Method of synthesizing retigabine

A retigabine and condensation reaction technology, which is applied in the field of synthesizing retigabine, can solve the problems of dangerous use and high toxicity, and achieve the effects of cost reduction, yield improvement, and simple route operation

Inactive Publication Date: 2014-02-12
BEIJING BEILU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthetic route reported in Chinese patent CN101921195 uses hydrazine hydrate, which is highly toxic and dangerous to use

Method used

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  • Method of synthesizing retigabine
  • Method of synthesizing retigabine
  • Method of synthesizing retigabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: Preparation of 2-amino-4-(4-fluorobenzylamino)-1-nitrobenzene

[0033] Add 20g of 2-nitro-1,4-phenylenediamine into a 500mL reaction flask, add 280mL of toluene, stir, then add 17.8g of 4-fluorobenzaldehyde, heat to reflux for 6-10h to separate water. The complete reaction of 2-nitro-1,4-phenylenediamine was detected by TLC as the end point of the reaction. After cooling down to room temperature, continue to stir for 3 hours, filter and dry to obtain 4.62Kg of 2-amino-5-[(4-fluorophenylmethylene)amino]-1-nitrobenzene with a yield of 91.2%.

[0034] Take 20g of 2-amino-5-[(4-fluorophenylmethylene)amino]-1-nitrobenzene and add it to a 500mL reaction flask, add 160mL of tetrahydrofuran, 40mL of ethanol, stir, and add sodium borohydride 5.9 g, react at 50°C for 5-8h after the addition. TLC detected that the reaction of 2-amino-5-[(4-fluorophenylmethylene)amino]-1-nitrobenzene was complete as the end point of the reaction. Evaporate the solvent, add 100mL ethyl...

Embodiment 2

[0035] Example 2: Synthesis of retigabine N-(2-amino-4-(4-fluorobenzylamino)phenyl) ethyl carbamate Take 4g of 10% Pd / C (water content 50%) to 500mL reaction Add 400 mL of ethanol and 20 g of 2-amino-4-(4-fluorobenzylamino)1-nitrobenzene into the bottle, and stir. Under normal pressure, hydrogen gas was introduced and heated to 40-60°C for about 8 hours. TLC detection of 2-amino-4-(4-fluorobenzylamino) 1-nitrobenzene completely reacted as the end point of the reaction. The reaction solution was filtered after cooling down to room temperature. The filtrate was added to a 500 mL three-necked flask, and 12.4 g of diethyl pyrocarbonate was added dropwise at a temperature controlled at 12°C. The end point of the raw material reaction was detected by TLC, and stirring was continued for 1 h. Cool down to below 10°C and stir for 3 hours, filter, wash the filter cake 3 times with ice ethanol, 500 mL each time, and dry to obtain a crude product. The crude product was recrystallized f...

Embodiment 3

[0036] Example 3: Synthesis of retigabine N-(2-amino-4-(4-fluorobenzylamino)phenyl) ethyl carbamate Take 4g of 10% Pd / C (50% water content) into 500mL reaction Add 400 mL of isopropanol and 20 g of 2-amino-4-(4-fluorobenzylamino)1-nitrobenzene into the bottle, and stir. Under normal pressure, hydrogen gas was introduced and heated to 40-60°C for about 8 hours. TLC detection of 2-amino-4-(4-fluorobenzylamino) 1-nitrobenzene completely reacted as the end point of the reaction. The reaction solution was filtered after cooling down to room temperature. The filtrate was added to a 500 mL three-necked flask, and 12.4 g of diethyl pyrocarbonate was added dropwise at a temperature of 15°C. The end point of the raw material reaction was detected by TLC, and stirring was continued for 1 h. Cool down to below 10°C and stir for 3 hours, filter, wash the filter cake 3 times with ice ethanol, 500 mL each time, and dry to obtain a crude product. The crude product was recrystallized from t...

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Abstract

The invention discloses a method of synthesizing retigabine. The method comprises the following steps: carrying out catalytic hydrogenation on a raw material 2-amino-4-(4-florobenzyl amino)-1-nitrobenzene in a reaction solvent by taking Pd/C as a catalyst; filtering a reaction liquid; and adding diethyl pyrocarbonate into the filtrate to carry out condensation reaction to obtain retigabine. The method disclosed by the invention connects Pd/C catalytic hydrogenation and acylation in series, so that the method is simple in line operation, reduces the cost and improves the safety. The yield of the method disclosed by the invention for synthesizing retigabine reaches 48% which is remarkably improved compared with that reported at present, so that the method has a good industrial application prospect.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a method for synthesizing retigabine. Background technique [0002] Retigabine, chemical name: ethyl N-(2-amino-4-(4-fluorobenzylamino)phenyl)carbamate, its structural formula is as follows: [0003] [0004] Retigabine is an antiepileptic drug with a novel mechanism of action. Retigabine (retigabine) was first developed by Valeant Pharmaceuticals and launched in the European Union in March 2011. It is currently the only broad-spectrum antiepileptic drug that works by promoting the opening of potassium channels. Studies have confirmed that the antiepileptic effect of retigabine is related to voltage-gated potassium ion channels (KCNQs), which mainly act on KCNQ2 / 3 channels to regulate M-type potassium currents ([Ik(M)]). The antiepileptic mechanism of retigabine determines that its action characteristics are different from other antiepileptic drugs. It does not act on neuronal N-meth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/28C07C269/04
Inventor 牛丽萍宗利武杰
Owner BEIJING BEILU PHARM CO LTD
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