CN105461656A

CN105461656A - Novel process for preparation of 1-[2-(2,4-dimethylphenylsulphanyl)phenyl] piperazine

Info

Publication number: CN105461656A
Application number: CN201510761975.0A
Authority: CN
Inventors: 闫起强; 赵国磊
Original assignee: Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
Current assignee: Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
Priority date: 2015-11-11
Filing date: 2015-11-11
Publication date: 2016-04-06

Abstract

The present invention discloses a novel process for the preparation of 1-[2-(2,4-dimethylphenylsulphanyl)phenyl] piperazine. The process uses o-halogenated benzenesulfonic acid and m-xylene as raw materials, which are subjected to dehydration condensation with methylsulfonic acid and phosphorus pentoxide as condensing agents to generate halogenated diarylsulfone. Halogenated diarylsulfone and piperazine are subjected to a substitution reaction in an aprotic solvent to produce piperazine ring substituted diarylsulfone; the piperazine ring substituted diarylsulfone is reduced by hexachlorodisilane in an aprotic solvent to obtain a product with high yield. This method has the advantages of cheap and easily available raw materials, avoidance of the usage of a noble metal catalyst and treatment of residual palladium, simple operation, mild reaction conditions, simple post-treatment, and potential application values.

Description

A kind ofly prepare the fertile novel process for Xi Ting

Technical field

The present invention relates to medicinal chemistry art, be specifically related to prepare the fertile novel process for Xi Ting.

Background technology

Fertile for western spit of fland chemistry 1-[2-(2 by name, 4-3,5-dimethylphenyl) sulfydryl] phenyl]-piperazine, it is serotonin transporter inhibitor, and Active Regulation is carried out to its acceptor, developed jointly by Ling Bei and military field, obtain U.S. FDA approval listing in September, 2013, trade(brand)name Brintellix, is clinically used for the treatment of major depressive disorder and breadth first algorithm.

Current Yuan Yan company discloses the preparation method (WO2007144005, CN101472906) of this compound, and this compound has three kinds of synthetic methods, and reaction scheme is as follows:

Method 1:

This reaction process has three steps, and wherein two-step reaction all uses palladium source, and cost is relatively high, is unsuitable for suitability for industrialized production.

Method 2:

Reaction process is one kettle way, and reaction process is fairly simple, but reaction process cannot effectively control, and a lot of side reaction may occur, the more difficult control of quality product

Method 3:

This reaction is two steps, although reaction process is fairly simple, operation is also relatively easy, reaction process uses palladium noble metal catalyst, is not suitable for suitability for industrialized production, and this patent has been authorized and entered, and need consider patent evasion.

Summary of the invention

In order to solve the problem existing for existing preparation method, the invention discloses the fertile novel process for Xi Ting of preparation, this method avoid use noble metal catalyst, raw material is cheap and easy to get, and reaction conditions is gentle, is beneficial to suitability for industrialized production.

Particular content is as follows:

Join in toluene solvant by bromothiophenol and N methyl piperazine, add salt of wormwood, be heated to 100 ~ 120 DEG C of backflows, reflection is spent the night, bromothiophenol and N methyl piperazine generation halogenating reaction, after question response terminates, stops heating, is cooled to room temperature.Aftertreatment obtains intermediate 1.Wherein temperature of reaction preferably 120 DEG C.

Intermediate 1 and 2,4-dimethyl iodobenzene are joined in toluene solvant, under nitrogen protection, adds Pddba ₂and rac-BINAP.Add NaOBu ^t.Be heated to 100 ~ 120 DEG C of backflows, reaction is spent the night.After question response terminates, aftertreatment obtains intermediate 2.Wherein temperature of reaction preferably 100 DEG C.

Intermediate 2 is dissolved in aprotic solvent, adds a certain amount of phenyl chloroformate, stirring at room temperature 4-18h, after question response terminates.Be cooled to room temperature, add moisture and go out organic phase, aqueous phase toluene extracts three times, and merge organic phase and obtain oily matter, underpressure distillation obtains intermediate 3.Wherein aprotic solvent is selected from acetone, tetrahydrofuran (THF), dioxane, preferred tetrahydrofuran (THF).Phenyl chloroformate add-on is 1-3 times of intermediate 2 mole number.

Intermediate 3 is dissolved in aprotic solvent, adds salt of wormwood, stirring heating, reaction 1-24h, preferred reaction 8h; After question response terminates.Be cooled to room temperature, aftertreatment obtains fertile for Xi Ting.Wherein aprotic solvent is selected from acetone, tetrahydrofuran (THF), dioxane, preferred acetone.

