CN111320592A - Preparation method of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine - Google Patents
Preparation method of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine Download PDFInfo
- Publication number
- CN111320592A CN111320592A CN201811540050.3A CN201811540050A CN111320592A CN 111320592 A CN111320592 A CN 111320592A CN 201811540050 A CN201811540050 A CN 201811540050A CN 111320592 A CN111320592 A CN 111320592A
- Authority
- CN
- China
- Prior art keywords
- nitrobenzene
- phenyl
- reaction
- preparation
- dimethylphenylsulfanyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- YQNWZWMKLDQSAC-UHFFFAOYSA-N vortioxetine Chemical compound CC1=CC(C)=CC=C1SC1=CC=CC=C1N1CCNCC1 YQNWZWMKLDQSAC-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims abstract description 6
- AMNLXDDJGGTIPL-UHFFFAOYSA-N 2,4-dimethylbenzenethiol Chemical compound CC1=CC=C(S)C(C)=C1 AMNLXDDJGGTIPL-UHFFFAOYSA-N 0.000 claims abstract description 5
- YMDZDFSUDFLGMX-UHFFFAOYSA-N 2-chloro-n-(2-chloroethyl)ethanamine;hydron;chloride Chemical compound [Cl-].ClCC[NH2+]CCCl YMDZDFSUDFLGMX-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- WHVBVBWXAJTOMC-UHFFFAOYSA-N 2-[2,4-bis(methylsulfanyl)phenyl]aniline Chemical compound CSC1=C(C=CC(=C1)SC)C1=C(N)C=CC=C1 WHVBVBWXAJTOMC-UHFFFAOYSA-N 0.000 claims description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 3
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical group OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 2
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 claims description 2
- -1 2, 4-dimethylphenylsulfanyl Chemical group 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical group Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 2
- ORPVVAKYSXQCJI-UHFFFAOYSA-N 1-bromo-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Br ORPVVAKYSXQCJI-UHFFFAOYSA-N 0.000 claims 1
- BFCFYVKQTRLZHA-IDEBNGHGSA-N 1-chloro-2-nitrobenzene Chemical group [O-][N+](=O)[13C]1=[13CH][13CH]=[13CH][13CH]=[13C]1Cl BFCFYVKQTRLZHA-IDEBNGHGSA-N 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- YJEJOODMOAVDJB-UHFFFAOYSA-N CC=1SC=C(C=1C1=C(C=CC=C1)[N+](=O)[O-])C Chemical compound CC=1SC=C(C=1C1=C(C=CC=C1)[N+](=O)[O-])C YJEJOODMOAVDJB-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- BJHMYQKFVFJZDC-UHFFFAOYSA-N 2-(2,4-dimethylphenyl)sulfanylaniline Chemical compound CC1=CC(C)=CC=C1SC1=CC=CC=C1N BJHMYQKFVFJZDC-UHFFFAOYSA-N 0.000 abstract description 6
- SHBWPKLGXVSPIP-UHFFFAOYSA-N 2,4-dimethyl-1-(2-nitrophenyl)sulfanylbenzene Chemical compound CC1=CC(C)=CC=C1SC1=CC=CC=C1[N+]([O-])=O SHBWPKLGXVSPIP-UHFFFAOYSA-N 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 238000006722 reduction reaction Methods 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229960002263 vortioxetine Drugs 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of 1- [2- (2, 4-dimethylphenylthio) -phenyl ] piperazine, which comprises the steps of carrying out substitution reaction on 2, 4-dimethylphenylthiol and 1-halogen-2-nitrobenzene to prepare 2- (2, 4-dimethylphenylthio) nitrobenzene, reducing to prepare 2- (2, 4-dimethylphenylthio) aniline, and carrying out ring closing reaction on the 2- (2, 4-dimethylphenylthio) aniline and bis (2-chloroethyl) amine hydrochloride to prepare 1- [2- (2, 4-dimethylphenylthio) -phenyl ] piperazine. The invention takes 2, 4-dimethyl thiophenol and 1-halogen-2-nitrobenzene as initial raw materials and prepares the compound through substitution reaction, reduction reaction and ring closing reaction. The three-step reaction has low cost, high yield, easy purification and easy industrialization.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a low-cost and high-yield synthesis method for preparing 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine.
Background
1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine is a diarylthioether amine and the hydrobromide salt thereof is Vortioxetine (Vortioxetine), a chemical antidepressant drug. Approved by the U.S. food and drug administration for the treatment of major adult depression in 2013, now manufactured by luneck corporation, usa.
