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Preparing method for caproic acid derivative

A derivative, hexanoic acid technology, applied in the field of preparation of hexanoic acid derivatives, can solve the problems of cumbersome post-processing steps, unsuitable for industrial production, long reaction 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

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 hexanoic acid derivative is provided because of defects such as production

Method used

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  • Preparing method for caproic acid derivative
  • Preparing method for caproic acid derivative
  • Preparing method for caproic acid derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0068]

[0069] 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 room temperature (20°C-30°C), then quenched by adding hydrochloric acid (6M, 1000mL), concentrated under reduced pressure, diluted with 500mL of water, 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 Buvaracetam intermediate III, yield 85.0%, purity: 97.2% (GC)

[0070] 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

[0072]

[0073] Under the protection of nitrogen, dissolve Buvaracetam Intermediate III (128.1g, 1mol) in 1L of dichloromethane, cool down to 0°C, add iodotrimethylsilane (150mL), and the reaction solution is heated at 20-30°C Stir for 2 hours. 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 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 hexanoic acid derivative IV (254.6 g, 99.5%) with a yield of 99.5%. Purity: 95.6% (GC).

Embodiment 3

[0075]

[0076] Under the protection of nitrogen, dissolve hexanoic acid derivative IV (1280.4g, 4mol) in 1500mL of toluene, slowly add thionyl chloride (951.8g, 8mol), and stir the reaction solution at room temperature (20°C-30°C) for 24 hours , and 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.

[0077] 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 ...

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Abstract

The invention discloses a preparing method for a caproic acid derivative and provides a preparing method for a caproic acid derivative IV. The method comprises the following steps that in a polar nonprotic organic solvent, a compound III and an iodization reagent are subjected to a nucleophilic substitution reaction under inert gas shielding, and the caproic acid derivative IV is obtained. Brivaracetam can be prepared from the caproic acid derivative IV only through two steps, the synthetic route is short, the reaction condition is mild, posttreatment is simple, the reaction yield is high, and the production cost is low. Racemization does not happen in the reaction process, further purification is conducted through crystallization instead of a chiral high-pressure liquid phase preparing column, the chiral purity of the brivaracetam I can be improved till the de value is larger than 99.80%, meanwhile, the content of other single impurities of the brivaracetam I is smaller than 0.1%, the API level is reached, and the method is suitable for industrial production. The expression is shown in the description.

Description

technical field [0001] The invention relates to a preparation method of hexanoic acid derivatives. 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 p...

Claims

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Application Information

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IPC IPC(8): C07D207/20C07C51/09C07C53/19C07C51/60C07C53/50
CPCC07C51/09C07C51/60C07D207/20C07D307/33C07C53/19C07C53/50
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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