Preparation method of vortioxetine

A technology of vortioxetine and dimethylphenylsulfanyl, which is applied in the field of preparation of vortioxetine, can solve the problems of unfavorable industrialization, difficult purification, cumbersome steps, etc., and achieve excellent quality, simple process and easy raw materials The effect

Active Publication Date: 2014-05-14
优标易站(苏州)电子商务有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] Inspecting the above synthetic routes and preparation methods, although the process is constantly being optimized, there are still disadvantages such as rare raw materials, cumbersome steps, low yield and difficult purification, which are not conducive to industrialization

Method used

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

Examples

Experimental program
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Effect test

Embodiment 1

[0034] In a dry reaction flask under a nitrogen atmosphere, add 2-nitrothiophenol (II) (7.75g, 0.05mol), 2,4-dimethylbromobenzene (III) (10.1g, 1.1eq) and toluene 100mL, add tris(dibenzylideneacetone)dipalladium (0.46g, 0.01eq) and racemic 1,1'-binaphthyl-2,2'-diphenylphosphine (0.31g, 0.01eq) under stirring, room temperature React for 15 minutes. Potassium tert-butoxide (6.2 g, 1.1 eq) was added, the temperature was raised to reflux, and the reaction was stirred for 2 hours. The temperature was lowered to 0°C, and the reaction was continued for 2 hours. After filtration, the filtrate was distilled under reduced pressure to obtain 12.0 g of light yellow viscous liquid 2-(2,4-dimethylphenylsulfanyl)nitrobenzene with a yield of 92.7%.

Embodiment 2

[0036] In a dry glass tube reactor under a nitrogen atmosphere, add cuprous iodide (0.95g, 0.1eq), sodium tert-butoxide (4.8g, 1.0eq) and 30mL of acetonitrile, and add 2-nitrothiophenol under shaking (II) (7.75g, 0.05mol), 2,4-dimethylbromobenzene (III) (10.1g, 1.1eq), sealed and reacted under mercury lamp light at 0°C for 12-15 hours. Reduce to normal pressure, distill off the solvent under reduced pressure, dissolve the residue with ethyl acetate, filter, and wash the filtrate with 5% dilute hydrochloric acid, saturated brine and pure water successively, and dry over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 10.4 g of light yellow viscous liquid 2-(2,4-dimethylphenylsulfanyl)nitrobenzene (IV), with a yield of 80.3%.

Embodiment 3

[0038] Add 2-(2,4-dimethylphenylsulfanyl) nitrobenzene (IV) (2.59g, 10mmol), ferric chloride (0.27g, 1mmol), activated carbon 0.4g and ethanol in the reaction flask 50mL, add 80% hydrazine hydrate (1.25g, 20mmol) dropwise at room temperature, after the addition, raise the temperature to 50-60°C, react for 4-5 hours, filter, concentrate to remove the solvent ethanol, and recrystallize the residue with isopropyl ether to obtain Off-white solid 2-(2,4-dimethylphenylsulfanyl)aniline (V) 2.1 g, yield 91.7%.

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Abstract

The invention discloses a preparation method of vortioxetine (I). The preparation method comprises the following steps: subjecting 2-substituted thiophenol shown in a formula (II) and 2,4-dimethylphenyl halide shown in a formula (III) to condensation to generate 2-(2,4-dimethylphenylthioalkyl)nitrobenzene (IV) or 2-(2,4-dimethylphenylthioalkyl)aniline (V) which is obtained by reducing the 2-(2,4-dimethylphenylthioalkyl)nitrobenzene (IV), and subjecting the 2-(2,4-dimethylphenylthioalkyl)aniline (V) and a compound shown in a formula (VI) to cyclization under alkaline conditions to obtain the vortioxetine (I). The preparation method is accessible in raw materials, is concise in process, is economical and environment-friendly and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of vortioxetine. Background technique [0002] Vortioxetine is a new antidepressant drug developed by Lundbeck of Denmark and Takeda Pharmaceutical of Japan. Because the compound does not have a standard Chinese translation name, the applicant hereby transliterates it as "vortioxetine". In September 2013, the drug was approved by the US Food and Drug Administration (FDA) under the trade name Brintellix. The drug is a 5-HT3, 5-HT7, 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, and a 5-HT transporter inhibitor. To antidepressant effect, for the treatment of major depressive disorder in adults. [0003] The chemical name of Vortioxetine is: 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine, and its structural formula is: [0004...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 许学农
Owner 优标易站(苏州)电子商务有限公司
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