CN110437136A

CN110437136A - 1- virtue oxygen ethyl piperidine -4- base methanone derivatives and its preparation method and application

Info

Publication number: CN110437136A
Application number: CN201910694327.6A
Authority: CN
Inventors: 仲琰; 方甜甜; 陈俐颐
Original assignee: Southeast University
Current assignee: Southeast University
Priority date: 2019-07-30
Filing date: 2019-07-30
Publication date: 2019-11-12

Abstract

1- virtue oxygen ethyl piperidine -4- base methanone derivatives and its preparation method and application, which is the free alkali or salt with general formula (I) structural compounds:Described salt is one of hydrochloride, hydrobromate, sulfate, trifluoroacetate, tartrate, lactate or mesylate；Wherein, R₁Independently represent alkyl, nitro, amino, itrile group, hydroxyl, alkoxy, aralkoxy, heterocyclylalkoxy groups, aryl, substituted heterocycle or substituted aryl that H, halogen, alkyl, halogen replace；R₂Independently represent alkyl, nitro, amino, itrile group, hydroxyl, alkoxy, aralkoxy, heterocyclylalkoxy groups, aryl, substituted heterocycle or substituted aryl that H, halogen, alkyl, halogen replace.1- virtue oxygen ethyl piperidine -4- base methanone derivatives are preparing the application in cerebral arterial thrombosis therapeutic agent.

Description

1- virtue oxygen ethyl piperidine -4- base methanone derivatives and its preparation method and application

Technical field

The invention belongs to pharmaceutical field, be related to a kind of substituted 1- virtue oxygen ethyl piperidine -4- base methanone derivatives and its Preparation method and the derivative are preparing the purposes in neuroprotection agent.

Background technique

Cerebral apoplexy is one of current lethality and the highest disease of disability rate, wherein nearly 80% cerebral apoplexy belongs to ischemic Cerebral apoplexy.The living or death of brain cell depends on the injured degree of neuronal cell after cerebral apoplexy occurs, that is, depends on being thin Born of the same parents provide the degree of the cerebral blood flow reduction of oxygen and nutrition.When cerebral arterial thrombosis occurs, the brain blood of ischemic core part Stream is serious to be reduced, and irreversible damage occurs in 60-90min tissues following MCAO in rats；And the ischemic penumbra of core part periphery, greatly Cerebral blood flow (CBF) is opposite to be reduced, but cell metabolism increases extremely, within a few hours after ischemic generation, abnormal electric work in ischemic area Dynamic and metabolic disorder forms a chain reaction, and referred to as " ischemic waterfall ", the final result of water fall effect is that ischemic core constantly expands Exhibition, penumbra fade away, this process is exactly the time window of Treatment of Cerebral Stroke.

Foreign countries proposed the Neuroprotective Therapy in Treating Acute of cerebral arterial thrombosis since nineteen nineties, at subsequent 10 years In have swift and violent development.The target of neuroprotection is the pathological biochemistry cascade reaction intervening ischemic penumbra and occurring, and is saved still Vigourous brain tissue prevents or postpones cell death.Neuroprotective agent type and mechanism of action are various at present, as voltage relies on The medicines such as property calcium channel blocker, glutamate receptor antagonists, antioxidant, free radical scavenger, nitric oxide synthase inhibitors Object has become the research hotspot of Treatment of Cerebral Stroke.

Summary of the invention

The technical issues of solution: the application technical issues that need to address first is that disclosing a kind of 1- with medical value Fragrant oxygen ethyl piperidine -4- base methanone derivatives.

The application technical issues that need to address second is that disclosing above-mentioned substituted 1- virtue oxygen ethyl piperidine -4- base Benzophenone Application of the derivative as neuroprotection agent in cerebral arterial thrombosis treatment, to overcome of the existing technology induce Blood, be difficult to through blood-brain barrier, oral administration biaavailability is poor, selectivity is low and Behavioral teratogenicity is big the defects of.

Technical solution:

1- virtue oxygen ethyl piperidine -4- base methanone derivatives, the compound are that have dissociating for general formula (I) structural compounds Alkali or salt:

The salt is hydrochloride, hydrobromate, sulfate, trifluoroacetate, tartrate, lactate or mesylate One of；

Wherein, R₁And R₂It is identical or different, it is independently represented each other alkyl, nitro, ammonia that H, halogen, alkyl, halogen replace Base, itrile group, hydroxyl, alkoxy, aralkoxy, heterocyclylalkoxy groups, aryl, substituted heterocycle or substituted aryl.

Preferably, the R₁Or R₂The aryl of representative is benzene, biphenyl or naphthalene, or is F, Cl, Br, I, C_1~10Alkyl, C_1~10Benzene, biphenyl or the naphthalene that alkoxy, nitro or amino replace.

Preferably, the R₁Or R₂The alkyl of representative refers to the alkyl or 2-10 of the linear chain or branched chain with 1-10 carbon atom The naphthenic base of the linear chain or branched chain of the alkenyl of the linear chain or branched chain of a carbon atom or 3-10 carbon atom；The alkoxy, aralkyl Alkyl in oxygroup or heterocyclylalkoxy groups refers to the alkyl of the linear chain or branched chain with 1-10 carbon atom；Abovementioned alkyl be methyl, Ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, sec-butyl, amyl, neopentyl, hexyl, heptyl, octyl, nonyl or Decyl；Above-mentioned alkenyl is vinyl, acrylic, allyl, cyclobutenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octene Base, nonenyl or decene base；Above-mentioned naphthenic base is cyclopropyl, cyclobutyl, cyclohexyl, suberyl, cyclooctyl, cyclononyl or the ring last of the ten Heavenly stems Base.

Preferably, the R₁Or R₂The substituted heterocycle or the heterocycle in heterocyclylalkoxy groups of representative refer to containing from oxygen, nitrogen, sulphur Optional one or more heteroatomic saturated heterocyclic or aromatic heterocycle in atom.

Preferably, the R₁Or R₂The halogen represented is F, Cl, Br or I.

Preferably, the R₁Or R₂Middle substituted aryl, substituent group are halogen, nitro, amino, hydroxyl, ether, carboxyl, ester Base and amide groups.

Preferably, the R₁Or R₂Amino in substituent group is NH₂、R₈NH or R₉R₁₀N；Wherein R₈、R₉Or R₁₀For alkyl, or Person R₉R₁₀N is ternary~eight circle heterocyclic rings of nitrogen atom, and the alkyl refers to the alkane of the linear chain or branched chain with 1-10 carbon atom The naphthenic base of the linear chain or branched chain of the alkenyl of the linear chain or branched chain of base or 2-10 carbon atom or 3-10 carbon atom.

The preparation method of 1- virtue oxygen ethyl piperidine -4- base methanone derivatives, comprising the following steps:

A. fortified phenol 50mmol, 1,2- Bromofume 75mmol and water 30mL are added in 100mL three-necked bottle, stirring rises 25% sodium hydroxide solution 75mmol is added dropwise to flowing back in temperature, and 35-40min is dripped off, and continues reflux 10 hours, and reaction solution is cooling Layering is stood, and is filtered, and filter cake is washed twice with 5% sodium hydroxide solution, is washed with water twice, with dehydrated alcohol recrystallization two It is secondary, obtain substituted benzene oxygen bromoethane (II)；

B. 4- piperidinecarboxylic acid 8mmo1 and acetic acid 10mL is added in the eggplant-shape bottle of 50mL, is heated to flowing back, reacted 10 hours Acetic anhydride 10mL is added afterwards, solvent is steamed after continuing reflux 1 hour, product cooling is formed blocks of solid, sufficiently washed with petroleum ether It washs, it is dry, obtain N- Acetylpiperidin -4- formic acid (III)；

C. N- Acetylpiperidin -4- formic acid 7.6mmol and 1,2- dichloroethanes 15mL are added in 100mL there-necked flask, control Temperature processed is at 40-50 DEG C, and the dropwise addition diluted thionyl chloride 14mmol of 1,2- dichloroethanes 3mL, continues at such a temperature dropwise After stirring 2 hours, substituted benzene 7.6mmol and alchlor 15mmol is added into reaction system, reflux was cooled to room after 4 hours Temperature is added ice water, is sufficiently stirred, stratification, and each 20ml is washed twice with water in organic layer, and the substitution of N- acetyl is concentrated under reduced pressure to obtain Above-mentioned N- acetyl substituted benzene formyl phenylpiperidines, water 10mL and concentrated hydrochloric acid 10mL are added in the mono- neck bottle of 50mL benzoyl piperidine, Reflux 10 hours stands cooling, washes twice each 20m with methylene chloride, water layer 5%NaOH solution adjusts pH=8-9, with two Chloromethanes extraction each 20ml three times, merges organic phase, dry by anhydrous MgSO4, filter, be concentrated to give 4- substituted benzoyl Piperidines (IV)；

D. by 4- substituted benzene formyl phenylpiperidines (IV) 5.3mmol, substituted benzene oxygen bromoethane (II) 6.9mmol, potassium iodide 10mmol and dehydrated alcohol 30mL is added in 100mL eggplant-shape bottle and is heated to reflux, and 20%KOH solution 5mL is added dropwise, drips within 10 minutes Finish, evaporating solvent under reduced pressure after reflux 24 hours, methylene chloride 30mL dissolution is added in residue, is washed three times with water 20mL, organic layer It is concentrated to give brown oil, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, by EA/PE=1/1 to 3/1 gradient elution, Column chromatography for separation obtains general formula (I) compound.

1- virtue oxygen ethyl piperidine -4- base methanone derivatives are preparing the application in cerebral arterial thrombosis therapeutic agent.

Compound (1- (2- (4- methoxyphenoxy) ethyl) piperidin-4-yl) (4- fluorophenyl) ketone, (1- (2- (4- bromine Phenoxy group) ethyl) piperidin-4-yl) (4- fluorophenyl) ketone, (1- (2- (2- naphthoxy) ethyl) piperidin-4-yl) (4- fluorobenzene Base) ketone, (1- (2- (4- methoxyphenoxy) ethyl) piperidin-4-yl) (4- methoxyphenyl) ketone, (1- (2- (4- bromobenzene Oxygroup) ethyl) piperidin-4-yl) (4- ethoxyl phenenyl) ketone, (1- (2- (4- chlorophenoxy) ethyl) piperidin-4-yl) (4- chlorine Phenyl) ketone, (1- (2- (4- methylphenoxy) ethyl) piperidin-4-yl) (4- chlorphenyl) ketone, (1- (2- (4- methoxybenzene Oxygroup) ethyl) piperidin-4-yl) (4- chlorphenyl) ketone, (1- (2- (4- bromobenzene oxygroup) ethyl) piperidin-4-yl) (4- chlorobenzene Base) ketone, (1- (2- (2- methylphenoxy) ethyl) piperidin-4-yl) (4- chlorphenyl) ketone, (1- (2- (4- methylenedioxy phenoxy Base) ethyl) piperidin-4-yl) (4- aminomethyl phenyl) ketone, (1- (2- (2- methylphenoxy) ethyl) piperidin-4-yl) (4- methyl Phenyl) ketone, (1- (2- (4- chlorophenoxy) ethyl) piperidin-4-yl) (4- aminomethyl phenyl) ketone, (1- (2- (2- naphthoxy) Ethyl) piperidin-4-yl) (4- aminomethyl phenyl) ketone preparing the application in cerebral arterial thrombosis therapeutic agent.

