Preparation method of vortioxetine

A technology of vortioxetine and compounds, which is applied in the field of preparation of vortioxetine, can solve the problems of high price and unfavorable industrial production, and achieve the effects of low cost, easy availability of raw materials, and high purity of products

Pending Publication Date: 2019-11-15
BENGBU COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the two-step reaction in this route uses expensive metal palladium and starting materials, so it is not conducive to industrial production. The synthetic route is as follows:

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] The preparation of o-aminothiophenol (III):

[0057]

[0058] Weigh 41.9g (0.31mol, 1.0eq.) of benzothiazole and place it in a 2.0L reactor, add 85.6g (0.62mol, 2.0eq.) of potassium carbonate, 500mL PEG 200 into the reactor, and raise the temperature to 110 °C and stirred for 24 hours, and TLC detected that the reaction was complete. Add 500mL of water to the reaction solution, then add 500mL of ethyl acetate for extraction, distill under reduced pressure at 40°C to obtain a crude product, and then obtain 30.1g of a pure oily product by column chromatography. Yield 80%. 1 H-NMR (400MHz, CDCl 3 ):d 7.40(d,J=7.5Hz,1H),7.14(t,J=9.3Hz,1H),6.77-6.70(m,2H),4.08(br-s,2H),3.10(s,1H ).

Embodiment 2

[0060] The preparation of o-aminothiophenol (III):

[0061]

[0062] Weigh 41.5g (0.31mol, 1.0eq.) of benzothiazole and place it in a 2.0L reactor, add 34.7g (0.62mol, 2.0eq.) of potassium hydroxide and 500mL PEG 200 into the reactor, and heat up to Stir at 110° C. for 24 hours, and TLC detects that the reaction is complete. 500 mL of water was added to the reaction solution, and then 500 mL of ethyl acetate was added for extraction. The crude product was obtained by distillation under reduced pressure at 40° C., and then 31.8 g of pure oily product was obtained by column chromatography. Yield 85%. 1 H-NMR (400MHz, CDCl3): d 7.40 (d, J = 7.5Hz, 1H), 7.14 (t, J = 9.3Hz, 1H), 6.77-6.70 (m, 2H), 4.08 (br-s, 2H ), 3.10(s,1H).

[0063] For a more concise description, Embodiment 3 to Embodiment 12 are provided in the form of a table, and the specific operation steps of Embodiment 3 to Embodiment 12 refer to Embodiment 1, and the general reaction formula is as follows:

[0064...

Embodiment 13

[0068] 2-(2,4-Dimethylphenylthio)aniline preparation:

[0069]

[0070] Weigh 41.9g (0.31mol, 1.0eq.) of benzothiazole into a 2.0L reactor, add 85.6g of potassium carbonate (0.62mol, 2.0eq), and 500mL of PEG 200 into the reactor, and heat up to 110°C Stir for 24 hours, and TLC detects that the reaction is complete. Add 72.2g (0.39mol, 1.3eq.) 2,4-dimethylbromobenzene and 2.0g (31.00mmol, 10mol%) copper powder to a 2.0L reaction flask, and stir the reaction at 200°C for 22h under nitrogen protection. TLC showed that the reaction was relatively complete.

[0071] Post-reaction treatment: cool down to 25°C, add 300mL ethyl acetate and 400mL water, stir well for 15min to make it uniform, then filter with diatomaceous earth, wash the filter cake twice with 200mL ethyl acetate, separate the liquid, and use acetic acid for the water phase Ethyl ester (200mL×2) was back-extracted twice, the organic phase was combined, and the organic layer was washed once with water, then 15mL co...

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Abstract

The invention discloses a preparation method of vortioxetine. A benzothiazole derivative (II) is dissociated into o-aminothiophenol (III) under the condition of alkali, and then the o-aminothiophenol(III) reacts with 2,4-dimethyl halogeno benzene under the catalysis of copper or a copper salt to generate 2-(2,4-dimethylphenylsulfanyl)aniline (V), the 2-(2,4-dimethylphenylsulfanyl)aniline (V) andbis(2-hydroxybenzenesulfonic acid)-4-methylbenzenesulfonamide (VI) are cyclized to obtain Ts-protected vortioxetine (VII), and the Ts-protected vortioxetine (VII) is converted into the vortioxetine (I) under the effect of Mg. The synthesis method has the advantages of easily available raw materials, simple process, low cost, high purity and suitability for industrial production.

Description

technical field [0001] The invention relates to a preparation method of vortioxetine. Background technique [0002] Vortioxetine is a new type of antidepressant drug developed by Lundbeck of Denmark and Takeda Pharmaceutical of Japan. It was approved by the U.S. Food and Drug Administration (FDA) in September 2013 under the trade name Brintellix for the treatment of major depressive disorder in adults. The mechanism of Vortioxetine's antidepressant effect is not fully understood, but it is thought to be by inhibiting the reuptake of serotonin (5-HT) and it enhances the activity of serotonin in the CNS. It also has several other activities, including 5-HT3 receptor antagonist and 5-HT1A receptor agonist. [0003] Vortioxetine is the active ingredient in the form of hydrobromic acid. The chemical name of Vortioxetine base (Vortioxetinebase) is: 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl-piperazine], and its structural formula is: [0004] [0005] Depression, also known a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 任磊于晓锋
Owner BENGBU COLLEGE
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