CN1696121A - 4-[2-(artyl sulfo) benzyl]-1-derivative of aryl-piperazine, preparation method and application - Google Patents

4-[2-(artyl sulfo) benzyl]-1-derivative of aryl-piperazine, preparation method and application Download PDF

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CN1696121A
CN1696121A CN 200510013526 CN200510013526A CN1696121A CN 1696121 A CN1696121 A CN 1696121A CN 200510013526 CN200510013526 CN 200510013526 CN 200510013526 A CN200510013526 A CN 200510013526A CN 1696121 A CN1696121 A CN 1696121A
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benzyl
piperazine
thiophenyl
methoxy
mole
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李爱军
刘东志
周雪琴
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Tianjin University
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Tianjin University
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Abstract

An anti-depression 4-[2-(arylthio) benzyl]-1-arylpiperazine derivative used to prepare the medicine for treating depression is prepared through Ullmann reaction between p-methoxy benzeneethiol and p-chlorobenzoic acid to generate thioether, reducing, chlorinating and N-alkylation.

Description

4-[2-(artyl sulfo) benzyl]-1-aryl piperazine derivative and preparation method and application
Technical field
The present invention relates to a kind of 4-[2-(artyl sulfo) benzyl with antidepressant activity]-structure of 1-aryl piperazine derivative and its production and application, this technology belongs to the pharmaceutical chemistry field.
Background technology
Dysthymia disorders is a kind of common mental disorder, belong to affective disorder, along with rhythm of life is constantly accelerated, people's stress also increases gradually, and dysthymia disorders has become the common disease of modern society, high morbidity, and its sickness rate is soaring fast: according to incompletely statistics, at present whole world patients with depression has accounted for 3% one 5% of world population, almost see each age level, its morbidity is about 3% in the general population, in the patient population of general hospital polyclinic's health care service about about 10%; And in patient's (as cardiovascular diseases, diabetes) of chronic physical disease, that suffers from depressive disorder can but, have only the patient of considerably less ratio identified up to 20%.By pharmacological agent, wherein about 2/3 patient can obtain different curative effects, as the end in time discern and treat they will bring more serious consequence (as commit suiside, disabled, too much medical resource waste etc.).The World Health Organization predicts the year two thousand twenty, and dysthymia disorders will become the 2nd big cause that causes deformity.
Nineteen fifty is for tricyclic antidepressant (TCA having occurred, Anticholinergic), 5-HT selectivity reuptake inhibitor class SSRI (Fluoxetine has appearred in the 1980's, Paroxetine, Sertaline, Citalopram, Fluvoxamine) because of its good antidepressant performance, replace TCA gradually and become leading product on the thymoleptic market, yet owing to the SSRI indirect action has nauseating in all 5-HT acceptors, anxiety, insomnia, sexual function side effect such as decrease, and maximum weakness is a lag-effect in clinical use, promptly generally after week antidepressant effect could appear at the 2-6 that begins to take medicine, therefore in order to seek safety, quick acting, the thymoleptic that side effect is little, the medicine scholars have carried out various trials.
The thymoleptic such as the NE/5-HT reuptake inhibitor SNRI (Venlaxine of some new role mechanism appearred in generation nineteen ninety so far, Milnacipran, Duloxetine, Nefezodone), selectivity oxidase inhibitor MAOI (Moclobe mide, Toloxatone), selective N E reuptake inhibitor NARI (Reboxetine), NE energy and specificity 5-HT energy antidepressive NaSSa (Mirtazapine), though these medicines are compared with the SSRI class, on curative effect and quick acting, be improved, but lag-phase in 1-2 week is still arranged, therefore very urgent to the drug research of quick acting more.
Reported first such as Artigas were with pindolol (blended 5-HT in 1993 1A/ beta-2 adrenoceptor antagonist) can significantly reduce lag-phase of SSRIS with the medication of SSRIS antidepressant medicament combination, strengthen antidepressant effect, patient symptom is significantly improved.Result of study subsequently shows, 5-HT 1AAntagonist WAY100635 and several SSRIS connection and medication also can show this effect.A kind of hypothesis of this phenomenon is thought it may is the 5-HT of preceding nerve synapse 1ATherefore the autonomous acceptor of nerve synapse 5-HT before the antagonistic action of autonomous acceptor can be blocked has increased the 5-HT concentration between the nerve synapse gap, thereby improves curative effect, reduces the lag-phase etc.
On this basis, present research focus mainly is with various 5-HT 1AThe primary structure of receptor antagonist or agonist primary structure and SSRIS is combined in the molecule and makes it 5-HT conducting band and 5-HT 1AAcceptor all has higher affinity, thereby brings into play dual antidepressant effect, and this kind idea is further extended, and has just formed so-called SSRI ' plus ' method.Under the guidance of this method, the compound that some new role mechanism occurred is in the clinical study stage at present, for example Flibanserin and Vilazodone, and they antidepressant effect can just occur after taking several days.
Summary of the invention
The object of the present invention is to provide a kind of 4-[2-(artyl sulfo) benzyl]-1-aryl piperazine derivative and preparation method and application, this compounds has 5-HT and 5-HT simultaneously 1AActivity can be used for preparing anti-depression drug.
The present invention is realized by following technical proposals, a kind of 4-[2-(artyl sulfo) benzyl]-the 1-aryl piperazine derivative, it is characterized in that structural formula is as follows:
Wherein: Ar is:
Or
R 1, R 2For: hydrogen, C 1-C 3Alkyl, five yuan of cycloaliphatic rings, hexa-atomic cycloaliphatic rings, the five-membered ring that contains S, N, O, the hexa-member heterocycle that contains S, N, O, phenyl, substituted-phenyl, hydroxyl, C 1-C 3Alkoxyl group, amino, substituted-amino, halogen, carboxylic acid, ester, acid amides, nitro, itrile group and trihalogenmethyl in a kind of, two or three; X, Y are: C, S, N or O.
