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CN109320458A - A kind of compound containing diarylimidazole and its preparation method and medical use - Google Patents

A kind of compound containing diarylimidazole and its preparation method and medical use Download PDF

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CN109320458A
CN109320458A CN201811189972.4A CN201811189972A CN109320458A CN 109320458 A CN109320458 A CN 109320458A CN 201811189972 A CN201811189972 A CN 201811189972A CN 109320458 A CN109320458 A CN 109320458A
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imidazoles
organic phase
substituted
sodium sulfate
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CN109320458B (en
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孙昊鹏
卢鑫
李琦
杨鸿瑜
陈瑶
李启航
冯锋
曲玮
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China Pharmaceutical University
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
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    • C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
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Abstract

本发明公开了如式(Ⅰ)所示的二芳基咪唑类化合物。本发明还公开了所述的二芳基咪唑类化合物在制备预防或治疗阿尔茨海默症药物中的应用。发明人以丁酰胆碱酯酶和IDO1抑制活性的筛选为载体来评价二芳基咪唑类化合物治疗阿尔茨海默症活性的，发现具有良好的体外活性，可作为进一步开发为通过抑制胆碱酯酶活性来发挥抗阿尔茨海默症作用的前体物质。

The present invention discloses diarylimidazole compounds represented by formula (I). The invention also discloses the application of the diarylimidazole compound in preparing a medicine for preventing or treating Alzheimer's disease. The inventors used the screening of butyrylcholinesterase and IDO1 inhibitory activities as carriers to evaluate the activity of diarylimidazole compounds in the treatment of Alzheimer's disease, and found that they have good in vitro activity, which can be further developed as a method for inhibiting choline Esterase activity to exert anti-Alzheimer's effect of precursor substances.

Description

One kind is containing diarylimidazoles and preparation method thereof and medical usage
Technical field
The invention belongs to field of medicaments, are related to diarylimidazoles and preparation method thereof and such compound It is applied in preparation treatment Alzheimer disease drug.
Background technique
Alzheimer's disease (Alzheimer's disease, AD) is a kind of neurodegenerative disease.Clinical manifestation is note Recall and is lost with the degeneration of cognitive function.According to Alzheimer disease association count, AD is that the U.S. has no idea to prevent, cure or One of big cause of death of the ten of delay of progression.By 2016, the whole world about 47,000,000 dementia patients, to this number of the year two thousand fifty Word will be more than 1.31 hundred million.Perhaps, these numbers are still below practical sufferer number, because this does not include that those are in disease earliest period Patient's number of clinical stage.AD patient needs prolonged nursing, and the U.S. in 2015 is in relation to AD and other dull-witted medical expenses Reach 81,800,000,000 dollars, it is contemplated that the disease of medical expense trillion dollars will be become within 2018.
China is the highest country of elderly population overall growth trend in the world, it is contemplated that will be increased from 2015 200000000 or so To 4.9 hundred million (the United Nations 2016) of the year two thousand fifty.Aging trend aggravates, and China is faced with baptism in terms for the treatment of AD, this It is not only required in the challenge and economic development of medical industry solve the problems, such as.According to " world's Alzheimer disease in 2015 Report " estimation, China have 9,500,000 people with dementia, the 20% of dementia total number of persons in the world are accounted for, to the year two thousand thirty, Chinese AD Patient is estimated to will be added to more than 1,600 ten thousand.The medical expense of AD is far more than diseases such as diabetes, apoplexy.China is about AD's Medical level is also in the primary stage, diagnose, the development that prevents, treats it is extremely urgent.To patient, patient home as long as the AD course of disease And entire society can all cause huge emotion and financial burden.Therefore, it finds and effective drug and treatment plan is treated to AD Slightly have become key problem urgently to be resolved in All Around The World field of medicaments.
AD pathogenic factors is extremely complex, is related to many aspects.Contemporary scientific men not yet come to a conclusion to the definite cause of disease of AD.It Main pathological characters include several aspects below: 1) beta amyloid peptide fragment: what extracellular autohemagglutination was formed has cell toxicant The A beta oligomers and fibrinogen of property；2) the excessive phosphorylation of Tau albumen is assembled in the cell forms neurofibrillary tangles (NFT)； 3) cholinergic conductive impairment caused by the damage of cholinergic nerve；4) missing of nerve synapse；5) neuroinflamation and intracellular Concentration of metal ions is excessively high；6) pathogenic factors such as disorder of oxidative stress and mitochondrial function.And for the pathological characters section of AD A variety of therapeutic strategies have been proposed in scholars.
Although having proposed the potential strategy of a variety for the treatment of AD, it is in phase of basic research.Clinically have at present The drug of effect is still based on anticholinesterase.Cholinergic system is mainly by acetylcholinesterase (AChE) and BuCh ester Enzyme (BuChE) composition hydrolyzes the neurotransmitter acetylcholine (Ach) to play an important role in cholinergic nerve transmitting.With AD The progress of the course of disease, the content of AChE gradually decreases in brain, and BuChE is remained unchanged or even increases to the 165% of normal level. In AD advanced stage, BuChE is responsible for the hydrolysis of acetylcholine in brain instead of AChE.BuChE is closely related with AChE one Kind enzyme passes through the adjusting that hydrolyse acetylcholine carries out cholinergic neurotransmitter.Although BuChE is considered adjusting brain ACh water Secondary role is played in flat, but it is reported that it is related with drug metabolism and removing toxic substances.Some evidences also indicate that, the activity of BuChE Raising plays an important role in the early stage A beta-aggregation that senile plaque is formed.The potential importance of BuChE is knocked out by AChE Mouse confirms model, wherein the shortage of the compensatory AChE of BuChE, maintains the normal cholinergic pathway in AChE failure animal.Currently, AChE inhibitor is widely used in restoring ACh horizontal, but patient takes " classics " AChE that inhibitor may generate nausea etc. Side effect and vomiting, these are with undesirable result mainly due to inhibiting periphery AChE.Selective BuChE inhibitor can advise Keep away classical cholinergic toxicity.This shows to inhibit effect of the BuChE compared to selectivity AChE more effective, in particular in Advanced stage AD.
Indoleamine 2,3-dioxygenase (indoleamine 2,3-dioxygenase, IDO), in the tissue of mammal Or wide expression in cell, especially lymphoid tissue and placenta, it is tryptophan (TRP) catabolism kynurenine pathway (KP) Rate-limiting enzyme.IDO plays an important role in immune system, and height expression IDO participates in the immunologic escape of tumour.At the same time, more Point out that IDO is related with the pathogenesis of AD come more evidences.The disturbance of KP is strongly related to AD.Compared with healthy individuals, AD L- kynurenin (L-KYN)/TRP ratio rate in the blood and cerebrospinal fluid of patient increases, with 3- hydroxyl in intracerebral IDO level and serum The increase of base kynurenin is consistent, and the increase of this ratio is positively correlated with cognitive disorder.In AD patient's hippocampal tissue Exempting from for IDO and quinolinic acid (quinolinic acid, QUIN) is observed in microglia, astroglia and neuron Epidemic disease reactivity, there is highest signals in the observation of the periphery of senile plaque for this immunoreactivity.Both it is twined in nerve fibril It is found in knot, and QUIN is present in the intracellular granular aggregation in cortical neuron.Aβ42Induce the expression of IDO1 and increasing Add the generation of QUIN in human macrophage and microglia.To human neure and mouse model studies have shown that A β42Raising It is active proinflammatory with induction IDO, TDO and kynurenin -3- monooxygenase (Kynurenine-3-monooxygenase, KMO) Cell factor is consistent to the induction of KP.In addition, causing to participate on the gene of Protein tau phosphorylation with QUIN processing human neure It adjusts, this may provide the mechanism that AD forms neurofibrillary tangles.Furthermore such as IDO, the KMO of the key enzyme in KP with it is well-known AD marker A β deposit, Tau protein hyperphosphorylation be in same location in brain.
The molecular effect of single target spot is limited, and the drawback of "-one target spot of a molecule " strategy gradually emerges, new drug design Strategy comes into being, and obtains the favor of more scientific research personnel.The principle of multiple target point strategy (MTDL), this strategy is one point Son can act on two or more associated targets simultaneously, and the combination of multi-effect is conducive to multifactor relevant pathologic conditions ratio Such as the treatment of AD.A large amount of multiple target point molecule emerges, and injects new vitality to the research for the treatment of AD.Although still without MTDL Drug enters clinical research, but this new layout strategy still has great potential.
The studies above absolutely proves that the design synthesis bis- target spot inhibitor of BuChE/IDO1 can possess single target spot on treatment AD The advantages for the treatment of hardly matches.Discovery, design and the biology for parsing its generation AD treatment of the bis- target spot inhibitor of BuChE/IDO1 Mechanism is not only worth with particularly important basic research, it may have wide application prospect.
Summary of the invention
The purpose of the invention is to provide a kind of diarylimidazoles with anti-Alzheimer disease effect.
The purpose of the present invention is what is be achieved through the following technical solutions:
The diarylimidazoles as shown in formula (I) or its pharmaceutically acceptable salt,
Wherein, A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted fragrant condensed ring； The substituent group of phenyl is halogen ,-NO2、-CN、Cl~C6The C that alkyl, halogen replace1~C4Alkyl, C1~C3Alkoxy, naphthalene Substituent group is halogen ,-NO2、-CN、-OH、Cl~C6Alkyl, the substituent group of heterocycle are halogen ,-NO2,-CN ,-OH, halogen replace C1~C4Alkyl, C1~C4Alkyl, C1~C3Alkoxy；L is selected from-O- ,-S- or-C (O) O-；N=1,2,3.
Preferably, A is selected from substituted or unsubstituted phenyl, unsubstituted naphthalene, unsubstituted heteroaromatic, unsubstituted miscellaneous Fragrant condensed ring is closed, the substituent group of phenyl is selected from the C that hydrogen, fluorine, chlorine, bromine, halogen replace1~C4Alkyl, C1~C4Alkyl, C1~C3Alcoxyl Base；L is selected from-O- ,-C (O) O-；N=1,2,3.
It is further preferred that A is selected from substituted or unsubstituted phenyl, unsubstituted naphthalene, thiophene, benzo [d] [1,3] two Oxole, the substituent group of phenyl are selected from the C that hydrogen, fluorine, chlorine, bromine replace1~C4Alkyl, C1~C4Alkyl or C1~C3Alcoxyl Base；L is selected from-O- ,-C (O) O；N=1,2,3.In certain embodiments of the present invention, the substituent group of phenyl be ortho position substitution, Position replaces, contraposition replaces, two replace or three replace.
Still further preferably, work as L=-O-, n=1；The substituted or unsubstituted phenyl of A, unsubstituted naphthalene, thiophene, benzene And [d] [1,3] dioxole, the substituent group of phenyl are selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxyl group, tertiary fourth Base；As L=-C (O) O, n=1,2,3, A are derived from 3,4- difluorophenyl.
When the phenyl substitution is not hydrogen, preferably 2,3,4,5 monosubstituted disubstituted or trisubstituted halogens, into One step preferably 2,3,4,5 disubstituted or trisubstituted fluorine or chlorine.
Diarylimidazoles of the present invention are selected from following compound, and structure is as shown in table 1:
Table 1
It is a further object to provide the preparation methods of diaryl imidazole compound, comprising:
Using substituted aryl ethyl ketone as raw material, alpha-brominated aryl methyl ketone, alpha-brominated aryl methyl ketone and miaow are obtained through bromine bromo Azoles N is alkylated to obtainIt reacts to obtain with sodium borohydride againFinally with 3- methoxyl group benzyl chloride Or the diarylimidazoles as shown in formula (I) are prepared in the aryl carboxylic acid reaction of different chain length.
Preparation method of the present invention, preferably includes:
Step (1), substituted aryl ethyl ketone, using chloroform as reaction dissolvent, in Br2Under effect, 1h is stirred at room temperature, instead After answering, saturated sodium sulfite quenching reaction, organic phase saturated sodium bicarbonate, saturated common salt water washing, anhydrous sodium sulfate After drying, solvent is removed in vacuum and obtains crude product；The substituted aryl ethyl ketone and Br2Molar ratio be 1:1~1.5；
Step (2) takes alpha-brominated aryl methyl ketone and imidazoles to be dissolved in tetrahydrofuran, potassium carbonate is added, after 3h is stirred at room temperature, very Sky removes reaction solution, adds water, is extracted with ethyl acetate.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate is dry, rotation It is dry, silica gel column chromatography separation.Wherein, the eluant, eluent of silica gel column chromatography is methylene chloride: methanol=100:1v/v；α-the bromine Molar ratio for aryl methyl ketone, imidazoles, potassium carbonate is 1:2:2~1:3:3；
Step (3) is incited somebody to actionIt is dissolved in anhydrous methanol, sodium borohydride is added under condition of ice bath, and under this condition Stirring 1 hour, is heated to reflux.Add water quenching reaction, extracted with ethyl acetate, merges organic phase, organic phase saturated salt solution It washes, anhydrous sodium sulfate is dry, is spin-dried for, and silica gel column chromatography separation obtainsWherein, eluant, eluent DCM:MeOH= 30:1v/v；DescribedMolar ratio with sodium borohydride is 1:2~1:3；
Step (4), when L be-O-, operate for willIt is dissolved in DMF, sodium hydride is added under ice bath, room temperature is anti- It answers 1 hour, 3- methoxybenzyl chloride is added under rear ice bath, then react at room temperature 1 hour.With water quenching reaction, extracted with ethyl acetate It takes, organic phase is successively washed with saturated common salt, and anhydrous sodium sulfate is dry, is spin-dried for, and silica gel column chromatography separation obtains shown in formula (I) Structural compounds；DescribedMolar ratio with NaH, 3- methoxybenzyl chloride is 1:1.2:1.2~1:1.2: 1.3；Eluant, eluent is DCM:MeOH=30:1v/v.When L be-C (O) O, operate for willIt is dissolved in DCM, dicyclohexylcarbodiimide is added under ice bath and to dimethylamino Pyridine reacts at room temperature 2 hours.Reaction solution water and saturated common salt water washing, anhydrous sodium sulfate is dry, is spin-dried for, silica gel column chromatography Separation, obtains structural compounds shown in formula (I).DescribedWithDicyclohexyl carbon Diimine and be 1:1:1:0.1~1:1.3:1.3:0.1 to the molar ratio of dimethylamino naphthyridine；Eluant, eluent is DCM:MeOH= 30:1v/v。
The synthetic route of diarylimidazoles of the present invention is as follows:
Diarylimidazoles of the present invention can inhibit butyrylcholine esterase and indoleamine 2,3-dioxygenase simultaneously, and And acetylcholinesterase is had good selectivity, it can be used as and be further developed as by inhibiting butyrylcholine esterase and indoles Amine 2,3- dioxygenase activity come play anti-Alzheimer disease effect precursor substance.
