CN101260075A - Aralkylpiperidine derivative and application thereof in preparing analgesic and sedative medicament - Google Patents

Aralkylpiperidine derivative and application thereof in preparing analgesic and sedative medicament Download PDF

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CN101260075A
CN101260075A CNA2007100378744A CN200710037874A CN101260075A CN 101260075 A CN101260075 A CN 101260075A CN A2007100378744 A CNA2007100378744 A CN A2007100378744A CN 200710037874 A CN200710037874 A CN 200710037874A CN 101260075 A CN101260075 A CN 101260075A
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phenacyl
piperidines
piperidines alcohol
iii
benzyl
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CN101260075B (en
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李建其
王冠
张桂森
马彦琴
季文华
张媛
郭琳
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Shanghai Institute of Pharmaceutical Industry
Nhwa Pharmaceutical Corp
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Shanghai Institute of Pharmaceutical Industry
Nhwa Pharmaceutical Corp
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Abstract

The invention relates to aralkyl piperidine derivatives, a compound thereof and an application in the preparation of a novel analgesic and sedative drug. The derivatives of the invention are free alkali or salt of the general formula compound. The pharmacological test shows that the compound of the invention has good analgesic and sedative activity and extremely small side effect.

Description

Aralkyl piperidine piperidine derivatives and the application in preparation analgesia, downern thereof
Technical field
The present invention relates to a kind of aralkyl piperidine piperidine derivatives and the application in preparation analgesia, downern.
Background technology
Serious acute and chronic pain is meant that various destructive stimuluses cause the nociceptor excitement, by nociceptive information transmission courier's impulsion, imports central nervous system into and causes the nociception and the pain sensation.Serious acute and chronic pain comprises the acute and chronic pain of relaxing tumor pain, post-operative pain, various outbreaks repeatedly etc., is perplexing the patient who counts in necessarily, is present clinical a great problem.
The drug addiction and the respiration inhibition of existing opioid analgesic, side effects such as peristole minimizing, limited being extensive use of of it, therefore seek and to keep strong analgesic effect, can overcome above-mentioned drawback again, being used safely in clinical central analgesia class medicine and being not only the main goal in research in analgesia field, also is the key areas of new medicine research.Although doing quite big effort aspect chemistry and the biology over past ten years, making progress very little.Therefore study the focus that novel central analgesia agent becomes this field.More external big drugmakers, as Pfizer Inc., the numerous and confused non-habituation sexual centre of the huge fund development of new analgesic agent of throwing such as Merck ﹠ Co., Inc..
The nonopioid analgesic thing is divided by mechanism of action and is mainly comprised at present: nmda receptor antagonist (as: chlore-ammonia ketone), pentahydroxy-look ammonia reuptake inhibitor (as: U-26225A), potassium-channel opener (as: flupirtine), cyclooxygenase two inhibitor (as: celecoxib), calcium-ion channel antagonists (as: Ziconotide) etc.Though the more previous medicine of these medicines is having certain improvement aspect habituation and the side effect, as: be described in detail among patent US6339105, US4481205, US5760068, the US5189020, but still have various habituation or big toxic side effect in various degree, and as: chlore-ammonia ketone, U-26225A and flupirtine still have habituation; Celecoxib has the potential cardiovascular side effects; Ziconotide easily causes postural hypotension etc.Simultaneously, because existing medicine also can not satisfy the requirement of different clinical patients pain controls far away, especially for some cancer pain, serious chronic pain and some neuropathic pains, there also do not have at present to be suitable, and therefore analgesic safely and effectively need constantly develop the chemical structure novelty, toxic side effect is little, therapeutic domain is wide, is used safely in clinical non-habituation analgesic drug, to satisfy the needs of different pain patients.In addition, the nonopioid analgesic thing has growing great market, and the analgesic appearance if any novelty also will produce very big social benefit and economic benefit.
The inventor discloses a kind of Aralkylone pipeazine derivative and this derivative as novel analgesia, ataractic application in the Chinese invention patent CN1381449 of application in 2002, this compounds has non-addicted central analgesia effect.Aralkyl piperidine piperidine derivatives of the present invention is a kind of brand-new compound that does not appear in the newspapers, and compares with above-mentioned patent, not only has different chemical structures, and has littler toxic side effect and the safety index of Geng Gao.
Summary of the invention
One of technical issues that need to address of the present invention are to disclose the aralkyl piperidines alcohol derivate compound that a class has medical value, to overcome the defective that existing medicine has side effects such as habituation and respiration inhibition, peristole minimizing, to solve a clinical difficult problem, satisfy people's needs that ease pain;
Two of the technical issues that need to address of the present invention are the application as novel analgesia, tranquilizer medicine of open above-claimed cpd;
Aralkyl piperidine piperidine derivatives of the present invention is free alkali or the salt with following structure general formula, salt is hydrochloride, hydrogen bromide salt, vitriol, trifluoroacetate or mesylate etc., preferred salt is hydrochloride, hydrogen bromide salt, and its salt can contain the crystal water of 0.5-3 molecule:
Figure A20071003787400071
Wherein:
A representative: OH, F, Cl, Br, (C 1-C 4) alkoxyl group, wherein (C 1-C 4) moieties of alkoxyl group can choose wantonly to be replaced and can also choose wantonly by amino or hydroxyl substituent by 1-3 fluorine atom and replace;
When B when adjacent carbon is connected with singly-bound, B represents OH;
When B when adjacent carbon is connected with two keys, B represents O or S;
Ar 1Representative:
Figure A20071003787400072
Or
Figure A20071003787400073
Ar 2Representative: Or
Figure A20071003787400075
X, Y are independent respectively to represent C, CH, N;
The Z representative contains N, O, S heteroatomic five yuan or hexa-atomic saturated or undersaturated aliphatic heterocycle or aromatic heterocycle, and wherein the heteroatoms sum is less than or equal to 3;
R 1, R 2Independent respectively hydrogen, the C of representing 1-C 4Alkyl, C 5Or C 6Cycloaliphatic ring, benzene and substituted-phenyl, hydroxyl, (C 1-C 4) a kind of in alkoxyl group, amino and substituted-amino, halogen, carboxylic acid and carboxylicesters, nitro or the acetonitrile etc., wherein C 1-C 4Alkyl, (C 1-C 4) alkoxyl group and C 5Or C 6Cycloaliphatic ring on moieties can choose wantonly to be replaced and can also choose wantonly and replace by amino or hydroxyl substituent by 1-3 fluorine atom;
R 3, R 4, R 5Independent respectively hydrogen, the C of representing 1-C 4Alkyl, C 5Or C 6Cycloaliphatic ring, five yuan or hexa-atomic one or two N, O, the heteroatomic saturated or undersaturated cycloaliphatic ring of S, benzene and substituted-phenyl, the hydroxyl, (C of containing 1-C 4) a kind of in alkoxyl group, amino and substituted-amino, halogen, carboxylic acid and carboxylicesters, nitro or the acetonitrile etc., wherein C 1-C 4Alkyl, (C 1-C 4) alkoxyl group and C 5Or C 6Cycloaliphatic ring on moieties can choose wantonly to be replaced and can also choose wantonly and replace by amino or hydroxyl substituent by 1-3 fluorine atom;
