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Preparation method of Vortioxetine

A technology of dimethylphenylthio group and cyclization reaction, applied in directions such as organic chemistry, can solve the problems of unsuitability for large-scale production, low yield and high cost, and achieve the effects of no toxic side effects, common reagents, and cost reduction

Inactive Publication Date: 2015-05-20
SHANGHAI INST OF PHARMA IND +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Chinese patent cn02819025 also mentions the synthesis of analogue 1-[2-(4-chlorophenylsulfanyl) phenyl]-3-methylpiperazine, by 2-(3-methylpiperazin-1-yl) After aniline diazotization, it is obtained by reacting with copper 4-chlorothiophenolate, but the yield is very low, only 11%, and it is not suitable for large-scale production
This method requires the use of expensive palladium catalysts and phosphine ligands, and the cost is relatively high

Method used

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  • Preparation method of Vortioxetine
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  • Preparation method of Vortioxetine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1: Preparation of 2-(2,4-dimethylphenylthio)nitrobenzene

[0022] 5.1g (36.2mmol) of o-fluoronitrobenzene, 5.0g (36.2mmol) of 2,4-dimethylthiophenol, and 3.0g (21.7mmol) of potassium carbonate were stirred in DMF (30ml) at 80°C for 3h until the reaction was complete , add water (50ml), extract with ethyl acetate (30ml×3), combine the organic layers, wash with brine, dry, concentrate to dryness, add petroleum ether (40ml), stir, filter, wash with petroleum ether, and dry 8.3g of yellow solid , yield 88.6%.

[0023] MS(m / z):260.08[M+H] + ; 1 H-NMR (400MH Z , CDCl 3 )δ:8.26(dd,J 1 =1.2H Z ,J 2 =8.4H Z ,1H),7.49(d,J=8Hz,1H),7.31(m,1H),7.20(m,2H),7.13(d,J=7.6Hz,1H),6.74(dd,J 1 =1.2Hz,J 2 =8.4Hz,1H),2.42(s,3H),2.33(s,3H).

Embodiment 2-4

[0024] Example 2-4: Preparation of 2-(2,4-dimethylphenylthio)aniline

[0025] 8.0 g (30.8 mmol) of the compound obtained in Example 1, 10% Pd / CO 0.8 g, and 40 ml of ethanol were hydrogenated at 50 °C for 12 h at normal pressure until the reaction was complete, filtered, washed with ethanol, and concentrated to dryness to obtain 7.0 g of oil. MS(m / z):230.11[M+H] + ; 1 H-NMR (400MH Z , CDCl 3 )δ:7.37(dd,J 1 =1.6Hz,J 2 =8Hz,1H),7.28(s,1H),7.23(m,1H),6.88(dd,J 1 =0.8Hz,J 2 =8Hz,1H),6.83(dd,J 1 =1.2Hz,J 2 =8Hz,1H),6.79(m,2H),4.09(bs,2H),2.42(s,3H),2.29(s,3H).

[0026] 1.0g (3.9mmol) of the compound obtained in Example 1, 1g of iron powder, and 20ml of acetic acid were stirred and reacted at 40°C. After 5 hours, the reaction was complete. Add 30ml of water, extract twice with 50ml of ethyl acetate, and combine the ethyl acetate layer, washed once with saturated brine, washed three times with 30ml 5% NaOH solution, washed twice with brine, dried, filtered, and concentrated ...

Embodiment 5-6

[0028] Example 5-6: Preparation of Vortioxetine·HBr

[0029] Reflux and stir 7.0g of the oil obtained in Example 2, 5.5g (30.8mmol) of bis(2-chloroethyl)amine hydrochloride, and 1,3,5-trimethylbenzene (40ml) overnight, and cool to 60°C , add 80ml of water. Separate the layers, extract the aqueous layer with ethyl acetate (30ml×2), combine the organic layers, wash with brine, dry, and filter. Add 40% hydrobromic acid (about 5ml) dropwise to the filtrate until pH = 1, stir, and wash out the solid. Filter, wash with ethyl acetate (20ml×2), and dry 4.5g of an earth-colored solid.

[0030] Concentrate the filtrate and evaporate ethyl acetate, add 40ml of petroleum ether, stir, pour out the supernatant, add 40ml of petroleum ether, stir and pour out the supernatant. The oil in the lower layer was neutralized with 5% sodium hydroxide solution, extracted with ethyl acetate (30ml×2), the organic layers were combined, washed with brine, dried, filtered, and concentrated to dryness. ...

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Abstract

The invention relates to the technical field of Vortioxetine preparation methods. Vortioxetine is prepared through the ring-closure reactions between 2-(2,4-dimethylthiophenyl)aniline and bis(2-chloroethyl)amine hydrochloride. Compared to the prior art, the Vortioxetine can be obtained through three steps of replacement reactions, reduction reactions, and ring-closure reactions in the provided preparation method, the total yield is four times as many as that of a conventional method, and the cost is greatly reduced. Moreover, the reagents used in the preparation method are common and cheap, and do not have any side or toxic effect; the reaction conditions are mild, and thus the preparation method is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of a preparation method of Vortioxetine. Background technique [0002] Vortioxetine belongs to a new generation of antidepressants developed for the treatment of patients with major depressive disorder. The drug is thought to work through a combination of 2 mechanisms of action: modulation of receptor activity and reuptake inhibition. In vitro studies have shown that vortioxetine is a 5-HT3 and 5-HT7 receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, and a serotonin transporter (SERT) inhibitor. In vivo non-clinical studies have shown that vortioxetine can enhance the levels of neurotransmitters - serotonin, norepinephrine, dopamine, acetylcholine, histamine - in specific areas of the brain. Vortioxetine's multimodal activity profile is expected to bring clinical benefits to patients with major depressive disorder not adequately controlled by existing medications. [0003] ...

Claims

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Application Information

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IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 吴雪松王芳徐浩张锴婷岑均达
Owner SHANGHAI INST OF PHARMA IND
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