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A kind of method of one-pot synthetic flupirtine maleate

A technology of flupirtine maleate and maleic acid, which is applied in the field of chemical drug preparation, can solve the problems of high preparation cost, high cost, and impossibility of continuous operation, so as to reduce production cost and improve product quality and yield , The effect of simplifying the operation process

Active Publication Date: 2017-09-29
江苏海岸药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Compared with the above patents, the patent CN201110112934.0 uses 2,6-dichloro-3-nitropyridine as a raw material, and it is easy to cause excessive reaction in the process of synthesizing the intermediate of 2-amino-3-nitro-6-chloropyridine. The product 2,6-diamino-3-nitropyridine must be purified to the 2-amino-3-nitro-6-chloropyridine obtained by ammonolysis before it can be put into the next step reaction, so the whole process route cannot be done continuous operation
Patents CN201210381705.3, CN201310292276.7 and CN201410344088.9 use 2-amino-3-nitro-6-chloropyridine as raw material, although the problem of generating impurity 2,6-diamino-3-nitropyridine is solved, it can Realize continuous operation, but 2-amino-3-nitro-6-chloropyridine is obviously more expensive than 2,6-dichloro-3-nitropyridine, and the preparation cost is higher

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Add 2,6-dichloro-3-nitropyridine (5kg, 25.9mol) into a reaction kettle filled with 50L of methanol, stir at 50-60°C until completely dissolved, then feed ammonia gas for 10 hours, monitor by TLC The reaction was stopped when the reaction of the raw materials was complete, and a yellow suspension was generated. After the reaction was cooled to room temperature, nitrogen gas was passed into the reaction solution to discharge the remaining ammonia gas in the reaction kettle, and p-fluorobenzaldehyde (3.5kg, 28.5mol) was slowly added dropwise under the protection of nitrogen gas, and the reaction was refluxed for about 8 hours, monitored by TLC Stop the reaction when the reaction of raw materials is complete. After the reaction solution was cooled to room temperature, 400 g of 10% Pd / C was added, and hydrogen gas was introduced at 25° C. for 20 hours. TLC monitored that the reaction of the raw materials was complete, and then stopped the reaction. Under the protection of n...

Embodiment 2

[0024] Add 2,6-dichloro-3-nitropyridine (5kg, 25.9mol) into a reaction kettle filled with 40L of ethanol, stir at 50-60°C until completely dissolved, and react with ammonia gas for 8 hours, monitored by TLC The reaction was stopped when the reaction of the raw materials was complete, and a yellow suspension was generated. After the reaction was cooled to room temperature, nitrogen gas was introduced into the reaction solution to discharge the remaining ammonia gas in the reaction kettle, and p-fluorobenzaldehyde (3.8kg, 31.1mol) was added dropwise under the protection of nitrogen gas, and the reaction was refluxed for about 4 hours, and the raw materials were monitored by TLC. Stop the reaction when the reaction is complete. After the reaction solution was cooled to room temperature, 500 g of 10% Pd / C and 9.8 kg of ammonium formate were added, and the reaction was continued under nitrogen protection under reflux for about 14 hours. TLC monitored that the reaction of the raw ma...

Embodiment 3

[0026]Add 2,6-dichloro-3-nitropyridine (5kg, 25.9mol) into a reaction kettle filled with 60L of isopropanol, stir at 50-60°C until completely dissolved, then pass through ammonia gas for 8 hours, TLC monitors that the reaction of the raw materials is complete and the reaction is stopped, and a yellow suspension is generated. After the reaction was cooled to room temperature, nitrogen gas was passed into the reaction solution to discharge the remaining ammonia gas in the reaction kettle, and p-fluorobenzaldehyde (3.5kg, 28.5mol) was added dropwise under the protection of nitrogen gas, and the reaction was refluxed for about 5 hours, and the raw materials were monitored by TLC. Stop the reaction when the reaction is complete. After the reaction solution was cooled to room temperature, 450 g of 10% Pd / C and 9.6 kg of ammonium formate were added. Under the protection of nitrogen, the reaction was continued under reflux for about 14 hours. TLC monitored that the reaction of the raw...

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Abstract

The invention discloses a method for synthesizing flupirtine maleate by use of a one-pot process. The method comprises the steps of taking 2,6-dichloro-3-nitropyridine as a starting material and performing ammonolysis to obtain a key intermediate 2,6-diamino-3-nitropyridine, and then condensing the key intermediate with p-fluorobenzaldehyde and performing Pd / C catalytic hydrogenation reduction, ethyl chloroformate acylation and maleic acid salifying to obtain the flupirtine maleate; the selected process route is simple and convenient to operate; the various steps are not separated and one-pot process production is realized; as a result, the production cost is effectively reduced, and the yield and the product purity are improved; in short, the method is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the technical field of chemical medicine preparation, and in particular relates to a method for synthesizing flupirtine maleate in one pot. Background technique [0002] Flupirtine maleate, chemical name: 2-amino-3-acylethoxyamino-6-p-fluorobenzylpyridine maleate, its structural formula is: . [0003] Flupirtine maleate is a central non-opioid analgesic developed by German AWD company. It is a triaminopyridine compound. Its mechanism of action is: flupirtine maleate is a selective central potassium ion Channel opener, which also has indirect aspartate (NMDA) receptor antagonist properties, can activate G-protein coupled receptors to stimulate potassium ion channels in nerve cells, resulting in hyperpolarization of nerve cell membranes and neuronal excitation The sex is reduced, which stabilizes the resting nerve cell membrane to achieve the purpose of analgesia. Its analgesic effect does not depend on any central opioid, i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/75
CPCC07D213/75
Inventor 侯振友杨尚彦温利民曹德峰陆良喆许清政宋利
Owner 江苏海岸药业有限公司
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