, and industrialization is easy to realize.

Description

technical field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a synthesis method of 2-aminobutyramide. Background technique

[0002] 2-Aminobutanamide is a pharmaceutical intermediate that can be used in the synthesis of antiepileptic drugs such as levetiracetam. There are many ways to synthesize it, and the main methods include the following:

[0003] (1) Adopt Strecker reaction, use propionaldehyde as raw material, react with sodium cyanide in the presence of ammonia, generate 2-aminobutyronitrile, hydrolyze to obtain 2-aminobutyric acid (Organic Syntheses Coll, 1:21-25, 1941; OrganicSynthesesColl, 2: 29-33, 1943), then generate 2-aminobutyramide through esterification and ammonia solution, but this method adopts the highly toxic compound sodium cyanide, which has very high requirements for the safety of operators, the treatment of three wastes and environmental protection .

[0004] (2) Conventional synthesis method: in pa...

Examples

Embodiment 1

[0022] Add 122.6g (1.0mol) 2-chlorobutyric acid and 130.9g (1.1mol) thionyl chloride in the dried 500ml four-necked flask equipped with a mechanical stirring device and a thermometer, start stirring, and then add 68.7g ( 0.5 mol) phosphorus trichloride, the temperature is controlled at 40±5°C, and the reaction is completed in 3 hours. After the reaction is completed, the temperature of the reaction solution is raised to 75±5° C., stirred and refluxed for 4 hours.

[0023] Put the obtained 2-chlorobutyryl chloride reaction solution into a dried 1L ammoniation reactor equipped with a mechanical stirring device and a thermometer, add 300ml of methanol, and slowly feed 85g (5.0mol) of ammonia gas into the reactor After passing the ammonia gas, raise the temperature in the reactor to 60±5°C, and control the pressure at 0.3-0.5MPa to react for 12 hours. After the reaction is completed, cool the reaction solution to 0±5°C, filter, and depressurize the filtrate at 40±5°C Distill unti...

Embodiment 2

[0025] Add 122.6g (1.0mol) 2-chlorobutyric acid and 142.8g (1.2mol) thionyl chloride in the dried 500ml four-necked flask equipped with a mechanical stirring device and a thermometer, start stirring, then add 62.5g ( 0.3mol) phosphorus pentachloride, temperature control at 40±5°C, and the reaction is completed in 4 hours. After the reaction is completed, the temperature of the reaction solution is raised to 75±5° C., stirred and refluxed for 4 hours.

[0026] The resulting 2-chlorobutyryl chloride reaction liquid is put into a 1L ammoniation reactor equipped with a mechanical stirring device and a thermometer, and 300ml of isopropanol is added, and 136g (8.0mol) is slowly introduced into the reactor. Ammonia gas, after passing the ammonia gas, raise the temperature in the reactor to 50±5°C, control the pressure at 0.4-0.5MPa and react for 8 hours, after the reaction is completed, cool the reaction solution to 0±5°C, filter, and the filtrate is 40±5°C Distill under reduced pre...

Embodiment 3

[0028] Add 122.6g (1.0mol) 2-chlorobutyric acid and 130.9g (1.1mol) thionyl chloride in the dried 500ml four-necked flask equipped with a mechanical stirring device and a thermometer, start stirring, then add 13.8g ( 0.1mol) phosphorus trichloride, temperature controlled at 50±5°C, and the reaction was completed in 6 hours. After the reaction is completed, the temperature of the reaction solution is raised to 75±5° C., stirred and refluxed for 4 hours.

