CN102924406A - 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 PDFInfo
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- CN102924406A CN102924406A CN2012104407785A CN201210440778A CN102924406A CN 102924406 A CN102924406 A CN 102924406A CN 2012104407785 A CN2012104407785 A CN 2012104407785A CN 201210440778 A CN201210440778 A CN 201210440778A CN 102924406 A CN102924406 A CN 102924406A
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- Prior art keywords
- ethyl
- piperazine
- methyl
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- -1 Substituted aryl oxygen ethylpiperazine derivative Chemical class 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 18
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims abstract description 15
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 11
- 125000003118 aryl group Chemical group 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 229940095064 tartrate Drugs 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 198
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 114
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 99
- 239000007787 solid Substances 0.000 claims description 87
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 75
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 71
- 238000003756 stirring Methods 0.000 claims description 65
- 239000000243 solution Substances 0.000 claims description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 52
- 238000006243 chemical reaction Methods 0.000 claims description 49
- 238000010025 steaming Methods 0.000 claims description 36
- 238000004440 column chromatography Methods 0.000 claims description 33
- 239000003480 eluent Substances 0.000 claims description 33
- 238000010828 elution Methods 0.000 claims description 33
- 239000000706 filtrate Substances 0.000 claims description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 32
- INMYWZOQVJWBQC-UHFFFAOYSA-N 1-[2-(4-methoxyphenoxy)ethyl]piperazine Chemical compound C1=CC(OC)=CC=C1OCCN1CCNCC1 INMYWZOQVJWBQC-UHFFFAOYSA-N 0.000 claims description 29
- 239000002904 solvent Substances 0.000 claims description 29
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 239000001301 oxygen Substances 0.000 claims description 27
- 229910052794 bromium Inorganic materials 0.000 claims description 26
- SIYDJAYNPQOVOK-UHFFFAOYSA-N 1-(2-naphthalen-2-yloxyethyl)piperazine Chemical compound C=1C=C2C=CC=CC2=CC=1OCCN1CCNCC1 SIYDJAYNPQOVOK-UHFFFAOYSA-N 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- UYGHEEKXUMTKTR-UHFFFAOYSA-N 1-[2-(2-methylphenoxy)ethyl]piperazine Chemical compound CC1=CC=CC=C1OCCN1CCNCC1 UYGHEEKXUMTKTR-UHFFFAOYSA-N 0.000 claims description 19
- WVWZECQNFWFVFW-UHFFFAOYSA-N methyl 2-methylbenzoate Chemical compound COC(=O)C1=CC=CC=C1C WVWZECQNFWFVFW-UHFFFAOYSA-N 0.000 claims description 19
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- NMTCQEIEKVUWQE-UHFFFAOYSA-N 1-[2-(4-methylphenoxy)ethyl]piperazine Chemical compound C1=CC(C)=CC=C1OCCN1CCNCC1 NMTCQEIEKVUWQE-UHFFFAOYSA-N 0.000 claims description 16
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 16
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- AETRCWQLVCVHMF-UHFFFAOYSA-N CCBr.[O] Chemical compound CCBr.[O] AETRCWQLVCVHMF-UHFFFAOYSA-N 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 238000000967 suction filtration Methods 0.000 claims description 14
- DTOPBQLBZBMIFT-UHFFFAOYSA-N 1-[2-(4-chlorophenoxy)ethyl]piperazine Chemical compound C1=CC(Cl)=CC=C1OCCN1CCNCC1 DTOPBQLBZBMIFT-UHFFFAOYSA-N 0.000 claims description 13
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 9
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
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- 239000002516 radical scavenger Substances 0.000 description 1
- 238000007347 radical substitution reaction Methods 0.000 description 1
- 150000003254 radicals Chemical group 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- CSYSULGPHGCBQD-UHFFFAOYSA-N s-ethylisothiouronium diethylphosphate Chemical compound CCSC(N)=N.CCOP(O)(=O)OCC CSYSULGPHGCBQD-UHFFFAOYSA-N 0.000 description 1
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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
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 the agent of preparation neuroprotection.
Background technology
Cerebral apoplexy is one of the highest disease of current lethality rate and disability rate, and wherein nearly 80% cerebral apoplexy belongs to cerebral infarction.The injured degree of neuronal cell was depended in the living or death of brain cell after cerebral apoplexy occured, and the degree that provides the cerebral blood flow of oxygen and nutrition to reduce for cell namely is provided.When cerebral infarction occured, the cerebral blood flow at ischemic core position seriously reduced, and at the 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 unusually, in a few hours after ischemic occurs, abnormal electrical activity and metabolism disorder form a chain reaction in the ischemic area, be referred to as " ischemic waterfall ", the final result of water fall effect is that the ischemic core is constantly expanded, penumbra fades away, and this process is exactly the time window of Treatment of Cerebral Stroke.
Propose the Neuroprotective Therapy in Treating Acute of cerebral infarction abroad since nineteen nineties, in subsequently 10 years, swift and violent development has been arranged.The target of neuroprotective is to intervene the pathological biochemistry cascade reaction that the ischemia penumbra occurs, and saves still vigourous cerebral tissue, prevents or postpones necrocytosis.Neuroprotective kind and mechanism of action are various at present, such 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 that solves: 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 replacement of medical value.