The preparation method of general formula (I) 1- virtue oxygen ethyl piperidine -4- base methanone derivatives of the present invention can be by synthesizing Schematic diagram 1~4 indicates:

A. the fragrant phenol replaced is condensed to yield the corresponding fragrant oxygen bromoethane replaced with glycol dibromide and (illustrates see synthesis Fig. 1)；

B.4- piperidinecarboxylic acid with acetic acid back flow reaction 10 hours, be added acetic anhydride continue back flow reaction after, remove under reduced pressure molten Agent obtains N- Acetylpiperidin -4- formic acid (see synthesis schematic diagram 2)；

C.N- Acetylpiperidin -4- formic acid reacts to obtain corresponding acyl chlorides with thionyl chloride, under the catalysis of alchlor Friedel-crafts acylation reaction occurs with substituted benzene and obtains corresponding N- acetyl group substituted benzene formyl phenylpiperidines, is lauched in hydrochloric acid catalysis Solution obtains corresponding substituted benzene formyl phenylpiperidines (see synthesis schematic diagram 3)；

D. the fragrant oxygen bromoethane replaced and substituted benzoyl piperidine are condensed to yield general formula (I) compound and (show see synthesis It is intended to 4).

The utility model has the advantages that

Currently, the zoopery of neuroprotection screening active ingredients is absent-minded using bilateral carotid and fan according to a conventional method Different compounds are observed to the influence of acute cerebral ischemia mouse survival time through desmurgia to carry out the drug effects of anti-cerebral ischemia drugs Learn preliminary assessment.Experimental data (detailed in Example 52) shows: it is preventative to give part of compounds of the present invention, urgency can be obviously prolonged Property cerebral ischemia mouse life span, have certain anti-cerebral ischemia neuroprotection.

Detailed description of the invention

Fig. 1 is synthesis schematic diagram 1；

Fig. 2 is synthesis schematic diagram 2；

Fig. 3 is synthesis schematic diagram 3；

Fig. 4 is synthesis schematic diagram 4.

Specific embodiment

The following examples can make those skilled in the art that the present invention be more fully understood, but not limit this in any way Invention.

Embodiment 1

2- (2- bromine oxethyl) naphthalene

By ethyl naphthol (7.2g, 50mmol), 1,2- Bromofume (6.5mL, 75mmol), tri- neck of 100mL is added in water 30mL In bottle, stirring is warming up to reflux, and 25% sodium hydroxide solution (12mL, 75mmol) is added dropwise, drips off within about 40 minutes.It flows back 10 small When, the cooling layering of reaction solution stands, has a large amount of aubergine solids to be precipitated.It filters, filter cake washs two with 5% sodium hydroxide solution It is secondary, it is washed with water twice, twice with dehydrated alcohol recrystallization, obtains white crystal 5.2g, yield 41.3%, TLC shows pure point.

Embodiment 2

1- (2- bromine oxethyl) -4- methoxybenzene

By p methoxy phenol (6.2g, 50mmol), 1,2- Bromofume (6.5mL, 75mmol), water 30ml is added In 100mL three-necked bottle, it is added dropwise 25% sodium hydroxide solution (12mL, 75mmol), drips off within about 45 minutes.Back flow reaction 13 hours. Liquid separation after reaction solution is cooling, organic layer are washed twice with 5% sodium hydroxide solution, are washed with water twice, and anhydrous magnesium sulfate is dry, It filters, organic solvent is evaporated off, obtains light achromaticity and clarification oily liquids.White solid 7.0g is chromatographed to obtain by eluant, eluent column of petroleum ether, Yield 61.4%, TLC show pure point.

Embodiment 3

1- (2- bromine oxethyl) -4- methylbenzene

By paracresol (6.5g, 60mmol), 1,2- Bromofume (7.8ml, 90mmol), tri- neck of 100mL is added in water 30mL In bottle, stirring is warming up to reflux, and 25% sodium hydroxide solution (14.4mL, 90mmol) is added dropwise, drips off within about 45 minutes.Reflux 10 Hour.Liquid separation after reaction solution is cooling, organic layer are washed twice with 5% sodium hydroxide solution, are washed with water twice, anhydrous magnesium sulfate It is dry, it filters, organic solvent is evaporated off, obtains faint yellow clear oil liquid.White solid is chromatographed to obtain by eluant, eluent column of petroleum ether 4.1g, yield 34.2%, TLC show pure point.

Embodiment 4

1- (2- bromine oxethyl) -2- methylbenzene

By o-cresol (6.5g, 60mmol), 1,2- Bromofume (7.8mL, 90mmol), tri- neck of 100mL is added in water 72mL In bottle, stirring is warming up to reflux, and 25% sodium hydroxide solution (14.4mL, 90mmol) is added dropwise, drips off within about 45 minutes.Reflux 13 Hour.Liquid separation after reaction solution is cooling, organic layer are washed twice with 5% sodium hydroxide solution, are washed with water twice, anhydrous magnesium sulfate It is dry, it filters, organic solvent is evaporated off, obtains faint yellow clear oil liquid.Colorless oil is chromatographed to obtain by eluant, eluent column of petroleum ether Liquid 5.5g, yield 42.5%, TLC show pure point.

Embodiment 5

1- (2- bromine oxethyl) -4- chlorobenzene

Parachlorophenol (15.4g, 120mmol), 1,2- Bromofume (15.6mL, 180mmol), water 72mL, 25% hydrogen-oxygen Change sodium solution (28.8mL, 180mmol), back flow reaction 12 hours.Liquid separation after reaction solution is cooling, 5% sodium hydroxide of organic layer Solution washes twice, and is washed with water twice, and anhydrous magnesium sulfate is dry, filters, organic solvent is evaporated off, obtains faint yellow clear oil liquid Body.White solid 22.8g, yield 81.2% are chromatographed to obtain by eluant, eluent column of petroleum ether, TLC shows pure point.

Embodiment 6

1- (2- bromine oxethyl) -4- bromobenzene

By p bromophenol (4.3g, 25mmol), 1,2- Bromofume (3.2mL, 37.5mmol), 100mL is added in water 30mL Three-necked bottle, 25% sodium hydroxide solution (6mL, 37.5mmol), back flow reaction 12.5 hours.Liquid separation after reaction solution is cooling, it is organic Layer is washed twice with 5% sodium hydroxide solution, is washed with water twice, and anhydrous magnesium sulfate is dry, filters, organic solvent is evaporated off, obtains Faint yellow clear oil liquid.White solid 5.4g is chromatographed to obtain by eluant, eluent column of petroleum ether, yield 50.0%, TLC shows pure Point.

Embodiment 7

N- Acetylpiperidin -4- formic acid

4- piperidinecarboxylic acid (1.03g, 8mmo1) and 10mL acetic acid are added in the eggplant-shape bottle of 50mL, are heated to flowing back, is reacted About 10 hours.10mL acetic anhydride is added, steams solvent after continuing reflux 1 hour.Blocks of solid is formed in product cooling.Use petroleum ether Sufficiently washing, it is dry, buff white solid 1.3g, yield 92.9% are obtained, TLC shows pure point.

Embodiment 8

4- (to fluoro benzoyl) piperidines

By N- Acetylpiperidin -4- formic acid (1.3g, 7.6mmol) and 15mL 1,2- dichloroethanes is added tri- mouthfuls of 100mL In bottle, temperature is controlled at 40-50 DEG C, is slowly added dropwise with the diluted thionyl chloride of 3mL solvent (1mL, 14mmol).Continue in the temperature After lower stirring 2 hours of degree, fluorobenzene (0.72mL, 7.6mmol) and alchlor (2.0g, 15mmol) are added into reaction system, Reflux 4 hours, is cooled to room temperature addition ice water, is sufficiently stirred, stratification.Organic layer is washed with water 20mL × 2, is concentrated under reduced pressure It obtains brown oil (N- acetyl -4- (to fluoro benzoyl) piperidines).By N- acetyl -4- (to fluoro benzoyl) piperidines, 10mL Water and 10mL concentrated hydrochloric acid are added in 50mL single port bottle, flow back 10 hours.Cooling is stood, is washed with methylene chloride 20mL × 2, water layer 5%NaOH solution adjusts pH=8-9, and methylene chloride 20mL × 3 is extracted, and merges organic phase, and anhydrous MgSO4 is dry.Filtering, concentration White solid is obtained, directly progress next step reaction.

Embodiment 9

4- (to methoxybenzoyl base) piperidines

By N- Acetylpiperidin -4- formic acid (1.3g, 7.6mmol) and 15mL 1,2- dichloroethanes is added tri- mouthfuls of 100mL In bottle, temperature is controlled at 40-50 DEG C, is slowly added dropwise with the diluted thionyl chloride of 3mL solvent (1mL, 14mmol).Continue in the temperature After the lower reaction of degree 2 hours, be added into reaction system methyl phenyl ethers anisole (0.72mL, 7.6mmol) and alchlor (2.0g, 15mmol), it flows back 4 hours, is cooled to room temperature addition ice water, is sufficiently stirred, stratification.Organic layer is washed with water 20mL × 2, Brown oil (N- acetyl -4- (to methoxybenzoyl base) piperidines) is concentrated under reduced pressure to obtain.By N- acetyl -4- (to methoxybenzene Formoxyl) piperidines, 10mL water and 10mL concentrated hydrochloric acid are added in 50mL single port bottle, flow back 10 hours.Cooling is stood, methylene chloride is used 20mL × 2 is washed, and water layer 5%NaOH solution adjusts pH=8-9, and methylene chloride 20mL × 3 is extracted, and merges organic phase, anhydrous MgSO4 is dry.It filters, be concentrated to give white solid, directly progress next step reaction.

Embodiment 10

4- (to benzoyl bromide) piperidines

By N- Acetylpiperidin -4- formic acid (1.3g, 7.6mmol) and 15mL 1,2- dichloroethanes is added tri- mouthfuls of 100mL In bottle, temperature is controlled at 40-50 DEG C, is slowly added dropwise with the diluted thionyl chloride of 3mL solvent (1mL, 14mmol).Continue in the temperature After lower reaction 2 hours of degree, bromobenzene (0.72mL, 7.6mmol) and alchlor (2.0g, 15mmol) are added into reaction system, Reflux 4 hours, is cooled to room temperature addition ice water, is sufficiently stirred, stratification.Organic layer is washed with water 20mL × 2.Organic layer subtracts Pressure is concentrated to give brown oil (N- acetyl -4- (to benzoyl bromide) piperidines).By N- acetyl -4- (to benzoyl bromide) piperazine Pyridine, 10mL water and 10mL concentrated hydrochloric acid are added in 50mL single port bottle, flow back 10 hours.Cooling is stood, is washed with methylene chloride 20mL × 2 It washs, water layer 5%NaOH solution adjusts pH=8-9, and methylene chloride 20mL × 3 is extracted, and merges organic phase, and anhydrous MgSO4 is dry.It crosses It filters, be concentrated to give white solid, directly progress next step reaction.

