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Synthesis method of brivaracetam intermediate and brivaracetam

A synthetic method and intermediate technology, applied in the field of medicine, can solve the problems of not being suitable for industrial production, difficult amide condensation, high production cost, etc., and achieve the advantages of synthetic cost advantages, easy control of reaction conditions, and large processing capacity.

Inactive Publication Date: 2019-01-04
LIVZON NEW NORTH RIVER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] CN101263113A discloses the route shown in formula 2, this route reaction is loaded down with trivial details, and production cost is too high, is not suitable for industrialized production
[0011] Due to the difficulty of leaving the chloro group, the route is difficult to condense with the amide, resulting in low yield and more impurities

Method used

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  • Synthesis method of brivaracetam intermediate and brivaracetam
  • Synthesis method of brivaracetam intermediate and brivaracetam
  • Synthesis method of brivaracetam intermediate and brivaracetam

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Preparation of Compound 2: Add Compound 1 (50g, 352mmol) into toluene (400ml), slowly add an aqueous solution of sodium borohydride (13.30g, 352mmol) dropwise under nitrogen atmosphere at 0°C, and react at room temperature for 4h. The reaction was quenched by slow dropwise addition of acetic acid. The aqueous phase was extracted twice with toluene. The organic phases were combined, washed with 10% sodium bicarbonate solution, washed with brine, and concentrated in vacuo to obtain an orange oil, namely compound 2.

[0087] The yield is 80%, HPLC>99%, 1 H NMR (300MHz, CDCl 3 ): δ5.83(s,1H), 4.73(s,2H), 2.38(t,2H), 1.55–1.70(m,2H), 1.00(t,3H).

[0088] The preparation of compound 3: put compound 2 (10.00g, 126.2mmol) and 80ml methanol into the hydrogenation kettle, drop into Raney nickel (0.20g) under nitrogen atmosphere, nitrogen replacement 3 times, hydrogen replacement 3 times, 0.45MPa hydrogen pressure, Reaction at 45°C for 5h. It was filtered through celite and c...

Embodiment 2

[0098] Preparation of compound 2: Add compound 1 (50g, 352mmol) into toluene (400ml), slowly add potassium borohydride (16.2g, 300mmol) aqueous solution dropwise under nitrogen atmosphere at 0°C, and react at room temperature for 4h. The reaction was quenched by slow dropwise addition of acetic acid. The aqueous phase was extracted twice with toluene. The organic phases were combined, washed with 10% sodium bicarbonate solution, washed with brine, and concentrated in vacuo to obtain an orange oil, namely compound 2.

[0099] Yield is 78%, HPLC>99%, 1 H NMR (300MHz, CDCl 3 ): δ5.83(s,1H),4.73(s,2H),2.38(t,J 1 / 4 7.6Hz, 2H), 1.55–1.70(m, 2H), 1.00(t, J 1 / 4 7.0Hz, 3H).

[0100]The preparation of compound 3: put compound 2 (10.00g, 126mmol) and 80ml methanol into the hydrogenation kettle, put 10% palladium carbon (0.20g) under nitrogen atmosphere, nitrogen replacement 3 times, hydrogen replacement 3 times, 1.2MPa hydrogen pressure, Reaction at room temperature for 4h....

Embodiment 3

[0110] Preparation of compound 2: Add compound 1 (75g, 528mmol) into toluene (600ml), under nitrogen atmosphere at 0°C, slowly add an aqueous solution of lithium borohydride (9.5g, 450mmol) dropwise, and react at room temperature for 5h. The reaction was quenched by slow dropwise addition of acetic acid. The aqueous phase was extracted twice with toluene. The organic phases were combined, washed with 10% sodium bicarbonate solution, washed with brine, and concentrated in vacuo to obtain an orange oil, namely compound 2.

[0111] Yield is 71%, HPLC>99%, 1 H NMR (300MHz, CDCl 3 ): δ5.83(s,1H),4.73(s,2H),2.38(t,J 1 / 4 7.6Hz, 2H), 1.55–1.70(m, 2H), 1.00(t, J 1 / 4 7.0Hz, 3H).

[0112] The preparation of compound 3: put compound 2 (20.00g, 252mmol) and 160ml methanol into the hydrogenation kettle, put 5% palladium carbon (0.45g) under nitrogen atmosphere, nitrogen replacement 3 times, hydrogen replacement 3 times, 2.0MPa hydrogen pressure, Reaction at room temperature fo...

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PUM

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Abstract

The invention discloses a synthesis method of a brivaracetam intermediate and brivaracetam. The synthesis method of the brivaracetam intermediate includes the steps of stripping carboxyl, triggering ahydrogenation reaction, and then conducting chiral resolution to obtain the brivaracetam intermediate which can be used for further synthesis of brivaracetam, wherein specific information is shown inthe description. According to the synthesis method of the brivaracetam intermediate, applied raw materials are easy to obtain, reaction operation is simple, and reaction conditions are easy to control. The synthesis method of brivaracetam is high in yield, the purity of synthesized brivaracetam can reach 99% or above, and the overall synthesis cost is lower.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a buvaracetam intermediate and a synthesis method of buvaracetam. Background technique [0002] Epilepsy is a recurrent nervous system disease. The seizure is a syndrome of transient brain dysfunction caused by paroxysmal abnormal high-frequency discharges caused by excessive excitation of neurons in local lesions of the brain caused by different causes and spreading around. The report of the World Health Organization shows that the prevalence of epilepsy is between 5% and 11.2%. It is estimated that there are currently about 50 million active epilepsy patients in the world (referring to frequent epileptic seizures and need to maintain anti-epileptic treatment), and 30% of them are refractory . [0003] Brivaracetam is a new type of antiepileptic drug developed by UCB in Belgium. It has good efficacy and tolerance. derivative. Brivaracetam's binding force is 10 times that o...

Claims

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Application Information

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IPC IPC(8): C07D307/33C07C231/12C07C235/74
CPCC07B2200/07C07C51/60C07C231/12C07C2601/08C07D307/33C07C235/74C07C53/50
Inventor 王龙书卢增杰姜桥陈果李成波陈月嫦
Owner LIVZON NEW NORTH RIVER PHARMA
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