Synthesis method of levetiracetam

A synthetic method and selected technology, applied in the field of drug synthesis, can solve the problems of low overall yield, high toxicity and corrosion

Active Publication Date: 2012-07-11
江苏八巨药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Phosphorus pentachloride belongs to the third category of monitored chemicals, and its production, import and export are under the control of the State Office of the Prohibition of Chemical Weapons (Ministry of Industry and Information Technology); oxalyl chloride is highly toxic and corrosive, and reacts violently with water to release toxic gas carbon monoxide, and the total yield Also low, the ring closure yield is only between 60% and 70%

Method used

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  • Synthesis method of levetiracetam
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  • Synthesis method of levetiracetam

Examples

Experimental program
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Embodiment 1

[0059] Alkylation reaction: add (S)-2-aminobutyric acid 1.00mol (103g), 500mL water and 87g alkaline reagent NaHCO into a 1000mL three-neck flask 3 , then lower the temperature to 0°C under stirring, control the temperature within the range of 0°C to 5°C, add 1.05mol (148g) of 4-chlorobutyryl chloride dropwise, and continue to keep the temperature at 0°C to 5°C The alkylation reaction was carried out for 3 hours. After the alkylation reaction was finished, post-treatment was carried out. The post-treatment was as follows: add 200 mL of extractant dichloromethane to the reaction solution, stir for 20 min, let stand for 30 min, separate layers, collect the organic phase, Then add 8 g of desiccant anhydrous sodium sulfate to the organic phase, stir and dry for 30 minutes, filter, collect the filtrate, carry out vacuum distillation to the obtained filtrate, control the temperature of the vacuum distillation to be 20° C. to 60° C., and carry out the vacuum distillation to No liquid...

Embodiment 2

[0064] Alkylation reaction: Add 1.00mol (103g) of (S)-2-aminobutyric acid, 500mL of water and 1.20mol (106g) of alkaline reagent Na to a 1000mL three-necked flask 2 CO 3 , then cooled down to -5°C under stirring, controlled the temperature in the range of -5°C to 0°C, added 1.20mol (169g) of 4-chlorobutyryl chloride dropwise, and continued to keep the temperature at -5°C to 0°C Under the condition of ℃, the alkylation reaction was carried out for 4 hours. After the alkylation reaction was completed, post-treatment was carried out. The post-treatment was as follows: add 200 mL of extractant ethyl acetate to the reaction solution, stir for 20 minutes, let stand for 30 minutes, separate layers, and collect Organic phase, then add 10 g of desiccant anhydrous sodium sulfate to the organic phase, stir and dry for 30 minutes, filter, collect the filtrate, carry out vacuum distillation to the obtained filtrate, control the temperature of vacuum distillation to be 40 ℃ ~ 50 ℃, reduce ...

Embodiment 3

[0069] Alkylation reaction: Add 1.00mol (103g) of (S)-2-aminobutyric acid, 500mL of water and 1.00mol (138g) of alkaline reagent K into a 1000mL three-necked flask 2 CO 3, then lower the temperature to 5°C under stirring, control the temperature within the range of 5°C to 10°C, add 1.15mol (162g) of 4-chlorobutyryl chloride dropwise, and continue to keep the temperature at 5°C to 10°C The alkylation reaction was carried out for 1 hour. After the alkylation reaction was completed, post-treatment was carried out. The post-treatment was as follows: add 200 mL of extractant 2-methyltetrahydrofuran to the reaction solution, stir for 20 min, let stand for 30 min, separate layers, and collect organic phase, then add 10 g of desiccant anhydrous sodium sulfate to the organic phase, stir and dry for 30 minutes, filter, collect the filtrate, carry out vacuum distillation on the obtained filtrate, control the temperature of the vacuum distillation to 30°C to 50°C, and depressurize Distil...

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Abstract

The invention relates to a synthesis method of levetiracetam and belongs to the technical field of medicine synthesis. The invention provides a synthesis method of levetiracetam for the purpose of solving the technical problems that in the prior art, a process in which thionyl chloride is used as a raw material or benzene is used for splitting is large in environment pollution, complicated in splitting and is disadvantageous to production. The method comprises the following steps of: carrying out alkylation reaction on (S)-2-reanal which is used as the raw material and 4-chlorobutyryl chloride; carrying out acylation reaction on a product obtained from the former step and an acylation agent; and then carrying out cyclization reaction through ammonolysis in the presence of a phase transfer catalyst to obtain the levetiracetam. The invention provides a bran-new synthesis method of levetiracetam. In the method, a splitting process is omitted so as to avoid the problem existing when benzene is used as a splitting agent; a thionyl chloride reagent is not used, so as to reduce human damage and environment pollution; and the yield and the quality of a product are high, the total molar yield of the product is more than 81%, the HPLC (high performance liquid chromatography) purity of the product is more than 98%, and the optical purity of the product is more than 99.0%.

Description

technical field [0001] The invention relates to an antiepileptic drug levetiracetam, in particular to a synthesis method of levetiracetam, which belongs to the technical field of drug synthesis. Background technique [0002] Levetiracetam (Levetiracetam) is a new type of antiepileptic drug developed by UCB Pharmaceuticals in Belgium. Its chemical name is (S)-2-(2-oxo-1-pyrrolidine) butanamide, and its English name is: (S)-2-(2-Oxopyrrolidin-1-yl)butananide, the molecular formula is: C 8 h 14 N 2 o 2 , the molecular weight is 170.21, and its chemical structural formula is: [0003] [0004] Levetiracetam is approved by the SFDA for the adjuvant treatment of epilepsy or partial seizures in adults and children over 4 years old. It was initially listed in Europe and the United States in 1999 for partial seizures in adults; in June 2005, its oral tablets and injections were approved for adjuvant treatment of partial seizures in children aged 4 or above; in 2007 It went on...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/27
Inventor 徐斌陈孔禄王玉钢马兆星
Owner 江苏八巨药业有限公司
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