Therefore it is a further object to provide the diarylimidazoles or its is pharmaceutically acceptable Salt preparation prevention or treatment Alzheimer disease drug in application.
The drug is effective with diarylimidazoles of the present invention or its pharmaceutically acceptable salt Ingredient or principle active component, are made with pharmaceutically acceptable carrier；The dosage form of the drug is capsule, pill, piece Agent, granule or injection.
A kind of composition is effective with diarylimidazoles of the present invention or its pharmaceutically acceptable salt Ingredient or principle active component, with pharmaceutically acceptable carrier.
The utility model has the advantages that
Diarylimidazoles of the present invention have centainly butyrylcholine esterase and indole amine 2,3-dioxygenase -1 Inhibitory activity, and acetylcholinesterase is had good selectivity.And compound of the present invention is in MTT experiment In, to PC-12 and SH-5YSY cell strain without overt toxicity under 50 μM of dosage, part of compounds has slight guarantor to cell Shield effect.To in the water maze laboratory of mouse behavioral study, compound 8 and 13 is equal under two dosage of 10mg/kg and 30mg/kg Show mouse cognitive disorder caused by effective reverse scopolamine, compound 13 (10mg/kg) is optimal, with control group phase When.In addition, in the acute liver toxicity evaluation experimental of mouse, under two dosage of 10mg/kg and 30mg/kg of compound 8 and 13, Do not have a significant impact to alanine aminotransferase and aspartate transaminase, does not cause the bad metamorphosis of liver, show Preliminary safety.In Alzheimer's disease early stage, 80% acetylcholine is responsible for hydrolysis, BuCh by acetylcholinesterase Esterase is almost without effect, and with the exacerbation of the course of disease, the horizontal decline of acetylcholinesterase, function is almost lost, at this point, butyryl gallbladder The level and function of alkali esterase are opposite to be promoted, and acetylcholinesterase is replaced to become the main metabolic enzyme of acetylcholine.Therefore, for The inhibitory activity of the treatment of severe Alzheimer's disease, butyrylcholine esterase is particularly important.Compared with healthy individuals, AD patient's L- kynurenin (L-KYN)/TRP ratio rate in blood and cerebrospinal fluid increases, the increasing with 3-HK in intracerebral IDO1 level and serum Add unanimously, and the increase of this ratio is positively correlated with cognitive disorder.It has been confirmed that inhibiting IDO1 that can subtract in animal model Light cognitive disorder.Diarylimidazoles of the present invention have good inhibitory activity to butyrylcholine esterase and IDO1, have It hopes and provides than single target inhibitor to the better therapeutic effect of Alzheimer's disease.
Detailed description of the invention
Fig. 1 mouse reaches the time of missing position of platform
Fig. 2 mouse reaches the representative track of missing position of platform
Influence of each embodiment compound of Fig. 3 to PC12 cell survival rate
Influence of each embodiment compound of Fig. 4 to SH-SY5Y cell survival rate
Fig. 5 is three time points, seven groups of mouse alanine aminotransferase levels；In figure, ns indicate and control group, model group without Significant difference.
Fig. 6 is three time points, seven groups of mouse aspartate transaminase levels；In figure, ns is indicated and control group, model group There was no significant difference.
Fig. 7 is mouse liver histopathology slide；Wherein, (A) control group mice liver section；(B) it is administered 36 hours Model group mouse liver is sliced afterwards；(C) Tacrine group mouse liver is sliced after being administered 36 hours；(D) chemical combination after being administered 36 hours Object 8 (10mg/kg) processing group mouse liver slice；(E) compound 8 (30mg/kg) processing group mouse liver after being administered 36 hours Slice；(F) compound 13 (10mg/kg) processing group mouse liver is sliced after being administered 36 hours；(G) compound after being administered 36 hours 13 (30mg/kg) processing group mouse livers slice.
Specific embodiment
Further supplementary explanation is made to technical solution of the present invention by the following examples, but should not be construed the present invention Range is only limitted to following instance.Technical solution according to the present invention, according to the ordinary technical knowledge and customary means of this field, not Under the premise of being detached from technical thought of the invention, the modification of other diversified forms, replacement and change can also be made, it is all to be based on this hair The technology that bright technical solution is realized all belongs to the scope of the present invention.
The structure of compound is determined by nuclear magnetic resonance (NMR).Instrument is Bruker AVANCE-300 Nuclear Magnetic Resonance, Measuring solvent is CDCl3, it is inside designated as TMS, chemical shift is 10-6ppm。
Embodiment 1
(1) synthesis of the bromo- 1- of 2- (4- fluorophenyl) second -1- ketone
4- fluoro acetophenone (1.38g, 10mmol) is taken, using chloroform as reaction dissolvent, in Br2(1.91g, 12mmol) makees Under, 1h is stirred at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase saturated sodium bicarbonate, saturation food Salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.1g.
(2) synthesis of 1- (4- fluorophenyl) -2- (1H- imidazoles -1- base) second -1- ketone
The bromo- 1- of 2- (4- fluorophenyl) second -1- ketone crude product (2.1g, 9.67mmol) and imidazoles (1.31g, 19.35mmol) are molten In 50ml tetrahydrofuran, it is added potassium carbonate (2.67g, 19.35mmol), after 3h is stirred at room temperature, reaction solution is removed in vacuum, adds water, It is extracted with ethyl acetate.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel column chromatography separation (DCM:MeOH=100:1v/v) yellow solid 1.4g, yield 64.5% are obtained.
(3) synthesis of 1- (4- fluorophenyl) -2- (1H- imidazoles -1- base) second -1- alcohol
1- (4- fluorophenyl) -2- (1H- imidazoles -1- base) second -1- ketone (1.02g, 5mmol) is dissolved in 50ml anhydrous methanol, ice Bath is lower to be added sodium borohydride (378mg, 10mmol), and stirring flows back 2 hours again after one hour.End of reaction adds water quenching to go out, with second Acetoacetic ester extraction, merges organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for obtaining pale yellow colored solid Body 880mg, as product are not necessarily to additional purification, yield 86.7%.
(4) synthesis of 1- (2- (4- fluorophenyl) -2- ((3- methoxy-benzyl) oxygroup) ethyl) -1H- imidazoles
1- (4- fluorophenyl) -2- (1H- imidazoles -1- base) second -1- alcohol (206mg, 1mmol) is dissolved in 2mlDMF, ice bath 3- methoxybenzyl chloride is added after room temperature reaction 1 hour in 60% sodium hydride of lower addition (48mg, 1.2mmol) under ice bath (180mg, 1.2mmol), then react at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase is successively with saturation Salt washing, anhydrous sodium sulfate are dry, are spin-dried for, and silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 141mg (compound 6), yield 43.1%.TLC is detected as a bit, has fluorescence under ultraviolet lamp 254nm.1H NMR(300MHz, CDCl3) δ 7.44 (s, 1H), 7.28 (d, J=4.5Hz, 1H), 7.24 (s, 1H), 7.23 (s, 1H), 7.09 (t, J=8.5Hz, 2H), 7.04 (s, 1H), 6.90 (s, 1H), 6.84 (d, J=7.4Hz, 1H), 6.74 (d, J=7.2Hz, 2H), 4.55 (dd, J1 =7.3, J2=4.3Hz, 1H), 4.47 (d, J=11.8Hz, 1H), 4.21 (d, J=11.8Hz, 1H), 4.16 (d, J= 7.4Hz,1H),4.09(dd,J1=14.3Hz, J2=4.2Hz, 1H), 3.80 (s, 3H) .ESI:m/z [M+H]+,calcd.for C19H19FN2O2:327.1431；found 327.1503.
Embodiment 2
(1) synthesis of the bromo- 1- of 2- (2,4 difluorobenzene base) second -1- ketone
It takes 2,4- difluoro acetophenone (1.56g, 10mmol) to be dissolved in 100ml chloroform, Br is slowly added dropwise under ice bath2 (1.91g, 12mmol), drop finish, and stir 1h at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase saturation Sodium bicarbonate, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.3g.
(2) synthesis of 1- (2,4 difluorobenzene base) -2- (1H- imidazoles -1- base) second -1- ketone
The bromo- 1- of 2- (2,4 difluorobenzene base) second -1- ketone crude product (2.3g, 9.78mmol) and imidazoles (1.33g, It 19.57mmol) is dissolved in 50ml tetrahydrofuran, is added potassium carbonate (2.7g, 19.57mmol), after 3h is stirred at room temperature, is removed in vacuum anti- Liquid is answered, water is added, is extracted with ethyl acetate.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silicagel column Chromatography (DCM:MeOH=100:1v/v) obtains yellow solid 1.6g, yield 72.7%.
(3) synthesis of 1- (2,4 difluorobenzene base) -2- (1H- imidazoles -1- base) second -1- alcohol
1- (2,4- difluorophenyl) -2- (1H- imidazoles -1- base) second -1- ketone (1.1g, 5mmol) is dissolved in 50ml anhydrous methanol, Sodium borohydride (378mg, 10mmol) is added under ice bath, stirring flows back 2 hours again after one hour.End of reaction adds water quenching to go out, with Ethyl acetate extraction, merges organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for faint yellow Solid 920mg, as product are not necessarily to additional purification, yield 83.7%.
(4) synthesis of 1- (2- (2,4 difluorobenzene base) -2- ((3- methoxy-benzyl) oxygroup) ethyl) -1H- imidazoles
1- (2,4- difluorophenyl) -2- (1H- imidazoles -1- base) second -1- alcohol (222mg, 1mmol) is dissolved in 2mlDMF, ice Bath is lower to be added 60% sodium hydride (48mg, 1.2mmol), and after room temperature reaction 1 hour, 3- methoxybenzyl chloride is added under ice bath (180mg, 1.2mmol), then react at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase is successively with saturation Salt washing, anhydrous sodium sulfate are dry, are spin-dried for, and silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 145mg (compound 7), yield 42.1%.TLC is detected as a bit, has fluorescence under ultraviolet lamp 254nm.1H NMR(300MHz, CDCl3) δ 7.55 (s, 1H), 7.44 (s, 1H), 7.24 (t, J=8.0Hz, 1H), 7.15 (d, J=8.3Hz, 2H), 7.04 (s, 1H), 6.90 (s, 1H), 6.84 (d, J=7.3Hz, 1H), 6.73 (d, J=7.6Hz, 2H), 4.53 (dd, J1=7.2, J2= 4.3Hz, 1H), 4.48 (d, J=11.9Hz, 1H), 4.21 (d, J=11.9Hz, 1H), 4.15 (d, J=7.2Hz, 1H), 4.09 (dd,J1=14.3Hz, J2=4.4Hz, 1H), 3.80 (s, 3H) .ESI:m/z [M+H]+,calcd.for C19H18F2N2O2: 345.1336；found.345.1409.
Embodiment 3
(1) synthesis of the bromo- 1- of 2- (3,4- difluorophenyl) second -1- ketone
It takes 3,4- difluoro acetophenone (1.56g, 10mmol) to be dissolved in 100ml chloroform, Br is slowly added dropwise under ice bath2 (1.91g, 12mmol), drop finish, and stir 1h at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase saturation Sodium bicarbonate, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.3g.
(2) synthesis of 1- (3,4- difluorophenyl) -2- (1H- imidazoles -1- base) second -1- ketone
The bromo- 1- of 2- (3,4- difluorophenyl) second -1- ketone crude product (2.3g, 9.78mmol) and imidazoles (1.33g, It 19.57mmol) is dissolved in 50ml tetrahydrofuran, is added potassium carbonate (2.7g, 19.57mmol), after 3h is stirred at room temperature, is removed in vacuum anti- Liquid is answered, water is added, is extracted with ethyl acetate.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silicagel column Chromatography (DCM:MeOH=100:1v/v) obtains yellow solid 1.6g, yield 72.7%.
(3) synthesis of 1- (3,4- difluorophenyl) -2- (1H- imidazoles -1- base) second -1- alcohol
1- (3,4- difluorophenyl) -2- (1H- imidazoles -1- base) second -1- ketone (1.1g, 5mmol) is dissolved in 50ml anhydrous methanol, Sodium borohydride (378mg, 10mmol) is added under ice bath, stirring flows back 2 hours again after one hour.End of reaction adds water quenching to go out, with Ethyl acetate extraction, merges organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for faint yellow Solid 920mg, as product are not necessarily to additional purification, yield 83.7%.
