CN106243062A

CN106243062A - A kind of fertile for western spit of fland industrialized preparing process

Info

Publication number: CN106243062A
Application number: CN201610624562.2A
Authority: CN
Inventors: 吕振阁; 蒋维; 胡孟奇
Original assignee: HEFEI YUANZHI PHARMACEUTICAL R & D Co Ltd
Current assignee: HEFEI YUANZHI PHARMACEUTICAL R & D Co Ltd
Priority date: 2016-07-31
Filing date: 2016-07-31
Publication date: 2016-12-21

Abstract

A kind of fertile for western spit of fland industrialized preparing process.According to mol ratio by neighbour's bromo-iodobenzene and 2,4 thiophenol dimethyl benzenes are dissolved in nitrogen protection in toluene, after catalysis, add potassium tert-butoxide, stirring, filter, and filter cake toluene washs, and filtrate concentrates dry, obtains WTXT 01；According to mol ratio by WTXT01 and BOC piperazine dissolved in dry toluene, add catalyst, reactant mixture cooled down, washing, be dried, kieselguhr filters, and concentrates and dry obtains WTXT02；WTXT02 grease being dissolved in methanol, regulates pH, add toluene, extracting yellow organic facies, wash 2 times in mixed liquor, be dried, organic facies obtains WTXT03 after concentrating；By WTXT03 organic facies, heating, separate out solid, filter, drying under reduced pressure, must irrigate for Xi Ting.The inventive method is produced to irrigate and is substantially shorter the production cycle for Xi Ting, saves production cost, and the method is safe and reliable, simple to operation, reproducible.

Description

A kind of fertile for western spit of fland industrialized preparing process

Technical field

The present invention relates to technical field of organic synthesis, be specifically related to a kind of fertile for western spit of fland industrialized preparing process.

Background technology

Fertile for Xi Ting (Vortioxetine), it is called for short WTXT, Chinese name: 1-[2-[(2,4-3,5-dimethylphenyl) sulfenyl] benzene Base] piperazine hydrobromide, Vortioxetine antidepressants mechanism of action is understood the most completely, but is thought and pass through in CNS with it Suppression 5-HT reuptake strengthens 5-HT and can activity be correlated with, and it also has other activity several to include 5-HT3,5-HT7,5-HT1D receptor Yi Zhiji &5-HT1A Shou Tijidongji &5-HT1B acceptor portion agonist, but not yet determine that these activity are to vortioxetine The contribution of antidepressants effect.But current method produce fertile for Xi Ting can the production cycle long, production cost is high, and operation is multiple Miscellaneous.

Summary of the invention

The technical problem to be solved in the present invention is the defect overcoming prior art, it is provided that a kind of fertile for western spit of fland industrialized production Method.

In order to solve above-mentioned technical problem, the invention provides following technical scheme: a kind of fertile for western spit of fland industry metaplasia Product method, its scheme is as follows:

1., according to mol ratio 1: 1～1: 1.5 by neighbour's bromo-iodobenzene and 2,4-thiophenol dimethyl benzene is dissolved in nitrogen in toluene and protects Protect, add 1% pair of (2-diphenylphosphine phenyl) ether and 0.5% 3 (dibenzalacetone) two palladium as catalyst after, solution Stirring 5min, system color is become orange from kermesinus, adds potassium tert-butoxide and forms heterogeneous muddy body, by reactant liquor at nitrogen It is heated to 100 degrees Celsius under protection, after stirring 1 hour, mixture is cooled to 0 DEG C, is stirred for 2 hours, filter (kieselguhr suction Attached), filter cake toluene washs, and concentrates dry by the filtrate merged, and obtains orange/red oil and is WTXT-01；

2. according to mol ratio 1:1.12～1: 1.5 by WTXT01 and BOC-piperazine dissolved in dry toluene, nitrogen deaerate After 5min, add 1% equivalent three (dibenzalacetone) two palladium, 3% equivalent of racemic 1,1'-dinaphthalene-2,2'-diphenyl phosphine sum Catalysis, after nitrogen deaerates 5 minutes, puts into the sodium tert-butoxide of 1.2 equivalents, and nitrogen protection is heated to 80 degrees Celsius of 15hr, will reaction Mixture is cooled to room temperature and washes twice with 15% saline, and anhydrous Na 2S04 is dried, after activated carbon refluxes 15 minutes, and kieselguhr Filter, concentrate and dry obtain brown oil WTXT02；

