CN102924406B - Substituted aryl oxygen ethylpiperazine derivative, preparation method of substituted aryl oxygen ethylpiperazine derivative and application of substituted aryl oxygen ethylpiperazine derivative - Google Patents

Substituted aryl oxygen ethylpiperazine derivative, preparation method of substituted aryl oxygen ethylpiperazine derivative and application of substituted aryl oxygen ethylpiperazine derivative Download PDF

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CN102924406B
CN102924406B CN201210440778.5A CN201210440778A CN102924406B CN 102924406 B CN102924406 B CN 102924406B CN 201210440778 A CN201210440778 A CN 201210440778A CN 102924406 B CN102924406 B CN 102924406B
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piperazine
ethyl
adds
methyl
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CN102924406A (en
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吴斌
戴兆慧
王晶
许逸
李萍
张晓平
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Nanjing University
Nanjing Medical University
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Nanjing Medical University
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Abstract

Provided are a substituted aryl oxygen ethylpiperazine derivative, a preparation method of the substituted aryl oxygen ethylpiperazine derivative and application of the substituted aryl oxygen ethylpiperazine derivative. A compound is free alkali or salt with a compound of a structure in a general formula (I), the salt is one of hydrochloride, hydrobromide, sulfate, trifluoroacetic acid salt, tartrate, lactate or mesylate, wherein an Ar independently stands for aryl groups, substituted heterocyclic rings or substituted aryl groups, an R1 and an R2 are same or different, and the R1 and the R2 independently stand for H, halogen, alkyl, halogen substituted alkyl, nitro, amino, nitrile groups, hydroxyl, alkoxy, aralkyl oxygroup, heterocyclic ring alkoxy, aryl group, the substituted heterocyclic rings or the substituted aryl groups respectively. The substituted aryl oxygen ethylpiperazine derivative is applied to preparation of cerebral arterial thrombosis therapeutic drugs.

Description

Replace fragrant oxygen ethyl piperazidine analog derivative and its preparation method and application
Technical field
The invention belongs to pharmacy field, relate to fragrant oxygen ethyl piperazidine analog derivative of a kind of replacement and preparation method thereof, and the purposes of this derivative in preparing neuroprotection agent.
Background technology
Cerebral apoplexy is one of disease that current lethality rate and disability rate are the highest, and wherein nearly 80% cerebral apoplexy belongs to cerebral infarction.After cerebral apoplexy occurs, the injured degree of neuronal cell is depended in the living or death of brain cell, and the degree that provides the cerebral blood flow of oxygen and nutrition to reduce for cell is namely provided.When cerebral infarction occurs, the cerebral blood flow at ischemic core position seriously reduces, and at 60-90min tissues following MCAO in rats, irreversible damage occurs; And the ischemic penumbra of periphery, core position, cerebral blood flow reduces relatively, but cellular metabolism is increased extremely, in a few hours after ischemic occurs, in ischemic area, abnormal electrical activity and metabolism disorder form a chain reaction, be referred to as " ischemic waterfall ", the final result of water fall effect is that ischemic core is constantly expanded, penumbra fades away, and this process is exactly the time window of Treatment of Cerebral Stroke.
Since nineteen nineties, propose the Neuroprotective Therapy in Treating Acute of cerebral infarction abroad, in subsequently 10 years, had swift and violent development.The target of neuroprotective is to intervene the pathological biochemistry cascade reaction that ischemia penumbra occurs, and saves still vigourous cerebral tissue, prevents or postpones necrocytosis.Neuroprotective kind and mechanism of action are various at present, as medicines such as voltage-dependent ca channel retarding agent, glutamate receptor antagonists, antioxidant, free-radical scavengers, nitric oxide synthase inhibitors, have become the study hotspot of Treatment of Cerebral Stroke.
Summary of the invention
The technical problem solving: one of technical issues that need to address of the present invention are to disclose a kind of fragrant oxygen ethyl piperazidine analog derivative with the replacement of medical value.
Two of the technical issues that need to address of the present invention are the fragrant oxygen ethyl piperazidine analog derivative application in cerebral infarction treatment as neuroprotection agent that disclose above-mentioned replacement, hemorrhage with bringing out of overcoming that prior art exists, be difficult to see through hemato encephalic barrier, the defect such as oral administration biaavailability is poor, selectivity is low and neurobehavioral toxicity is large.
Technical scheme:
Replace fragrant oxygen ethyl piperazidine analog derivative, this compound is free alkali or the salt with logical formula I structural compounds:
Said salt is a kind of in hydrochloride, hydrobromate, vitriol, trifluoroacetate, tartrate, lactic acid salt or mesylate;
Wherein, Ar represents aryl, substituted heterocycle or substituted aryl independently;
R 1and R 2identical or different, represent independently of one another alkyl, nitro, amino, itrile group, hydroxyl, alkoxyl group, aralkoxy, heterocycle alkoxyl group, aryl, substituted heterocycle or substituted aryl that H, halogen, alkyl, halogen replace.
Described R 1, R 2the aryl of representative or the aryl in aralkoxy, be benzene, biphenyl or naphthalene, or be F, Cl, Br, I, C 1～10alkyl, C 1～10alkoxyl group, nitro or amino benzene, biphenyl or the naphthalene replacing.
Described R 1, R 2the alkyl of representative refers to have the alkyl of the straight or branched of 1-10 carbon atom, or the thiazolinyl of the straight or branched of 2-10 carbon atom, or the cycloalkyl of the straight or branched of 3-10 carbon atom; Alkyl in described alkoxyl group, aralkoxy or heterocycle alkoxyl group refers to have the alkyl of the straight or branched of 1-10 carbon atom; Abovementioned alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl, heptyl, octyl group, nonyl or decyl; Above-mentioned thiazolinyl is vinyl, propenyl, allyl group, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonene base or decene base; Above-mentioned cycloalkyl is cyclopropyl, cyclobutyl, cyclohexyl, suberyl, ring octyl group, ring nonyl or ring decyl.
Described R 1, R 2substituted heterocycle or the heterocyclic radical in heterocycle alkoxyl group of representative refer to contain one or more heteroatomic saturated heterocyclic or aromatic heterocycle optional from oxygen, nitrogen, sulphur atom.
Described R 1, R 2the halogen of representative is F, Cl, Br or I.
Described R 1, R 2middle substituted aryl, its substituting group is halogen, nitro, amino, hydroxyl, ether, carboxyl, ester group and amide group.
Described amino is NH 2, R 8nH or R 9r 10n; R wherein 8, R 9or R 10for alkyl, or R 9r 10n is the ternary ~ eight yuan heterocycle of nitrogen atom, and described alkyl refers to have the alkyl of the straight or branched of 1-10 carbon atom, or the thiazolinyl of the straight or branched of 2-10 carbon atom, or the cycloalkyl of the straight or branched of 3-10 carbon atom.The preparation method who replaces fragrant oxygen ethyl piperazidine analog derivative, is characterized in that comprising the following steps:
(note: the Ar in compound ii, III, IV, V, VI, VII, VIII, R 1with R 2the substituting group of representative is identical with above-mentioned restriction in chemical compounds I).
