CN103073524A - 4-[4-(substituted phenyl) piperazine piperazinyl-1]-butylcarbamic acid substituted aromatic ester derivative and preparation method thereof - Google Patents
4-[4-(substituted phenyl) piperazine piperazinyl-1]-butylcarbamic acid substituted aromatic ester derivative and preparation method thereof Download PDFInfo
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- CN103073524A CN103073524A CN2013100332267A CN201310033226A CN103073524A CN 103073524 A CN103073524 A CN 103073524A CN 2013100332267 A CN2013100332267 A CN 2013100332267A CN 201310033226 A CN201310033226 A CN 201310033226A CN 103073524 A CN103073524 A CN 103073524A
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- HBGGXOJOCNVPFY-UHFFFAOYSA-N diisononyl phthalate Chemical class CC(C)CCCCCCOC(=O)C1=CC=CC=C1C(=O)OCCCCCCC(C)C HBGGXOJOCNVPFY-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title claims description 33
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title abstract 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 117
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 96
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 84
- 239000000543 intermediate Substances 0.000 claims abstract description 38
- -1 amine hydrochloride Chemical class 0.000 claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims abstract description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 17
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000011230 binding agent Substances 0.000 claims abstract description 14
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006698 hydrazinolysis reaction Methods 0.000 claims abstract description 7
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 239000003054 catalyst Substances 0.000 claims abstract description 3
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- 238000006243 chemical reaction Methods 0.000 claims description 140
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 90
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 53
- 238000001035 drying Methods 0.000 claims description 51
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 42
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- 238000001953 recrystallisation Methods 0.000 claims description 27
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 26
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- 235000019253 formic acid Nutrition 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 14
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- NQNZNONJZASOKL-UHFFFAOYSA-N 1-phenylpiperazin-4-ium;chloride Chemical class Cl.C1CNCCN1C1=CC=CC=C1 NQNZNONJZASOKL-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 150000001448 anilines Chemical class 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
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- 125000005393 dicarboximide group Chemical group 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
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- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 4
- 235000011152 sodium sulphate Nutrition 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 230000036571 hydration Effects 0.000 claims description 2
- 238000006703 hydration reaction Methods 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 235000010755 mineral Nutrition 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
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- 239000011734 sodium Substances 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
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- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims 1
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 abstract description 25
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- UXFWTIGUWHJKDD-UHFFFAOYSA-N 2-(4-bromobutyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCCBr)C(=O)C2=C1 UXFWTIGUWHJKDD-UHFFFAOYSA-N 0.000 abstract 1
- 102000004073 Dopamine D3 Receptors Human genes 0.000 abstract 1
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- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract 1
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- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 23
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Abstract
The invention discloses a phenyl piperazidine heterocyclic medicinal compound. The compound has high affinity to a dopamine D3 receptor, so that the compound can be used for treating addiction to and dependence on medicines such as ***e, and a central nervous system disorder relevant to the addiction and the dependence. The compound is a 4-[4-(substituted phenyl) piperazine piperazinyl-1]-butylcarbamic acid substituted aromatic ester derivative with a structural formula as Formula (1) as shown in the specification. A synthetic method of the derivate comprises the steps that substituted aniline and 2-(beta-chloroethyl) amine hydrochloride reacts in a solvent by taking inorganic base as an acid-binding agent to form corresponding substituted phenyl piperazidine hydrochloride 1; substituted phenyl piperazidine hydrochloride 1 and N-(delta-bromobutyl) phthalimide react in acetonitrile by taking K2CO3 as an acid-binding agent and under catalysis of KI to form a reaction intermediate 2; the intermediate 2 is subjected to hydrazinolysis to form an intermediate 3; and the intermediate 3 and an intermediate 5 are condensed by taking triethylamine as an acid-binding agent and a catalyst to form a target product I. The intermediate 5 is obtained in a manner that triphosgene and substituted aromatic phenol conduct partial condensation reaction in methylene chloride.
Description
Technical field
The present invention relates to class medicinal compound and preparation method thereof, a class phenylpiperazine heterocyclic compound specifically, such medicinal compound is to dopamine D
3Acceptor presents high-affinity, can be used for drug habits and the treatment that produces dependency and relative central nervous system disorder such as Cocaines.
Background technology
Document (Science1997,278:58-63, Eur J Neurosci2002,15(12): 2016-2026, Trends Pharmacol Sci1994,15:374-379) etc. achievement in research shows D
3Acceptor and middle limbic brain Dopamine HCL path have close dependency, and it is the critical sites that dependence producing drug produces glad and reward effect that the volt nucleocapsid district Dopamine HCL among the mesolimbic system discharges increase.
The achievements in research such as document (Crit Rev Neurobiol1998,12:37-67, Brain Res Brain Res Rev2000,31:277-287, Nature1999,400:371-375, Eur Psychiatry2000,15:140-146) are thought dopamine D
3Acceptor portion agonist has preferably result for the treatment of to drug habits such as Cocaines.
In the document (Natrue1990,347:146-151), the people such as Sokoloff P. have synthesized and have had 4-Phenylpiperazinyl structural compounds.Such as 9H-fluorenes-3-carboxamides derivatives NGB2904, naphthalene-2-carboxamides derivatives BP897 etc.
All be shown as D with experiment in vitro in the BP897 body
3Acceptor portion agonist, studies show that, BP897 can suppress medicine to be strengthened and the award effect, weakens conditioned place preference, reduction behavior sensitization, inhibition drug-seeking behavior or the drug craving of animal, and does not have strengthening effect or the KE of common dopamine-receptor stimulant or antagonist.BP897 just is being developed for to drug habits and the treatment that produces dependency and relative central nervous system disorder such as Cocaines, has now entered II phase clinical stage.
Summary of the invention
The object of the present invention is to provide a kind of novel phenylpiperazine heterocyclic medicinal compound, such medicinal compound is to dopamine D
3Acceptor presents high-affinity, can be used for drug habits and the treatment that produces dependency and relative central nervous system disorder such as Cocaines.
Another object of the present invention is to provide a kind of method for preparing above-mentioned novel phenylpiperazine heterocyclic medicinal compound.
Phenylpiperazine heterocyclic medicinal compound of the present invention is a kind of 4-[4-(substituted-phenyl by formula (1) expression) piperazinyl-1]-butylamine formic acid substituted aroma ester derivative:
In the formula
R
1For H or be in any the position of substitution of phenyl ring and replace arbitrarily halogen, alkyl, alkoxyl group, the nitro of number;
R
2Be aryl or substituted aryl.
R in the formula (1)
1Be preferably o-Cl, m-Cl, p-Cl, 2,3-di-Cl, 3,4-di-Cl, p-F, p-CH
3, 2,3-di-Me, o-OCH
3Or p-OCH
3
Phenylpiperazine heterocyclic compound of the present invention is on the document basis, for further groping the structure activity relationship of Phenylpiperazine derivatives, according to medicinal design principles such as isosteres, has designed and synthesized a series of R
1Adjacent at phenyl,, to one or more positions, R
2The brand-new compound (I) of the aromatic base that replaces for different groups.
Annotate: o-, m-, p-represent respectively ortho position, a position and the contraposition of phenyl ring, and the following content representation of this patent herewith.
