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Rivastigmine hydrogen tartrate preparation method and application thereof

A technology of flupirtine maleate and pyridine is applied in the preparation field of flupirtine maleate, can solve the problems of high synthesis cost, difficult to control synthesis conditions, etc., achieves low production cost, strong controllability of preparation process, The effect of mild reaction conditions

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

[0005] The general synthesis of flupirtine maleate bulk drug requires high-pressure hydrogenation, acylation, catalysis and other steps, the synthesis conditions are difficult to control, the synthesis cost is relatively high, and its crystal form needs to be controlled

Method used

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  • Rivastigmine hydrogen tartrate preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] A preparation method of flupirtine maleate includes the following steps:

[0025] A. Synthesis of 2-amino-3-nitro-6-(p-fluorobenzylamino)pyridine

[0026] Add 10 kg of isopropanol and 3.2 kg of p-fluorobenzylamine into the reaction kettle, stir, add 4 kg of 2-amino-3-nitro-6-chloropyridine and 12.8 kg of triethylamine, and reflux at 85-110°C for reaction 5- After 6h, cooling to 60℃, sampling to monitor the reaction is complete, adding 1kg sodium hydroxide solution, concentrating under reduced pressure until no solvent flows out, centrifuging to obtain a solid, and drying to obtain 2-amino-3-nitro-6-(p-fluorobenzyl) Amino) pyridine;

[0027] B. Synthesis of 2-amino-3-carbamic acid ethyl ester-6-(p-fluorobenzylamino)pyridine

[0028] Add 24.3kg of isopropanol, 5.8kg of 2-amino-3-nitro-6-(p-fluorobenzylamino)pyridine and 0.5kg of activated carbon to impregnate palladium salt in the autoclave, seal the autoclave, and then pass in argon and hydrogen. , Where the hydrogen pressure ...

Embodiment 2

[0032] A preparation method of flupirtine maleate includes the following steps:

[0033] A. Synthesis of 2-amino-3-nitro-6-(p-fluorobenzylamino)pyridine

[0034] Add 10kg of isopropanol and 6.8kg of p-fluorobenzylamine into the reaction kettle, stir, add 4kg of 2-amino-3-nitro-6-chloropyridine and 10kg of triethylamine, reflux for 5-6h at 85-110℃ After cooling to 60℃, sampling and monitoring the reaction is complete, add 1kg sodium hydroxide solution, concentrate under reduced pressure until no solvent flows out, centrifuge to obtain a solid, and dry to obtain 2-amino-3-nitro-6-(p-fluorobenzylamine) 基)pyridine;

[0035] B. Synthesis of 2-amino-3-carbamic acid ethyl ester-6-(p-fluorobenzylamino)pyridine

[0036] Add 24.3kg of isopropanol, 5.8kg of 2-amino-3-nitro-6-(p-fluorobenzylamino)pyridine and 0.5kg of activated carbon to impregnate palladium salt in the autoclave, seal the autoclave, and then pass in argon and hydrogen. , Where the hydrogen pressure is 5.0~8.0Mpa; the hydrogenat...

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PUM

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Abstract

The invention relates to the technical field of medicinal chemistry production, in particular to a rivastigmine hydrogen tartrate preparation method and an application thereof. To be specific, rivastigmine hydrogen tartrate is prepared from 2-amino-3-nitro-6-chloropyridine and p-fluorobenzylamine used as raw materials, the reaction condition is mild, the production cost is low, and the method is simple to operate, adopts a preparation process with high controllability, has the low requirement for production equipment and is suitable for industrial production.

Description

Technical field [0001] The invention relates to the technical field of medicinal chemistry production, in particular to a preparation method of flupirtine maleate and its use. Background technique [0002] Rivastigmine Hydrogen Tartrate is 2-amino-3-acetic acid amino-6-(p-fluoroaniline)-pyridine, ethyl-2-amino-6-[(p-fluorophenyl) Amino] The general name of 3-pyridine-carbamic acid maleate, and its structural formula is: [0003] [0004] Flupirtine maleate is a new type of analgesic. Flupirtine maleate is currently only imported from AWD in Germany. There is currently no approved and marketed raw material of flupirtine maleate in my country. The price of 10 tablets / box of flupirtine capsules (Kodadrolone) is 128 yuan / box, and the daily cost is 38.4 yuan based on the patient’s dose of at least 3 tablets per day. If the dose is increased, the cost will increase. . Therefore, domestic enterprises have an urgent demand for the production of flupirtine maleate capsules. [0005] The gen...

Claims

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Application Information

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IPC IPC(8): C07D213/75C07C51/41C07C51/43C07C57/145
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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