A. fragrant phenol (II) 0.10mol replacing, glycol dibromide 0.15mol, water 60mL stirs and is warming up to backflow, drips 25%wt sodium hydroxide solution 24mL, within 30 minutes, drips off; Backflow 10-13 hour, the cooling standing over night of reaction solution, while having solid to separate out, suction filtration, filter cake washes twice with water, dehydrated alcohol recrystallization; While separating out without solid, separatory, organic layer dissolves with methylene dichloride 20mL, with 5%wt sodium hydroxide solution 30mL washing three times, then water 30mL washing three times, anhydrous magnesium sulfate drying, suction filtration, filtrate decompression is steamed to desolventize and is obtained the corresponding fragrant oxygen monobromethane (III) replacing;
B. Piperazine anhydrous 0.08mol, dehydrated alcohol 86mL, water 12mL drips 40%wt Hydrogen bromide 0.08mol in the situation that constantly stirring, and within 20 minutes, drips off, and continues to stir 5 minutes; Fragrant oxygen monobromethane (III) 0.04mol replacing divides three times and adds above-mentioned reaction solution, is heated with stirring to and refluxes 6 hours, and in refrigerator, 4 ℃ of refrigerations are spent the night; Filtering insolubles, filtrate steaming removal solvent, in resistates, add 5%wt sodium hydroxide solution 50mL, stir 4 hours, with methylene dichloride 40mL extraction three times, merge organic layer, steam except organic solvent, gained resistates obtains the corresponding fragrant oxygen ethyl piperazidine (IV) replacing with dehydrated alcohol 20mL recrystallization;
C. benzophenone (V) 0.2mol and the sodium borohydride 0.18mol that replace, dehydrated alcohol 350mL reflux 2 hours, add 20mL water, produce white milk, concentrate to obtain solid, the 280mL that adds methylene chloride dissolves, and adds 200mL water washing, separatory, the benzhydrol that organic phase evaporate to dryness must replace; The benzhydrol 0.02mol replacing, anhydrous methylene chloride 40mL, thionyl chloride 0.024mol, 1 of pyridine, stirring at room 4 hours, adds anhydrous cyclohexane 40mL, Piperazine anhydrous 0.2mol, reflux 16 hours in concentrated gained resistates; Concentration of reaction solution, adds methylene dichloride 350mL in gained solid, with the NaOH solution 150mL washing of 1mol/L, separatory, organic phase evaporate to dryness obtains the benzhydryl piperazidine (VI) replacing;
D. the nuclear substituted toluene of benzene (VII) 0.07mol, N-bromo-succinimide 0.07mol, azo diisobutyl nitrile 0.007mol, tetracol phenixin 108mL adds in eggplant-shape bottle, under incandescent light irradiates, stirs and is warming up to back flow reaction 1 hour, cooling, standing, in solution, add hexanaphthene 108mL, jolting, suction filtration, filtrate steaming removal solvent, in residual solution, add acetonitrile 75mL, after shake well, steaming desolventizes, and obtains corresponding Bromomethyl Substituted benzene (VIII);
E. by fragrant oxygen monobromethane (III) 0.010mol replacing, the benzhydryl piperazidine of replacement (VI) 0.008mol, triethylamine 0.029mol, acetonitrile 74mL adds in eggplant-shape bottle, under the condition existing, is heated with stirring to backflow at nitrogen protection or zinc powder; Reflux 20 hours, filter, it is eluent that filtrate steaming removal solvent be take ethyl acetate and sherwood oil mixed solution, ethyl acetate: sherwood oil volume ratio=1: 10 to 1: 1, and gradient elution, column chromatography for separation; Maybe by fragrant oxygen ethyl piperazidine (IV) 0.005mol replacing, Bromomethyl Substituted benzene (VIII) 0.005mol, triethylamine 0.005mol, acetonitrile 24mL adds in three-necked bottle, under the condition existing, is heated with stirring to backflow at nitrogen protection or zinc powder.Reflux 20 hours, filtered while hot, it is eluent that filtrate steaming removal solvent be take ethyl acetate and sherwood oil mixed solution, ethyl acetate: sherwood oil volume ratio=1:10 to 1:1, gradient elution, column chromatography for separation must logical formula I compound.
Replace the application of fragrant oxygen ethyl piperazidine analog derivative in preparing cerebral infarction medicine.
Compound 2-((4-(2-(2-naphthyloxy) ethyl) piperazine)-1-yl) methyl-toluate, 1-(4-chlorophenylmethyl)-4-(2-(2-naphthyloxy) ethyl) piperazine, 1-(4-Brombenzyl)-4-(2-(2-naphthyloxy) ethyl) piperazine, 2-((4-(2-(4-methylphenoxy) ethyl) piperazine)-1-yl) methyl-toluate, 1-(4-Brombenzyl)-4-(2-(4-methylphenoxy) ethyl) piperazine, 1-(4-chlorophenylmethyl)-4-(2-(2-methylphenoxy) ethyl) piperazine, 1-(4-Brombenzyl)-4-(2-(2-methylphenoxy) ethyl) piperazine, 2-((4-(2-(4-methoxyphenoxy) ethyl) piperazine)-1-yl) methyl-toluate, 1-(4-chlorophenylmethyl)-4-(2-(4-methoxyphenoxy) ethyl) piperazine, 1-(4-phenetole methyl)-4-(2-(4-methoxyphenoxy) ethyl) piperazine, 1-(4-Brombenzyl)-4-(2-(4-chlorophenoxy) ethyl) piperazine, 1-(pair-(4-p-methoxy-phenyl) methyl)-4-(2-(2-naphthyloxy) ethyl) piperazine, 1-(pair-(4-p-methoxy-phenyl) methyl)-4-(2-(4-methoxyphenoxy) ethyl) piperazine or 1-(pair-(4-bromophenyl) methyl)-4-(2-(4-methoxyphenoxy) ethyl) application of piperazine in preparing cerebral infarction medicine.
The preparation method of the fragrant oxygen ethyl piperazidine analog derivative that the logical formula I the present invention relates to replaces can be represented by synthetic schematic diagram 1 ~ 3:
The fragrant phenol of the replacement a. replacing and glycol dibromide condensation obtain the corresponding fragrant oxygen monobromethane replacing, and then obtain the corresponding fragrant oxygen ethyl piperazidine replacing (seeing synthetic schematic diagram 1) with Piperazine anhydrous condensation;
B. the benzophenone replacing obtains the benzhydryl piperazidine (seeing synthetic schematic diagram 2) replacing through reduction, halo, replacement;
C. the nuclear substituted toluene of benzene carries out free radical substitution reaction with N-bromo-succinimide and obtains corresponding Bromomethyl Substituted benzene (see synthetic schematic diagram 3) in the situation that of illumination;
D. by the fragrant oxygen monobromethane replacing and the benzhydryl piperazidine condensation of replacement, or the fragrant oxygen ethyl piperazidine and the condensation of Bromomethyl Substituted benzene that replace, prepared the fragrant oxygen ethyl piperazidine analog derivative (see and synthesize schematic diagram 4) of a series of new replacements;
E. by condensation products therefrom dehydrated alcohol recrystallization, obtain target compound.
Beneficial effect:
At present, the experimentation on animals of neuroprotection screening active ingredients is to adopt bilateral carotid and vagus nerve ligation method to observe different compounds the impact of acute cerebral ischemia mouse survival time to be carried out to the pharmacodynamics preliminary assessment of anti-cerebral ischemia drugs according to a conventional method.Experimental data (referring to embodiment 49) shows: preventatively give part of compounds of the present invention, can obviously extend the survival time of acute cerebral ischemia mouse, have certain anti-cerebral ischemia neuroprotective.
Accompanying drawing explanation
Fig. 1 is synthetic schematic diagram 1;
Fig. 2 is synthetic schematic diagram 2;
Fig. 3 is synthetic schematic diagram 3;
Fig. 4 is synthetic schematic diagram 4.
Embodiment
The following examples can make the present invention of those skilled in the art comprehend, but do not limit the present invention in any way.
Embodiment 1
2-(2-bromine oxethyl) naphthalene
By ethyl naphthol (14.4g, 0.10mol), glycol dibromide (13mL, 0.15mol), water (60mL) adds in three-necked bottle, stirs and is warming up to backflow, drips the sodium hydroxide solution (24mL) of 25%wt, within approximately 30 minutes, drips off.Reflux 10 hours, the cooling layering of reaction solution, standing over night, a large amount of solids are separated out.Suction filtration, filter cake washes twice with water, and dehydrated alcohol recrystallization twice obtains white crystal 13.4g, yield 54.3%, TLC shows pure point.
Embodiment 2
1-(2-bromine oxethyl)-4-methylbenzene
By p-cresol (13g, 0.12mol), glycol dibromide (15.6mL, 0.18mol), water (72mL) adds in three-necked bottle, stirs and is warming up to backflow, drips the sodium hydroxide solution (28.8mL) of 25%wt, within approximately 45 minutes, drips off.Reflux 10 hours, the cooling layering of reaction solution, standing over night, separates out without solid.Separatory, 40mL water washing twice for organic layer, anhydrous magnesium sulfate drying, suction filtration, steams except organic solvent, obtains faint yellow clarification oily liquid.Underpressure distillation, collects the cut of 108 ℃/0.08mmHg, and this cut is initially clear colorless oil shape liquid after coagulation and becomes white solid.The final white solid 8.2g that obtains, yield 34.2%, TLC shows pure point.
Embodiment 3
1-(2-bromine oxethyl)-2-methylbenzene
By ortho-cresol (13g, 0.12mol), glycol dibromide (15.6mL, 0.18mol), water (72mL) adds in three-necked bottle, stirs and is warming up to backflow, drips the sodium hydroxide solution (28.8mL) of 25%wt, within approximately 45 minutes, drips off.Reflux 13 hours, the cooling layering of reaction solution, standing over night, separates out without solid.Separatory, organic layer dissolves with 20mL methylene dichloride, washs three times, then use 30mL water washing three times with the sodium hydroxide solution of 30mL 5%wt, anhydrous magnesium sulfate drying, suction filtration, filtrate steaming removal solvent, obtain faint yellow clarification oily liquid 10.9g, yield 42.3%, TLC shows pure point.
Embodiment 4
1-(2-bromine oxethyl)-4-anisole
Preparation method is with embodiment 3, p methoxy phenol (14.9g, 0.12mol), glycol dibromide (15.6mL, 0.18mol), water (72mL), 25%wt sodium hydroxide solution (28.8mL), back flow reaction 13 hours.Obtain white solid 14.1g, yield 50.8%, TLC shows pure point.
