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Preparation method of brivaracetam

A technology of intermediates and molar quantities, which is applied in the field of medicine, can solve the problems of long preparation steps, high cost, and unsuitability for industrial production, and achieve short preparation routes, reduce production costs, and avoid chiral resolution or column chromatographic separation. Effect

Inactive Publication Date: 2018-12-07
BEIJING VENTUREPHARM BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] According to the existing literature reports, the existing synthetic routes basically require chiral resolution or column chromatography separation and purification steps, and the general preparation steps are long, the cost is high, and it is not suitable for industrial production. Therefore, in this field, a new method is developed. The preparation process of buvaracetam with simple process and simple separation and purification is very meaningful

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] A: Dissolve (R)-4-propyl-dihydrofuran-2-one 10.0g (78.1mmol) in 100mL DMF, add sodium carbonate 9.1g (85.9mmol), (S)-2-aminobutyric acid 8.9g (86.4mmol), heat up to 80°C, stir for 10h, the temperature of the reaction solution drops to 0-5°C, dilute with water, adjust the pH to 3 with 2N hydrochloric acid solution, extract three times with dichloromethane, and combine the organic phases , dried, and concentrated to obtain 15.5g of Intermediate II with a yield of 86.1%.

[0034] B: Add 8.4g (71.2mmol) of thionyl chloride to 200mL methanol, raise the temperature and reflux for 1h, add 15.0g (64.9mmol) of intermediate II, and continue to reflux for 2h. Add 200mL DMF to the mixture, then add 7.2g (71.6mmol) of triethylamine, add 8.4g (71.2mmol) of thionyl chloride under stirring at room temperature, continue stirring for 3h, add 4.9g (32.7mmol) of sodium iodide to the reaction solution ), heated up to 80°C again, then added 3.6 g (64.9 mmol) of potassium hydroxide to the re...

Embodiment 2

[0037] A: Dissolve (R)-4-propyl-dihydrofuran-2-one 10.0g (78.1mmol) in 100mL DMSO, add sodium carbonate 9.1g (85.9mmol), (S)-2-aminobutyric acid 9.7g (93.7mmol), heat up to 80°C, stir and react for 10h, the temperature of the reaction solution drops to 0-5°C, dilute with water, adjust the pH to 3 with 2N hydrochloric acid solution, extract three times with dichloromethane, and combine the organic phases , dried, and concentrated to obtain 15.1 g of intermediate II with a yield of 83.9%.

[0038]b: Add 8.4g (71.2mmol) of thionyl chloride to 200mL of methanol, raise the temperature and reflux for 1h, add 15.0g (64.9mmol) of intermediate II, and continue to reflux for 2h. Add 200mL DMSO to the compound, then add 5.7g (71.6mmol) of pyridine, add 8.4g (71.2mmol) of thionyl chloride under stirring at room temperature, continue stirring for 3h, add 4.9g (32.7mmol) of sodium iodide to the reaction solution, Stir for 30mins, then add 2.6g (64.9mmol) of sodium hydride to the reaction s...

Embodiment 3

[0041] A: Dissolve (R)-4-propyl-dihydrofuran-2-one 10.0g (78.1mmol) in 100mL DMF, add potassium carbonate 11.9g (85.9mmol), (S)-2-aminobutyric acid 8.9g (86.4mmol), heat up to 50°C, stir for 15h, the temperature of the reaction solution drops to 0-5°C, dilute with water, adjust the pH to 3 with 2N hydrochloric acid solution, extract three times with dichloromethane, and combine the organic phases , dried, and concentrated to obtain 16.2g of Intermediate II with a yield of 90.0%.

[0042] B: Add 8.4g (71.2mmol) of thionyl chloride to 200mL methanol, raise the temperature and reflux for 1h, add 15.0g (64.9mmol) of intermediate II, and continue to reflux for 2h. Add 200mL dioxane to the mixture, then add 7.2g (71.6mmol) of triethylamine, add 8.4g (71.2mmol) of thionyl chloride under stirring at room temperature, continue to stir for 2h, add 4.9g of sodium iodide to the reaction solution (32.7mmol), raised the temperature to 80°C again, then added 5.2g (96mmol) of sodium methoxid...

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Abstract

The invention discloses a preparation method of brivaracetam (formula IV). The preparation method comprises the following steps: carrying out ammonolysis on (R)-4-propyl-dihydrofuran-2-one and (S)-2-amino butyric acid as raw materials to obtain an intermediate II, then carrying out steps of esterification, chlorination and cyclization to obtain an intermediate III, and finally, carrying out an ammonolysis step to obtain the brivaracetam (IV), wherein the steps of esterification, chlorination and cyclization are operated in a combination mode. The preparation method provided by the invention ismild in condition, is simple and convenient to operate, has easily obtained raw materials, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine. Background technique [0002] Brivaracetam is newly developed by Belgian pharmaceutical giant UCB. It has high affinity and can selectively bind to synaptic vesicle protein 2A (SV2A). It is a broad-spectrum antiepileptic drug (AED) left Site of action of etiracetam (Keppra®). The affinity of brivaracetam is 15-30 times that of levetiracetam, making its dosage about 10 times lower. [0003] On February 18, 2016, the US Food and Drug Administration (FDA) approved Brivaracetam (Briviact®) as an adjuvant treatment for partial-onset seizures in patients ≥16 years old. Brivaracetam is the first FDA-approved antiepileptic drug (AED) for the treatment of partial-onset seizures since the approval of eslicarbazepine (Aptiom®) in 2013. [0004] The European Medicines Agency (EMA) approved the marketing of brivaracetam on January 14, 2016, for the partial onset of epilepsy in adults and adolescents aged ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/27
CPCC07D207/27
Inventor 马翔赵国磊赵云萍
Owner BEIJING VENTUREPHARM BIOTECH
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