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A kind of convenient preparation method of perampanel

A pyridine and compound technology, which is applied in the field of simple preparation of perampanel, can solve the problems of high environmental hazard, complicated operation, low yield and the like, and achieves high reaction atom economy, high yield and purity, and simple process operation. Effect

Active Publication Date: 2020-07-17
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The raw materials used in the above two routes are 2,5-dibromopyridine, 2-chloro-5-acetylpyridine or 2-methoxy-5-acetylpyridine, phenylboronic acid, 2-cyanophenylboronic acid ester, palladium acetate High price, not easy to obtain, the reaction route involves precious metal catalysis many times, and the residue of heavy metal is high
The reaction route is long, the operation is cumbersome, the amount of waste water is large, and the reaction atom economy is poor
In addition, the 2-pyridine tri-tert-butyltin used in route 2 is highly toxic and has poor safety operability
To sum up, the existing synthetic technology has problems of cumbersome operation, high cost, high heavy metal residue, low yield, and serious environmental hazards.

Method used

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  • A kind of convenient preparation method of perampanel
  • A kind of convenient preparation method of perampanel
  • A kind of convenient preparation method of perampanel

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Example 1: 3-Anilino-2-(pyridin-2-yl)propionitrile (II 1 , L=CN) Preparation

[0070] Into a 500 ml four-necked flask connected with a stirring, thermometer and reflux condenser, add 50 g methanol, 80 g water, 11.8 g (0.1 mol) pyridine-2-acetonitrile, 5.0 g (0.17 mol) paraformaldehyde, 10.0 G (0.11 mol) of aniline, 0.2 g of 30% hydrochloric acid, stirred at 70-72°C for 5 hours, cooled to 20-25°C, extracted with dichloromethane 3 times, 50 g of dichloromethane each time, combined the dichloromethane phases, 10.0 g of 5% sodium bicarbonate aqueous solution was washed once, and the solvent was recovered by distillation to obtain 22.1 g of light yellow viscous liquid 3-anilino-2-(pyridin-2-yl)propionitrile (Ⅱ) 1 ), the yield is 99.1%, and the gas phase purity is 99.8%.

Embodiment 2

[0071] Example 2: 3-Anilino-2-(pyridin-2-yl)propionitrile (II 1 , L=CN) Preparation

[0072] Into a 500 ml four-necked flask connected with a stirring, thermometer, and reflux condenser, add 20 g of ethanol, 70 g of water, 11.8 g (0.1 mol) of pyridine-2-acetonitrile, 20.0 g (0.2 mol) of 30% formaldehyde aqueous solution, 10.0 g (0.11 mol) of aniline, 0.1 g of 70% phosphoric acid, stirred at 80~82℃ for 4 hours, cooled to 20~25℃, extracted with dichloromethane 3 times, 50 g of dichloromethane each time, combined the dichloromethane phases , 10.0 g of 5% sodium bicarbonate aqueous solution was washed once, and the solvent was recovered by distillation to obtain 21.9 g of pale yellow viscous liquid 3-anilino-2-(pyridin-2-yl)propionitrile (Ⅱ) 1 ), the yield is 98.2%, and the gas phase purity is 99.9%.

Embodiment 3

[0073] Example 3: N-phenyl-N-[2-cyano-2-(pyridin-2-yl)]ethyl-2-cyanobenzeneacetamide (IV 1 ) Preparation

[0074] Into a 500 ml four-necked flask connected with a stirring, thermometer and distillation system, add 100 g of N,N-dimethylformamide and 22.5 g (0.1 mole) of 3-anilino-2-(pyridin-2-yl) Propionitrile (Ⅱ 1 ), 19.3 g (0.11 mol) of methyl 2-cyanophenylacetate, reacted at 100-105°C for 4 hours, and the removed methanol is distilled off at the same time, and the gas phase detection reaction is completed. N,N-dimethylformamide was recovered by distillation under reduced pressure, the temperature was lowered to 50-60°C, 50 g of methyl tert-butyl ether was added, the temperature was reduced to room temperature, and the filter cake was washed with 20 g of methyl tert-butyl ether and dried. 34.3 g of N-phenyl-N-[2-cyano-2-(pyridin-2-yl)]ethyl-2-cyanobenzeneacetamide (IV 1 ), the yield is 93.5%, and the gas phase purity is 99.9%.

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Abstract

The invention relates to a simple preparation method of perampanel. The method comprises: (1) carrying out an amidation reaction on a compound represented by a formula II and a compound represented bya formula III in a solvent or under a solvent-free condition to prepare a compound represented by a formula IV; and (2) carrying out condensation on the compound represented by the formula IV and a methylenenation reagent in a solvent in the presence of a catalyst to obtain a compound represented by a formula V, and removing hydrogen cyanide or hydrogen chloride under the action of an alkaline reagent to form a ring so as to prepare perampanel. According to the present invention, the method has advantages of cheap and easily available raw materials, simple process operation, high reaction selectivity of the unit, high yield and high purity of the product, less three-waste, high reaction atom economy and environmental protection.

Description

Technical field [0001] The invention relates to a simple preparation method of perampanel and belongs to the technical field of medicinal chemistry. Background technique [0002] Perampanel (I), English name Perampanel, trade name Fycompa, developed and listed by Eisai company. Perampanel is the first and only non-competitive AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole acid) receptor antagonist approved by the FDA. It inhibits the post-synaptic AMPA receptor antagonist. The body's glutamate activity reduces the excessive excitement of neurons and takes effect. Approved by the U.S. Food and Drug Administration (FDA) for marketing in October 2012, clinically used for partial seizures of 12 years and older with or without secondary generalized seizures, as well as primary generalized seizures Adjuvant treatment of tonic-clonic seizures. Perampanel, the chemical name is 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one, chemical structure As follows: [0003] [0...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/64
CPCC07D213/64
Inventor 戚聿新鞠立柱张明峰
Owner XINFA PHARMA
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