Embodiment 5
1-(2-bromine oxethyl)-4-chlorobenzene
Preparation method is with embodiment 3, para-chlorophenol (15.4g, 0.12mol), glycol dibromide (15.6mL, 0.18mol), water (72mL), 25%wt sodium hydroxide solution (28.8mL), back flow reaction 12 hours.Obtain pale yellow oily liquid 22.8g, yield 81.2%, TLC shows pure point.
Embodiment 6
1-(2-bromine oxethyl)-4-bromobenzene
Preparation method is with embodiment 3, p bromophenol (8.6g, 0.05mol), glycol dibromide (6.5mL, 0.075mol), water (30mL), 25%wt sodium hydroxide solution (12mL), back flow reaction 13 hours.Obtain white paste solid 8.8g, yield 58.6%, TLC shows pure point.
Embodiment 7
1-(2-(4-methylphenoxy) ethyl) piperazine
By Piperazine anhydrous (6.9g, 0.08mol), dehydrated alcohol (86mL), water (12mL) adds in eggplant-shape bottle, stirs and makes piperazine dissolved.The Hydrogen bromide (0.08mol) that drips 40%wt in the situation that constantly stirring, drips off for approximately 20 minutes, continues to stir 5 minutes.Divide and add 1-(2-bromine oxethyl three times)-4-methylbenzene (8.6g, 0.04mol), be heated with stirring to backflow.Reflux 6 hours, in refrigerator, 4 ℃ of refrigerations are spent the night, and have long needle-like crystal (piperazine two hydrobromates) to separate out.Filter, filtering crystal, filtrate steaming removal solvent obtains yellowish white paste.Add 50mL 5%wt sodium hydroxide solution, stir 4 hours, use 40mL dichloromethane extraction three times, merge organic layer, steam except organic solvent, obtain faint yellow paste, TLC shows impure.With 20mL dehydrated alcohol recrystallization, obtain white solid 2.8g, yield 31.8%, TLC shows pure point.
Embodiment 8
1-(2-(2-naphthyloxy) ethyl) piperazine
By Piperazine anhydrous (5.2g, 0.06mol), dehydrated alcohol (66mL), water (8.7mL) adds in eggplant-shape bottle, stirring and dissolving.The Hydrogen bromide (0.06mol) that drips 40%wt in the situation that constantly stirring, drips off for approximately 20 minutes, continues to stir 5 minutes.Divide and add 2-(2-bromine oxethyl three times) naphthalene (7.5g, 0.03mol), be heated with stirring to backflow.Reflux 6 hours, in refrigerator, 4 ℃ of refrigerations are spent the night, and a large amount of solids are separated out.Filter, filter cake washes with water to be removed for three times after piperazine two hydrobromates, merges with filtrate, adds 10mL 30%wt sodium hydroxide solution, is warming up to backflow.Reflux 5 hours, cooling, concentrated.Resistates adds 40mL water, with methylene dichloride 30mL extraction three times, merge organic layer, anhydrous magnesium sulfate drying, suction filtration, filtrate steaming removal solvent, obtain white solid 7.3g, yield 95.1%, TLC shows the great impurity of micro-polarity, this impurity does not affect next step operation, directly carries out next step reaction.
Embodiment 9
1-(2-(2-methylphenoxy) ethyl) piperazine
Preparation method is with embodiment 8, Piperazine anhydrous (8.7g, 0.10mol), dehydrated alcohol (108mL), water (15mL), 40%wt Hydrogen bromide (0.10mol), 1-(2-bromine oxethyl)-2-methylbenzene (10.9g, 0.05mol), back flow reaction 6 hours.In refrigerator, 4 ℃ of refrigerations are spent the night, the long needle-like crystal of filtering (piperazine two hydrobromates).Add 10mL 30%wt sodium hydroxide solution, stir and be warming up to backflow.Reflux 5 hours, cooling, concentrated.Resistates adds 40mL water, uses 30mL dichloromethane extraction three times, merges organic layer, steam except organic solvent, obtain yellow oily liquid 8.1g, yield 72.2%, TLC shows the great impurity of micro-polarity, and this impurity does not affect next step operation, directly carries out next step reaction.
Embodiment 10
1-(2-(4-methoxyphenoxy) ethyl) piperazine
Preparation method is with embodiment 8, Piperazine anhydrous (10.5g, 0.12mol), dehydrated alcohol (130mL), water (18mL), 40%wt Hydrogen bromide (0.12mol), 1-(2-bromine oxethyl)-4-anisole (14.1g, 0.06mol), back flow reaction 5 hours.Obtain white paste solid 13g, yield 90.2%, TLC shows the great impurity of micro-polarity, and this impurity does not affect next step operation, directly carries out next step reaction.
Embodiment 11
1-(2-(4-chlorophenoxy) ethyl) piperazine
Preparation method is with embodiment 8, Piperazine anhydrous (8.7g, 0.10mol), dehydrated alcohol (100mL), water (15mL), 40%wt Hydrogen bromide (0.10mol), 1-(2-bromine oxethyl)-4-chlorobenzene (11.8g, 0.05mol), back flow reaction 6 six hours.Obtain white solid 9.1g, yield 75.8%, TLC shows the great impurity of micro-polarity, and this impurity does not affect next step operation, directly carries out next step reaction.
Embodiment 12
1-brooethyl-2-phenetole
By ortho-cresol (10.8g, 0.10mol), water (60mL) adds in three-necked bottle, stirs and is warming up to 60 ℃.Add Tetrabutyl amonium bromide (2.6g, 0.008mol), with 20%wt sodium hydroxide solution (20mL), adjust pH=13, continue to be stirred to ortho-cresol and all dissolve and be clear liquor, be warming up to backflow.In the situation that constantly stirring, drip ethyl sulfate (16mL, 0.10mol), within approximately 30 minutes, drip off, add 20%wt sodium hydroxide solution (5mL) after dripping off, reaction solution is alkalescence.Back flow reaction 14 hours, standing, cooling, reaction solution layering.Separatory, organic layer adds 30mL toluene, washs three times, then use 30mL water washing three times with the sodium hydroxide solution of 30mL 5%wt, anhydrous magnesium sulfate drying, suction filtration, filtrate is concentrated, obtain faint yellow clarification oily o-methyl-benzene ether 9.8g, yield 72.1%, TLC shows pure point.
Previous step is reacted to the product o-methyl-benzene ether (9.8g, 0.07mol) of gained, N-bromo-succinimide (12.8g, 0.07mol), azo diisobutyl nitrile (1.1g, 0.007mol), tetracol phenixin (108mL) adds in eggplant-shape bottle, under incandescent light irradiates, stirs and is warming up to backflow.Illumination back flow reaction 1 hour, standing, observe visible solid and all float on upper strata.In solution, add 108mL hexanaphthene, jolting, suction filtration, filtrate steaming removal solvent, obtains deep yellow oily liquid.Add 75mL acetonitrile, after shake well, steaming desolventizes, and obtains pale yellow oily liquid, standing after cooling faint yellow solid 15.2g, yield 98.1%, TLC shows pure point.
Embodiment 13
1-brooethyl-4-phenetole
Preparation method is with embodiment 12, p-cresol (10.8g, 0.10mol), water (60mL), Tetrabutyl amonium bromide (2.6g, 0.008mol), 20%wt sodium hydroxide solution (25mL), ethyl sulfate (16mL, 0.10mol), back flow reaction 14 hours, obtains faint yellow clarification oily p-tolyl ethyl ether 8.8g, yield 64.7%, TLC shows pure point.
The product p-tolyl ethyl ether (4g, 0.03mol) of previous step reaction gained, N-bromo-succinimide (5.2g, 0.03mol), azo diisobutyl nitrile (0.44g, 0.003mol), tetracol phenixin (45mL), illumination back flow reaction 1 hour.In solution, add 45mL hexanaphthene, jolting, suction filtration, filtrate steaming removal solvent, obtains deep yellow oily liquid.Add 25mL acetonitrile, after shake well, steaming desolventizes, standing after cooling faint yellow solid 6g, yield 96.8%, TLC shows pure point.
Embodiment 14
2-brooethyl-methyl benzoate
By o-methyl benzoic acid methyl ester (15g, 0.10mol), N-bromo-succinimide (18g, 0.10mol), azo diisobutyl nitrile (1.6g, 0.001mol), tetracol phenixin (150mL) adds in eggplant-shape bottle, under incandescent light irradiates, stirs and is warming up to backflow.Illumination back flow reaction 1 hour, standing, observe visible solid and all float on upper strata.In solution, add 150mL hexanaphthene, jolting, suction filtration, filtrate steaming removal solvent, obtains deep yellow oily liquid.Add 90mL acetonitrile, after shake well, steaming desolventizes, and obtains pale yellow oily liquid, standing after cooling faint yellow solid 24g, yield 100%, TLC shows pure point.