R 6, R 7, R 8Independent respectively hydrogen, the C of representing 1-C 4Alkyl, C 5Or C 6Cycloaliphatic ring, five yuan or hexa-atomic one or two N, O, the heteroatomic saturated or undersaturated cycloaliphatic ring of S, benzene and substituted-phenyl, the hydroxyl, (C of containing 1-C 4) a kind of in alkoxyl group, halogen, carboxylic acid and carboxylicesters, nitro or the acetonitrile etc., wherein C 1-C 4Alkyl, (C 1-C 4) alkoxyl group and C 5Or C 6Cycloaliphatic ring on moieties can choose wantonly to be replaced and can also choose wantonly and replace by amino or hydroxyl substituent by 1-3 fluorine atom;
N=0,1,2,3; M=1,2,3; Work as n, m=2,, substituent R at 3 o'clock 1And R 2Can directly link to each other with any one or more carbon on the carbochain;
Preferred A is: OH, a kind of among F or the Cl;
Preferred R 1, R 2For: hydrogen, C 1-C 4Alkyl or benzene and substituted-phenyl in a kind of;
Preferred R 3, R 4, R 5For: hydrogen, C 1-C 4Alkyl, hydroxyl, first, oxyethyl group, amino and substituted-amino, morpholine, tetramethyleneimine, piperidines, a kind of in halogen or the nitro;
Preferred R 6, R 7, R 8For: hydrogen, C 1-C 4Alkyl, hydroxyl, first, oxyethyl group, halogen, morpholine, a kind of in tetramethyleneimine or the piperidines;
Preferred compound comprises:
III-1N-benzyl-4-phenacyl-4-piperidines alcohol
III-2N-p-chlorobenzyl-4-phenacyl-4-piperidines alcohol
III-3N-is to luorobenzyl-4-phenacyl-4-piperidines alcohol
III-4N-is to nitrobenzyl-4-phenacyl-4-piperidines alcohol
III-5N-PAB-4-phenacyl-4-piperidines alcohol
III-6N-acetparaminosalol benzyl-4-phenacyl-4-piperidines alcohol
III-7N-diphenyl-methyl-4-phenacyl-4-piperidines alcohol
III-8N-(2-pyridyl) methyl-4-phenacyl-4-piperidines alcohol
III-9N-(2-pyrimidyl)-4-phenacyl-4-piperidines alcohol
III-10N-(2-pyrimidyl) methyl-4-phenacyl-4-piperidines alcohol
III-11N-(2-quinolyl)-4-phenacyl-4-piperidines alcohol
III-12N-(2 '-p-methoxy-phenyl)-4-phenacyl-4-piperidines alcohol
III-13N-(3 ', 4 '-methylenedioxy benzyl)-4-phenacyl-4-piperidines alcohol
III-14N-(3 ', 4 ', 5 '-trimethoxy benzyl)-4-phenacyl-4-piperidines alcohol
III-15N-is to methoxy-benzyl-4-phenacyl-4-piperidines alcohol
III-16N-styroyl-4-phenacyl-4-piperidines alcohol
III-17N-(1R-phenylethyl)-4-phenacyl-4-piperidines alcohol
III-18N-(1S-phenylethyl)-4-phenacyl-4-piperidines alcohol
III-19N-(p-methoxyphenyl ethyl)-4-phenacyl-4-piperidines alcohol
III-20N-(to the fluorophenyl ethyl)-4-phenacyl-4-piperidines alcohol
III-21N-(p-aminophenyl ethyl)-4-phenacyl-4-piperidines alcohol
III-22N-(3 ', 4 '-methylenedioxyphenyl ethyl)-4-phenacyl-4-piperidines alcohol
III-23N-(α-menaphthyl)-4-phenacyl-4-piperidines alcohol
III-24N-(4 '-pyrrolidyl benzyl)-4-phenacyl-4-piperidines alcohol
III-25N-((4 '-pyrrolidyl) phenylethyl)-4-phenacyl-4-piperidines alcohol
III-26N-(4 '-morpholinyl benzyl)-4-phenacyl-4-piperidines alcohol
III-27N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-piperidines alcohol
III-28N-(4 '-piperidyl benzyl)-4-phenacyl-4-piperidines alcohol
III-29N-(5-(2-oxoindoline base)) methyl-4-phenacyl-4-piperidines alcohol
III-30N-(5-indolinyl) methyl-4-phenacyl-4-piperidines alcohol
III-31N-benzyl-4-(to the fluorobenzoyl methyl)-4-piperidines alcohol
III-32N-benzyl-4-(to the methoxybenzoyl methyl)-4-piperidines alcohol
III-33N-benzyl-4-(to the chlorobenzoyl methyl)-4-piperidines alcohol
III-34N-benzyl-4-(2-pyridine formyl methyl)-4-piperidines alcohol
III-35N-benzyl-4-(4-pyrrolidyl phenacyl)-4-piperidines alcohol
III-36N-benzyl-4-(4 '-morpholinyl phenacyl)-4-piperidines alcohol
III-37N-benzyl-4-((5-indolinyl) formyl methyl)-4-piperidines alcohol
III-38N-benzyl-4-(3 ', 4 '-methylene-dioxy benzoyl methyl)-4-piperidines alcohol
III-39N-benzyl-4-(1 '-benzoyl ethyl)-4-piperidines alcohol
V-1N-is to methoxy-benzyl-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
V-2N-acetparaminosalol benzyl-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
V-3N-diphenyl-methyl-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
V-4N-(3 ', 4 '-methylenedioxy benzyl)-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
V-5N-(2 '-p-methoxy-phenyl)-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
V-6N-(5-indolinyl) methyl-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
V-7N-((4 '-pyrrolidyl) phenylethyl)-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
V-8N-((4 '-morpholinyl) phenylethyl)-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
VIII-1N-acetparaminosalol benzyl-4-phenacyl-4-methoxyl group piperidines
VIII-2N-p-methoxyphenyl ethyl-4-phenacyl-4-methoxyl group piperidines
VIII-3N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-methoxyl group piperidines
IX-1N-p-methoxyphenyl ethyl-4-phenacyl-4-fluorine piperidines
IX-2N-(3 ', 4 '-methylenedioxy benzyl)-4-phenacyl-4-fluorine piperidines
IX-3N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-fluorine piperidines
IX-4N-((4 '-pyrrolidyl) phenylethyl)-4-phenacyl-4-fluorine piperidines
IX-5N-p-methoxyphenyl ethyl-4-phenacyl-4-Chloperastine
IX-6N-(3 ', 4 '-methylenedioxy benzyl)-4-phenacyl-4-Chloperastine
IX-7N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-Chloperastine particular chemical formula is as shown in table 1:
Table 1
Figure A20071003787400101
Figure A20071003787400111
Wherein, further preferred compound comprises:
III-5N-PAB-4-phenacyl-4-piperidines alcohol
III-7N-diphenyl-methyl-4-phenacyl-4-piperidines alcohol
III-15N-is to methoxy-benzyl-4-phenacyl-4-piperidines alcohol
V-3N-diphenyl-methyl-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
IX-1N-p-methoxyphenyl ethyl-4-phenacyl-4-fluorine piperidines
Compound of the present invention can adopt following method to synthesize:
Synthetic route one:
Figure A20071003787400131
a：CeCl 3/NaI/THF；
Figure A20071003787400132
b：CF 3COOH/CH 2Cl 2
c：Et 3N/CH 2Cl 2or K 2CO 3/KI/CH 3COCH 3；
X：Cl，Br
The compound of being addressed is a starting raw material with the 4-piperidone of tertbutyloxycarbonyl protection; at first carry out nucleophilic addition with corresponding arone halides; remove protecting group through acidic hydrolysis again, carry out the N-hydrocarbyl reaction with corresponding halides and obtain target compound (III).Adopt the reaction of the C-C formation of Cerium II Chloride-sodium iodide system mediation α-Lu Daitong and cyclic ketones, (J.CHEM.SOC.PERKIN TRANS.I, 1473,1987) have carried out detailed elaboration in pertinent literature.This patent forms the carbon-carbon bond that this method is applied between arone halides and the 4-piperidone analog derivative in the reaction, synthetic series compound with unique new texture type.This synthesising method reacting condition gentleness, the reaction times is short, and is simple to operate, yield 30-50%.It is solvent that the N-hydrocarbyl reaction generally can adopt chloroform, and triethylamine is the disacidify agent, also can adopt to nucleophilic reagent seldom polar aprotic solvent acetone, dioxane, DMF, the DMSO etc. of solvation be action solvent, K 2CO 3Be the disacidify agent, reaction can be carried out under the 50-100 degree, and yield reaches about 50-80%.If temperature of reaction is higher, the reaction times is longer, will influence the quality and the yield of product.
Synthetic route two:
c：Et 3N/CH 2Cl 2or K 2CO 3/KI/CH 3COCH 3；
Figure A20071003787400135
a：CeCl 3/NaI/THF；
Figure A20071003787400136
X：Cl，Br
The compound of being addressed is a starting raw material with the 4-piperidone, at first carries out the N-hydrocarbyl reaction with corresponding halides, obtains target compound (III) with corresponding arone halides generation nucleophilic reaction again.It is solvent that the hydrocarbyl reaction of N generally adopts methylene dichloride or chloroform, and triethylamine reacts for the disacidify agent.When the substituted radical steric hindrance was big, also can adopt polar aprotic solvent acetone, DMF, dioxane etc. was action solvent, K 2CO 3Be the disacidify agent, reaction can be carried out under the 20-100 degree, and yield reaches 50-90%.Higher when temperature of reaction, the reaction times is longer, and when disacidify agent alkalescence was strong, side reaction was more, influences the quality and the yield of product.
Halo among a virtue formyl alkylate can be bought by the commercial channel, also can adopt the ordinary method of bibliographical information, carries out halogenating reaction with bromine or cupric bromide with corresponding aralkyl ketone and prepares.