The present invention prepares the 4-[4-(substituted-phenyl) piperazinyl-1]-method of butylamine formic acid aromatic ester derivative or its pharmacy acceptable salt, it is characterized in that may further comprise the steps:
Step 1: substituted aniline and two-(β-chloroethyl) amine hydrochlorate is in organic solvent, and take mineral alkali as acid binding agent, reaction obtains intermediate 1, i.e. corresponding substituted phenylpiperazine hydrochloride;
Step 2: substituted phenylpiperazine hydrochloride 1 and N-(δ-bromo butyl) phthalic imidine is in acetonitrile, with K
2CO
3For reaction under acid binding agent, the KI catalysis obtains reaction intermediate 2, i.e. N-{4-[4-(substituted-phenyl) piperazinyl-1]-butyl } the adjacent dicarboximide of benzo;
Step 3: intermediate 2 obtains intermediate 3 behind hydrazinolysis, i.e. 1-(δ-aminobutyl)-the 4-(substituted-phenyl) piperazine;
Step 4: intermediate 3 and intermediate 5 are take triethylamine as acid binding agent and catalyzer, and condensation obtains target product 4-[4-(substituted-phenyl) piperazinyl-1]-butylamine formic acid substituted aromatic ester derivative I; Wherein, intermediate 5 is trichlorine methoxyl group formic acid substituted aromatic ester, and it is obtained with the condensation reaction of certain mol proportion generation part in methylene dichloride by triphosgene and substituted aroma phenol.
Described step 1 is specially: under nitrogen protection, substituted aniline and two-(β-chloroethyl) amine hydrochlorate, take propyl carbinol, the trimethyl carbinol, chlorobenzene, DMF, DMA or ethylene glycol as solvent, preferred propyl carbinol, stirring reaction under certain temperature, the preferred backflow reacted 24-48 hour, with TLC detection reaction progress; After reaction is finished, be cooled to room temperature, with an amount of methyl alcohol reaction mixture is all dissolved, pass into hydrogen chloride gas and make reaction solution be acid, add subsequently excessive ether and separate out precipitation, suction filtration, with a small amount of ether washing, get corresponding substituted phenylpiperazine hydrochloride crude product, with organic solvent methyl alcohol, ethanol, Virahol or 95% ethyl alcohol recrystallization, preferred dehydrated alcohol obtains sterling.
Described step 2 is specially: N-(δ-bromo butyl) reaction of phthalic imidine and substituted phenylpiperazine hydrochloride is: with acetone, acetonitrile, dimethyl formamide DMF, N, accelerine DMA, dioxane or pyridine are solvent, preferred acetonitrile; With K
2CO
3, Na
2CO
3, NaHCO
3, NaOH or CaCO
3Be acid binding agent, preferred K
2CO
3Take NaI or KI as catalyzer, preferred KI; Back flow reaction 24-48 hour, with TLC detection reaction progress; Be cooled to room temperature after reaction is finished, with in the slow impouring frozen water of reaction solution, separate out solid under the rapid stirring, filter after washing, dry to get intermediate 2.
Described step 3 is specially: the reaction of described intermediate 2 hydrazinolysis is: with water, methyl alcohol, ethanol, Virahol or the trimethyl carbinol as solvent, preferred alcohol; 30%-80% hydration hydrazinolysis, preferred 50% hydrazine hydrate; 20-85 ℃ of reaction, the preferred backflow; With TLC detection reaction progress, concentrated solvent after reaction is finished, solid is got three times with methylene dichloride, trichloromethane, ethyl acetate, toluene or 1,2-ethylene dichloride solvent with water dissolution, preferred methylene dichloride; Collect organic phase, concentrated with filtering behind anhydrous sodium sulphate or the anhydrous magnesium sulfate drying, get intermediate 3.
Described step 4 is specially: be dissolved in an amount of monochloro methane, methylene dichloride, trichloromethane or 1,2-ethylene dichloride solvent with described intermediate 3, preferred trichloromethane; Add catalyst of triethylamine, pyridine, diisopropyl ethyl amine or dimethyl formamide, preferred triethylamine; In addition with an amount of same solvent dissolving intermediate 5, it slowly is added dropwise in intermediate 3 solution, drip and finish rear continuation stirring after 15-30 minute, be warming up to back flow reaction, the TLC monitoring, until complete should be fully after, stopped reaction, reaction solution be with water washing 2-3 time, anhydrous sodium sulphate or anhydrous magnesium sulfate drying, filter, concentrate to get crude product; Crude product gets target product I with the mixed solvent recrystallization of methyl alcohol, ethanol, Virahol or they and methylene dichloride, trichloromethane.
The preparation of intermediate 5 is specially in the described step 4:
Triphosgene and the condensation of substituted aroma phenol moieties obtain trichlorine methoxyl group formic acid substituted aromatic ester: at monochloro methane, methylene dichloride, trichloromethane, 1, in 2-ethylene dichloride or their mixed solvent, take triethylamine, pyridine, diisopropyl ethyl amine or dimethyl formamide as acid binding agent, preferred triethylamine; React under refluxing in room temperature; Wherein triphosgene and substituted aroma phenol mol ratio are 1.0:1.0~3.0, preferred 1:2.5; Reacted 2-10 hour, TLC detection reaction progress is reacted complete rear adding water washing reaction solution 2-3 time, and anhydrous sodium sulfate drying filters, and the concentration and recovery solvent gets trichlorine methoxyl group formic acid substituted aromatic ester, not purifiedly is directly used in next step reaction.
N-(δ-bromo butyl in the described step 2) preparation of phthalic imidine is specially:
Get the adjacent dicarboximide potassium of an amount of benzo and be dissolved in a certain amount of acetone, other gets an amount of Isosorbide-5-Nitrae-dibromobutane and is dissolved in the acetone, is added drop-wise in the three-necked bottle in one hour, drips and finishes, and backflow is spent the night; Concentrated, slowly in the impouring frozen water, left standstill 30 minutes, filter, the filter cake washing, oven dry, and get final product.
Above synthesis step represents with synthetic route in addition can be suc as formula shown in the II:
Synthetic 4-[4-(substituted-phenyl of the present invention) piperazinyl-1]-beneficial effect of butylamine formic acid substituted aroma ester derivative is embodied in:
(1) the present invention has obtained the special new compound 4-[4-(substituted-phenyl of a class formation) piperazinyl-1]-butylamine formic acid aromatic ester derivative, show through pharmacological evaluation, such medicinal compound is to dopamine D
3Acceptor presents high-affinity, can be effective to drug habits and the treatment that produces dependency and relative central nervous system disorder such as Cocaines.
(2) adopt solvent of the present invention and reaction conditions, but higher yields obtain target product, and convenient post-treatment, a plurality of intermediates need not further to purify with separate can be directly as next step raw material.
(3) intermediate need not to adopt the methods such as column chromatography or thin-layer chromatography as wanting purifying, only needs to carry out recrystallizing and refining with the solvent that has fewer environmental impacts in right amount such as ethanol, and requirement is also very limited.
(4) technological operation is simple, reaction conditions is gentle, safe, reaction yield is stable, product purity is high, environmental pollution is little.
Embodiment
The invention will be further described below by specific embodiment, but protection scope of the present invention is not limited to this.