Above-mentioned R 1, R 2For: hydrogen, C 1-C 3Alkyl, hydroxyl, C 1-C 3Alkoxyl group, amino, substituted-amino, halogen, carboxylic acid and derivative thereof, nitro, itrile group and trihalogenmethyl in a kind of, two or three.
Above-mentioned 4-[2-(artyl sulfo) benzyl]-the 1-aryl piperazine derivative comprises following compound:
4-[2-(2-methoxy thiophenyl) benzyl]-1-(3-chloro-phenyl-) piperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-1-(2, the 3-dichlorophenyl) piperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-1-(2, the 3-3,5-dimethylphenyl) piperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-the 1-phenylpiperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-1-(2-pyridyl) piperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-1-(2-pyrimidyl) piperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-1-(2-p-methoxy-phenyl) piperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-1-(4-p-methoxy-phenyl) piperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-1-(3-trifluoromethyl) piperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-1-(1-naphthyl) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(3-chloro-phenyl-) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(2, the 3-dichlorophenyl) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(2, the 3-3,5-dimethylphenyl) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-the 1-phenylpiperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(2-pyridyl) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(2-pyrimidyl) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(2-p-methoxy-phenyl) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(4-p-methoxy-phenyl) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(3-trifluoromethyl) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(1-naphthyl) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(3-chloro-phenyl-) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(2, the 3-dichlorophenyl) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(2, the 3-3,5-dimethylphenyl) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-the 1-phenylpiperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(2-pyridyl) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(2-pyrimidyl) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(2-p-methoxy-phenyl) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(4-p-methoxy-phenyl) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(3-trifluoromethyl) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(1-naphthyl) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(3-chloro-phenyl-) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(2, the 3-dichlorophenyl) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(2, the 3-3,5-dimethylphenyl) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-the 1-phenylpiperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(2-pyridyl) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(2-pyrimidyl) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(2-p-methoxy-phenyl) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(4-p-methoxy-phenyl) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(3-trifluoromethyl) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(1-naphthyl) piperazine
Above-mentioned 4-[2-(artyl sulfo) benzyl]-preparation method of 1-aryl piperazine derivative, its preparation general formula is:
Figure A20051001352600071
A:K 2CO 3, DMF, Cu; B:LAH, THF; C:SOCl 2, CHCl 3D:(1) aryl piperazines, TEA, DMF, (2) HCle: aryl piperazines, TEA, CHCl 3
It is characterized in that comprising following process:
One of method comprises following process: with the 0-chloro-benzoic acid of 1 mole aryl thiophenol and 1～1.5 mole in the presence of the copper powder of 1～3 mole Anhydrous potassium carbonate or anhydrous sodium carbonate and 0.1～1.0 mole or cuprous halide in N, carry out Ullmann thioetherification reaction in 80～150 ℃ in the N dimethyl formamide (DMF) and generate 2-(2-aryl thiophenyl) phenylformic acid; In tetrahydrofuran (THF) (THF), be reduced to 2-(2-aryl thiophenyl) benzylalcohol with 0.5～2 mole of lithium aluminum hydride or borine with 1 mole 2-(2-aryl thiophenyl) phenylformic acid in 30～85 ℃; Is 2-(2-aryl thiophenyl) benzyl chlorine in the room temperature chlorination with 1～5 mole sulfur oxychloride with 1 mole 2-(2-aryl thiophenyl) benzylalcohol in chloroform; With the aryl piperazines of 1 mole 2-(2-aryl thiophenyl) benzyl chlorine and 1～3 mole in the presence of 1～2 mole of triethylamine in DMF 50～80 ℃ of reactions generate 4-[2-(artyl sulfo) benzyls]-the 1-aryl piperazine derivative.
Two of method comprises following process: with the 0-chloro-benzoic acid of 1 mole aryl thiophenol and 1～1.5 mole in the presence of the copper powder of 1～3 mole Anhydrous potassium carbonate or anhydrous sodium carbonate and 0.1～1.0 mole or cuprous halide in N, carry out Ullmann thioetherification reaction in 80～150 ℃ in the N dimethyl formamide (DMF) and generate 2-(2-aryl thiophenyl) phenylformic acid; With 1 mole 2-(2-aryl thiophenyl) phenylformic acid, in chloroform, be 2-(2-aryl thiophenyl) Benzoyl chloride in the room temperature chlorination with 1～5 mole sulfur oxychloride; The aryl piperazines of 1 mole 2-(2-anisole sulfenyl) Benzoyl chloride and 1～3 mole in the presence of 1～3 mole triethylamine 0～50 ℃ in chloroform reaction generate 4-[2-(2-aryl thiophenyl) benzoyl]-the 1-aryl piperazines; 1 mole 4-[2-(2-aryl thiophenyl) benzoyl]-the 1-aryl piperazines is reduced to 4-[2-(artyl sulfo) benzyl in 30～85 ℃ with 0.5～5 mole lithium aluminum hydride or borine in tetrahydrofuran (THF) (THF)]-the 1-aryl piperazine derivative.
Above-mentioned 4-[2-(artyl sulfo) benzyl]-application of 1-aryl piperazine derivative, be that form with its free alkali or salt is used to prepare the medicine of protesting strongly fragrant disease, salt is organic salts such as inorganic salt such as hydrochloride, hydrobromate, vitriol, trifluoroacetate, mesylate, maleate.
The invention has the advantages that simple, the no High Temperature High Pressure operation of its preparation process, yield height.Prepared product has 5-HT and 5-HT simultaneously 1AActivity can be used for preparing the medicine of protesting strongly fragrant disease.