Depression is a psychotic disorder with altered emotional state. At present, with the rapid development of society and the accelerated pace of life of people, patients suffering from depression are increasing. The vortioxetine serving as a novel antidepressant drug has the advantages of faster onset time, smaller toxic and side effects and better antidepressant activity.
In the existing synthesis method, if palladium catalytic reaction is adopted, expensive palladium catalyst and phosphine ligand are needed, and the cost is high. Or dangerous and toxic reagents are needed in the reaction process, so that the method is high in toxicity, high in price, high in operation requirement and not beneficial to industrial production.
Therefore, there is a need for a convenient, low-cost, high-yield process for the preparation of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine.
Disclosure of Invention
The invention aims to provide a preparation method of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine, which has high yield and low cost and is suitable for large-scale industrial production.
The technical scheme for realizing the purpose of the invention is as follows:
a preparation method of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine comprises the following steps:
(1) the reaction temperature is 60-100 ℃, 2, 4-dimethyl thiophenol shown in a formula I and 1-halogen-2-nitrobenzene shown in a formula II are used as raw materials, and acetonitrile, tetrahydrofuran, dimethyl sulfoxide or N, N-dimethylformamide is used as a solvent; sodium hydroxide, potassium hydroxide and potassium carbonate are used as acid-binding agents to react to generate 2- (2, 4-dimethyl phenylthio) nitrobenzene shown in a formula III.
Wherein the molar ratio of the 2, 4-dimethylthiophenol (I) to the 1-halo-2-nitrobenzene (II) is 1:1 to 1.5.
(2) The reaction temperature is 40-90 ℃, 2- (2, 4-dimethylphenylthio) nitrobenzene shown in the formula III is used as a raw material, water, methanol, ethanol and isopropanol are used as solvents, hydrazine hydrate, iron powder and zinc powder are used as reducing agents, ferric chloride, hydrochloric acid, glacial acetic acid and sulfuric acid are used as catalysts, and the 2- (2, 4-dimethylphenylthio) aniline shown in the formula IV is generated by reaction.
(3) The reaction temperature is 110-180 ℃, 2- (2, 4-dimethylphenylthio) aniline shown in a formula IV is used as a raw material, chlorobenzene, dimethyl sulfoxide, N-methylpyrrolidone and N, N-dimethylformamide are used as solvents, and the raw material and di (2-chloroethyl) amine hydrochloride react to generate 1- [2- (2, 4-dimethylphenylthio) -phenyl ] piperazine shown in a formula V.
Wherein the molar ratio of the 2- (2, 4-dimethylphenylthio) aniline (IV) to the bis (2-chloroethyl) amine hydrochloride is 1: 1-1.2.
The invention has the following advantages:
the preparation method of the 1- [2- (2, 4-dimethylphenylthio) -phenyl ] piperazine only needs three steps of substitution, reduction and ring closing reaction to prepare the high-purity 1- [2- (2, 4-dimethylphenylthio) -phenyl ] piperazine. Avoids the use of expensive palladium complex catalyst, has simple and convenient synthesis process and low cost, and is suitable for industrial production.
Drawings
FIG. 1 is a hydrogen spectrum of compound 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine;
FIG. 2 is a carbon spectrum diagram of a compound 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine
Detailed Description
The present invention is further illustrated by the following specific examples, which are intended to be illustrative, not limiting and are not intended to limit the scope of the invention.
The reaction route involved in the invention is as follows:
example 1
The preparation method of 2- (2, 4-dimethylphenylthio) nitrobenzene comprises the following steps:
adding 2, 4-dimethylthiophenol, 1-fluoro-2-nitrobenzene, potassium carbonate and N, N-dimethylformamide into a 100mL reaction bottle, heating to 90 ℃, and stirring for 5-6 hours under heat preservation. Cooling to room temperature, adding 100mL of water and 100mL of ethyl acetate for extraction, combining organic phases, washing with 100mL of saturated saline solution, drying with anhydrous magnesium sulfate, filtering, carrying out vacuum spin-drying, adding n-hexane or cyclohexane, stirring, and filtering to obtain the yield of 86%.
1H-NMR(CDCl3/TMS)δ:8.25(s,1H),7.48(s,1H),7.31(s,1H),7.21(s,2H), 7.12(s,1H),6.71(s,1H),2.35(d,J＝39.2Hz,6H).