Although solvent, acid binding agent, catalyzer and the reaction conditions etc. that disclosed each step reaction of summary of the invention are not adopted in the specific embodiment of the invention are embodied one by one in an embodiment, but our experiments show that, in fact all can realize the object of the invention, only be presented as preferred version among the embodiment.
One, the preparation of intermediate 1-substituted phenylpiperazine hydrochloride (1a-1k)
Implement 1
Phenylpiperazine hydrochloride (1a)
1, in the 100ml there-necked flask of mechanical stirring, reflux exchanger, thermometer is housed, add two-(β-chloroethyl) amine hydrochlorate 8.93g(0.05mol), aniline 4.65g(0.05mol), 20ml propyl carbinol, salt of wormwood 13.8g(0.10mmol), N
2Protection, back flow reaction is with TLC detection reaction progress.After reaction is finished, filtered while hot, filtrate is down to room temperature, separates out solid, adding an amount of methyl alcohol all dissolves solid, pass into hydrogen chloride gas and make solution be acid, add subsequently excessive ether and separate out precipitation, suction filtration, filter cake washs with a small amount of ether, get 1-php hydrochloride crude product, crude product can be directly used in next step reaction, then obtains sterling with the dehydrated alcohol recrystallization.(U.S. wears peace U3000, HPLC:t
R=2.50min, λ=254nm, CH
3CN:H
2O=9:1, T
f=1.0ml/min, content 98.5%), fusing point: 245~249 ℃.IRυ
max(KBr)/cm
-1:3349,3035,2940,2846,1638,1551,1496,1433,1366,831。
Other substituted phenylpiperazine hydrochloride prepares as stated above: (other substituted aniline amount of substances are identical with above-mentioned aniline, and respective quality presses amount of substance and this substituted aniline molar mass converts)
(4-fluorophenyl) piperazine hydrochloride (1b)
(U.S. wears peace U3000, HPLC:t
R=2.63min, λ=254nm, CH
3CN:H
2O=9:1, T
f=1.0ml/min, content 98.8%), fusing point: 230~234 ℃.IRυ
max(KBr)/cm
-1:3350,3037,2942,2845,1638,1553,1498,1435,1368,830。
(4-chloro-phenyl-) piperazine hydrochloride (1c)
(U.S. wears peace U3000, HPLC:t
R=2.58min, λ=254nm, CH
3CN:H
2O=9:1, T
f=1.0ml/min, content 98.7%), fusing point: 215~218 ℃.IRυ
max(KBr)/cm
-1:3350,3039,2944,2845,1639,1555,1497,1435,1369,832。
(4-p-methoxy-phenyl) piperazine hydrochloride (1d)
(U.S. wears peace U3000, HPLC:t
R=2.71min, λ=254nm, CH
3CN:H
2O=9:1, T
f=1.0ml/min, content 99.0%), fusing point: 190~192 ℃.IRυ
max(KBr)/cm
-1:3350,3036,2940,2847,1639,1553,1496,1432,1366,830。
(4-aminomethyl phenyl) piperazine hydrochloride (1e)
(U.S. wears peace U3000, HPLC:t
R=2.65min, λ=254nm, CH
3CN:H
2O=9:1, T
f=1.0ml/min, content 98.7%), fusing point: 220~223 ℃.IRυ
max(KBr)/cm
-1:3349,3033,2941,2847,1640,1552,1498,1433,1368,829。
(2,3-dichlorophenyl) piperazine hydrochloride (1f)
(U.S. wears peace U3000, HPLC:t
R=2.71min, λ=254nm, CH
3CN:H
2O=9:1, T
f=1.0ml/min, content 98.5%), fusing point: 246~248 ℃.IRυ
max(KBr)/cm
-1:3354,3038,2942,2847,1638,1550,1498,1433,1366,825。
(3,4-dichlorophenyl) piperazine hydrochloride (1g)
(U.S. wears peace U3000, HPLC:t
R=2.71min, λ=254nm, CH
3CN:H
2O=9:1, T
f=1.0ml/min, content 98.0%), fusing point: 206~208 ℃.IRυ
max(KBr)/cm
-1:3349,3035,2940,2846,1638,1551,1496,1433,1366,831。
(2-p-methoxy-phenyl) piperazine hydrochloride (1h)
(U.S. wears peace U3000, HPLC:t
R=2.71min, λ=254nm, CH
3CN:H
2O=9:1, T
f=1.0ml/min, content 99.2%), fusing point: 213~217 ℃.IRυ
max(KBr)/cm
-1:3349,3035,2940,2846,1638,1551,1496,1433,1366,831.
(2,3-3,5-dimethylphenyl) piperazine hydrochloride (1i)
(U.S. wears peace U3000, HPLC:t
R=2.70min, λ=254nm, CH
3CN:H
2O=9:1, T
f=1.0ml/min, content 99.5%) fusing point: 220~223 ℃.IRυ
max(KBr)/cm
-1:3349,3035,2940,2846,1638,1551,1496,1433,1366,831.
(2-chloro-phenyl-) piperazine hydrochloride (1j)
(U.S. wears peace U3000, HPLC:t
R=2.65min, λ=254nm, CH
3CN:H
2O=9:1, T
f=1.0ml/min, content 98.9%), fusing point: 219~221 ℃.IRυ
max(KBr)/cm
-1:3356,3050,2940,2846,1630,1545,1490,1433,1366,836.
(3-chloro-phenyl-) piperazine hydrochloride (1k)
(U.S. wears peace U3000, HPLC:t
R=2.65min, λ=254nm, CH
3CN:H
2O=9:1, T
f=1.0ml/min, content 99.1%), fusing point: 209~211 ℃.IRυ
max(KBr)/cm
-1:3354,3050,2942,2846,1629,1545,1490,1431,1365,837.
Two, the preparation of intermediate product 5-trichlorine methoxyl group formic acid substituted benzene ester (5a-5g)
Implement 2
Intermediate product trichlorine methoxyl group formic acid is to fluorobenzene ester (5a)
Get 17.78g triphosgene (0.06mol), be dissolved in the 100mL methylene dichloride, place altogether the 250mL three-necked bottle, electric stirring; Other gets 16.86g(0.15mol) p-fluorophenol, the 16.9mL triethylamine is dissolved in the 45mL methylene dichloride, slowly is added dropwise in the triphosgene solution, after dripping end, stirred 30 minutes, reflux is after TLC monitoring reaction finishes, stopped heating behind the cool to room temperature, adds 50mL water, stirred 30 minutes, standing demix, organic layer is with 20mL water washing 2 times, anhydrous sodium sulfate drying filters, and concentrating under reduced pressure reclaims solvent, get white solid, dry weighing 13.38g, yield 80.5%.(U.S. wears peace U3000, HPLC:t
R=10.5min, λ=254nm, CH
3OH:H
2O=7:3, T
f=1.0ml/min, content 98.5%), fusing point: 114-118 ℃.IRυ
max(KBr)/cm
-1:3064,1770,1598,1508,1466,1289,1023,830.
1HNMR(CDCl
3,TMS,400MHz,δppm):7.05(dd,J=8.9,2.7Hz,2H,Ar-H),6.94(dd,J=8.9,2.8Hz,2H,Ar-H).EIMS?m/z(%):272(M
+,100),274(96),276(32),273(9),275(9),278(3),277(3)。
Other trichlorine methoxyl group formic acid substituted aromatic ester prepares as stated above: (other substituted aroma phenol amount of substances are identical with above-mentioned p-fluorophenol, and respective quality presses amount of substance and this substituted aroma phenol molar mass converts).