Its technical process is as follows:

Concrete embodiment

Following example is to describe the present invention in detail, but should not be construed as limiting the invention.

Embodiment 1:

Bromothiophenol (4.7g, 25mmol) and N methyl piperazine (2.5g, 25mmol) are dissolved in 60ml toluene solvant, be heated to 120 DEG C, reaction is spent the night, bromothiophenol and N methyl piperazine generation halogenating reaction, after question response terminates, stop heating, be cooled to room temperature.Add 50ml water, filter to isolate aqueous phase, organic phase saturated aqueous common salt and clear water washing, merge aqueous phase toluene and extract.Removed under reduced pressure toluene, obtains intermediate 1, product 4.4g, yield 85%.

Embodiment 2:

By intermediate 1(4.2g, 20mmol) be dissolved in 40ml toluene, add 2,4-dimethyl iodobenzene (4.6g, 20mmol), add Pddba _2,rac-BINAP and NaOBu ^t.Reflux to 100 DEG C, reaction is spent the night.After reaction terminates, stop heating, be cooled to room temperature.Add water, filter to isolate aqueous phase, organic phase salt solution and clear water washing, merge aqueous phase toluene and extract.Removed under reduced pressure toluene, obtains intermediate 2.Product 5.4g, yield 87%.

Embodiment 3:

By intermediate 2(3.1g, 10mmol) and phenyl chloroformate (1.6g, 10mmol) in, be dissolved in 30mL tetrahydrofuran (THF), stirring at room temperature 4h, after question response terminates.Be cooled to room temperature, reaction solution joins in 200mL water, stirred at ambient temperature 2 hours, filters, is washed to neutrality, dry product 3.8g, productive rate 91%.

Embodiment 4:

By intermediate 3(4.2g, 10mmol) be dissolved in acetone 20mL, add salt of wormwood, stirring heating, reaction 8h, after question response terminates.Be cooled to room temperature, reaction solution joins in 200mL water, stirred at ambient temperature 2 hours, filters, is washed to neutrality, obtains product 2.8g, yield 94%.

Claims

1. prepare a fertile novel process for Xi Ting, its operational path is as follows:

(1) be dissolved in toluene solvant by bromothiophenol and N methyl piperazine, add salt of wormwood, reacting by heating is spent the night, and after question response terminates, stop heating, be cooled to room temperature, aftertreatment obtains intermediate 1;

(2) intermediate 1 and 2,4-dimethyl iodobenzene are joined in toluene solvant, under nitrogen protection, add Pddba ₂and rac-BINAP, add NaOBu ^t, reflux, reaction is spent the night, and after question response terminates, aftertreatment obtains intermediate 2;

(3) intermediate 2 is dissolved in aprotic solvent, adds a certain amount of phenyl chloroformate, stirring at room temperature 4-18h, after question response terminates, be cooled to room temperature, add moisture and go out organic phase, aqueous phase toluene extracts three times, and merge organic phase and obtain oily matter, underpressure distillation obtains intermediate 3;

(4) be dissolved in aprotic solvent by intermediate 3, add salt of wormwood, stirring heating, reaction 1-24h, after question response terminates, is cooled to room temperature, and aftertreatment obtains fertile for Xi Ting.

2. method as claimed in claim 1, step (1) is characterized in that: join in toluene solvant by bromothiophenol and N methyl piperazine, add salt of wormwood, is heated to 100 ~ 120 DEG C of backflows; Wherein preferable reaction temperature is 120 DEG C.

3. method as claimed in claim 1, step (2) is characterized in that: join in toluene solvant by intermediate 1 and 2,4-dimethyl iodobenzene, under nitrogen protection, add Pddba ₂and rac-BINAP, add NaOBu ^t, be heated to 100 ~ 120 DEG C of backflows; Wherein preferable reaction temperature is 100 DEG C.

4. method as claimed in claim 1, step (3) is characterized in that: be dissolved in aprotic solvent by intermediate 2, and wherein aprotic solvent is selected from acetone, tetrahydrofuran (THF), dioxane, preferred tetrahydrofuran (THF).

5. method as described in claim 1,4, is characterized in that, phenyl chloroformate add-on is 1-3 times of intermediate 2 mole number.

6. method as claimed in claim 1, step (4) is characterized in that: be dissolved in aprotic solvent by intermediate 3, and wherein aprotic solvent is selected from the one in acetone, tetrahydrofuran (THF) and dioxane, preferred acetone.

7. method as described in claim 1,6, is characterized in that the reaction times is 1-24h, preferred 8h.