(4) synthesis of 1- (2- (3,4- difluorophenyl) -2- ((3- methoxy-benzyl) oxygroup) ethyl) -1H- imidazoles
1- (2,4- difluorophenyl) -2- (1H- imidazoles -1- base) second -1- alcohol (222mg, 1mmol) is dissolved in 2mlDMF, ice Bath is lower to be added 60% sodium hydride (48mg, 1.2mmol), and after room temperature reaction 1 hour, 3- methoxybenzyl chloride is added under ice bath (180mg, 1.2mmol), then react at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase is successively with saturation Salt washing, anhydrous sodium sulfate are dry, are spin-dried for, and silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 170mg (compound 8), yield 48.5%.TLC is detected as a bit, has fluorescence under ultraviolet lamp 254nm.1H NMR(300MHz, CDCl3)δ7.43(s,1H),7.29–7.24(m,1H),7.23–7.17(m,1H),7.15–7.09(m,1H),7.04(s,1H), 7.01–6.94(m,1H),6.89(s,1H),6.87–6.82(m,1H),6.76–6.70(m,2H),4.55–4.52(m,1H), 4.49 (d, J=11.7Hz, 1H), 4.22 (d, J=11.9Hz, 1H), 4.14 (d, J=7.2Hz, 1H), 4.08 (dd, J1= 14.3Hz,J2=4.4Hz, 1H), 3.80 (s, 3H) .ESI:m/z [M+H]+,calcd.for C19H18F2N2O2:345.1336； found.345.1421
Embodiment 4
(1) synthesis of the bromo- 1- of 2- (4- chlorphenyl) second -1- ketone
It takes 4- chloro-acetophenone (1.54g, 10mmol) to be dissolved in 100ml chloroform, Br is slowly added dropwise under ice bath2(1.91g, 12mmol), drop finishes, and stirs 1h at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase unsaturated carbonate hydrogen Sodium, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.3g.
(2) synthesis of 1- (4- chlorphenyl) -2- (1H- imidazoles -1- base) second -1- ketone
The bromo- 1- of 2- (4- chlorphenyl) second -1- ketone crude product (2.3g, 9.87mmol) and imidazoles (1.34g, 19.7mmol) are dissolved in 50ml tetrahydrofuran is added potassium carbonate (2.7g, 19.7mmol), after 3h is stirred at room temperature, reaction solution is removed in vacuum, adds water, with second Acetoacetic ester extraction.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel column chromatography separation (DCM: MeOH=100:1v/v yellow solid 1.6g, yield 72.7%) are obtained.
(3) synthesis of 1- (4- chlorphenyl) -2- (1H- imidazoles -1- base) second -1- alcohol
1- (4- chlorphenyl) -2- (1H- imidazoles -1- base) second -1- ketone (1.1g, 5mmol) is dissolved in 50ml anhydrous methanol, ice bath Lower addition sodium borohydride (378mg, 10mmol), stirring flow back 2 hours again after one hour.End of reaction adds water quenching to go out, with acetic acid Ethyl ester extraction, merges organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for obtaining faint yellow solid 980mg, as product are not necessarily to additional purification, yield 89.1%.
(4) synthesis of 1- (2- (4- chlorphenyl) -2- ((3- methoxy-benzyl) oxygroup) ethyl) -1H- imidazoles
1- (4- chlorphenyl) -2- (1H- imidazoles -1- base) second -1- alcohol (222mg, 1mmol) is dissolved in 2mlDMF, under ice bath Be added 60% sodium hydride (48mg, 1.2mmol), room temperature reaction 1 hour after, under ice bath be added 3- methoxybenzyl chloride (180mg, 1.2mmol), it then reacts at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase successively uses saturated salt solution It washes, anhydrous sodium sulfate drying, is spin-dried for, silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 160mg (change Close object 9), yield 47.8%.TLC is detected as a bit, has fluorescence under ultraviolet lamp 254nm.1H NMR(300MHz,CDCl3)δ7.45 (s, 1H), 7.38 (d, J=8.1Hz, 2H), 7.26 (d, J=8.4Hz, 1H), 7.21 (d, J=8.1Hz, 2H), 7.04 (s, 1H), 6.90 (s, 1H), 6.84 (d, J=8.6Hz, 1H), 6.73 (d, J=7.4Hz, 2H), 4.54 (dd, J1=7.0Hz, J2= 4.5Hz, 1H), 4.47 (d, J=11.8Hz, 1H), 4.21 (d, J=12.0Hz, 1H), 4.15 (d, J=7.4Hz, 1H), 4.09 (dd,J1=14.3Hz, J2=4.2Hz, 1H), 3.80 (s, 3H) .ESI:m/z [M+H]+,calcd.for C19H19ClN2O2: 343.1135；found.343.1218
Embodiment 5
(1) synthesis of the bromo- 1- of 2- (3- chlorphenyl) second -1- ketone
It takes 3- chloro-acetophenone (1.54g, 10mmol) to be dissolved in 100ml chloroform, Br is slowly added dropwise under ice bath2(1.91g, 12mmol), drop finishes, and stirs 1h at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase unsaturated carbonate hydrogen Sodium, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.3g.
(2) synthesis of 1- (3- chlorphenyl) -2- (1H- imidazoles -1- base) second -1- ketone
The bromo- 1- of 2- (3- chlorphenyl) second -1- ketone crude product (2.3g, 9.87mmol) and imidazoles (1.34g, 19.7mmol) are dissolved in 50ml tetrahydrofuran is added potassium carbonate (2.7g, 19.7mmol), after 3h is stirred at room temperature, reaction solution is removed in vacuum, adds water, with second Acetoacetic ester extraction.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel column chromatography separation (DCM: MeOH=100:1v/v yellow solid 1.6g, yield 72.7%) are obtained.
(3) synthesis of 1- (3- chlorphenyl) -2- (1H- imidazoles -1- base) second -1- alcohol
1- (3- chlorphenyl) -2- (1H- imidazoles -1- base) second -1- ketone (1.1g, 5mmol) is dissolved in 50ml anhydrous methanol, ice bath Lower addition sodium borohydride (378mg, 10mmol), stirring flow back 2 hours again after one hour.End of reaction adds water quenching to go out, with acetic acid Ethyl ester extraction, merges organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for obtaining faint yellow solid 980mg, as product are not necessarily to additional purification, yield 89.1%.
(4) synthesis of 1- (2- (3- chlorphenyl) -2- ((3- methoxy-benzyl) oxygroup) ethyl) -1H- imidazoles
1- (3- chlorphenyl) -2- (1H- imidazoles -1- base) second -1- alcohol (222mg, 1mmol) is dissolved in 2mlDMF, under ice bath Be added 60% sodium hydride (48mg, 1.2mmol), room temperature reaction 1 hour after, under ice bath be added 3- methoxybenzyl chloride (180mg, 1.2mmol), it then reacts at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase successively uses saturated salt solution It washes, anhydrous sodium sulfate drying, is spin-dried for, silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 199mg (change Close object 10), yield 58.1%.TLC is detected as a bit, has fluorescence under ultraviolet lamp 254nm.1H NMR(300MHz,CDCl3)δ7.47 (s, 1H), 7.36 (d, J=2.0Hz, 1H), 7.35-7.30 (m, 2H), 7.24 (t, J=8.1Hz, 1H), 7.15 (ddd, J1= 3.7Hz,J2=2.8Hz, J3=1.5Hz, 1H), 7.05 (s, 1H), 6.92 (t, J=1.1Hz, 1H), 6.87-6.81 (m, 1H), 6.73 (t, J=4.1Hz, 2H), 4.56-4.53 (m, 1H), 4.50 (d, J=11.7Hz, 1H), 4.23 (d, J=11.9Hz, 1H), 4.16 (d, J=7.6Hz, 1H), 4.09 (dd, J1=14.3Hz, J2=4.1Hz, 1H) .ESI:m/z [M+H]+, calcd.for C19H19ClN2O2:343.1135；found.343.1206
Embodiment 6
(1) synthesis of the bromo- 1- of 2- (2- chlorphenyl) second -1- ketone
It takes 2- chloro-acetophenone (1.54g, 10mmol) to be dissolved in 100ml chloroform, Br is slowly added dropwise under ice bath2(1.91g, 12mmol), drop finishes, and stirs 1h at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase unsaturated carbonate hydrogen Sodium, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.3g.
(2) synthesis of 1- (2- chlorphenyl) -2- (1H- imidazoles -1- base) second -1- ketone
The bromo- 1- of 2- (2- chlorphenyl) second -1- ketone crude product (2.3g, 9.87mmol) and imidazoles (1.34g, 19.7mmol) are dissolved in 50ml tetrahydrofuran is added potassium carbonate (2.7g, 19.7mmol), after 3h is stirred at room temperature, reaction solution is removed in vacuum, adds water, with second Acetoacetic ester extraction.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel column chromatography separation (DCM: MeOH=100:1v/v yellow solid 1.6g, yield 72.7%) are obtained.
(3) synthesis of 1- (2- chlorphenyl) -2- (1H- imidazoles -1- base) second -1- alcohol
1- (2- chlorphenyl) -2- (1H- imidazoles -1- base) second -1- ketone (1.1g, 5mmol) is dissolved in 50ml anhydrous methanol, ice bath Lower addition sodium borohydride (378mg, 10mmol), stirring flow back 2 hours again after one hour.End of reaction adds water quenching to go out, with acetic acid Ethyl ester extraction, merges organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for obtaining faint yellow solid 980mg, as product are not necessarily to additional purification, yield 89.1%.
(4) synthesis of 1- (2- (2- chlorphenyl) -2- ((3- methoxy-benzyl) oxygroup) ethyl) -1H- imidazoles
1- (2- chlorphenyl) -2- (1H- imidazoles -1- base) second -1- alcohol (222mg, 1mmol) is dissolved in 2mlDMF, under ice bath Be added 60% sodium hydride (48mg, 1.2mmol), room temperature reaction 1 hour after, under ice bath be added 3- methoxybenzyl chloride (180mg, 1.2mmol), it then reacts at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase successively uses saturated salt solution It washes, anhydrous sodium sulfate drying, is spin-dried for, silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 130mg (change Close object 11), yield 38.1%.TLC is detected as a bit, has fluorescence under ultraviolet lamp 254nm.1H NMR(300MHz,CDCl3)δ7.51 (s, 1H), 7.48-7.41 (m, 2H), 7.35-7.33 (m, 1H), 7.31 (dd, J=3.4,1.7Hz, 1H), 7.28 (s, 1H), 5.06 (dd, J=7.8,2.8Hz, 1H), 4.49 (d, J=11.6Hz, 1H), 4.26 (d, J=3.9Hz, 1H), 4.24-4.20 (m, 1H), 4.08 (dd, J=14.4,7.8Hz, 1H), 3.81 (s, 3H) .ESI:m/z [M+H]+,calcd.for C19H19ClN2O2:343.1135；found.343.1202
Embodiment 7
(1) synthesis of the bromo- 1- of 2- (3,4- dichlorophenyl) second -1- ketone
It takes 3,4- dichloroacetophenone (1.89g, 10mmol) to be dissolved in 100ml chloroform, Br is slowly added dropwise under ice bath2 (1.91g, 12mmol), drop finish, and stir 1h at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase saturation Sodium bicarbonate, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.5g.
(2) synthesis of 1- (3,4- dichlorophenyl) -2- (1H- imidazoles -1- base) second -1- ketone
The bromo- 1- of 2- (3,4- dichlorophenyl) second -1- ketone crude product (2.5g, 9.36mmol) and imidazoles (1.27g, 18.7mmol) It is dissolved in 50ml tetrahydrofuran, is added potassium carbonate (2.58g, 18.7mmol), after 3h is stirred at room temperature, reaction solution is removed in vacuum, adds water, It is extracted with ethyl acetate.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel column chromatography separation (DCM:MeOH=100:1v/v) yellow solid 1.4g, yield 54.7% are obtained.
(3) synthesis of 1- (3,4- dichlorophenyl) -2- (1H- imidazoles -1- base) second -1- alcohol
1- (3,4- dichlorophenyl) -2- (1H- imidazoles -1- base) second -1- ketone (1.29g, 5mmol) is dissolved in 50ml without water beetle Sodium borohydride (378mg, 10mmol) is added under ice bath in alcohol, and stirring flows back 2 hours again after one hour.End of reaction adds water quenching It goes out, is extracted with ethyl acetate, merge organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for Faint yellow solid 900mg, as product are not necessarily to additional purification, yield 69.7%.
(4) synthesis of 1- (2- (3,4- dichlorophenyl) -2- ((3- methoxy-benzyl) oxygroup) ethyl) -1H- imidazoles
1- (3,4- dichlorophenyl) -2- (1H- imidazoles -1- base) second -1- alcohol (257mg, 1mmol) is dissolved in 2mlDMF, ice Bath is lower to be added 60% sodium hydride (48mg, 1.2mmol), and after room temperature reaction 1 hour, 3- methoxybenzyl chloride is added under ice bath (180mg, 1.2mmol), then react at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase is successively with saturation Salt washing, anhydrous sodium sulfate are dry, are spin-dried for, and silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 160mg (compound 12), yield 42.4%.TLC is detected as a bit, has fluorescence under ultraviolet lamp 254nm.1H NMR(300MHz, CDCl3) δ 7.47 (d, J=8.1Hz, 1H), 7.41 (d, J=2.0Hz, 1H), 7.25 (t, J=7.9Hz, 1H), 7.09 (dd, J =8.3,2.0Hz, 1H), 7.06 (s, 1H), 6.90 (s, 1H), 6.88-6.82 (m, 1H), 6.72 (d, J=7.1Hz, 1H), 4.55-4.51 (m, 1H), 4.49 (d, J=8.7Hz, 1H), 4.22 (d, J=14.0Hz, 1H), 4.14 (d, J=7.3Hz, 1H), 4.09(dd,J1=14.4Hz, J2=4.3Hz, 1H), 3.80 (s, 2H) .ESI:m/z [M+H]+,calcd.for C19H18Cl2N2O2:377.0745；found.377.0822
Embodiment 8
(1) synthesis of the bromo- 1- of 2- (2,4- dichloro, 5- fluorophenyl) second -1- ketone
2,4- dichloro is taken, 5- fluoro acetophenone (2.07g, 10mmol) is dissolved in 100ml chloroform, is slowly added dropwise under ice bath Br2(1.91g, 12mmol), drop finish, and stir 1h at room temperature, and after reaction, saturated sodium sulfite quenching reaction, organic phase is used Saturated sodium bicarbonate, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.85g.