Embodiment 11

4- (to ethoxybenzo) piperidines

By N- Acetylpiperidin -4- formic acid (1.3g, 7.6mmol) and 15mL 1,2- dichloroethanes is added tri- mouthfuls of 100mL In bottle, temperature is controlled at 40-50 DEG C, is slowly added dropwise with the diluted thionyl chloride of 3mL solvent (1mL, 14mmol).Continue in the temperature After the lower reaction of degree 2 hours, be added into reaction system phenetole (0.72mL, 7.6mmol) and alchlor (2.0g, 15mmol), it flows back 4 hours, is cooled to room temperature addition ice water, is sufficiently stirred, stratification.Organic layer is washed with water 20mL × 2. Organic layer is concentrated to give brown oil (N- acetyl -4- (to ethoxybenzo) piperidines).By N- acetyl -4- (to ethyoxyl Benzoyl) piperidinyl-1 0mL water and 10mL concentrated hydrochloric acid be added in 50mL single port bottle, flow back 10 hours.Cooling is stood, dichloromethane is used Alkane 20mL × 2 is washed, and water layer 5%NaOH solution adjusts pH=8-9, and methylene chloride 20mL × 3 is extracted, and merges organic phase, anhydrous MgSO4 is dry.It filters, be concentrated to give white solid, directly progress next step reaction.

Embodiment 12

4- (to chlorobenzene formacyl) piperidines

By N- Acetylpiperidin -4- formic acid (1.3g, 7.6mmol) and 15mL 1,2- dichloroethanes is added tri- mouthfuls of 100mL In bottle, temperature is controlled at 40-50 DEG C, is slowly added dropwise with the diluted thionyl chloride of 3mL solvent (1mL, 14mmol).Continue in the temperature After lower reaction 2 hours of degree, chlorobenzene (0.72mL, 7.6mmol) and alchlor (2.0g, 15mmol) are added into reaction system, Reflux 4 hours, is cooled to room temperature addition ice water, is sufficiently stirred, stratification.Organic layer is washed with water 20mL × 2.Organic layer is dense Contract to obtain brown oil (N- acetyl -4- (to chlorobenzene formacyl) piperidines).By N- acetyl -4- (to chlorobenzene formacyl) piperidines, 10mL water and 10mL concentrated hydrochloric acid are added in 50mL single port bottle, flow back 10 hours.Cooling is stood, is washed with methylene chloride 20mL × 2, Water layer 5%NaOH solution adjusts pH=8-9, and methylene chloride 20mL × 3 is extracted, and merges organic phase, and anhydrous MgSO4 is dry.Filtering, It is concentrated to give white solid, directly progress next step reaction.

Embodiment 13

4- (to methyl benzoyl) piperidines

By N- Acetylpiperidin -4- formic acid (1.3g, 7.6mmol) and 15mL 1,2- dichloroethanes is added tri- mouthfuls of 100mL In bottle, temperature is controlled at 40-50 DEG C, is slowly added dropwise with the diluted thionyl chloride of 3mL solvent (1mL, 14mmol).Continue in the temperature After lower reaction 2 hours of degree, toluene (0.72mL, 7.6mmol) and alchlor (2.0g, 15mmol) are added into reaction system, Reflux 4 hours, is cooled to room temperature addition ice water, is sufficiently stirred, stratification.Organic layer is washed with water 20mL × 2.Organic layer is dense Contract to obtain brown oil (N- acetyl -4- (to methyl benzoyl) piperidines).By N- acetyl -4- (to methyl benzoyl) piperazine Pyridine, 10mL water and 10mL concentrated hydrochloric acid are added in 50mL single port bottle, flow back 10 hours.Cooling is stood, is washed with methylene chloride 20mL × 2 It washs, water layer 5%NaOH solution adjusts pH=8-9, and methylene chloride 20mL × 3 is extracted, and merges organic phase, and anhydrous MgSO4 is dry.It crosses It filters, be concentrated to give white solid, directly progress next step reaction.

Embodiment 14

4- (2,4- dimethylbenzoyl) piperidines

By N- Acetylpiperidin -4- formic acid (1.3g, 7.6mmol) and 15mL 1,2- dichloroethanes is added tri- mouthfuls of 100mL In bottle, temperature is controlled at 40-50 DEG C, is slowly added dropwise with the diluted thionyl chloride of 3mL solvent (1mL, 14mmol).Continue in the temperature After lower reaction 2 hours of degree, fluorobenzene (0.72mL, 7.6mmol) and alchlor (2.0g, 15mmol) are added into reaction system, Reflux 4 hours, is cooled to room temperature addition ice water, is sufficiently stirred, stratification.Organic layer is washed with water 20mL × 2.Organic layer is dense Contract to obtain brown oil (N- acetyl -4- (2,4- dimethylbenzoyl) piperidines).By N- acetyl -4- (2,4- dimethyl benzene first Acyl group) piperidinyl-1 0mL water and 10mL concentrated hydrochloric acid be added in 50mL single port bottle, flow back 10 hours.Cooling is stood, methylene chloride is used 20mL × 2 is washed, and water layer 5%NaOH solution adjusts pH=8-9, and methylene chloride 20mL × 3 is extracted, and merges organic phase, anhydrous MgSO4 is dry.It filters, be concentrated to give red solid, directly progress next step reaction.

Embodiment 15

(1- (2- (4- methoxyphenoxy) ethyl) piperidin-4-yl) (4- fluorophenyl) ketone (WY-1)

By 4- (4- fluoro benzoyl) piperidines (1.1g, 5.3mmol), 1- (2- bromine oxethyl) -4- methoxybenzene (1.6g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Solvent is evaporated off in reflux 24 hours, and the dissolution of 30mL methylene chloride is added, and three times with 20mL washing, has Machine layer is concentrated to give brown oil, and using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs light yellow Solid 0.83g, yield 42.3%, m.p.83.9-85.1 DEG C.HRMS calcd for C₂₁H₂₄FNO₂[M+H]⁺358.1818, found 358.1821.¹H NMR(CDCl₃,500MHz)δ:1.88-1.89(bs,4H,COCH(CH₂)₂),2.32(bs,2H,CH₂ of piperidine),2.84(t,2H,OCH₂CH₂, J=5.5Hz), 3.08-3.10 (m, 2H, CH₂ of piperidine), 3.18-3.23(m,1H,CH),3.73-3.80(s,3H,OCH₃),4.07-4.11(t,2H,OCH₂, J=5.5Hz), 6.81- 7.97(m,8H,ArH).¹³C NMR(CDCl₃,75MHz)δ:28.6,43.3,53.2,55.6,57.4,66.6,76.5,76.9, 77.4,114.2,114.6,115.8,130.4,130.7,130.8,132.4,152.8,153.9,163.9,167.2,200.8。

Embodiment 16

(1- (2- (4- bromobenzene oxygroup) ethyl) piperidin-4-yl) (4- fluorophenyl) ketone (WY-2)

By 4- (4- fluoro benzoyl) piperidines (1.1g, 5.3mmol), 1- (2- bromine oxethyl) -4- bromobenzene (1.9g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Solvent is evaporated off in reflux 22 hours, and the dissolution of 30mL methylene chloride is added, and three times with 20mL washing, has Machine layer is concentrated to give brown oil, and using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain light brown Solid 1.37g, yield 63.7%, m.p.108.8-103.3 DEG C.HRMS calcd for C₂₀H₂₁BrFNO₂[M+H]⁺ 406.0818,found 406.822.¹H NMR(CDCl₃,500MHz)δ:1.883(bs,4H,COCH(CH₂)₂),2.32(bs, 2H,CH₂ of piperidine),2.85(t,2H,OCH₂CH₂, J=5.5Hz), 3.06-3.08 (m, 2H, CH₂ of piperidine),3.20-3.23(m,1H,CH),4.10(t,2H,OCH₂, J=5.5Hz), 6.78-7.98 (m, 8H, ArH) .¹³C NMR(CDCl₃,75MHz)δ:28.5,43.3,53.5,57.1,66.2,76.5,76.9,77.4,112.8,115.5, 115.8,116.3,130.7,130.8,132.1,157.8,163.8,167.2,200.7。

Embodiment 17

(1- (2- (4- chlorophenoxy) ethyl) piperidin-4-yl) (4- fluorophenyl) ketone (WY-3)

By 4- (4- fluoro benzoyl) piperidines (1.1g, 5.3mmol), 1- (2- bromine oxethyl) -4- chlorobenzene (1.6g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Solvent is evaporated off in reflux 22 hours, and the dissolution of 30mL methylene chloride is added, and three times with 20mL washing, has Machine layer is concentrated to give brown oil, and using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain light brown Solid 0.71g, yield 36.8%, m.p.80.1-83.2 DEG C.HRMS calcd for C₂₀H₂₁ClFNO₂[M+H]⁺362.1323, found 362.1326.¹H NMR(CDCl₃,300MHz)δ:1.93(bs,4H,COCH(CH₂)₂),2.44(bs,2H,CH₂ of piperidine),2.92(t,2H,OCH₂CH₂, J=5.7Hz), 3.11-3.15 (m, 2H, CH₂ of piperidine), 3.21-3.31(m,1H,CH),4.12-4.16(t,2H,OCH₂, J=5.7Hz), 6.81-7.98 (m, 8H, ArH)¹³C NMR (CDCl₃,75MHz)δ:21.6,27.4,42.2,52.6,56.5,65.4,115.6,115.7,115.9,125.8,129.2, 130.7,130.8,156.9,163.9,167.3,175.5,200.4。

Embodiment 18

(1- (2- (2- naphthoxy) ethyl) piperidin-4-yl) (4- fluorophenyl) ketone (WY-4)

By 4- (4- fluoro benzoyl) piperidines (1.1g, 5.3mmol), 1- (2- bromine oxethyl) naphthalene (1.7g, 6.9mmol), KI (1.6g, 10mmol) and ethyl alcohol 30mL is added in 100mL eggplant-shape bottle and is heated to reflux, dropwise addition 5mL 20%KOH solution, and 10 minutes It is added dropwise.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer is washed three times with 20mL, and organic layer is dense Contracting, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain brown solid 1.31g, yield 65.0%, m.p.89.9-90.1 DEG C.HRMS calcd for C₂₄H₂₄FNO₂[M+H]⁺378.1869,found378.1872.¹H NMR(CDCl₃,300MHz)δ:1.92(m,4H,COCH(CH₂)₂),2.3402.42(m,2H,CH₂ of piperidine), 2.95(t,2H,OCH₂CH₂, J=5.7Hz), 3.12-3.19 (m, 2H, CH₂ of piperidine),3.22-3.29(m,1H, CH),4.27(t,2H,OCH₂, J=5.7Hz), 7.11-7.99 (m, 11H, ArH)¹³C NMR(CDCl₃,75MHz)δ:28.6, 43.3,53.5,57.2,65.9,106.6,115.4,115.7,118.8,123.5,126.2,126.6,127.5,129.2, 130.6,130.9,132.3,134.4,156.6,163.7,167.1,200.7。