13C-NMR(CDCl3)δ:145.17,143.40,141.33,139.60,137.45,133.76,132.49,128.67,127.5,126.25,124.84,21.59,20.70.
Example 2
The preparation method of the 2- (2, 4-dimethyl thiophenyl) aniline comprises the following specific steps:
adding 10g of reducing iron powder and 70mL of water into a 250mL three-necked flask, adding 0.6mL of glacial acetic acid while stirring at room temperature, adjusting the pH value to 3-4, heating to 100 ℃, keeping the temperature and stirring for 1h, cooling to 70 ℃, adding 6g of 2- (2, 4-dimethylphenylthio) nitrobenzene and 70mL of acetonitrile, heating to 90 ℃, keeping the temperature and stirring for 5-6 h. Cooling to room temperature, adjusting pH to 7-8 with saturated sodium carbonate aqueous solution, adding dichloromethane 100mL, stirring for 1h, filtering with a Buchner funnel filled with diatomaceous earth, separating, retaining organic phase, and extracting aqueous phase with dichloromethane 50 mL. The combined organic phases were dried over anhydrous magnesium sulfate and dried by vacuum spin-drying to give 4.51g of an orange-yellow oil with a yield of 85.0%.
1H-NMR(CDCl3)δ：7.32(s,1H),7.21(s,1H),7.15-6.73(m,5H),5.30(s,2H), 2.32(d,J＝45.3Hz,6H).
13C-NMR(CDCl3)δ:148.05,136.39,135.76,135.30,131.59,131.10,130.32,127.23,126.63,118.86,115.33,20.70,19.95.
Example 3
The preparation method of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine comprises the following steps:
4.51g of 2- (2, 4-dimethylphenylthio) aniline, 5.24g of bis (2-chloroethyl) amine hydrochloride and 30mL of NMP are sequentially added into a 100mL reaction bottle, the temperature is raised to 130 ℃, and the mixture is kept warm and stirred for 22-24 h. Cooling to room temperature, adding 200mL of water and 80mL of dichloromethane for extraction, combining organic phases, washing with 150mL of saturated saline solution, drying with anhydrous magnesium sulfate, carrying out vacuum spin-drying, adding 50mL of ethyl acetate, filtering, adding 35mL of 2M sodium hydroxide aqueous solution into a filter cake while stirring, extracting with 80mL of ethyl acetate, washing the organic phase with 100mL of water, drying with anhydrous magnesium sulfate, adding 0.3g of activated carbon, heating to 55-60 ℃, carrying out heat preservation and stirring for 1-2h, filtering with a Buchner funnel filled with kieselguhr, and carrying out vacuum spin-drying on the filtrate to obtain 1.97g of crude vortioxetine as a yellow solid, wherein the yield is 38%.
1H-NMR(CDCl3)δ:7.36(s,1H),7.15(s,1H),7.07(s,3H),6.87(s,1H),6.51 (s,1H),4.07(s,1H),3.55-3.00(m,8H),2.34(d,J＝18.8Hz,6H).
13C-NMR(CDCl3)δ:148.51,139.24,136.00,134.62,131.68,127.78,126.32,125.58,124.86,120.08,50.80,45.22,21.13,20.53.
HRMS(EI)m/z[M+H]+calcd for C18H23N2S:299.1582；found:299.1587。
Claims (4)
1. A preparation method of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine is characterized in that: the reaction process is as follows:
the method comprises the steps of carrying out substitution reaction on 2, 4-dimethylthiophenol and 1-halogen-2-nitrobenzene to prepare 2- (2, 4-dimethylthiophenyl) nitrobenzene, reducing to prepare 2- (2, 4-dimethylthiophenyl) aniline, carrying out cyclization reaction on the 2- (2, 4-dimethylthiophenyl) aniline and bis (2-chloroethyl) amine hydrochloride to prepare 1- [2 [ -2 ]- (2, 4-dimethylphenylsulfanyl) -phenyl]Piperazine of which X1，X2And X3Each independently represents halogen fluorine, chlorine, bromine.
2. A process for the preparation of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine according to claim 1, characterized in that: wherein in the preparation of III from I and II, the 1-halo-2-nitrobenzene is selected from 1-chloro-2-nitrobenzene, 1-bromo-2-nitrobenzene or 1-fluoro-2-nitrobenzene; the reaction solvent is selected from one or a mixture of any two of acetonitrile, tetrahydrofuran, dimethyl sulfoxide or N, N-dimethylformamide; reacting under an alkaline condition, wherein the alkali is sodium hydroxide, potassium hydroxide or potassium carbonate.