(2) synthesis of 1- (2,4- dichloro, 5- fluorophenyl) -2- (1H- imidazoles -1- base) second -1- ketone
The bromo- 1- of 2- (2,4- dichloro, 5- fluorophenyl) second -1- ketone crude product (2.85g, 10mmol) and imidazoles (1.36g, It 20mmol) is dissolved in 50ml tetrahydrofuran, is added potassium carbonate (2.76g, 20mmol), after 3h is stirred at room temperature, reaction solution is removed in vacuum, Add water, is extracted with ethyl acetate.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel column chromatography Separation (DCM:MeOH=100:1v/v) obtains yellow solid 1.8g, yield 65.9%.
(3) synthesis of 1- (2,4- dichloro, 5- fluorophenyl) -2- (1H- imidazoles -1- base) second -1- alcohol
1- (2,4- dichloros, 5- fluorophenyl) -2- (1H- imidazoles -1- base) second -1- ketone (1.37g, 5mmol) be dissolved in 50ml without Sodium borohydride (378mg, 10mmol) is added under ice bath in water methanol, and stirring flows back 2 hours again after one hour.End of reaction adds water It is quenched, is extracted with ethyl acetate, merge organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for Faint yellow solid 1.27mg, as product are obtained, additional purification, yield 92.7% are not necessarily to.
(4) synthesis of 1- (2- (2,4- dichloro, 5- fluorophenyl) -2- ((3- methoxy-benzyl) oxygroup) ethyl) -1H- imidazoles
1- (2,4- dichloro, 5- fluorophenyl) -2- (1H- imidazoles -1- base) second -1- alcohol (275mg, 1mmol) is dissolved in 2mlDMF In, it is added under ice bath 60% sodium hydride (48mg, 1.2mmol), after room temperature reaction 1 hour, the chlorination of 3- methoxyl group is added under ice bath Benzyl (180mg, 1.2mmol), then react at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase is successively with full It is dry with salt washing, anhydrous sodium sulfate, it is spin-dried for, silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 120mg (compound 13), yield 30.3%.TLC is detected as a bit, has fluorescence under ultraviolet lamp 254nm.1H NMR(300MHz, CDCl3) δ 7.50 (d, J=6.4Hz, 1H), 7.28 (d, J=2.5Hz, 1H), 7.26-7.22 (m, 1H), 7.06 (s, 1H), 6.93 (s, 1H), 6.86 (dd, J=8.3,2.5Hz, 1H), 6.74 (t, J=5.4Hz, 1H), 4.95 (dd, J1=7.5Hz, J2= 2.4Hz, 1H), 4.49 (d, J=11.6Hz, 1H), 4.25 (d, J=11.8Hz, 1H), 4.20 (dd, J1=14.6Hz, J2= 2.9Hz,1H),4.05(dd,J1=14.5Hz, J2=7.6Hz, 1H), 3.81 (s, 2H) .ESI:m/z [M+H]+,calcd.for C19H17Cl2FN2O2:395.0651；found.395.0721
Embodiment 9
(1) synthesis of the bromo- 1- of 2- (4- bromophenyl) second -1- ketone
It takes 4- bromoacetophenone (1.99g, 10mmol) to be dissolved in 100ml chloroform, Br is slowly added dropwise under ice bath2(1.91g, 12mmol), drop finishes, and stirs 1h at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase unsaturated carbonate hydrogen Sodium, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.78g.
(2) synthesis of 1- (4- bromophenyl) -2- (1H- imidazoles -1- base) second -1- ketone
The bromo- 1- of 2- (4- bromophenyl) second -1- ketone crude product (2.78g, 10mmol) and imidazoles (1.36g, 20mmol) are dissolved in 50ml tetrahydrofuran is added potassium carbonate (2.76g, 20mmol), after 3h is stirred at room temperature, reaction solution is removed in vacuum, adds water, with acetic acid Ethyl ester extraction.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel column chromatography separation (DCM: MeOH=100:1v/v yellow solid 2.0g, yield 74.9%) are obtained.
(3) synthesis of 1- (4- bromophenyl) -2- (1H- imidazoles -1- base) second -1- alcohol
1- (4- bromophenyl) -2- (1H- imidazoles -1- base) second -1- ketone (1.36g, 5mmol) is dissolved in 50ml anhydrous methanol, ice Bath is lower to be added sodium borohydride (378mg, 10mmol), and stirring flows back 2 hours again after one hour.End of reaction adds water quenching to go out, with second Acetoacetic ester extraction, merges organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for obtaining pale yellow colored solid Body 1.27g, as product are not necessarily to additional purification, yield 92.7%.
(4) synthesis of 1- (2- (4- bromophenyl) -2- ((3- methoxy-benzyl) oxygroup) ethyl) -1H- imidazoles
1- (4- bromophenyl) -2- (1H- imidazoles -1- base) second -1- alcohol (267mg, 1mmol) is dissolved in 2mlDMF, under ice bath Be added 60% sodium hydride (48mg, 1.2mmol), room temperature reaction 1 hour after, under ice bath be added 3- methoxybenzyl chloride (180mg, 1.2mmol), it then reacts at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase successively uses saturated salt solution It washes, anhydrous sodium sulfate drying, is spin-dried for, silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 170mg (change Close object 14), yield 43.9%.TLC is detected as a bit, has fluorescence under ultraviolet lamp 254nm.1H NMR(300MHz,CDCl3)δ7.47 (s, 1H), 7.31 (d, J=6.6Hz, 1H), 7.29 (s, 1H), 7.24 (d, J=7.6Hz, 1H), 7.04 (s, 1H), 6.94 (d, J =7.5Hz, 2H), 6.87 (s, 1H), 6.84 (s, 1H), 4.92 (dd, J1=6.7Hz, J2=4.1Hz, 1H), 4.48 (d, J= 11.7Hz, 1H), 4.26 (d, J=11.7Hz, 1H), 4.20 (d, J=10.6Hz, 1H), 4.14 (dd, J1=13.8Hz, J2= 6.5Hz,2H),3.81(s,3H).ESI:m/z[M+H]+,calcd.for C19H19BrN2O2:389.0630； found.389.0691
Embodiment 10
(1) synthesis of the bromo- 1- of 2- (3- bromophenyl) second -1- ketone
It takes 3- bromoacetophenone (1.99g, 10mmol) to be dissolved in 100ml chloroform, Br is slowly added dropwise under ice bath2(1.91g, 12mmol), drop finishes, and stirs 1h at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase unsaturated carbonate hydrogen Sodium, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.78g.
(2) synthesis of 1- (3- bromophenyl) -2- (1H- imidazoles -1- base) second -1- ketone
The bromo- 1- of 2- (3- bromophenyl) second -1- ketone crude product (2.78g, 10mmol) and imidazoles (1.36g, 20mmol) are dissolved in 50ml tetrahydrofuran is added potassium carbonate (2.76g, 20mmol), after 3h is stirred at room temperature, reaction solution is removed in vacuum, adds water, with acetic acid Ethyl ester extraction.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel column chromatography separation (DCM: MeOH=100:1v/v yellow solid 1.6g, yield 61.5%) are obtained.
(3) synthesis of 1- (3- bromophenyl) -2- (1H- imidazoles -1- base) second -1- alcohol
1- (3- bromophenyl) -2- (1H- imidazoles -1- base) second -1- ketone (1.36g, 5mmol) is dissolved in 50ml anhydrous methanol, ice Bath is lower to be added sodium borohydride (378mg, 10mmol), and stirring flows back 2 hours again after one hour.End of reaction adds water quenching to go out, with second Acetoacetic ester extraction, merges organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for obtaining pale yellow colored solid Body 1.2g, as product are not necessarily to additional purification, yield 88.2%.
(4) synthesis of 1- (2- (3- bromophenyl) -2- ((3- methoxy-benzyl) oxygroup) ethyl) -1H- imidazoles
1- (3- bromophenyl) -2- (1H- imidazoles -1- base) second -1- alcohol (267mg, 1mmol) is dissolved in 2mlDMF, under ice bath Be added 60% sodium hydride (48mg, 1.2mmol), room temperature reaction 1 hour after, under ice bath be added 3- methoxybenzyl chloride (180mg, 1.2mmol), it then reacts at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase successively uses saturated salt solution It washes, anhydrous sodium sulfate drying, is spin-dried for, silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 150mg (change Close object 15), yield 38.9%.1H NMR(300MHz,CDCl3) δ 7.54-7.50 (m, 1H), 7.48 (t, J=1.7Hz, 1H), 7.46(s,1H),7.29–7.23(m,2H),7.19(dt,J1=7.7Hz, J2=1.2Hz, 1H), 7.05 (s, 1H), 6.91 (t, J =1.2Hz, 1H), 6.88-6.82 (m, 1H), 6.73 (t, J=4.1Hz, 2H), 4.55-4.51 (m, 1H), 4.49 (d, J= 7.6Hz, 1H), 4.23 (d, J=11.9Hz, 1H), 4.17 (t, J=7.2Hz, 1H), 4.09 (dd, J1=14.3Hz, J2= 4.1Hz,1H),3.80(s,3H).ESI:m/z[M+H]+,calcd.for C19H19BrN2O2:387.0630； found.387.0698
Embodiment 11
(1) synthesis of the bromo- 1- of 2- (4- tert-butyl-phenyl) second -1- ketone
It takes 4- tert-butylacetophenone (1.76g, 10mmol) to be dissolved in 100ml chloroform, Br is slowly added dropwise under ice bath2 (1.91g, 12mmol), drop finish, and stir 1h at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase saturation Sodium bicarbonate, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.55g.
(2) synthesis of 1- (4- tert-butyl-phenyl) -2- (1H- imidazoles -1- base) second -1- ketone
The bromo- 1- of 2- (4- tert-butyl-phenyl) second -1- ketone crude product (2.55g, 10mmol) and imidazoles (1.36g, 20mmol) are molten In 50ml tetrahydrofuran, it is added potassium carbonate (2.76g, 20mmol), after 3h is stirred at room temperature, reaction solution is removed in vacuum, adds water, with second Acetoacetic ester extraction.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel column chromatography separation (DCM: MeOH=100:1v/v white solid 1.5g, yield 62.0%) are obtained.
(3) synthesis of 1- (4- tert-butyl-phenyl) -2- (1H- imidazoles -1- base) second -1- alcohol
1- (4- tert-butyl-phenyl) -2- (1H- imidazoles -1- base) second -1- ketone (1.21g, 5mmol) is dissolved in 50ml without water beetle Sodium borohydride (378mg, 10mmol) is added under ice bath in alcohol, and stirring flows back 2 hours again after one hour.End of reaction adds water quenching It goes out, is extracted with ethyl acetate, merge organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for Faint yellow solid 1.0g, as product are not necessarily to additional purification, yield 83.3%.
(4) synthesis of 1- (2- ((3- methoxy-benzyl) oxygroup) -2- (4- tert-butyl-phenyl) ethyl) -1H- imidazoles
1- (3- bromophenyl) -2- (1H- imidazoles -1- base) second -1- alcohol (244mg, 1mmol) is dissolved in 2mlDMF, under ice bath Be added 60% sodium hydride (48mg, 1.2mmol), room temperature reaction 1 hour after, under ice bath be added 3- methoxybenzyl chloride (180mg, 1.2mmol), it then reacts at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase successively uses saturated salt solution It washes, anhydrous sodium sulfate drying, is spin-dried for, silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 199mg (change Close object 16), yield 54.4%.1H NMR(300MHz,CDCl3) δ 7.48 (s, 1H), 7.43 (d, J=8.3Hz, 2H), 7.27 (d, J=10.3Hz, 2H), 7.24-7.22 (m, 2H), 7.05 (s, 1H), 6.96 (s, 1H), 6.83 (dd, J1=9.0Hz, J2= 1.7Hz,1H),6.77–6.72(m,3H),4.54(dd,J1=8.1Hz, J2=3.8Hz, 1H), 4.49 (d, J=11.9Hz, 1H), 4.22 (d, J=8.2Hz, 1H), 4.20-4.15 (m, 1H), 4.08 (dd, J1=14.3Hz, J2=3.8Hz, 1H), 3.79 (s,3H),1.36(s,9H).ESI:m/z[M+H]+,calcd.for C23H28N2O2:365.2151；found.365.2227
Embodiment 12
(1) synthesis of the bromo- 1- of 2- (4- methoxyphenyl) second -1- ketone
It takes 4- methoxyacetophenone (1.5g, 10mmol) to be dissolved in 100ml chloroform, Br is slowly added dropwise under ice bath2 (1.91g, 12mmol), drop finish, and stir 1h at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase saturation Sodium bicarbonate, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.29g.
(2) synthesis of 1- (4- methoxyphenyl) -2- (1H- imidazoles -1- base) second -1- ketone
The bromo- 1- of 2- (4- methoxyphenyl) second -1- ketone crude product (2.29g, 10mmol) and imidazoles (1.36g, 20mmol) are molten In 50ml tetrahydrofuran, it is added potassium carbonate (2.76g, 20mmol), after 3h is stirred at room temperature, reaction solution is removed in vacuum, adds water, with second Acetoacetic ester extraction.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel column chromatography separation (DCM: MeOH=100:1v/v white solid 1.9g, yield 87.9%) are obtained.
(3) synthesis of 1- (4- methoxyphenyl) -2- (1H- imidazoles -1- base) second -1- alcohol
1- (4- methoxyphenyl) -2- (1H- imidazoles -1- base) second -1- ketone (1.09g, 5mmol) is dissolved in 50ml without water beetle Sodium borohydride (378mg, 10mmol) is added under ice bath in alcohol, and stirring flows back 2 hours again after one hour.End of reaction adds water quenching It goes out, is extracted with ethyl acetate, merge organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for Faint yellow solid 1.1g, as product are not necessarily to additional purification, yield 90.2%.
