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The preparation method of perampanel intermediate

An intermediate and pyridine technology, which is applied in the field of preparation of the pyrampanel intermediate 5--2-pyridone, can solve the problems of unfavorable industrial production, complicated operation, and few preparation methods, and achieve novel process routes and simplified processes The effect of operation and shortening the production cycle

Active Publication Date: 2017-04-05
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among the synthesis methods reported in the literature above, method 1 requires the use of butyllithium to prepare compound 13, which requires ultra-low temperature reaction (<-70°C), or the use of highly toxic tin reagents, which also lead to complicated operations and are not conducive to industrial production.
In the second method, highly toxic tin reagents are also used, and methyl protection and deprotection are required, which prolongs the preparation process and increases the production cycle, which is not conducive to industrial production
[0009] 5-(pyridin-2-yl)-2(1H)-pyridone, as an important intermediate of perampanel, is not sold in the market, and there are few existing preparation methods, so it is urgent to find a method with low production cost and simple process. , a new process suitable for industrial production

Method used

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  • The preparation method of perampanel intermediate
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  • The preparation method of perampanel intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Example 1: Synthesis of 6-chloronicotinyl chloride (compound BL01)

[0026] Add 1.4kg of 6-chloronicotinic acid into 7L of toluene, stir and disperse. Then add 4.2Kg of thionyl chloride, heat to 80-90°C, and react for 10 hours. After the reaction was complete, it was concentrated to dryness under reduced pressure to obtain compound BL01, which was kept for future use.

Embodiment 2

[0027] Example 2: Synthesis of N-methoxy-N-methyl-6-chloronicotinamide (compound BL02)

[0028] 1.5 kg of dimethylhydroxylamine hydrochloride was dispersed in 10 L of dichloromethane, and the 6-nicotinoyl chloride obtained in Example 1 was slowly added dropwise into the reaction system, and reacted for 1 hour. After the reaction was completed, it was washed with water and saturated sodium chloride successively. It was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.65kg of compound BL02.

[0029] 1 H NMR (CDCl 3 ,δppm):3.39(s,3H),3.73(s,3H),7.32-7.37(m,1H),7.73-7.80(m,1H),8.59-8.61(m,1H); MS(ES+)m / z 210.6.

Embodiment 3

[0030] The synthesis of embodiment 3,2-chloro-5-acetylpyridine (compound BL03)

[0031] 1.6kg of compound BL02 was dispersed in 8L of tertiary methyl ether, and 3L of methylmagnesium chloride solution was added dropwise. React for 1 hour. Stop the reaction, pour the reaction solution into 10L of water, and extract with dichloromethane. The organic phase was washed with water and saturated sodium chloride in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.2 kg of compound BL03.

[0032] 1 H NMR (CDCl 3 , δppm): 3.98 (s, 3H), 7.34-7.39 (m, 1H), 7.65-7.76 (m, 1H), 8.59-8.61 (m, 1H); MS (ES+) m / z 157.1.

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Abstract

The invention relates to a preparation method of a perampanel intermediate 5-(pyridin-2-yl)-2(1H)-pyridinone which has the advantages of simplicity in operation, easily available raw materials, low production cost and good quality of the product and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical production, and in particular relates to a preparation method of a perampanel intermediate 5-(pyridin-2-yl)-2(1H)-pyridone. Background technique [0002] Perampanel, the chemical name is 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate, It is an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (α-amino-3-hydroxy-5-methyl-4-isoxa-zolep-propionate acid, AMPA) receptor antagonist , which reduces neuronal hyperexcitation by inhibiting postsynaptic AMPA receptor glutamate activity. This is the first anti-epileptic drug with this mechanism of action approved by the FDA. It is clinically used as an adjuvant treatment for patients with partial seizures of epilepsy aged 12 and above. Food and Drug Administration (FDA) approved marketing, trade name Fycompa. [0003] The literature reports the following two synthetic methods of perampanel: [0004] Method 1: 2,5-dibromopy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/64
CPCC07D213/61C07D213/64
Inventor 包金远徐峰吴启光蒋玉伟张孝清
Owner NANJING HUAWE MEDICINE TECH DEV