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High efficient synthesis method of flupirtine maleate

A technology of flupirtine maleate and a synthesis method is applied in the separation/purification of carboxylic acid compounds, the preparation of carboxylate salts, organic chemistry, etc., can solve problems such as increasing industrial production costs, and achieves easy control of reaction conditions and process. Simple route, high purity effect

Inactive Publication Date: 2017-02-15
合肥美利康医药技术股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the process of preparing the key intermediate 2-amino-3-nitro-6-chloropyridine, because the ammonolysis agent (ammonia gas or ammonia water) cannot be quantitatively controlled, it is very easy to react excessively to produce 2,6-diamino-3 -Nitropyridine needs to be further purified and processed in subsequent steps and quality control is carried out to the process impurities that are subsequently produced by 2,6-diamino-3-nitropyridine, which increases the industrial production cost of the whole route, which It is the biggest problem in the process of preparing flupirtine maleate

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] A highly efficient synthetic method of flupirtine maleate, comprising the following steps:

[0020] (1) Add di-tert-butyl dicarbonate to 1L of ethanol, then add 4-dimethylaminopyridine and 0.5mol 2-amino-3-nitro-6-chloropyridine, stir well, and then Continuously add 0.9mol of p-fluorobenzylamine dropwise, heat and reflux at 80°C for 5h, after the reaction is completed, add deionized water to the reaction solution, a large amount of solid precipitates, and filter to obtain 2-amino-3-nitro-6-p-fluoro Benzylaminopyridine;

[0021] (2) Add 2-amino-3-nitro-6-p-fluorobenzylaminopyridine to 1L of ethanol, add 0.05mol palladium chloride, stir well and add 4mol hydrazine hydrate, then feed inert gas and heat up to 70 °C, heated to reflux for 90 minutes to obtain 2,3-diamino-6-p-fluorobenzylaminopyridine;

[0022] (3) Under the protection of nitrogen, the reaction solution in step (2) was lowered to room temperature, 1.1mol ethyl chloroformate was added, and reacted at 58° C. f...

Embodiment 2

[0026] A highly efficient synthetic method of flupirtine maleate, comprising the following steps:

[0027] (1) Add di-tert-butyl dicarbonate in 1L of isopropanol, then add sodium thiomethyldisilazide and 0.5mol 2-amino-3-nitro-6-chloropyridine, after stirring evenly, in Under the condition of stirring, 0.75mol of fluorobenzylamine was continuously added dropwise, heated and refluxed at 80°C for 6 hours, after the reaction was completed, deionized water was added to the reaction solution, a large amount of solid was precipitated, and 2-amino-3-nitro- 6-p-fluorobenzylaminopyridine;

[0028] (2) Add 2-amino-3-nitro-6-p-fluorobenzylaminopyridine to 1L of isopropanol, add 0.25mol of palladium chloride, stir well, add 2mol of hydrazine hydrate, then pass in an inert gas and heat up Heat to 80°C and reflux for 60 minutes to obtain 2,3-diamino-6-p-fluorobenzylaminopyridine;

[0029] (3) Under the protection of nitrogen, the reaction solution in step (2) was lowered to room temperatu...

Embodiment 3

[0033] A highly efficient synthetic method of flupirtine maleate, comprising the following steps:

[0034] (1) Add di-tert-butyl dicarbonate to a mixed solution of 1L ethanol and methanol, then add diisopropylethylamine and 0.5mol 2-amino-3-nitro-6-chloropyridine, and stir evenly, Continuously add 0.8 mol of p-fluorobenzylamine dropwise under the condition of stirring, heat and reflux at 70°C for 8 hours, after the reaction is completed, add deionized water to the reaction solution, a large amount of solids are precipitated, and filtered to obtain 2-amino-3-nitro -6-p-fluorobenzylaminopyridine;

[0035] (2) Add 2-amino-3-nitro-6-p-fluorobenzylaminopyridine to a mixed solution of 1L ethanol and methanol, add 0.1mol palladium chloride, stir well, add 4mol hydrazine hydrate, and then pass into an inert Gas, heated to 80°C, heated to reflux for 60 minutes to obtain 2,3-diamino-6-p-fluorobenzylaminopyridine;

[0036] (3) Under the protection of nitrogen, the reaction solution in ...

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PUM

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Abstract

The invention provides a high efficient synthesis method of flupirtine maleate, and relates to the technical field of drug preparation. According to the synthesis method, flupirtine maleate is taken as the raw material; flupirtine maleate is obtained after steps of condensation reactions, reduction reactions (in the presence of a reducing agent), ethyl chloroformate acylation reaction, and maleic acid salt forming reactions; during the synthesis process, the yield of product can reach 93%, the product purity is high, the generation of byproducts is avoided, moreover, the technology route is simple, the reaction conditions are easy to control, better reaction conditions are provided for industrial production, the equipment requirements are largely reduced, and the synthesis method can be better applied to the industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a high-efficiency synthesis method of flupirtine maleate. Background technique [0002] Flupirtine maleate is a central non-opioid analgesic, which is a triaminopyridine compound, and its mechanism of action is: flupirtine maleate is a selective central potassium channel opener, which also has Indirect aspartic acid (NMDA) receptor antagonist properties, can activate G-protein coupled receptors to stimulate the potassium channel of nerve cells, resulting in hyperpolarization of nerve cell membranes and decreased excitability of neurons, making rest Stabilize the nerve cell membrane to achieve the purpose of analgesia. Its analgesic effect does not depend on any central opioid, is not antagonized by naloxone, does not induce any dependence or does not require an increase in dose to maintain clinical efficacy, and does not have any affinity with known opioid receptors...

Claims

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Application Information

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IPC IPC(8): C07D213/75C07C57/145C07C51/41C07C51/43
CPCC07D213/75
Inventor 赵冬生方从彬方存杰孙明哲孙延标徐奎
Owner 合肥美利康医药技术股份有限公司
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