Embodiment 15
1-brooethyl-4-chlorobenzene
Preparation method is with embodiment 14, parachlorotoluene (12.7mL, 0.10mol), N-bromo-succinimide (17.8g, 0.10mol), azo diisobutyl nitrile (1.6g, 0.001mol), tetracol phenixin (150mL) illumination back flow reaction 1 hour.Obtain faint yellow solid 19.4g, yield 94.6%, TLC shows pure point.
Embodiment 16
1-brooethyl-4-bromobenzene
Preparation method is with embodiment 14, para-bromo toluene (13g, 0.08mol), N-bromo-succinimide (13.5g, 0.08mol), azo diisobutyl nitrile (1.2g, 0.008mol), tetracol phenixin (114mL) illumination back flow reaction 1 hour.Obtain faint yellow solid 18.4g, yield 97.0%, TLC shows pure point.
Embodiment 17
1-(pair-(4-p-methoxy-phenyl) methyl) piperazine
By 1-(pair-(4-p-methoxy-phenyl) methyl) alcohol (15g, 0.06mol), anhydrous methylene chloride (120mL) adds in eggplant-shape bottle, and stirring and dissolving adds thionyl chloride (4.5mL, 0.06mol), pyridine (1), room temperature adds drying tube and stirs 4 hours, and TLC demonstration reacts completely, steaming desolventizes to obtain light green oily matter, directly carries out next step reaction.
Previous step is hexanaphthene (120mL) dissolving for product, add Piperazine anhydrous (51.8g, 0.60mol), stirring heating refluxes 16 hours, steaming desolventizes to obtain off-white color solid, and add methylene chloride (150mL) dissolves, by NaOH solution (100mL) washed twice of 1mol/L, separatory, organic phase evaporate to dryness obtains yellowish white solid 18.5g.Dehydrated alcohol recrystallization, obtains white solid 14.6g, yield 76.4%, and TLC shows pure point.
Embodiment 18
1-(pair-(4-aminomethyl phenyl) methyl) piperazine
Preparation method is with embodiment 17, and 1-(is two-(4-aminomethyl phenyl) methyl) alcohol (8g, 0.04mol), anhydrous methylene chloride (74mL), thionyl chloride (2.8mL, 0.04mol), pyridine (1d), room temperature adds drying tube and stirs four hours, obtains faint yellow oily matter, directly carries out next step reaction.
Previous step is anhydrous cyclohexane (74mL) dissolving for product, add Piperazine anhydrous (19.9g, 0.23mol), stirring heating refluxes 16 hours, steams and desolventizes to obtain off-white color solid, (150mL) dissolving adds methylene chloride, with NaOH solution (100mL) washed twice of 1mol/L, separatory, organic phase evaporate to dryness obtains faint yellow oily matter 8.8g, yield 83.0%, TLC shows pure point.
Embodiment 19
1-(pair-(4-bromophenyl) methyl) piperazine
Preparation method is with embodiment 17, and 1-(is two-(4 – bromophenyl) methyl) alcohol (8g, 0.02mol), anhydrous methylene chloride (74mL), thionyl chloride (1.9mL, 0.02mol), pyridine (1), room temperature adds drying tube and stirs four hours, obtains faint yellow oily matter, directly carries out next step reaction.
Previous step is anhydrous cyclohexane (74mL) dissolving for product, add Piperazine anhydrous (13g, 0.15mol), stirring heating refluxes 16 hours, steams and desolventizes to obtain off-white color solid, (150mL) dissolving adds methylene chloride, with NaOH solution (100mL) washed twice of 1mol/L, separatory, organic phase evaporate to dryness obtains faint yellow solid 9g, yield 94.2%, TLC shows pure point.
Embodiment 20
2-((4-(2-(2-naphthyloxy) ethyl) piperazine)-1-yl) methyl-toluate (DZH-1)
By 1-(2-(2-naphthyloxy) ethyl) piperazine (1.4g, 0.005mol), 2-brooethyl-methyl benzoate (1.1g; 0.005mol), triethylamine (0.7mL, 0.005mol); acetonitrile (24mL) adds in three-necked bottle, under nitrogen protection condition, is heated with stirring to backflow.Reflux 20 hours, filtered while hot, filtrate steaming removal solvent obtains brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution is eluent, gradient elution (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), column chromatography obtains white solid 0.6g, yield 30.9%, m.p.75.1-76.5 ℃.HRMS?calcd?for?C 25H 29N 2O 3[M+H] +405.2178,found?405.2180; 1HNMR(δ,ppm,CDCl 3,300MHz):2.516(bs,4H,N(CH 2) 2);2.621(bs,4H,N(CH 2) 2);2.869-2.905(t,2H,NCH 2,J=5.4Hz);3.779(s,2H,PhCH 2);3.882(s,3H,COOCH 3);4.216-4.253(t,2H,OCH 2,J=5.4Hz);7.128-7.167(m,11H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):29.64;51.94;52.87;53.82;57.19;60.44;65.99;106.81;118.97;123.61;126.33;126.73;126.94;127.61;129.01;129.34;129.59;129.87;131.69;134.54;156.73;169.22。
Embodiment 21
2-((4-(2-(2-naphthyloxy) ethyl) piperazine)-1-yl) methyl-toluate (DZH-1)
By 1-(2-(2-naphthyloxy) ethyl) piperazine (2.8g, 0.01mol), 2-brooethyl-methyl benzoate (2.2g, 0.01mol), triethylamine (1.4mL, 0.01mol), acetonitrile (48mL) adds in three-necked bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, filtered while hot, filtrate steaming removal solvent obtains brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution is eluent, gradient elution (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), column chromatography obtains white solid 1.22g, yield 31.2%, m.p.75.2-76.8 ℃.HRMS?calcd?for?C 25H 29N 2O 3[M+H] +405.2178,found?405.2180; 1HNMR(δ,ppm,CDCl 3,300MHz):2.518(bs,4H,N(CH 2) 2);2.622(bs,4H,N(CH 2) 2);2.871-2.907(t,2H,NCH 2,J=5.4Hz);3.781(s,2H,PhCH 2);3.883(s,3H,COOCH 3);4.217-4.254(t,2H,OCH 2,J=5.4Hz);7.130-7.167(m,11H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):29.68;51.91;52.90;53.84;57.18;60.46;65.97;106.85;118.97;123.58;126.34;126.69;126.94;127.57;129.05;129.37;129.55;129.92;131.73;134.54;156.71;169.31。
Embodiment 22
1-(4-chlorophenylmethyl)-4-(2-(2-naphthyloxy) ethyl) piperazine (DZH-2)
By 1-(2-(2-naphthyloxy) ethyl) piperazine (1.8g, 0.007mol), 1-brooethyl-4-chlorobenzene (1.5g, 0.007mol), triethylamine (1.0mL, 0.007mol), acetonitrile (40mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, filtered while hot, filtrate steaming removal solvent obtains brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains white solid 0.7g, yield 26.2%, m.p.76.8-78.5 ℃.HRMS?calcd?for?C 23H 26ClN 2O[M+H] +381.1734,found?381.1737; 1HNMR(δ,ppm,CDCl 3,300MHz):2.514(bs,4H,N(CH 2) 2);2.660(bs,4H,N(CH 2) 2);2.873-2.912(t,2H,NCH 2,J=5.4Hz);3.481(s,2H,PhCH 2);4.209-4.248(t,2H,OCH 2,J=5.4Hz);7.126-7.766(m,11H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):52.95,53.62,57.16,62.20,65.92,118.96,123.63,126.34,126.72,127.62,128.36,129.35,130.41,132.76,134.53,136.70。
Embodiment 23
1-(4-Brombenzyl)-4-(2-(2-naphthyloxy) ethyl) piperazine (DZH-3)
By 1-(2-(2-naphthyloxy) ethyl) piperazine (2.0g, 0.008mol), 1-brooethyl-4-bromobenzene (1.9g, 0.008mol), triethylamine (1.1mL, 0.008mol), acetonitrile (40mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, filtered while hot, filtrate steaming removal solvent obtains brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains white solid 0.6g, yield 18.2%, m.p.85.6-87.3 ℃.HRMS?calcd?for?C 23H 26BrN 2O[M+H] +425.1228,found?425.1232; 1HNMR(δ,ppm,CDCl 3,300MHz):2.501(bs,4H,N(CH 2) 2);2.665(bs,4H,N(CH 2) 2);2.859-2.895(t,2H,NCH 2,J=5.4Hz);3.425(s,2H,PhCH 2);4.181-4.218(t,2H,OCH 2,J=5.4Hz);7.047-7.700(m,11H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):52.91,53.56,57.08,62.18,65.85,106.68,118.90,123.54,126.25,126.64,127.54,129.26,130.69,131.22,134.44,137.21,156.64。