Embodiment 19

(1- (2- (2- methylphenoxy) ethyl) piperidin-4-yl) (4- fluorophenyl) ketone (WY-5)

By 4- (4- fluoro benzoyl) piperidines (1.1g, 5.3mmol), 1- (2- bromine oxethyl) -4- methoxybenzene (1.5g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL Secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain brown solid 1.45g, yield 79.4%, m.p.88.7-89.9 DEG C.HRMS calcd for C₂₁H₂₄FNO₂[M+H]⁺342.1869,found 342.1872.¹H NMR(CDCl₃,300MHz)δ:1.89-1.91(m,4H,COCH(CH₂)₂),2.22(s,3H,CH₃),2.32- 2.40(m,2H,CH₂ of piperidine),2.89(t,2H,OCH₂CH₂, J=5.7Hz), 3.09-3,13 (m, 2H, CH₂ of piperidine),3.14-3.24(m,1H,CH),4.14(t,2H,OCH₂, J=5.7Hz), 7.11-7.99 (m, 8H, ArH) .¹³C NMR(CDCl₃,75MHz)δ:16.2,28.6,43.3,53.5,57.39,66.2,76.5,76.9,77.4,110.9, 115.5,115.7,120.3,126.6,130.5,130.7,130.8,132.3,132.4,156.8,163.8,167.2, 200.8。

Embodiment 20

(1- (2- (4- methylphenoxy) ethyl) piperidin-4-yl) (4- fluorophenyl) ketone (WY-6)

4- (4- fluoro benzoyl) piperidines (1.1g, 5.3mmol), 1- (2- methyl ethoxy) -4- methylbenzene (1.5g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which will be added in 100mL eggplant-shape bottle, is heated to reflux, and 5mL 20%KOH is added dropwise Solution is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL Secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain brown solid 0.45g, yield 25.0%, m.p.90.3-91.0 DEG C.HRMS calcd for C₂₁H₂₄FNO₂[M+H]⁺342.1869,found 342.1872.¹H NMR(CDCl₃,300MHz)δ:189-1.90(m,4H,COCH(CH₂)₂),2.285(s,3H,CH₃),2.32 (m,2H,CH₂ of piperidine),2.86(t,2H,OCH₂CH₂, J=5.7Hz), 3..08-3,12 (m, 2H, CH₂ of ), piperidine 3.20-3.25 (m, 1H, CH), 4.12 (t, 2H, OCH2, J=5.7Hz), 6.79-7.98 (m, 8H, ArH) .¹³C NMR(CDCl₃,75MHz)δ:20.4,28.6,43.4,53.5,57.4,66.0,114.4,115.5,115.8,129.8, 130.7,130.8,167.3,200.8。

Embodiment 21

(1- (2- (4- methoxyphenoxy) ethyl) piperidin-4-yl) (4- methoxyphenyl) ketone (WY-7)

By 4- (4- methoxybenzoyl base) piperidines (1.2g, 5.3mmol), 1- (2- bromine oxethyl) -4- methoxybenzene (1.6g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol are added in 100mL eggplant-shape bottle and are heated to reflux, and 5mL is added dropwise 20%KOH solution is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer is used 20mL is washed three times, and organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs light Yellow solid 0.76g, yield 37.4%, m.p.90.4-91.3 DEG C.HRMS calcd for C₂₂H₂₇NO₄[M+H]⁺ 370.2018,found370.2021.¹H NMR(CDCl₃,300MHz)δ:1.91(m,4H,COCH(CH₂)₂),2.34(m,2H, CH₂ of piperidine),2.87(bs,2H,OCH₂CH₂),3..10-3,14(m,2H,CH₂ of piperidine),3.26 (m,1H,COCH),3.76(s,3H,OCH₃),3.87(s,3H,OCH₃),4.24(bs,2H,OCH₂),6.82-7.94(m,8H, ArH).¹³C NMR(CDCl₃,75MHz)δ:28.8,43.1,43.2,53.7,55.4,55.7,57.3,57.5,66.5,66.80, 113.8,114.6,115.6,115.9,129.3,130.4,152.9,163.3,201.0。

Embodiment 22

(1- (2- (4- chlorophenoxy) ethyl) piperidin-4-yl) (4- methoxyphenyl) ketone (WY-8)

By 4- (4- methoxybenzoyl base) piperidines (1.2g, 5.3mmol), 1- (2- bromine oxethyl) -4- chlorobenzene (1.6g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL Secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain white solid 0.55g, yield 27.8%, m.p.98.6-98.9 DEG C.HRMS calcd for C₂₁H₂₄ClNO₃[M+H]⁺374.1523,found 374.1527.¹H NMR(CDCl₃,300MHz)δ:1.94(bs,4H,COCH(CH₂)₂),2.42(bs,2H,CH₂ of piperidine),2.91(bs,2H,OCH₂CH₂),3.10-3,14(m,2H,CH₂ of piperidine),3.27(bs,1H, CH),3.8(s,3H,OCH₃),4.16(bs,2H,OCH2),6.83-7.94(m,8H,ArH).¹³C NMR(CDCl₃,75MHz)δ: 28.7,53.6,55.4,57.2,66.3,66.4,113.8,115.9,129.3,130.4,152.9,163.3,201.0。

Embodiment 23

(1- (2- (4- bromobenzene oxygroup) ethyl) piperidin-4-yl) (4- methoxyphenyl) ketone (WY-9)

By 4- (4- methoxybenzoyl base) piperidines (1.2g, 5.3mmol), 1- (2- bromine oxethyl) -4- bromobenzene (1.9g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL Secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain faint yellow solid 0.60g, yield 27.8%, m.p.97.3-98.0 DEG C.HRMS calcd for C₂₁H₂₄BrNO₃[M+H]⁺418.1018,found 418.1022.¹H NMR(CDCl₃,300MHz)δ:1.88-1.93(m,4H,COCH(CH₂)₂),2.32(m,2H,CH₂ of piperidine),2.86(t,2H,OCH₂CH_2,), J=5.7Hz 3.07-3.10 (m, 2H, CH₂ of piperidine), 3.21-3.26(m,1H,CH),3.88(s,3H,OCH₃),4.11(t,2H,OCH_2,), J=5.7Hz 6.83-7.94 (m, 8H, ArH).¹³C NMR(CDCl₃,75MHz)δ:28.6,29.6,42.9,53.6,55.4,57.1,66.2,112.8,113.7, 116.4,128.9,130.4,132.2,157.8,163.3,200.9。

Embodiment 24

(1- (2- (4- methylphenoxy) ethyl) piperidin-4-yl) (4- methoxyphenyl) ketone (WY-10)

By 4- (4- methoxybenzoyl base) piperidines (1.2g, 5.3mmol), 1- (2- bromine oxethyl) -4- methylbenzene (1.5g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol are added in 100mL eggplant-shape bottle and are heated to reflux, and 5mL is added dropwise 20%KOH solution is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer is used 20mL is washed three times, and organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs white Color solid 1.51g, yield 78.9%, m.p.95.7-97.0 DEG C.HRMS calcd for C₂₂H₂₇NO₃[M+H]⁺354.2069, found 354.2073.¹H NMR(CDCl₃,300MHz)δ:1.89(bs,4H,COCH(CH₂)₂),2.28-2.32(bs,5H,CH₃ and CH₂ of piperidine),2.86(s,2H,OCH₂CH₂),3.05-3.12(m,2H,CH₂ of piperidine), 3.23(bs,1H,CH),3.87(s,3H,OCH₃),4.05-4.12(m,2H,OCH₂),6.79-7.94(m,8H,ArH).¹³C NMR(CDCl₃,75MHz)δ:20.3,28.7,43.1,48.7,53.6,55.3,57.3,66.0,67.4,113.7,114.5, 128.9,129.8,130.4,156.5,163.2,200.9。

Embodiment 25

(1- (2- (2- naphthoxy) ethyl) piperidin-4-yl) (4- methoxyphenyl) ketone (WY-11)

By 4- (4- methoxybenzoyl base) piperidines (1.2g, 5.3mmol), 2- (2- bromine oxethyl) naphthalene (1.7g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL Secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain white solid 1.62g, yield 77.6%, m.p.95.6-96.7 DEG C.HRMS calcd for C₂₅H₂₇NO₃[M+H]⁺354.2069,found 354.2072.¹H NMR(CDCl₃,300MHz)δ:188-1.95(m,4H,COCH(CH₂)₂),2.36(m,2H,CH₂ of piperidine),2.94(t,2H,OCH₂CH₂, J=6.0Hz), 3.12-3.16 (m, 2H, CH₂ of piperidine), 3.23-3.27(m,1H,CH),3.88(s,3H,OCH₃),4.27(t,2H,OCH₂, J=6.0Hz), 6.94-7.96 (m, 11H, ArH).¹³C NMR(CDCl₃,75MHz)δ:16.1,28.7,53.5,57.2,66.4,110.9,120.3,126.65,127.9, 129.7,130.5,131.8,134.7,156.8,201.3。

Embodiment 26

(1- (2- (2- methylphenoxy) ethyl) piperidin-4-yl) (4- methoxyphenyl) ketone (WY-12)

By 4- (4- methoxybenzoyl base) piperidines (1.2g, 5.3mmol), 1- (2- bromine oxethyl) -2- methylbenzene (1.5g, 6.9mmol), KI (1.6g, 10mmol) and 30mL are added ethyl alcohol in 100mL eggplant-shape bottle and are heated to reflux, and 5mL is added dropwise 20%KOH solution is added dropwise for 10 minutes.Reflux 24 hours, solvent is evaporated off in, is extracted with 30mL methylene chloride, and organic layer is used 20mL is washed three times, and organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs white Color solid 1.45g, yield 77.5%, m.p.96.2-98.3 DEG C.HRMS calcd for C₂₂H₂₇NO₃[M+H]⁺390.2069, found 390.2073.¹H NMR(CDCl₃,300MHz)δ:1.88-1.89(m,4H,COCH(CH₂)₂),2.23(s,3H,CH₃), 2.38(bs,2H,CH₂ of piperidine),2.91(t,2H,OCH₂CH₂, J=5.7Hz), 3.11-3.15 (m, 2H, CH₂ of piperidine),3.21-3.26(m,1H,CH),3.87(s,3H,OCH₃),4.15(t,2H,OCH₂, J=5.7Hz), 6.82-7.96(m,8H,ArH).¹³C NMR(CDCl₃,75MHz)δ:28.7,42.9,53.6,55.2,57.2,65.9,106.6, 113.6,118.8,123.4,126.2,126.6,127.4,128.8,129.2,130.3,134.4,156.6,163.2, 200.8。

