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Novel compound 1-[2-(2,4-dimethylphenylthio)phenyl]-2-oxopiperazine and its preparation method and use in vortixetine synthesis

A technology of dimethylphenylsulfanyl and vortioxetine, which is applied in the application field of vortioxetine (vortixetine) synthesis, can solve problems such as unsolved problems of side reactions of piperazine ring, and achieves low cost and avoidance of vortioxetine. Side reactions, the effect of relatively high yield

Active Publication Date: 2015-08-12
SHANDONG BESTCOMM PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0025] Although route 5 avoids the palladium metal catalyst of the condensation step, it still does not solve the side reaction problem when closing the piperazine ring

Method used

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  • Novel compound 1-[2-(2,4-dimethylphenylthio)phenyl]-2-oxopiperazine and its preparation method and use in vortixetine synthesis
  • Novel compound 1-[2-(2,4-dimethylphenylthio)phenyl]-2-oxopiperazine and its preparation method and use in vortixetine synthesis
  • Novel compound 1-[2-(2,4-dimethylphenylthio)phenyl]-2-oxopiperazine and its preparation method and use in vortixetine synthesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Example 1: Preparation of N-2-(2,4-dimethylphenylsulfanyl)phenyl-chloroacetamide of formula (IV)

[0072] Add 43.0g (187.4mmol) of the compound of formula (V) 2-(2,4-dimethylphenylsulfanyl)aniline and 24.7g (244.1mmol) of triethylamine into the three-necked flask, add 200ml of dichloromethane, stir and cool down To -30°C, add 200ml of chloroacetyl chloride-dichloromethane solution with a concentration of 0.1375g / ml dropwise, that is, the solution contains 27.5g (243.5mmol) of chloroacetyl chloride, and after the addition is completed, keep it at -30°C for 3 hours. , add 300ml of saturated potassium carbonate solution to wash, then wash with 300ml of water, add 8.2g of anhydrous magnesium sulfate to the organic phase, filter, and concentrate the filtrate to dryness under reduced pressure to obtain 56.2g of a purple-black solid, namely the compound of formula (V), with a yield of 98.1 %, mass spectrogram see figure 1 .

[0073] MS: 306.2[M+H]

Embodiment 2

[0074] Embodiment 2: Preparation of N-2-(2,4-dimethylphenylsulfanyl)phenyl-chloroacetamide of formula (IV) compound

[0075] Add 43.0g (187.4mmol) of the compound of formula (V) 2-(2,4-dimethylphenylsulfanyl)aniline, 24.2g (187.2mmol) of diisopropylethylamine into the three-necked flask, and add 130ml of dichloromethane , stirred and cooled to 30°C, and 200ml of chloroacetyl chloride-dichloromethane solution with a concentration of 0.106g / ml was added dropwise, that is, the solution contained 21.2g (187.7mmol) of chloroacetyl chloride, and the dropwise addition was completed at 30°C and kept for 0.5h. After the reaction was completed, 300ml of saturated potassium carbonate solution was added for washing, followed by 300ml of water, 8.2g of anhydrous magnesium sulfate was added to the organic phase, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 51.7g of a purple-black solid, namely the compound of formula (V). The rate is 90.2%.

Embodiment 3

[0076] Example 3: Preparation of N-2-(2,4-dimethylphenylsulfanyl)phenyl-chloroacetamide of formula (IV)

[0077] Add 43.0g (187.4mmol) of the compound of formula (V) 2-(2,4-dimethylphenylsulfanyl)aniline and 37.9g ​​(374.5mmol) of triethylamine into the three-necked flask, add 650ml of dichloromethane, stir and cool down To 30°C, 200ml of chloroacetyl chloride-dichloromethane solution with a concentration of 0.2115g / ml was added dropwise, that is, the solution contained 42.3g (374.5mmol) of chloroacetyl chloride, and the reaction was incubated for 1h after the addition was completed. After the reaction was completed, 300ml of saturated potassium carbonate solution was added for washing, and then 300ml of water was added for washing. The organic phase was added with 8.2g of anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 56.4g of a purple-black solid, namely the compound of formula (V). The rate is 98.4%.

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Abstract

The invention relates to a novel compound 1-[2-(2,4-dimethylphenylthio)phenyl]-2-oxopiperazine and its preparation method and use in vortixetine synthesis. 2-(2,4-dimethylthiophenyl)aniline and chloroacetyl chloride as initial raw materials undergo a synthesis reaction to produce N-2-(2,4-dimethylphenylthio)phenyl-chloroacetamide and the N-2-(2,4-dimethylphenylthio)phenyl-chloroacetamide undergoes a classical Mitsunobu ring closing reaction to produce 1-[2-(2,4-dimethylphenylthio)phenyl]-2-oxopiperazine. The preparation method needs a low reaction temperature and prevents side reactions caused by ring closing high temperature conditions of other routes. The novel compound is used for vortixetine synthesis and has the advantages of simple processes, easy acquisition of raw materials, low cost, mild reaction conditions, safety, environmental friendliness, short reaction time, simple processes and after-treatment, high yield, high product purity and industrial production feasibility.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and relates to a new compound 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]-2-oxopiperazine and its preparation method and its use in vortioxetine (vortixetine) synthesis. Background technique [0002] Vortioxetine, Chinese name Vortioxetine, is a new type of antidepressant drug jointly developed by Lundbeck of Denmark and Takeda Pharmaceutical of Japan for the treatment of major depressive disorder (MDD). On September 30, 2013, Vortioxetine Hydrobromide Tablets was approved by the US Food and Drug Administration (FDA), under the trade name Brintellix. On December 18, 2013, Vortioxetine Hydrobromide Tablets and Vortioxetine Lactate Oral Drops were approved in the EU (trade name: Brintellix). The mechanism of action of vortioxetine is related to direct regulation of serotonin receptor activity and inhibition of serotonin (5-HT) transporter. This medicine is 5-HT 3 , 5-HT 7 ,...

Claims

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Application Information

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IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 高冈李永吉张志强范松朱官花
Owner SHANDONG BESTCOMM PHARMA CO LTD
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