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Synthesis method of levetiracetam intermediate

A synthesis method and intermediate technology are applied in the field of synthesis of levetiracetam intermediates, which can solve the problems of low atom utilization rate and long process route, and achieve reliable sterilization effect, uniform temperature, and rapid and balanced heating and cooling. Effect

Pending Publication Date: 2022-07-05
ABA CHEM CORP
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The commonly used synthesis method in industry adopts the traditional chemical resolution method to construct the chiral center, the process route is long, and the utilization rate of atoms is low

Method used

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  • Synthesis method of levetiracetam intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] The present embodiment provides a method for synthesizing a levetiracetam intermediate, comprising the following steps:

[0022] S1. Add the mixture containing (R)-α-ethyl-2-oxo-1-pyrrolidineacetic acid and (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid to the strong base aqueous solution , heat up to 60 ℃, keep stirring for 2 hours; the strong base is selected from sodium hydroxide, the mass percentage concentration range of the strong base solution is 25%, and the consumption of the base is (R)-α-ethyl-2-oxo-1- 1 times the total molar amount of the mixture of pyrrolidine acetic acid and (S)-α-ethyl-2-oxo-1-pyrrolidine acetic acid;

[0023] S2. Add an appropriate amount of water to dilute and cool down to 40°C, add 60% hydrochloric acid dropwise, and stir evenly; the amount of water is (R)-α-ethyl-2-oxo-1-pyrrolidineacetic acid and (S)-α- 1.5 times the total mass of the ethyl-2-oxo-1-pyrrolidine acetic acid mixture;

[0024] S3, heat up to 60 ℃, add 10% hydrochloric acid...

Embodiment 2

[0028] The present embodiment provides a method for synthesizing a levetiracetam intermediate, comprising the following steps:

[0029] S1. Add the mixture containing (R)-α-ethyl-2-oxo-1-pyrrolidineacetic acid and (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid to the strong base aqueous solution , heat up to 80 ℃, keep stirring for 5 hours; the strong base is selected from sodium hydroxide or potassium hydroxide, the mass percentage concentration range of the strong base solution is 40%, and the consumption of the base is (R)-α-ethyl-2-oxygen 3 times the total molar amount of the mixture of substituted-1-pyrrolidineacetic acid and (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid;

[0030] S2. Add an appropriate amount of water to dilute and cool down to 60°C, add 70% hydrochloric acid dropwise, and stir evenly; the amount of water is (R)-α-ethyl-2-oxo-1-pyrrolidineacetic acid and (S)-α- 5 times the total mass of the ethyl-2-oxo-1-pyrrolidine acetic acid mixture;

[0031] S3, heat up t...

Embodiment 3

[0035] The present embodiment provides a method for synthesizing a levetiracetam intermediate, comprising the following steps:

[0036] S1. Add the mixture containing (R)-α-ethyl-2-oxo-1-pyrrolidineacetic acid and (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid to the strong base aqueous solution , heat up to 70 ℃, keep stirring for 3 hours; the strong base is selected from sodium hydroxide or potassium hydroxide, the mass percentage concentration range of the strong base solution is 30%, and the consumption of the base is (R)-α-ethyl-2-oxygen 2 times the total molar amount of the mixture of substituted-1-pyrrolidineacetic acid and (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid;

[0037] S2. Add an appropriate amount of water to dilute and cool down to 50°C, add 65% hydrochloric acid dropwise, and stir evenly; the water consumption is (R)-α-ethyl-2-oxo-1-pyrrolidine acetic acid and 1.5 to 5 times the total mass of the ethyl-2-oxo-1-pyrrolidine acetic acid mixture;

[0038] S3, heat u...

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Abstract

The invention discloses a synthesis method of a levetiracetam intermediate, which comprises the following steps: S1, adding a mixture into a strong alkali aqueous solution, heating to 60-80 DEG C, and carrying out heat preservation and stirring for 2-5 hours; s2, adding a proper amount of water for dilution, cooling to 40-60 DEG C, dropwise adding 60-70% hydrochloric acid, and uniformly stirring; s3, heating to 60-80 DEG C, dropwise adding 10-20% hydrochloric acid, and uniformly stirring; s4, cooling to 40-60 DEG C, dropwise adding the residual hydrochloric acid, and adjusting the pH value to 3-4.5; and S5, cooling to room temperature, and then filtering, filling, sterilizing and packaging. According to the method, the acid is added at different temperatures, and the pH value is adjusted to a proper range, so that unknown impurities generated in a strong alkali racemization process can be separated out in a system, sufficient dissolution can be ensured, and the content of the obtained intermediate subjected to racemization recovery is qualified.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparation preparation, in particular to a method for synthesizing a levetiracetam intermediate. Background technique [0002] Levetiracetam is a broad-spectrum antiepileptic drug with high efficacy and few toxic and side effects developed by Belgian UCB Company. It is mainly used for the treatment of localized and secondary generalized epilepsy. yl-2-oxo-1-pyrrolidineacetamide. [0003] At present, there are many reports on the preparation method of levetiracetam at home and abroad, mainly adopting the chemical separation method. The main methods are: 1) The starting material is methionine, which is prepared by multi-step reaction and finally reduction and desulfurization. 2) Using (S)-2-aminobutyramide with a chiral center, which can avoid splitting during the reaction, is prepared by a two-step cyclization reaction with 4-chlorobutyryl chloride, as disclosed in EP1566376A1. 3) is a c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/27
CPCC07D207/27Y02P20/55
Inventor 徐军蒋信义张敏华周宇徐萌
Owner ABA CHEM CORP
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