Embodiment 27

(1- (2- (4- chlorophenoxy) ethyl) piperidin-4-yl) (4- bromophenyl) ketone (WY-13)

By 4- (4- benzoyl bromide) piperidines (1.4g, 5.3mmol), 1- (2- bromine oxethyl) -4- chloro benzene (1.6g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL Secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain faint yellow solid 0.93g, yield 40.9%, m.p.99.1-102.4 DEG C.HRMS calcd for C₂₀H₂₁BrClNO₂[M+H]⁺422.0522, found 422.0526.¹H NMR(CDCl₃,300MHz)δ:1.91-1.99(bs,4H,COCH(CH₂)₂),2.33-2.34(bs, 2H,CH₂ of piperidine),2.89-2.89(bs,2H,OCH₂CH₂),3.09-3.13(m,2H,CH₂ of piperidine),3.20-3.24(m,1H,CH),4.14(t,2H,OCH₂),6.82-7.80(m,8H,ArH).¹³C NMR (CDCl₃,75MHz)δ:28.5,43.3,53.5,57.2,66.4,115.9,125.6,127.9,129.2,129.7,131.9, 134.7,157.3,201.3。

Embodiment 28

(1- (2- (2- methylphenoxy) ethyl) piperidin-4-yl) (4- bromophenyl) ketone (WY-14)

By 4- (4- benzoyl bromide) piperidines (1.4g, 5.3mmol), 1- (2- bromine oxethyl) -2- methylbenzene (1.5g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL Secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain brown solid 1.41g, yield 66.7%, m.p.96.2-98.3 DEG C.HRMS calcd for C₂₁H₂₄BrNO₂[M+H]⁺402.1069,found 402.1073.¹H NMR(CDCl₃,300MHz)δ:1.91-1.99(bs,4H,COCH(CH₂)₂),2.32-2.32(bs,2H, CH₂of piperidine),2.89-2.89(bs,2H,OCH₂CH₂),3.09-3.12(m,2H,CH₂ of piperidine), 3.20-3.24(m,1H,CH),4.14(t,2H,OCH₂),6.82-7.80(m,8H,ArH).¹³C NMR(CDCl₃,75MHz)δ: 16.2,28.6,43.4,53.5,57.4,66.3,110.9,120.3,126.7,127.9,129.7,130.5,131.8, 134.7,156.8,201.3。

Embodiment 29

(1- (2- (4- bromobenzene oxygroup) ethyl) piperidin-4-yl) (4- bromophenyl) ketone (WY-15)

By 4- (4- benzoyl bromide) piperidines (1.4g, 5.3mmol), 1- (2- bromine oxethyl) -4- bromobenzene (1.9g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL Secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain white solid 2.3g, Yield 92.0%, m.p.97.5-98.6 DEG C.HRMS calcd for C₂₀H₂₁Br₂NO₂[M+H]⁺466.0017,found 467.0014.¹H NMR(CDCl₃,300MHz)δ:1.863-1.873(s,4H,COCH(CH₂)₂),2.321(s,2H,CH₂ of piperidine),2.820-2.859(t,2H,OCH₂CH₂, J=6Hz), 3.047-3.086 (m, 2H, CH₂ of piperidine),3.172-3.220(m,1H,CH),4.072-4.111(t,2H,OCH₂, J=6Hz), 6.775-7.913 (m, 8H,ArH).¹³C NMR(CDCl₃,75MHz)δ:28.37,43.16,53.32,56.97,66.09,112.63,116.18, 127.73,129.53,131.70,131.95,132.03,134.47,157.62,201.06。

Embodiment 30

(1- (2- (4- methoxyphenoxy) ethyl) piperidin-4-yl) (4- bromophenyl) ketone (WY-16)

By 4- (4- benzoyl bromide) piperidines (1.4g, 5.3mmol), 1- (2- bromine oxethyl) -4- methoxybenzene (1.6g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL Secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain orange/yellow solid 0.82g, yield 36.4%, m.p.94.1-95.8 DEG C.HRMS calcd for C₂₁H₂₄BrNO₃[M+H]⁺418.1018,found 418.1023.¹H NMR(CDCl₃,300MHz)δ:1.90(bs,4H,COCH(CH₂)₂),2.02-2.06(bs,2H,CH₂ of piperidine),2.85(t,2H,OCH₂CH₂, J=5.7Hz), 3.05-3.13 (m, 2H, CH₂ of piperidine), 3.17-3.24(m,1H,CH),3.78(s,3H,CH₃),4.11(t,2H,OCH₂, J=6Hz), 6.82-7.83 (m, 8H, ArH) .¹³C NMR(CDCl₃,75MHz)δ:28.5,43.4,53.5,53.6,55.6,57.4,66.6,114.2,114.6,115.6, 127.9,128.1,128.6,129.7,130.4,131.9,132.8,134.7,152.8,153.8,201.4。

Embodiment 31

(1- (2- (4- methylphenoxy) ethyl) piperidin-4-yl) (4- bromophenyl) ketone (WY-17)

By 4- (4- benzoyl bromide) piperidines (1.4g, 5.3mmol), 1- (2- bromine oxethyl) -4- methylbenzene (1.5g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL Secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain white solid 1.95g, yield 90.5%, m.p.85.0-87.1 DEG C.HRMS calcd for C₂₁H₂₄BrNO₂[M+H]⁺402.1069,found 402.1073.¹H NMR(CDCl₃,300MHz)δ:1.91(bs,4H,COCH(CH₂)₂),2.30-2.34(bs,5H,CH₃ and CH₂ of piperidine),2.89(s,2H,OCH₂CH₂),3.10-3.14(m,2H,CH₂ of piperidine),3.29 (m,1H,CH),4.15(s,2H,OCH₂),6.81-7.82(m,8H,ArH).¹³C NMR(CDCl₃,75MHz)δ:20.2,28.4, 43.2,53.3,57.2,65.8,66.4,114.2,114.3,115.5,127.7,129.5,129.6,131.7,134.5, 156.5,201.1。

Embodiment 32

(1- (2- (2- naphthoxy) ethyl) piperidin-4-yl) (4- bromophenyl) ketone (WY-18)

By 4- (4- benzoyl bromide) piperidines (1.4g, 5.3mmol), 2- (2- bromine oxethyl) naphthalene (1.5g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, to be heated to reflux, dropwise addition 5mL 20%KOH solution, and 10 minutes It is added dropwise.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer is washed three times with 20mL, and organic layer is dense Contracting, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain beige solid 2.10g, yield 89.1%, m.p.80.2-82.4 DEG C.HRMS calcd for C₂₄H₂₄BrNO₂[M+H]⁺438.1069,found 438.1072.¹H NMR(CDCl₃,300MHz)δ:1.92-2.06(bs,4H,COCH(CH₂)₂),2.35(bs,2H,CH₂ of piperidine),2.97(t,2H,OCH₂CH₂, J=5.7Hz), 3.13-3.17 (m, 2H, CH₂ of piperidine), 3.22-3.24(m,1H,CH),4.29(t,2H,OCH₂, J=5.7Hz), 7.16-7.84 (m, 11H, ArH)¹H NMR(CDCl₃, 300MHz)δ:28.5,43.3,53.5,57.3,65.9,106.6,118.8,123.51,126.2,126.6,127.5,127.8, 128.8,129.2,129.6,131.8,134.4,134.6,156.6,201.2。

Embodiment 33

(1- (2- (4- methoxyphenoxy) ethyl) piperidin-4-yl) (4- ethoxyl phenenyl) ketone (WY-19)

By 4- (4- ethoxybenzo) piperidines (1.2g, 5.3mmol), 1- (2- bromine oxethyl) -4- methoxybenzene (1.6g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol are added in 100mL eggplant-shape bottle and are heated to reflux, and 5mL is added dropwise 20%KOH solution is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer is used 20mL is washed three times, and organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs grey White solid 1.33g, yield 65.0%, m.p.94.3-95.6 DEG C.HRMS calcd for C₂₃H₂₉NO₄[M+H]⁺ 384.2175,found 384.2179.¹H NMR(CDCl₃,300MHz)δ:1.41-1.46(t,3H,CH₂CH₃, J=6.9Hz), 1.87-1.95(m,4H,COCH(CH₂)₂),2.30(bs,2H,CH₂ of piperidine),2.80-2.84(m,2H, OCH₂CH₂),3.06-3.10(m,2H,CH₂ of piperidine),3.16-3.23(m,1H,CH),3.74(s,3H,OCH₃), 4.06-4.13(m,4H,OCH₂CH₃ and OCH₂CH₂),6.80-7.93(m,8H,ArH).¹³C NMR(CDCl₃,75MHz)δ: 14.5,28.8,43.2,53.6,55.6,57.5,67.6,66.8,114.2,114.6,115.6,128.9,130.3,152.9, 153.9,162.7,200.8。

Embodiment 34

(1- (2- (2- naphthoxy) ethyl) piperidin-4-yl) (4- ethoxyl phenenyl) ketone (WY-20)

By 4- (4- ethoxybenzo) piperidines (1.2g, 5.3mmol), 2- (2- bromine oxethyl) naphthalene (1.7g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL Secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain white solid 1.71g, yield 78.7%, m.p.98.2-100.3 DEG C.HRMS calcd for C₂₆H₂₉NO₃[M+H]⁺404.2226,found 404.2229.¹H NMR(CDCl₃,300MHz)δ:1.46(t,3H,CH₂CH₃, J=6.9Hz), 1.95 (bs, 4H, COCH (CH₂)₂),2.39(bs,2H,CH₂ of piperidine),2.99(bs,2H,OCH₂CH₂),3.16-3.19(m,2H,CH₂ of piperidine),3.28-3.31(m,1H,CH),4.09-4.16(q,2H,OCH₂CH₃, J=6.9Hz), 4.31 (bs, 2H, OCH₂CH₂),6.93-7.95(m,11H,ArH).¹³C NMR(CDCl₃,75MHz)δ:14.6,28.9,43.5,53.7,57.3, 63.7,66.2,106.9,107.2,114.3,118.9,123.5,123.7,126.3,126.3,126.7,127.6,129.0, 129.00,129.3,130.4,134.6,156.8,162.7,200.9。

Embodiment 35

(1- (2- (4- methylphenoxy) ethyl) piperidin-4-yl) (4- ethoxyl phenenyl) ketone (WY-21)

