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Synthetic method of vortioxetine

A technology of vortioxetine and a synthesis method, applied in the field of medicinal chemistry, can solve problems such as unfavorable commercial production, low product purity, high price, etc., and achieve the effects of avoiding high-cost post-processing, high purity and low cost

Active Publication Date: 2014-12-24
SUNDIA MEDITECH COMPANY LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The above methods have all adopted a palladium complex catalyst, which is expensive and difficult to purchase, which is unfavorable for commercial production; method (4) two (2-2-chloroethyl) amine hydrochloride itself is easily ring-closed and has carcinogenicity. And there will be many by-products of intermolecular nucleophilic substitution, so that the product purity is not high; use two (2-Y to replace) ethylamine in the method (5), can produce a lot of by-products of chain structure after the reaction, so that the purity of the obtained product is not high

Method used

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  • Synthetic method of vortioxetine
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Embodiment 1 (the first step):

[0039] Add 341.6g of o-chloronitrobenzene (I), 500g of 2,4-dimethylthiophenol (II), 876g of potassium carbonate, and 3L of acetone into the reaction flask, and react under reflux at 65°C for 18h. After stopping the reaction, distill off the solvent, then add 4L of water, stir for 1h, filter with suction to obtain a solid, add 1L of n-heptane: 2N aqueous sodium hydroxide solution = 1L: 1L, stir for 1 hour, filter with suction, and dry at 55°C for 12h ,, 491 g of 2-(2,4-dimethylphenylsulfanyl) nitrobenzene (Ⅲ) was obtained, with a yield of 87.3% and a purity of 95.8%.

Embodiment 2

[0040] Embodiment 2 (the first step)

[0041] Add 438g of o-bromonitrobenzene, 500g of 2,4-dimethylthiophenol, 876g of potassium carbonate, and 3L of acetone into the reaction flask, and react under reflux at 65°C for 18h. After stopping the reaction, distill off the solvent, then add 4L of water, stir for 1h, filter with suction to obtain a solid, add 1L of n-heptane: 2N aqueous sodium hydroxide solution = 1L: 1L, stir for 1 hour, filter with suction, and dry at 55°C for 12h ,, 499 g of 2-(2,4-dimethylphenylsulfanyl) nitrobenzene (Ⅲ) was obtained, with a yield of 88.7% and a purity of 92.7%.

Embodiment 3

[0042] Embodiment 3 (the second step)

[0043] Add 360g of 2-(2,4-dimethylphenylsulfanyl)nitrobenzene (Ⅲ), 233g of iron powder, 297.5g of ammonium chloride, 1.44L of methanol, 1.44L of tetrahydrofuran, and 0.576L of water into the three-necked flask . Replaced with nitrogen, reacted at 60°C for 5.5h. Stop the reaction, let stand for 18h, centrifuge, and then filter with suction, and distill the filtrate to remove the solvent. Add 2L ethyl acetate, dissolve it, add water to wash twice, add 1L each time, then wash with 1L saturated brine, add anhydrous sodium sulfate 500g and dry for 1 hour, evaporate ethyl acetate to obtain the product 2-(2,4 -Dimethylphenylsulfanyl)aniline (IV) 303.0 g, yield 96.8%, purity 96.9%.

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Abstract

The invention discloses a synthetic method of vortioxetine. The synthetic method comprises the following steps of by adopting a compound as shown in a formula (I) as a raw material, carrying out substitution reaction on the compound and 2,4-dimethyl thiophenol (II) to generate 2-(2,4-dimethyl phenyl alkyl sulfide) nitrobenzene (III); reducing 2-(2,4-dimethyl phenyl alkyl sulfide) nitrobenzene (III) to obtain 2-(2,4-dimethyl phenyl alkyl sulfide) phenylamine (IV); cyclizing 2-(2,4-dimethyl phenyl alkyl sulfide) phenylamine (IV) and N,N-bis(2-chloroethyl)-4-methyl benzsulfamide (VI) to obtain Tos-protecting vortioxetine (V); and preparing vortioxetine (VII) from Tos-protecting vortioxetine (V) under the action of a phenol additive. The synthetic method disclosed by the invention has the advantages of easily available raw material, simple process, low cost and high purity, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a synthetic method of vortioxetine. Background technique [0002] Vortioxetine is a new type of 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] [0005] The synthetic method of vortioxetine mainly contains...

Claims

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Application Information

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IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 苏忠海崔阳文杨超
Owner SUNDIA MEDITECH COMPANY LTD
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