Embodiment 24
2-((4-(2-(4-methylphenoxy) ethyl) piperazine)-1-yl) methyl-toluate (DZH-4)
By 1-(2-(4-methylphenoxy) ethyl) piperazine (1.7g, 0.008mol), 2-brooethyl-methyl benzoate (1.8g, 0.008mol), triethylamine (1.1mL, 0.008mol), acetonitrile (40mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, filtered while hot, filtrate steaming removal solvent obtains brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains white solid 0.9g, yield 32.1%, m.p.54.4-55.8 ℃.HRMS?calcd?for?C 22H 29N 2O 3[M+H] +369.2178,found?369.2182; 1HNMR(δ,ppm,CDCl 3,300MHz):2.271(s,3H,PhCH 3);2.447(bs,4H,N(CH 2) 2);2.558(bs,4H,N(CH 2) 2);2.761-2.800(t,2H,NCH 2,J=5.7Hz);3.759(s,2H,PhCH 2);3.872(s,3H,COOCH 3);4.045-4.084(t,2H,OCH 2,J=5.7Hz);6.771-7.694(m,8H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):51.90,52.78,53.70,57.19,60.40,65.89,114.41,126.88,129.52,129.80,129.91,130.78,130.88,131.63。
Embodiment 25
1-(4-chlorophenylmethyl)-4-(2-(4-methylphenoxy) ethyl) piperazine (DZH-5)
By 1-(2-(4-methylphenoxy) ethyl) piperazine (2.0g, 0.009mol), 1-brooethyl-4-chlorobenzene (1.9g, 0.009mol), triethylamine (1.3mL, 0.009mol), acetonitrile (46mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, filtered while hot, filtrate steaming removal solvent obtains brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains brown solid 2.8g, yield 87.5%, m.p.56.9-58.7 ℃.HRMS?calcd?for?C 20H 26ClN 2O[M+H] +345.1734,found?345.1738; 1HNMR(δ,ppm,CDCl 3,300MHz):2.293(s,3H,PhCH 3);2.490(bs,4H,N(CH 2) 2);2.611(bs,4H,N(CH 2) 2);2.787-2.826(t,2H,NCH 2,J=5.7Hz);3.471(s,2H,PhCH 2);4.057-4.096(t,2H,OCH 2,J=5.7Hz);6.774-7.300(m,8H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):51.95,53.57,57.21,62.19,65.92,114.43,128.30,129.83,130.37,132.67,136.73,156.60。
Embodiment 26
1-(4-Brombenzyl)-4-(2-(4-methylphenoxy) ethyl) piperazine (DZH-6)
By 1-(2-(4-methylphenoxy) ethyl) piperazine (2.0g, 0.006mol), 1-brooethyl-4-bromobenzene (1.4g, 0.006mol), triethylamine (0.8mL, 0.006mol), acetonitrile (28mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, filtered while hot, filtrate steaming removal solvent obtains brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains brown solid 1.1g, yield 52.4%, m.p.60.5-62.7 ℃.HRMS?calcd?for?C 20H 26BrN 2O[M+H] +389.1228,found?389.1232; 1HNMR(δ,ppm,CDCl 3,300MHz):2.282(s,3H,PhCH 3);2.502(bs,4H,N(CH 2) 2);2.628(bs,4H,N(CH 2) 2);2.800-2.839(t,2H,NCH 2,J=5.7Hz);3.461(s,2H,PhCH 2);4.067-4.106(t,2H,OCH 2,J=5.7Hz);6.785-7.447(m,8H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):52.96,53.54,53.57,57.21,57.23,62.24,65.94,114.44,120.77,128.31,129.83,130.74,131.27,137.27,156.62。
Embodiment 27
1-(4-phenetole methyl)-4-(2-(4-methylphenoxy) ethyl) piperazine (DZH-7)
By 1-(2-(4-methylphenoxy) ethyl) piperazine (1.6g, 0.007mol), 1-brooethyl-4-phenetole (1.5g, 0.007mol), triethylamine (1.0mL, 0.007mol), acetonitrile (39mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, filtered while hot, filtrate steaming removal solvent obtains brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains faint yellow solid 1.2g, yield 48.0%, m.p.88.3-90.5 ℃.HRMS?calcd?for?C 22H 31N 2O 2[M+H] +355.2386,found?355.2390; 1HNMR(δ,ppm,CDCl 3,300MHz):1.378-1.424(t,3H,CH 2(CH 3),J=6.9Hz);2.272(s,3H,PhCH 3);2.493(bs,4H,N(CH 2) 2);2.605(bs,4H,N(CH 2) 2);2.776-2.816(t,2H,NCH 2,J=6.0Hz);3.450(s,2H,PhCH 2);3.979-4.048(q,2H,O(CH 2)CH 3,J=6.9Hz);4.048-4.087(t,2H,OCH 2,J=6.0Hz);6.772-7.255(m,8H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):14.85;20.42;29.68;52.89,53.62,57.25,62.42,63.41,65.99,114.18,114.49,129.84,130.36,156.67,15811。
Embodiment 28
2-((4-(2-(2-methylphenoxy) ethyl) piperazine)-1-yl) methyl-toluate (DZH-8)
By 1-(2-(2-methylphenoxy) ethyl) piperazine (3.0g, 0.01mol), 2-brooethyl-methyl benzoate (3.1g, 0.01mol), triethylamine (2.0mL, 0.01mol), acetonitrile (71mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, filtered while hot, filtrate steaming removal solvent obtains brown liquid.TLC shows impure, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1: 10 to 1: 1), gradient elution, and column chromatography obtains faint yellow clarification oily liquid 2.2g, yield 43.9%.HRMS?calcd?for?C 22H 29N 2O 3[M+H] +369.2178,found?369.2132; 1HNMR(δ,ppm,CDCl 3,300MHz):2.200(s,3H,PhCH 3);2.467(bs,4H,N(CH 2) 2);2.585(bs,4H,N(CH 2) 2);2.801-2.840(t,2H,NCH 2,J=5.7Hz);3.756(s,2H,PhCH 2);3.784(s,3H,COOCH 3);4.078-4.116(t,2H,OCH 2,J=5.7Hz);6.781-7.697(m,8H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):51.88,52.91,53.79,57.24,60.42,66.29,110.91,120.31,126.66,126.71,126.75,126.85,129.49,129.78,130.54,130.86,131.59。
Embodiment 29
1-(4-chlorophenylmethyl)-4-(2-(2-methylphenoxy) ethyl) piperazine (DZH-9)
By 1-(2-(2-methylphenoxy) ethyl) piperazine (2.1g, 0.01mol), 1-brooethyl-4-chlorobenzene (1.9g, 0.01mol), triethylamine (1.4mL, 0.01mol), acetonitrile (50mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, filtered while hot, filtrate steaming removal solvent obtains brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains white solid 1.8g, yield 54.9%, m.p.48.8-49.7 ℃.HRMS?calcd?for?C 20H 26ClN 2O[M+H] +345.1734,found?345.1738; 1HNMR(δ,ppm,CDCl 3,300MHz):2.213(s,3H,PhCH 3);2.503(bs,4H,N(CH 2) 2);2.669(bs,4H,N(CH 2) 2);2.850-2.888(t,2H,NCH 2,J=5.7Hz);3.480(s,2H,PhCH 2);4.106-4.144(t,2H,OCH 2,J=5.7Hz);6.792-7.277(m,8H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):53.08,53.66,57.30,62.24,66.34,111.02,120.42,126.73126.82,128.35,130.39,130.64,132.74,136.77,156.91。
Embodiment 30
1-(4-Brombenzyl)-4-(2-(2-methylphenoxy) ethyl) piperazine (DZH-10)
By 1-(2-(2-methylphenoxy) ethyl) piperazine (2.6g, 0.01mol), 1-brooethyl-4-bromobenzene (2.9g, 0.01mol), triethylamine (1.7mL, 0.01mol), acetonitrile (60mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, filtered while hot, filtrate steaming removal solvent obtains brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains white solid 1.4g, yield 32.8%, m.p.59.9-62.4 ℃.HRMS?calcd?for?C 20H 26BrN 2O[M+H] +389.1228,found?389.1232; 1HNMR(δ,ppm,CDCl 3,300MHz):2.209(s,3H,PhCH 3);2.518(bs,4H,N(CH 2) 2);2.689(bs,4H,N(CH 2) 2);2.865-2.903(t,2H,NCH 2,J=5.7Hz);3.470(s,2H,PhCH 2);4.116-4.154(t,2H,OCH 2,J=5.7Hz);6.790-7.460(m,8H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):53.06,57.29,62.27,66.31,111.02,120.43,126.73,130.64,130.77,131.32,137.28,156.90。
Embodiment 31
2-((4-(2-(4-methoxyphenoxy) ethyl) piperazine)-1-yl) methyl-toluate (DZH-11)