By 4- (4- ethoxybenzo) piperidines (1.2g, 5.3mmol), 1- (2- bromine oxethyl) -4- methylbenzene (1.5g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol are added in 100mL eggplant-shape bottle and are heated to reflux, and 5mL is added dropwise 20%KOH solution is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer is used 20mL is washed three times, and organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs white Color solid 0.62g, yield 30.8%, m.p.99.3-101.3 DEG C.HRMS calcd for C₂₃H₂₉NO₃[M+H]⁺368.2226, found 368.2230.¹H NMR(CDCl₃,300MHz)δ:1.44(t,3H,CH₂CH₃, J=6.9Hz), 1.86 (bs, 4H, COCH(CH₂)₂),2.28(m,5H,ArCH₃ and CH₂ of piperidine),2.81-2.85(t,2H,OCH₂CH₂, J= 5.7Hz),3.08(d,2H,CH₂Of piperidine, J=11.4Hz), 3.18-3.23 (m, 1H, CH), 4.06-4.12 (m, 4H,OCH₂CH₃ and OCH₂CH₂),6.72-7.93(m,8H,ArH).¹³C NMR(CDCl₃,75MHz)δ:14.5,20.3, 28.8,43.2,53.5,57.4,63.7,66.3,66.6,66.8,114.3,114.5,114.6,114.7,129.0,129.8, 129.9,130.4,156.7,162.8,200.9。

Embodiment 36

(1- (2- (2- methylphenoxy) ethyl) piperidin-4-yl) (4- ethoxyl phenenyl) ketone (WY-22)

By 4- (4- ethoxybenzo) piperidines (1.2g, 5.3mmol), 1- (2- bromine oxethyl) -2- methylbenzene (1.5g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol are added in 100mL eggplant-shape bottle and are heated to reflux, and 5mL is added dropwise 20%KOH solution is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer is used 20mL is washed three times, and organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs white Color solid 1.45g, yield 74.4%, m.p.91.9-92.5 DEG C.HRMS calcd for C₂₃H₂₉NO₃[M+H]⁺368.2226, found 368.2229.¹H NMR(CDCl₃,300MHz)δ:1.44(t,3H,CH₂CH₃, J=6.9Hz), 1.88 (bs, 4H, COCH(CH₂)₂),2.228(s,3H,CH₃),2.34(bs,2H,CH₂ of piperidine),2.89(bs,2H,OCH₂CH₂), 3.09-3.13(m,2H,CH₂ of piperidine),3.13-3.22(m,1H,CH),4.06-4.16(m,4H,OCH₂CH₃ and OCH₂CH₂),6.81-7.93(m,8H,ArH).¹³C NMR(CDCl₃,75MHz)δ:14.5,16.1,28.8,43.0, 53.6,57.4,63.6,69.5,111.1,114.2,120.3,120.6,126.6,128.9,130.3,130.5,156.9, 162.7,200.8。

Embodiment 37

(1- (2- (4- chlorophenoxy) ethyl) piperidin-4-yl) (4- ethoxyl phenenyl) ketone (WY-23)

By 4- (4- ethoxybenzo) piperidines (1.2g, 5.3mmol), 1- (2- bromine oxethyl) -4- chlorobenzene (1.6g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL Secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain faint yellow solid 1.54g, yield 74.8%, m.p.91.5-92.8 DEG C.HRMS calcd for C₂₂H₂₆ClNO₃[M+H]⁺388.1679,found 388.1683.¹H NMR(CDCl₃,300MHz)δ:1.44(t,3H,CH₂CH₃, J=6.9Hz), 1.87-1.93 (m, 4H, COCH (CH₂)₂),2.31(bs,2H,CH₂ of piperidine),2.84(t,2H,OCH₂CH₂, J=5.7Hz), 3.05-3.09 (m, 2H,CH₂ of piperidine),3.19-3.24(m,1H,CH),4.06-4.13(m,4H,OCH₂CH₃ and OCH₂CH₂), 6.82-7.94(m,8H,ArH).¹³C NMR(CDCl₃,75MHz)δ:14.6,28.8,43.2,53.7,57.3,63.73,66.6, 114.3,116.0,129.0,129.3,130.4,157.5,162.8,200.9。

Embodiment 38

(1- (2- (4- bromobenzene oxygroup) ethyl) piperidin-4-yl) (4- ethoxyl phenenyl) ketone (WY-24)

By 4- (4- ethoxybenzo) piperidines (1.2g, 5.3mmol), 1- (2- bromine oxethyl) -4- bromobenzene (1.9g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL It is secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatograph canescence is solid 1.23g, yield 53.7%, m.p.93.9-95.0 DEG C.HRMS calcd for C₂₂H₂₆BrNO₃[M+H]⁺372.1730,found 372.1734.¹H NMR(CDCl₃,300MHz)δ:1.42-1.47(t,3H,CH₂CH₃, J=6.9Hz), 1.89 (bs, 4H, COCH (CH₂)₂),2.31(bs,2H,CH₂ of piperidine),2.85(bs,2H,OCH₂CH₂),3.06-3.10(m,2H,CH₂ of piperidine),3.23(m,1H,CH),4.07-4.13(m,4H,OCH₂CH₃ and OCH₂CH₂),6.79-7.93(m,8H, ArH).¹³C NMR(CDCl₃,75MHz)δ:14.5,28.6,42.9,53.5,57.1,63.6,66.4,112.8,114.2, 116.4,128.8,130.3,132.1,157.8,162.7,200.7。

Embodiment 39

(1- (2- (4- chloro phenoxy group) ethyl) piperidin-4-yl) (2,4- 3,5-dimethylphenyl) ketone (WY-25)

By 4- (2,4- dimethylbenzoyl) piperidines (1.2g, 5.3mmol), 1- (2- bromine oxethyl) -4- chlorobenzene (1.6g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol are added in 100mL eggplant-shape bottle and are heated to reflux, and 5mL is added dropwise 20%KOH solution is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer is used 20mL is washed three times, and organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs red Brown solid 0.85g, yield 43.1%, m.p.98.4-99.7 DEG C.HRMS calcd for C₂₀H₂₆ClNO₂[M+H]⁺ 432.1174,found 432.1178.¹H NMR(CDCl₃,300MHz)δ:1.80-1.84(m,4H,COCH(CH₂)₂),2.21- 2.25(m,2H,CH₂ of piperidine),2.34(s,3H,CH₃),2.40(s,3H,CH₃),2.81(t,2H,OCH₂CH₂,J =6Hz), 3.00-3.04 (m, 3H, CH₂ of piperidine and CH),4.08(t,2H,OCH₂CH₂, J=6Hz), 6.81-7.44(m,8H,ArH).¹³C NMR(CDCl₃,75MHz)δ:20.7,21.2,28.3,46.3,53.7,57.3,66.7, 116.0,126.1,127.7,129.3,132.6,135.4,137.89 141.0,157.5,206.5。

Embodiment 40

(1- (2- (4- chlorophenoxy) ethyl) piperidin-4-yl) (4- chlorphenyl) ketone (WY-26)

By 4- (4- chlorobenzene formacyl) piperidines (1.2g, 5.3mmol), 1- (2- bromine oxethyl) -4- chlorobenzene (1.6g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL It is secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatograph brown color is solid 1.13g, yield 56.5%, m.p.86.7-88.2 DEG C.HRMS calcd for C₂₀H₂₁Cl₂NO₂[M+H]⁺378.1028, found 378.1031.¹H NMR(CDCl₃,300MHz)δ:1.88(bs,4H,COCH(CH₂)₂),2.33(bs,2H,CH₂ of piperidine),2.85(t,2H,OCH₂CH₂, J=5.7Hz), 3.06-3.10 (m, 2H, CH₂ of piperidine), 3.19-3.24(m,1H,CH),4.11(t,2H,OCH₂CH₂, J=5.7Hz), 6.82-7.88 (m, 8H, ArH)¹³C NMR (CDCl₃,75MHz)δ:28.5,43.3,53.5,57.1,66.3,115.8,125.6,128.9,129.2,129.6,135.3, 139.3,157.3,201.1。

Embodiment 41

(1- (2- (4- methylphenoxy) ethyl) piperidin-4-yl) (4- chlorphenyl) ketone (WY-27)

By 4- (4- chlorobenzene formacyl) piperidines (1.2g, 5.3mmol), 1- (2- bromine oxethyl) -4- methylbenzene (1.5g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL It is secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatograph grey consolidates 0.73g, Yield 38.4%, m.p.96.2-98.3 DEG C.HRMS calcd for C₂₁H₂₄ClNO₂[M+H]⁺358.1574,found 358.1578.¹H NMR(CDCl₃,300MHz)δ:1.87-1.88(bs,4H,COCH(CH₂)₂),2.28(s,3H,CH₃),2.31 (bs,2H,CH₂ of piperidine),2.85(t,2H,OCH₂CH₂, J=5.7Hz), 3.07-3.11 (m, 2H, CH₂ of piperidine),3.18-3.23(m,1H,CH),4.11(t,2H,OCH₂CH₂, J=5.7Hz), 6.79-7.88 (m, 8H, ArH).¹³C NMR(CDCl₃,75MHz)δ:20.4,28.5,43.3,53.4,57.4,66.0,114.5,129.0,129.7, 129.9,134.3,139.3,156.6,201.2。

Embodiment 42

(1- (2- (2- naphthoxy) ethyl) piperidin-4-yl) (4- chlorphenyl) ketone (WY-28)

By 4- (4- chlorobenzene formacyl) piperidines (1.2g, 5.3mmol), 2- (2- bromine oxethyl) naphthalene (1.7g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, to be heated to reflux, dropwise addition 5mL 20%KOH solution, and 10 minutes It is added dropwise.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer is washed three times with 20mL, and organic layer is dense Contracting, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain gray solid 1.01g, yield 47.6%, m.p.94.2-96.0 DEG C.HRMS calcd for C₂₄H₂₄ClNO₂[M+H]⁺394.1574,found 394.1577.¹H NMR(CDCl₃,300MHz)δ:1.91(m,4H,COCH(CH₂)₂),2.37(bs,2H,CH₂ of piperidine),2.96(bs,2H,OCH₂CH₂),3.14-3.23(m,3H,CH₂ of piperidine and CH),4.28 (bs,2H,OCH₂CH₂),7.14-7.89(m,11H,ArH).¹³C NMR(CDCl₃,75MHz)δ:28.5,43.4,53.5,57.2, 65.9,106.7,118.9,123.5,126.3,126.6,127.5,128.8,129.3,129.6,134.5,134.4,139.5, 156.6,201.1。

Embodiment 43

(1- (2- (4- methoxyphenoxy) ethyl) piperidin-4-yl) (4- chlorphenyl) ketone (WY-29)

By 4- (4- chlorobenzene formacyl) piperidines (1.2g, 5.3mmol), 1- (2- bromine oxethyl) -4- methoxybenzene (1.5g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL Secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain brown solid 1.93g, yield 97.0%, m.p.97.2-99.0 DEG C.HRMS calcd for C₂₁H₂₄ClNO₃[M+H]⁺374.1523,found 374.1527.¹H NMR(CDCl₃,300MHz)δ:1.88(bs,4H,COCH(CH₂)₂),2.32(bs,2H,CH₂ of piperidine),2.85(bs,2H,OCH₂CH₂),3.08-3.11(m,2H,CH₂ of piperidine),3.21(m,1H, CH),3.77(s,3H,OCH₃),4.09(bs,2H,OCH₂CH₂),6.827.89(m,8H,ArH).¹³C NMR(CDCl₃,75MHz) δ:28.5,43.4,53.5,55.6,57.4,66.6,67.3,114.6,115.5,115.7,128.9,129.6,134.3, 139.2,152.9,153.8,201.2。