[0029] Put the obtained 2-chlorobutyryl chloride reaction solution into a dried 1L ammoniation reactor equipped with a mechanical stirring device and a thermometer, add 300ml of methanol, and slowly feed 51g (3.0mol) of ammonia gas into the reactor After passing the ammonia gas, raise the temperature in the reactor to 60±5°C, control the pressure at 0.1-0.3MPa and react for 48 hours. After the reaction is completed, cool the reaction solution to 0±5°C, filter, and depressurize the filtrate at 40±5°C Distill until solid precip...

technical field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a synthesis method of 2-aminobutyramide. Background technique

[0002] 2-Aminobutanamide is a pharmaceutical intermediate that can be used in the synthesis of antiepileptic drugs such as levetiracetam. There are many ways to synthesize it, and the main methods include the following:

[0003] (1) Adopt Strecker reaction, use propionaldehyde as raw material, react with sodium cyanide in the presence of ammonia, generate 2-aminobutyronitrile, hydrolyze to obtain 2-aminobutyric acid (Organic Syntheses Coll, 1:21-25, 1941; OrganicSynthesesColl, 2: 29-33, 1943), then generate 2-aminobutyramide through esterification and ammonia solution, but this method adopts the highly toxic compound sodium cyanide, which has very high requirements for the safety of operators, the treatment of three wastes and environmental protection .

[0004] (2) Conventional synthesis method: in pa...

Examples

Embodiment 1

[0022] Add 122.6g (1.0mol) 2-chlorobutyric acid and 130.9g (1.1mol) thionyl chloride in the dried 500ml four-necked flask equipped with a mechanical stirring device and a thermometer, start stirring, and then add 68.7g ( 0.5 mol) phosphorus trichloride, the temperature is controlled at 40±5°C, and the reaction is completed in 3 hours. After the reaction is completed, the temperature of the reaction solution is raised to 75±5° C., stirred and refluxed for 4 hours.

[0023] Put the obtained 2-chlorobutyryl chloride reaction solution into a dried 1L ammoniation reactor equipped with a mechanical stirring device and a thermometer, add 300ml of methanol, and slowly feed 85g (5.0mol) of ammonia gas into the reactor After passing the ammonia gas, raise the temperature in the reactor to 60±5°C, and control the pressure at 0.3-0.5MPa to react for 12 hours. After the reaction is completed, cool the reaction solution to 0±5°C, filter, and depressurize the filtrate at 40±5°C Distill unti...

Embodiment 2

[0025] Add 122.6g (1.0mol) 2-chlorobutyric acid and 142.8g (1.2mol) thionyl chloride in the dried 500ml four-necked flask equipped with a mechanical stirring device and a thermometer, start stirring, then add 62.5g ( 0.3mol) phosphorus pentachloride, temperature control at 40±5°C, and the reaction is completed in 4 hours. After the reaction is completed, the temperature of the reaction solution is raised to 75±5° C., stirred and refluxed for 4 hours.

[0026] The resulting 2-chlorobutyryl chloride reaction liquid is put into a 1L ammoniation reactor equipped with a mechanical stirring device and a thermometer, and 300ml of isopropanol is added, and 136g (8.0mol) is slowly introduced into the reactor. Ammonia gas, after passing the ammonia gas, raise the temperature in the reactor to 50±5°C, control the pressure at 0.4-0.5MPa and react for 8 hours, after the reaction is completed, cool the reaction solution to 0±5°C, filter, and the filtrate is 40±5°C Distill under reduced pre...

Embodiment 3

[0028] Add 122.6g (1.0mol) 2-chlorobutyric acid and 130.9g (1.1mol) thionyl chloride in the dried 500ml four-necked flask equipped with a mechanical stirring device and a thermometer, start stirring, then add 13.8g ( 0.1mol) phosphorus trichloride, temperature controlled at 50±5°C, and the reaction was completed in 6 hours. After the reaction is completed, the temperature of the reaction solution is raised to 75±5° C., stirred and refluxed for 4 hours.

[0029] Put the obtained 2-chlorobutyryl chloride reaction solution into a dried 1L ammoniation reactor equipped with a mechanical stirring device and a thermometer, add 300ml of methanol, and slowly feed 51g (3.0mol) of ammonia gas into the reactor After passing the ammonia gas, raise the temperature in the reactor to 60±5°C, control the pressure at 0.1-0.3MPa and react for 48 hours. After the reaction is completed, cool the reaction solution to 0±5°C, filter, and depressurize the filtrate at 40±5°C Distill until solid precip...

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