3. WTXT02 grease is dissolved in methanol and 6M HCl, and after refluxing 1 hour, HPLC detects complete deprotection After, it is cooled to room temperature, concentrates removing and remove methanol, drip concentrated NaOH solution, regulate pH to 13-14, mixed liquor adds toluene, Extracting yellow organic facies, then wash 2 times with 15% saline, anhydrous Na 2S04 is dried, and organic facies is stand-by after concentrating, and obtains product WTXT03；

4. by WTXT03 organic facies, being heated to 70 degrees Celsius, be subsequently adding HBr and water, reactant liquor is down to room temperature and is stirred Mix overnight, separate out solid, filter, 60 degrees Celsius of drying under reduced pressure, must irrigate for Xi Ting.

The inventive method is produced to irrigate and is substantially shorter the production cycle for Xi Ting, saves production cost, and the method is safe and reliable, Simple to operation, reproducible.

Detailed description of the invention

Embodiment 1

1. prepared by intermediate WTXT01:

According to mol ratio 1:1 by neighbour's bromo-iodobenzene and 2,4-thiophenol dimethyl benzene is dissolved in nitrogen protection in toluene, adds 1% After double (2-diphenylphosphine phenyl) ethers and 0.5% 3 (dibenzalacetone) two palladium are as catalyst, solution stirring 5min, body It is that color is become orange from kermesinus, adds potassium tert-butoxide and form heterogeneous muddy body, reactant liquor is heated under nitrogen protection To 100 degrees Celsius, after stirring 1 hour, mixture being cooled to 0 DEG C, be stirred for 2 hours, filter (diatomite adsorption), filter cake is used Toluene washs, and concentrates dry by the filtrate merged, and obtains orange/red oil and is intermediate WTXT01, and 99% productivity is pure Degree > 96%, intermediate WTXT01 structural formula is as follows:

2. prepared by intermediate WTXT02:

According to mol ratio 1: 1.12 by intermediate WTXT01 and BOC-piperazine dissolved in dry toluene, nitrogen degassing 5min After, add 1% equivalent three (dibenzalacetone) two palladium, 3% equivalent of racemic 1,1'-dinaphthalene-2, urging of 2'-diphenyl phosphine sum Changing, after nitrogen deaerates 5 minutes, put into the sodium tert-butoxide of 1.2 equivalents, nitrogen protection is heated to 80 degrees Celsius of 15hr, reaction is mixed Compound is cooled to room temperature and washes twice with 15% saline, and anhydrous Na 2S04 is dried, after activated carbon refluxes 15 minutes, and kieselguhr mistake Filter, concentrates and dry obtains brown oil intermediate WTXT02, purity 95%, and intermediate WTXT02 structural formula is as follows:

3. prepared by intermediate WTXT03:

WTXT02 grease is dissolved in methanol and 6M HCl (aqueous solution), and after refluxing 1 hour, HPLC detection is the most de- After protection, it is cooled to room temperature, concentrates removing and remove methanol, drip concentrated NaOH solution, regulate pH to 13, mixed liquor adds first Benzene, extracting yellow organic facies, then wash 2 times with 15% saline, anhydrous Na 2S04 is dried, and organic facies is stand-by after concentrating, and obtains product Intermediate WTXT03, intermediate WTXT03 structural formula is as follows:

Prepared by 4.WTXT:

By WTXT03 organic facies, being heated to 70 degrees Celsius, be subsequently adding HBr (48%) and water, reactant liquor is down to room Temperature is stirred overnight, and separates out solid, filters, 60 degrees Celsius of drying under reduced pressure, must irrigate for western spit of fland WTXT, the structural formula of Li Gelieting WTXT As follows:

Embodiment 2

1. prepared by intermediate WTXT01:

According to mol ratio 1:1.5 by neighbour's bromo-iodobenzene and 2,4-thiophenol dimethyl benzene is dissolved in nitrogen protection in toluene, adds After 1.2% pair of (2-diphenylphosphine phenyl) ether and 0.6% 3 (dibenzalacetone) two palladium are as catalyst, solution stirring 5min, system color is become orange from kermesinus, adds potassium tert-butoxide and forms heterogeneous muddy body, is protected at nitrogen by reactant liquor Under be heated to 100 degrees Celsius, after stirring 1 hour, mixture is cooled to 0 DEG C, is stirred for 2 hours, filter (diatomite adsorption), Filter cake toluene washs, and concentrates dry by the filtrate merged, and obtains orange/red oil and is intermediate WTXT01.

