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Refining method of tianeptine

A technology of tianeptine and a purification method, applied in the field of medicine, can solve problems such as the removal of tianeptine without reports, and achieve the effects of improving quality and safety requirements, meeting quality and safety requirements, and improving quality

Inactive Publication Date: 2020-04-14
山东诚汇双达药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The internal control quality standard of tianuptine requires impurity A≦0.10%. The chemical properties of impurity A and tianuptine are very close. Previous literature has not reported the method of removing impurity A in tianuptine; from the perspective of technology, its impurity A is unavoidable, and it is difficult to remove it by conventional methods such as recrystallization, activated carbon adsorption and solvent extraction, which shows the difficulty of removing impurity A

Method used

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  • Refining method of tianeptine
  • Refining method of tianeptine
  • Refining method of tianeptine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 600kg of ethanol and 250kg of water were placed in a 2000L reactor and stirred and added with 100kg of tianuptine crude product (liquid phase purity 97.909%, impurity A1.787%), heated to 70°C to dissolve, then slowly added 1kg of concentrated sulfuric acid and 50kg of water dilution, pay attention to slowly add, react for 3 hours to precipitate solids, and centrifuge to remove solids. The filtrate in the reaction kettle was cooled and crystallized with ice salt water, centrifuged when the temperature dropped to -5-0°C, and the solid material was rinsed with 30kg of cold ethanol to obtain a wet product of tianuptine, which was dried to obtain a dry product of 93.8kg, which was refined and collected The rate is 93.8%. The liquid phase detection spectrum of refined tianuptine is shown in figure 2 , figure 2 As can be seen in the figure, according to the area normalization method, the liquid phase purity of high-quality tianuptine is 99.857% (4.833min at the peak retent...

Embodiment 2

[0039] Put 600kg of methanol and 250kg of water in a 2000L reaction kettle and add 100kg of crude tianuptine (liquid phase purity 97.909%, impurity A1.787%) under stirring, heat to 60°C to dissolve, then slowly add 1.5kg of concentrated sulfuric acid And the diluent of 50kg water, pay attention to adding slowly, react for 3 hours to precipitate solids, and centrifuge to remove solids. The filtrate in the reaction kettle was cooled and crystallized with ice salt water, centrifuged when the temperature dropped to -5-0°C, and the solid material was rinsed with 30kg of cold methanol to obtain a wet product of tianuptine, which was dried to obtain 92.5kg of a dry product, which was refined and collected The yield is 92.5%, the liquid phase purity is 99.708%, and the impurity A is 0.083%.

Embodiment 3

[0041] 500kg of ethanol and 160kg of water were placed in a 1000L reactor and stirred and added with 100kg of tianuptine crude product (liquid phase purity 97.909%, impurity A1.787%), heated to 75°C to dissolve, then slowly added 1kg of concentrated sulfuric acid and 40kg water dilution, pay attention to slowly add, react for 3 hours to precipitate solid, centrifuge to remove solid. The filtrate in the reactor was cooled and crystallized with ice salt water, centrifuged when the temperature dropped to -5-0°C, and the solid material was rinsed with 30kg of cold ethanol to obtain a wet product of tianuptine, which was dried to obtain a dry product of 94.7kg, which was refined and collected The yield is 94.7%, the liquid phase purity is 99.764%, and the impurity A is 0.076%.

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Abstract

The invention belongs to the technical field of medicine, and particularly relates to a refining method of tianeptine. The method can remove an impurity A namely [7-[N(3-chloro-6,11-dihydro-5,5-dioxo-6-methyldibenzo-[c,f][1,2]thiazole-11-yl)N-ethyl]amino] heptanoic acid in tianeptine. The method comprises the following steps: heating and dissolving ttianeptine containing an impurity A in a mixed solvent of ethanol and water, adding concentrated sulfuric acid, crystallizing, filtering to remove impurities; cooling, and then crystallizing to obtain a refined product of tianeptine. By adopting the refining method provided by the invention, the refined product of tianeptine is obtained, and the refining yield is 92% or above. The liquid phase purity of refined tianeptine reaches 99.7% or more,and the content of the impurity A is reduced to 0.1% or less.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for refining tianuptine, which can remove the impurity A[7-[N(3-chloro-6,11-dihydro-5, 5-Dioxy-6-methyldibenzo-[c,f][1,2]thiazopin-11-yl)N-ethyl]amino]heptanoic acid. Background technique [0002] Tianuptine chemical name: 7-[(3-Chloro-6,11-dihydro-5,5-dioxo-6-methyldibenzo-[c,f][1,2]thiazopine- 11-yl) amino] heptanoic acid, the structural formula is as follows: [0003] [0004] Tianuptine is indicated for the treatment of mild, moderate or severe depression, neurogenic and reactive depression, anxiety and depression with somatic, especially gastrointestinal discomfort, anxiety and depression in alcohol-dependent patients during withdrawal disease. Tianuptine is effective for anxiety symptoms, and the HAMA score reduction rate at the end of the sixth week is slightly higher than that of amitriptyline, which is consistent with the literature reports. ...

Claims

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Application Information

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IPC IPC(8): C07D281/02
CPCC07D281/02
Inventor 王庭见王永广张涛赵忠贵樊可军王志刚
Owner 山东诚汇双达药业有限公司