(4) synthesis of 1- (2- ((3- methoxy-benzyl) oxygroup) -2- (4- methoxyphenyl) ethyl) -1H- imidazoles
1- (4- methoxyphenyl) -2- (1H- imidazoles -1- base) second -1- alcohol (218mg, 1mmol) is dissolved in 2mlDMF, ice Bath is lower to be added 60% sodium hydride (48mg, 1.2mmol), and after room temperature reaction 1 hour, 3- methoxybenzyl chloride is added under ice bath (180mg, 1.2mmol), then react at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase is successively with saturation Salt washing, anhydrous sodium sulfate are dry, are spin-dried for, and silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 210mg (compound 17), yield 62.1%.1H NMR(300MHz,CDCl3) δ 7.24 (d, J=7.9Hz, 1H), 7.21-7.17 (m, 2H), 6.91 (d, J=2.0Hz, 2H), 6.89-6.80 (m, 2H), 6.75-6.71 (m, 2H), 6.70-6.67 (m, 1H), 4.51(dd,J1=7.6Hz, J2=4.2Hz, 1H), 4.46 (d, J=11.9Hz, 1H), 4.21 (t, J=3.7Hz, 1H), 4.17 (d, J=7.8Hz, 1H), 4.08 (dd, J1=14.2Hz, J2=4.2Hz, 1H), 3.83 (s, 2H), 3.78 (s, 3H) .ESI:m/z [M+H]+,calcd.for C20H22N2O3:339.1630；found.339.1707
Embodiment 13
(1) synthesis of the bromo- 1- of 2- (4- trifluoromethyl) second -1- ketone
It takes 4- trifluoromethyl acetophenone (1.88g, 10mmol) to be dissolved in 100ml chloroform, Br is slowly added dropwise under ice bath2 (1.91g, 12mmol), drop finish, and stir 1h at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase saturation Sodium bicarbonate, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.67g.
(2) synthesis of 1- (4- trifluoromethyl) -2- (1H- imidazoles -1- base) second -1- ketone
The bromo- 1- of 2- (4- trifluoromethyl) second -1- ketone crude product (2.67g, 10mmol) and imidazoles (1.36g, 20mmol) It is dissolved in 50ml tetrahydrofuran, is added potassium carbonate (2.76g, 20mmol), after 3h is stirred at room temperature, reaction solution is removed in vacuum, adds water, with Ethyl acetate extraction.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel column chromatography separation (DCM:MeOH=100:1v/v) white solid 1.7g, yield 66.9% are obtained.
(3) synthesis of 1- (4- trifluoromethyl) -2- (1H- imidazoles -1- base) second -1- alcohol
1- (4- trifluoromethyl) -2- (1H- imidazoles -1- base) second -1- ketone (1.27g, 5mmol) is dissolved in 50ml without water beetle Sodium borohydride (378mg, 10mmol) is added under ice bath in alcohol, and stirring flows back 2 hours again after one hour.End of reaction adds water quenching It goes out, is extracted with ethyl acetate, merge organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for Faint yellow solid 1.08g, as product are not necessarily to additional purification, yield 85.0%.
(4) synthesis of 1- (2- ((3- methoxy-benzyl) oxygroup) -2- (4- trifluoromethyl) ethyl) -1H- imidazoles
1- (4- trifluoromethyl) -2- (1H- imidazoles -1- base) second -1- alcohol (256mg, 1mmol) is dissolved in 2mlDMF, It is added under ice bath 60% sodium hydride (48mg, 1.2mmol), after room temperature reaction 1 hour, 3- methoxybenzyl chloride is added under ice bath (180mg, 1.2mmol), then react at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase is successively with saturation Salt washing, anhydrous sodium sulfate are dry, are spin-dried for, and silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 221mg (compound 18), yield 58.9%.1H NMR(300MHz,CDCl3) δ 7.66 (d, J=8.1Hz, 1H), 7.42 (d, J= 5.3Hz,1H),7.39(s,1H),7.29–7.21(m,1H),7.04(s,1H),6.90(s,1H),6.87–6.82(m,1H), 6.76–6.71(m,1H),4.64(dd,J1=7.0Hz, J2=4.4Hz, 1H), 4.49 (d, J=11.8Hz, 1H), 4.24 (d, J =11.8Hz, 1H), 4.17 (d, J=7.3Hz, 1H), 4.12 (dd, J1=14.4Hz, J2=4.5Hz, 1H), 3.79 (s, 3H) .ESI:m/z[M+H]+,calcd.for C20H19F3N2O2:377.1399；found 377.1468
Embodiment 14
(1) synthesis of the bromo- 1- of 2- (4- aminomethyl phenyl) second -1- ketone
It takes 4- methyl acetophenone (1.34g, 10mmol) to be dissolved in 100ml chloroform, Br is slowly added dropwise under ice bath2 (1.91g, 12mmol), drop finish, and stir 1h at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase saturation Sodium bicarbonate, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.13g.
(2) synthesis of 1- (4- aminomethyl phenyl) -2- (1H- imidazoles -1- base) second -1- ketone
The bromo- 1- of 2- (4- aminomethyl phenyl) second -1- ketone crude product (2.13g, 10mmol) and imidazoles (1.36g, 20mmol) are dissolved in 50ml tetrahydrofuran is added potassium carbonate (2.76g, 20mmol), after 3h is stirred at room temperature, reaction solution is removed in vacuum, adds water, with acetic acid Ethyl ester extraction.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel column chromatography separation (DCM: MeOH=100:1v/v white solid 1.5g, yield 75.1%) are obtained.
(3) synthesis of 1- (4- aminomethyl phenyl) -2- (1H- imidazoles -1- base) second -1- alcohol
1- (4- aminomethyl phenyl) -2- (1H- imidazoles -1- base) second -1- ketone (1.0g, 5mmol) is dissolved in 50ml anhydrous methanol, ice Bath is lower to be added sodium borohydride (378mg, 10mmol), and stirring flows back 2 hours again after one hour.End of reaction adds water quenching to go out, with second Acetoacetic ester extraction, merges organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for obtaining pale yellow colored solid Body 900mg, as product are not necessarily to additional purification, yield 90.0%.
(4) synthesis of 1- (2- ((3- methoxy-benzyl) oxygroup) -2- (4- aminomethyl phenyl) ethyl) -1H- imidazoles
1- (4- aminomethyl phenyl) -2- (1H- imidazoles -1- base) second -1- alcohol (202mg, 1mmol) is dissolved in 2mlDMF, ice bath 3- methoxybenzyl chloride is added after room temperature reaction 1 hour in 60% sodium hydride of lower addition (48mg, 1.2mmol) under ice bath (180mg, 1.2mmol), then react at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase is successively with saturation Salt washing, anhydrous sodium sulfate are dry, are spin-dried for, and silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 120mg (compound 19), yield 37.1%.1H NMR(300MHz,CDCl3)δ7.45(s,1H),7.24(s,1H),7.21(s, 2H), 7.18 (d, J=8.2Hz, 2H), 7.04 (s, 1H), 6.94 (s, 1H), 6.83 (d, J=7.5Hz, 1H), 6.74 (d, J= 6.8Hz,2H),4.53(dd,J1=7.8Hz, J2=4.0Hz, 1H), 4.48 (d, J=11.9Hz, 1H), 4.22 (d, J= 6.1Hz, 1H), 4.18 (d, J=8.0Hz, 1H), 4.08 (dd, J1=14.2Hz, J2=4.1Hz, 1H), 3.80 (s, 3H), 2.40 (s,3H).ESI:m/z[M+H]+,calcd.for C20H122N2O2:323.1681；found.323.1753.
Embodiment 15
(1) synthesis of the bromo- 1- of 2- (2- aminomethyl phenyl) second -1- ketone
It takes 3- methyl acetophenone (1.34g, 10mmol) to be dissolved in 100ml chloroform, Br is slowly added dropwise under ice bath2 (1.91g, 12mmol), drop finish, and stir 1h at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase saturation Sodium bicarbonate, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.13g.
(2) synthesis of 1- (3- aminomethyl phenyl) -2- (1H- imidazoles -1- base) second -1- ketone
The bromo- 1- of 2- (3- aminomethyl phenyl) second -1- ketone crude product (2.13g, 10mmol) and imidazoles (1.36g, 20mmol) are dissolved in 50ml tetrahydrofuran is added potassium carbonate (2.76g, 20mmol), after 3h is stirred at room temperature, reaction solution is removed in vacuum, adds water, with acetic acid Ethyl ester extraction.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel column chromatography separation (DCM: MeOH=100:1v/v white solid 1.5g, yield 75.1%) are obtained.
(3) synthesis of 1- (3- aminomethyl phenyl) -2- (1H- imidazoles -1- base) second -1- alcohol
1- (4- aminomethyl phenyl) -2- (1H- imidazoles -1- base) second -1- ketone (1.0g, 5mmol) is dissolved in 50ml anhydrous methanol, ice Bath is lower to be added sodium borohydride (378mg, 10mmol), and stirring flows back 2 hours again after one hour.End of reaction adds water quenching to go out, with second Acetoacetic ester extraction, merges organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for obtaining pale yellow colored solid Body 880mg, as product are not necessarily to additional purification, yield 88.0%.
(4) synthesis of 1- (2- ((3- methoxy-benzyl) oxygroup) -2- (3- aminomethyl phenyl) ethyl) -1H- imidazoles
1- (3- aminomethyl phenyl) -2- (1H- imidazoles -1- base) second -1- alcohol (202mg, 1mmol) is dissolved in 2mlDMF, ice bath 3- methoxybenzyl chloride is added after room temperature reaction 1 hour in 60% sodium hydride of lower addition (48mg, 1.2mmol) under ice bath (180mg, 1.2mmol), then react at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase is successively with saturation Salt washing, anhydrous sodium sulfate are dry, are spin-dried for, and silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 134mg (compound 20), yield 41.4%.1H NMR(300MHz,CDCl3)δ7.46(s,1H),7.29(s,2H),7.20(s, 1H), 7.11 (s, 2H), 7.04 (s, 1H), 6.92 (s, 1H), 6.85 (s, 1H), 6.75 (s, 2H), 4.50 (d, J=12.3Hz, 2H), 4.25 (s, 1H), 4.19 (d, J=13.8Hz, 1H), 4.11 (s, 1H), 3.80 (s, 3H), 2.39 (s, 3H) .ESI:m/z [M+H]+,calcd.for C20H22N2O2:323.1681；found.323.1753
Embodiment 16
(1) synthesis of the bromo- 1- of 2- (2,5- 3,5-dimethylphenyl) second -1- ketone
It takes 2,5- dimethyl acetophenone (1.48g, 10mmol) to be dissolved in 100ml chloroform, Br is slowly added dropwise under ice bath2 (1.91g, 12mmol), drop finish, and stir 1h at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase saturation Sodium bicarbonate, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.28g.
(2) synthesis of 1- (2,5- 3,5-dimethylphenyl) -2- (1H- imidazoles -1- base) second -1- ketone
The bromo- 1- of 2- (2,5- 3,5-dimethylphenyl) second -1- ketone crude product (2.28g, 10mmol) and imidazoles (1.36g, 20mmol) It is dissolved in 50ml tetrahydrofuran, is added potassium carbonate (2.76g, 20mmol), after 3h is stirred at room temperature, reaction solution is removed in vacuum, adds water, with Ethyl acetate extraction.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel column chromatography separation (DCM:MeOH=100:1v/v) white solid 1.55g, yield 72.4% are obtained.
(3) synthesis of 1- (2,5- 3,5-dimethylphenyl) -2- (1H- imidazoles -1- base) second -1- alcohol
1- (2,5- 3,5-dimethylphenyl) -2- (1H- imidazoles -1- base) second -1- ketone (1.08g, 5mmol) is dissolved in 50ml without water beetle Sodium borohydride (378mg, 10mmol) is added under ice bath in alcohol, and stirring flows back 2 hours again after one hour.End of reaction adds water quenching It goes out, is extracted with ethyl acetate, merge organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for White solid 870g, as product are not necessarily to additional purification, yield 80.6%.
(4) synthesis of 1- (2- (2,5- 3,5-dimethylphenyl) -2- ((3- methoxy-benzyl) oxygroup) ethyl) -1H- imidazoles
1- (2,5- 3,5-dimethylphenyl) -2- (1H- imidazoles -1- base) second -1- alcohol (216mg, 1mmol) is dissolved in 2mlDMF, It is added under ice bath 60% sodium hydride (48mg, 1.2mmol), after room temperature reaction 1 hour, 3- methoxybenzyl chloride is added under ice bath (180mg, 1.2mmol), then react at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase is successively with saturation Salt washing, anhydrous sodium sulfate are dry, are spin-dried for, and silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 220mg (compound 21), yield 65.3%.1H NMR(300MHz,CDCl3)δ7.50(s,1H),7.28–7.20(m,2H), 7.09 (s, 2H), 7.05 (s, 1H), 6.93 (s, 1H), 6.84 (d, J=7.8Hz, 1H), 6.73 (d, J=6.3Hz, 2H), 4.77 (dd,J1=8.2Hz, J2=3.6Hz, 1H), 4.49 (d, J=11.7Hz, 1H), 4.18 (d, J=11.6Hz, 1H), 4.13 (d, J =8.1Hz, 1H), 4.02 (dd, J1=14.3Hz, J2=3.5Hz, 1H), 3.79 (s, 3H), 2.36 (s, 3H), 2.20 (s, 3H) .ESI:m/z[M+H]+,calcd.for C21H24N2O2:337.1838；found.337.1911
Embodiment 17
(1) synthesis of the bromo- 1- phenylethyl -1- ketone of 2-
It takes acetophenone (1.2g, 10mmol) to be dissolved in 100ml chloroform, Br is slowly added dropwise under ice bath2(1.91g, 12mmol), drop finishes, and stirs 1h at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase unsaturated carbonate hydrogen Sodium, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.00g.