Embodiment
Embodiment 1:4-[2-(2-methoxy thiophenyl) benzyl]-1-(3-trifluoromethyl) piperazine hydrochloride
Step 1: 2-(2-anisole sulfenyl) phenylformic acid
(48mmol 6.72g) and in the mixture of DMF (120ml), adds Anhydrous potassium carbonate (144mmol at o-methoxythiophenol, 19.9g), copper powder (12.6mmol, 0.8g), 0-chloro-benzoic acid (40mmol, 6.26g), reaction mixture is warming up to 100 ℃ of high degree of agitation reaction 24h, cooling, add 600ml distilled water in the mixture, filter filtrate activated carbon decolorizing 30min, filter, filtrate 6mol/L hydrochloric acid is transferred pH7.0, filters, and filtrate is transferred pH3.0 again, separate out white crystals, filter washing (20ml * 3), vacuum-drying, get white crystals (7.85g, 75.5%).
mp：198.0～200.0℃. 1H-NMR(CDCl 3)δ：8.14(d，1H)，7.58(d，2H)，7.57(t，1H)，7.28(m，2H)，7.17(t，3H)，7.04(m，2H)，6.82(d，2H)，3.80(s，3H). 13H-NMRδ：170.68，160.34，143.14，137.70，132.98，132.27，131.64，127.30，125.75，124.41，121.69，119.88，111.66，55.99.MS?m/z：260.0(M +，100)，200.0(18)，171.0(21)，137.0(40)，124.0(18)，82.9(20)，45.0(17).
Step 2: 2-(2-anisole sulfenyl) phenylcarbinol
With lithium aluminum hydride (0.044mol, 1.67g) be dissolved in the tetrahydrofuran (THF) (80ml), (64 ℃) drip 2-(2-anisole sulfenyl) phenylformic acid (0.02mol under the reflux temperature in 30min, 5.2g) tetrahydrofuran (THF) (100ml) solution, drip complete back flow reaction 5h, be chilled to 0 ℃, add distilled water (2ml) successively, 15% sodium hydroxide (2ml), distilled water (6ml), mixture high degree of agitation 30min filters, filtrate adds distilled water (120ml), chloroform extraction (100ml * 3), dry (anhydrous sodium sulphate) removes solvent under reduced pressure, obtain yellow thickness oily matter (4.52g, 91.8%).
1H-NMR(CDCl 3)δ：7.51(d，1H)，7.36(t，2H)，7.26(m，2H)，6.93(m，3H)，4.79(s，2H)，3.86(s，3H)，2.55(s，1H). 13H-NMRδ：156.86，142.88，134.32，131.74，130.45，128.69，124.28，121.34，110.89，63.77，55.84，29.66.MS?m/z：246.1(M +，100)，197.1(14)，171.1(7)，140.1(86)，77.0(61)，51.0(24).
Step 3: 2-(2-anisole sulfenyl) benzyl chlorine
With 2-(2-anisole sulfenyl) phenylcarbinol (0.0184mol, 4.55g) be dissolved in the chloroform (120ml), add 5 of DMF, and sulfur oxychloride (0.055mol, 4ml), stirring at room 4h, remove solvent and excess chlorination sulfoxide under reduced pressure, get yellow oil, cooling curing becomes light brown solid (4.38g, 89.5%), product is directly used in next step reaction without purification.
mp：85-88℃. 1H-NMR(CDCl 3)δ：7.52(t，2H)，7.33(m，2H)，7.26(m，2H)，6.91(m，3H)，4.81(s，2H)，3.85(s，3H). 13H-NMRδ：157.08，139.27，134.06，130.70，129.28，128.33，124.21，121.31，110.88，55.89，44.45，29.66.MS?m/z：264.0(M +，100)，227.1(34)，213.1(28)，184.1(17)，152.1(12)，125.0(39)，89.0(26)，63.0(34)，27.0(6).
Step 4: 4-[2-(2-methoxy thiophenyl) benzyl]-1-(3-trifluoromethyl) piperazine hydrochloride
2-(2-anisole sulfenyl) benzyl chlorine (0.00325mol, 0.8g) be dissolved among the DMF (50ml), the adding triethylamine (0.00465mol, 0.71ml), the catalytic amount anhydrous sodium iodide, add 1-(3-trifluoromethyl) piperazine hydrochloride (0.00357mol, 0.952g) the 80 ℃ of reaction 5h that heat up, reaction solution is chilled to room temperature, adds entry (100ml), chloroform extraction (50ml * 3), washing (50ml * 10), chloroform solution drying (anhydrous sodium sulphate) is passed through filtered through silica gel, remove solvent under reduced pressure, get light yellow oil (1.10g, 73.8%), it is dissolved in the anhydrous diethyl ether (60ml), the dripping hydrochloric acid diethyl ether solution, separate out white solid, filter drying under reduced pressure, get white solid (0.83g, 51.0%).
mp：213.0～214.0℃. 1H-NMR(CDCl 3)δ：13.29(s，1H，)，8.18(d，1H)，7.68(s，1H)，7.61(d，1H)，7.53(t，1H)，7.45(m，2H)，7.36(t，2H)，7.27(m，2H)，6.93(m，3H)，4.58(s，2H)，4.36(m，2H)，3.81(s，3H)，3.73(s，2H)，3.62(d，4H). 13H-NMRδ：157.18，145.68，136.23，134.01，133.57，132.67，131.51，129.26，122.81，116.45，111.32，57.25，55.93，49.78，48.69.MS?m/z：458.1(M +，5)，230.1(26)，188.1(100)，145.0(14)，56.0(20)，29.0(9).
Embodiment 2:4-[2-(2-methoxy thiophenyl) benzyl]-1-(3-chloro-phenyl-) piperazine hydrochloride
The step 1 of present embodiment, step 2, step 3 are with embodiment one.