Two of the technical issues that need to address of the present invention be above-mentioned replacement disclosed fragrant oxygen ethyl piperazidine analog derivative as the application of neuroprotection agent in the cerebral infarction treatment, hemorrhage with bringing out of overcoming that prior art exists, be difficult to see through hemato encephalic barrier, the defective 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 the 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 the aralkoxy are benzene, biphenyl or naphthalene, perhaps are F, Cl, Br, I, C
1～10Alkyl, C
1～10Alkoxyl group, nitro or amino benzene, biphenyl or the naphthalene that replaces.
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 the 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
2The substituted heterocycle of representative or the heterocyclic radical in the heterocycle alkoxyl group 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 are 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
10Be alkyl, perhaps R
9R
10N is the ternary ~ eight yuan of heterocycles 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.Replace the preparation method of fragrant oxygen ethyl piperazidine analog derivative, it is characterized in that may further comprise the steps:
(annotate: the Ar in compound ii, III, IV, V, VI, VII, the 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 that replaces, glycol dibromide 0.15mol, water 60mL stir and are warming up to backflow, drip 25%wt sodium hydroxide solution 24mL, drip off in 30 minutes; Backflow 10-13 hour, reaction solution cooling standing over night, when having solid to separate out, suction filtration, filter cake washes twice with water, the dehydrated alcohol recrystallization; When separating out without solid, separatory, organic layer dissolves with methylene dichloride 20mL, with 5%wt sodium hydroxide solution 30mL washing three times, water 30mL washing is three times again, anhydrous magnesium sulfate drying, suction filtration, filtrate decompression steam and desolventize the fragrant oxygen monobromethane (III) that is replaced accordingly;
B. Piperazine anhydrous 0.08mol, dehydrated alcohol 86mL, water 12mL drips 40%wt Hydrogen bromide 0.08mol in the situation that constantly stir, and drips off in 20 minutes, continues to stir 5 minutes; Fragrant oxygen monobromethane (III) 0.04mol that replaces divides three times and adds above-mentioned reaction solution, is heated with stirring to reflux 6 hours, and 4 ℃ of refrigerations are spent the night in the refrigerator; The filtering insolubles, filtrate steaming removal solvent, add 5%wt sodium hydroxide solution 50mL in the resistates, stirred 4 hours, with methylene dichloride 40mL extraction three times, merge organic layer, steam except organic solvent the fragrant oxygen ethyl piperazidine (IV) that the gained resistates is replaced accordingly 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 get solid, the 280mL that adds methylene chloride dissolving adds the 200mL water washing, separatory, the benzhydrol that the organic phase evaporate to dryness must replace; The benzhydrol 0.02mol that replaces, 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 the concentrated gained resistates; Concentration of reaction solution adds methylene dichloride 350mL in the gained solid, with the NaOH solution 150mL washing of 1mol/L, separatory, the benzhydryl piperazidine that the organic phase evaporate to dryness obtains replacing (VI);
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 the eggplant-shape bottle, and the incandescent light irradiation is lower, stirs and is warming up to back flow reaction 1 hour, cooling is left standstill, and adds hexanaphthene 108mL in solution, jolting, suction filtration, filtrate steaming removal solvent, add acetonitrile 75mL in the residual solution, behind the shake well, steaming desolventizes, and gets corresponding Bromomethyl Substituted benzene (VIII);
Fragrant oxygen monobromethane (III) 0.010mol that e. will replace, the benzhydryl piperazidine of replacement (VI) 0.008mol, triethylamine 0.029mol, acetonitrile 74mL add in the eggplant-shape bottle, under the condition of nitrogen protection or zinc powder existence, are heated with stirring to backflow; Refluxed 20 hours, and filtered, filtrate steaming removal solvent is 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 for separation; Fragrant oxygen ethyl piperazidine (IV) 0.005mol that maybe will replace, Bromomethyl Substituted benzene (VIII) 0.005mol, triethylamine 0.005mol, acetonitrile 24mL add in the three-necked bottle, under the condition of nitrogen protection or zinc powder existence, are heated with stirring to backflow.Refluxed 20 hours, filtered while hot, filtrate steaming removal solvent is 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 for separation must logical formula I compound.
Replace the application of fragrant oxygen ethyl piperazidine analog derivative in preparation cerebral infarction medicine.
Compound 2-((4-(2-(2-naphthyloxy) ethyl) piperazine)-and the 1-yl) methyl-toluate, the 1-(4-chlorophenylmethyl)-and the 4-(2-(2-naphthyloxy) ethyl) piperazine, the 1-(4-Brombenzyl)-and the 4-(2-(2-naphthyloxy) ethyl) piperazine, the 2-((4-(2-(4-methylphenoxy) ethyl) piperazine)-and the 1-yl) methyl-toluate, the 1-(4-Brombenzyl)-and the 4-(2-(4-methylphenoxy) ethyl) piperazine, the 1-(4-chlorophenylmethyl)-and the 4-(2-(2-methylphenoxy) ethyl) piperazine, the 1-(4-Brombenzyl)-and the 4-(2-(2-methylphenoxy) ethyl) piperazine, the 2-((4-(2-(4-methoxyphenoxy) ethyl) piperazine)-and the 1-yl) methyl-toluate, the 1-(4-chlorophenylmethyl)-and the 4-(2-(4-methoxyphenoxy) ethyl) piperazine, 1-(4-phenetole methyl)-and the 4-(2-(4-methoxyphenoxy) ethyl) piperazine, the 1-(4-Brombenzyl)-and the 4-(2-(4-chlorophenoxy) ethyl) piperazine, 1-(pair-(4-p-methoxy-phenyl) methyl)-the 4-(2-(2-naphthyloxy) ethyl) piperazine, 1-(pair-(4-p-methoxy-phenyl) methyl)-the 4-(2-(4-methoxyphenoxy) ethyl) piperazine or 1-(pair-(4-bromophenyl) methyl)-the 4-(2-(4-methoxyphenoxy) ethyl) application of piperazine in preparation cerebral infarction medicine.