Halo aralkyl compound among the c can be bought by the commercial channel, also can adopt the ordinary method of bibliographical information, carry out halogenating reaction or carry out the halogenating reaction preparation with sulfur oxychloride, hydrochloric acid, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, Hydrogen bromide etc. and corresponding aralkyl alkylol cpd with bromine and corresponding aralkyl compound.
Adopt the step in synthetic route one and the synthetic route two, can obtain target compound III-1 to III-39.
Synthetic route three:
Figure A20071003787400141
d：NaBH 4 or KBH 4；CH 3OH or C 2H 5OH
The compound of being addressed adopts the method in the synthetic route one to prepare its midbody compound (III) earlier, prepares target compound (V) through sodium borohydride or potassium borohydride reduction again.Adopt above-mentioned steps to obtain target compound V-1 to V-8.
Synthetic route four:
Figure A20071003787400142
e：HOCH 2CH 2OH，p-CH 3C 6H 4COOH
f：RI，60％NaH
g：HCl/C 2H 5OH
The compound of being addressed adopts the method in the synthetic route one to prepare its midbody compound (III) earlier, and through ethylene glycol protection ketone carbonyl, alkylated reaction, deprotection reaction prepare target compound (VIII) again.Adopt above-mentioned steps can obtain target compound VIII-1 to VIII-3.
Synthetic route five:
Figure A20071003787400151
X：F，Cl，Br
h：DAST or SOCl 2 or PBr 3，CH 2Cl 2；
The compound of being addressed adopts the method in the synthetic route one to prepare its midbody compound (III) earlier, adopts halide reagent (fluorination reagent DAST, chlorination reagent SOCl again 2, bromide reagent PBr 3, etc.) prepare target compound (IX) through halogenating reaction.Adopt above-mentioned steps can obtain target compound IX-1 to IX-7.
The present invention is in the process of the compound (III) of preparation novel texture, the piperidone that replaces with N-is that the reaction that C-C forms takes place in Cerium II Chloride-sodium iodide system for raw material and corresponding α-Lu Daitong, the reaction that this patent carries out in the piperidone compounds of nitrogen atom this method first Application as raw material above-mentioned carbon-carbon bond forms, and be applied to the synthetic of compound (III) and important intermediate compound (II) thereof.Synthesized compound III-1 to III-39 by the application of above-mentioned novel synthesis.
Piperidone and α-Lu Daitong that this reaction adopts N-to replace are raw material, and its mol ratio is between 0.5: 1～2: 1, and during the reaction in 1: 1 of mol ratios such as employing, yield is the highest.
This method adopts Cerium II Chloride-sodium iodide system, CeCl 3The mol ratio of/NaI wherein adopted 1: 3 within 1: 1～1: 5 scope, and yield is good.
The solvent that this method adopted comprises: THF, ether, ether solvents such as dioxane.
The temperature of reaction of this method is between 0-100 ℃, and the reaction times is between 0.5-10 hour.
Animal experiment proves that aralkyl piperidine piperidine derivatives of the present invention can be used for preparation analgesia, tranquilizer.
The present invention relates to the medicine that described aralkyl piperidine piperidine derivatives also may be used to prepare other central nervous system disorder disease.For example: be used for the treatment of neuropathic pain, mania, anxiety disorder, various dysthymia disorders, schizophrenia, Parkinson's disease (PD), Huntington Chorea (HD), Alzheimer, senile dementia, Alzheimers type dementia, dysmnesia, execution afunction, vascular dementia and other dementia, and with intelligence, study or the relevant medicines such as functional disorder disease of memory.
The present invention finds that aralkyl piperidines class series new compound causes on the pain pharmacological model at the mouse chemical, and the anti-pain writhing response effect that most compound exhibits are stronger has analgesia and sedative activity.The hot plate pharmacological model test of mouse shows that also compound has analgesic activity.
Research of Animal Model for Study result shows that III-15 has obvious analgesic activity, and oral absorption is better.Do not show resistance after many medications of III-15, the pharmacological dependence begetting power is very low, the Salmonella reversion test feminine gender, and therapeutic index is bigger, possesses the potential value as novel non-habituation analgesic agent exploitation.
Derivative of the present invention can composition form be applied to the patient who needs this treatment by modes such as oral, injections.Dosage was generally 0.5～10mg/ days. and kg body weight specifically can be determined by the doctor according to patient's the state of an illness, age etc.
Described composition is an activeconstituents to contain the derivative of the present invention for the treatment of significant quantity, and contains one or more medically acceptable conventional carriers.
The carrier of being addressed is meant the carrier of pharmaceutical field routine, for example: thinner, vehicle such as water etc.; Tackiness agent such as derivatived cellulose, gelatin, polyvinylpyrrolidone etc.; Weighting agent such as starch etc.; Agent such as lime carbonate, sodium bicarbonate burst apart; Lubricant such as calcium stearate or Magnesium Stearate etc.In addition, can also in composition, add other auxiliarys such as flavouring agent and sweeting agent.Be used for when oral, it can be prepared into conventional solid preparation such as tablet, pulvis or capsule etc.; When being used to inject, it can be prepared into injection liquid.
The various formulations of composition of the present invention can adopt the method for medical field routine to be prepared, and wherein the content of activeconstituents is 0.1%～99.5% (weight ratio).
The inventor finds that derivative toxicity of the present invention is lower, and neural side reaction is little.
Embodiment
Logical method one: the preparation of 4-aralkyl formyl alkyl-4-piperidines alcohol (II) hydrochloride
With anhydrous cerium chloride (0.99g, 4.0mmol) and sodium iodide (1.8g 12.0mmol) joins in the 10ml anhydrous tetrahydro furan solvent, forms suspension liquid.(0.80g 4.0mmol) is dissolved in the 10ml anhydrous tetrahydro furan, this drips of solution is added in the above-mentioned suspension liquid room temperature reaction 2 hours for halo aralkyl formyl alkyl (4.0mmol) and N-tertbutyloxycarbonyl-4-piperidone.With saturated aqueous sodium thiosulfate 20ml termination reaction, remove tetrahydrofuran (THF) under reduced pressure, chloroform extraction (3 * 20ml), merge organic phase, water (1 * 10ml) washing, (1 * 10ml) washing of saturated aqueous common salt water, drying is filtered, steam desolventize reddish-brown oily matter.
Above-mentioned oily matter is dissolved in the 5ml methylene dichloride, and the ice-water bath cooling below temperature control 10 degree, drips trifluoroacetic acid (40mmol), after dropwising, is warming up to stirring at room reaction 0.5 hour.The ice-water bath cooling below temperature control 10 degree, drips saturated aqueous sodium carbonate, transfers PH＞10.With ethyl acetate extraction (6 * 20ml), merge organic phase, (filtration is concentrated into 20ml, uses HC1/C for 1 * 20ml) washing, ethyl acetate solution anhydrous sodium sulfate drying to use saturated aqueous common salt water again 2H 5OH (5N) transfers PH＜3, and solid is separated out, and crosses filter solid, gets target compound (II), yield 30-42%.
Logical method two: N 1The preparation of-aralkyl-4-aralkyl formyl alkyl-4-piperidines alcohol (III) hydrochloride
With 4-aralkyl formyl alkyl-4-piperidines alcohol (II) hydrochloride (10mmol), halo aralkyl (11mmol), potassiumiodide (1mmol) and anhydrous K 2CO 3(35mmol) place DMF (50ml) or anhydrous propanone (80ml), 25 ℃-80 ℃ stirring reaction 8-12 hour, filter, the evaporated under reduced pressure solvent adds water 50ml, with AcOEt (100ml
Figure A20071003787400171
3) extract, merge the ester layer, water 20ml successively, saturated NaCl solution 30ml washes MgSO 4Dry.Filter, boil off solvent, add ethyl acetate 30ml dissolving, use HCl/C 2H 5OH (5N) transfers pH=2, filters the solid of separating out, and ethanol/water or ethanol/re-crystallizing in ethyl acetate get target compound (III), yield 60-85%.
Logical method three: the preparation of N-aralkyl-4-aralkyl formyl alkyl-4-piperidines alcohol (III) hydrochloride
With anhydrous cerium chloride (0.99g, 4.0mmol) and sodium iodide (1.8g 12.0mmol) joins in the 10ml anhydrous tetrahydro furan solvent, forms suspension liquid.Halo aralkyl formyl alkyl (4.0mmol) and N-aralkyl-4-piperidone (4.0mmol) is dissolved in the 10ml anhydrous tetrahydro furan, this drips of solution is added in the above-mentioned suspension liquid room temperature reaction 2 hours.With saturated aqueous sodium thiosulfate 20ml termination reaction, remove tetrahydrofuran (THF) under reduced pressure, chloroform extraction (3 * 20ml), merge organic phase, water (1 * 10ml) washing, and saturated aqueous common salt water (1 * 10ml) washing, drying is filtered, boil off solvent, add ethyl acetate 20ml dissolving, use HCl/C 2H 5OH (5N) transfers pH=2, filters the solid of separating out, and ethanol/water or ethanol/re-crystallizing in ethyl acetate get N-aralkyl-4-aralkyl formyl alkyl-4-piperidines alcohol hydrochloride, yield 30-40%.
