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Synthetic method of perampanel, intermediate of perampanel and synthetic method of intermediate

A synthesis method and body technique, applied in the field of medicinal chemical synthesis, can solve problems such as difficult removal of raw materials and impurities, incomplete reaction, and low yield, so as to increase drug safety, reduce residue, improve reaction yield and product The effect of purity

Active Publication Date: 2014-08-13
ZHEJIANG YONGNING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The defect of this route is: used highly toxic tin reagent in the reaction process; Last step reaction is incomplete, it is difficult to remove raw material and impurity by the method for column chromatography or recrystallization; This step reaction introduces the catalyst containing Pd, because has Pd residue, the final product has low purity and low yield, and is not suitable for drug development

Method used

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  • Synthetic method of perampanel, intermediate of perampanel and synthetic method of intermediate
  • Synthetic method of perampanel, intermediate of perampanel and synthetic method of intermediate
  • Synthetic method of perampanel, intermediate of perampanel and synthetic method of intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Synthesis of 5-Acetyl-1,2-dihydropyridin-2-one

[0066]

[0067] Add 63ml of 35% hydrochloric acid solution to 155g of 2-chloro-5-acetylpyridine, and reflux at 100°C. After the reaction was complete, the pH of the reaction solution was adjusted to 7 to 8 with potassium carbonate solution, and 935 ml of THF and 32 g of brine were added under stirring. After the solution was separated, the aqueous phase was washed with 935 ml THF and 32 g brine, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in ethyl acetate and cooled to 0-5°C to crystallize. It was filtered and dried to obtain 130.1 g of the target compound (95% yield, 99.7% purity).

Embodiment 2

[0069] Synthesis of 5-Acetyl-1,2-dihydropyridin-2-one

[0070]

[0071] Add 32ml of 35% hydrochloric acid solution to 75.6g of 2-methoxy-5-acetylpyridine, and reflux at 100°C for reaction. After the reaction was complete, the pH of the reaction solution was adjusted to 7 to 8 with potassium carbonate solution, and 468 ml of THF and 16 g of brine were added under stirring. After the solution was separated, the aqueous phase was washed with 468 ml THF and 16 g brine, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in ethyl acetate and cooled to 0-5°C to crystallize. It was filtered and dried to obtain 56.2 g of the target compound (yield 82%, purity 99.0%).

Embodiment 3

[0073] Synthesis of 5-Acetyl-1,2-dihydropyridin-2-one

[0074]

[0075] Add 63ml of 35% hydrobromic acid solution to 155g of 2-chloro-5-acetylpyridine, and reflux at 100°C. After the reaction was complete, the pH of the reaction solution was adjusted to 7 to 8 with potassium carbonate solution, and 935 ml of THF and 32 g of brine were added under stirring. After the solution was separated, the aqueous phase was washed with 935 ml THF and 32 g brine, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in ethyl acetate and cooled to 0-5°C to crystallize. It was filtered and dried to obtain 117.8 g of the target compound (yield 86%, purity 99.3%).

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Abstract

The invention relates to the field of medicinal chemical synthesis and in particular relates to a synthetic method of perampanel, an intermediate of the perampanel and a synthetic method of the intermediate. The provided synthetic method of the perampanel comprises the following steps: carrying out a cyclization reaction on a compound shown in a formula V and a compound shown in a formula VI, so that a compound shown in a formula VII is obtained, wherein the formulas V, VI and VII are described in the specification, and R1 is alkyl amino, amino or alkoxy. The invention also aims at providing a synthetic method of an intermediate of the perampanel. In a synthetic process, phenyl, cyano phenyl and 2-pyridyl are sequentially introduced, compared with the prior art, a sequence of introducing substituent groups is changed, so that the problems that reaction yield is low and byproducts are many and can not be removed as 2-pyridyl is firstly introduced and then cyano phenyl is introduced can be solved; a route is changed, and a Pd containing catalyst is not used in reaction of the last step, so that Pd residue is reduced, drug safety is improved, and reaction yield and product purity are greatly improved, so that the synthetic method of the perampanel is applicable to industrial production.

Description

technical field [0001] The invention relates to the field of chemical synthesis of medicines, in particular to a method for synthesizing perampanel, an intermediate, and a method for synthesizing the intermediate. Background technique [0002] The chemical name of perampanel is: 3-(2-cyanophenyl)-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one, which The structural formula is as follows: [0003] [0004] Perampanel is an α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor antagonist developed by Eisai, which inhibits postsynaptic AMPA receptors Glutamate activity in the body, reducing neuronal hyperexcitability. The product was approved by the U.S. Food and Drug Administration (FDA) on October 22, 2012. Its trade name is Fycompa, which is used for the adjuvant treatment of partial seizures in patients with epilepsy over 12 years old, regardless of whether the patients are accompanied by secondary seizures or not. Full blown. [0005] Patent US20070142...

Claims

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Application Information

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IPC IPC(8): C07D213/64
CPCC07D213/64
Inventor 叶天健郁光亮马苏旺
Owner ZHEJIANG YONGNING PHARMA
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