Step 4: 4-[2-(2-methoxy thiophenyl) benzyl]-1-(3-chloro-phenyl-) piperazine hydrochloride
(0.004226mol 1.04g) is dissolved among the DMF (50ml) 2-(2-anisole sulfenyl) benzyl chlorine, adds triethylamine (0.005071mol, 0.71ml), the catalytic amount anhydrous sodium iodide adds 1-(3-chloro-phenyl-) piperazine (0.004649mol, 0.9144g), the 80 ℃ of reaction 6.5h that heat up, reaction solution is chilled to room temperature, add entry (100ml), chloroform extraction (50ml * 3), washing (50ml * 10), chloroform solution drying (anhydrous sodium sulphate), pass through filtered through silica gel, remove solvent under reduced pressure, get light yellow oil, it is dissolved in the anhydrous diethyl ether (60ml), the dripping hydrochloric acid diethyl ether solution, separate out white solid, filter drying under reduced pressure, get white solid (1.55g, 77.3%).
mp：215.0～217.0℃. 1H-NMR(CDCl 3)δ：13.34(s，1H)，8.18(d，1H)，7.47(m，2H)，7.37(m，4H)，7.27(m，2H)，7.20(d，1H)，6.94(m，3H)，4.56(s，2H)，4.37(t，2H)，3.81(s，3H)，3.78(m，2H)，3.64(m，4H). 13H-NMRδ：157.23，145.81，136.28，135.92，134.07，133.58，131.56，129.30，126.81，122.38，121.51，120.00，117.63，111.35，57.32，55.97，49.64，48.92.MS?m/z：424.1(M +，43)，286.0(10)，229.0(41)，197.0(66)，154.0(34)，56.0(100)，36.0(53).
Embodiment 3:4-[2-(2-methoxy thiophenyl) benzyl]-1-phenylpiperazine hydrochloride
The step 1 of present embodiment, step 2, step 3 are with embodiment one.
Step 4: 4-[2-(2-methoxy thiophenyl) benzyl]-1-phenylpiperazine hydrochloride
(0.002mol 0.5g) is dissolved among the DMF (50ml) 2-(2-anisole sulfenyl) benzyl chlorine, adds triethylamine (0.0023mol, 0.32ml), the catalytic amount anhydrous sodium iodide adds 1-phenylpiperazine (0.0022mol, 0.357g), the 80 ℃ of reaction 7.5h that heat up, reaction solution is chilled to room temperature, add entry (100ml), chloroform extraction (50ml * 3), washing (50ml * 10), chloroform solution drying (anhydrous sodium sulphate), pass through filtered through silica gel, remove solvent under reduced pressure, get light yellow oil, it is dissolved in the anhydrous diethyl ether (60ml), the dripping hydrochloric acid diethyl ether solution, separate out white solid, filter drying under reduced pressure, get white solid (0.214g, 22.5%).
mp：234.0～236.0℃. 1H-NMR(DMSO-d 6)δ：11.82(s，1H)，10.99(s，1H)，8.10(d，1H)，7.48(m，2H)，7.33(m，4H)，7.09(d，2H)，7.01(d，1H)，6.99(d，2H)，6.93(m，3H)，4.56(s，2H)，3.79(s，3H)，3.76(bs，2H)，3.48(m，2H，)，3.38(t，2H)，3.27(d，2H). 13H-NMRδ：156.85，149.15，135.53，133.52，131.05，129.15，122.58，121.39，120.33，116.13，111.73，55.92，50.46，45.34，40.13，39.92，39.71，39.50，39.29，39.08，38.87.MS?m/z：390.1(M +，100)，282.1(9)，229.1(28)，197.0(45)，161.1(48)，56.1(30)，35.9(28).
Embodiment 4:4-[2-(2-methoxy thiophenyl) benzyl]-1-(2-pyridyl) piperazine hydrochloride
The step 1 of present embodiment, step 2, step 3 are with embodiment one.
Step 4: 4-[2-(2-methoxy thiophenyl) benzyl]-1-(2-pyridyl) piperazine hydrochloride
(0.002mol 0.5g) is dissolved among the DMF (50ml) 2-(2-anisole sulfenyl) benzyl chlorine, adds triethylamine (0.0023mol, 0.32ml), the catalytic amount anhydrous sodium iodide adds 1-(2-pyridyl) piperazine (0.0022mol, 0.36g) 80 ℃ of reaction 8.0h heat up, reaction solution is chilled to room temperature, adds entry (100ml), chloroform extraction (50ml * 3), washing (50ml * 10), chloroform solution drying (anhydrous sodium sulphate) by filtered through silica gel, removes solvent under reduced pressure, get light yellow oil, it is dissolved in the anhydrous diethyl ether (60ml), and the dripping hydrochloric acid diethyl ether solution is separated out white solid, filter, drying under reduced pressure gets white solid (0.397g, 42.8%).
mp：213.0～214.5℃. 1H-NMR(CDCl 3)δ：12.65(s，1H)，8.08(d，2H)，7.94(s，1H)，7.35(t，1H)，7.28(m，4H)，6.95(s，1H)，6.89(d，2H)，6.84(m，2H)，4.55(m，4H)，4.17(s，2H)，3.76(s，3H)，3.70(m，2H)，3.44(m，2H). 13H-NMRδ：157.24，151.98，144.96，137.91，136.30，133.43，131.83，131.01，129.35，129.03，128.44，121.93，121.45，114.43，112.68，111.24，57.00，56.00，50.57，44.27.MS?m/z：391.1(M +，7)，284.0(11)，229.1(45)，197.0(17)，146.0(24)，107.1(100)，35.9(13).
Embodiment 5:4-[2-(2-methoxy thiophenyl) benzyl]-1-(2-pyrimidyl) piperazine hydrochloride
The step 1 of present embodiment, step 2, step 3 are with embodiment one.
