Preparation method of vortioxetine hydrobromide

A technology of vortioxetine and ammonium formate, applied in the field of drug preparation, can solve the problems of increased production process and production cycle, low actual yield of reaction, unfavorable industrial production, etc., to save production time, avoid competitive side reactions, The effect of avoiding the risk of explosion

Inactive Publication Date: 2016-10-05
山东康美乐医药科技有限公司
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Problems solved by technology

[0015] The synthetic method of preparing vortioxetine hydrobromide disclosed in the above prior art is more complicated, and route 1 needs to use expensive phosphorus ligand and palladium catalyst, has increased production cost, and aftertreatment operation is loaded down with trivial details, has increased production procedure and The production cycle is not conducive to industrial production; both "one-pot cooking" methods require the use of expensive raw materials 2,4-dimethyliodobenzene or o-bromoiodobenzene, phosphorus ligands and palladium catalysts, and the competing side reactions of dihalogens The actual yield of the reaction is low, and the operation is cumbersome
The cost of the product is high and the total yield is not high

Method used

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  • Preparation method of vortioxetine hydrobromide
  • Preparation method of vortioxetine hydrobromide

Examples

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Embodiment 1

[0049] Preparation of compound (4) 2-(2,4-dimethylsulfanyl)nitrobenzene

[0050] In a 250ml reaction flask, dissolve 2,4-dimethylthiophenol (10.0g, 75mmol), o-bromonitrobenzene (18.2g, 90mmol), potassium carbonate (15.5g, 113mmol) in 150ml tetrahydrofuran, 65 Reaction at ℃ for 8 hours, the reaction was completed, lowered to room temperature, the reaction solution was concentrated, 250ml of water was added, stirred, and suction filtered to obtain 16.2g of a yellow-brown solid, the yield was 83.7%, ESI-MS: 260 (MH+), 1H-NMR ( DMSO-d6)δ8.1( m, 1H), 7. 6( m, 1H), 7.5( m, 2H), 7.4( s,1H), 7. 2(d, 1H), 7.0 (d, 1H), 2.5(s, 3H), 2.3(s, 3H).

[0051] Preparation of compound (5) 2-(2,4-dimethylphenylthio)aniline

[0052] In a 250ml reaction flask, dissolve compound (4) (13.0g, 50mmol) in 150mL methanol, add 1.0g 10% Pd / C, ammonium formate (12.6g, 200mmol), and continue to stir the reaction at 25°C After 1 h, suction filtration, the filtrate was concentrated under reduced pressure, t...

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Abstract

The invention relates to the technical field of preparation of vortioxetine hydrobromide, in particular to a preparation method of vortioxetine hydrobromide. The preparation method comprises the following steps: taking 2,4-dimethyl thiophenol as a raw material to react with o-bromonitrobenzene so as to generate a compound (IV); treating the compound (IV) via a normal pressure catalytic hydrogenation method to obtain a compound (V); treating the compound (V) via a Sandmeyer reaction to obtain a compound (VI); and reacting a compound (VII) with piperazine, and then performing a reaction with hydrobromic acid to generate a salt, thereby obtaining a target compound (I). The method for preparing vortioxetine hydrobromide is relatively short in route, relatively mild in reaction condition, simple, convenient and feasible in after treatment, and more suitable for industrial production requirements.

Description

technical field [0001] The invention relates to a preparation method of a medicine, in particular to a preparation method of a novel antidepressant Vortioxetine Hydrobromide. . Background technique [0002] Vortioxetine Hydrobromide (Vortioxetine Hydrobromide) is a new type of antidepressant, trade name Brintellix, jointly developed by Takeda of Japan and Lundbeck of Denmark, for the treatment of depression and anxiety. In September 2013, it was approved by the U.S. FDA for the treatment of severe depression in adults. In October of the same year, Vortioxetine’s Marketing Authorization Application (MAA) was approved by the European Medicines Agency (EMA) Human Medicinal Products Committee ( CHMP) positive opinion, CHMP recommends approval of Brintellix for severe depression (MDD) For the treatment of adult patients, in December 2013, the EMA European Commission granted Vortioxetine the right to sell in the entire EU. There are four marketing specifications of Vortioxetine:...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/096
Inventor 耿凤娈范明伟刘云峰苑增飞刘晓君
Owner 山东康美乐医药科技有限公司
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