Logical method four: the preparation of N-aralkyl-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol (V) hydrochloride
N-aralkyl-4-phenacyl-4-piperidines alcohol (III) (4.0mmol) is dissolved in the 30ml ethanolic soln, adds sodium borohydride (4.4mmol) in batches, mix the back stirring at room to reacting completely.The frozen water cooling drips 3N hydrochloric acid and transfers to PH=4 under ℃ condition of temperature control＜20, stirred 0.5 hour.Transfer to neutrality with saturated sodium bicarbonate aqueous solution again, add entry 10ml, revolve and boil off except that ethanol usefulness 10%NaOH aqueous solution accent PH=10, usefulness ethyl acetate extraction (2 * 20ml), merge organic phase, with saturated aqueous common salt 20ml washing, add the anhydrous magnesium sulfate drying organic phase, filter, steam and remove ethyl acetate, use HCl/C to remaining about 20ml 2H 5OH (5N) transfers pH=2, filters the solid of separating out, and ethanol/water or ethanol/re-crystallizing in ethyl acetate get N-aralkyl-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol (V) hydrochloride, yield 60-80%.
Logical method five: the preparation of N-aralkyl-4-phenacyl-4-methoxyl group piperidines (VIII) hydrochloride
With N-aralkyl-4-phenacyl-4-piperidines alcohol (III) (4.0mmol), ethylene glycol (8.0mmol) is dissolved in the 30ml benzene, adds tosic acid (0.20mmol), is warming up to backflow, and benzene reacts to reacting completely for water.Cool off reaction solution to room temperature, the usefulness saturated sodium bicarbonate aqueous solution (2 * 20ml) washings, water washing (1 * 20ml), and the saturated common salt water washing (1 * 20ml), solvent evaporated.Residuum is dissolved in the 20ml benzene, and ((4.0mmol) stirred 0.5 hour, and (5.0mmol, 5ml), stirring at room is to reacting completely to drip the benzole soln of methyl iodide in reaction solution slowly to add 60% NaH.Water washing (1 * 20ml), and the saturated common salt water washing (1 * 20ml), solvent evaporated.
Residuum is dissolved with 10ml hydrochloric acid (1mol/L)) to handle and slough the ethylene glycol protection, ethyl acetate extraction is used in alkalization, uses HCl/C again 2H 5OH (5N) transfers pH=2, and solvent evaporated gets solids, and ethanol/water or ethanol/re-crystallizing in ethyl acetate get N-aralkyl-4-phenacyl-4-methoxyl group piperidines (VIII) hydrochloride, total recovery 40-50%.
Logical method six: the preparation of N-aralkyl-4-phenacyl-4-fluorine piperidines (IX) hydrochloride
N-aralkyl-4-phenacyl-4-piperidines alcohol (III) (4.0mmol) is dissolved in the exsiccant 20ml methylene dichloride, dry ice-propanone cooling, temperature control＜-70 ℃, drip in the nitrogen protection downhill reaction liquid DAST dichloromethane solution (8mol, 25ml).After being added dropwise to complete, keep-75 ℃ of reactions 1 hour, slowly heat up, keep-10 ℃ of reactions 2 hours.Drip water 30ml, unsaturated carbonate aqueous solutions of potassium 10ml uses Et 2O extraction (4 * 30ml), merge organic phase, with the saturated common salt water washing (1 * 30ml), drying concentrates, column chromatography for separation, the petrol ether/ethyl acetate wash-out, oily matter.Through HCl/C2H5OH acidifying salify, ethanol/re-crystallizing in ethyl acetate gets N-aralkyl-4-phenacyl-4-fluorine piperidines (IX) hydrochloride, yield 35-50%.
Logical method seven: the preparation of N-aralkyl-4-phenacyl-4-Chloperastine (IX) hydrochloride
N-aralkyl-4-phenacyl-4-piperidines alcohol (III) (4.0mmol) is dissolved in the exsiccant 20ml methylene dichloride, the frozen water cooling, 0 ℃ of temperature control drips SOCl in reaction solution 2Dichloromethane solution (8mol, 25ml).After being added dropwise to complete, slowly be warming up to room temperature reaction 1 hour.Drip water 30ml, unsaturated carbonate aqueous solutions of potassium 10ml stirred 30 minutes, left standstill separatory, water CH 2Cl 2Extraction (4 * 30ml), merge organic phase, (1 * 30ml), drying is concentrated into driedly, and residuum is through HCl/C with the saturated common salt water washing 2H 5OH acidifying salify, ethanol/re-crystallizing in ethyl acetate gets N-aralkyl-4-phenacyl-4-Chloperastine (IX) hydrochloride, yield 30-45%.
Embodiment 1
The preparation of III-1N-benzyl-4-phenacyl-4-piperidines alcohol hydrochloride and N-benzyl-4-phenacyl-4-piperidines alcohol hydrobromate:
With anhydrous cerium chloride (1.98g, 8.0mmol) and sodium iodide (3.6g 24.0mmol) joins in the 20ml anhydrous tetrahydro furan solvent, forms suspension liquid.Bromoacetophenone 1.60 (8.0mmol) and N-benzyl-4-piperidone 1.51g (8.0mmol) is dissolved in the 10ml anhydrous tetrahydro furan, this drips of solution is added in the above-mentioned suspension liquid, by the synthetic of logical method three and post-treating method operation, obtain white crystal 1.05g, yield 36%.
Through method for preparing N-benzyl-4-phenacyl-4-piperidines alcohol, adopt Hydrogen bromide/ethanolic soln acidifying salify in the last handling process, get white crystal through ethyl acetate/ethyl alcohol recrystallization, yield 32%.
Ultimate analysis: C 20H 23NO 2
Figure A20071003787400181
HCl
Figure A20071003787400182
H 2O (theoretical value %:C 66.01, and H 7.20, and N 3.85, Cl 9.74 experimental value %:C 65.83, and H 7.07, and N 3.96, Cl 9.82)
C 20H 23NO 2
Figure A20071003787400183
HBr
Figure A20071003787400184
H 2O (theoretical value %:C 58.83, and H 6.42, and N 3.43, Br 19.57 experimental value %:C 58.63, and H 6.57, and N 3.65, Br 19.82)
1HNMR (DMSO-d 6):
Figure A20071003787400185
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.13 (s, 2H, CH 2CO), 4.25 (s, 2H, PhCH 2), 5.01 (s, 1H, piperidines-N HCl), and 7.20-8.10 (m, 10H, ArH), 9.5-12.0 (2B, 1H, piperidines-OH).
MS：m/z310(M+1)
Embodiment 2
III-2N-p-chlorobenzyl-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again will be to chlorine bromobenzyl 1.76 (8.8mmol) and 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol) place anhydrous propanone (60ml), back flow reaction 8 hours, the post-processing operation by logical method two obtains white crystal 2.25g, yield 70.5%.
Ultimate analysis: C 20H 22ClNO 2
Figure A20071003787400191
HCl
Figure A20071003787400192
H 2O (theoretical value %:C 60.31, and H 6.33, and N 3.52, Cl17.80 experimental value %:C 60.42, and H 6.15, and N 3.30, Cl 17.96)
1HNMR (DMSO-d 6):
Figure A20071003787400193
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.15 (s, 2H, CH 2CO), 4.25-4.40 (m, 2H, PhCH 2), 4.98 (s, 1H, piperidines-N HCl), and 7.20-8.10 (m, 9H, ArH), 10.5-11.5 (2B, 1H, piperidines-OH).
MS：m/z 344(M +)
Embodiment 3
III-3N-is to luorobenzyl-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again will be to fluorine bromobenzyl 1.66 (8.8mmol) and 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol) place anhydrous propanone (60ml), back flow reaction 8 hours, the post-processing operation by logical method two obtains white crystal 2.06g, yield 67.5%.
Ultimate analysis: C 20H 22FNO 2 HCl
Figure A20071003787400195
H 2O (theoretical value %:C 62.90, and H 6.60, and N 3.67, Cl 9.28 experimental value %:C 60.87, and H 6.45, and N 3.39, Cl 9.56)
1HNMR (DMSO-d 6):
Figure A20071003787400196
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.13 (s, 2H, CH 2CO), 4.25-4.40 (m, 2H, PhCH 2), 5.02 (s, 1H, piperidines-N HCl), and 7.20-8.10 (m, 9H, ArH), 10.6-11.2 (2B, 1H, piperidines-OH).