The preparation method of the fragrant oxygen ethyl piperazidine analog derivative that the logical formula I that the present invention relates to replaces can be represented by synthetic schematic diagram 1 ~ 3:
The fragrant phenol of the replacement that a. replaces and the fragrant oxygen monobromethane that the glycol dibromide condensation is replaced accordingly, the fragrant oxygen ethyl piperazidine (see and synthesize schematic diagram 1) that is then replaced accordingly with the Piperazine anhydrous condensation;
B. the benzhydryl piperazidine that the benzophenone that replaces obtains replacing through reduction, halo, replacement (seeing synthetic schematic diagram 2);
C. the nuclear substituted toluene of benzene obtains corresponding Bromomethyl Substituted benzene (seeing synthetic schematic diagram 3) in the situation that illumination is carried out the free radical substitution reaction with the N-bromo-succinimide;
The fragrant oxygen monobromethane that d. will replace and the benzhydryl piperazidine condensation of replacement, or the fragrant oxygen ethyl piperazidine and the condensation of Bromomethyl Substituted benzene that replace have prepared the fragrant oxygen ethyl piperazidine analog derivative (see and synthesize schematic diagram 4) of a series of new replacements;
E. with condensation products therefrom dehydrated alcohol recrystallization, get 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 carry out anti-cerebral ischemia drugs on the impact of acute cerebral ischemia mouse survival time pharmacodynamics preliminary assessment according to a conventional method.Experimental data (seeing embodiment 49 for details) shows: preventatively give part of compounds of the present invention, can obviously prolong the survival time of acute cerebral ischemia mouse, have certain anti-cerebral ischemia neuroprotective.
Description of drawings
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
The 2-(2-bromine oxethyl) naphthalene
With ethyl naphthol (14.4g, 0.10mol), glycol dibromide (13mL, 0.15mol), water (60mL) add in the three-necked bottle, stir and are warming up to backflow, drip the sodium hydroxide solution (24mL) of 25%wt, approximately drip off in 30 minutes.Refluxed 10 hours, reaction solution cooling layering, standing over night, a large amount of solids are separated out.Suction filtration, filter cake washes twice with water, and dehydrated alcohol recrystallization twice gets white crystal 13.4g, and yield 54.3%, TLC show pure point.
Embodiment 2
The 1-(2-bromine oxethyl)-the 4-methylbenzene
With p-cresol (13g, 0.12mol), glycol dibromide (15.6mL, 0.18mol), water (72mL) add in the three-necked bottle, stir and are warming up to backflow, drip the sodium hydroxide solution (28.8mL) of 25%wt, approximately drip off in 45 minutes.Refluxed 10 hours, reaction solution cooling layering, standing over night is separated out without solid.Separatory, organic layer 40mL water washing twice, anhydrous magnesium sulfate drying, suction filtration steams except organic solvent, gets faint yellow clarification oily liquid.The cut of 108 ℃/0.08mmHg is collected in underpressure distillation, and this cut is initially clear colorless oil shape liquid after coagulation and becomes white solid.The final white solid 8.2g that gets, yield 34.2%, TLC show pure point.
Embodiment 3
The 1-(2-bromine oxethyl)-the 2-methylbenzene
With ortho-cresol (13g, 0.12mol), glycol dibromide (15.6mL, 0.18mol), water (72mL) add in the three-necked bottle, stir and are warming up to backflow, drip the sodium hydroxide solution (28.8mL) of 25%wt, approximately drip off in 45 minutes.Refluxed 13 hours, reaction solution cooling layering, standing over night is separated out without solid.Separatory, organic layer uses the sodium hydroxide solution of 30mL 5%wt to wash three times with the dissolving of 20mL methylene dichloride, uses the 30mL water washing three times again, anhydrous magnesium sulfate drying, suction filtration, filtrate steaming removal solvent, get faint yellow clarification oily liquid 10.9g, yield 42.3%, TLC show pure point.
Embodiment 4
The 1-(2-bromine oxethyl)-the 4-anisole
The 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.Get white solid 14.1g, yield 50.8%, TLC show pure point.
Embodiment 5
The 1-(2-bromine oxethyl)-the 4-chlorobenzene
The 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.Get pale yellow oily liquid 22.8g, yield 81.2%, TLC show pure point.
Embodiment 6
The 1-(2-bromine oxethyl)-the 4-bromobenzene
The 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.Get white paste solid 8.8g, yield 58.6%, TLC show pure point.