3. A process for the preparation of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine according to claim 1, characterized in that: wherein when preparing IV from III, the reaction solvent is selected from water, methanol, ethanol, isopropanol or the mixed solvent of water and any solvent; the reducing agent is selected from hydrazine hydrate, iron powder and zinc powder; the catalyst is selected from ferric trichloride, hydrochloric acid, glacial acetic acid or sulfuric acid.
4. A process for the preparation of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine according to claim 1, characterized in that: when the V is prepared from the IV, the reaction solvent is one or a mixture of chlorobenzene, dimethyl sulfoxide, N-methylpyrrolidone and N, N-dimethylformamide; the reaction temperature is 110-180 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811540050.3A CN111320592A (en) | 2018-12-17 | 2018-12-17 | Preparation method of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811540050.3A CN111320592A (en) | 2018-12-17 | 2018-12-17 | Preparation method of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111320592A true CN111320592A (en) | 2020-06-23 |
Family
ID=71163152
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811540050.3A Pending CN111320592A (en) | 2018-12-17 | 2018-12-17 | Preparation method of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111320592A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115181077A (en) * | 2022-07-27 | 2022-10-14 | 安徽峆一药业股份有限公司 | Synthetic method of vortioxetine with low impurity content |
Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103788019A (en) * | 2014-01-22 | 2014-05-14 | 苏州明锐医药科技有限公司 | Preparation method of vortioxetine |
| CN103936694A (en) * | 2014-04-23 | 2014-07-23 | 中国药科大学 | Preparation method of antidepressant vortioxetine |
| CN104230852A (en) * | 2014-08-29 | 2014-12-24 | 成都倍特药业有限公司 | Synthetic method of vortioxetine |
| CN104628676A (en) * | 2013-11-08 | 2015-05-20 | 上海医药工业研究院 | Preparation method of Vortioxetine |
| CN104829557A (en) * | 2015-04-23 | 2015-08-12 | 济南百诺医药科技开发有限公司 | Novel compound 1-[2-(2,4-dimethylphenylthio)phenyl]-2-oxopiperazine and its preparation method and use in vortixetine synthesis |
| CN105283442A (en) * | 2013-04-04 | 2016-01-27 | 斯洛文尼亚莱柯制药股份有限公司 | New process for the synthesis of 1-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine |
| CN105348220A (en) * | 2015-11-10 | 2016-02-24 | 山东川成医药股份有限公司 | Synthetic method for vortioxetine hydrobromide |
| CN105669594A (en) * | 2014-11-19 | 2016-06-15 | 康普药业股份有限公司 | Preparation method of anti-depression drug 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (VI) |
| CN105777667A (en) * | 2014-12-18 | 2016-07-20 | 康普药业股份有限公司 | Preparation method of anti-depression drug 1-[2-(2,4-dimethylphenylthio)phenyl]piperazine |
| US20170189394A1 (en) * | 2014-04-28 | 2017-07-06 | Alembic Pharmaceuticals Limited | Novel polymorphic forms of vortioxetine and its pharmaceutically acceptable salts |
| CN107915694A (en) * | 2016-10-09 | 2018-04-17 | 北京阜康仁生物制药科技有限公司 | 1 [2 (2,4 3,5-dimethylphenyl sulfydryl) phenyl] piperazine hydrochloride and preparation method thereof |
-
2018
- 2018-12-17 CN CN201811540050.3A patent/CN111320592A/en active Pending
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105283442A (en) * | 2013-04-04 | 2016-01-27 | 斯洛文尼亚莱柯制药股份有限公司 | New process for the synthesis of 1-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine |
| CN104628676A (en) * | 2013-11-08 | 2015-05-20 | 上海医药工业研究院 | Preparation method of Vortioxetine |
| CN103788019A (en) * | 2014-01-22 | 2014-05-14 | 苏州明锐医药科技有限公司 | Preparation method of vortioxetine |
| CN103936694A (en) * | 2014-04-23 | 2014-07-23 | 中国药科大学 | Preparation method of antidepressant vortioxetine |
| US20170189394A1 (en) * | 2014-04-28 | 2017-07-06 | Alembic Pharmaceuticals Limited | Novel polymorphic forms of vortioxetine and its pharmaceutically acceptable salts |