MS：m/z 328(M +)
Embodiment 4
III-4N-is to nitrobenzyl-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again will be to nitro bromobenzyl 1.90 (8.8mmol) and 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol) place anhydrous propanone (60ml), back flow reaction 8 hours, the post-processing operation by logical method two obtains white crystal 2.68g, yield 81.9%.
Ultimate analysis: C 20H 22N 2O 4
Figure A20071003787400197
HCl
Figure A20071003787400198
H 2(theoretical value %:C 58.75, and H 6.16, and N 6.85, and Cl 8.67 for O; Experimental value %:C 58.52, H 6.28, and N 7.04, Cl 8.95)
1HNMR (DMSO-d 6):
Figure A20071003787400201
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.13 (s, 2H, CH 2CO), 4.25 (s, 2H, PhCH 2), 7.20-8.10 (m, 9H, ArH), 10.5-11.5 (2B, 1H, piperidines-OH).
MS：355(M+1)
Embodiment 5
III-5N-PAB-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by embodiment 4 prepares N-to nitrobenzyl-4-phenacyl-4-piperidines alcohol (III-4) hydrochloride earlier, get (III-4) hydrochloride of 1.23g (3.0mmol), stannous chloride dihydrate 3.05g (13.5mmol), place the methanol aqueous solution (50%) of 80ml, 40-50 ℃ was reacted 20 hours.Transfer reaction solution to neutral with the NaOH aqueous solution (5N), steam and remove methyl alcohol, use the NaOH aqueous solution (5N) that reaction solution is transferred PH=12 again, ethyl acetate extraction (4 * 20ml), merge organic phase, and the saturated common salt water washing (1 * 20ml), anhydrous MgSO4 drying, merge organic phase, (1 * 20ml), anhydrous MgSO4 drying is filtered in the saturated common salt water washing, steam solvent to the 30ml, use HCl/C 2H 5OH (5N) transfers pH=2, filter crude product, obtain white crystal 0.75g through the ethanol/water recrystallization, yield 57.7%.
Ultimate analysis: C 20H 22N 2O 42HCl
Figure A20071003787400202
H 2(theoretical value %:C 55.43, and H 6.98, and N 6.46, and Cl 16.36 for O; Experimental value %:C 55.56, H 6.72, and N 6.18, Cl 16.69)
1HNMR (DMSO-d 6):
Figure A20071003787400203
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.16 (s, 2H, CH 2CO), 4.03-4.10 (m, 2H, PhCH 2), 4.96 (s, H, piperidines-N HCl), 5.29 (s, 2H, Ar 1-NH 2), 7.20-8.10 (m, 9H, ArH), 9.6-10.2 (2B, 1H, piperidines-OH).
MS：325(M+1)。
Embodiment 6
III-6N-acetparaminosalol benzyl-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by embodiment 5 prepares N-PAB-4-phenacyl-4-piperidines alcohol (III-5) hydrochloride earlier, get 1.34g (3.0mmol) (III-5) hydrochloride be dissolved in the 10ml water, add salt of wormwood and transfer PH＞12, with ethyl acetate extraction (4 * 20ml), merge organic phase, saturated common salt water washing (1 * 20ml), anhydrous MgSO4 drying, filter, steam solvent to the 30ml, drip diacetyl oxide 0.31g (3.0mmol), stirring at room reaction 1 hour, solvent evaporated gets solid crude product, obtains white crystal 1.12g through the ethanol/water recrystallization, yield 88.7%.
Ultimate analysis: C 22H 26N 2O 3
Figure A20071003787400204
HCl
Figure A20071003787400205
H 2(theoretical value %:C 62.77, and H 6.94, and N 6.66, and Cl 8.42 for O; Experimental value %:C 62.56, H 7.08, and N 6.92, Cl 8.84)
1HNMR (DMSO-d 6):
Figure A20071003787400206
1.80-2.10 (m, 4H, piperidines-H), 2.04 (s, 3H), 3.00-3.20 (m, 4H, piperidines-H), 3.16 (s, 2H, CH 2CO), 4.03-4.10 (m, 2H, PhCH 2), 4.95 (s, H, piperidines-N HCl), 8.09 (s, 1H, Ar 1-NH), and 7.20-8.10 (m, 9H, ArH), 9.6-10.2 (2B, 1H, piperidines-OH).
MS：267(M+1)
Embodiment 7
III-7N-diphenyl-methyl-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with diphenyl-bromomethane 1.98g (8.8mmol) and 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol) place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 2.53g, yield 74.9%.
Ultimate analysis: C 26H 27NO 2
Figure A20071003787400211
(theoretical value %:C 74.01, and H 6.69, and N 3.32, and Cl 8.40 for HCl; Experimental value %:C 74.12, H 6.89, and N 3.51, Cl 8.80)
1HNMR (DMSO-d 6):
Figure A20071003787400212
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.16 (s, 2H, CH 2CO), 4.03-4.10 (m, H, Ph 2CH), 4.95 (s, H, piperidines-N HCl), 5.29 (s, 2H, Ar 1-NH 2), 7.20-8.10 (m, 15H, ArH), 9.6-10.2 (2B, 1H, piperidines-OH).
MS：m/z 286(M+1)。
Embodiment 8
III-8N-(2-pyridyl) methyl-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 2-bromo methyl cycloheptapyridine 1.51g (8.8mmol) and 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol) place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 2.16g, yield 67.3%.
Ultimate analysis: C 19H 22N 2O 2
Figure A20071003787400213
2HCl
Figure A20071003787400214
H 2(theoretical value %:C 56.86, and H 6.53, and N 6.98, and Cl 17.67 for O; Experimental value %:C 56.68, H 6.77, and N 6.83, Cl 17.84)
1HNMR (DMSO-d 6):
Figure A20071003787400215
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.16 (s, 2H, CH 2CO), and 4.06-4.13 (m, 2H), 4.97 (s, H, piperidines-N HCl), and 7.20-8.60 (m, 9H), 9.6-10.2 (2B, 1H, piperidines-OH).
MS：m/z 311(M+1)
Embodiment 9
III-9N-(2-pyrimidyl)-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 2-bromo pyrimi piperidine 1.40g (8.8mmol) and 4-phenacyl-4-piperidines alcohol 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol) place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 1.67g, yield 59.4%.
Ultimate analysis: C 18H 21N 3O 2
Figure A20071003787400216
HCl H 2(theoretical value %:C 58.03, and H 6.30, and N 11.94, and Cl 10.08 for O; Experimental value %:C 58.27, H 6.49, and N 11.78, Cl 10.22)
1HNMR (DMSO-d 6):
Figure A20071003787400221
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.16 (s, 2H, CH 2CO), 4.97 (s, H, piperidines-N HCl), and 7.20-8.70 (m, 8H), 9.6-10.2 (2B, 1H, piperidines-OH).
MS：m/z 312(M+1)
Embodiment 10
III-10N-(2-pyrimidyl) methyl-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 2-brooethyl pyrimidine 1.52g (8.8mmol) and 4-phenacyl-4-piperidines alcohol 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol) place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 2.25g, yield 76.8%.
Ultimate analysis: C 18H 21N 3O 2
Figure A20071003787400222
HCl H 2(theoretical value %:C 59.09, and H 6.61, and N 11.49, and Cl 9.69 for O; Experimental value %:C 59.27, H 6.89, and N 11.68, Cl 10.02)
1HNMR (DMSO-d 6):
Figure A20071003787400223
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.16 (s, 2H, CH 2CO), 4.03-4.10 (m, 2H, PhCH 2), 4.97 (s, H, piperidines-N HCl), and 7.20-8.70 (m, 8H), 9.6-10.2 (2B, 1H, piperidines-OH).
MS：m/z 324(M+1)
Embodiment 11
III-11N-(2-quinolyl)-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 2-bromoquinoline 1.83g (8.8mmol) and 4-phenacyl-4-piperidines alcohol 1.75g (8.0mmol), and anhydrous K 2CO 33.53g (25.6mmol) place DMF (60ml), 120 ℃ were reacted 12 hours, the post-processing operation by logical method two obtains white crystal 1.58g, yield 45.1%.