Embodiment 7
The 1-(2-(4-methylphenoxy) ethyl) piperazine
With Piperazine anhydrous (6.9g, 0.08mol), dehydrated alcohol (86mL), water (12mL) add in the eggplant-shape bottle, stir and make piperazine dissolved.In the situation that constantly stir the Hydrogen bromide (0.08mol) that drips 40%wt, approximately dripped off in 20 minutes, continue to stir 5 minutes.Divide three times and add the 1-(2-bromine oxethyls)-4-methylbenzene (8.6g, 0.04mol), be heated with stirring to backflow.Refluxed 6 hours, 4 ℃ of refrigerations are spent the night in the refrigerator, have minute hand shape crystal (piperazine two hydrobromates) to separate out.Filter, filtering crystal, filtrate steaming removal solvent get the yellowish white paste.Add 50mL 5%wt sodium hydroxide solution, stirred 4 hours, use 40mL dichloromethane extraction three times, merge organic layer, steam except organic solvent, get faint yellow paste, TLC shows impure.With 20mL dehydrated alcohol recrystallization, get white solid 2.8g, yield 31.8%, TLC show pure point.
Embodiment 8
The 1-(2-(2-naphthyloxy) ethyl) piperazine
With Piperazine anhydrous (5.2g, 0.06mol), dehydrated alcohol (66mL), water (8.7mL) add in the eggplant-shape bottle, stirring and dissolving.In the situation that constantly stir the Hydrogen bromide (0.06mol) that drips 40%wt, approximately dripped off in 20 minutes, continue to stir 5 minutes.Divide three times and add the 2-(2-bromine oxethyls) naphthalene (7.5g, 0.03mol), be heated with stirring to backflow.Refluxed 6 hours, 4 ℃ of refrigerations are spent the night in the refrigerator, and a large amount of solids are separated out.Filter, filter cake merges with filtrate after washing with water and removing piperazine two hydrobromates three times, adds 10mL 30%wt sodium hydroxide solution, is warming up to backflow.Refluxed 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, get white solid 7.3g, yield 95.1%, TLC show the great impurity of micro-polarity, this impurity does not affect next step operation, directly carries out next step reaction.
Embodiment 9
The 1-(2-(2-methylphenoxy) ethyl) piperazine
The 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.4 ℃ of refrigerations are spent the night in the refrigerator, filtering minute hand shape crystal (piperazine two hydrobromates).Add 10mL 30%wt sodium hydroxide solution, stir and be warming up to backflow.Refluxed 5 hours, cooling, concentrated.Resistates adds 40mL water, uses 30mL dichloromethane extraction three times, merges organic layer, steam except organic solvent, get 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
The 1-(2-(4-methoxyphenoxy) ethyl) piperazine
The 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.Get white paste solid 13g, yield 90.2%, TLC show the great impurity of micro-polarity, and this impurity does not affect next step operation, directly carries out next step reaction.
Embodiment 11
The 1-(2-(4-chlorophenoxy) ethyl) piperazine
The 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.Get white solid 9.1g, yield 75.8%, TLC show 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
With ortho-cresol (10.8g, 0.10mol), water (60mL) adds in the three-necked bottle, stirs and is warming up to 60 ℃.Add Tetrabutyl amonium bromide (2.6g, 0.008mol), transfer pH=13 with 20%wt sodium hydroxide solution (20mL), continue to be stirred to ortho-cresol and all dissolve and be clear liquor, be warming up to backflow.Drip ethyl sulfate (16mL, 0.10mol) in the situation that constantly stir, approximately dripped off in 30 minutes, add 20%wt sodium hydroxide solution (5mL) after dripping off, reaction solution is alkalescence.Back flow reaction 14 hours leaves standstill, cooling, reaction solution layering.Separatory, organic layer adds 30mL toluene, uses the sodium hydroxide solution of 30mL 5%wt to wash three times, uses the 30mL water washing three times again, anhydrous magnesium sulfate drying, suction filtration, filtrate is concentrated, get faint yellow clarification oily o-methyl-benzene ether 9.8g, yield 72.1%, TLC show pure point.
Previous step is reacted 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 the eggplant-shape bottle, and the incandescent light irradiation is lower, stirs and is warming up to backflow.Illumination back flow reaction 1 hour leaves standstill, and observes visible solid and all floats on the upper strata.In solution, add the 108mL hexanaphthene, jolting, suction filtration, filtrate steaming removal solvent gets deep yellow oily liquid.Add the 75mL acetonitrile, behind the shake well, steaming desolventizes, and gets pale yellow oily liquid, leaves standstill after the cooling to get faint yellow solid 15.2g, and yield 98.1%, TLC show pure point.
Embodiment 13
1-brooethyl-4-phenetole
The 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 gets faint yellow clarification oily p-tolyl ethyl ether 8.8g, yield 64.7%, TLC show 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 the 45mL hexanaphthene, jolting, suction filtration, filtrate steaming removal solvent gets deep yellow oily liquid.Add the 25mL acetonitrile, behind the shake well, steaming desolventizes, and leaves standstill after the cooling to get faint yellow solid 6g, and yield 96.8%, TLC show pure point.
Embodiment 14
2-brooethyl-methyl benzoate
With 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) add in the eggplant-shape bottle, and the incandescent light irradiation is lower, stirs and is warming up to backflow.Illumination back flow reaction 1 hour leaves standstill, and observes visible solid and all floats on the upper strata.In solution, add the 150mL hexanaphthene, jolting, suction filtration, filtrate steaming removal solvent gets deep yellow oily liquid.Add the 90mL acetonitrile, behind the shake well, steaming desolventizes, and gets pale yellow oily liquid, leaves standstill after the cooling to get faint yellow solid 24g, and yield 100%, TLC show pure point.