Intermediate product trichlorine methoxyl group formic acid is to chlorobenzene ester (5b)
Yield: 84.8%, product is liquid.(U.S. wears peace U3000, HPLC:t
R=9.9min, λ=254nm, CH
3OH:H
2O=7:3, T
f=1.0ml/min, content 99.2%).IRυ
max(KBr)/cm
-1:3064,1768,1596,1508,1464,1289,1023,831.
1HNMR(CDCl
3,TMS,400MHz,δppm):7.23(dd,J=8.8,2.6Hz,2H,Ar-H),7.01(dd,J=8.8,2.7Hz,2H,Ar-H);EIMS?m/z(%):290(M
+,100),288(78),292(49),294(10),291(9),289(7),293(4)。
Intermediate product trichlorine methoxyl group formic acid p-nitrophenyl ester (5c)
Yield: 91.5%, fusing point: 128-132 ℃.(U.S. wears peace U3000, HPLC:t
R=9.5min, λ=254nm, CH
3OH:H
2O=7:3, T
f=1.0ml/min, content 99.1%).IRυ
max(KBr)/cm
-1:3116,3084,1783,1592,1520,1489,1348,1227,1010,859,838.
1HNMR(CDCl
3,TMS,400MHz,δppm):8.16(dd,J=9.5,2.7Hz,2H,Ar-H),7.01(dd,J=9.5,2.8Hz,2H,Ar-H);EIMS?m/z(%):299(M
+,100),301(96),303(31),300(9),302(9),305(4),304(3),301(1),303(1)。
Intermediate product trichlorine methoxyl group formic acid is to methoxyl group phenyl ester (5d)
Yield: 79.6%, fusing point: 84-86 ℃.(U.S. wears peace U3000, HPLC:t
R=10.5min, λ=254nm, CH
3OH:H
2O=7:3, T
f=1.0ml/min, content 97.5%).IRυ
max(KBr)/cm
-1:3050,1724,1590,1482,1420,1228,1017,830.
1HNMR(CDCl
3,TMS,400MHz,δppm):6.96(dd,J=8.3,2.6Hz,2H,Ar-H),6.74(dd,J=8.3,2.7Hz,2H,Ar-H),3.73(s,3H,OCH
3);EIMSm/z(%):284(M
+,100),286(96),288(32),285(10),287(10),290(3),289(3),286(1)。
Intermediate product trichlorine methoxyl group formic acid-2-naphthalene ester (5e)
Yield: 84.3%, fusing point: 164-168 ℃.(U.S. wears peace U3000, HPLC:t
R=10.5min, λ=254nm, CH
3OH:H
2O=7:3, T
f=1.0ml/min, content 98.1%).IRυ
max(KBr)/cm
-1:3064,1768,1596,1508,1464,1289,1023,831;
1HNMR(CDCl
3,TMS,400MHz,δppm):7.23(dd,J=8.8,2.6Hz,2H,Ar-H),7.01(dd,J=8.8,2.7Hz,2H,Ar-H);EIMS?m/z(%):304(M
+,100),306(97),308(32),305(14),307(13),309(4),310(4)。
Intermediate product trichlorine methoxyl group formic acid-1-naphthalene ester (5f)
Yield: 80.6%, fusing point: 129-132 ℃.(U.S. wears peace U3000, HPLC:t
R=10.4min, λ=254nm, CH
3OH:H
2O=7:3, T
f=1.0ml/min, content 98.3%).IRυ
max(KBr)/cm
-1:3063,1769,1599,1509,1464,1389,1238,1215,799;
1HNMR(CDCl
3,TMS,400MHz,δppm):6.64(dd,J=8.3,2.3Hz,1H,Ar-H),7.17(dd,J=8.3,8.5Hz,1H,Ar-H),7.31(dd,J=8.5,2.3Hz,1H,Ar-H),7.68(dd,J=8.3,8.5Hz,1H,Ar-H),7.35(dd,J=8.3,8.5Hz,1H,Ar-H),7.38(dd,J=8.3,8.5Hz,1H,Ar-H),8.08(dd,J=8.3,8.5Hz,1H,Ar-H);EIMSm/z(%):304(M
+,100),306(96),308(31),305(14),307(13),309(4),310(4),306(1),308(1)。
Intermediate product trichlorine methoxy methyl acid phenenyl ester (5g)
Yield 76.5%.Fusing point: 113-115 ℃.(U.S. wears peace U3000, HPLC:t
R=10.3min, λ=254nm, CH
3OH:H
2O=7:3, T
f=1.0ml/min, content 98.5%).IRυ
max(KBr)/cm
-1:3064,1768,1596,1508,1464,1289,1023,831;
1HNMR(CDCl
3,TMS,400MHz,δppm):7.23(dd,J=8.8,2.6Hz,2H,Ar-H),7.01(dd,J=8.8,2.7Hz,2H,Ar-H);EIMS?m/z(%):290(M
+,100),288(78),292(49),294(10),291(9),289(7),293(4)。
Three, the compound 4-N-(δ-bromo butyl) preparation of phthalic imidine
Get the adjacent dicarboximide potassium of an amount of benzo and be dissolved in a certain amount of acetone, other gets an amount of Isosorbide-5-Nitrae-dibromobutane and is dissolved in the acetone, is added drop-wise in the three-necked bottle in one hour, drips and finishes, and backflow is spent the night.Concentrated, slowly in the impouring frozen water, left standstill 30 minutes, filter, the filter cake washing, oven dry gets white powder solid chemical compound 4.
Four, target product 4-[4-(substituted-phenyl) piperazinyl-1]-preparation of butylamine formic acid substituted aroma ester derivative (6a-6v)
Embodiment 3: the preparation of compound 6a
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1a that obtains;
Step 2: be intermediate 2a suc as formula synthetic compound 2a(shown in the step B among the II, below similar).Specific as follows:
With compound 1a15.6g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2a25.8g, yield 90%.
Step 3: be intermediate 3a suc as formula synthetic compound 3a(shown in the step C among the II, below similar).Specific as follows:
Get compound 2a25.4g(0.070mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 12.2g of colloidal liquid, yield 73.8%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5g that obtain.
Step 5: suc as formula the 6a of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3a1.17g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5g1.27g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes, standing demix is after the organic layer 10ml water washing, anhydrous sodium sulfate drying, filter, concentrated, get brown solid.With ethyl alcohol recrystallization, get 6a.Fusing point: 74-77 ℃, yield 74.5%.IRυ
max(KBr)/cm
-1:3425,3056,?2922,1760,1590,1490,1456,1180,1156;
1H?NMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):352.20(M
+,100),353.21(23.1),354.21(3.0),353.20(1.1)。Embodiment 4: the preparation of compound 6b
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1f that obtains;
Step 2: suc as formula synthetic compound 2f shown in the step B among the II.Specific as follows:
With compound 1f21.0g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2f29.0g, yield 88%.
Step 3: suc as formula synthetic compound 3f shown in the step C among the II.Specific as follows:
Get compound 2f28.1g(0.065mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.3g of colloidal liquid, yield 75.3%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5g that obtain.
