Compounds and preparation methods thereof, and uses of compounds in synthesis of brivaracetam

A compound and reaction technology, applied in the field of drug synthesis, to achieve high quality and avoid waste

Active Publication Date: 2017-02-01
SUZHOU PENGXU PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are not many foreign related patent reports, such as patents US 6,784,197, US 7,629,474, US 8,957,226, US8,338,621, US 8,076,493 and related patents reporting the synthesis of brivaracetam, among which US6,784,197, US 7,629,474 reported some synthetic routes , the existing problems of these synthetic routes are mainly focused on the inability to synthesize brivaracetam with sufficient optical purity with high yield and high selectivity, and the need for column chromatography purification, chiral high performance liquid chromatography purification, etc. is not conducive to industrial How to scale up production

Method used

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  • Compounds and preparation methods thereof, and uses of compounds in synthesis of brivaracetam
  • Compounds and preparation methods thereof, and uses of compounds in synthesis of brivaracetam
  • Compounds and preparation methods thereof, and uses of compounds in synthesis of brivaracetam

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1 preparation formula II compound

[0049] Anhydrous zinc chloride (2.5 g, 18.3 mmol) was added to the reaction flask containing 20 mL of thionyl chloride, and the compound of formula I (12.0 g, 93.7 mmol) was added. Put the reaction bottle in an oil bath at 55°C for reaction, and stop the reaction when there is no raw material left after detection by gas chromatography (detection by gas chromatography), then stop the reaction, cool the system to room temperature, spin out thionyl chloride, and then distill under reduced pressure to obtain a yellowish liquid. Formula II compound, yield 68%. The nuclear magnetic data of formula II compound is as follows: 1 H NMR (400MHz, CDCl 3 ): δ3.67(1H,dd), 3.59(1H,dd), 2.58(1H,dd), 2.40(1H,dd), 2.20-2.31(1H,m), 1.25-1.53(4H,m), 0.93(3H,t).

[0050] The specific rotation of compound II is: [α] 23 D =+2.9 (C=10, CHCl 3 )

Embodiment 2

[0051] Embodiment 2 preparation formula II compound

[0052] Anhydrous zinc chloride (40 g, 0.29 mol) was added to the reaction flask containing 400 mL of thionyl chloride, and the compound of formula I (188 g, 1.47 mol) was added. Put the reaction bottle in an oil bath at 85°C for reaction. After GC detects that there are no remaining raw materials, stop the reaction, cool the system to room temperature, spin out thionyl chloride, and then distill under reduced pressure to obtain the compound of formula II as a light yellow liquid. The yield is 63.5%.

[0053] The nuclear magnetic data of formula II compound is as follows: 1 H NMR (400MHz, CDCl 3 ): 1 HNMR (400MHz, CDCl 3 ): δ3.67(1H,dd), 3.59(1H,dd), 2.58(1H,dd), 2.40(1H,dd), 2.20-2.31(1H,m), 1.25-1.53(4H,m), 0.93(3H,t).

[0054] The specific rotation of compound II is: [α] 23 D =+2.9 (C=10, CHCl 3 )

Embodiment 3

[0055] Embodiment 3 preparation formula IV compound

[0056] Add the compound of formula III (1.67g, 12mol) (purchased from Beijing Coupling Technology Co., Ltd.) into 40mL of dry dichloromethane, add triethylamine (2.43g, 24mmol), stir at room temperature for 30 minutes, then add formula II dropwise Compound (2.0 g, 10.8 mmol), after the dropwise addition was completed, stirred at room temperature until no raw material was detected by TLC. Add 30mL water, 4mL ethanol, extract and separate the organic phase, extract twice with 40mL dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, after drying, filter, and concentrate the filtrate to obtain the crude product of the compound of formula IV, the yield is 96.7% .

[0057] Purification by column chromatography (developing solvent polarity: ethyl acetate 100%) obtains the NMR data of the purified formula IV compound as follows: 1 H NMR (400MHz, CDCl 3 )δ6.20-6.45 (2H, m), 5.69 (1H, brs), 4.46 (1H, ...

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Abstract

The present invention provides compounds represented by formulas II and IV. The invention further provides uses of the compound represented by the formula II in synthesis of brivaracetam, and a synthesis method. According to the present invention, the used raw materials are easy to obtain and have low price, and the high optical-purity brivaracetam can be prepared. The formulas II and IV are defined in the specification.

Description

technical field [0001] The present application relates to the field of drug synthesis, in particular, to the compound, its preparation method and its use in the synthesis of buvaracetam. The present application also relates to a method for synthesizing Buvaracetam. Background technique [0002] Epilepsy is a common disease of the nervous system, with an incidence rate of 0.6% to 1.1% in the population, and 60% to 70% of patients will still have seizures while taking antiepileptic drugs, causing some patients to stop drug treatment by themselves. At present, there are more than 6 million epilepsy patients in my country, and 650,000 to 700,000 new epilepsy patients are diagnosed every year, and about 25% of them are refractory epilepsy. Although great progress has been made in the diagnosis and treatment of epilepsy, the number of patients with intractable epilepsy is increasing day by day. Generalized intractable epilepsy refers to epilepsy and epilepsy syndromes that canno...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C53/50C07C51/58C07D307/33C07D207/27C07C237/22C07C231/02
CPCC07C51/58C07C53/50C07C231/02C07C237/22C07D207/27C07D307/33
Inventor 李丕旭王鹏魏强
Owner SUZHOU PENGXU PHARM TECH CO LTD
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