Ultimate analysis: C 22H 22N 2O 2
Figure A20071003787400224
2HCl
Figure A20071003787400225
H 2(theoretical value %:C 60.42, and H 5.99, and N 6.41, and Cl 16.21 for O; Experimental value %:C 60.65, H 6.12, and N 6.24, Cl 16.01)
1HNMR (DMSO-d 6):
Figure A20071003787400226
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.16 (s, 2H, CH 2CO), 5.01 (s, H, piperidines-N HCl), and 7.20-8.50 (m, 11H), 9.6-10.2 (2B, 1H, piperidines-OH).
MS：m/z 347(M+1)。
Embodiment 12
III-12N-(2 '-p-methoxy-phenyl)-4-phenacyl-4-piperidines alcohol hydrochloride
With anhydrous cerium chloride (0.99g, 4.0mmol) and sodium iodide (1.8g 12.0mmol) joins in the 10ml anhydrous tetrahydro furan solvent, forms suspension liquid.Bromoacetophenone 0.80g (4.0mmol) and N-(2 '-p-methoxy-phenyl)-4-piperidone 0.82g (4.0mmol) is dissolved in the 10ml anhydrous tetrahydro furan, this drips of solution is added in the above-mentioned suspension liquid, post-processing operation by logical method three obtains white crystal 0.5g, yield 38.5%.
Ultimate analysis: C 20H 23NO 3 (theoretical value %:C 66.38, and H 6.69, and N 3.87, and Cl 9.80 for HCl; Experimental value %:C 66.16, H 6.81, and N 4.18, Cl 10.02)
1HNMR (DMSO-d 6):
Figure A20071003787400232
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.15 (s, 2H, CH 2CO), 3.75 (s, 3H ,-OCH 3), 4.98 (s, 1H, piperidines-NHCl), 6.60-8.20 (m, 9H, ArH), 9.5-12.0 (2B, 1H, piperidines-OH).
MS：m/z 326(M+1)
Embodiment 13
III-13N-(3 ', 4 '-methylenedioxy benzyl)-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 3 ', 4 '-methylene-dioxy bromobenzyl 1.89g (8.8mmol), and 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), and anhydrous K 2CO 33.53g (25.6mmol) place anhydrous propanone (60ml), back flow reaction 8 hours, the post-processing operation by logical method two obtains white crystal 2.13g, yield 65.3%.
Ultimate analysis: C 21H 23NO 4HCl H 2(theoretical value %:C 61.84, and H 6.42, and N 3.43, and Cl 8.69 for O; Experimental value %:C 61.62, H 6.27, and N 3.73, Cl 8.86)
1HNMR (DMSO-d 6):
Figure A20071003787400233
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.13 (s, 2H, CH 2CO), 4.25 (s, 2H), 5.03 (s, 1H, piperidines-NHCl), 5.92 (s, 2H), 6.90-8.10 (m, 8H, ArH), 9.5-11.6 (2B, 1H, piperidines-OH).
MS：m/z 354(M+1)。
Embodiment 14
III-14N-(3 ', 4 ', 5 '-trimethoxy benzyl)-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 3 ', 4 ', and 5 '-trimethoxy bromobenzyl 2.30g (8.8mmol), 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), and anhydrous K 2CO 33.53g (25.6mmol) place anhydrous propanone (60ml), back flow reaction 8 hours, the post-processing operation by logical method two obtains white crystal 2.05g, yield 56.5%.
Ultimate analysis: C 23H 29NO 5 HCl H 2(theoretical value %:C 60.85, and H 7.11, and N 3.09, and Cl 7.81 for O; Experimental value %:C 61.03, H 7.40, and N 3.21, Cl 8.04)
1HNMR (DMSO-d 6):
Figure A20071003787400236
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.13 (s, 2H, CH 2CO), 3.75 (s, 9H ,-OCH 3), 4.87 (s, 2H), 5.01 (s, 1H, piperidines-N HCl), and 6.10-8.05 (m, 7H, ArH), 9.5-12.0 (2B, 1H, piperidines-OH).
MS：m/z 400(M+1)
Embodiment 15
III-15N-is to methoxy-benzyl-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again will be to methoxyl group bromobenzyl 1.77g (8.8mmol), and 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), and anhydrous K 2CO 33.53g (25.6mmol) place anhydrous propanone (60ml), back flow reaction 8 hours, the post-processing operation by logical method two obtains white crystal 1.93g, yield 61.3%.
Ultimate analysis: C 21H 25NO 3HCl H 2(theoretical value %:C 64.03, and H 7.16, and N 3.56, and Cl 9.00 for O; Experimental value %:C 64.32, H 7.33, and N 3.80, Cl 9.27)
1HNMR (DMSO-d 6):
Figure A20071003787400241
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.13 (s, 2H, CH 2CO), 3.81 (s, 3H ,-OCH 3), 4.25 (s, 2H), 5.01 (s, 1H, piperidines-N HCl), and 7.20-8.10 (m, 9H, ArH), 9.5-12.0 (2B, 1H, piperidines-OH).
MS：m/z 340(M+1)。
Embodiment 16
III-16N-styroyl-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 1-bromo ethyl phenenyl 1.63g (8.8mmol), and 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol) place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 2.18g, yield 72.1%.
Ultimate analysis: C 21H 25NO 2
Figure A20071003787400242
HCl
Figure A20071003787400243
H 2(theoretical value %:C 66.74, and H 7.47, and N 3.71, and Cl 9.38 for O; Experimental value %:C 66.98, H 7.67, and N 3.83, Cl 9.52)
1HNMR (DMSO-d 6):
Figure A20071003787400244
1.35 (d, 3H, CH 3), 1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.16 (s, 2H, CH 2CO), and 4.03-4.10 (m, 1H, PhCH), 4.95 (s, 1H, piperidines-N HCl), and 7.20-8.10 (m, 10H, ArH), 9.6-10.2 (2B, 1H, piperidines-OH).
MS：m/z 324(M+1)
Embodiment 17
III-17N-(1R-phenylethyl)-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with R-1-bromo ethyl phenenyl 1.63g (8.8mmol), 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol) place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 2.21g, yield 73.1%.
Ultimate analysis: C 21H 25NO 2 HCl
Figure A20071003787400246
H 2(theoretical value %:C 66.74, and H 7.47, and N 3.71, and Cl 9.38 for O; Experimental value %:C 66.98, H 7.67, and N 3.83, Cl 9.52)
MS：m/z 324(M+1)
Embodiment 18
III-18N-(1S-phenylethyl)-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with S-1-bromo ethyl phenenyl 1.63g (8.8mmol), 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol) place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 2.08g, yield 68.8%.
Ultimate analysis: C 21H 25NO 2
Figure A20071003787400251
HCl
Figure A20071003787400252
H 2(theoretical value %:C 66.74, and H 7.47, and N 3.71, and Cl 9.38 for O; Experimental value %:C 66.98, H 7.67, and N 3.83, Cl 9.52)
MS：m/z 324(M+1)
Embodiment 19
III-19N-(p-methoxyphenyl ethyl)-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 1-(bromotrifluoromethane)-4-anisole 1.89g (8.8mmol), 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol) place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 2.33g, yield 71.5%.
Ultimate analysis: C 22H 27NO 3
Figure A20071003787400253
HCl
Figure A20071003787400254
H 2(theoretical value %:C 64.77, and H 7.41, and N 3.43, and Cl 8.69 for O; Experimental value %:C 64.99, H 7.52, and N 3.31, Cl 8.92)
1HNMR (DMSO-d 6): 1.35 (d, 3H, CH 3), 1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.17 (s, 2H, CH 2CO), 3.82 (s, 3H), 4.03-4.10 (m, 1H), 4.99 (s, 1H, piperidines-N HCl), and 7.00-8.10 (m, 9H, ArH), 9.6-11.2 (2B, 1H, piperidines-OH).
MS：m/z 354(M+1)
Embodiment 20
III-20N-(to the fluorophenyl ethyl)-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 1-(1-bromotrifluoromethane)-4-fluorobenzene 1.79g (8.8mmol), 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol) place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 2.39g, yield 75.5%.
Ultimate analysis: C 21H 24FNO 2
Figure A20071003787400256
HCl
Figure A20071003787400257
H 2(theoretical value %:C 63.71, and H 6.87, and N 3.54, and Cl 8.96 for O; Experimental value %:C 63.96, H 6.65, and N 3.32, Cl 9.12)
1HNMR (DMSO-d 6):
Figure A20071003787400261
1.35 (d, 3H, CH 3), 1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.16 (s, 2H, CH 2CO), and 4.03-4.10 (m, 1H, PhCH), 5.01 (s, 1H, piperidines-N HCl), and 7.20-8.10 (m, 9H, ArH), 9.6-10.2 (2B, 1H, piperidines-OH).
