Preparation method of (S)-(+)-2-aminobutanamide hydrochloride

A technology of aminobutyramide and aminobutyric acid, which is applied in the preparation of carboxylic acid amides, organic compounds, cyanide reaction, etc., can solve the problems of unfavorable industrial production and decreased purity, and achieve high atom utilization and easy operation , the effect of high product purity

Pending Publication Date: 2020-07-24
贵州阜康仁制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The (S)-(+)-2-aminobutyramide hydrochloride purity that this method ammonolysis obtains has only 86%, and along with charging amount increases, purity will further decline, is unfavorable for suitability for industrialized production

Method used

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  • Preparation method of (S)-(+)-2-aminobutanamide hydrochloride
  • Preparation method of (S)-(+)-2-aminobutanamide hydrochloride
  • Preparation method of (S)-(+)-2-aminobutanamide hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] (1) Esterification

[0034] Reaction equation:

[0035]

[0036] The specific operations are as follows:

[0037] Add 50g of L-2-aminobutyric acid (0.48mol), 250ml (5v / w) of methanol into a 1L four-necked flask, and add 70g (0.59mol) of thionyl chloride dropwise to 20-40℃. The addition is complete. After keeping the temperature for 2 hours, the reaction of TLC and L-2-aminobutyric acid is completed, and the reaction is stopped. The system is about 300ml, and the system is transferred to a single-neck bottle, and the remaining is 150ml after being concentrated under reduced pressure. The concentration is stopped and used directly in the next reaction.

[0038] (2) Ammoniolysis

[0039] Reaction equation:

[0040]

[0041] The specific operations are as follows:

[0042] Add the 150mL solution of step 1 to a 1L four-necked flask, cool to 0-10°C, ventilate ammonia, adjust the system pH=7-8, and keep it unchanged for half an hour, stop ventilating ammonia. Filter the system, rinse t...

Embodiment 2

[0044] (1) Esterification

[0045] Reaction equation:

[0046]

[0047] The specific operations are as follows:

[0048] Add 400g of L-2-aminobutyric acid (3.88mol), 2L of methanol (5v / w) into a 3L four-necked flask, and add 646.20g (5.43mol) of thionyl chloride dropwise to 20-40℃. After 3 hours of heat preservation, the TLC and L-2-aminobutyric acid reaction is completed, and the reaction is stopped. The system is about 3L, and the system is transferred to a single-neck bottle, concentrated under reduced pressure to the remaining 2.4L, stop concentration, and directly used in the next reaction.

[0049] (2) Ammoniolysis

[0050] Reaction equation:

[0051]

[0052] The specific operations are as follows:

[0053] Add 2.4L of the solution of step 1 to a 5L four-necked flask, cool to 0-10°C, ventilate ammonia, adjust the system pH=7-8, and keep it unchanged for half an hour, stop ventilating ammonia. Filter the system, rinse the filter cake with 800 mL of methanol (2v / w), combine the fi...

Embodiment 3

[0055] (1) Esterification

[0056] Reaction equation:

[0057]

[0058] The specific operations are as follows:

[0059] Add 3Kg of L-2-aminobutyric acid (29.09mol), 15L of methanol (5v / w) into a 30L glass reactor, and add 4.50Kg (37.82mol) of thionyl chloride dropwise to 20-40℃. After 3 hours of heat preservation, the TLC and L-2-aminobutyric acid reaction is completed, and the reaction is stopped. The system is about 18L, the system is transferred to a single-neck bottle, the remaining is 9L after concentration under reduced pressure, the concentration is stopped, and it is directly used in the next reaction.

[0060] (2) Ammoniolysis

[0061] Reaction equation:

[0062]

[0063] The specific operations are as follows:

[0064] Add 9L of the solution of step 1 to a 30L glass reactor, cool to 0-10°C, vent ammonia, adjust the pH of the system to 7-8, and keep it unchanged for half an hour, stop venting ammonia. Filter the system, rinse the filter cake with methanol 12L (4v / w), combine ...

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PUM

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Abstract

The invention discloses a preparation method of (S)-(+)-2-aminobutanamide hydrochloride, and relates to a preparation method of a levetiracetam key intermediate, and the method comprises the followingspecific steps: carrying out esterification reaction on L-2-aminobutyric acid serving as a starting material and thionyl chloride, and concentrating part of solvent after the reaction is finished; introducing ammonia gas to neutralize generated hydrogen chloride and residual thionyl chloride; and filtering, introducing ammonia gas, and carrying out an ammonolysis reaction to obtain the (S)-2-aminobutanamide hydrochloride after the treating is finished. According to the preparation method, the starting material is simple and easy to obtain, the one-pot method is adopted, the atom utilization rate is high, operation is easy and convenient, and the obtained product quality is high.

Description

Technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for preparing a key intermediate (S)-(+)-2-aminobutanamide hydrochloride of levetiracetam. Background technique [0002] Epilepsy disease is a chronic disease. The common clinical manifestations include paroxysmal convulsions and sudden mental disorders. Although the treatment of epilepsy is difficult, as long as the treatment is timely and appropriate, the condition of about 80% of patients can be completely controlled or even cured. Therefore, drugs with good curative effects, good pharmacokinetic properties, small adverse reactions, and few drug interactions have a promising market prospect. [0003] Levetiracetam (Levetiracetam, trade name Keppra) is a new type of antiepileptic drug developed by the Belgian company UCB. It was listed in the United States in December 1999, and in China in March 2007 (trade name: Kaipulan). It is an acetylpyrrolidine compound whose ...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C237/06
CPCC07C231/02C07C227/18C07C237/06C07C229/08
Inventor 王宁童元峰严轶东牛庆升齐书耀王進京
Owner 贵州阜康仁制药有限公司
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