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Synthetic method of flupirtine maleate A-type crystal compound and midbody

A technology of flupirtine maleate and an intermediate, which is applied in the field of synthesis of flupirtine maleate A crystal form compounds, can solve the problem of inability to obtain high-purity A crystal form flupirtine maleate samples and the purification effect of impurities problems such as poor solubility and low solubility, to achieve the effect of reducing the types of residual solvents, reducing environmental pollution and reducing difficulty

Inactive Publication Date: 2013-05-08
吉林修正药业新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, during the recrystallization of isopropanol, the crystallization process takes a long time, and high-purity crystal form A flupirtine maleate samples cannot be obtained. At the same time, because the solubility is too small, its refining effect on impurities is very poor, and it is not easy to obtain Obtain flupirtine maleate product with low impurity

Method used

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  • Synthetic method of flupirtine maleate A-type crystal compound and midbody
  • Synthetic method of flupirtine maleate A-type crystal compound and midbody
  • Synthetic method of flupirtine maleate A-type crystal compound and midbody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Add 100g of 2-amino-3-nitro-6-chloropyridine, 87.5g of triethylamine, 20g of pyridine and 400ml of ethanol into a three-necked flask, heat to reflux under stirring, slowly add 80g of p-fluorobenzylamine dropwise, and react 3 After ~4 hours, after the reaction was completed, 500ml of purified water was added dropwise, slowly cooled to room temperature with stirring, filtered, and dried to obtain 2-amino-3-nitro-6-p-fluorobenzylaminopyridine.

[0062] Dissolve 41g of ferric chloride hexahydrate in 500ml of purified water, add 77.5g of activated carbon, heat to 50°C, add 30g of saturated sodium hydroxide solution (16g of sodium hydroxide dissolved in 14ml of water), stir at 60°C for 1 hour, and drop to room temperature, filtered, and dried to obtain ferric hydroxide / activated carbon catalyst.

[0063] Add 104.8g of 2-amino-3-nitro-6-p-fluorobenzylaminopyridine, 54.4g of ferric hydroxide / activated carbon catalyst into a 2L reaction flask, add 1600ml of 95% ethanol, and heat...

Embodiment 2

[0067] Add 98g of 2-amino-3-nitro-6-chloropyridine, 63.7g of triethylamine, 5g of pyridine and 200ml of ethanol into a three-necked flask, heat to reflux under stirring, slowly add 80g of p-fluorobenzylamine dropwise, and react 5 hours, after the reaction was completed, 500ml of purified water was added dropwise, slowly cooled to room temperature with stirring, filtered, and dried to obtain 2-amino-3-nitro-6-p-fluorobenzylaminopyridine.

[0068] Dissolve 41g of ferric chloride hexahydrate in 1000ml of purified water, add 300g of activated carbon, heat to 50°C, add 90g of saturated sodium hydroxide solution (48g of sodium hydroxide dissolved in 42ml of water), stir at 60°C for 1 hour, and cool to room temperature , filtered, and dried to obtain ferric hydroxide / activated carbon catalyst.

[0069] Add 104.8g of 2-amino-3-nitro-6-p-fluorobenzylaminopyridine, 80g of ferric hydroxide / activated carbon catalyst into a 2L reaction flask, add 2000ml of 95% ethanol, and heat to 70~90°C ...

Embodiment 3

[0073] Add 246g of 2-amino-3-nitro-6-chloropyridine, 254g of triethylamine and 800ml of ethanol into a three-necked flask, heat to reflux under stirring, slowly add 80g of p-fluorobenzylamine dropwise, react for 6 hours, and the reaction is complete Afterwards, 500 ml of purified water was added dropwise, slowly cooled to room temperature with stirring, filtered, and dried to obtain 2-amino-3-nitro-6-p-fluorobenzylaminopyridine.

[0074] Dissolve 41g of ferric chloride hexahydrate in 200ml of purified water, add 20g of activated carbon, heat to 50°C, add 45g of saturated sodium hydroxide solution (24g of sodium hydroxide dissolved in 21ml of water), stir at 60°C for 1 hour, and cool to room temperature , filtered, and dried to obtain ferric hydroxide / activated carbon catalyst.

[0075] Add 104.8g of 2-amino-3-nitro-6-p-fluorobenzylaminopyridine, 20g of ferric hydroxide / activated carbon catalyst into a 2L reaction flask, add 1200ml of 95% ethanol, and heat to 90°C under stirrin...

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Abstract

The invention discloses a synthetic method of flupirtine maleate A-type crystal compound and midbody. The synthetic method comprises the following steps of (1) synthetizing 2-amino-3-nitryl-6-p-fluorobenzyl aminopyridine by fluorobenzylamine and 2-amino-3-nitryl-6-chloropyridine organic alkali; (2) carrying out mixing and reduction reaction on the 2-amino-3-nitryl-6-p-fluorobenzyl aminopyridine, a catalyst and a solvent to obtain 2,3-diamido-6-p-fluorobenzyl aminopyridine; (3) reacting by the 2,3-diamido-6-p-fluorobenzyl aminopyridine, ethyl chloroformate and the organic alkali to obtain flupirtine, and continuing to add maleic acid aqueous solution to obtain flupirtine maleate-2-amino-6-(((4-fluorophenyl)methyl)amino)-3-pyridyl) ethyl carbamate maleate crude product; and (4) recrystallizing the 2-amino-6-(((4-fluorophenyl)methyl)amino)-3-pyridyl) ethyl carbamate maleate crude product by methanol or ethanol to obtain pure A-type crystal flupirtine maleate. The synthetic method has the beneficial effects that the water supply volume is reduced; the operation is safe; the reaction step is shortened; and the A-type flupirtine maleate is high in purity.

Description

technical field [0001] The invention belongs to the field of chemical medicines, and in particular relates to a synthesis method of a flupirtine maleate A crystal compound and a synthesis method of an intermediate. Background technique [0002] The chemical name of flupirtine maleate is 2-amino-6-(((4-fluorophenyl)methyl)amino)-3-pyridyl) ethyl carbamate maleate, as shown in the structural formula I show: [0003] [0004] I [0005] Flupirtine maleate is a new type of non-opioid central analgesic developed by AWD Company in Germany, which is easy to absorb when taken orally. Its mechanism of action is a selective neurogenic potassium channel opener with triple effects of analgesia, muscle relaxation and neuroprotection. Animal experiments have shown that flupirtine has analgesic effects in various pain model experiments such as mice, rats, hot plate method, and dental pulp electrical stimulation method. Its analgesic intensity (ED50) is weaker than methadone, bupreno...

Claims

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Application Information

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IPC IPC(8): C07D213/74C07D213/75
Inventor 林子琦阎君曹翠白冰王化录高仁东张启峰刑妍
Owner 吉林修正药业新药开发有限公司
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