Synthetic method of A-803467 key intermediate

An intermediate and key technology, applied in the field of organic synthesis, can solve the problems of low atom utilization rate, use of toxic and harmful raw materials, harsh reaction conditions, etc., and achieve extremely easy control of reaction conditions, improve the quality of diazonium salts, and simplify the reaction operation. Effect

Inactive Publication Date: 2013-08-28
ZHENGZHOU UNIV
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  • Abstract
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Problems solved by technology

[0010] This type of reaction prepares the yield of 5-(4-chlorophenyl)-2-furancarboxylic acid to be 22-77%, and there are many defects in the reaction: many raw materials used are not produced in the domestic market, and imported products are expensive; palladium complexes The catalyst is more expensive; a small amount of oxygen in the system during the reaction will deactivate the palladium catalyst, and N 2 Or Ar protection makes the system strictly anaerobic, making the reaction conditions harsh and difficult to control
[0020] Visible, there are weak points in the preparation method of existing 5-(4-chlorophenyl)-2-furan carboxylic acid, such as expensive raw material reagents, high preparation cost, low atom utilization rate, problems such as using toxic and harmful raw materials, urgently need Development of a new method for the synthesis of 5-(4-chlorophenyl)-2-furancarboxylic acid that is environmentally friendly, highly atom-economical, and easy to operate

Method used

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  • Synthetic method of A-803467 key intermediate
  • Synthetic method of A-803467 key intermediate
  • Synthetic method of A-803467 key intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Add 4.6g (0.041mol) of furanic acid, 12.76g (0.1mol) of p-chloroaniline, 40ml of acetone, 3.5g of CuCl in the three-necked flask 2 2H 240ml of aqueous solution of O, stirred, and slowly dripped 5ml of tert-butyl nitrite into the system with a constant pressure funnel, and controlled the rate of addition so that the temperature of the system did not exceed 10°C. : ethanol: sherwood oil: 4: 1) tracking to complete reaction. There is red insoluble matter in the system, open the door overnight, filter with suction, extract the filtrate under reduced pressure for 20 minutes, then extract with ethyl acetate, take the upper organic phase, and dissolve the obtained red filter cake in the organic phase, use Extract with an appropriate amount of saturated sodium bicarbonate, separate liquids while hot, wash the aqueous phase with 10% hydrochloric acid aqueous solution until acidic, a large amount of white solid appears in the system, filter with suction, dry to a constant weight...

Embodiment 2

[0037] Add 2.3g (0.020mol) of furanic acid, 12.76g (0.1mol) of p-chloroaniline, 40ml of ethanol, 1.75g ​​of CuCl in a three-necked flask 2 2H 2 40ml of aqueous solution of O, stir, slowly drop 5ml of isopropyl nitrite solution into the system with a constant pressure funnel, control the rate of addition so that the system temperature does not exceed 20°C, after the addition is completed, keep the reaction for 5h, TLC (developing agent: Ethanol:petroleum ether: 4:1) track until the reaction is complete. There is red insoluble matter in the system, open the door overnight, filter with suction, extract the filtrate under reduced pressure for 20 minutes, then extract with ethyl acetate, take the upper organic phase, and dissolve the obtained red filter cake in the organic phase, use Extract with an appropriate amount of saturated sodium bicarbonate, separate liquids while hot, wash the aqueous phase with 10% hydrochloric acid aqueous solution until acidic, a large amount of white...

Embodiment 3

[0039] In a 250ml three-necked flask, add 7.8g (0.07mol) of furanic acid, 12.76g (0.1mol) of p-chloroaniline, 50ml of acetone, 6g of CuBr 2 40ml of aqueous solution, stirred, and slowly dripped 10ml of tert-butyl nitrite into the system with a constant pressure funnel, and controlled the rate of addition so that the system temperature did not exceed 30°C. Ethanol:petroleum ether: 4:1) track until the reaction is complete. There is red insoluble matter in the system, open the door overnight, filter with suction, extract the filtrate under reduced pressure for 20 minutes, then extract with ethyl acetate, take the upper organic phase, and dissolve the obtained red filter cake in the organic phase, use Extract with an appropriate amount of saturated sodium bicarbonate, separate liquids while hot, wash the aqueous phase with 10% hydrochloric acid aqueous solution until acidic, a large amount of white solid appears in the system, filter with suction, dry to a constant weight of 12.1...

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Abstract

The invention discloses a preparation method of a key intermediate 5-(4-chlorphenyl)-2-furoic acid of a Nav1.8 selective retardant dosage form tool medicine A-803467, relates to a method for preparing 5-(4-chlorphenyl)-2-furoic acid by adopting alkyl nitrite as a diazotization reagent and belongs to the technical field of organic synthesis. The preparation method comprises the following steps of: dissolving parachloroaniline and furoic acid into an organic solvent, slowly dropwise adding alkyl nitrite into a mixed liquor in the presence of a catalyst, keeping a system temperature to be 0-40 DEG C, and carrying out a diazotization reaction and a Meerwein condensation reaction to obtain 5-(4-chlorphenyl)-2-furoic acid. By adopting the preparation method, 5-(4-chlorphenyl)-2-furoic acid can be prepared with high economy and high yield, and yield can be 78%; and reaction selectivity is high, conditions are mild, aftertreatment is simple, and the preparation method is environmentally friendly and applicable to large-scale preparation.

Description

technical field [0001] The invention relates to a preparation method of the key intermediate 5-(4-chlorophenyl)-2-furancarboxylic acid of Nav1.8 selective blocker dosage form tool drug A-803467, belonging to the technical field of organic synthesis. Background technique [0002] A-803467 is a furoyl small molecule Nav1.8 selective blocker developed by Abbott in 2008. It is a tool drug for the research of drugs based on sodium channel blockade, especially in the research of neuropathic pain drugs. It has significant analgesic effects in multiple acute and chronic pain models with less off-target effects. The compound has been commercialized at present, and there is no domestic production, and the imported product is expensive. [0003] [0004] [0005] 5-(4-Chlorophenyl)-2-furancarboxylic acid is the key intermediate for the preparation of A-803467, and is also widely used in various innovative drug development and pesticide research, such as Ca-based 2+ Induced mitoch...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/68
Inventor 李雯王盼盼吴桂英刘春霞张华张文亚鲁鹏任鹏飞
Owner ZHENGZHOU UNIV
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