(2) synthesis of 2- (1H- imidazoles -1- base) -1- phenylethyl -1- ketone
The bromo- 1- phenylethyl -1- ketone crude product (2.00g, 10mmol) of 2- and imidazoles (1.36g, 20mmol) are dissolved in 50ml tetra- Hydrogen furans is added potassium carbonate (2.76g, 20mmol), after 3h is stirred at room temperature, reaction solution is removed in vacuum, adds water, is extracted with ethyl acetate It takes.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel column chromatography separates (DCM:MeOH= 100:1v/v) obtain white solid 1.5g, yield 75.1%.
(3) synthesis of 2- (1H- imidazoles -1- base) -1- phenylethyl -1- alcohol
2- (1H- imidazoles -1- base) -1- phenylethyl -1- ketone (1.0g, 5mmol) is dissolved in 50ml anhydrous methanol, adds under ice bath Enter sodium borohydride (378mg, 10mmol), stirring flows back 2 hours again after one hour.End of reaction adds water quenching to go out, with ethyl acetate Extraction merges organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for obtaining faint yellow solid 900mg, as product are not necessarily to additional purification, yield 90.0%.
(4) synthesis of 1- (2- ((3- methoxy-benzyl) oxygroup) -2- phenylethyl) -1H- imidazoles
1- (4- aminomethyl phenyl) -2- (1H- imidazoles -1- base) second -1- alcohol (188mg, 1mmol) is dissolved in 2mlDMF, ice bath 3- methoxybenzyl chloride is added after room temperature reaction 1 hour in 60% sodium hydride of lower addition (48mg, 1.2mmol) under ice bath (180mg, 1.2mmol), then react at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase is successively with saturation Salt washing, anhydrous sodium sulfate are dry, are spin-dried for, and silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 120mg (compound 22), yield 38.9%.1H NMR(300MHz,CDCl3)δ7.49(s,1H),7.43–7.37(m,3H), 7.31 (d, J=2.4Hz, 1H), 7.28 (s, 1H), 7.24 (t, J=8.1Hz, 1H), 7.05 (s, 1H), 6.93 (s, 1H), 6.87–6.82(m,1H),6.77–6.72(m,2H),4.57(dd,J1=7.7, J2=4.0Hz, 1H), 4.49 (d, J= 11.9Hz,1H),4.25(s,1H),4.21–4.16(m,1H),4.11(dd,J1=14.3, J2=4.1Hz, 1H), 3.80 (s, 3H).ESI:m/z[M+H]+,calcd.for C19H20N2O2:309.1525；found.309.1597
Embodiment 18
(1) synthesis of the bromo- 1- of 2- (naphthalene -2- base) second -1- ketone
It takes 2- acetonaphthone (1.7g, 10mmol) to be dissolved in 100ml chloroform, Br is slowly added dropwise under ice bath2(1.91g, 12mmol), drop finishes, and stirs 1h at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase unsaturated carbonate hydrogen Sodium, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.49g.
(2) synthesis of 2- (1H- imidazoles -1- base) -1- (naphthalene -2- base) ethyl -1- ketone
The bromo- 1- of 2- (naphthalene -2- base) second -1- ketone crude product (2.49g, 10mmol) and imidazoles (1.36g, 20mmol) are dissolved in 50ml Tetrahydrofuran is added potassium carbonate (2.76g, 20mmol), after 3h is stirred at room temperature, reaction solution is removed in vacuum, adds water, with ethyl acetate Extraction.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel column chromatography separates (DCM:MeOH= 100:1v/v) obtain white solid 1.5g, yield 75.1%.
(3) synthesis of 2- (1H- imidazoles -1- base) -1- (naphthalene -2- base) ethyl -1- alcohol
2- (1H- imidazoles -1- base) -1- phenylethyl -1- ketone (1.18g, 5mmol) is dissolved in 50ml anhydrous methanol, under ice bath It is added sodium borohydride (378mg, 10mmol), stirring flows back 2 hours again after one hour.End of reaction adds water quenching to go out, with acetic acid second Ester extraction, merges organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for obtaining faint yellow solid 948mg, as product are not necessarily to additional purification, yield 80.3%.
(4) synthesis of 1- (2- ((3- methoxyl group) oxygroup) -2- (naphthalene -2- base) ethyl) -1H- imidazoles
2- (1H- imidazoles -1- base) -1- (naphthalene -2- base) ethyl -1- alcohol (238mg, 1mmol) is dissolved in 2mlDMF, under ice bath Be added 60% sodium hydride (48mg, 1.2mmol), room temperature reaction 1 hour after, under ice bath be added 3- methoxybenzyl chloride (180mg, 1.2mmol), it then reacts at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase successively uses saturated salt solution It washes, anhydrous sodium sulfate drying, is spin-dried for, silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains white solid 190mg (chemical combination Object 23), yield 52.9%.1H NMR(300MHz,CDCl3)δ7.88(ddd,J1=11.2Hz, J2=7.4Hz J3=4.4Hz, 1H), 7.76 (s, 1H), 7.57 (t, J=3.4Hz, 1H), 7.54 (d, J=3.3Hz, 1H), 7.50 (s, 1H), 7.43 (dd, J1 =8.5Hz, J2=1.7Hz, 1H), 7.28 (d, J=2.7Hz, 1H), 7.24 (d, J=8.1Hz, 1H), 7.06 (s, 1H), 6.95 (s,1H),6.85(dd,J1=8.3Hz, J2=1.5Hz, 1H), 6.76 (dd, J1=4.2Hz, J2=2.6Hz, 1H), 4.74 (dd,J1=7.8Hz, J2=4.0Hz, 1H), 4.54 (d, J=11.9Hz, 1H), 4.32 (dd, J1=11.4Hz, J2=4.8Hz, 1H), 4.27 (d, J=6.0Hz, 1H), 4.22 (d, J=4.0Hz, 1H) .ESI:m/z [M+H]+,calcd.for C23H22N2O2: 359.1681；found.359.1755
Embodiment 19
(1) synthesis of the bromo- 1- of 2- (thiophene -2- base) second -1- ketone
It takes 2- acetyl thiophene (1.26g, 10mmol) to be dissolved in 100ml chloroform, Br is slowly added dropwise under ice bath2(1.91g, 12mmol), drop finishes, and stirs 1h at room temperature, after reaction, saturated sodium sulfite quenching reaction, organic phase unsaturated carbonate hydrogen Sodium, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum and obtains crude product 2.05g.
(2) synthesis of 2- (1H- imidazoles -1- base) -1- (thiophene -2- base) ethyl -1- ketone
The bromo- 1- of 2- (thiophene -2- base) second -1- ketone crude product (2.05g, 10mmol) and imidazoles (1.36g, 20mmol) are dissolved in 50ml tetrahydrofuran is added potassium carbonate (2.76g, 20mmol), after 3h is stirred at room temperature, reaction solution is removed in vacuum, adds water, with acetic acid Ethyl ester extraction.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel column chromatography separation (DCM: MeOH=100:1v/v white solid 1.3g, yield 67.7%) are obtained.
(3) synthesis of 2- (1H- imidazoles -1- base) -1- (naphthalene -2- base) ethyl -1- alcohol
2- (1H- imidazoles -1- base) -1- (thiophene -2- base) ethyl -1- ketone (960mg, 5mmol) is dissolved in 50ml anhydrous methanol, Sodium borohydride (378mg, 10mmol) is added under ice bath, stirring flows back 2 hours again after one hour.End of reaction adds water quenching to go out, with Ethyl acetate extraction, merges organic phase.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for faint yellow Solid 840mg, as product are not necessarily to additional purification, yield 87.5%.
(4) synthesis of 1- (2- ((3- methoxyl group) oxygroup) -2- (thiophene -2- base) ethyl) -1H- imidazoles
2- (1H- imidazoles -1- base) -1- (thiophene -2- base) ethyl -1- alcohol (194mg, 1mmol) is dissolved in 2mlDMF, ice bath 3- methoxybenzyl chloride is added after room temperature reaction 1 hour in 60% sodium hydride of lower addition (48mg, 1.2mmol) under ice bath (180mg, 1.2mmol), then react at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase is successively with saturation Salt washing, anhydrous sodium sulfate are dry, are spin-dried for, and silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains brown oil 186mg (compound 24), yield 59.2%.1H NMR(300MHz,CDCl3)δ7.48(s,1H),7.40–7.35(m,1H), 7.27–7.20(m,1H),7.04(dd,J1=5.1Hz, J2=3.5Hz, 2H), 6.99-6.94 (m, 2H), 6.88-6.80 (m, 1H), 6.75 (t, J=4.1Hz, 2H), 4.82 (dd, J1=7.8Hz, J2=4.2Hz, 1H), 4.57 (d, J=11.8Hz, 1H), 4.35-4.30 (m, 1H), 4.28 (d, J=8.0Hz, 1H), 4.18 (dd, J1=14.2Hz, J2=4.2Hz 1H), 3.80 (s, 3H).ESI:m/z[M+H]+,calcd.for C17H18N2O2S:315.1089；found.315.1155
Embodiment 20
(1) synthesis of 1- (benzo [d] [1,3] dioxole -5- base) bromo- 1- ketone of -2-
1- (benzo [d] [1,3] dioxole -5- base) second -1- ketone (1.64g, 10mmol) is taken to be dissolved in 100ml trichlorine Br is slowly added dropwise under ice bath in methane2(1.91g, 12mmol), drop finish, and stir 1h at room temperature, after reaction, are saturated sulfurous acid Sodium quenching reaction, organic phase saturated sodium bicarbonate, saturated common salt water washing.After anhydrous sodium sulfate is dry, solvent is removed in vacuum Obtain crude product 2.43g.
(2) synthesis of 1- (benzo [d] [1,3] dioxole -5- base) -2- (1H- imidazoles -1- base) ethyl -1- ketone
1- (benzo [d] [1,3] dioxole -5- base) the bromo- 1- ketone crude product (2.43g, 10mmol) of -2- and imidazoles (1.36g, 20mmol) is dissolved in 50ml tetrahydrofuran, is added potassium carbonate (2.76g, 20mmol), after 3h is stirred at room temperature, is removed in vacuum Reaction solution adds water, is extracted with ethyl acetate.Organic phase water, saturated common salt water washing, anhydrous sodium sulfate are dry.It is spin-dried for, silica gel Column chromatography for separation (DCM:MeOH=100:1v/v) obtains white solid 1.4g, yield 60.8%.
(3) synthesis of 1- (benzo [d] [1,3] dioxole -5- base) -2- (1H- imidazoles -1- base) ethyl -1- alcohol
1- (benzo [d] [1,3] dioxole -5- base) -2- (1H- imidazoles -1- base) ethyl -1- ketone (1.15g, It 5mmol) is dissolved in 50ml anhydrous methanol, sodium borohydride (378mg, 10mmol) is added under ice bath, stirring flows back 2 small again after one hour When.End of reaction adds water quenching to go out, and is extracted with ethyl acetate, merges organic phase.It is organic phase water, saturated common salt water washing, anhydrous Sodium sulphate is dry.It is spin-dried for obtaining faint yellow solid 960mg, as product, is not necessarily to additional purification, yield 83.5%.
(4) 1- (2- benzo [d] [1,3] dioxole -5- base) -2- ((3- methoxy-benzyl) oxygroup) ethyl) - The synthesis of 1H- imidazoles
2- (1H- imidazoles -1- base) -1- (thiophene -2- base) ethyl -1- alcohol (232mg, 1mmol) is dissolved in 2mlDMF, ice bath 3- methoxybenzyl chloride is added after room temperature reaction 1 hour in 60% sodium hydride of lower addition (48mg, 1.2mmol) under ice bath (180mg, 1.2mmol), then react at room temperature 1 hour.It with water quenching reaction, is extracted with ethyl acetate, organic phase is successively with saturation Salt washing, anhydrous sodium sulfate are dry, are spin-dried for, and silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 110mg (compound 25), yield 31.2%.1H NMR(300MHz,CDCl3)δ7.49(s,1H),7.28(s,1H),7.05(s, 1H), 6.92 (s, 1H), 6.80 (s, 4H), 6.74 (s, 2H), 6.00 (s, 2H), 4.49 (d, J=8.8Hz, 2H), 4.23 (d, J =10.9Hz, 2H), 4.17 (s, 1H), 4.08 (d, J=13.8Hz, 1H), 3.80 (s, 3H) .ESI:m/z [M+H]+, calcd.for C20H20N2O2:353.1423；found.353.1487
Embodiment 21
With 3 step of embodiment (1), (2), (3) are all the same
(4) synthesis of 2- (3- methoxyphenyl) acetic acid 1- (3,4- difluorophenyl) -2- (1H- imidazoles -1- base) ethyl ester
1- (2,4 difluorobenzene base) -2- (1H- imidazoles -1- base) second -1- alcohol (112mg, 0.5mmol) and 3- methoxybenzene second Sour (83mg, 0.5mmol) is dissolved in 5mlDCM, dicyclohexylcarbodiimide (103mg, 0.5mmol) is added under ice bath and to diformazan Aminopyridine (6mg, 0.05mmol) continues stirring 0.5 hour.Move to room temperature reaction 2 hours.Reaction solution successively uses water, saturation Brine It.Anhydrous sodium sulfate is dry, is spin-dried for, and silica gel column chromatography separates (DCM:MeOH=30:1v/v) and obtains colorless oil 130mg (compound 26), yield 69.9%.