MS：m/z 342(M+1)
Embodiment 21
III-21N-(p-aminophenyl ethyl)-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 1-bromotrifluoromethane-4-oil of mirbane 2.02g (8.8mmol), 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol) place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 2.64g, yield 78.1%.
Get 2.64g (6.2mmol) N-(p-nitrophenyl ethyl)-4-phenacyl-4-piperidines alcohol hydrochloride, stannous chloride dihydrate 5.62g (25.0mmol) places the methanol aqueous solution (50%) of 80ml, 40-50 ℃ of reaction 20 hours.Transfer reaction solution to neutral with the NaOH aqueous solution (5N), steam and remove methyl alcohol, use the NaOH aqueous solution (5N) that reaction solution is transferred PH=12 again, ethyl acetate extraction (4 * 20ml), merge organic phase, and the saturated common salt water washing (1 * 20ml), anhydrous MgSO4 drying, merge organic phase, (1 * 20ml), anhydrous MgSO4 drying is filtered in the saturated common salt water washing, steam solvent to the 30ml, use HCl/C 2H 5OH (5N) transfers pH=2, filter crude product, obtain white crystal 1.34g through the ethanol/water recrystallization, yield 50.3%.
Ultimate analysis: C 21H 26N 2O 2
Figure A20071003787400262
2HCl H 2(theoretical value %:C 58.74, and H 7.04, and N 6.52, and Cl 16.51 for O; Experimental value %:C 58.91, H 6.86, and N 6.50, Cl16.83)
1HNMR (DMSO-d 6):
Figure A20071003787400264
1.35 (d, 3H, CH 3), 1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.17 (s, 2H, CH 2CO), and 4.03-4.10 (m, 1H, PhCH), 4.99 (s, 1H, piperidines-N HCl), 5.30 (s, 2H, Ar 1-NH 2), 7.20-8.10 (m, 9H, ArH), 9.6-11.2 (2B, 1H, piperidines-OH).
MS：m/z 339(M+1)
Embodiment 22
III-22N-(3 ', 4 '-methylenedioxyphenyl ethyl)-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 1-bromotrifluoromethane-3 ', 4 '-methylenedioxybenzenes 2.02g (8.8mmol), 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol), place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 2.23g, yield 66.2%.
Ultimate analysis: C 21H 26N 2O 2
Figure A20071003787400265
2HCl H 2(theoretical value %:C 62.63, and H 6.69, and N 3.32, and Cl 8.40 for O; Experimental value %:C 62.74, H 6.85, and N 3.52, Cl 8.69)
1HNMR (DMSO-d 6):
Figure A20071003787400267
1.36 (d, 3H, CH 3), 1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.17 (s, 2H, CH 2CO), and 4.03-4.10 (m, 1H, PhCH), 4.97 (s, 1H, piperidines-N HCl), 5.92 (s, 2H), 6.80-8.10 (m, 8H, ArH), 9.6-11.2 (2B, 1H, piperidines-OH).
MS：m/z 368(M+1)
Embodiment 23
III-23N-(α-menaphthyl)-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 2-(brooethyl)-naphthalene 2.07g (8.8mmol), 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol), place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 2.15g, yield 64.0%.
Ultimate analysis: C 25H 27NO 2
Figure A20071003787400271
HCl 1/2H 2(theoretical value %:C 71.67, and H 6.98, and N 3.34, and Cl 8.46 for O; Experimental value %:C 71.28, H 7.06, and N 3.12, Cl 8.59)
1HNMR (DMSO-d 6):
Figure A20071003787400273
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.14 (s, 2H, CH 2CO), 4.24 (s, 2H, PhCH 2), 5.01 (s, 1H, piperidines-N HCl), and 7.10-8.20 (m, 12H, ArH), 9.9-11.5 (2B, 1H, piperidines-OH).
MS：m/z 374(M+1)
Embodiment 24
III-24N-(4 '-pyrrolidyl benzyl)-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 4-pyrrolidyl bromobenzyl 2.11g (8.8mmol), 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol), place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 2.67g, yield 71.0%.
Ultimate analysis: C 24H 30N 2O 2
Figure A20071003787400274
2HCl
Figure A20071003787400275
H 2(theoretical value %:C 61.40, and H 7.30, and N 5.97, and Cl 15.10 for O; Experimental value %:C 61.28, H 7.45, and N 6.07, Cl 15.34)
1HNMR (DMSO-d 6):
Figure A20071003787400276
1.75-2.10 (m, 8H), 2.88-3.20 (m, 8H), 3.15 (s, 2H, CH 2CO), 4.03-4.10 (m, 2H, PhCH 2), 4.98 (s, 1H), 6.80-8.10 (m, 9H, ArH), 9.6-11.0 (2B, 1H, piperidines-OH).
MS：m/z 379(M+1)
Embodiment 25
III-25N-((4 '-pyrrolidyl) phenylethyl)-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 1-bromotrifluoromethane-4-pyrrolidyl benzene 2.24g (8.8mmol), 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol), place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 2.72g, yield 70.3%.
Ultimate analysis: C 25H 32N 2O 2 2HCl
Figure A20071003787400282
H 2(theoretical value %:C 62.11, and H 7.51, and N 5.79, and Cl 14.67 for O; Experimental value %:C 61.34, H 7.24, and N 6.03, Cl 15.01)
1HNMR (DMSO-d 6): 1.37 (d, 3H, CH 3), 1.75-2.10 (m, 8H), 2.88-3.20 (m, 8H), 3.15 (s, 2H, CH 2CO), 4.02-4.09 (m, 1H), 4.98 (s, 1H), 6.80-8.10 (m, 9H, ArH), 9.6-11.0 (2B, 1H, piperidines-OH).
MS：m/z 393(M+1)
Embodiment 26
III-26N-(4 '-morpholinyl benzyl)-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 4 '-morpholinyl bromobenzyl 2.25g (8.8mmol), 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol), place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 2.59g, yield 64.3%.
Ultimate analysis: C 24H 30N 2O 3
Figure A20071003787400284
2HCl 2H 2(theoretical value %:C 57.26, and H 7.21, and N 5.56, and Cl 14.08 for O; Experimental value %:C 57.57, H 7.32, and N 5.81, Cl 14.35)
1HNMR (DMSO-d 6):
Figure A20071003787400286
1.75-2.10 (m, 4H), 2.80-3.80 (m, 12H), 3.16 (s, 2H, CH 2CO), 4.01-4.10 (m, 2H, PhCH 2), 4.98 (s, 1H), 6.80-8.10 (m, 9H, ArH), 9.6-11.0 (2B, 1H, piperidines-OH).
MS：m/z 395(M+1)
Embodiment 27
III-27N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 1-bromotrifluoromethane-4-morpholinyl benzene 2.38g (8.8mmol), 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol), place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 2.50g, yield 60.4%.
Ultimate analysis: C 25H 32N 2O 3
Figure A20071003787400287
2HCl
Figure A20071003787400288
2H 2(theoretical value %:C 58.02, and H 7.40, and N 5.41, and Cl 13.70 for O; Experimental value %:C 59.27, H 7.55, and N 5.67, Cl 14.01)
1HNMR (DMSO-d 6):
Figure A20071003787400289
1.37 (d, 3H, CH 3), 1.76-2.10 (m, 4H), 2.80-3.90 (m, 12H), 3.15 (s, 2H, CH 2CO), 4.02-4.09 (m, 1H), 5.02 (s, 1H), 6.80-8.10 (m, 9H, ArH, 9.6-11.0 (2B, 1H, piperidines-OH).
MS：m/z 409(M+1)
Embodiment 28
III-28 N-(4 '-piperidyl benzyl)-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 4 '-pyrrolidyl bromobenzyl 2.24g (8.8mmol), 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol), place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 2.86g, yield 73.9%.
Ultimate analysis: C 25H 32N 2O 2
Figure A20071003787400291
2HCl
Figure A20071003787400292
H 2(theoretical value %:C 62.11, and H 7.51, and N 5.79, and Cl 14.67 for O; Experimental value %:C 62.28, H 7.76, and N 6.07, Cl 14.84)
1HNMR (DMSO-d 6):
Figure A20071003787400293
1.55-2.10 (m, 10H), 2.90-3.20 (m, 8H), 3.15 (s, 2H, CH 2CO), 4.03-4.10 (m, 2H, PhCH 2), 5.01 (1B, 1H), 6.80-8.10 (m, 9H, ArH), 9.6-11.0 (2B, 1H, piperidines-OH).
MS：m/z 393(M+1)
Embodiment 29
III-29N-(5-(2-oxoindoline base)) methyl-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 5-brooethyl-2-oxoindoline 2.00g (8.8mmol), 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol), potassiumiodide 0.03g (0.2mmol) and anhydrous K 2CO 33.53g (25.6mmol), place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 2.86g, yield 73.9%.
