Method for preparing furanone compounds

A compound, the technology of furanone, which is applied in the field of preparation of furanone compounds, can solve the problems of low product purity, low total yield, cumbersome post-processing steps, etc.

Active Publication Date: 2017-04-26
上海云晟研新生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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, hi

Method used

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  • Method for preparing furanone compounds
  • Method for preparing furanone compounds
  • Method for preparing furanone compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066]

[0067] (R)-3-methoxycarbonylhexanoic acid (174.1 g, 1 mol, ee value 99.2%) was dissolved in 500 mL of methanol, cooled to 0 °C, added with 500 mL of water, cooled to 0 °C, followed by powdered chlorine Calcium chloride (115.8 g, 1.1 mol) and sodium borohydride in ethanol (2M, 800 mL). The reaction solution was stirred at (20°C ~ 30°C) overnight (about 12 hours), hydrochloric acid was added to quench the reaction (6M, 1000 mL), concentrated under reduced pressure, diluted with 500 mL of water, extracted with dichloromethane (3×150 mL), combined The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 108.9 g of furanone compound III, yield 85.0%, purity: 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, and the ee value is greater than 99.0%.

Embodiment 2

[0070]

[0071] Under nitrogen protection, furanone compound III (128.1 g, 1 mol) was dissolved in 1 L of dichloromethane, cooled to 0 °C, trimethylsilyl iodide (150 mL) was added, and the reaction solution was stirred at 20 to 30 °C for 2 Hour. Then add hydrochloric acid solution (1M, 800mL) and sodium thiosulfate aqueous solution (mass percent is 10%, described mass percent refers to the percentage of the quality of sodium thiosulfate and the total mass of sodium thiosulfate aqueous solution, 400mL.) , the aqueous phase was extracted with 1 L of dichloromethane, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain brivaracetam intermediate IV (254.6 g), yield 99.5%, purity : 95.6% (GC).

Embodiment 3

[0073]

[0074] Under nitrogen protection, brivaracetam intermediate IV (1280.4 g, 4 mol) was dissolved in 1500 mL of toluene, thionyl chloride (951.8 g, 8 mol) was slowly added, and the reaction solution was stirred 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 (0.32 mmHg, 90-95° C.) to obtain 1310 g of compound V as a pale yellow transparent liquid.

[0075] 1310 g of the obtained compound V was dissolved in 2.5 L of dichloromethane solution. 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), tetrabutyl bromide In the dichloromethane solution (12.5L) of ammonium (49g, 0.14mol), the reaction solution was stirred at 20-30°C for 18 hours, then diatomaceous earth was added for filtration, and the filtrate was concentrated ...

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Abstract

The invention discloses a method for preparing furanone compounds, and provides a method for preparing a furanone compound III. The method includes the following steps that in a solvent, in the presence of inorganic salt, a compound II and a reducing agent are subjected to a reduction reaction, and the furanone compound III is obtained; the solvent is a fatty alcohol solvent or a mixed solvent of a fatty alcohol solvent and water. The brivaracetam can be prepared with the furanone compound III only with the three steps, and the synthetic route is short; the ee value of the compound II is larger than 99.0%, racemization does not occur in the reaction process, and the de value of a brivaracetam I crude product is larger than 99.0%; the brivaracetam I crude product is further purified through a crystal instead of a chirality high-pressure-liquid-phase preparing column, and the chirality purity of brivaracetam I can be further increased to be the de value of 99.80% or above; meanwhile, the content of other individual impurities of the brivaracetam I is smaller than 0.1%, and reaches the API level, and the method is suitable for industrial production. The formula is defined in the description.

Description

technical field [0001] The present invention relates to a preparation method of furanone compounds. Background technique [0002] Brivaracetam I is a racetam derivative with broad antiepileptic activity and high safety profile. Belgian pharmaceutical giant UCB (UCB) has published data from a 12-week phase III study of the epilepsy drug brivaracetam, which showed that brivaracetam significantly reduced the frequency of partial seizures and improved response rates. The tolerability of brivaracetam in the study was consistent with previous studies. UCB submitted the New Drug Application and Marketing Authorization Application for brivaracetam to the FDA and the European Medicines Agency (EMA) respectively in 2015 and has been approved, making brivaracetam the third of UCB's flagship epilepsy franchise Marketed product, the company is conducting late-stage studies seeking approval for the drug in pediatric patients, as well as as a monotherapy in adult patients. [0003] ...

Claims

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Application Information

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IPC IPC(8): C07D307/33C07D207/27C07C51/09C07C53/19C07C51/60C07C53/50
CPCC07C51/09C07C51/60C07D207/27C07D307/33C07C53/19C07C53/50
Inventor 应述欢皮红军陈健周威张爵明
Owner 上海云晟研新生物科技有限公司
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