1H NMR(300MHz,CDCl3) δ 7.29 (d, J=1.8Hz, 1H), 7.21 (s, 1H), 7.11 (dt, J1=9.9, J2 =8.2Hz, 1H), 6.99 (s, 1H), 6.96-6.91 (m, 1H), 6.87 (d, J=8.7Hz, 1H), 6.85-6.80 (m, 2H), 6.79-6.76 (m, 1H), 6.65 (s, 1H), 5.89 (t, J=5.6Hz, 1H), 4.21 (s, 1H), 4.19 (s, 1H), 3.82 (s, 3H),3.65(s,2H).ESI:m/z[M+H]+,calcd.for C20H18F2N2O3:373.1285；found.353.1357
Embodiment 22
Referring to the method for embodiment 21,3- methoxyphenylacetic acid is replaced with into 3- (3- methoxyphenyl) propionic acid, obtains nothing Color grease 150mg, yield 77.7% (compound 27).It is identified as 3- (3- methoxyphenyl) propionic acid 1- (3,4- difluorobenzene Base) -2- (1H- imidazoles -1- base) ethyl ester.1H NMR(300MHz,CDCl3) δ 7.28 (s, 1H), 7.21 (t, J=7.9Hz, 1H), 7.12(dt,J1=10.0, J2=8.2Hz, 1H), 7.03 (s, 1H), 7.00-6.91 (m, 1H), 6.89-6.82 (m, 1H), 6.80-6.74 (m, 2H), 6.71 (d, J=1.9Hz, 1H), 6.02-5.71 (m, 1H), 4.27-4.12 (m, 1H), 3.79 (s, 2H), 2.92 (t, J=7.5Hz, 1H), 2.71 (t, J=7.2Hz, 1H) .ESI:m/z [M+H]+,calcd.for C21H20N2O2: 387.1442；found.387.1525
Embodiment 23
Referring to the method for embodiment 21,3- methoxyphenylacetic acid is replaced with into 4- (3- methoxyphenyl) butyric acid, obtains nothing Color grease 160mg, yield 80.0% (compound 28).It is identified as 4- (4- methoxyphenyl) butyric acid 1- (3,4- difluorobenzene Base) -2- (1H- imidazoles -1- base) ethyl ester.
1H NMR(300MHz,CDCl3)δ7.34(s,1H),7.19(ddd,J1=11.3, J2=10.0, J3=4.9Hz, 2H), 7.12-7.05 (m, 1H), 7.04 (s, 1H), 6.97-6.91 (m, 1H), 6.82 (t, J=1.2Hz, 1H), 6.79-6.73 (m, 2H), 6.71 (d, J=2.0Hz, 1H), 5.95-5.87 (m, 1H), 4.27 (dd, J1=13.5, J2=5.5,1H), 4.21 (dd,J1=13.5, J2=4.2Hz, 1H), 3.81 (s, 3H), 2.60 (t, J=7.5Hz, 2H), 2.38 (t, J=7.5Hz, 2H), 1.94 (p, J=7.5Hz, 2H) .ESI:m/z [M+H]+,calcd.for C22H22F2N2O3:401.1598；found.401.1685
The measurement of 24 cholinesterase inhibition of embodiment
Drug and reagent: compound made from embodiment 6-28, AChE (E.C.3.1.1.7, Type VI-S, selected from electricity Eel), BuChE (E.C.3.1.1.8, be selected from horse serum), 5,5 '-two sulphur bis- (2- nitrobenzoic acid) (DTNB), acetyl thio gallbladder Alkali (ATC) iodide and Butyryl thiocholine (BTC) iodide are purchased from Sigma Corporation；Tacrine is synthesized by this laboratory (purity > 95%).
Instrument: THERMO Varioskan Flash all-wave length multi-function microplate reader.
Experimental method:
(1) prepare buffer: 13.6g potassium dihydrogen phosphate is dissolved in 1L water, adjusts pH=8 ± 0.1 with potassium hydroxide.Solution It is saved in 4 DEG C, it is spare.
(2) it prepares 0.01M DTNB solution: 0.396g DTNB and 0.15g sodium bicarbonate being dissolved in 100mL water and is made 0.01M DTNB solution is saved in -20 DEG C, spare.
(3) 0.075M ATC, BTC solution are prepared: 0.217g ATC being dissolved in 10mL water, 0.075M ATC and BTC is made Solution is saved in -20 DEG C, spare；0.237g BTC is dissolved in 10mL water, 0.075M BTC solution is made, saved in -20 DEG C, It is spare.
(4) AChE, BuChE solution are prepared: the AChE of 5000 units being dissolved in the gel solution of 1mL 1%, is then used It is 5 units/mL AChE solution that water, which is diluted to 100mL and concentration is made, is saved in -20 DEG C, spare；By the BuChE of 5000 units It is dissolved in the gel solution of 1mL 1%, being then diluted with water to 100mL and concentration is made is 5 units/mL BuChE solution, in- 30 DEG C of preservations, it is spare.
(5) it prepares tested material solution: test-compound being dissolved in ethyl alcohol so that concentration is made as 10-3(ethyl alcohol is or not the solution of M Influence test result), being then diluted with water and concentration is made respectively is 10-4、10-5、10-6、10-7、10-8、10-9The solution of M.
Experiment start before, solution used is heated up to room temperature, and by AChE, BuChE solution be diluted with water one times be made it is dense Degree is 2.5 units/mL enzyme solutions.Background UV absorption is measured with plain buffer (3mL).First by 100 μ L test-compounds Solution, 100 μ L DTNB solution, 100 μ L enzyme solutions add in 3mL buffer, and the triggering reaction of 20 μ L ATC or BTC solution is added Timing immediately simultaneously quickly mixes test solution simultaneously afterwards, measures ultraviolet absorptivity under 412nM wavelength after 2min.Blank control group Tested material solution is replaced to measure with the water of isometric(al).All equal operation repetitives of test are three times.With the UV absorption of blank control group Value is used as 100%, records absorbance (OD value) of the test-compound under each concentration, acquired results GraphPad PrismTM (GraphPad Software, San Diego, CA, USA) software is with Nonlinear regression analysis mode (non- Linear regression analysis model) calculate to obtain corresponding IC50Value, as shown in table 2.
Interpretation of result: 14 compounds have inhibitory activity (IC to BuChE501.9 μM~126 μM), wherein compound 8, 13,27 and 28 activity is best, and these compounds do not have AChE inhibitory activity, illustrates that they are that selectivity is good BuChE inhibitor.
Test result of each compound of table 2 to AChE, BuChE and IDO1
Note: data are expressed as average value ± SEM (n=3), and NA indicates that no active, nd indicate not determined.
The measurement of -1 inhibitory activity of 25 indole amine 2,3-dioxygenase of embodiment
Drug and reagent: embodiment 6-28 compound, rhIDO-1 enzyme (expression of this seminar), ascorbic acid, hydrogen peroxide Enzyme, subunit base is blue, and L-Trp, p- dimethylaminobenzaldehyde, trichloroacetic acid are purchased from Aladdin company.
Instrument: THERMO Varioskan Flash all-wave length multi-function microplate reader.
Experimental method:
(1) prepare buffer: 13.6g potassium dihydrogen phosphate is dissolved in 1L water, adjusts pH=6.5 ± 0.1 with hydrochloric acid.Solution in 4 DEG C of preservations, it is spare.
(2) configure Substrate cocktail: a) 0.4M PBS match 80mmol/L ascorbic acid, b) PBS match 400ug/mL peroxidating Hydrogen enzyme, 40umol/L methylene blue, 800umol/LL- tryptophan, c) it mixes in equal volume a), b), each component concentration is as follows: 40mmol/L ascorbic acid, 200ug/mL catalase, 20umol/L methylene blue, 400umol/L L-Trp.
(3) prepare the acetic acid solution of 2% p- dimethylaminobenzaldehyde: 149mg paradime thylaminobenzaldehyde is dissolved in 7.45ml Acetic acid.
(4) it prepares tested material solution: test-compound is dissolved in dimethyl sulfoxide (< 0.1%) so that concentration is made as 10-3M Solution (dimethyl sulfoxide does not influence test result), be then diluted with water respectively be made concentration be 10-4、10-5、10-6、10-7、 10-8、10-9The solution of M.
In 500uL reaction system, first by 50mmol/LPBS buffer (pH6.5), 40mmol/L ascorbic acid, 200ug/mL catalase, 20umol/L methylene blue, substrate L-Trp and sample to be tested mixing, 37 DEG C of mixed liquor preheatings 5 minutes, 0.05umol/L rhIDO1 enzyme is added, 30% trichloroacetic acid 200uL is added in 37 DEG C of reaction 30min after enzymatic reaction Reaction is terminated, reaction solution heats 15 minutes at 65 DEG C, and 12000rpm is centrifuged 5 minutes, takes supernatant 100uL and isometric 2% p- two The acetic acid solution of methylamino phenenyl formaldehyde mixes, and reacts the yellow color of generation in 480nm observation kynurenin using microplate reader. All equal operation repetitives of test are three times.Using the ultraviolet absorption value of blank control group as 100%, test-compound is recorded each Absorbance (OD value) under concentration, acquired results with GraphPad Prism6 (GraphPad Software, San Diego, CA, USA) software with Nonlinear regression analysis mode (non-linear regression analysis model) calculates to obtain phase The IC answered50The results are shown in Table 2 for value.
Interpretation of result: compound has inhibitory activity to IDO1, wherein the IC of 13 compounds50<100μM.6 He of compound 15 is best, IC50Respectively 16.6 μM and 15.2 μM.Comprehensive two target spots, compound 8 and 13 pair BuChE and IDO1 have phase When inhibitory activity.
26 water maze laboratory of embodiment
Drug and reagent: 8,13 compound of embodiment, scopolamine hydrobromide purchased from Aladdin Reagent Company (S107418, Shanghai), Tacrine (purity > 95%).
Instrument: 3.0 behaviouristics video analyzer of Panlab SMART
Animal: it is purchased from Yangzhou University medical center within bull ICR mouse (8-10 weeks, 20-25 grams of weight)
Experimental method: 56 mouse are randomly divided into 7 subgroups (every group of 8 mouse): (i) carrier is as blank control Group, (ii) hyoscine adds hyoscine as positive control as model group, (iii) Tacrine, and (iv) compound 8 (10mg/kg) plus hyoscine are as test group, and (v) as test group, (vi) changes for compound 8 (30mg/kg) plus hyoscine Object 13 (100mg/kg) plus hyoscine are closed as test group, (vii) compound 13 (30mg/kg) plus hyoscine as test Group.Model group mouse, Tacrine group, 8 groups of compound (10mg/kg), 8 groups of compound (30mg/kg), 13 groups of (10mg/ of compound Kg) and 13 groups of compound (30mg/kg) intraperitoneal injection hyoscines (1mg/kg), blank control group pump pickle.After 30 minutes, By Tacrine group, 8 groups of compound (10mg/kg), 8 groups of compound (30mg/kg), 13 groups of compound (10mg/kg) and compound 13 groups (30mg/kg) intraperitoneal injection hyoscines, control group injecting normal saline.
It is fixed an escape platform (10 centimetres of diameter) in round pool (120 centimetres of diameter, 60 centimetres high), and fills 40 The fresh water (being maintained at 25 DEG C) of centimetre depth constitutes water maze.It is placed in a bright room.In learning and memory training 5 days Afterwards, in the 6th day progress probe test.In order to assess cognitive function, every mouse (is marked, 5cm high) in visible platform with penoncel Upper individually training 2 days, the 3rd day to the 5th day in the water maze training for hiding platform (being placed on underwater 1cm).All mouse are every It carries out 2 training tests, each test duration 90 seconds.Record the time (successfully escaping) that every mouse finds platform.If Mouse failed to reach platform in 90 seconds, then terminated and test and mouse is carefully placed into platform with hand.It is either successful with No, every mouse will all be kept 30 seconds on platform.In last day (the 6th day), platform is taken out from pond, mouse is tried Test, allow every mouse 90 seconds with search platform.Record time and track that mouse reaches missing position of platform.Experimental result is such as Table 3, Fig. 1
Interpretation of result: in conjunction with table 3, Fig. 1 it is found that compared with the control group, model group mouse reaches the average time tool of platform There is significant difference, show that hyoscine can result in mouse memory defect, illustrates modeling success.Relative to model group, he gram Woods group spent time and distance all significantly reduce, and show that Tacrine has changing for conspicuousness for the memory of mouse and cognitive function It is kind.And the mouse of 8 processing group of compound, 13 processing group of compound reaches the average time of platform and distance is below model group, Show that compound 8, compound 13 have improvement to mouse memory and cognitive function.Wherein 13 processing group of compound two Effect under dosage is superior to 8 processing group of compound, and the effect phase of (10mg/kg) the processing group of compound 13 and control group When, show compound 13 can be good at reverse hyoscine can result in mouse memory defect.Fig. 2 is the representative of each group mouse Property trajectory diagram, the track of model group mouse are considerably longer more chaotic relative to blank group；The performance of Tacrine group mouse is compared with model Group significantly improves, and shows that Tacrine has the memory of mouse and cognitive function the improvement of conspicuousness；8 processing group of compound is changed The track for closing 13 processing group of object also increases relative to model group, wherein compound 8 (10mg/kg), 13 (10mg/ of compound Kg) and compound 13 (30mg/kg) is better than Tacrine group, show the improvement of its mouse memory and cognitive function better than him gram Woods.
3 mouse of table reaches the platform position time
Data are expressed as average value ± SEM (n=8；There was no significant difference by ns=, and * p < 0.05, * * p < 0.01, * * * p < 0.001vs model group).
27 MTT experiment of embodiment
Drug and reagent: 3- (4,5- dimethylthiazole -2- base) -2,5- diphenyltetrazolium bromide (MTT) (is purchased from me Fourth)
Instrument: THERMO Varioskan Flash all-wave length multi-function microplate reader.
Experimental method: by target cell (5 × 103, volume 0.1ml) and it is placed in 96 hole flat-bottomed plates, make cell 37 It stays overnight the bottom that plate is adhered at DEG C.It is handled cell 24 hours with the compound of various concentration.MTT reagent is added in hole, by plate It is incubated for 4 hours at 37 DEG C.0.1ml lysis buffer is added in hole and destroys cell.They are kept again at 37 DEG C after hatching 24 hours, chromogenic reaction was measured in 570nm using microplate reader.All groups of parallel 3 progress.Experimental result such as table 4, Fig. 3 and Fig. 4 It is shown.
Interpretation of result: all compounds under 50 μM of concentration to PC12 and SH-SY5Y cell without overt toxicity, only change Closing object 13 has mild toxicity to PC12 cell.For nerve cell SH-SY5Y, most compounds have slight protective effect.With Above statistics indicate that the preliminary safety of compound.The cytotoxicity of most compounds is respectively less than positive control Tacrine, shows The potential safety of compound.