Embodiment 15
1-brooethyl-4-chlorobenzene
The 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.Get faint yellow solid 19.4g, yield 94.6%, TLC show pure point.
Embodiment 16
1-brooethyl-4-bromobenzene
The 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.Get faint yellow solid 18.4g, yield 97.0%, TLC show pure point.
Embodiment 17
1-(pair-(4-p-methoxy-phenyl) methyl) piperazine
With 1-(pair-(4-p-methoxy-phenyl) methyl) alcohol (15g, 0.06mol), anhydrous methylene chloride (120mL) adds in the eggplant-shape bottle, and stirring and dissolving adds thionyl chloride (4.5mL, 0.06mol), pyridine (1), room temperature add drying tube and stirred 4 hours, and the TLC demonstration reacts completely, steaming desolventizes to get light green oily matter, directly carries out next step reaction.
The previous step product dissolves with hexanaphthene (120mL), add Piperazine anhydrous (51.8g, 0.60mol), stirring heating refluxed 16 hours, steaming desolventizes to get the off-white color solid, and (150mL) dissolving that adds methylene chloride is with NaOH solution (100mL) washed twice of 1mol/L, separatory, organic phase evaporate to dryness get yellowish white solid 18.5g.The dehydrated alcohol recrystallization gets white solid 14.6g, and yield 76.4%, TLC show pure point.
Embodiment 18
1-(pair-(4-aminomethyl phenyl) methyl) piperazine
The 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 stirred four hours, gets faint yellow oily thing, directly carries out next step reaction.
The previous step product dissolves with anhydrous cyclohexane (74mL), add Piperazine anhydrous (19.9g, 0.23mol), stirring heating refluxed 16 hours, steamed to desolventize to get the off-white color solid, (150mL) dissolving adds methylene chloride, with NaOH solution (100mL) washed twice of 1mol/L, separatory, organic phase evaporate to dryness get faint yellow oily thing 8.8g, yield 83.0%, TLC show pure point.
Embodiment 19
1-(pair-(4-bromophenyl) methyl) piperazine
The 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 stirred four hours, gets faint yellow oily thing, directly carries out next step reaction.
The previous step product dissolves with anhydrous cyclohexane (74mL), add Piperazine anhydrous (13g, 0.15mol), stirring heating refluxed 16 hours, steamed to desolventize to get the off-white color solid, (150mL) dissolving adds methylene chloride, with NaOH solution (100mL) washed twice of 1mol/L, separatory, the organic phase evaporate to dryness gets faint yellow solid 9g, yield 94.2%, TLC show pure point.
Embodiment 20
The 2-((4-(2-(2-naphthyloxy) ethyl) piperazine)-and the 1-yl) methyl-toluate (DZH-1)
With the 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 the three-necked bottle, under the nitrogen protection condition, is heated with stirring to backflow.Refluxed 20 hours, filtered while hot, filtrate steaming removal solvent gets 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), column chromatography gets white solid 0.6g to gradient elution, 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
The 2-((4-(2-(2-naphthyloxy) ethyl) piperazine)-and the 1-yl) methyl-toluate (DZH-1)
With the 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 the three-necked bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, filtered while hot, filtrate steaming removal solvent gets 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), column chromatography gets white solid 1.22g to gradient elution, 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
The 1-(4-chlorophenylmethyl)-and the 4-(2-(2-naphthyloxy) ethyl) piperazine (DZH-2)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, filtered while hot, filtrate steaming removal solvent gets brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get white solid 0.7g, yield 26.2%, m.p.76.8-78.5 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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
The 1-(4-Brombenzyl)-and the 4-(2-(2-naphthyloxy) ethyl) piperazine (DZH-3)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, filtered while hot, filtrate steaming removal solvent gets brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get white solid 0.6g, yield 18.2%, m.p.85.6-87.3 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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
The 2-((4-(2-(4-methylphenoxy) ethyl) piperazine)-and the 1-yl) methyl-toluate (DZH-4)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, filtered while hot, filtrate steaming removal solvent gets brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get white solid 0.9g, yield 32.1%, m.p.54.4-55.8 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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
The 1-(4-chlorophenylmethyl)-and the 4-(2-(4-methylphenoxy) ethyl) piperazine (DZH-5)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, filtered while hot, filtrate steaming removal solvent gets brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get brown solid 2.8g, yield 87.5%, m.p.56.9-58.7 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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
The 1-(4-Brombenzyl)-and the 4-(2-(4-methylphenoxy) ethyl) piperazine (DZH-6)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, filtered while hot, filtrate steaming removal solvent gets brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get brown solid 1.1g, yield 52.4%, m.p.60.5-62.7 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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)-and the 4-(2-(4-methylphenoxy) ethyl) piperazine (DZH-7)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, filtered while hot, filtrate steaming removal solvent gets brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get faint yellow solid 1.2g, yield 48.0%, m.p.88.3-90.5 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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
The 2-((4-(2-(2-methylphenoxy) ethyl) piperazine)-and the 1-yl) methyl-toluate (DZH-8)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, filtered while hot, filtrate steaming removal solvent gets brown liquid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1: 10 to 1: 1), gradient elution, column chromatography get faint yellow clarification oily liquid 2.2g, yield 43.9% as eluent take ethyl acetate and sherwood oil mixed solution.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
The 1-(4-chlorophenylmethyl)-and the 4-(2-(2-methylphenoxy) ethyl) piperazine (DZH-9)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, filtered while hot, filtrate steaming removal solvent gets brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get white solid 1.8g, yield 54.9%, m.p.48.8-49.7 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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
The 1-(4-Brombenzyl)-and the 4-(2-(2-methylphenoxy) ethyl) piperazine (DZH-10)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, filtered while hot, filtrate steaming removal solvent gets brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get white solid 1.4g, yield 32.8%, m.p.59.9-62.4 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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
The 2-((4-(2-(4-methoxyphenoxy) ethyl) piperazine)-and the 1-yl) methyl-toluate (DZH-11)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, filtered while hot, filtrate steaming removal solvent gets brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get white solid 1.1g, yield 26.2%, m.p.51.8-53.9 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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)-and the 4-(2-(4-methoxyphenoxy) ethyl) piperazine (DZH-12)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, reaction solution steams and desolventizes to get brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get faint yellow solid 1.1g, yield 31.9%, m.p.73.2-74.8 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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