Step 5: suc as formula the 6b of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3f1.51g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5g1.27g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6b with ethyl alcohol recrystallization.Fusing point: 174-178 ℃, yield 90.5%.IRυ
max(KBr)/cm
-1:3427,3060,2926,1756,1590,1488,1458,1180,1090;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),6.90(dd,J=8.8,8.7Hz,1H,Ar-H),6.56(dd,J=8.8,2.5Hz,1H,Ar-H),6.41(dd,J=8.7,2.5Hz,1H,Ar-H),2.95(dt,2H,CH
2),2.38(t,2H,CH
2),1.57(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):420.12(M
+,100),422.13(64),421.13(23),423.12(15),424.12(10),422.13(3),425.12(2.5),424.13(1.9),421.12(1.1)。
Embodiment 5: the preparation of compound 6c
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1j that obtains;
Step 2: suc as formula synthetic compound 2j shown in the step B among the II.Specific as follows:
With compound 1j18.4g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2j28.1g, yield 89.5%.
Step 3: suc as formula synthetic compound 3j shown in the step C among the II.Specific as follows:
Get compound 2j27.8g(0.070mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.2g of colloidal liquid, yield 75.8%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5g that obtain.
Step 5: suc as formula the 6c of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3j1.34g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5g1.27g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6c with ethyl alcohol recrystallization.Fusing point: 72-76 ℃, yield 89.0%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),7.07(dd,J=8.7,2.4Hz,1H,Ar-H),6.93(m,1H,Ar-H),6.55(m,1H,Ar-H),6.52(dd,J=8.8,2.5Hz,1H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.56(m,2H,CH
2),1.40,(m,2H,CH
2);EIMS?m/z(%):387(M
+,100),389(32),388(25),390(8),389(3)。
Embodiment 6: the preparation of compound 6d
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1k that obtains;
Step 2: suc as formula synthetic compound 2k shown in the step B among the II.Specific as follows:
With compound 1k18.4g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2k27.5g, yield 87.5%.
Step 3: suc as formula synthetic compound 3k shown in the step C among the II.Specific as follows:
Get compound 2k27.8g(0.070mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.6g of colloidal liquid, yield 77.8%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5g that obtain.
Step 5: suc as formula the 6d of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3k1.34g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound trichlorine methoxy methyl acid phenenyl ester 1.27g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6d with ethyl alcohol recrystallization.Fusing point: 163-165 ℃, yield 86.5%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),7.07(dd,J=8.7,2.4Hz,1H,Ar-H),6.93(m,1H,Ar-H),6.55(m,1H,Ar-H),6.52(dd,J=8.8,2.5Hz,1H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.56(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):387(M
+,100),389(32),388(25),390(8),389(3)。
Embodiment 7: the preparation of compound 6e
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1g that obtains;
Step 2: suc as formula synthetic compound 2g shown in the step B among the II.Specific as follows:
With compound 1g21.0g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2g30.4g, yield 89%.
Step 3: suc as formula synthetic compound 3g shown in the step C among the II.Specific as follows:
Get compound 2g28.1g(0.065mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.4g of colloidal liquid, yield 73.6%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5g that obtain.
Step 5: suc as formula the 6e of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3g1.51g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5g1.27g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6e with ethyl alcohol recrystallization.Fusing point: 73-75 ℃, yield 88.5%.IRυ
max(KBr)/cm
-1:3427,3060,2926,1756,1590,1488,1458,1180,1090;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),6.90(dd,J=8.8,8.7Hz,1H,Ar-H),6.56(dd,J=8.8,2.5Hz,1H,Ar-H),6.41(dd,J=8.7,2.5Hz,1H,Ar-H),2.95(dt,2H,CH
2),2.38(t,2H,CH
2),1.57(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):421(M
+,100),423(67),422(25),424(16),425(12),426(3)。
Embodiment 8: the preparation of compound 6f
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1c that obtains;
Step 2: suc as formula synthetic compound 2c shown in the step B among the II.Specific as follows:
With compound 1c18.4g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2c28.7g, yield 91.5%.
Step 3: suc as formula synthetic compound 3c shown in the step C among the II.Specific as follows:
Get compound 2c27.8g(0.070mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.8g of colloidal liquid, yield 78.8%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5g that obtain.
Step 5: suc as formula the 6f of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3g1.34g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5g1.27g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6f with ethyl alcohol recrystallization.Fusing point: 207-210 ℃, yield 84.5%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),7.07(dd,J=8.7,2.4Hz,1H,Ar-H),6.93(m,1H,Ar-H),6.55(m,1H,Ar-H),6.52(dd,J=8.8,2.5Hz,1H,Ar-H),3.44(t,?4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.56(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):387(M
+,100),389(32),388(25),390(8),389(3)。
Embodiment 9: the preparation of compound 6g
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1e that obtains;
Step 2: suc as formula synthetic compound 2e shown in the step B among the II.Specific as follows:
With compound 1e16.8g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2e27.7g, yield 93.1%.
Step 3: suc as formula synthetic compound 3e shown in the step C among the II.Specific as follows:
Get compound 2e26.4g(0.070mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 13.6g of colloidal liquid, yield 78.8%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5g that obtain.
Step 5: suc as formula the 6g of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3e1.24g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5g1.27g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6g with ethyl alcohol recrystallization.Fusing point: 181-183 ℃, yield 84.5%.IRυ
max(KBr)/cm
-1:3432,3059,2927,1756,1590,1490,1456,1180,1156;
1H?NMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),7.07(dd,J=8.7,2.4Hz,1H,Ar-H),6.93(m,1H,Ar-H),6.55(m,1H,Ar-H),6.52(dd,J=8.8,2.5Hz,1H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.56(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):367(M
+,100),368(25),369(4),390(8),368(1)。
Embodiment 10: the preparation of compound 6h
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1e that obtains;
Step 2: suc as formula synthetic compound 2e shown in the step B among the II.Specific as follows:
With compound 1e16.8g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2e27.7g, yield 93.1%.
Step 3: suc as formula synthetic compound 3e shown in the step C among the II.Specific as follows:
Get compound 2e26.4g(0.070mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 13.6g of colloidal liquid, yield 78.8%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5a that obtain.
Step 5: suc as formula the 6h of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3e1.24g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5a1.35g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6h with ethyl alcohol recrystallization.Fusing point: 134-138 ℃, yield 83.5%.IRυ
max(KBr)/cm
-1:3432,3059,2927,1756,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),7.07(dd,J=8.7,2.4Hz,1H,Ar-H),6.93(m,1H,Ar-H),6.55(m,1H,Ar-H),6.52(dd,J=8.8,2.5Hz,1H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.56(m,2H,CH
2),1.40(m,2H,CH
2);EIMSm/z(%):385(M
+,100),386(25),387(4),386(1)。
Embodiment 11: the preparation of compound 6i
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1f that obtains;
Step 2: suc as formula synthetic compound 2f shown in the step B among the II.Specific as follows:
With compound 1f21.0g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2f29.0g, yield 88%.
Step 3: suc as formula synthetic compound 3f shown in the step C among the II.Specific as follows:
Get compound 2f28.1g(0.065mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.3g of colloidal liquid, yield 75.3%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5a that obtain.
