Preparation method of antidepressant vortioxetine

A vortioxetine and preparation process technology, applied in the field of drug synthesis, can solve the problems of complicated operation, high price and the like, and achieve the effects of cheap and easy-to-obtain reaction raw materials, convenient handling, and avoiding the use of palladium catalysts

Inactive Publication Date: 2014-07-23
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0021] In the above two "one-pot cooking" methods, expensive palladium catalysts and expensive raw m

Method used

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  • Preparation method of antidepressant vortioxetine
  • Preparation method of antidepressant vortioxetine
  • Preparation method of antidepressant vortioxetine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Synthesis of 2-(2,4-Dimethylphenylsulfanyl)nitrobenzene(IV)

[0037] In a 500ml eggplant-shaped bottle, 2,4-dimethylthiophenol (47g, 0.341mol) was mixed with 150ml of methanol, sodium methoxide (22g, 0.409mol) was added under ice-cooling, and the reaction was stopped for 0.5 hours. Remove the solvent, add N,N-dimethylformamide (200ml) and o-chloronitrobenzene (59g, 0.375mol) to it, protect with nitrogen, react at 10°C for 24 hours, stop the reaction, pour into 600ml of water, Cool, filter with suction to obtain a tan solid, and recrystallize from absolute ethanol to obtain 79.3 g of pale yellow needle-like crystals, with a yield of 90.0%, m.p.94°C-96°C. .

[0038] 1H-NMR (300MHz, DMSO-d6), δ (ppm): 8.23 ​​(1H, d, J=8.1Hz), 7.55~7.32 (4H, m, -ArH), 7.29 (1H, s), 7.16 (1H , d, J=7.8Hz), 6.64(1H, d, J=7.8Hz), 2.33(3H, s), 2.21(3H, s).

[0039] Synthesis of 2-(2,4-Dimethylphenylsulfanyl)aniline (V)

[0040] In a 1L three-necked flask, add compound IV (79g, 0.305mol) and...

Embodiment 2

[0049] Synthesis of 2-(2,4-Dimethylphenylsulfanyl)nitrobenzene(IV)

[0050] In a 500ml eggplant-shaped bottle, add 2,4-dimethylthiophenol (47g, 0.341mol) and potassium hydroxide (22.9g, 0.409mol), add acetonitrile (200ml) and o-fluoronitrobenzene (43g, 0.375mol), nitrogen protection, reflux reaction after 12 hours, stop the reaction, spin off the acetonitrile, extract with ethyl acetate (200ml×3), combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, and suction filter, The solvent was spin-dried to obtain a tan solid, which was recrystallized from absolute ethanol to obtain 63.3 g of pale yellow needle-like crystals, with a yield of 72.6%, m.p.94°C-96°C. .

[0051] 1H-NMR (300MHz, DMSO-d6), δ (ppm): 8.23 ​​(1H, d, J=8.1Hz), 7.55~7.32 (4H, m, -ArH), 7.29 (1H, s), 7.16 (1H , d, J=7.8Hz), 6.64(1H, d, J=7.8Hz), 2.33(3H, s), 2.21(3H, s).

[0052] Synthesis of 2-(2,4-Dimethylphenylsulfanyl)aniline (V)

[0053] In a 1L three-necked flask, add ...

Embodiment 3

[0062] Synthesis of 2-(2,4-Dimethylphenylsulfanyl)nitrobenzene(IV)

[0063] In a 500ml eggplant-shaped bottle, add 2,4-dimethylthiophenol (47g, 0.341mol) and potassium hydroxide (22.9g, 0.409mol), add dimethylsulfoxide (200ml) and o-fluoronitro Benzene (43g, 0.375mol), protected by nitrogen, refluxed for 12 hours, stopped the reaction, poured into 600ml of water, extracted with ethyl acetate (200ml×3), combined the organic layers, washed with saturated brine, and dried over anhydrous sodium sulfate Suction filter overnight, and spin dry the solvent to obtain a tan solid, which was recrystallized from absolute ethanol to obtain 65.6 g of pale yellow needle-like crystals, with a yield of 75.6%, m.p.94°C-96°C. .

[0064] 1H-NMR (300MHz, DMSO-d6), δ (ppm): 8.23 ​​(1H, d, J=8.1Hz), 7.55~7.32 (4H, m, -ArH), 7.29 (1H, s), 7.16 (1H , d, J=7.8Hz), 6.64(1H, d, J=7.8Hz), 2.33(3H, s), 2.21(3H, s).

[0065] Synthesis of 2-(2,4-Dimethylphenylsulfanyl)aniline (V)

[0066] In a 1L three-n...

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Abstract

The invention relates to the field of medicine synthesis, and particularly relates to a preparation method of antidepressant vortioxetine (I) shown in the specification. The preparation method comprises the following steps: reacting 2-(2,4-diphenylmethylthio)aniline (V) with bis(2-chloroethyl)amine hydrochloride (VI) to obtain vortioxetine hydrochloride (VII), and neutralizing VII through a base, to obtain vortioxetine (I). The total yield of vortioxetine hydrochloride (VII) prepared by the method is 59.8%, the raw materials are low-cost and easily available, and the treatment after reaction is convenient.

Description

technical field [0001] The invention relates to the field of drug synthesis. In particular, it relates to a preparation method of vortioxetine (I), which is used for antidepressant. Background technique [0002] Vortioxetine, whose chemical name is 1-[2-(2,4-methylphenylthio)phenyl]piperazine, was approved by the U.S. Food and Drug Administration (FDA) in September 2013. It is used for the treatment of major depressive disorder in adults and is now produced by Lundbeck Company of the United States. The structural formula of vortioxetine is as follows: [0003] [0004] Depression is a mental illness with morbid emotional changes. The patient may be depressed, have strong sadness and disappointment, refrain from speaking, or be noisy and restless, with high emotions and abnormally increased activities. At present, with the rapid development of society and the acceleration of people's life rhythm, the number of patients suffering from depression is increasing day by day,...

Claims

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Application Information

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IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 朱启华董广平徐云根
Owner CHINA PHARM UNIV
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