Step 4: 4-[2-(2-methoxy thiophenyl) benzyl]-1-(2-pyrimidyl) piperazine hydrochloride
(0.002mol 0.5g) is dissolved among the DMF (50ml) 2-(2-anisole sulfenyl) benzyl chlorine, adds triethylamine (0.0023mol, 0.32ml), the catalytic amount anhydrous sodium iodide adds 1-(2-pyrimidyl) piperazine (0.0022mol, 0.361g) 80 ℃ of reaction 7.5h heat up, reaction solution is chilled to room temperature, adds entry (100ml), chloroform extraction (50ml * 3), washing (50ml * 10), chloroform solution drying (anhydrous sodium sulphate) by filtered through silica gel, removes solvent under reduced pressure, get light yellow oil, it is dissolved in the anhydrous diethyl ether (60ml), and the dripping hydrochloric acid diethyl ether solution is separated out white solid, filter, drying under reduced pressure gets white solid (0.385g, 41.4%).
mp：218.0～219.0℃. 1H-NMR(CDCl 3)δ：13.62(s，1H)，8.57(d，2H)，8.23(d，1H)，7.47(t，1H)，7.37(m，2H)，7.25(t，1H)，6.93(m，4H)，5.16(d，2H)，4.51(s，2H)，3.82(s，3H)，3.72(m，4H)，3.60(m，2H). 13H-NMRδ：157.35，157.13，136.14，133.91，131.73，131.41，129.53，129.27，122.27，121.76，111.45，110.80，58.63，57.16，56.21，50.95，42.72.MS?m/z：392.0(M +，11)，284.0(16)，229.0(41)，197.0(15)，163.0(13)，56.1(31)，35.9(100).
Embodiment 6:4-[2-(2-methoxy thiophenyl) benzyl]-1-(2-p-methoxy-phenyl) piperazine hydrochloride
Step 1: 2-(2-anisole sulfenyl) Benzoyl chloride
With 2-(2-anisole sulfenyl) phenylformic acid (0.015mol, 3.9g) be dissolved in the chloroform (60ml), add 5 of DMF, room temperature 30min dripping thionyl chloride (0.024mol, 1.8ml) chloroformic solution (30ml), backflow (61 ℃) stirring reaction 6h removes solvent and excess chlorination sulfoxide under reduced pressure, gets yellow crystal 4.0g.Product is directly used in next step reaction without purification.
Step 2: 4-[2-(2-anisole sulfenyl) benzoyl]-1-(2-p-methoxy-phenyl) piperazine
2-(2-anisole sulfenyl) Benzoyl chloride (4.0g) adds chloroform (90ml), and triethylamine (30mmol, 5.7ml), 1-(2-p-methoxy-phenyl) piperazine hydrobromide (12mmol, 3.3g), room temperature reaction 4h, 2mol/L sodium hydroxide (90ml * 3) successively, water (90ml * 3) is washed, dry (anhydrous sodium sulphate), filter, remove solvent under reduced pressure, leave standstill cooling, be solidified into yellow crystal, 60% aqueous ethanolic solution 60ml recrystallization gets white crystals (3.47g, 66.6%).
mp：135.0～137.0℃. 1H-NMR(CDCl 3)δ：7.24(m，5H)，3.96(s，2H)，3.84(s，3H)，3.78(s，3H)，3.46(s，2H)，3.12(t，2H)，2.96(m，2H). 13H-NMRδ：168.44，158.00，152.38，140.95，138.33，133.14，132.72，131.71，129.44，129.15，127.11，127.02，123.53，122.76，121.39，121.12，118.58，111.46，111.23，55.90，55.53，50.99，50.69，47.30，41.95.MS?m/z：434.1(M +，47)，243.1(30)，191.1(29)，69.1(83)，41.0(37)
Step 3: 4-[2-(2-methoxy thiophenyl) benzyl]-1-(2-p-methoxy-phenyl) piperazine hydrochloride
With lithium aluminum hydride (4.5mmol; 0.171g) be dissolved in the tetrahydrofuran (THF) (30ml); (64 ℃) drip 4-[2-(2-anisole sulfenyl) benzoyl under the reflux temperature in 30min]-1-(2-p-methoxy-phenyl) piperazine (1mmol; 0.434g) tetrahydrofuran (THF) (30ml) solution; drip complete back flow reaction 8h; be chilled to 0 ℃, add distilled water (1ml) successively, 15% sodium hydroxide (1ml); distilled water (3ml); mixture high degree of agitation 30min filters, and filtrate adds distilled water (50ml); chloroform extraction (50ml * 3); dry (anhydrous sodium sulphate) removes solvent under reduced pressure, obtains yellow thickness oily matter.It is dissolved in the anhydrous diethyl ether (30ml), and the dripping hydrochloric acid diethyl ether solution is separated out white solid, filters, and drying under reduced pressure gets white solid (0.23g, 46.6%).
mp：198.0～199.5℃. 1H-NMR(CDCl 3)δ：7.53(s，1H)，7.29(m，2H)，7.19(t，2H)，6.98(m，1H)，6.98-6.79(m，8H)，3.85(s，3H)，3.83(s，3H)，3.74(s，2H)，3.05(s，4H)，2.67(s，4H). 13H-NMRδ：157.02，152.32，133.60，130.66，129.95，127.62(d)，122.72，121.20，120.96，118.25，111.22，110.80，60.27，55.91，55.34，53.15，50.71，29.69.MS?m/z：420.2(M +，100)，284.2(13)，257.2(34)，191.2(55)，136.1(69)，56.1(85)，43.1(55).
Embodiment 7:4-[2-(2-methoxy thiophenyl) benzyl]-1-(4-p-methoxy-phenyl) piperazine hydrochloride
Step 1: with the step 1 of embodiment 6.