Step 5: suc as formula the 6a of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3f1.51g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5a1.35g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6i with ethyl alcohol recrystallization.Fusing point: 80-84 ℃, yield 84.5%.IRυ
max(KBr)/cm
-1:3427,3060,2926,1756,1590,1488,1458,1180,1090;
1HNMR(CDCl
3,TMS,400MHz,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),6.90(dd,J=8.8,8.7Hz,1H,Ar-H),6.56(dd,J=8.8,2.5Hz,1H,Ar-H),6.41(dd,J=8.7,2.5Hz,1H,Ar-H),2.95(dt,2H,CH
2),2.38(t,2H,CH
2),1.57(m,2H,CH
2),1.40(m,2H,CH
2);EIMSm/z(%):454(M
+,100),456(64),455(25),457(16),458(10),456(4),459(3),458(2),455(1)。
Embodiment 12: the preparation of compound 6j
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1i that obtains;
Step 2: suc as formula synthetic compound 2i shown in the step B among the II.Specific as follows:
With compound 1i17.9g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2i29.3g, yield 95.0%.
Step 3: suc as formula synthetic compound 3i shown in the step C among the II.Specific as follows:
Get compound 2i27.4g(0.070mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.6g of colloidal liquid, yield 79.8%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5g that obtain.
Step 5: suc as formula the 6a of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3i1.29g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5g1.27g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6j with ethyl alcohol recrystallization.Fusing point: 191-194 ℃, yield 86.0%.IRυ
max(KBr)/cm
-1:3427,3060,2926,1756,1590,1488,1458,1180,1090;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),6.90(dd,J=8.8,8.7Hz,1H,Ar-H),6.56(dd,J=8.8,2.5Hz,1H,Ar-H),6.41(dd,J=8.7,2.5Hz,1H,Ar-H),2.95(dt,2H,CH
2),2.38(t,2H,CH
2),1.57(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):381(M
+,100),382(27),384(4)。
Embodiment 13: the preparation of compound 6k
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1a that obtains;
Step 2: suc as formula synthetic compound 2a shown in the step B among the II.Specific as follows:
With compound 1a15.6g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2a25.8g, yield 90%.
Step 3: suc as formula synthetic compound 3a shown in the step C among the II.Specific as follows:
Get compound 2a25.4g(0.070mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 12.2g of colloidal liquid, yield 73.8%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5d that obtain.
Step 5: suc as formula the 6k of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3a1.17g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5d1.42g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6k with ethyl alcohol recrystallization.Fusing point: 92-95 ℃, yield 83.0%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):383(M
+,100),384(26),385(4)。
Embodiment 14: the preparation of compound 6l
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1c that obtains;
Step 2: suc as formula synthetic compound 2c shown in the step B among the II.Specific as follows:
With compound 1c18.4g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2c28.7g, yield 91.5%.
Step 3: suc as formula synthetic compound 3c shown in the step C among the II.Specific as follows:
Get compound 2c27.8g(0.070mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.8g of colloidal liquid, yield 78.8%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5d that obtain.
Step 5: suc as formula the 6l of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3c1.34g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5d1.42g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6l with pure recrystallization.Fusing point: 125-130 ℃, yield 89.2%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):383(M
+,100),384(26),385(4)。
Embodiment 15: the preparation of compound 6m
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1c that obtains;
Step 2: suc as formula synthetic compound 2c shown in the step B among the II.Specific as follows:
With compound 1c18.4g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2c28.7g, yield 91.5%.
Step 3: suc as formula synthetic compound 3c shown in the step C among the II.Specific as follows:
Get compound 2c27.8g(0.070mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.8g of colloidal liquid, yield 78.8%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5b that obtain.
Step 5: suc as formula the 6m of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3c1.34g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5b1.45g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6m with ethyl alcohol recrystallization.Fusing point: 145-149 ℃, yield is 88.7%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):421(M
+,100),423(67),422(25),424(16),425(12),426(3)。Embodiment 16: the preparation of compound 6n
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1f that obtains;
Step 2: suc as formula synthetic compound 2f shown in the step B among the II.Specific as follows:
With compound 1f21.0g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2f29.0g, yield 88%.
Step 3: suc as formula synthetic compound 3f shown in the step C among the II.Specific as follows:
Get compound 2f28.1g(0.065mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.3g of colloidal liquid, yield 75.3%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5f that obtain.
Step 5: suc as formula the 6n of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3f1.51g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5f1.52g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6n with ethyl alcohol recrystallization.Fusing point: 86-90 ℃, yield 87.6%.IRυ
max(KBr)/cm
-1:3427,3060,2926,1756,1590,1488,1458,1180,1090;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),6.90(dd,J=8.8,8.7Hz,1H,Ar-H),6.56(dd,J=8.8,2.5Hz,1H,Ar-H),6.41(dd,J=8.7,2.5Hz,1H,Ar-H),2.95(dt,2H,CH
2),2.38(t,2H,CH
2),1.57(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):471(M
+,100),473(68),472(29),474(18),475(13),476(3)。
Embodiment 17: the preparation of compound 6o
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1f that obtains;
Step 2: suc as formula synthetic compound 2f shown in the step B among the II.Specific as follows:
With compound 1f21.0g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2f29.0g, yield 88%.
Step 3: suc as formula synthetic compound 3f shown in the step C among the II.Specific as follows:
Get compound 2f28.1g(0.065mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.3g of colloidal liquid, yield 75.3%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5e that obtain.
Step 5: suc as formula the 6o of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3f1.51g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5e1.52g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6o with ethyl alcohol recrystallization.Fusing point: 179-183 ℃, yield 87.2%.IRυ
max(KBr)/cm
-1:3427,3060,2926,1756,1590,1488,1458,1180,1090;
1HNMR(CDCl
3,TMS,400MHz,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),6.90(dd,J=8.8,8.7Hz,1H,Ar-H),6.56(dd,J=8.8,2.5Hz,1H,Ar-H),6.41(dd,J=8.7,2.5Hz,1H,Ar-H),2.95(dt,2H,CH
2),2.38(t,2H,CH
2),1.57(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):471(M
+,100),473(68),472(29),474(18),475(13),476(3)。
Embodiment 18: the preparation of compound 6p
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1f that obtains;
Step 2: suc as formula synthetic compound 2f shown in the step B among the II.Specific as follows:
With compound 1f21.0g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2f29.0g, yield 88%.
Step 3: suc as formula synthetic compound 3f shown in the step C among the II.Specific as follows:
Get compound 2f28.1g(0.065mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.3g of colloidal liquid, yield 75.3%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5c that obtain.
Step 5: suc as formula the 6p of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3f1.51g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5c1.50g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6p with ethyl alcohol recrystallization.Fusing point: 174-178 ℃, yield 84.5%.IRυ
max(KBr)/cm
-1:3427,3060,2926,1756,1590,1488,1458,1180,1090;
1HNMR(CDCl
3,TMS,400MHz,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),6.90(dd,J=8.8,8.7Hz,1H,Ar-H),6.56(dd,J=8.8,2.5Hz,1H,Ar-H),6.41(dd,J=8.7,2.5Hz,1H,Ar-H),2.95(dt,2H,CH
2),2.38(t,2H,CH
2),1.57(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):465(M
+,100),467(68),466(24),468(15),469(13),470(3)。
Embodiment 19: the preparation of compound 6q
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1h that obtains;
Step 2: suc as formula synthetic compound 2h shown in the step B among the II.Specific as follows:
With compound 1h18.1g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2h29.9g, yield 96.2%.
