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Preparation method of olopatadine

A technology of olopatadine and tetrahydrofuran, which is applied in the field of chemical drug preparation, can solve the problems of high cost, explosion, and long reaction time of olopatadine, and achieve the effects of shortening reaction time, reducing safety risks, and low environmental sensitivity

Inactive Publication Date: 2016-10-26
北京京卫燕康药物研究所有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is very dangerous to deal with excess sodium hydride after reaction. It will burn when it encounters water and may explode, which poses a great safety hazard.
And the reaction time is very long, and the production cost of olopatadine is high

Method used

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  • Preparation method of olopatadine
  • Preparation method of olopatadine
  • Preparation method of olopatadine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1 (reference patent US20070232814)

[0044] Under the protection of nitrogen, add 2.4L of anhydrous-treated tetrahydrofuran into a 5L dry reaction kettle, stir and add 262g (6.56mol) of sodium hydride (60%), add hydrobromic acid-3-dimethylaminopropyl triphenyl bromide 816 g (1.6 mol) of phosphonium was stirred at room temperature for 1 hour, and the temperature was raised to 55-60° C. for 16 hours to react, turning blood red (gas was always generated). Cool to 20-25° C., add 216 g (0.8 mol) of isoket acid, and react at room temperature for 24 hours. TLC detection shows that the reaction is complete.

[0045] Cool to 10-15°C, add water and tetrahydrofuran solution (water: 100mL, THF: 400mL) dropwise, (severe heat release, a large amount of gas is generated), take about 4 hours, continue stirring for 30 minutes, filter, and rinse the filter cake with 500mLTHF . Combine the filtrates, stir and add concentrated hydrochloric acid to pH ~ 2, continue stirring for...

Embodiment 2

[0046] Embodiment 2 (adding N,N-dimethylformamide)

[0047] Under the protection of nitrogen, add 240mL of anhydrous-treated tetrahydrofuran and 8ml of N,N-dimethylformamide into a 500mL dry reaction kettle, cool in a water bath, stir and add 16.3g (0.41mol) of sodium hydride (60%), and add hydrogen Bromic acid-3-dimethylaminopropyltriphenylphosphonium bromide 81.6g (0.16mol), stirred at room temperature for 2 hours, heated to 55-60°C and reacted for 12 hours, turning blood red. Cool to 20-25° C., add 21.6 g (0.08 mol) of isoket acid, and react at room temperature for 24 hours. TLC detection shows that the reaction is not complete.

Embodiment 3

[0048] Embodiment 3 (adding dimethyl sulfoxide)

[0049] Under nitrogen protection, add 2.4 L of anhydrous-treated tetrahydrofuran and 80 ml of dimethyl sulfoxide into a 5 L dry reaction kettle, cool in a water bath, add 163 g (4.08 mol) of sodium hydride (60%) with stirring, and add 3-hydrobromic acid 816 g (1.6 mol) of dimethylaminopropyl triphenylphosphonium bromide was stirred at room temperature for 1.5 to 2 hours, then heated to 45°C for 1 hour. Cool to 20-25°C, add 216g (0.8mol) of isoket acid, react at room temperature for 10-12 hours, TLC detection shows that the reaction is complete.

[0050] Cool to 10-15°C, add water and tetrahydrofuran (water: 100mL, THF: 200mL) dropwise for about 1 hour, continue stirring for 30 minutes, filter, and rinse the filter cake with 500mL THF. Combine the filtrates, stir and add concentrated hydrochloric acid to pH ~ 2, continue stirring for 30 minutes, and filter. The filter cake was washed with 200 mL of tetrahydrofuran and dried in t...

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Abstract

The invention provides an industrial preparation method of olopatadine. The method can accelerate the reaction speed and lower the environmental sensitivity, the process controllability is improved, the production cost is lowered, and safety is improved.

Description

technical field [0001] The invention relates to the field of chemical drug preparation, in particular to a preparation method of olopatadine. Background technique [0002] Olopatadine hydrochloride is a highly selective inhibitor of H1 receptors and a mast cell membrane stabilizer. It has no effect on α-adrenal receptors, dopamine receptors, M1 and M2 receptors, and has low side effects. [0003] The chemical name of olopatadine is: (Z)-11-(3-dimethylaminopropylene)-6,11-dihydrodibenzo[b,e]oxazepine-2-acetic acid. [0004] The structure of olopatadine hydrochloride is as follows: [0005] [0006] The common synthetic method of olopatadine is to adopt Wittig (wittig) reaction preparation, and technique is as follows: [0007] [0008] Ohshima E et al. (Journal of medicinal chemistry, 1992, 35(11): 2074-84) prepared olopatadine by using n-butyllithium as a base for wittig reaction. At 0°C under the protection of nitrogen, slowly add n-butyllithium solution dropwise t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D313/12
CPCC07D313/12
Inventor 王德平胡光灿贾保艳
Owner 北京京卫燕康药物研究所有限公司
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