Step 2: 4-[2-(2-anisole sulfenyl) benzoyl]-1-(4-p-methoxy-phenyl) piperazine
2-(2-anisole sulfenyl) Benzoyl chloride (2.6g) adds chloroform (60ml), and triethylamine (20mmol, 3.8ml), 1-(4-p-methoxy-phenyl) piperazine hydrochloride (8mmol, 2.2g), room temperature reaction 4h, 2mol/NaOH sodium hydroxide (50ml * 3) successively, water (50ml * 3) is washed, dry (anhydrous sodium sulphate), filter, remove solvent under reduced pressure, leave standstill cooling, be solidified into yellow crystal, 60% aqueous ethanolic solution 50ml recrystallization gets white crystals (2.84g, 81.7%).
mp：120.0～121.5℃. 1H-NMR(CDCl 3)δ：7.27(m，5H)，7.16(m，1H)，6.89-6.79(m，6H)，3.94(t，2H)，3.76(s，3H)，3.74(s，3H)，3.41(s，2H)，3.12(s，2H)，2.97(s，2H). 13H-NMRδ：168.20，157.85，154.28，145.23，137.83，133.12，132.61，131.37，129.32，129.10，126.89，126.80，122.29，121.19，118.88，114.41，111.08，55.70，55.45，51.11，50.85，46.85.MS?m/z：434.1(M +，69)，281.0(19)，243.0(42)，191.1(26)，162.1(100)，56.0(61)，39.0(6).
Step 3: 4-[2-(2-methoxy thiophenyl) benzyl]-1-(4-p-methoxy-phenyl) piperazine hydrochloride
With lithium aluminum hydride (4.5mmol; 0.171g) be dissolved in the tetrahydrofuran (THF) (30ml); (64 ℃) drip 4-[2-(2-anisole sulfenyl) benzoyl under the reflux temperature in 30min]-1-(4-p-methoxy-phenyl) piperazine (1mmol; 0.434g) tetrahydrofuran (THF) (30ml) solution; drip complete back flow reaction 8h; be chilled to 0 ℃, add distilled water (1ml) successively, 15% sodium hydroxide (1ml); distilled water (3ml); mixture high degree of agitation 30min filters, and filtrate adds distilled water (50ml); chloroform extraction (50ml * 3); dry (anhydrous sodium sulphate) removes solvent under reduced pressure, obtains yellow thickness oily matter.It is dissolved in the anhydrous diethyl ether (30ml), and the dripping hydrochloric acid diethyl ether solution is separated out white solid, filters, and drying under reduced pressure gets white solid (0.25g, 50.7%).
mp：231.0～233.0℃. 1H-NMR(CDCl 3)δ：13.50(bs，1H)，8.11(d，1H)，7.79(d，2H)，7.44(d，1H)，7.36(d，2H)，7.25(m，1H)，7.00-6.85(m，5H)，4.73(s，2H)，4.58(s，2H)，4.27(s，2H)，3.83-3.83(t，6H)，3.59-3.45(m，4H). 13H-NMRδ：157.00，153.77，145.67，134.04，133.55，130.66，130.16，127.97(t)，124.95，121.20，118.25(d)，114.38，110.81，59.80，55.86，55.52，53.40，52.86，50.41，49.38，29.65.MS?m/z：420.1(M +，12)，228.2(24)，185.1(20)，129.0(36)，73.0(86)，43.0(100).
Embodiment 8:4-[2-(2-anisole sulfenyl) benzoyl]-1-(2,3-dimethylphenylpiperazinium hydrochloride
Step 1: with the step 1 of embodiment 6.
Step 2: 4-[2-(2-anisole sulfenyl) benzoyl]-1-(2, the 3-3,5-dimethylphenyl) piperazine
2-(2-anisole sulfenyl) Benzoyl chloride (2.6g) adds chloroform (60ml), and triethylamine (30mmol, 5.7ml), 1-(2, the 3-3,5-dimethylphenyl) piperazine hydrochloride (8mmol, 1.81g), room temperature reaction 3h, 2mol/NaOH sodium hydroxide (50ml * 3) successively, water (50ml * 3) is washed, dry (anhydrous sodium sulphate) filters, and removes solvent under reduced pressure, leave standstill cooling, be solidified into yellow crystal, 60% aqueous ethanolic solution 50ml recrystallization, get white crystals (2.56g, 59.5%).
mp：97.0～99.0℃. 1H-NMR(CDCl 3)δ：7.31-7.24(m.，5H)，7.22(d，1H)，7.17(m，1H)，6.93(m，3H)，6.85(d，1H)，3.97(bs，2H)，3.79(s，3H)，3.45(s，2H)，2.94(s，2H)，2.82(s，2H)，2.27-2.24(d，6H). 13H-NMRδ：168.31，157.88，150.89，137.94，133.22，132.61，131.20，129.21，126.80，125.75，125.33，122.26，121.17，116.73，111.05，55.67，52.19，51.98，47.34，41.98，20.48，13.75.MS?m/z：432.2(M +，23)，285.1(8)，243.1(29)，189.1(24)，160.1(100)，56.0(38)，28.0(5).
Step 3: 4-[2-(2-methoxy thiophenyl) benzyl]-1-(2, the 3-3,5-dimethylphenyl) piperazine hydrochloride
With lithium aluminum hydride (4.5mmol; 0.171g) be dissolved in the tetrahydrofuran (THF) (30ml); (64 ℃) drip 4-[2-(2-anisole sulfenyl) benzoyl under the reflux temperature in 30min]-1-(2; the 3-3,5-dimethylphenyl) piperazine (1mmol; 0.432g) tetrahydrofuran (THF) (30ml) solution, drip complete back flow reaction 8h, be chilled to 0 ℃; add distilled water (1ml) successively; 15% sodium hydroxide (1ml), distilled water (3ml), mixture high degree of agitation 30min; filter; filtrate adds distilled water (50ml), chloroform extraction (50ml * 3), dry (anhydrous sodium sulphate); remove solvent under reduced pressure, obtain yellow thickness oily matter.It is dissolved in the anhydrous diethyl ether (30ml), and the dripping hydrochloric acid diethyl ether solution is separated out white solid, filters, and drying under reduced pressure gets white solid (0.31g, 68.1%).
mp：180.0～184.0℃. 1H-NMR(CDCl 3)δ：12.89(bs，1H)，8.33(d，1H)，7.45(s，1H)，7.39-7.33(m，2H)，7.27(t，1H)，7.10(m，2H)，7.01(t，1H)，6.91-6.84(m，3H)，4.56(s，2H)，3.95(br，2H)，3.84(s，3H)，3.45(s，4H)，3.17(d，2H)，2.27(d，6H). 13H-NMRδ：157.26，138.91，135.94，134.47，133.99，131.42，131.18，130.26，129.58，129.24，127.78，126.76，123.09，121.74，117.94，111.43，57.26，56.15，51.48，49.51，20.78，14.50.MS?m/z：418.1(M +，70)，284.0(8)，229.0(34)，189.1(49)，132.0(75)，56.0(1?00)，39.0(25).
