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Preparation method and intermediate of vortioxetine

A volume and time technology, applied in sulfide preparation, organic chemistry, etc., can solve problems such as danger, environmental pollution, harsh reaction conditions, etc.

Active Publication Date: 2016-02-10
上海谷方盟医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The technical problem to be solved by the present invention is to provide a preparation method of vortioxetine in order to overcome the defects of existing vortioxetine preparation methods such as high cost, harsh reaction conditions, complicated operation, danger, environmental pollution, and low yield. The preparation method and its intermediate, the preparation method of the present invention has low cost, mild reaction conditions, simple operation, safety and environmental protection, high yield, and is suitable for industrial production

Method used

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  • Preparation method and intermediate of vortioxetine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Example 1 Preparation of intermediate 2-(2,4-dimethylthiophenol) benzonitrile (III) from 2-fluorobenzonitrile (Ia)

[0080]

[0081] Add 2-fluorobenzonitrile (compound as shown in formula Ia) (12.1g, 100mmol), potassium carbonate (16.6g, 120mmol), DMF (100ml) into a 250ml reaction flask, and add 2,4-dimethylbenzene Thiophenol (compound represented by formula II) (14.5 g, 105 mmol) was heated to 100° C. and reacted for 4 hours, and the reaction was completed by TLC dot plate detection. The reaction system was lowered to room temperature, ice water (200ml) was added, and stirred at room temperature for one hour. A white solid was slowly precipitated. The filter cake was washed with 20ml ice water and dried under vacuum at 50°C to obtain 2-(2,4-dimethylthiophenol). ) Benzonitrile (compound as shown in formula III) crude product 24g, yield 100%.

[0082] mp=58.9-60.2℃; MS(m / z): 240[M+H]+; 1HNMR(400MHz, CDCl 3 ,TMS)δ: 7.70(dd,J=8.2,1.2Hz,1H),7.48(d,J=7.8Hz,1H),7.36-7.40(m,1H),7....

Embodiment 2

[0083] Example 2 Preparation of intermediate 2-(2,4-dimethylthiophenol)benzonitrile (III) from 2-chlorobenzonitrile (Ib)

[0084]

[0085] Add 2-chlorobenzonitrile (the compound represented by formula Ib) (13.7g, 100mmol), potassium carbonate (16.6g, 120mmol), DMF (100ml) into the 250ml reaction flask, and then add 2,4-dimethylbenzene Thiophenol (compound represented by formula II) (14.5 g, 105 mmol) was heated to 100° C. and reacted for 4 hours, and the reaction was completed by TLC dot plate detection. The reaction system was lowered to room temperature, ice water (200ml) was added, and stirred at room temperature for one hour. A white solid was slowly precipitated. The filter cake was washed with 20ml ice water and dried under vacuum at 50°C to obtain 2-(2,4-dimethylthiophenol). ) Benzoonitrile (compound as shown in formula III) (23.5g, yield 98%).

[0086] mp=58.9-60.2°C; MS(m / z): 240[M+H] + ; 1 HNMR(400MHz, CDCl 3 ,TMS)δ: 7.70(dd,J=8.2,1.2Hz,1H),7.48(d,J=7.8Hz,1H),7.36-7.40(m...

Embodiment 3a

[0087] Example 3a Preparation of intermediate 2-(2,4-dimethylthiophenol)benzamide (IV)

[0088]

[0089] Add 2-(2,4-dimethylthiophenol)benzonitrile (compound as shown in formula III) (12.0g, 50mmol), potassium hydroxide (11.2g, 200mmol), isopropanol into a 250ml reaction flask (50ml), heated to 80°C and reacted for 2h, the reaction was completed. The reaction system was lowered to room temperature, concentrated under reduced pressure to remove the solvent to obtain a white paste, which was separated by silica gel column chromatography (PE / EA=2 / 1) to obtain a white solid, which was dried under vacuum at 50°C to obtain 12 g of product (as shown in Formula IV) The compound shown), the yield was 93%.

[0090] mp=148.5-150.0℃; MS(m / z): 258[M+H] + ; 1 HNMR(400MHz, CDCl 3 ,TMS)δ: 7.75(dd,J=8.2,1.2Hz,1H), 7.36(d,J=8.0Hz,1H),7.18-7.25(m,3H),7.12(d,J=7.8Hz,1H ), 6.82 (dd, J=8.5, 1.2 Hz, 1H), 6.30 (brs, 2H), 2.42 (s, 3H), 2.35 (s, 3H).

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Abstract

The invention discloses a preparation method and intermediate of vortioxetine. The preparation method of vortioxetine includes the following steps that 1, a compound V is prepared according to a preparation method of the compound V; 2, the compound V and dichloro ethylamine or salt of dichloro ethylamine are subjected to a cyclization reaction in a high-boiling-point solvent to prepare vortioxetine, wherein the boiling point of the high-boiling-point solvent is above 120 DEG C at normal pressure. The preparation method is low in cost, easy to implement, safe, environmentally friendly, high in yield and suitable for industrial production, and reaction conditions are mild.

Description

Technical field [0001] The invention relates to a preparation method of vortioxetine and its intermediates. Background technique [0002] Vortioxetine is an antidepressant jointly developed by Lundbeck and Takeda. Its trade name is Brintellix. It was approved for marketing by the FDA on September 30, 2013. It is clinically used for major depression (MDD). For the treatment of adult patients with generalized anxiety disorder, the molecular structure of its main active ingredient is 1-[2-(2,4-methylphenylthio)phenyl]piperazine, and the structural formula is as follows: [0003] [0004] The initial preparation method of the compound (WO2003 / 029232A1) is to use a ferrocene complex of resin-protected piperazine and o-dichlorobenzene to carry out a nucleophilic substitution reaction, and then carry out an affinity reaction with 2,4-dimethylthiophenol. Nucleus substitution, decomplexing by visible light, resin cleavage to obtain crude product, and finally preparation and purification wi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C323/37C07C319/20C07D295/096C07C323/62C07C319/14
Inventor 张福利沈创倪国伟徐上虎赵传猛潘林玉
Owner 上海谷方盟医药科技有限公司
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