Embodiment 44

(1- (2- (4- bromobenzene oxygroup) ethyl) piperidin-4-yl) (4- chlorphenyl) ketone (WY-30)

By 4- (4- chlorobenzene formacyl) piperidines (1.2g, 5.3mmol), 1- (2- bromine oxethyl) -4- bromobenzene (1.9g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL It is secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatograph yellow consolidates 1.88g, Yield 83.9%, m.p.97.5-98.9 DEG C.HRMS calcd for C₂₀H₂₁BrClNO₂[M+H]⁺422.0522,found 422.0526.¹H NMR(CDCl₃,300MHz)δ:1.88-1.89(m,4H,COCH(CH₂)₂),2.32-2.33(bs,2H,CH₂of piperidine),2.83-2.87(t,2H,OCH₂CH₂, J=5.7Hz), 3.06-3.10 (m, 2H, CH₂ of piperidine),3.17-3.27(m,1H,CH),4.09-4.12(t,2H,OCH₂CH₂, J=5.7Hz), 6.79-7.90 (m, 8H,ArH).¹³C NMR(CDCl₃,75MHz)δ:28.5,43.3,53.5,57.1,66.3,112.8,116.3,128.87, 129.6,132.1,134.3,139.2,157.8,201.1。

Embodiment 45

(1- (2- (2- methylphenoxy) ethyl) piperidin-4-yl) (4- chlorphenyl) ketone (WY-31)

By 4- (4- chlorobenzene formacyl) piperidines (1.2g, 5.3mmol), 1- (2- bromine oxethyl) -2- methylbenzene (1.5g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Reflux 24 hours, is evaporated off solvent, is dissolved with 30mL methylene chloride, and organic layer washes three with 20mL Secondary, organic layer concentration, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain brown solid 0.84g, yield 44.2%, m.p.96.2-98.3 DEG C.HRMS Calcd for C₂₁H₂₄ClNO₂[M+H]⁺358.1574,found 358.1577.¹H NMR(CDCl₃,300MHz)δ:1.89(m,4H,COCH(CH₂)₂),2.34(s,3H,CH₃),2.38(bs,2H, CH₂ of piperidine),2.92(t,2H,OCH₂CH₂, J=5.7Hz), 3.12-3.20 (m, 2H, CH₂ of piperidine),3.23-3.25(m,1H,CH),4.16(t,2H,OCH₂CH₂, J=5.7Hz), 6.89-7.91 (m, 8H, ArH).¹³C NMR(CDCl₃,75MHz)δ:16.1,28.7,43.5,53.5,57.4,66.4,111.2,120.4,126.7, 128.8,129.5,9130.6,134.5,139.2,156.9,201.1。

Embodiment 46

(1- (2- (4- methylphenoxy) ethyl) piperidin-4-yl) (4- aminomethyl phenyl) ketone (WY-32)

By 4- (4- methyl benzoyl) piperidines (1.1g, 5.3mmol), 1- (2- bromine oxethyl) -4- methylbenzene (1.5g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Solvent is evaporated off in reflux 24 hours, and the dissolution of 30mL methylene chloride is added, and three times with 20mL washing, has Machine layer is concentrated to give brown oil, and using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain light brown Solid 0.44g, yield 24.4%, m.p.84.8-86.1 DEG C.HRMS calcd for C₂₂H₂₇NO₂[M+H]⁺338.2120, found 338.2124.¹H NMR(CDCl₃,300MHz)δ:1.91(m,4H,COCH(CH₂)₂),2.30-2.34(m,5H, CH₃and CH₂ of piperidine),2.43(s,3H,CH₃),2.88(bs,2H,OCH₂CH₂),3.09-3.13(m,2H,CH₂ of piperidine),3.27(m,1H,CH),4.094.14(m,2H,OCH₂CH₂),6.82-7.87(m,8H,ArH).¹³C NMR(CDCl₃,75MHz)δ:20.4,21.5,28.6,43.4,53.6,57.4,66.2,114.6,128.4,129.3,129.9, 129.9。

Embodiment 47

(1- (2- (2- methylphenoxy) ethyl) piperidin-4-yl) (4- aminomethyl phenyl) ketone (WY-33)

By 4- (4- methyl benzoyl) piperidines (1.1g, 5.3mmol), 1- (2- bromine oxethyl) -2- methylbenzene (1.5g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Solvent is evaporated off in reflux 24 hours, and the dissolution of 30mL methylene chloride is added, and three times with 20mL washing, has Machine layer is concentrated to give brown oil, and using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs white solid Body 1.45g, yield 80.6%, m.p.88.9-89.8 DEG C.HRMS calcd for C₂₂H₂₇NO₂[M+H]+338.2120, found338.2123.¹H NMR(CDCl₃,300MHz)δ:1.87(bs,4H,COCH(CH₂)₂),2.22(m,3H,CH₃),2.35 (bs,2H,CH₂ of piperidine),2.40(s,3H,CH₃),2.88-2.90(m,2H,OCH₂CH₂),3.08-3.12(m, 2H,CH₂ of piperidine),3.21-3.25(m,1H,CH),4.14(t,2H,OCH₂CH₂, J=5.4Hz), 6.81-7.85 (m,8H,ArH).¹³C NMR(CDCl₃,75MHz)δ:16.2,21.4,28.7,43.3,53.6,57.4,66.3,76.5,76.9, 77.4,110.9,120.3,126.6,128.2,129.2,130.5,133.5,133.5,143.52,156.8_,202.1。

Embodiment 48

(1- (2- (4- chlorophenoxy) ethyl) piperidin-4-yl) (4- aminomethyl phenyl) ketone (WY-34)

By 4- (4- methyl benzoyl) piperidines (1.1g, 5.3mmol), 1- (2- bromine oxethyl) -4- chlorobenzene (1.6g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Solvent is evaporated off in reflux 24 hours, and the dissolution of 30mL methylene chloride is added, and three times with 20mL washing, has Machine layer is concentrated to give brown oil, and using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs faint yellow Solid 1.57g, yield 82.6%, m.p.83.5-86.7 DEG C.HRMS calcd for C₂₁H₂₄ClNO₂[M+H]+358.1574, found 358.1577.¹H NMR(CDCl₃,300MHz)δ:1.89(bs,4H,COCH(CH₂)₂),2.23-2.32(m,2H,CH₂ of piperidine),2.41(s,3H,CH₃),2.85(m,2H,OCH₂CH₂),3.05-3.10(m,2H,CH₂ of piperidine),3.25(m,1H,CH),4.04-4.11(m,2H,OCH₂CH₂),6.8-7.85(m,8H,ArH).¹³C NMR (CDCl₃,75MHz)δ:21.5,28.7,43.3,53.7,57.3,66.6,116.0,125.7,128.3,129.3,133.71, 143.5,157.5,202.0。

Embodiment 49

(1- (2- (2- naphthoxy) ethyl) piperidin-4-yl) (4- aminomethyl phenyl) ketone (WY-35)

By 4- (4- methyl benzoyl) piperidines (1.1g, 5.3mmol), 2- (2- bromine oxethyl) naphthalene (1.7g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Solvent is evaporated off in reflux 24 hours, and the dissolution of 30mL methylene chloride is added, and three times with 20mL washing, has Machine layer is concentrated to give brown oil, and using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs to obtain light brown Solid 1.96g, yield 98.0%, m.p.99.4-100.7 DEG C.HRMS calcd for C₂₅H₂₇NO₂[M+H]⁺374.2120, found 374.2124.¹H NMR(CDCl₃,300MHz)δ:1.91(bs,4H,COCH(CH₂)₂),2.36-2.41(m,5H,CH₂ of piperidine and CH₃),2.94(m,2H,OCH₂CH₂),3.11-3.15(m,2H,CH₂ of piperidine), 3.24-3.26(m,1H,CH),4.27(m,2H,OCH₂CH₂),7.15-7.86(m,11H,ArH).¹³C NMR(CDCl₃,75MHz) δ:21.5,28.8,43.4,53.7,57.4,66.2,107.0,118.9,123.6,126.3,126.7,127.6,128.3, 129.1,129.3,129.3,133.8,134.6 143.5,156.8,202.1。

Embodiment 50

(1- (2- (4- methoxyphenoxy) ethyl) piperidin-4-yl) (4- aminomethyl phenyl) ketone (WY-36)

By 4- (4- methyl benzoyl) piperidines (1.1g, 5.3mmol), 1- (2- bromine oxethyl) -4- methoxybenzene (1.6g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol are added in 100mL eggplant-shape bottle and are heated to reflux, and 5mL is added dropwise 20%KOH solution is added dropwise for 10 minutes.Solvent is evaporated off in reflux 24 hours, the dissolution of 30mL methylene chloride is added, with 20mL water It washes three times, organic layer is concentrated to give brown oil, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column layer Analyse to obtain faint yellow solid 0.86g, yield 45.3%, m.p.93.5-95.1 DEG C.HRMS calcd for C₂₂H₂₇NO₃[M+H]⁺ 354.2026,found 354.2073.¹H NMR(CDCl₃,300MHz)δ:1.88(bs,4H,COCH(CH₂)₂),2.30(m, 2H,CH₂ of piperidine),2.41(s,3H,CH₃),2.83-2.85(m,2H,OCH₂CH₂),3.06-3.10(m,2H,CH₂ of piperidine),3.24(m,1H,CH),3.77(s,3H,OCH₃),4.09(t,2H,OCH₂CH₂, J=5.7Hz), 6.84- 7.85(m,8H,ArH).¹³C NMR(CDCl₃,75MHz)δ:21.49,28.77,43.45,53.69,55.74,57.53, 66.95,114.75,115.74,128.33,129.29,133.78,143.52,153.09,154.04,202.07。

Embodiment 51

(1- (2- (4- bromobenzene oxygroup) ethyl) piperidin-4-yl) (4- aminomethyl phenyl) ketone (WY-37)

By 4- (4- methyl benzoyl) piperidines (1.1g, 5.3mmol), 1- (2- bromine oxethyl) -4- bromobenzene (1.9g, 6.9mmol), KI (1.6g, 10mmol) and 30mL ethyl alcohol, which are added in 100mL eggplant-shape bottle, is heated to reflux, and it is molten that 5mL 20%KOH is added dropwise Liquid is added dropwise for 10 minutes.Solvent is evaporated off in reflux 24 hours, and the dissolution of 30mL methylene chloride is added, and three times with 20mL washing, has Machine layer is concentrated to give brown oil, and using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, gradient elution, column chromatographs white solid Body 1.45g, yield 69.0%, m.p.87.9-88.6 DEG C.HRMS calcd for C₂₁H₂₄BrNO₂[M+H]⁺402.1069, found 402.1072.¹H NMR(CDCl₃,300MHz)δ:1.88(bs,4H,COCH(CH₂)₂),2.32(m,2H,CH₂ of piperidine),2.41(s,3H,CH₃),2.84(bs,2H,OCH₂CH₂),3.05-3.08(m,2H,CH₂ of piperidine),3.24(m,1H,CH),4.10(m,2H,OCH₂CH₂),6.78-7.84(m,8H,ArH).¹³C NMR(CDCl₃, 75MHz)δ:21.0,28.3,42.9,53.2,56.8,66.1,112.4,116.0,127.8,128.8,131.7,133.2, 143.0,157.5,201.5。

Embodiment 52

Influence of the target compound to the acute cerebral ischemia mouse survival time in embodiment.