The 1-(4-chlorophenylmethyl)-and the 4-(2-(4-methoxyphenoxy) ethyl) piperazine (DZH-13)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, filtered while hot, filtrate steaming removal solvent gets brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get white solid 1.5g, yield 32.8%, m.p.81.5-82.8 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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
The 1-(4-Brombenzyl)-and the 4-(2-(4-methoxyphenoxy) ethyl) piperazine (DZH-14)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, filtered while hot, filtrate steaming removal solvent gets brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get white solid 1.4g, yield 31.4%, m.p.80.9-82.9 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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)-and the 4-(2-(4-methoxyphenoxy) ethyl) piperazine (DZH-15)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, filtered while hot, filtrate steaming removal solvent gets brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get faint yellow solid 0.8g, yield 21.6%, m.p.84.3-86.2 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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
The 2-((4-(2-(4-chlorophenoxy) ethyl) piperazine)-and the 1-yl) methyl-toluate (DZH-16)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, reaction solution steams and desolventizes to get brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get white solid 2.0g, yield 70.7%, m.p.59.6-61.8 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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
The 1-(4-chlorophenylmethyl)-and the 4-(2-(4-chlorophenoxy) ethyl) piperazine (DZH-17)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, reaction solution steams and desolventizes to get brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get white solid 0.9g, yield 32.1%, m.p.52.2-53.9 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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
The 1-(4-Brombenzyl)-and the 4-(2-(4-chlorophenoxy) ethyl) piperazine (DZH-18)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, reaction solution steams and desolventizes to get brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get white solid 1.5g, yield 47.2%, m.p.59.3-61.5 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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)-the 4-(2-(2-naphthyloxy) ethyl) piperazine (DZH-19)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, reaction solution steams and desolventizes to get brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get white solid 1.3g, yield 32.5%, m.p.125.7-126.1 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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)-the 4-(2-(2-naphthyloxy) ethyl) piperazine (DZH-20)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, reaction solution steams and desolventizes to get brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get white solid 0.7g, yield 40.2%, m.p.180.2-181.2 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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)-the 4-(2-(4-methoxyphenoxy) ethyl) piperazine (DZH-21)
With the 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) add in the eggplant-shape bottle, add catalytic amount zinc powder (0.8g), be heated with stirring to backflow.Refluxed 20 hours, reaction solution steams and desolventizes to get brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get white solid 2.9g, yield 72.8%, m.p.84.6-86.8 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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)-the 4-(2-(4-methoxyphenoxy) ethyl) piperazine (DZH-22)
With the 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) add in the eggplant-shape bottle, add catalytic amount zinc powder (0.8g), be heated with stirring to backflow.Refluxed 20 hours, reaction solution steams and desolventizes to get brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get white solid 2.8g, yield 67.8%, m.p.99.0-99.6 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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)-the 4-(2-(4-methoxyphenoxy) ethyl) piperazine (DZH-23)
With the 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) add in the eggplant-shape bottle, add catalytic amount zinc powder (0.8g), be heated with stirring to backflow.Refluxed 20 hours, reaction solution steams and desolventizes to get brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get white solid 1.3g, yield 38.8%, m.p.132.4-134.0 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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)-the 4-(2-(2-methylphenoxy) ethyl) piperazine (DZH-24)
With the 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) add in the eggplant-shape bottle, add catalytic amount zinc powder (0.8g), be heated with stirring to backflow.Refluxed 20 hours, reaction solution steams and desolventizes to get brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1: 10 to 1: 1), gradient elution, column chromatography get white solid 2.6g, yield 73.6%, m.p.68.2-70.2 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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)-the 4-(2-(2-methylphenoxy) ethyl) piperazine (DZH-25)
With the 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) add in the eggplant-shape bottle, add catalytic amount zinc powder (0.8g), be heated with stirring to backflow.Refluxed 20 hours, reaction solution steams and desolventizes to get brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1: 10 to 1: 1), gradient elution, column chromatography get white solid 1.2g, yield 37.9%, m.p.147.6-148.7 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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)-the 4-(2-(2-methylphenoxy) ethyl) piperazine (DZH-26)
With the 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) add in the eggplant-shape bottle, add catalytic amount zinc powder (0.8g), be heated with stirring to backflow.Refluxed 20 hours, reaction solution steams and desolventizes to get pale yellow oily liquid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get faint yellow thickness oily matter 1.8g, yield 55.0% as eluent take ethyl acetate and sherwood oil mixed solution.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)-the 4-(2-(4-chlorophenoxy) ethyl) piperazine (DZH-27)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, reaction solution steams and desolventizes to get brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1:1), gradient elution, column chromatography get white solid 1.2g, yield 37.9%, m.p.117.7-119.1 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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)
With the 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 the eggplant-shape bottle, adds catalytic amount zinc powder (0.8g), is heated with stirring to backflow.Refluxed 20 hours, reaction solution steams and desolventizes to get brown solid.It is impure that TLC shows, (ethyl acetate: sherwood oil volume ratio=1:10 to 1: 1), gradient elution, column chromatography get white solid 2.4g, yield 71.4%, m.p.13.7-135.3 ℃ as eluent take ethyl acetate and sherwood oil mixed solution.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
Target compound is on the impact of acute cerebral ischemia mouse survival time among the embodiment.
