Preparation method for vortioxetine

A technology of vortioxetine and chlorobenzene, which is applied in the field of drug synthesis, can solve the problems of potential safety hazards, high equipment requirements, product adsorption, etc., and achieve the effects of reducing production costs, easy access to raw materials, and simple processes

Active Publication Date: 2015-02-18
合肥创新医药技术有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0019] From the perspective of these two research and development ideas reported, they are roughly the same. They both use 2,4-dimethylthiophenol and 2-halogennitrobenzene as starting materials, and undergo condensation, reduction, and cyclization to obtain Vortisib Ting, this method does not use the expensive 2-bromoiodobenzene in the original research patent, so the cost is lower than that of the original research route, but hydrazine hydrate, iron powder, stannous chloride or hydrogen are used in the reduction step of the nitro group Reductants such as hydrazine hydrate are high-energy substances, and there are potential safety hazards during use; when iron powder or stannous chloride is used as a reducing agent, there are defects such as difficult post-processing and serious product adsorption, which will seriously affect product yield; The hydrogenation reaction needs to be carried out under high pressure and requires high equipment. These factors are not conducive to industrial production

Method used

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  • Preparation method for vortioxetine
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  • Preparation method for vortioxetine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] ① Synthesis of 2-(2,4-dimethylphenylthio)chlorobenzene:

[0042]Add 14g of 2,6-dimethylthiophenol (101.4mmol), 29.8g of o-dichlorobenzene (202.8mmol), 965mg of CuI (5.1mmol) and 29.2g of NaOtBu (304.2mmol) into 210mL of In toluene, start stirring. The entire reaction system was replaced with nitrogen for 3 times (reaction needs to be carried out under the protection of nitrogen), the temperature of the external temperature oil bath was raised to 120°C, and the reaction system was kept in a reflux state, and the reaction was kept at this temperature for 16 hours. The reaction mixture was cooled, 50 mL of water was added, and stirred for 1 hour, then the resulting mixture was filtered through filter aid. The filtrate was washed with saturated brine (3*100 mL). Next, the combined aqueous phases were extracted with 200 ml of toluene. Then, the combined toluene phases were concentrated under reduced pressure to obtain 21.4 g of oil (86% yield).

[0043] ②Synthesis and pu...

Embodiment 2

[0047] ③ Synthesis of 2-(2,4-dimethylphenylthio)chlorobenzene:

[0048] Add 14g of 2,6-dimethylthiophenol (101.4mmol), 29.1g of 2-bromochlorobenzene (152.1mmol), 965mg of CuI (5.1mmol) and 29.2g of NaOtBu (304.2mmol) to 210mL In toluene, start stirring. The entire reaction system was replaced with nitrogen for 3 times (reaction needs to be carried out under the protection of nitrogen), the temperature of the external temperature oil bath was raised to 120°C, and the reaction system was kept in a reflux state, and the reaction was kept at this temperature for 16 hours. The reaction mixture was cooled, 50 mL of water was added, and stirred for 1 hour, then the resulting mixture was filtered through filter aid. The filtrate was washed with saturated brine (3*100 mL). Next, the combined aqueous phases were extracted with 200 ml of toluene. Then, the combined toluene phases were concentrated under reduced pressure to obtain 22.9 g of an oil (91% yield).

[0049] ④ Synthesis and...

Embodiment 3

[0053] ⑤ Synthesis of 2-(2,4-dimethylphenylthio)chlorobenzene:

[0054] Add 14 g of 2,6-dimethylthiophenol (101.4 mmol), 25.4 g of 2-iodochlorobenzene (106.5 mmol), 965 mg of CuI (5.1 mmol) and 29.2 g of NaOtBu (304.2 mmol) in sequence In 210 mL of toluene, start stirring. The entire reaction system was replaced with nitrogen for 3 times (reaction needs to be carried out under the protection of nitrogen), the temperature of the external temperature oil bath was raised to 120°C, and the reaction system was kept in a reflux state, and the reaction was kept at this temperature for 16 hours. The reaction mixture was cooled, 50 mL of water was added, and stirred for 1 hour, then the resulting mixture was filtered through filter aid. The filtrate was washed with saturated brine (3*100 mL). Next, the combined aqueous phases were extracted with 200 ml of toluene. Then, the combined toluene phases were concentrated under reduced pressure to obtain 22.7 g of oil (90% yield).

[0055...

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Abstract

The invention relates to the field of medicament synthesis, in particular to a novel preparation method for an antidepressant medicament intermediate vortioxetine. The method comprises the following steps of reacting 2,4-dimethylthiophenol with 2-halogen chlorobenzene to obtain an intermediate 2-(2,4-dimethylthiophenyl) chlorobenzene, and reacting the intermediate with piperazine to obtain vortioxetine. According to the method, the total yield can reach 68 to 75 percent, the method has the advantages of starting materials are low in cost and easy to obtain, the process is simple, and the requirements of large-scale production are met.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a new method for preparing an antidepressant drug intermediate, vortioxetine. Background technique [0002] Vortioxetine, English name Vortioxetine, CAS registration number: 508233-74-7, is a drug jointly developed by Takeda Pharmaceutical Company of the United States and Lundbeck Pharmaceutical Company of the United States for the treatment of adult patients with severe depression. Its chemical structure is as follows : [0003] [0004] The U.S. FDA approved the listing of Brintellix (Vortioxetine, Vortioxetine) in September 2013. In addition, on December 27, 2013, Brintellix (vortioxetine) also obtained the final approval in the European Union, and applied for the import registration of the drug in my country. Veroxetin Acid Tablets were also submitted to the National Drug Evaluation Center in June 2014. [0005] Decision Resources, the world's leading research and consulting...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 曹明成
Owner 合肥创新医药技术有限公司
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