| CN104230852A (en) * | 2014-08-29 | 2014-12-24 | 成都倍特药业有限公司 | Synthetic method of vortioxetine |
| CN105669594A (en) * | 2014-11-19 | 2016-06-15 | 康普药业股份有限公司 | Preparation method of anti-depression drug 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (VI) |
| CN105777667A (en) * | 2014-12-18 | 2016-07-20 | 康普药业股份有限公司 | Preparation method of anti-depression drug 1-[2-(2,4-dimethylphenylthio)phenyl]piperazine |
| CN104829557A (en) * | 2015-04-23 | 2015-08-12 | 济南百诺医药科技开发有限公司 | Novel compound 1-[2-(2,4-dimethylphenylthio)phenyl]-2-oxopiperazine and its preparation method and use in vortixetine synthesis |
| CN105348220A (en) * | 2015-11-10 | 2016-02-24 | 山东川成医药股份有限公司 | Synthetic method for vortioxetine hydrobromide |
| CN107915694A (en) * | 2016-10-09 | 2018-04-17 | 北京阜康仁生物制药科技有限公司 | 1 [2 (2,4 3,5-dimethylphenyl sulfydryl) phenyl] piperazine hydrochloride and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115181077A (en) * | 2022-07-27 | 2022-10-14 | 安徽峆一药业股份有限公司 | Synthetic method of vortioxetine with low impurity content |
| CN115181077B (en) * | 2022-07-27 | 2024-03-29 | 安徽峆一药业股份有限公司 | Synthesis method of vortioxetine with low impurity content |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103936694A (en) | Preparation method of antidepressant vortioxetine | |
| WO2020147861A1 (en) | Electrochemical preparation method for β-trifluoromethylamide compound | |
| JP4852419B2 (en) | Process for producing 4- (4-aminophenyl) -3-morpholinone | |
| CN102295594B (en) | 4-N-replaces-1-(3-methoxy-propyl)-4-piperidinamines compound and Synthesis and applications | |
| CN104356092B (en) | Preparation method for vortioxetine | |
| AU2011281421A1 (en) | Process for preparing aminobenzoylbenzofuran derivatives | |
| JP2019519474A (en) | Heterocyclic carboxamide ligands and their use in copper-catalyzed coupling of aryl halides | |
| CN110003037B (en) | Method for preparing 2-amino-3, 5-dichloro-N-isopropylbenzamide | |
| CN110511207A (en) | Aryl -2- thiohydantoin class compound intermediate, preparation method and application | |
| CN111925304A (en) | Compound for preparing kalilazine and preparation method thereof | |
| CN102532057B (en) | Copper catalytic synthesis phenothiazine compound | |
| CN102884043B (en) | Synthetic method | |
| CN103880762B (en) | A kind of preparation method of 1,2,3-triazole compound | |
| CN111320592A (en) | Preparation method of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine | |
| CN104326923B (en) | A kind of synthetic method of succsinic acid desmethylvenlafaxine | |
| CN104829557B (en) | A kind of noval chemical compound 1 [2（2,4 3,5-dimethylphenyl sulfenyls）Phenyl] 2 oxygen piperazines and preparation method thereof and the application in Vortioxetine synthesis | |
| CN107915694A (en) | 1 [2 (2,4 3,5-dimethylphenyl sulfydryl) phenyl] piperazine hydrochloride and preparation method thereof | |
| CN113754606B (en) | Phenoxazine diamine derivative and/or phenothiazine diamine derivative and preparation method thereof | |
| CN115385903A (en) | Preparation method of cyano-substituted benzoxazine-4-one derivative | |
| CN108409648B (en) | Preparation method of sorafenib tosylate related intermediate | |
| CN109369645B (en) | Base-catalyzed green synthesis method of 3-arylthio-7-azaindole compound | |
| WO2016155596A1 (en) | Method of synthesizing 3-halo-d-alanine methyl ester or acid salt thereof | |
| CN108218730B (en) | A kind of method that the copper that ligand is recyclable catalyzes and synthesizes 2- methyl -4- methoxy diphenylamine | |
| CN105837528A (en) | Preparation method of 2-(methyl sulphonyl)-10H-phenothiazine | |
| CN107540646B (en) | Synthesis method of vilazodone intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200623 |
|
| RJ01 | Rejection of invention patent application after publication |