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Method for preparing brivaracetam

A compound and solvent technology, applied in the field of preparation of brivaracetam, can solve the problems of low product purity, low total yield, unsuitable for industrial production and the like

Active Publication Date: 2017-04-26
SHANGHAI BOCIMED PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The technical problem to be solved by the present invention is to overcome the long reaction steps, low total yield, cumbersome post-processing steps, low purity of the obtained product, high production cost and unsuitability for industrialization in the synthesis method of buvaracetam in the prior art. A kind of preparation method of buvaracetam is provided because of defects such as production

Method used

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  • Method for preparing brivaracetam
  • Method for preparing brivaracetam
  • Method for preparing brivaracetam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066]

[0067] Dissolve (R)-3-methoxycarbonylhexanoic acid (174.1g, 1mol, ee value 99.2%) in 500mL methanol, cool to 0℃, add 500mL water, cool to 0℃, add powdered chlorine in turn An ethanol solution (2M, 800 mL) of calcium phosphate (115.8 g, 1.1 mol) and sodium borohydride. After the reaction solution was stirred overnight (about 12 hours) at room temperature (20℃~30℃), the reaction was quenched by adding hydrochloric acid (6M, 1000mL), concentrated under reduced pressure, diluted with 500mL water, and extracted with dichloromethane (3×150mL) The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 108.9 g of Compound III, with a yield of 85.0%, and a purity of 97.2% (GC).

[0068] R-3-methoxycarbonylhexanoic acid can be prepared according to the method described in Angewandte Chemie International Edition, 1998, 37(13-14), 1931-1933, with an ee value greater than 99.0%.

Embodiment 2

[0070]

[0071] Under the protection of nitrogen, dissolve Buwaxitan Intermediate III (128.1g, 1mol) in 1L dichloromethane, lower the temperature to 0℃, add trimethylsilyl iodide (150mL), and keep the reaction solution at 20-30℃ Stir for 2 hours. Then add hydrochloric acid solution (1M, 800mL) and sodium thiosulfate aqueous solution (mass percentage is 10%, the mass percentage refers to the percentage of the mass of sodium thiosulfate to the total mass of sodium thiosulfate aqueous solution, 400mL.) , The aqueous phase was extracted with 1L of dichloromethane, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Buwaxitam intermediate IV (254.6g), yield 99.5%, purity : 95.6% (GC).

Embodiment 3

[0073]

[0074] Under the protection of nitrogen, dissolve Buwaxitan intermediate IV (1280.4g, 4mol) in 1500mL toluene, slowly add thionyl chloride (951.8g, 8mol), and stir the reaction solution at room temperature (20℃~30℃) For 24 hours, the solvent was concentrated under reduced pressure. The residue was rectified under reduced pressure with a vacuum pump (0.32mmHg, 90-95°C) to obtain 1310g of compound V as a pale yellow transparent liquid.

[0075] The compound V 1310g obtained was dissolved in 2.5L dichloromethane solution, and then the above solution was added containing L-2-aminobutanamide hydrochloride (428.9g, 4.2mol), 4A molecular sieve (500g), potassium hydroxide (500g) ), anhydrous sodium sulfate (500g), tetrabutylammonium bromide (49g, 0.14mol) in dichloromethane solution (12.5L), the reaction solution was stirred at 20℃~30℃ for 18 hours and then added diatomaceous earth After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain the c...

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Abstract

The invention discloses a method for preparing brivaracetam. The method for preparing brivaracetam comprises the following step that in an organic solvent, under the condition of anhydrous and inert gas shielding, a compound V and L-2-aminobutanamide are subjected to a condensation reaction to obtain brivaracetam I. According to the method for preparing brivaracetam, brivaracetam is prepared through only four steps of reacting, the reaction steps are short, the total yield is high, aftertreatment steps and purifying methods are simple, a product with the de value larger than 99.80% can be prepared only through recrystallization, the grade API is reached, the production cost is low, and the method is suitable for industrial production. The formula is shown in the description.

Description

Technical field [0001] The invention relates to a preparation method of Buwaxitan. Background technique [0002] Buwaxitan I is a derivative of racetams, which has a wide range of anti-epileptic activities and high safety. The drug can exert anti-epileptic effects by combining with synaptic vesicle protein 2A (SV2A). Data from a 12-week Phase III study of the epilepsy drug Buwaxitan released by the Belgian pharmaceutical giant UCB (UCB) shows that Buwaxitan can significantly reduce the frequency of partial seizures and improve the response rate. The tolerance of Buwaxitan in the study is consistent with previous studies. UCB submitted the new drug application and marketing authorization application for Buwaxitan to the FDA and the European Medicines Agency (EMA) in 2015 and has been approved. Buwaxitan has become the third UCB franchise for epilepsy. For the marketed product, the company is carrying out late-stage studies to seek approval of the drug for pediatric patients and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/20
CPCC07D207/20
Inventor 应述欢皮红军陈健周威张爵明
Owner SHANGHAI BOCIMED PHARMA CO LTD
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