Target compound and positive control drug nimodipine are made into the suspension of desired concn before use with the 0.5%wt Xylo-Mucine; Experimental animal is the ICR mouse, body weight 19-25g, male and female half and half.Mouse is pressed sex random packet, 10 every group, male and female half and half.Gavage gives tested medicine 0.2mL/10g respectively, the blank group waits capacity NS, positive controls waits capacity nimodipine 80mg/Kg, 1 hour etherization after the administration, neck medisection after fixing separates bilateral carotid and vagus nerve and ligation, and the record mouse survival time, (the per minute frequency of respiration was less than or equal to 5 times, namely think dead mouse), the results are shown in Table 1,2.
Table 1: target compound is on the impact (min) of acute cerebral ischemia mouse survival time
Table 2, Compound D ZH-1 are on the impact of acute cerebral ischemia mouse survival time
Compare * P＜0.05 with the 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 prolong the acute cerebral ischemia mouse survival time, treating cerebral ischemia is particularly evident, and wherein Compound D ZH-1 effect is the strongest.
Claims (10)
1. replace fragrant oxygen ethyl piperazidine analog derivative, it is characterized in that 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 the 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.
2. the fragrant oxygen ethyl piperazidine of replacement according to claim 1 analog derivative is characterized in that: R
1, R
2The aryl of representative or the aryl in the aralkoxy are benzene, biphenyl or naphthalene, perhaps are F, Cl, Br, I, C
1～10Alkyl, C
1 ~ 10Alkoxyl group, nitro or amino benzene, biphenyl or the naphthalene that replaces.
3. the fragrant oxygen ethyl piperazidine of replacement according to claim 1 analog derivative is characterized in that: 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 the 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.
4. the fragrant oxygen ethyl piperazidine of replacement according to claim 1 analog derivative is characterized in that: R
1, R
2The substituted heterocycle of representative or the heterocyclic radical in the heterocycle alkoxyl group refer to contain one or more heteroatomic saturated heterocyclic or aromatic heterocycle optional from oxygen, nitrogen, sulphur atom.
5. the fragrant oxygen ethyl piperazidine of replacement according to claim 1 analog derivative is characterized in that: R
1, R
2The halogen of representative is F, Cl, Br or I.
6. the fragrant oxygen ethyl piperazidine of replacement according to claim 1 analog derivative is characterized in that: R
1, R
2Middle substituted aryl, its substituting group are halogen, nitro, amino, hydroxyl, ether, carboxyl, ester group and amide group.
7. the fragrant oxygen ethyl piperazidine of replacement according to claim 1 analog derivative is characterized in that: the amino NH of being
2, R
8NH or R
9R
10N; R wherein
8, R
9Or R
10Be alkyl, perhaps R
9R
10N is the ternary ~ eight yuan of heterocycles 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.
