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Synthesis method of flupirtine maleate

A technology of flupirtine maleate and a synthesis method, applied in the field of medicine, can solve problems such as inability to stabilize pure A crystal form, and achieve the effects of white product appearance, low production equipment requirements, and complete reaction

Active Publication Date: 2014-10-08
SICHUAN XINSIDUN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthesis process uses isopropanol to recrystallize, and the obtained flupirtine maleate is crystal form B or a mixture of crystal forms A and B, and the pure crystal form A that was originally developed and marketed cannot be stably obtained.

Method used

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  • Synthesis method of flupirtine maleate
  • Synthesis method of flupirtine maleate
  • Synthesis method of flupirtine maleate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] A kind of synthetic method of flupirtine maleate, its processing step is as follows:

[0035] A. Synthesis of 2-amino-3-nitro-6-(p-fluorobenzylamino)pyridine (I)

[0036] Add isopropanol and p-fluorobenzylamine into the reaction kettle, stir, add 2-amino-3-nitro-6-chloropyridine and triethylamine, reflux at 70°C for 12 hours, take samples to monitor the completion of the reaction, and then add hydrogen The sodium oxide solution was concentrated under reduced pressure until no solvent flowed out, centrifuged to obtain a solid, and dried to obtain 2-amino-3-nitro-6-(p-fluorobenzylamino)pyridine (I).

[0037]

[0038]

[0039] B. Synthesis of ethyl 2-amino-3-carbamate-6-(p-fluorobenzylamino)pyridine (Ⅲ)

[0040] Add isopropanol, 2-amino-3-nitro-6-(p-fluorobenzylamino)pyridine (I) and Raney nickel into the autoclave, seal the autoclave, and feed nitrogen and hydrogen successively, at 60°C Carry out the hydrogenation reaction. After the hydrogenation reaction is comple...

Embodiment 2

[0047] A kind of synthetic method of flupirtine maleate, its processing step is as follows:

[0048] A. Synthesis of 2-amino-3-nitro-6-(p-fluorobenzylamino)pyridine

[0049] Add isopropanol and p-fluorobenzylamine into the reaction kettle, stir, add 2-amino-3-nitro-6-chloropyridine and triethylamine, reflux at 80°C for 8 hours, take samples to monitor the completion of the reaction, add hydrogen The sodium oxide solution was concentrated under reduced pressure until no solvent flowed out, centrifuged to obtain a solid, and dried to obtain 2-amino-3-nitro-6-(p-fluorobenzylamino)pyridine.

[0050]B. Synthesis of 2-amino-3-carbamate ethyl-6-(p-fluorobenzylamino)pyridine

[0051] Add isopropanol, 2-amino-3-nitro-6-(p-fluorobenzylamino)pyridine and Raney nickel into the autoclave, seal the autoclave, feed nitrogen and hydrogen in sequence, and carry out hydrogenation reaction at 70°C , after the hydrogenation reaction is completed, reduce the pressure to normal pressure, under th...

Embodiment 3

[0055] A kind of synthetic method of flupirtine maleate, its processing step is as follows:

[0056] A. Synthesis of 2-amino-3-nitro-6-(p-fluorobenzylamino)pyridine

[0057] Add isopropanol and p-fluorobenzylamine into the reaction kettle, stir, add 2-amino-3-nitro-6-chloropyridine and triethylamine, reflux at 75°C for 10 hours, take samples to monitor the completion of the reaction, and then add hydrogen The sodium oxide solution was concentrated under reduced pressure until no solvent flowed out, centrifuged to obtain a solid, and dried to obtain 2-amino-3-nitro-6-(p-fluorobenzylamino)pyridine.

[0058] B. Synthesis of 2-amino-3-carbamate ethyl-6-(p-fluorobenzylamino)pyridine

[0059] Add isopropanol, 2-amino-3-nitro-6-(p-fluorobenzylamino)pyridine and Raney nickel into the autoclave, close the autoclave, feed nitrogen and hydrogen in sequence, and carry out hydrogenation reaction at 65°C , after the hydrogenation reaction is completed, reduce the pressure to normal pressu...

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Abstract

The invention provides a synthesis method of flupirtine maleate. Recrystallization by use of methanol is carried out in the refining step of the crude product of the flupirtine maleate so that the product is white in appearance and high in purity, and the crystal form of the product is pure A crystal and same as the crystal form of the commercial products. The optimal reaction solvent, reaction time and reaction temperature are explored and found out by use of a simplified process flow, and a method for preparing the flupirtine maleate in the pure A crystal form, which is high in yield, low in cost and simple to operate, uses easily available raw materials and is applicable to the industrial production is found.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for synthesizing analgesic flupirtine maleate. Background technique [0002] Flupirtine maleate (Rivastigmine Hydrogen Tartrate) is 2-amino-3-acetic acid amino-6-(p-fluoroanilino)-pyridine, ethyl-2-amino-6-[(p-fluorophenyl) Amino]-3-pyridine-carbamic acid maleate common name, its structural formula is: [0003] [0004] Flupirtine maleate is a new type of analgesic. At present, flupirtine maleate is only imported from German AWD company. At present, there is no flupirtine maleate raw material approved and marketed in my country. The price of flupirtine acid capsules (Coda Delong) is 128 yuan per box for 10 capsules / box, and the daily cost is 38.4 yuan if the patient takes at least 3 capsules per day. If the dosage is increased, the cost will increase . Therefore, the demand of domestic enterprises for the production of flupirtine maleate capsules is very...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75C07C51/41C07C51/43C07C57/145
CPCC07D213/75
Inventor 庄惠祥杜丰蔡孙均
Owner SICHUAN XINSIDUN PHARMA
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