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A kind of preparation method of furanone compound

A compound and furanone technology, applied in the field of preparation of furanone compounds, can solve the problems of low product purity, high production cost, unsuitable for industrial production and the like

Active Publication Date: 2019-02-01
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 of the synthetic method of buvaracetam in the prior art. Production and other defects provide a preparation method of furanone compounds

Method used

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  • A kind of preparation method of furanone compound
  • A kind of preparation method of furanone compound
  • A kind of preparation method of furanone compound

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 of methanol, cool down to 0°C, add 500mL of water, cool to 0°C, add powdered chlorine Calcium chloride (115.8 g, 1.1 mol) and sodium borohydride in ethanol (2M, 800 mL). The reaction solution was stirred overnight (about 12 hours) at (20°C-30°C) and then quenched by adding hydrochloric acid (6M, 1000mL), concentrated under reduced pressure, diluted with 500mL of water, extracted with dichloromethane (3×150mL), and 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 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, 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, trimethyl iodosilane (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 percentage is 10%, described mass percent refers to the percentage of the quality of sodium thiosulfate and sodium thiosulfate aqueous solution gross mass, 400mL) successively. , the aqueous phase was extracted with 1L dichloromethane, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Buvaracetam intermediate IV (254.6g), yield 99.5%, purity : 95.6% (GC).

Embodiment 3

[0073]

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

[0075] 1310 g of the obtained compound V was dissolved in 2.5 L of dichloromethane solution. Subsequently, the above solution was added to a mixture containing L-2-aminobutyramide hydrochloride (428.9g, 4.2mol), 4A molecular sieves (500g), potassium hydroxide (500g), anhydrous sodium sulfate (500g), tetrabutyl bromide In dichloromethane solution (12.5L) of ammonium (49g, 0.14mol), the reaction solution was stirred at 20-30°C for 18 hours, then filtered with diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure to obt...

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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 invention relates to a preparation method of furanone compounds. Background technique [0002] Buvaracetam I is a racetam derivative with extensive antiepileptic activity and high safety. The drug can exert antiepileptic effect by binding to synaptic vesicle protein 2A (SV2A). Belgian pharmaceutical giant UCB (UCB) announced data from a 12-week phase III study of the epilepsy drug brivaracetam, showing that brivaracetam can significantly reduce the frequency of partial seizures and improve response rates. The tolerance of brivaracetam in the study was consistent with previous studies. In 2015, UCB submitted the New Drug Application and Marketing Authorization Application for Brivaracetam to the FDA and the European Medicines Agency (EMA) respectively and have been approved. Brivaracetam has become the third of UCB’s flagship epilepsy franchise marketed product, the company is conducting late-stage studies seeking approval for the drug in pediatri...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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 SHANGHAI BOCIMED PHARMA CO LTD
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