New synthesis process for vortioxetine hydrobromide

A technology of vortioxetine hydrobromide and a synthetic method, which is applied in the field of medicine and chemical industry, can solve the problems of high equipment requirements, low yield, and increased cost, and achieve short method routes, easily available raw materials, and few by-products Effect

Inactive Publication Date: 2017-10-20
山东鲁宁药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Above-mentioned method Raney nickel reduction reaction is under high pressure, and equipment requirement is high, and cost increases, and yield is lower

Method used

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  • New synthesis process for vortioxetine hydrobromide
  • New synthesis process for vortioxetine hydrobromide
  • New synthesis process for vortioxetine hydrobromide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] The synthesis of embodiment 1. compound 3:

[0022] Under nitrogen atmosphere, the FeCl 3 (3.2g, 0.2eq), trans-1,2 cyclohexanediamine (5.6g, 0.4eq), benzothiazole (13.5g), 2,4-dimethyliodobenzene (34.5g) NaOH (12g, 3eq), and 100mL of water were placed in a 250mL round-bottomed flask and reacted at 110°C for 4 hours. After the reaction was completed, it was extracted with ethyl acetate, dried, and separated by column chromatography to obtain 18g of the target product with a yield of 78.3%.

Embodiment 2

[0023] Embodiment 2, the synthesis of compound 4:

[0024] Compound 4 (18g, 78mmol) was dissolved in 150mL of acetonitrile, added dichloroethylamine hydrochloride (14.3g, 80mmol), and DIEA (32g, 4eq), refluxed for 4 hours, concentrated, diluted with water, ethyl acetate Extraction, drying, and the resulting crude product were used directly in the next step without purification.

Embodiment 3

[0025] Embodiment 3, the synthesis of compound 5:

[0026] The crude product obtained in the previous step was redissolved in 70 ml of ethanol, and 23 g of HBr aqueous solution with a mass fraction of 40% was added under stirring, heated until the solution was clear, then gradually cooled to 0° C., a white solid was precipitated, filtered , the filter cake was washed with cold ethanol solution (15mL*2) and dried to obtain a white solid 18.4g, yield 61%, purity 98.5%, mp 231.1-232.3°C. MS(m / z): 299[M+H] + ; 1 H NMR (400MHz, CDCl 3 +D 2 O): 7.32(d, J=7.8Hz, 1H), 7.15(s, 1H), 7.09(d, J=3.9Hz, 2H), 7.03(d, J=7.2Hz, 1H), 6.99~6.85( m, 1H), 6.54 (d, J=7.8Hz, 1H), 3.46 (dd, J=15.8, 5.4Hz, 8H). 2.33 (d, J=24.5Hz, 6H).

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Abstract

The invention relates to a preparation method of vortioxetine hydrobromide. The method is characterized by: subjecting benzothiazole and dimethyliodobenzen to ring opening reaction under the catalysis of ferric trichloride, then cooperating with dichloroethylamine hydrochloride to generate vortioxetine, and then conducting hydrobromination so as to obtain the target product. The process provided by the invention has the advantages of easily available raw materials, concise technology, high overall yield, few by-product, and simple post-treatment, thus being suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, in particular to a method for synthesizing vortioxetine. Background technique [0002] Vortioxetine is a new drug for severe depression in adults jointly developed by Lundbeck Pharmaceutical Company of Denmark and Takeda Pharmaceutical Company of Japan. Named Brintellix. The listed vortioxetine hydrobromide is a tablet, which is a local agonist of serotonin 1A. After oral absorption, the drug acts on serotonin 1A in the form of vortioxetine. It has a high affinity with the 5-HT transporter, which makes it bind to the transporter and inhibit the reuptake of 5-HT by the human body, thus playing an anti-major depression effect. [0003] According to the molecular structure of vortioxetine hydrochloride, using molecular retrosynthesis analysis, the introduction of phenylthio group and the formation of piperazine ring, as well as the production method and introduction sequence of functi...

Claims

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Application Information

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IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 不公告发明人
Owner 山东鲁宁药业有限公司
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