Step 3: suc as formula synthetic compound 3h shown in the step C among the II.Specific as follows:
Get compound 2h27.5g(0.070mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.9g of colloidal liquid, yield 80.8%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5g that obtain.
Step 5: suc as formula the 6q of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3h1.32g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5g1.27g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6q with ethyl alcohol recrystallization.Fusing point: 130-132 ℃, yield 84.5%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):352(M
+,100),354(25),355(3)。
Embodiment 20: the preparation of compound 6r
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1h that obtains;
Step 2: suc as formula synthetic compound 2h shown in the step B among the II.Specific as follows:
With compound 1h18.1g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2h29.9g, yield 96.2%.
Step 3: suc as formula synthetic compound 3h shown in the step C among the II.Specific as follows:
Get compound 2h27.5g(0.070mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.9g of colloidal liquid, yield 80.8%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5a that obtain.
Step 5: suc as formula the 6r of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3h1.32g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5a1.35g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6r with ethyl alcohol recrystallization.Fusing point: 113-117 ℃, yield 87.4%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2).EIMSm/z(%):400(M
+,100),401(25),402(3)。
Embodiment 21: the preparation of compound 6s
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1h that obtains;
Step 2: suc as formula synthetic compound 2h shown in the step B among the II.Specific as follows:
With compound 1h18.1g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2h29.9g, yield 96.2%.
Step 3: suc as formula synthetic compound 3h shown in the step C among the II.Specific as follows:
Get compound 2h27.5g(0.070mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.9g of colloidal liquid, yield 80.8%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5f that obtain.
Step 5: suc as formula the 6s of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3h1.32g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5f1.50g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6s with ethyl alcohol recrystallization.Fusing point: 112-116 ℃, yield 89.2%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):432(M
+,100),433(30),434(4)。
Embodiment 22: the preparation of compound 6t
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1h that obtains;
Step 2: suc as formula synthetic compound 2h shown in the step B among the II.Specific as follows:
With compound 1h18.1g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2h29.9g, yield 96.2%.
Step 3: suc as formula synthetic compound 3h shown in the step C among the II.Specific as follows:
Get compound 2h27.5g(0.070mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.9g of colloidal liquid, yield 80.8%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5e that obtain.
Step 5: suc as formula the 6t of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3h1.32g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5e1.50g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6t with ethyl alcohol recrystallization.Fusing point: 98-101 ℃, yield 88.4%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):432(M
+,100),433(30),434(4)。
Embodiment 23: the preparation of compound 6u
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1h that obtains;
Step 2: suc as formula synthetic compound 2h shown in the step B among the II.Specific as follows:
With compound 1h18.1g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2h29.9g, yield 96.2%.
Step 3: suc as formula synthetic compound 3h shown in the step C among the II.Specific as follows:
Get compound 2h27.5g(0.070mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.9g of colloidal liquid, yield 80.8%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5d that obtain.
Step 5: suc as formula the 6u of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3h1.32g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5d1.42g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6u with ethyl alcohol recrystallization.Fusing point: 123-125 ℃, yield 91.2%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):412(M
+,100),413(26),414(4)。
Embodiment 24: the preparation of compound 6v
Step 1: suc as formula among the II shown in the steps A, according to the example 1 synthetic compound 1h that obtains;
Step 2: suc as formula synthetic compound 2h shown in the step B among the II.Specific as follows:
With compound 1h18.1g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and the 500mL acetonitrile join in the 1000mL three-necked bottle, behind the mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake are dried to get 2h29.9g, yield 96.2%.
Step 3: suc as formula synthetic compound 3h shown in the step C among the II.Specific as follows:
Get compound 2h27.5g(0.070mol) be dissolved in the 500mL dehydrated alcohol, place the 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip the complete backflow that is heated to, solution has suspendible to become clarification, flocks occurs after reaction for some time.Reaction solution is concentrated, is dissolved in water, and chloroform extraction three times, the extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, get approximately 14.9g of colloidal liquid, yield 80.8%.
Step 4: suc as formula method shown in the step D among the II, according to the example 2 synthetic compound 5b that obtain.
Step 5: suc as formula the 6v of synthetic compound shown in the step e among the II.Specific as follows:
Get compound 3h1.32g(5mmol), be dissolved in the 50mL methylene dichloride, add the 5mL triethylamine, place the 150mL three-necked bottle; Other gets compound 5b1.45g(5mmol), be dissolved in the 15mL methylene dichloride, slowly be added drop-wise in the three-necked bottle under the rapid stirring, be warmed up to backflow after dripping end, TLC monitoring reaction process, having treated should be complete, add 20ml water, stir after 15 minutes standing demix, after the organic layer 10ml water washing, anhydrous sodium sulfate drying filters, and is concentrated, residue gets 6v with ethyl alcohol recrystallization.Fusing point: 134-136 ℃, yield 87.1%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS?m/z(%):416(M
+,100),417(25),418(36),419(8),420(1)。
Pharmacological evaluation
Compound is to human D
3The affinity of acceptor can by [
3H] spiperone combination (spiperone binding) mensuration (seeing Table 4).
The Chinese hamster ovary celI transfection coding human D
3Acceptor (Hd
3) cDNA.In the medium that contains 120mM NaCl, 5mM KCl and 50mM Tris HCl pH7.4, contain under the condition of 2.5-5 μ g membranin, carry out [
3H] spiperone (0.5-2nM) combination; Incubation is 60 minutes under the room temperature.In the presence of 10 μ M haloperidol, assess non-specific binding.In the non-transfected cells without any specific binding.Use the LIGAND formula to borrow nonlinear regression analysis to measure the Ki value.
The tabulation of table 1. intermediate phenylpiperazine hydrochloride
compd | R 1 | formula | M.w. | mp,℃ |
1a | H | C 10H 14N 2·HCl | 198.69 | 245~249 |
1b | p-F | C 10H 13N 2F·HCl | 216.68 | 230~234 |
1c | p-Cl | C 10H 13N 2Cl·HCl | 233.14 | 215~218 |
1d | p-OCH 3 | C 11H 16N 2O·HCl | 228.72 | 190~192 |
1e | p-CH 3 | C 11H 16N 2·HCl | 212.72 | 220~223 |
1f | 2,3-di-Cl | C 10H 12N 2Cl 2·HCl | 266.13 | 246~248 |
1g | 3,4-di-Cl | C 10H 12N 2Cl 2·HCl | 266.13 | 206~208 |
1h | o-OCH 3 | C 11H 16N 2O·HCl | 228.72 | 213~217 |
1i | 2,3-di-CH 3 | C 12H 18N 2·HCl | 226.75 | 220~223 |
1j | o-Cl | C 10H 13N 2Cl·HCl | 233.14 | 219~221 |
1k | m-Cl | C 10H 13N 2Cl·HCl | 233.14 | 209~211 |
The tabulation of table 2. intermediate trichlorine methoxyl group formic acid aromatic ester
The tabulation of table 3. target compound
Table 4. target compound is to human D
3The receptor affinity tabulation
compd | Ki(nM) | compd | Ki(nM) |
6a | 243.8 | 6l | 9.5 |
6b | 48.0 | 6m | 441.8 |
6c | 23.6 | 6n | 657.6 |
6d | 68.9 | 6o | 36.2 |
6e | 371.2 | 6p | 774.4 |
6f | 142.5 | 6q | 52.1 |
6g | 45.3 | 6r | 321.0 |
6h | 228.7 | 6s | 25.5 |
6i | 56.0 | 6t | 830.9 |
6j | 668.1 | 6u | 1024.7 |
6k | 1132.0 | 6v | 117.6 |
Claims (10)
1. 4-[4-(substituted-phenyl by formula (1) expression) piperazinyl-1]-butylamine formic acid substituted aroma ester derivative:
In the formula
R
1For H or be in any the position of substitution of phenyl ring and replace arbitrarily halogen, alkyl, alkoxyl group, the nitro of number;
R
2Be aryl or substituted aryl.