By 1-(2-(4-methoxyphenoxy) ethyl) piperazine (2.6g, 0.01mol), 2-brooethyl-methyl benzoate (2.5g, 0.01mol), triethylamine (1.5mL, 0.01mol), acetonitrile (59mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, filtered while hot, filtrate steaming removal solvent obtains brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains white solid 1.1g, yield 26.2%, m.p.51.8-53.9 ℃.HRMS?calcd?for?C 22H 29N 2O 4[M+H] +385.2127,found?385.2131; 1HNMR(δ,ppm,CDCl 3,300MHz):2.472(bs,4H,N(CH 2) 2);2.554(bs,4H,N(CH 2) 2);2.745-2.784(t,2H,NCH 2,J=5.7Hz);3.755(s,5H,PhCH 2;PhOCH 3);3.873(s,3H,COOCH 3);4.021-4.060(t,2H,OCH 2,J=5.7Hz);6.783-7.694(m,8H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):51.94,52.83,53.76,55.72,60.43,66.58,114.65,115.61,126.93,129.57,129.87,130.92,131.69,152.94,153.92。
Embodiment 32
1-(2-phenetole methyl)-4-(2-(4-methoxyphenoxy) ethyl) piperazine (DZH-12)
By 1-(2-(4-methoxyphenoxy) ethyl) piperazine (2.2g, 0.01mol), 1-brooethyl-2-phenetole (1.9g, 0.01mol), triethylamine (3.0mL, 0.02mol), acetonitrile (50mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, reaction solution steams and desolventizes to obtain brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains faint yellow solid 1.1g, yield 31.9%, m.p.73.2-74.8 ℃.HRMS?calcd?for?C 22H 31N 2O 3[M+H] +371.2335,found?371.2338; 1HNMR(δ,ppm,CDCl 3,300MHz):1.370-1.416(t,3H,CH 2(CH 3),J=6.9Hz);2.570(bs,4H,N(CH 2) 2);2.625(bs,4H,N(CH 2) 2);2.776-2.815(t,2H,NCH 2,J=5.7Hz);3.541(s,2H,PhCH 2);3.757(s,3H,PhOCH 3);3.950-4.020(q,2H,O(CH 2)CH 3,J=6.9Hz);4.035-4.074(t,2H,OCH 2,J=5.7Hz);6.683-7.475(m,8H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):14.79;52.89,53.74,55.43,55.73,57.35,64.01,66.53,112.71,113.16,114.64,115.62,130.47,132.87,152.99,153.91,156.28。
Embodiment 33
1-(4-chlorophenylmethyl)-4-(2-(4-methoxyphenoxy) ethyl) piperazine (DZH-13)
By 1-(2-(4-methoxyphenoxy) ethyl) piperazine (3.0g, 0.01mol), 1-brooethyl-4-chlorobenzene (2.6g, 0.01mol), triethylamine (1.7mL, 0.01mol), acetonitrile (68mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, filtered while hot, filtrate steaming removal solvent obtains brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains white solid 1.5g, yield 32.8%, m.p.81.5-82.8 ℃.HRMS?calcd?for?C 20H 26ClN 2O 2[M+H] +361.1683,found?361.1687; 1HNMR(δ,ppm,CDCl 3,300MHz):2.511(bs,4H,N(CH 2) 2);2.630(bs,4H,N(CH 2) 2);2.786-2.824(t,2H,NCH 2,J=5.7Hz);3.476(s,2H,PhCH 2);3.754(s,3H,PhOCH 3);4.041-4.079(t,2H,OCH 2,J=5.7Hz);6.803-7.297(m,8H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):52.96,53.60,55.72,57.30,62.21,66.59,114.65,115.61,128.33,130.39,132.72,152.95,153.92。
Embodiment 34
1-(4-Brombenzyl)-4-(2-(4-methoxyphenoxy) ethyl) piperazine (DZH-14)
By 1-(2-(4-methoxyphenoxy) ethyl) piperazine (2.6g, 0.01mol), 1-brooethyl-4-bromobenzene (2.8g, 0.01mol), triethylamine (1.5mL, 0.01mol), acetonitrile (59mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, filtered while hot, filtrate steaming removal solvent obtains brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains white solid 1.4g, yield 31.4%, m.p.80.9-82.9 ℃.HRMS?calcd?for?C 20H 26BrN 2O 2[M+H] +405.1178,found?405.1182; 1HNMR(δ,ppm,CDCl 3,300MHz):2.522(bs,4H,N(CH 2) 2);2.647(bs,4H,N(CH 2) 2);2.801-2.839(t,2H,NCH 2,J=5.7Hz);3.468(s,2H,PhCH 2);3.759(s,3H,PhOCH 3);4.054-4.092(t,2H,OCH 2,J=5.7Hz);6.824-7.445(m,8H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):52.92,53.58,55.72,57.28,62.23,66.56,114.65,115.61,120.83,130.77,132.30,152.93,153.94。
Embodiment 35
1-(4-phenetole methyl)-4-(2-(4-methoxyphenoxy) ethyl) piperazine (DZH-15)
By 1-(2-(4-methoxyphenoxy) ethyl) piperazine (2.4g, 0.01mol), 1-brooethyl-4-phenetole (1.9g, 0.01mol), triethylamine (1.9mL, 0.01mol), acetonitrile (55mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, filtered while hot, filtrate steaming removal solvent obtains brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains faint yellow solid 0.8g, yield 21.6%, m.p.84.3-86.2 ℃.HRMS?calcd?for?C 22H 31N 2O 3[M+H] +371.2335,found?371.2339; 1HNMR(δ,ppm,CDCl 3,500MHz):1.387-1.415(t,3H,CH 2(CH 3),J=6.5Hz);2.495(bs,4H,N(CH 2) 2);2.604(bs,4H,N(CH 2) 2);2.773-2.796(t,2H,NCH 2,J=5.0Hz);3.452(s,2H,PhCH 2);3.759(s,3H,PhOCH 3);3.997-4.037(q,2H,O(CH 2)CH 3,J=6.5Hz);4.037-4.059(t,2H,OCH 2,J=5.0Hz);6.819-7.259(m,8H,PhH); 13CNMR(δ,ppm,CDCl 3,125MHz):14.85;29.63;29.68;31.91;52.85;53.59;55.72;57.30;62.40;63.41;66.58;114.19;114.64;115.61;130.38;152.97;153.91;158.13。
Embodiment 36
2-((4-(2-(4-chlorophenoxy) ethyl) piperazine)-1-yl) methyl-toluate (DZH-16)
By 1-(2-(4-chlorophenoxy) ethyl) piperazine (1.8g, 0.007mol), 2-brooethyl-methyl benzoate (2.0g, 0.009mol), triethylamine (3.5mL, 0.025mol), acetonitrile (65mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, reaction solution steams and desolventizes to obtain brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains white solid 2.0g, yield 70.7%, m.p.59.6-61.8 ℃.HRMS?calcd?for?C 21H 26ClN 2O 3[M+H] +389.1632,found?389.1634; 1HNMR(δ,ppm,CDCl 3,300MHz):2.470(bs,4H,N(CH 2) 2);2.546(bs,4H,N(CH 2) 2);2.754-2.793(t,2H,NCH 2,J=5.7Hz);3.760(s,2H,PhCH 2);3.873(s,3H,COOCH 3);4.032-4.071(t,2H,OCH 2,J=5.7Hz);6.796-7.696(m,8H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):51.92,52.86,53.81,57.11,60.44,66.36,115.90,126.93,129.27,129.58,129.85,130.92,139.28,157.40,169.22。
Embodiment 37
1-(4-chlorophenylmethyl)-4-(2-(4-chlorophenoxy) ethyl) piperazine (DZH-17)
By 1-(2-(4-chlorophenoxy) ethyl) piperazine (2.0g, 0.008mol), 1-brooethyl-4-chlorobenzene (2.0g, 0.010mol), triethylamine (3.9mL, 0.028mol), acetonitrile (72mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, reaction solution steams and desolventizes to obtain brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains white solid 0.9g, yield 32.1%, m.p.52.2-53.9 ℃.HRMS?calcd?for?C 19H 23Cl 2N 2O[M+H] +365.1187,found365.1189; 1HNMR(δ,ppm,CDCl 3,300MHz):2.479(bs,4H,N(CH 2) 2);2.593(bs,4H,N(CH 2) 2);2.772-2.811(t,2H,NCH 2,J=5.7Hz);3.461(s,2H,PhCH 2);4.034-4.073(t,2H,OCH 2,J=5.7Hz);6.784-7.289(m,8H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):52.95,53.62,57.08,62.20,66.32,115.90,125.68,128.35,129.28,130.38,132.74,136.73,157.39。
Embodiment 38
1-(4-Brombenzyl)-4-(2-(4-chlorophenoxy) ethyl) piperazine (DZH-18)
By 1-(2-(4-chlorophenoxy) ethyl) piperazine (2.0g, 0.008mol), 1-brooethyl-4-bromobenzene (2.4g, 0.010mol), triethylamine (3.9mL, 0.028mol), acetonitrile (72mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, reaction solution steams and desolventizes to obtain brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains white solid 1.5g, yield 47.2%, m.p.59.3-61.5 ℃.HRMS?calcd?for?C 19H 23BrClN 2O[M+H] +409.0682,found?409.0684; 1HNMR(δ,ppm,CDCl 3,300MHz):2.490(bs,4H,N(CH 2) 2);2.607(bs,4H,N(CH 2) 2);2.787-2.825(t,2H,NCH 2,J=5.7Hz);3.457(s,2H,PhCH 2);4.047-4.086(t,2H,OCH 2,J=5.7Hz);6.801-7.443(m,8H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):52.93,53.60,57.08,62.23,66.29,115.90,120.84,125.69,129.28,130.76,131.31,137.22,157.38。