8. the preparation method of the fragrant oxygen ethyl piperazidine of the described replacement of claim 1 analog derivative is characterized in that may further comprise the steps:
A. fragrant phenol (II) 0.10mol that replaces, glycol dibromide 0.15mol, water 60mL stir and are warming up to backflow, drip 25%wt sodium hydroxide solution 24mL, drip off in 30 minutes; Backflow 10-13 hour, reaction solution cooling standing over night, when having solid to separate out, suction filtration, filter cake washes twice with water, the dehydrated alcohol recrystallization; When separating out without solid, separatory, organic layer dissolves with methylene dichloride 20mL, with 5%wt sodium hydroxide solution 30mL washing three times, water 30mL washing is three times again, anhydrous magnesium sulfate drying, suction filtration, filtrate decompression steam and desolventize the fragrant oxygen monobromethane (III) that is replaced accordingly;
B. Piperazine anhydrous 0.08mol, dehydrated alcohol 86mL, water 12mL drips 40%wt Hydrogen bromide 0.08mol in the situation that constantly stir, and drips off in 20 minutes, continues to stir 5 minutes; Fragrant oxygen monobromethane (III) 0.04mol that replaces divides three times and adds above-mentioned reaction solution, is heated with stirring to reflux 6 hours, and 4 ℃ of refrigerations are spent the night in the refrigerator; The filtering insolubles, filtrate steaming removal solvent, add 5%wt sodium hydroxide solution 50mL in the resistates, stirred 4 hours, with methylene dichloride 40mL extraction three times, merge organic layer, steam except organic solvent the fragrant oxygen ethyl piperazidine (IV) that the gained resistates is replaced accordingly 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 get solid, the 280mL that adds methylene chloride dissolving adds the 200mL water washing, separatory, the benzhydrol that the organic phase evaporate to dryness must replace; The benzhydrol 0.02mol that replaces, 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 the concentrated gained resistates; Concentration of reaction solution adds methylene dichloride 350mL in the gained solid, with the NaOH solution 150mL washing of 1mol/L, separatory, the benzhydryl piperazidine that the organic phase evaporate to dryness obtains replacing (VI);
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 the eggplant-shape bottle, and the incandescent light irradiation is lower, stirs and is warming up to back flow reaction 1 hour, cooling is left standstill, and adds hexanaphthene 108mL in solution, jolting, suction filtration, filtrate steaming removal solvent, add acetonitrile 75mL in the residual solution, behind the shake well, steaming desolventizes, and gets corresponding Bromomethyl Substituted benzene (VIII);
Fragrant oxygen monobromethane (III) 0.010mol that e. will replace, the benzhydryl piperazidine of replacement (VI) 0.008mol, triethylamine 0.029mol, acetonitrile 74mL add in the eggplant-shape bottle, under the condition of nitrogen protection or zinc powder existence, are heated with stirring to backflow; Refluxed 20 hours, and filtered, filtrate steaming removal solvent is 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 for separation; Fragrant oxygen ethyl piperazidine (IV) 0.005mol that maybe will replace, Bromomethyl Substituted benzene (VIII) 0.005mol, triethylamine 0.005mol, acetonitrile 24mL add in the three-necked bottle, under the condition of nitrogen protection or zinc powder existence, are heated with stirring to backflow.Refluxed 20 hours, filtered while hot, filtrate steaming removal solvent is 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 for separation must logical formula I compound.
9. replace the application of fragrant oxygen ethyl piperazidine analog derivative in preparation cerebral infarction medicine.
10. compound 2-((4-(2-(2-naphthyloxy) ethyl) piperazine)-and the 1-yl) methyl-toluate, the 1-(4-chlorophenylmethyl)-and the 4-(2-(2-naphthyloxy) ethyl) piperazine, the 1-(4-Brombenzyl)-and the 4-(2-(2-naphthyloxy) ethyl) piperazine, the 2-((4-(2-(4-methylphenoxy) ethyl) piperazine)-and the 1-yl) methyl-toluate, the 1-(4-Brombenzyl)-and the 4-(2-(4-methylphenoxy) ethyl) piperazine, the 1-(4-chlorophenylmethyl)-and the 4-(2-(2-methylphenoxy) ethyl) piperazine, the 1-(4-Brombenzyl)-and the 4-(2-(2-methylphenoxy) ethyl) piperazine, the 2-((4-(2-(4-methoxyphenoxy) ethyl) piperazine)-and the 1-yl) methyl-toluate, the 1-(4-chlorophenylmethyl)-and the 4-(2-(4-methoxyphenoxy) ethyl) piperazine, 1-(4-phenetole methyl)-and the 4-(2-(4-methoxyphenoxy) ethyl) piperazine, the 1-(4-Brombenzyl)-and the 4-(2-(4-chlorophenoxy) ethyl) piperazine, 1-(pair-(4-p-methoxy-phenyl) methyl)-the 4-(2-(2-naphthyloxy) ethyl) piperazine, 1-(pair-(4-p-methoxy-phenyl) methyl)-the 4-(2-(4-methoxyphenoxy) ethyl) piperazine or 1-(pair-(4-bromophenyl) methyl)-the 4-(2-(4-methoxyphenoxy) ethyl) application of piperazine in preparation cerebral infarction medicine.
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| CN103724296A (en) * | 2013-12-12 | 2014-04-16 | 南京医科大学 | Aryl substituted piperazine carbonyl derivative as well as preparation method and application thereof |
| CN110128369A (en) * | 2019-05-27 | 2019-08-16 | 东南大学 | Benzo [d] isothiazole -3 (2H) -one derivative and its preparation method and application |
| CN110437136A (en) * | 2019-07-30 | 2019-11-12 | 东南大学 | 1- virtue oxygen ethyl piperidine -4- base methanone derivatives and its preparation method and application |
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| CN103724296A (en) * | 2013-12-12 | 2014-04-16 | 南京医科大学 | Aryl substituted piperazine carbonyl derivative as well as preparation method and application thereof |
| CN103724296B (en) * | 2013-12-12 | 2015-09-02 | 南京医科大学 | Piperazine carbonyl derivative that aryl replaces and its preparation method and application |
| CN110128369A (en) * | 2019-05-27 | 2019-08-16 | 东南大学 | Benzo [d] isothiazole -3 (2H) -one derivative and its preparation method and application |
| CN110437136A (en) * | 2019-07-30 | 2019-11-12 | 东南大学 | 1- virtue oxygen ethyl piperidine -4- base methanone derivatives and its preparation method and application |
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