Embodiment 9:4-[2-(2-methoxy thiophenyl) benzyl]-1-(2, the 3-dichlorophenyl) piperazine hydrochloride
Step 1: with the step 1 of embodiment 6
Step 2: 4-[2-(2-anisole sulfenyl) benzoyl]-1-(2, the 3-dichlorophenyl) piperazine
2-(2-anisole sulfenyl) Benzoyl chloride (2.6g) adds chloroform (60ml), and triethylamine (30mmol, 5.7ml), 1-(2, the 3-dichlorophenyl) piperazine hydrochloride (8mmol, 2.14g), room temperature reaction 4.5h, 2mol/NaOH sodium hydroxide (50ml * 3) successively, water (50ml * 3) is washed, dry (anhydrous sodium sulphate) filters, and removes solvent under reduced pressure, leave standstill cooling, be solidified into yellow crystal, 60% aqueous ethanolic solution 70ml recrystallization, get white crystals (3.0g, 63.4%).
mp：170.0～171.0℃. 1H-NMR(CDCl 3)δ：7.29-7.23(m，5H)，7.17-7.10(m，3H)，6.91-6.86(m，3H)，3.97(br?s，2H)，3.77(s，3H)，3.47(s，2H)，3.10(d，2H)，2.95(s，2H). 13H-NMRδ：168.31，157.88，150.58，137.60，133.94，133.30，132.66，131.05，129.29(d)，127.53(d)，126.80(d)，124.93，122.04，121.19，118.71，111.07，55.67，51.49，50.95，47.03，41.64.MS?m/z：472.1(M +，11)，285.0(17)，243.0(100)，200.0(42)，123.1(23)，56.0(83)，29.0(9).
Step 3: 4-[2-(2-methoxy thiophenyl) benzyl]-1-(2, the 3-dichlorophenyl) piperazine hydrochloride
With lithium aluminum hydride (4.5mmol; 0.171g) be dissolved in the tetrahydrofuran (THF) (30ml); (64 ℃) drip 4-[2-(2-anisole sulfenyl) benzoyl under the reflux temperature in 30min]-1-(2; the 3-dichlorophenyl) piperazine (1mmol; 0.434g) tetrahydrofuran (THF) (30ml) solution, drip complete back flow reaction 8h, be chilled to 0 ℃; add distilled water (1ml) successively; 15% sodium hydroxide (1ml), distilled water (3ml), mixture high degree of agitation 30min; filter; filtrate adds distilled water (50ml), chloroform extraction (50ml * 3), dry (anhydrous sodium sulphate); remove solvent under reduced pressure, obtain yellow thickness oily matter.It is dissolved in the anhydrous diethyl ether (30ml), and the dripping hydrochloric acid diethyl ether solution is separated out white solid, filters, and drying under reduced pressure gets white solid (0.33g, 66.6%).
mp：223.0～225.0℃. 1H-NMR(CDCl 3)δ：12.88(s，lH)，8.35(d，1H)，7.47(t，1H)，7.40(m，2H)，7.29-7.23(m，1H)，7.21(d，1H)，7.16(t，1H)，6.70(d，1H)，6.92(m，3H)，4.56(d，2H)，3.84(s，3H)，3.72(q，2H)，3.50(d，2H)，3.31(d，2H)，3.20(q，2H). 13H-NMRδ：156.90，148.98，135.53，134.28，134.09，133.74，130.98(d)，130.09，129.36，128.97，127.77，127.48，126.00，122.80，121.49，119.24，111.15，56.90，55.86，51.73，47.85.MS?m/z：458.1(M +，30)，350.1(6)，284.0(7)，229.0(52)，197.0(48)，150.0(23)，56.0(100)，42.0(14).

Claims (6)

1. a 4-[2-(artyl sulfo) benzyl]-the 1-aryl piperazine derivative, it is characterized in that structural formula is as follows:
Wherein: Ar is:
Or
R 1, R 2For: hydrogen, C 1-C 3Alkyl, five yuan of cycloaliphatic rings, hexa-atomic cycloaliphatic rings, the five-membered ring that contains S, N, O, the hexa-member heterocycle that contains S, N, O, phenyl, substituted-phenyl, hydroxyl, C 1-C 3Alkoxyl group, amino, substituted-amino, halogen, carboxylic acid, ester, acid amides, nitro, itrile group and trihalogenmethyl in a kind of, two or three; X, Y are: C, S, N or O.
2. by the described 4-[2-of claim 1 (artyl sulfo) benzyl]-the 1-aryl piperazine derivative, it is characterized in that R 1, R 2For: hydrogen, C 1-C 3Alkyl, hydroxyl, C 1-C 3Alkoxyl group, amino, substituted-amino, halogen, carboxylic acid and derivative thereof, nitro, itrile group and trihalogenmethyl in a kind of, two or three.