Embodiment 39
1-(pair-(4-p-methoxy-phenyl) methyl)-4-(2-(2-naphthyloxy) ethyl) piperazine (DZH-19)
By 2-(2-bromine oxethyl) naphthalene (2.5g, 0.010mol), 1-(pair-(4-p-methoxy-phenyl) methyl) piperazine (2.6g, 0.008mol), triethylamine (4.1mL, 0.029mol), acetonitrile (74mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, reaction solution steams and desolventizes to obtain brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains white solid 1.3g, yield 32.5%, m.p.125.7-126.1 ℃.HRMS?calcd?for?C 31H 35N 2O 3[M+H] +483.2648,found?483.2650; 1HNMR(δ,ppm,CDCl 3,300MHz):2.446(bs,4H,N(CH 2) 2);2.649(bs,4H,N(CH 2) 2);2.874-2.897(t,2H,NCH 2,J=5.7Hz);3.749(s,6H,OCH 3×2);4.154(s,1H,NCH(Ph) 2);4.209-4.232(t,2H,OCH 2,J=5.7Hz);6.760-7.751(m,15H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):53.99,55.19,106.82,113.84,118.92,123.62,126.33,126.73,127.60,128.81,129.34。
Embodiment 40
1-(pair-(4-bromophenyl) methyl)-4-(2-(2-naphthyloxy) ethyl) piperazine (DZH-20)
By 2-(2-bromine oxethyl) naphthalene (0.9g, 0.004mol), 1-(pair-(4-bromophenyl) methyl) piperazine (1.3g, 0.003mol), triethylamine (1.5mL, 0.011mol), acetonitrile (28mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, reaction solution steams and desolventizes to obtain brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains white solid 0.7g, yield 40.2%, m.p.180.2-181.2 ℃.HRMS?calcd?for?C 29H 29Br 2N 2O[M+H] +579.0647,found?579.0649; 1HNMR(δ,ppm,CDCl 3,300MHz):2.453(bs,4H,N(CH 2) 2);2.673(bs,4H,N(CH 2) 2);2.900-2.924(t,2H,NCH 2,J=3.6Hz);4.182(s,1H,NCH(Ph) 2);4.224-4.248(t,2H,OCH 2,J=3.6Hz);6.935-7.751(m,15H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):53.72,56.99,106.87,118.80,121.04,123.72,126.40,126.74,127.61,129.42,129.45,131.80,134.49,141.02。
Embodiment 41
1-(pair-(4-fluorophenyl) methyl)-4-(2-(4-methoxyphenoxy) ethyl) piperazine (DZH-21)
By 1-(2-bromine oxethyl)-4-anisole (2.5g, 0.010mol), 1-(pair-(4-fluorophenyl) methyl) piperazine (2.6g, 0.009mol), triethylamine (4.4mL, 0.032mol), acetonitrile (80mL) adds in eggplant-shape bottle, add catalytic amount zinc powder (0.8g), be heated with stirring to backflow.Reflux 20 hours, reaction solution steams and desolventizes to obtain brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains white solid 2.9g, yield 72.8%, m.p.84.6-86.8 ℃.HRMS?calcd?for?C 26H 29F 2N 2O 2[M+H] +439.2197,found?439.2200; 1HNMR(δ,ppm,CDCl 3,300MHz):2.410(bs,4H,N(CH 2) 2);2.600(bs,4H,N(CH 2) 2);2.772-2.795(t,2H,NCH 2,J=3.6Hz);3.750(s,3H,PhOCH 3);4.027-4.051(t,2H,OCH 2,J=3.6Hz);4.216(s,1H,NCH(Ph) 2);6.810-7.345(m,12H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):51.65,533.85,55.72,57.25,66.59,114.65,115.27,115.44,115.60,129.23,129.30,138.19,152.92,153.94,160.84,162.80。
Embodiment 42
1-(pair-(4-p-methoxy-phenyl) methyl)-4-(2-(4-methoxyphenoxy) ethyl) piperazine (DZH-22)
By 1-(2-bromine oxethyl)-4-anisole (2.5g, 0.011mol), 1-(pair-(4-p-methoxy-phenyl) methyl) piperazine (2.8g, 0.009mol), triethylamine (4.4mL, 0.032mol), acetonitrile (80mL) adds in eggplant-shape bottle, add catalytic amount zinc powder (0.8g), be heated with stirring to backflow.Reflux 20 hours, reaction solution steams and desolventizes to obtain brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains white solid 2.8g, yield 67.8%, m.p.99.0-99.6 ℃.HRMS?calcd?for?C 28H 35N 2O 4[M+H] +463.2597,found?463.2600; 1HNMR(δ,ppm,CDCl 3,300MHz):2.418(bs,4H,N(CH 2) 2);2.588(bs,4H,N(CH 2) 2);2.764-2.788(t,2H,NCH 2,J=3.6Hz);3.748(s,9H,OCH 3×3);4.024-4.048(t,2H,OCH 2,J=3.6Hz);4.139(s,1H,NCH(Ph) 2);6.790-7.297(m,12H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):51.66,53.96,55.19,55.72,57.26,66.52,113.83,114.64,115.60,128.81,135.17,158.46。
Embodiment 43
1-(pair-(4-bromophenyl) methyl)-4-(2-(4-methoxyphenoxy) ethyl) piperazine (DZH-23)
By 1-(2-bromine oxethyl)-4-anisole (1.7g, 0.007mol), 1-(pair-(4-bromophenyl) methyl) piperazine (2.5g, 0.006mol), triethylamine (3.0mL, 0.021mol), acetonitrile (54mL) adds in eggplant-shape bottle, add catalytic amount zinc powder (0.8g), be heated with stirring to backflow.Reflux 20 hours, reaction solution steams and desolventizes to obtain brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains white solid 1.3g, yield 38.8%, m.p.132.4-134.0 ℃.HRMS?calcd?for?C 26H 29Br 2N 2O 2[M+H] +559.0596,found?559.0599; 1HNMR(δ,ppm,CDCl 3,300MHz):2.415(bs,4H,N(CH 2) 2);2.604(bs,4H,N(CH 2) 2);2.772-2.810(t,2H,NCH 2,J=5.7Hz);3.754(s,3H,PhOCH 3);4.022-4.060(t,2H,OCH 2,J=5.7Hz);4.162(s,1H,NCH(Ph) 2);6.813-7.408(m,12H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):51.63,53.77,55.72,57.22,66.56,114.65,115.60,120.96,129.49,131.74,141.16,152.89,153.95。
Embodiment 44
1-(pair-(4-p-methoxy-phenyl) methyl)-4-(2-(2-methylphenoxy) ethyl) piperazine (DZH-24)
By 1-(2-bromine oxethyl)-2-methylbenzene (2.1g, 0.010mol), 1-(pair-(4-p-methoxy-phenyl) methyl) piperazine (2.5g, 0.008mol), triethylamine (3.9mL, 0.028mol), acetonitrile (70mL) adds in eggplant-shape bottle, add catalytic amount zinc powder (0.8g), be heated with stirring to backflow.Reflux 20 hours, reaction solution steams and desolventizes to obtain brown solid.TLC shows impure, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1: 10 to 1: 1), gradient elution, and column chromatography obtains white solid 2.6g, yield 73.6%, m.p.68.2-70.2 ℃.HRMS?calcd?for?C 28H 35N 2O 3[M+H] +447.2648,found?447.2651; 1HNMR(δ,ppm,CDCl 3,300MHz):2.192(s,3H,PhCH 3);2.424(bs,4H,N(CH 2) 2);2.642(bs,4H,N(CH 2) 2);2.831-2.869(t,2H,NCH 2,J=5.7Hz);3.752(s,6H,OCH 3×2);4.086-4.125(t,2H,OCH 2,J=5.7Hz);4.135(s,1H,NCH(Ph) 2);6.776-7.311(m,12H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):51.88,54.04,55.19,57.29,66.35,111.03,113.83,120.39,126.72,130.62,135.23,158.45。
Embodiment 45
1-(pair-(4-bromophenyl) methyl)-4-(2-(2-methylphenoxy) ethyl) piperazine (DZH-25)
By 1-(2-bromine oxethyl)-2-methylbenzene (1.5g, 0.007mol), 1-(pair-(4-bromophenyl) methyl) piperazine (2.4g, 0.006mol), triethylamine (2.9mL, 0.021mol), acetonitrile (52mL) adds in eggplant-shape bottle, add catalytic amount zinc powder (0.8g), be heated with stirring to backflow.Reflux 20 hours, reaction solution steams and desolventizes to obtain brown solid.TLC shows impure, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1: 10 to 1: 1), gradient elution, and column chromatography obtains white solid 1.2g, yield 37.9%, m.p.147.6-148.7 ℃.HRMS?calcd?for?C 26H 29Br 2N 2O[M+H] +543.0647,found?543.0649; 1HNMR(δ,ppm,CDCl 3,300MHz):2.194(s,3H,PhCH 3);2.411(bs,4H,N(CH 2) 2);2.646(bs,4H,N(CH 2) 2);2.835-2.872(t,2H,NCH 2,J=5.7Hz);4.083-4.120(t,2H,OCH 2,J=5.7Hz);4.159(s,1H,NCH(Ph) 2);6.774-7.412(m,12H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):51.73,53.80,57.20,66.25,111.01,120.47,120.97,126.74,129.49,130.65,131.75,141.17。