4 PC12 and SH-SY5Y cell survival rate of table
The research of 27 acute liver toxicity of experimental example
Animal: it is purchased from Yangzhou University medical center within bull ICR mouse (8-10 weeks, 20-25 grams of weight).
Instrument: Biochemical Analyzer (HITACHI 7020, Japan)；Ultra-thin semi-automatic slicer (Leica RM2245, moral State).
Grouping: 42 mouse are randomly divided into 7 groups (every group of 6 mouse): control group, model group, Tacrine group, compound 12 processing groups, 15 processing group of compound.
Experimental method: by Tacrine (30mg/kg), 8 two dosage of compound (10mg/kg and 30mg/kg), compound 13 Two dosage (10mg/kg and 30mg/kg) are dissolved in CMC-Na solution (0.5g CMC-Na, 100mL distilled water) respectively, are filled Stomach administration.Control group mice stomach-filling physiological saline, model group mouse peritoneal inject hyoscine (1mg/kg).Administration 8 hours, Respectively from obtaining test tube of hepari serum after ball in neuropile after 22 hours and 36 hours.Pass through commercially available assay kit: mouse paddy third Transaminase kit (EF551, EF550) measures alanine aminotransferase (ALT), AST detection kit (EH027, EF548) measurement Two kinds of hepatic injury indexs of aspartate transaminase (AST).Mouse is put to death behind 1 hour of blood after last time collection ball, is taken out Liver carries out Senile Mouse by immunohistochemical method.Extremely using ultra-thin semi-automatic slicer separation liver door portion Two 3mm at left side siphonal lobe edge are sliced, and are immediately placed in 10% buffered formaldehyde liquid, are fixed two days, embedded with paraffin, are made For at 5 μm of paraffin sections, deparaffnize carries out histopathological examination with h and E dyeing.Experimental result such as table 5, table 6, shown in Fig. 5-7.
Interpretation of result: compound 8 (10mg/kg), (30mg/kg) processing of compound 8 group, at compound 13 (10mg/kg) Reason group and (30mg/kg) the processing group of compound 13 are suitable in ALT, AST level and control group and model group at three time points, no There are significant difference, illustrate that compound has preliminary safety.In addition, histopathology chart is bright, with control group (figure 7A) to compare, compound 8 (Fig. 7 D and Fig. 7 E) and compound 13 (Fig. 7 F and Fig. 7 G) do not cause the bad metamorphosis of liver, These results all show the safety of compound, imply this kind of compound with good potential applicability in clinical practice.
5 three time point mouse alanine aminotransferase levels of table
6 three time point mouse aspartate transaminase levels of table

Claims (10)

1.如式(Ⅰ)所示的二芳基咪唑类化合物或其药学上可接受的盐，1. A diarylimidazole compound represented by formula (I) or a pharmaceutically acceptable salt thereof, 其中，A选自取代或未取代的苯基、取代或未取代的杂环、取代或未取代的芳稠环；苯基的取代基为卤素、-NO2、-CN、Cl～C6烷基、卤素取代的C1～C4烷基、C1～C3烷氧基，萘基的取代基为卤素、-NO2、-CN、-OH、Cl～C6烷基，杂环的取代基为卤素、-NO2、-CN、-OH、卤素取代的C1～C4烷基、C1～C4烷基、C1～C3烷氧基；L选自-O-，-S-或-C(O)O-；n＝1，2，3。Wherein, A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aromatic fused ring; the substituent of phenyl is halogen, -NO 2 , -CN, C 1 -C 6 Alkyl, halogen-substituted C 1 -C 4 alkyl, C 1 -C 3 alkoxy, naphthyl substituents are halogen, -NO 2 , -CN, -OH, C 1 -C 6 alkyl, heterocyclic The substituents of the ring are halogen, -NO 2 , -CN, -OH, halogen-substituted C 1 -C 4 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkoxy; L is selected from -O -, -S- or -C(O)O-; n=1, 2, 3. 2.根据权利要求1所述的二芳基咪唑类化合物，其特征在于，A选自取代或未取代的苯基、未取代的萘基、未取代的芳杂环、未取代的杂合芳稠环，苯基的取代基选自卤素、卤素取代的C1～C4烷基、C1～C4烷基、C1～C3烷氧基；L选自-O-,-C(O)O-；n＝1,2,3。2. diarylimidazole compound according to claim 1, is characterized in that, A is selected from substituted or unsubstituted phenyl, unsubstituted naphthyl, unsubstituted aromatic heterocycle, unsubstituted heterozygous aromatic Condensed ring, the substituent of phenyl is selected from halogen, halogen-substituted C 1 -C 4 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkoxy; L is selected from -O-, -C( O) O-; n=1,2,3. 3.根据权利要求2所述的二芳基咪唑类化合物，其特征在于A选自取代或未取代的苯基、未取代的萘基、噻吩、苯并[d][1,3]二氧杂环戊烯，苯基的取代基选自氢、氟、氯、溴取代的C1～C4烷基，C1～C4烷基，或C1～C3烷氧基；L选自-O-,-C(O)O-；n＝1,2,3。3 . The diarylimidazole compound according to claim 2 , wherein A is selected from substituted or unsubstituted phenyl, unsubstituted naphthyl, thiophene, benzo[d][1,3]dioxy Heterocyclopentene, the substituent of phenyl is selected from hydrogen, fluorine, chlorine, bromine substituted C 1 -C 4 alkyl, C 1 -C 4 alkyl, or C 1 -C 3 alkoxy; L is selected from -O-, -C(O)O-; n=1,2,3. 4.根据权利要求3所述的二芳基咪唑类化合物，其特征在于当L为-O-时,n＝1，A选自取代或未取代的苯基、未取代的萘基、噻吩、芳苯并[d][1,3]二氧杂环戊烯，苯基的取代基选自氢、氟、氯、溴、甲基、三氟甲基、甲氧基、叔丁基，取代位置选自2、3、4、5位中的一个或多个，A优选氟、氯在2、3、4、5位中多个位置取代的苯基；当L＝-C(O)O-，n＝1,2,3，A取自氟、氯多取代的苯基，优选3,4-二氟苯基。4. diarylimidazole compounds according to claim 3, is characterized in that when L is -O-, n=1, A is selected from substituted or unsubstituted phenyl, unsubstituted naphthyl, thiophene, Arylbenzo[d][1,3]dioxole, the substituent of phenyl is selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, tert-butyl, substituted The position is selected from one or more of the 2, 3, 4, and 5 positions, and A is preferably a phenyl group substituted by fluorine and chlorine at multiple positions in the 2, 3, 4, and 5 positions; when L=-C(O)O -, n=1, 2, 3, A is taken from fluorine, chlorine polysubstituted phenyl, preferably 3,4-difluorophenyl. 5.根据权利要求1所述的二芳基咪唑类化合物，其特征在于所述的二芳基咪唑类化合物选自：5. diarylimidazole compound according to claim 1 is characterized in that described diarylimidazole compound is selected from: 6.权利要求1所述的二芳基咪唑类化合物的制备方法，其特征在于包括：以取代芳基乙酮为原料，经溴素溴代得到α-溴代芳基乙酮，α-溴代芳基乙酮与咪唑N烷基化得到再和硼氢化钠反应得到最后与3-甲氧基氯苄或不同链长的芳基羧酸反应制备得到如式(Ⅰ)所示的二芳基咪唑类化合物。6. the preparation method of the described diarylimidazole compound of claim 1, it is characterized in that comprising: take substituted aryl ethyl ketone as raw material, obtain α-bromo aryl ethyl ketone through bromine bromination, α-bromo ethyl ketone N-alkylation of substituted aryl ethyl ketones with imidazoles to obtain Reaction with sodium borohydride to obtain Finally, react with 3-methoxy benzyl chloride or aryl carboxylic acids with different chain lengths to prepare diarylimidazole compounds represented by formula (I). 7.根据权利要求6所述的二芳基咪唑类化合物的制备方法，其特征在于包括如下步骤：7. the preparation method of diarylimidazole compound according to claim 6 is characterized in that comprising the steps: 步骤(1)取代芳基乙酮，以三氯甲烷为反应溶剂，在Br2作用下，25-30℃下搅拌1～1.5h，反应结束后，饱和亚硫酸钠淬灭反应，有机相用饱和碳酸氢钠，饱和食盐水洗涤，无水硫酸钠干燥后，真空除去溶剂得到α-溴代芳基乙酮粗品；所述的取代芳基乙酮与Br2的摩尔比为1:1～1.5；Step (1) Substitute aryl ethyl ketone, use chloroform as the reaction solvent, under the action of Br 2 , stir at 25-30 ° C for 1-1.5 h, after the reaction is completed, quench the reaction with saturated sodium sulfite, and use saturated carbonic acid for the organic phase Sodium hydrogen, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain a crude α-bromo aryl ethyl ketone; the molar ratio of the substituted aryl ethyl ketone to Br 2 was 1:1 to 1.5; 步骤(2)取α-溴代芳基乙酮与咪唑溶于四氢呋喃，加入碳酸钾，室温搅拌2～3h后，真空除去反应液，加水，以乙酸乙酯萃取；有机相用水、饱和食盐水洗涤，无水硫酸钠干燥，旋干，硅胶柱层析分离得到其中，硅胶柱层析的洗脱剂为二氯甲烷:甲醇＝100:1v/v；所述的α-溴代芳基乙酮、咪唑、碳酸钾的摩尔比为1:2:2～1:3:3；Step (2) Dissolve α-bromoaryl ethyl ketone and imidazole in tetrahydrofuran, add potassium carbonate, stir at room temperature for 2-3 h, remove the reaction solution in vacuo, add water, and extract with ethyl acetate; the organic phase is water and saturated brine Washed, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography to obtain Wherein, the eluent of silica gel column chromatography is methylene chloride: methanol=100:1 v/v; the molar ratio of described α-bromoaryl ethyl ketone, imidazole and potassium carbonate is 1:2:2～1 :3:3; 步骤(3)将溶于无水甲醇，冰浴条件下加入硼氢化钠，并在该温度下搅拌1～1.5小时，后加热回流2～3小时，加水淬灭反应，以乙酸乙酯萃取，合并有机相，有机相依次用饱和食盐水洗、无水硫酸钠干燥，旋干，硅胶柱层析分离，得到；其中，洗脱剂为DCM:MeOH＝30:1v/v；所述的与硼氢化钠的摩尔比为1:2～1:3；Step (3) will Dissolve in anhydrous methanol, add sodium borohydride under ice bath, stir at this temperature for 1-1.5 hours, then heat under reflux for 2-3 hours, add water to quench the reaction, extract with ethyl acetate, combine the organic phases, organic The phases were washed successively with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography to obtain; wherein, the eluent was DCM:MeOH=30:1 v/v; the described The molar ratio to sodium borohydride is 1:2～1:3; 步骤(4)、当L为-O-,操作为将溶于DMF中，冰浴下加入氢化钠，室温反应1～1.5小时，后冰浴下加入3-甲氧基氯化苄，再室温反应1～1.5小时，以水淬灭反应，以乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，旋干，硅胶柱层析分离，得到式(Ⅰ)所示结构化合物；所述的与NaH、3-甲氧基氯化苄的摩尔比为1:1.2:1.2～1:1.2:1.3；洗脱剂为DCM:MeOH＝30:1v/v；当L为-C(O)O-，操作为将和相应的羧酸溶于DCM，冰浴下加入二环己基碳二亚胺和对二甲氨基吡啶，室温反应2～3小时；反应液用水和饱和食盐水洗涤，无水硫酸钠干燥，旋干，硅胶柱层析分离，得到式(Ⅰ)所示结构化合物；所述的与羧酸、二环己基碳二亚胺和对二甲氨基吡啶的摩尔比为1:1:1:0.1～1：1.3:1.3:0.1；洗脱剂为DCM:MeOH＝30:1v/v。Step (4), when L is -O-, the operation is to Dissolve in DMF, add sodium hydride under ice bath, react at room temperature for 1-1.5 hours, then add 3-methoxybenzyl chloride under ice bath, react at room temperature for 1-1.5 hours, quench the reaction with water, add ethyl acetate Ester extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography to obtain the compound represented by formula (I); The molar ratio with NaH and 3-methoxybenzyl chloride is 1:1.2:1.2～1:1.2:1.3; the eluent is DCM:MeOH=30:1v/v; when L is -C(O)O -, the operation is to And the corresponding carboxylic acid was dissolved in DCM, dicyclohexylcarbodiimide and p-dimethylaminopyridine were added under ice bath, and the reaction was carried out at room temperature for 2 to 3 hours; the reaction solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and spun. dry, and separated by silica gel column chromatography to obtain the structural compound represented by formula (I); the The molar ratio with carboxylic acid, dicyclohexylcarbodiimide and p-dimethylaminopyridine is 1:1:1:0.1～1:1.3:1.3:0.1; the eluent is DCM:MeOH=30:1v/v . 8.权利要求1-5中任意一项所述的二芳基咪唑类化合物或其药学上可接受的盐在制备预防或治疗阿尔茨海默症药物中的应用。8. Use of the diarylimidazole compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating Alzheimer's disease. 9.根据权利要求8所述的应用，其特征在于所述的药物以所述的二芳基咪唑类化合物或其药学上可接受的盐为有效成分或主要有效成分，与药学上可接受的载体制成；所述药物的剂型为胶囊剂、丸剂、片剂、颗粒剂或注射剂。9. application according to claim 8 is characterized in that described medicine takes described diarylimidazole compound or its pharmaceutically acceptable salt as active ingredient or main active ingredient, and pharmaceutically acceptable The carrier is prepared; the dosage form of the medicine is capsule, pill, tablet, granule or injection. 10.一种药用组合物，其特征在于含有权利要求1-5中任意一项所述的二芳基咪唑类化合物或其药学上可接受的盐。10. A pharmaceutical composition, characterized in that it contains the diarylimidazole compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof.
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