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A compound, its preparation method and its use in the synthesis of Buvaracetam

A compound, the technology of cuprous iodide, applied in the field of compound and its preparation, and the synthesis of brivaracetam, can solve the problems of unconstructed butyrolactam and uneconomical use of raw materials

Active Publication Date: 2018-06-26
SUZHOU PENGXU PHARM TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] None of the above-mentioned routes have constructed the chiral center of the n-propyl group on butyrolactam, but obtained optically pure brivaracetam in the final product through chiral high-performance liquid phase purification, and the utilization of raw materials is not economical

Method used

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  • A compound, its preparation method and its use in the synthesis of Buvaracetam
  • A compound, its preparation method and its use in the synthesis of Buvaracetam
  • A compound, its preparation method and its use in the synthesis of Buvaracetam

Examples

Experimental program
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Effect test

Embodiment 1

[0071] Embodiment 1 prepares compound 3

[0072] Sodium methoxide (2.05 g, 38 mmol) was added into 80 mL of absolute ethanol to dissolve completely. The reaction flask was placed in an ice-water bath, and diethyl malonate was added. Stirring at this temperature for 10 minutes, the system was raised to room temperature, and (R)-epichlorohydrin (ee 98%) (2.7 mL, 35 mmol) (purchased from Anaiji Chemicals) was slowly added to the reaction system, and the addition was completed. The system was reacted under reflux for 18 hours, the reaction was stopped, the system was cooled to room temperature, the solvent was spin-dried, 100 mL of water was added, and extracted 3 times with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered after drying, and the filtrate was spin-dried to obtain compound 3, which was distilled under reduced pressure to obtain a colorless liquid with a yield of 55%. Compound 3 chiral HPLC (ee 98%)

[0073] ...

Embodiment 2

[0074] Embodiment 2 prepares compound 4

[0075] Add CuI (9.5g, 50mol) into 100mL of dry THF, place the reaction flask in a low-temperature reaction bath at -30°C, add a THF solution of ethyl Grignard reagent (1.0M, 300mL, 300mmol) into the reaction flask and stir for 1 hour , and then the dry THF solution of compound 3 (20 g, 117 mmol) prepared by the method described in Example 1 was added dropwise to the reaction flask. After the dropwise addition was completed, after stirring at this temperature for 30 minutes, the temperature was slowly raised to -15°C. The reaction was quenched with saturated ammonium chloride, 1 L of water was added, extracted three times with 1 L of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, after drying, filtered, and the filtrate was concentrated to obtain crude compound 4.

[0076] Purification by column chromatography (developing solvent polarity: petroleum ether / ethyl acetate=10 / 1) to obtain the nuclea...

Embodiment 3

[0078] Embodiment 3 prepares compound 5

[0079] The compound 4 crude product (in terms of 117mmol) prepared as described in Example 2 was added to DMSO / H 2 O (400 mL / 20 mL), LiCl (14.7 g, 350 mmol) was added to the reaction flask. After the system was reacted at 140°C for 18 hours, it was poured into 400 mL of water, extracted three times with 400 mL of ethyl acetate, the organic phases were combined, washed once with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to obtain a crude product, and compound 5 was obtained by distillation under reduced pressure. , colorless liquid, together with embodiment 2 two-step total yield 50%

[0080] The NMR data of compound 5 are as follows: 1 H NMR (400MHz, CDCl 3 )δ4.42(1H,dd),3.92(1H,dd),2.52-2.65(2H,m),2.18(1H,dd),1.40-1.47(2H,m),1.40-1.47(2H,m) ,1.27-1.39(2H,m),0.94(3H,t).

[0081] The specific rotation of compound 5 is: [α] 23 D =+3.9 (C=10, CHCl 3 )

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Abstract

The application provides a compound of formula I and a preparation method thereof. The application also provides the use of the compound of formula I for synthesizing buvaracetam and the synthesis method. The raw materials involved in the method described in this application are easy to obtain and cheap, and can prepare brivaracetam with high optical purity.

Description

technical field [0001] The application relates to the field of drug synthesis, in particular, to a compound, its preparation method and its use in synthesizing 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 cannot be terminate...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/33C07D207/27
CPCC07D207/27C07D307/33
Inventor 李丕旭王鹏魏强
Owner SUZHOU PENGXU PHARM TECH CO LTD
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