Embodiment 46
1-(pair-(4-aminomethyl phenyl) methyl)-4-(2-(2-methylphenoxy) ethyl) piperazine (DZH-26)
By 1-(2-bromine oxethyl)-2-methylbenzene (2.0g, 0.009mol), 1-(pair-(4-aminomethyl phenyl) methyl) piperazine (2.2g, 0.008mol), triethylamine (3.8mL, 0.028mol), acetonitrile (69mL) adds in eggplant-shape bottle, add catalytic amount zinc powder (0.8g), be heated with stirring to backflow.Reflux 20 hours, reaction solution steams and desolventizes to obtain pale yellow oily liquid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains faint yellow thickness oily matter 1.8g, yield 55.0%.HRMS?calcd?for?C 28H 35N 2O[M+H] +415.2749,found?415.2749; 1HNMR(δ,ppm,CDCl 3,300MHz):2.189(s,3H,OPhCH 3);2.268(s,6H,PhCH 3×2);2.430(bs,4H,N(CH 2) 2);2.633(bs,4H,N(CH 2) 2);2.819-2.858(t,2H,NCH 2,J=5.7Hz);4.075-4.114(t,2H,OCH 2,J=5.7Hz);4.141(s,1H,NCH(Ph) 2);6.772-7.298(m,12H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):16.23;21.04;29.73;52.01;54.06;57.34;66.42;111.05;126.75;126.85;127.78;129.17;130.64;136.36;140.09;156.98。
Embodiment 47
1-(pair-(4-fluorophenyl) methyl)-4-(2-(4-chlorophenoxy) ethyl) piperazine (DZH-27)
By 1-(2-bromine oxethyl)-4-chlorobenzene (2.0g, 0.009mol), 1-(pair-(4-fluorophenyl) methyl) piperazine (2.1g, 0.007mol), triethylamine (3.5mL, 0.025mol), acetonitrile (65mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, reaction solution steams and desolventizes to obtain brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography obtains white solid 1.2g, yield 37.9%, m.p.117.7-119.1 ℃.HRMS?calcd?for?C 25H 26ClF 2N 2O[M+H] +443.1702,found?443.1705; 1HNMR(δ,ppm,CDCl 3,300MHz):2.408(bs,4H,N(CH 2) 2);2.594(bs,4H,N(CH 2) 2);2.773-2.812(t,2H,NCH 2,J=5.7Hz);4.031-4.770(t,2H,OCH 2,J=5.7Hz);4.217(s,1H,NCH(Ph) 2);6.778-7.367(m,12H,PhH); 13CNMR(δ,ppm,CDCl 3,75MHz):51.65,53.88,57.04,66.33,115.28,115.45,115.89,125.70,129.23,129.29,138.17,157.36,160.85,162.80。
Embodiment 48
1-(pair-(4-fluorophenyl) methyl)-4-(2-(4-bromine phenoxy group) ethyl) piperazine (DZH-28)
By 1-(2-bromine oxethyl)-4-bromobenzene (2.3g, 0.008mol), 1-(pair-(4-fluorophenyl) methyl) piperazine (2.0g, 0.007mol), triethylamine (3.5mL, 0.025mol), acetonitrile (65mL) adds in eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Reflux 20 hours, reaction solution steams and desolventizes to obtain brown solid.It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution as eluent (ethyl acetate: sherwood oil volume ratio=1:10 to 1: 1), gradient elution, column chromatography obtains white solid 2.4g, yield 71.4%, m.p.13.7-135.3 ℃.HRMS?calcd?for?C 25H 26BrF 2N 2O[M+H] +487.1197,found?487.1199; 1HNMR(δ,ppm,CDCl 3,500MHz):2.414(bs,4H,N(CH 2) 2);2.604(bs,4H,N(CH 2) 2);2.789-2.812(t,2H,NCH 2,J=6.0Hz);4.045-4.068(t,2H,OCH 2,J=6.0Hz);4.218(s,1H,NCH(Ph) 2);6.749-7.360(m,12H,PhH); 13CNMR(δ,ppm,CDCl 3,125MHz):51.59;53.86;57.00;66.20;113.00;115.29;115.46;116.41;129.22;129.29;132.24;138.14;157.83;160.85;162.81。
Embodiment 49
The impact of target compound on acute cerebral ischemia mouse survival time in embodiment.
Target compound and positive control drug nimodipine are made into the suspension of desired concn before use with 0.5%wt Xylo-Mucine; Experimental animal is ICR mouse, body weight 19-25g, male and female half and half.Mouse is pressed to sex random packet, 10 every group, male and female half and half.Gavage gives tested medicine 0.2mL/10g respectively, blank group waits capacity NS, positive controls waits capacity nimodipine 80mg/Kg, 1 hour etherization after administration, neck medisection after fixing, separated bilateral carotid and vagus nerve ligation, record the mouse survival time that (per minute frequency of respiration is less than or equal to 5 times, think dead mouse), the results are shown in Table 1,2.
Table 1: target compound is on the impact of acute cerebral ischemia mouse survival time (min)
Table 2, the impact of Compound D ZH-1 on acute cerebral ischemia mouse survival time
Compare * P<0.05 with NS group
Above-mentioned test-results shows, above-claimed cpd all has certain treating cerebral ischemia, wherein Compound D ZH-1, DZH-2, DZH-3, DZH-4, DZH-6, DZH-9, DZH-10, DZH-11, DZH-13, DZH-15, DZH-18, DZH-19, DZH-22, DZH-23 can obviously extend acute cerebral ischemia mouse survival time, treating cerebral ischemia is particularly evident, and wherein Compound D ZH-1 effect is the strongest.

Claims (3)

1.2-((4-(2-(2-naphthyloxy) ethyl) piperazine)-1-yl) methyl-toluate, is characterized in that this compound is to have following structure:
2. the preparation method of 2-((4-(2-(2-naphthyloxy) ethyl) piperazine)-1-yl) methyl-toluate described in claim 1, it is characterized in that comprising the following steps: by 0.06mol Piperazine anhydrous, 66mL dehydrated alcohol, 8.7mL water adds in eggplant-shape bottle, stirring and dissolving; The Hydrogen bromide 0.06mol that drips 40%wt in the situation that constantly stirring, drips off for 20 minutes, continues to stir 5 minutes; Divide and add 0.03mol2-(2-bromine oxethyl) naphthalene for three times, be heated with stirring to backflow; Reflux 6 hours, in refrigerator, 4 ℃ of refrigerations are spent the night, and a large amount of solids are separated out; Filter, filter cake washes with water to be removed for three times after piperazine two hydrobromates, merges with filtrate, adds 10mL30%wt sodium hydroxide solution, is warming up to backflow; Reflux 5 hours, cooling, concentrated; Resistates adds 40mL water, with methylene dichloride 30mL extraction three times, merge organic layer, anhydrous magnesium sulfate drying, suction filtration, filtrate steaming removal solvent, obtain white solid 7.3g, yield 95.1%, TLC shows the great impurity of micro-polarity, this impurity does not affect next step operation, directly carries out next step reaction; The 0.01mol1-that aforesaid method is obtained (2-(2-naphthyloxy) ethyl) piperazine, 0.01mol2-brooethyl-methyl benzoate, 0.01mol triethylamine, 48mL acetonitrile adds in three-necked bottle, adds catalytic amount zinc powder 0.8g, is heated with stirring to backflow; Reflux 20 hours, filtered while hot, filtrate steaming removal solvent obtains brown solid; It is impure that TLC shows, take ethyl acetate and sherwood oil mixed solution is eluent, gradient elution, ethyl acetate: sherwood oil volume ratio=1:10 to 1:1, column chromatography obtains white solid 1.22g, yield 31.2%, m.p.75.2-76.8 ℃.
3.2-((4-(2-(2-naphthyloxy) ethyl) the piperazine)-1-yl) application of methyl-toluate in preparing cerebral infarction medicine.
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