2. 4-[4-(substituted-phenyl according to claim 1) piperazinyl-1]-butylamine formic acid substituted aroma ester derivative, it is characterized in that the R in the formula (1)
1Be o-Cl, m-Cl, p-Cl, 2,3-di-Cl, 3,4-di-Cl, p-F, p-CH
3, 2,3-di-Me, o-OCH
3Or p-OCH
3
4. one kind prepares such as claim 1 or 2 or 3 described 4-[4-(substituted-phenyls) piperazinyl-1]-butylamine formic acid aromatic ester derivative, it is characterized in that may further comprise the steps:
Step 1: substituted aniline and two-(β-chloroethyl) amine hydrochlorate is in organic solvent, and take mineral alkali as acid binding agent, reaction obtains intermediate 1, i.e. corresponding substituted phenylpiperazine hydrochloride;
Step 2: substituted phenylpiperazine hydrochloride 1 and N-(δ-bromo butyl) phthalic imidine is in acetonitrile, with K
2CO
3For reaction under acid binding agent, the KI catalysis obtains reaction intermediate 2, i.e. N-{4-[4-(substituted-phenyl) piperazinyl-1]-butyl } the adjacent dicarboximide of benzo;
Step 3: intermediate 2 obtains intermediate 3 behind hydrazinolysis, i.e. 1-(δ-aminobutyl)-the 4-(substituted-phenyl) piperazine;
Step 4: intermediate 3 and intermediate 5 are take triethylamine as acid binding agent and catalyzer, and condensation obtains target product 4-[4-(substituted-phenyl) piperazinyl-1]-butylamine formic acid substituted aromatic ester derivative I; Wherein, intermediate 5 is trichlorine methoxyl group formic acid substituted aromatic ester, and it is obtained with certain mol proportion generation condensation reaction in methylene dichloride by triphosgene and substituted aroma phenol.
5. method as claimed in claim 4 is characterized in that described step 1 is specially:
Under nitrogen protection, substituted aniline and two-(β-chloroethyl) amine hydrochlorate, take propyl carbinol, the trimethyl carbinol, chlorobenzene, DMF, DMA or ethylene glycol as solvent, stirring reaction under certain temperature reacted 24-48 hour, with TLC detection reaction progress; After reaction is finished, be cooled to room temperature, with methyl alcohol reaction mixture is all dissolved, pass into hydrogen chloride gas and make reaction solution be acid, add subsequently excessive ether and separate out precipitation, suction filtration, wash with ether, get corresponding substituted phenylpiperazine hydrochloride crude product, with organic solvent methyl alcohol, dehydrated alcohol, Virahol or 95% ethyl alcohol recrystallization, obtain sterling.
6. method as claimed in claim 4 is characterized in that described step 2 is specially:
N-(δ-bromo butyl) reaction of phthalic imidine and substituted phenylpiperazine hydrochloride is: take acetone, acetonitrile, dimethyl formamide DMF, DMA DMA, dioxane or pyridine as solvent; With K
2CO
3, Na
2CO
3, NaHCO
3, NaOH or CaCO
3Be acid binding agent; Take NaI or KI as catalyzer; Back flow reaction 24-48 hour, with TLC detection reaction progress; Be cooled to room temperature after reaction is finished, with in the slow impouring frozen water of reaction solution, separate out solid under the rapid stirring, filter after washing, dry to get intermediate 2.
7. method as claimed in claim 4 is characterized in that described step 3 is specially:
The reaction of described intermediate 2 hydrazinolysis is: with water, methyl alcohol, ethanol, Virahol or the trimethyl carbinol as solvent; 30%-80% hydration hydrazinolysis; 20-85 ℃ of reaction; With TLC detection reaction progress, concentrated solvent after reaction is finished, solid is got three times with methylene dichloride, trichloromethane, ethyl acetate, toluene or 1,2-ethylene dichloride solvent with water dissolution; Collect organic phase, concentrated with filtering behind anhydrous sodium sulphate or the anhydrous magnesium sulfate drying, get intermediate 3.
8. method as claimed in claim 4 is characterized in that described step 4 is specially:
Be dissolved in monochloro methane, methylene dichloride, trichloromethane or 1,2-ethylene dichloride solvent with described intermediate 3; Add catalyst of triethylamine, pyridine, diisopropyl ethyl amine or dimethyl formamide; In addition with an amount of same solvent dissolving intermediate 5, it slowly is added dropwise in intermediate 3 solution, drip and finish rear continuation stirring after 15-30 minute, be warming up to back flow reaction, the TLC monitoring, until complete should be fully after, stopped reaction, reaction solution be with water washing 2-3 time, anhydrous sodium sulphate or anhydrous magnesium sulfate drying, filter, concentrate to get crude product; Crude product gets target product I with the mixed solvent recrystallization of methyl alcohol, ethanol, Virahol or they and methylene dichloride, trichloromethane.
9. method as claimed in claim 4 is characterized in that the preparation of intermediate 5 in the described step 4 is specially:
Triphosgene and the condensation of substituted aroma phenol obtain trichlorine methoxyl group formic acid substituted aromatic ester: at monochloro methane, methylene dichloride, trichloromethane, 1, in 2-ethylene dichloride or their mixed solvent, take triethylamine, pyridine, diisopropyl ethyl amine or dimethyl formamide as acid binding agent; React under refluxing in room temperature; Wherein triphosgene and substituted aroma phenol mol ratio are 1.0:1.0~3.0; Reacted 2-10 hour, TLC detection reaction progress is reacted complete rear adding water washing reaction solution 2-3 time, and anhydrous sodium sulfate drying filters, and the concentration and recovery solvent gets trichlorine methoxyl group formic acid substituted aromatic ester, not purifiedly is directly used in next step reaction.
10. method as claimed in claim 4 is characterized in that N-(δ-bromo butyl in the described step 2) preparation method of phthalic imidine is:
Get the adjacent dicarboximide potassium of an amount of benzo and be dissolved in a certain amount of acetone, other gets an amount of Isosorbide-5-Nitrae-dibromobutane and is dissolved in the acetone, is added drop-wise in the three-necked bottle in one hour, drips and finishes, and backflow is spent the night; Concentrated, slowly in the impouring frozen water, left standstill 30 minutes, filter, the filter cake washing, oven dry, and get final product.
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