Preparation method of brivaracetam and intermediate thereof

A compound, halomethyl technology, applied in the field of medicinal chemistry, can solve the problems of high substance content, difficult operation, difficult crystallization, etc.

Active Publication Date: 2017-05-31
CHENGDU GUOHONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] After the reaction in step 1 of this route, the racemate of compound (a) is obtained, and the follow-up reaction is carried out with this racemate to obtain buvaracetam, but the applicant finds that the crude product of brivaracetam prepared according to this method is It is a brown-black viscous liquid, which makes it difficult to operate during recrystallization, crystallization is difficult, and the crystallization time is very long; and high-performance liquid chromatography detection shows that the chemical purity of brivaracetam is between 83% and 88%, and related substances high content

Method used

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  • Preparation method of brivaracetam and intermediate thereof
  • Preparation method of brivaracetam and intermediate thereof
  • Preparation method of brivaracetam and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] Dissolve 10 g of (R)-4-n-propyl-dihydrofuran-2-one (gas chromatography purity 85%, optical purity 95%) in acetonitrile, cool down to about -10°C, and dropwise add 8.4 g trimethyl Chlorosilane was added with 11.6g of sodium iodide, after the addition was complete, the reaction was monitored by TLC. After the reaction was complete, the reaction was quenched with dilute hydrochloric acid, extracted with DCM / water, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain (R)-3-iodomethyl n-hexanoic acid (optical purity 94.6%), directly used in the next step reaction. δ H (300 MHz, CDCl 3): 0.9-0.95(3H, m), 1.29-1.36 (4H, m), 1.71-1.74 (1H, m), 2.37-2.49 (2H, m),3.27-3.41 (2H, m), 11.07(1H ,s).

[0113] (R)-3-Iodomethyl n-hexanoic acid was dissolved in 20 ml of dichloromethane, and 36.8 g of phosphorus pentachloride was added at 10°C. The reaction was carried out at 10°C, and the r...

Embodiment 2

[0116] Dissolve 10g of (R)-4-n-propyl-dihydrofuran-2-one (gas chromatography purity 90%, optical purity 98%) in cyclohexane, heat up to 70°C, add 7g hydrobromic acid dropwise , the addition was completed, and the reaction was monitored by TLC. After the reaction was complete, the reaction was quenched with dilute hydrochloric acid, extracted with DCM / water, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain (R)-3-bromomethyl-n-hexanoic acid (optical purity 97.3%), directly used in the next step reaction.

[0117] Dissolve (R)-3-bromomethyl n-hexanoic acid in 20ml of cyclohexane, and add 19.4g of oxalyl chloride at the boiling point of the solvent. The reaction was carried out at the boiling point of the solvent, and monitored by TLC. After the reaction was complete, it was concentrated to dryness under reduced pressure to obtain (R)-3-bromomethyl-n-hexanoyl chloride, which was dir...

Embodiment 3

[0120] Dissolve 10 g of (R)-4-n-propyl-dihydrofuran-2-one (gas chromatography purity 80%, optical purity 94%) in acetone, adjust the temperature to the boiling point of the solvent, and add 8.4 g of trimethyl Chlorosilane, add 23.2g of sodium iodide, after the addition is complete, TLC monitors the reaction. After the reaction was complete, the reaction was quenched with dilute hydrochloric acid, extracted with DCM / water, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain (R)-3-iodomethyl n-hexanoic acid (optical purity 93.41%), directly used in the next step reaction.

[0121] (R)-3-Iodomethyl n-hexanoic acid was dissolved in 20 ml of methylene chloride, and 62.4 g of thionyl chloride was added. The reaction was carried out at 80°C, and the reaction was monitored by TLC. After the reaction was complete, it was concentrated under reduced pressure to dryness to obtain (R)-3-iodomet...

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Abstract

The invention relates to a preparation method of brivaracetam and an intermediate thereof, wherein the brivaracetam is prepared with high-optical-purity (R)-4-n-propyl-dihydrofuran-2-one as a raw material. The preparation method is low in requirement on production equipment and can be used for preparing a brivaracetam crude product at higher chemical and optical purities and higher yield. The method greatly reduces the cost of large-scale industrial production of the brivaracetam.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of buvaracetam and an intermediate thereof. Background technique [0002] Brivaracetam, chemical name (2S)-2-[(4R)-2-oxo-4-n-propyl-1-pyrrolidinyl]butyramide, is a drug developed by UCB An antiepileptic drug indicated for the adjunctive treatment of partial-onset seizures in epileptic patients over 16 years of age. Based on the results of the phase III study of brivaracetam, UCB has submitted a new drug application to the US Food and Drug Administration (FDA) and a marketing authorization application to the European Medicines Agency (EMA) on January 25, 2015. According to the clinical research data of the original research company, the anti-convulsant ability of brivaracetam is 10 times stronger than that of levetiracetam, the first brand drug in the field of epilepsy drugs, and its affinity for the target neuronal synaptic vesicle protein SV2A...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C53/19C07D207/27
CPCC07C53/19C07D207/27
Inventor 王锐武永财郭礼新郭晖
Owner CHENGDU GUOHONG PHARMA
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