3. by the described 4-[2-of claim 1 (artyl sulfo) benzyl]-the 1-aryl piperazine derivative, it is characterized in that derivative comprises following compound:
4-[2-(2-methoxy thiophenyl) benzyl]-1-(3-chloro-phenyl-) piperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-1-(2, the 3-dichlorophenyl) piperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-1-(2, the 3-3,5-dimethylphenyl) piperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-the 1-phenylpiperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-1-(2-pyridyl) piperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-1-(2-pyrimidyl) piperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-1-(2-p-methoxy-phenyl) piperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-1-(4-p-methoxy-phenyl) piperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-1-(3-trifluoromethyl) piperazine; 4-[2-(2-methoxy thiophenyl) benzyl]-1-(1-naphthyl) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(3-chloro-phenyl-) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(2, the 3-dichlorophenyl) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(2, the 3-3,5-dimethylphenyl) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-the 1-phenylpiperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(2-pyridyl) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(2-pyrimidyl) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(2-p-methoxy-phenyl) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(4-p-methoxy-phenyl) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(3-trifluoromethyl) piperazine; 4-[2-(3-methoxy thiophenyl) benzyl]-1-(1-naphthyl) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(3-chloro-phenyl-) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(2, the 3-dichlorophenyl) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(2, the 3-3,5-dimethylphenyl) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-the 1-phenylpiperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(2-pyridyl) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(2-pyrimidyl) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(2-p-methoxy-phenyl) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(4-p-methoxy-phenyl) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(3-trifluoromethyl) piperazine; 4-[2-(2-amino-benzene sulfenyl) benzyl]-1-(1-naphthyl) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(3-chloro-phenyl-) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(2, the 3-dichlorophenyl) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(2, the 3-3,5-dimethylphenyl) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-the 1-phenylpiperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(2-pyridyl) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(2-pyrimidyl) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(2-p-methoxy-phenyl) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(4-p-methoxy-phenyl) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(3-trifluoromethyl) piperazine; 4-[2-(2-methylol thiophenyl) benzyl]-1-(1-naphthyl) piperazine
4. one kind by the described 4-[2-of claim 1 (artyl sulfo) benzyl]-preparation method of 1-aryl piperazine derivative, it is characterized in that preparing general formula and be:
Figure A2005100135260003C1
A:K 2CO 3, DMF, Cu; B:LAH, THF; C:SOCl 2, CHCl 3D:(1) aryl piperazines, TEA, DMF, (2) HCl preparation process comprises:
With the 0-chloro-benzoic acid of 1 mole o-methoxythiophenol and 1～1.5 mole in the presence of the copper powder of 1～3 mole Anhydrous potassium carbonate or anhydrous sodium carbonate and 0.1～1.0 mole or cuprous halide in N, carry out Ullmann thioetherification reaction in 80～150 ℃ in the N dimethyl formamide (DMF) and generate 2-(2-anisole sulfenyl) phenylformic acid; In tetrahydrofuran (THF) (THF), be reduced to 2-(2-anisole sulfenyl) benzylalcohol with 0.5～2 mole of lithium aluminum hydride or borine with 1 mole 2-(2-anisole sulfenyl) phenylformic acid in 30～85 ℃; Is 2-(2-anisole sulfenyl) benzyl chlorine in the room temperature chlorination with 1～5 mole sulfur oxychloride with 1 mole 2-(2-anisole sulfenyl) benzylalcohol in chloroform; With the aryl piperazines of 1 mole 2-(2-anisole sulfenyl) benzyl chlorine and 1～3 mole in the presence of 1～2 mole of triethylamine in DMF 50～80 ℃ of reactions generate 4-[2-(artyl sulfo) benzyls]-the 1-aryl piperazine derivative.
5. one kind by the described 4-[2-of claim 1 (artyl sulfo) benzyl]-preparation method of 1-aryl piperazine derivative, its feature at the preparation general formula is:
A:K 2CO 3, DMF, Cu; B:SOCl 2, CHCl 3C: aryl piperazines, TEA, CHCl 3, d:LAH, the THF preparation process comprises:
With the 0-chloro-benzoic acid of 1 mole o-methoxythiophenol and 1～1.5 mole in the presence of the copper powder of 1～3 mole Anhydrous potassium carbonate or anhydrous sodium carbonate and 0.1～1.0 mole or cuprous halide in N, carry out Ullmann thioetherification reaction in 80～150 ℃ in the N dimethyl formamide (DMF) and generate 2-(2-anisole sulfenyl) phenylformic acid; With 1 mole 2-(2-anisole sulfenyl) phenylformic acid, in chloroform, be 2-(2-anisole sulfenyl) Benzoyl chloride in the room temperature chlorination with 1～5 mole sulfur oxychloride; The aryl piperazines of 1 mole 2-(2-anisole sulfenyl) Benzoyl chloride and 1～3 mole in the presence of 1～3 mole triethylamine 0～50 ℃ in chloroform reaction generate 4-[2-(2-anisole sulfenyl) benzoyl]-the 1-aryl piperazines; 1 mole 4-[2-(2-anisole sulfenyl) benzoyl]-the 1-aryl piperazines is reduced to 4-[2-(artyl sulfo) benzyl in 30～85 ℃ with 0.5～5 mole lithium aluminum hydride or borine in tetrahydrofuran (THF) (THF)]-the 1-aryl piperazine derivative.
6. the described 4-[2-of claim 1 (artyl sulfo) benzyl]-application of 1-aryl piperazine derivative, it is characterized in that it being that form with its free alkali or salt is used to prepare the medicine of protesting strongly fragrant disease, salt is hydrochloride, hydrobromate, vitriol, trifluoroacetate, mesylate, maleate.
CN 200510013526 2005-05-19 2005-05-19 4-[2-(artyl sulfo) benzyl]-1-derivative of aryl-piperazine, preparation method and application Pending CN1696121A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109053460A (en) * 2018-07-20 2018-12-21 中山大学 A method of catalysis benzalcohol derivatives amination

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109053460A (en) * 2018-07-20 2018-12-21 中山大学 A method of catalysis benzalcohol derivatives amination
CN109053460B (en) * 2018-07-20 2022-01-04 中山大学 Method for catalyzing amination of benzyl alcohol compound

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