Target compound and positive control drug Nimodipine are dense needed for being made into before use with 0.5%wt sodium carboxymethylcellulose The suspension of degree；Experimental animal is ICR mouse, and weight 19-25g is male.Mouse is grouped at random, every group 10.Respectively Test medicine 0.2mL/10g is given in stomach-filling, and blank control group gives equal capacity NS, and positive controls, which are given, waits capacity Nimodipine 80mg/Kg, etherization in 1 hour after administration, neck midsection after fixing separate bilateral carotid and vagus nerve and tie It pricks, the record mouse survival time (respiration rate per minute is less than or equal to 5 times, that is, thinks dead mouse), the results are shown in Table 1,2.

Table 1: influence (min) of the target compound to the acute cerebral ischemia mouse survival time

Table 2: influence of the target compound to the acute cerebral ischemia mouse survival time

Conclusion: compound WY-2, WY-30, WY-31, WY-32, WY-33, WY-34, WY-35 are in high dose group (200mg/ Kg the death time of acute cerebral ischemia mouse) can significantly be extended, but middle dosage and low dose group are without positive effect；Compound WY-23, WY-24, WY-27, WY-29 show certain toxicity (200mg/Kg) in high dose group, and wherein WY-27, WY-29 exist Middle dose group (100mg/Kg) can significantly extend the death time of acute cerebral ischemia mouse, but low dose group is without positive effect；

Compound WY-1, WY-4, WY-7, WY-26 are except small part dosage group is without positive effect (12.5mg/Kg or 6.25mg/ Kg) outside, most of dosage group can significantly extend the time-to-live of acute cerebral ischemia mouse, to acute cerebral ischemia mouse have compared with Good neuroprotective activity.

Claims

1.1- virtue oxygen ethyl piperidine -4- base methanone derivatives, which is characterized in that the compound is with general formula (I) structuring Close the free alkali or salt of object:

The salt is in hydrochloride, hydrobromate, sulfate, trifluoroacetate, tartrate, lactate or mesylate It is a kind of；

Wherein, R₁And R₂It is identical or different, be independently represented each other H, halogen, alkyl, halogen replace alkyl, nitro, amino, Itrile group, hydroxyl, alkoxy, aralkoxy, heterocyclylalkoxy groups, aryl, substituted heterocycle or substituted aryl.

2. 1- virtue oxygen ethyl piperidine -4- base methanone derivatives according to claim 1, it is characterised in that: the R₁Or R₂ The aryl of representative is benzene, biphenyl or naphthalene, or is F, Cl, Br, I, C_1~10Alkyl, C_1~10What alkoxy, nitro or amino replaced Benzene, biphenyl or naphthalene.

3. 1- virtue oxygen ethyl piperidine -4- base methanone derivatives according to claim 1, which is characterized in that the R₁Or R₂ The alkyl of representative refers to the alkene of the alkyl of the linear chain or branched chain with 1-10 carbon atom or the linear chain or branched chain of 2-10 carbon atom The naphthenic base of the linear chain or branched chain of base or 3-10 carbon atom；Alkyl in the alkoxy, aralkoxy or heterocyclylalkoxy groups Refer to the alkyl with the linear chain or branched chain of 1-10 carbon atom；Abovementioned alkyl is methyl, ethyl, propyl, isopropyl, butyl, different Butyl, tert-butyl, sec-butyl, amyl, neopentyl, hexyl, heptyl, octyl, nonyl or decyl；Above-mentioned alkenyl is vinyl, third Alkenyl, allyl, cyclobutenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl or decene base；Above-mentioned ring Alkyl is cyclopropyl, cyclobutyl, cyclohexyl, suberyl, cyclooctyl, cyclononyl or cyclodecyl.

4. 1- virtue oxygen ethyl piperidine -4- base methanone derivatives according to claim 1, it is characterised in that: the R₁Or R₂ The substituted heterocycle or the heterocycle in heterocyclylalkoxy groups of representative refer to containing one or one optional from oxygen, nitrogen, sulphur atom with On heteroatomic saturated heterocyclic or aromatic heterocycle.

5. 1- virtue oxygen ethyl piperidine -4- base methanone derivatives according to claim 1, it is characterised in that: the R₁Or R₂ The halogen represented is F, Cl, Br or I.

6. 1- virtue oxygen ethyl piperidine -4- base methanone derivatives according to claim 1, it is characterised in that: the R₁Or R₂ Middle substituted aryl, substituent group are halogen, nitro, amino, hydroxyl, ether, carboxyl, ester group and amide groups.

7. 1- virtue oxygen ethyl piperidine -4- base methanone derivatives according to claim 1, it is characterised in that: the R₁Or R₂ Amino in substituent group is NH₂、R₈NH or R₉R₁₀N；Wherein R₈、R₉Or R₁₀For alkyl or R₉R₁₀N be nitrogen atom ternary ~ Eight circle heterocyclic rings, the alkyl refer to the alkyl of the linear chain or branched chain with 1-10 carbon atom or the straight chain of 2-10 carbon atom or The naphthenic base of the linear chain or branched chain of the alkenyl of branch or 3-10 carbon atom.

8. the preparation method of 1- virtue oxygen ethyl piperidine -4- base methanone derivatives described in claim 1, which is characterized in that including Following steps:

A. 50 mmol of fortified phenol, 1,2- Bromofume, 75 mmol and 30 mL of water are added in 100 mL three-necked bottles, stirring rises 25% sodium hydroxide solution 75 mmol is added dropwise to flowing back in temperature, and 35-40 min is dripped off, and continues reflux 10 hours, and reaction solution is cooling Layering is stood, and is filtered, and filter cake is washed twice with 5% sodium hydroxide solution, is washed with water twice, with dehydrated alcohol recrystallization two It is secondary, obtain substituted benzene oxygen bromoethane (II)；

B. 8 mmo1 of 4- piperidinecarboxylic acid and 10 mL of acetic acid is added in the eggplant-shape bottle of 50 mL, is heated to flowing back, reacted 10 hours 10 mL of acetic anhydride is added afterwards, solvent is steamed after continuing reflux 1 hour, product cooling is formed blocks of solid, sufficiently washed with petroleum ether It washs, it is dry, it obtainsNAcetylpiperidin -4- formic acid (III)；

C. willNIn Acetylpiperidin -4- formic acid 7.6 mmol and 1,15 mL of 2- dichloroethanes 100 mL there-necked flasks of addition, control Temperature is in 40-50 oC, and dropwise addition diluted 14 mmol of thionyl chloride of 1,2- dichloroethanes, 3 mL, continues at such a temperature dropwise After stirring 2 hours, 7.6 mmol of substituted benzene and 15 mmol of alchlor is added into reaction system, it is cooling after reflux 4 hours To room temperature, ice water is added, is sufficiently stirred, stratification, 20 ml every time is washed twice with water in organic layer, is concentrated under reduced pressureNSecond Acyl substituted benzene formyl phenylpiperidines, will be above-mentionedN50 mL are added in acetyl substituted benzene formyl phenylpiperidines, 10 mL of water and 10 mL of concentrated hydrochloric acid It in single neck bottle, flows back 10 hours, stands cooling, wash twice 20 ml every time with methylene chloride, 5% NaOH solution of water layer is adjusted 20 ml every time is extracted with dichloromethane three times in pH=8-9, merges organic phase, filtering dry by anhydrous MgSO4, concentration Obtain 4- substituted benzene formyl phenylpiperidines (IV)；

D. by (IV) 5.3 mmol of 4- substituted benzene formyl phenylpiperidines, substituted (II) 6.9 mmol of benzene oxygen bromoethane, potassium iodide 10 Mmol and 30 mL of dehydrated alcohol is added in 100 mL eggplant-shape bottles and is heated to reflux, and 20% KOH solution, 5 mL is added dropwise, and is added dropwise within 10 minutes It finishes, evaporating solvent under reduced pressure after reflux 24 hours, 30 mL of methylene chloride dissolution is added in residue, is washed three times, is had with 20 mL of water Machine layer is concentrated to give brown oil, using ethyl acetate and petroleum ether mixed liquor as eluant, eluent, by the gradient of EA/PE=1/1 to 3/1 Elution, column chromatography for separation obtain general formula (I) compound.

9.1- virtue oxygen ethyl piperidine -4- base methanone derivatives are preparing the application in cerebral arterial thrombosis therapeutic agent.

Compound 10. (1-(2-(4- methoxyphenoxy) ethyl) piperidin-4-yl) (4- fluorophenyl) ketone, (1-(2-(4- bromine Phenoxy group) ethyl) piperidin-4-yl) (4- fluorophenyl) ketone, (1-(2-(2- naphthoxy) ethyl) piperidin-4-yl) (4- fluorobenzene Base) ketone, (1-(2-(4- methoxyphenoxy) ethyl) piperidin-4-yl) (4- methoxyphenyl) ketone, (1-(2-(4- bromobenzene Oxygroup) ethyl) piperidin-4-yl) (4- ethoxyl phenenyl) ketone, (1-(2-(4- chlorophenoxy) ethyl) piperidin-4-yl) (4- chlorine Phenyl) ketone, (1-(2-(4- methylphenoxy) ethyl) piperidin-4-yl) (4- chlorphenyl) ketone, (1-(2-(4- methoxybenzene Oxygroup) ethyl) piperidin-4-yl) (4- chlorphenyl) ketone, (1-(2-(4- bromobenzene oxygroup) ethyl) piperidin-4-yl) (4- chlorobenzene Base) ketone, (1-(2-(2- methylphenoxy) ethyl) piperidin-4-yl) (4- chlorphenyl) ketone, (1-(2-(4- methylenedioxy phenoxy Base) ethyl) piperidin-4-yl) (4- aminomethyl phenyl) ketone, (1-(2-(2- methylphenoxy) ethyl) piperidin-4-yl) (4- methyl Phenyl) ketone, (1-(2-(4- chlorophenoxy) ethyl) piperidin-4-yl) (4- aminomethyl phenyl) ketone, (1-(2-(2- naphthoxy) Ethyl) piperidin-4-yl) (4- aminomethyl phenyl) ketone preparing the application in cerebral arterial thrombosis therapeutic agent.