2. prepared by intermediate WTXT02:

According to mol ratio 1:1.5 by intermediate WTXT01 and BOC-piperazine dissolved in dry toluene, nitrogen degassing 5min After, add 1.2% equivalent three (dibenzalacetone) two palladium, 3.2% equivalent of racemic 1,1'-dinaphthalene-2,2'-diphenyl phosphine sum Catalysis, after nitrogen deaerates 5 minutes, puts into the sodium tert-butoxide of 1.3 equivalents, and nitrogen protection is heated to 80 degrees Celsius of 15hr, will reaction Mixture is cooled to room temperature and washes twice with 15% saline, and anhydrous Na 2S04 is dried, after activated carbon refluxes 15 minutes, and kieselguhr Filter, concentrate and dry obtain brown oil intermediate WTXT02.

3. prepared by intermediate WTXT03:

WTXT02 grease is dissolved in methanol and 6M HCl (aqueous solution), and after refluxing 1 hour, HPLC detection is the most de- After protection, it is cooled to room temperature, concentrates removing and remove methanol, drip concentrated NaOH solution, regulate pH to 13.6, mixed liquor adds first Benzene, extracting yellow organic facies, then wash 2 times with 15% saline, anhydrous Na 2S04 is dried, and organic facies is stand-by after concentrating, and obtains product Intermediate WTXT03, intermediate WTXT03 structural formula is as follows:

Prepared by 4.WTXT:

By WTXT03 organic facies, being heated to 65 degrees Celsius, be subsequently adding HBr (48%) and water, reactant liquor is down to room Temperature is stirred overnight, and separates out solid, filters, 60 degrees Celsius of drying under reduced pressure, must irrigate for western spit of fland WTXT.

Claims

1. irrigate for western spit of fland industrialized preparing process for one kind, it is characterised in that its scheme is as follows:

1, according to mol ratio 1:1～1:1.5 by neighbour's bromo-iodobenzene and 2,4-thiophenol dimethyl benzene is dissolved in nitrogen protection in toluene, adds Enter 1% pair of (2-diphenylphosphine phenyl) ether and 0.5% 3 (dibenzalacetone) two palladium as catalyst after, solution stirring 5min, system color is become orange from kermesinus, adds potassium tert-butoxide and forms heterogeneous muddy body, is protected at nitrogen by reactant liquor Under be heated to 100 degrees Celsius, after stirring 1 hour, mixture is cooled to 0 DEG C, is stirred for 2 hours, filter (diatomite adsorption), Filter cake toluene washs, and concentrates dry by the filtrate merged, and obtains orange/red oil and is WTXT-01；

2, according to mol ratio 1:1.12～1:1.5 by WTXT01 and BOC-piperazine dissolved in dry toluene, nitrogen degassing 5min After, add 1% equivalent three (dibenzalacetone) two palladium, 3% equivalent of racemic 1,1'-dinaphthalene-2, urging of 2'-diphenyl phosphine sum Changing, after nitrogen deaerates 5 minutes, put into the sodium tert-butoxide of 1.2 equivalents, nitrogen protection is heated to 80 degrees Celsius of 15hr, reaction is mixed Compound is cooled to room temperature and washes twice with 15% saline, and anhydrous Na 2S04 is dried, after activated carbon refluxes 15 minutes, and kieselguhr mistake Filter, concentrates and dry obtains brown oil WTXT02；

3, WTXT02 grease is dissolved in methanol and 6M HCl, and after refluxing 1 hour, after HPLC detects complete deprotection, fall Warm to room temperature, concentrate removing and remove methanol, drip concentrated NaOH solution, regulate pH to 13-14, mixed liquor adds toluene, takes Huang Color organic facies, then wash 2 times with 15% saline, anhydrous Na 2S04 is dried, and organic facies is stand-by after concentrating, and obtains product WTXT03；

4, by WTXT03 organic facies, being heated to 70 degrees Celsius, be subsequently adding HBr and water, reactant liquor is down to be stirred at room temperature At night, separate out solid, filter, 60 degrees Celsius of drying under reduced pressure, must irrigate for Xi Ting.