Ultimate analysis: C 22H 24N 2O 3
Figure A20071003787400294
HCl H 2(theoretical value %:C 63.08, and H 6.50, and N 6.69, and Cl 8.46 for O; Experimental value %:C 63.25, H 6.86, and N 6.47, Cl 8.77)
1HNMR (DMSO-d 6): 1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H), 3.13 (s, 2H, CH 2CO), 3.49 (s, 2H), 4.02-4.08 (m, 2H), 5.01 (s, 1H, piperidines-N HCl), and 6.90-8.10 (m, 8H, ArH), 9.5-11.8 (3B, 2H).
MS：m/z 365(M+1)
Embodiment 30
III-30N-(5-indolinyl) methyl-4-phenacyl-4-piperidines alcohol hydrochloride
Synthetic and post-treating method by logical method one prepares 4-phenacyl-4-piperidines alcohol (II) earlier, again with 5-brooethyl-indoline 1.87g (8.8mmol), and 4-phenacyl-4-piperidines alcohol (II) 1.75g (8.0mmol) and anhydrous K 2CO 33.53g (25.6mmol), place anhydrous propanone (60ml), back flow reaction 12 hours, the post-processing operation by logical method two obtains white crystal 1.29g, yield 36.5%.
Ultimate analysis: C 22H 26N 2O 2 2HCl
Figure A20071003787400298
H 2(theoretical value %:C 59.86, and H 6.85, and N 6.35, and Cl 16.06 for O; Experimental value %:C 59.55, H 6.96, and N 6.45, Cl 16.03)
1HNMR (DMSO-d 6):
Figure A20071003787400301
1.80-2.10 (m, 4H, piperidines-H), 2.80-3.20 (m, 6H), 3.15 (s, 2H, CH 2CO), and 3.40-3.50 (m, 2H), 4.02-4.15 (m, 3H), 5.03 (s, 1H, piperidines-N HCl), and 6.90-8.10 (m, 8H, ArH), 9.5-11.0 (2B, 1H, piperidines-OH).
MS：m/z 351(M+1)
Embodiment 31
III-31N-benzyl-4-(to the fluorobenzoyl methyl)-4-piperidines alcohol hydrobromate
With anhydrous cerium chloride (0.99g, 4.0mmol) and sodium iodide (1.8g 12.0mmol) joins in the 10ml anhydrous tetrahydro furan solvent, forms suspension liquid.2-bromo-1-(4-fluorophenyl)-ethyl ketone 0.87g (4.0mmol) and N-benzyl-4-piperidone 0.76g (4.0mmol) is dissolved in the 10ml anhydrous tetrahydro furan, this drips of solution is added in the above-mentioned suspension liquid room temperature reaction 2 hours.By the post-processing operation of logical method three, through Hydrogen bromide/ethanolic soln acidifying salify, ethyl acetate/ethyl alcohol recrystallization gets white crystal 0.58g, yield 34.0%.
Ultimate analysis: C 20H 22FNO 2
Figure A20071003787400302
HBr
Figure A20071003787400303
H 2O (theoretical value %:C 56.35, and H 5.91, and N 3.29, Br 18.74 experimental value %:C 56.62, and H 5.83, and N 3.46, Br 18.57)
1HNMR (DMSO-d 6):
Figure A20071003787400304
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.14 (s, 2H, CH 2CO), 4.10 (s, 2H, PhCH 2), 4.92 (s, 1H, piperidines-N HBr), and 7.20-8.10 (m, 9H, ArH), 9.6-11.2 (2B, 1H, piperidines-OH).
MS：m/z 328(M+1)
Embodiment 32
III-32N-benzyl-4-(to the methoxybenzoyl methyl)-4-piperidines alcohol hydrobromate
With anhydrous cerium chloride (0.99g, 4.0mmol) and sodium iodide (1.8g 12.0mmol) joins in the 10ml anhydrous tetrahydro furan solvent, forms suspension liquid.2-bromo-1-(4-p-methoxy-phenyl)-ethyl ketone 0.92g (4.0mmol) and N-benzyl-4-piperidone 0.76g (4.0mmol) is dissolved in the 10ml anhydrous tetrahydro furan, this drips of solution is added in the above-mentioned suspension liquid room temperature reaction 2 hours.By the post-processing operation of logical method three, through Hydrogen bromide/ethanolic soln acidifying salify, ethyl acetate/ethyl alcohol recrystallization gets white crystal 0.61g, yield 34.9%.
Ultimate analysis: C 21H 25NO 3HBr H 2(theoretical value %:C 57.54, and H 6.44, and N 3.20, Br18.23 for O; Experimental value %:C 57.33, H 6.53, and N 3.39, Cl 18.41)
1HNMR (DMSO-d 6):
Figure A20071003787400305
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.14 (s, 2H, CH 2CO), 3.94 (s, 3H), 4.05 (s, 2H, PhCH 2), 4.92 (s, 1H, piperidines-N HBr), and 7.20-8.10 (m, 9H, ArH), 9.6-11.0 (2B, 1H, piperidines-OH).
MS：m/z 340(M+1)
Embodiment 33
III-33 N-benzyl-4-(to the chlorobenzoyl methyl)-4-piperidines alcohol hydrobromate
With anhydrous cerium chloride (0.99g, 4.0mmol) and sodium iodide (1.8g 12.0mmol) joins in the 10ml anhydrous tetrahydro furan solvent, forms suspension liquid.2-bromo-1-(4-chlorophenyl) ethyl ketone 0.98g (4.0mmol) and N-benzyl-4-piperidone 0.76g (4.0mmol) is dissolved in the 10ml anhydrous tetrahydro furan, this drips of solution is added in the above-mentioned suspension liquid room temperature reaction 2 hours.By the post-processing operation of logical method three, through Hydrogen bromide/ethanolic soln acidifying salify, ethyl alcohol recrystallization gets white crystal 0.65g, yield 36.7%.
Ultimate analysis: C 20H 22ClNO 2
Figure A20071003787400311
HBr H 2(theoretical value %:C 54.25, and H 5.69, and N 6.18, and Cl 8.01, Br18.05 for O; Experimental value %:C 54.27, H 5.77, and N 6.37, and Cl 8.13, Br 18.26)
1HNMR (DMSO-d 6):
Figure A20071003787400313
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.15 (s, 2H, CH 2CO), 4.08 (s, 2H, PhCH 2), 4.92 (s, 1H, piperidines-N HBr), and 7.20-8.10 (m, 9H, ArH), 9.8-11.0 (2B, 1H, piperidines-OH).
MS：m/z 344(M+1)
Embodiment 34
III-34N-benzyl-4-(2-pyridine formyl methyl)-4-piperidines alcohol hydrobromate
With anhydrous cerium chloride (0.99g, 4.0mmol) and sodium iodide (1.8g 12.0mmol) joins in the 10ml anhydrous tetrahydro furan solvent, forms suspension liquid.2-bromo-1-(2-pyridyl) ethyl ketone 0.80g (4.0mmol) and N-benzyl-4-piperidone 0.76g (4.0mmol) is dissolved in the 10ml anhydrous tetrahydro furan, this drips of solution is added in the above-mentioned suspension liquid room temperature reaction 2 hours.Post-processing operation by logical method three obtains white crystal 0.53g, yield 36.3%.
Ultimate analysis: C 19H 22N 2O 2
Figure A20071003787400314
HBr
Figure A20071003787400315
H 2(theoretical value %:C 55.75, and H 6.16, and N 6.84, and Br 19.52 for O; Experimental value %:C 55.81, H 6.32, and N 6.57, Br 19.801)
1HNMR (DMSO-d 6): 1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.17 (s, 2H, CH 2CO), 4.01 (s, 2H), 4.91 (s, H, piperidines-N HBr), and 7.20-8.60 (m, 9H), 9.6-11.0 (2B, 1H, piperidines-OH).
MS：m/z 311(M+1)
Embodiment 35
III-35N-benzyl-4-(4 '-pyrrolidyl phenacyl)-4-piperidines alcohol hydrochloride
With anhydrous cerium chloride (0.99g, 4.0mmol) and sodium iodide (1.8g 12.0mmol) joins in the 10ml anhydrous tetrahydro furan solvent, forms suspension liquid.2-bromo-1-(4 '-pyrrolidyl phenyl)-ethyl ketone 1.07g (4.0mmol) and N-benzyl-4-piperidone 0.76g (4.0mmol) is dissolved in the 10ml anhydrous tetrahydro furan, this drips of solution is added in the above-mentioned suspension liquid room temperature reaction 2 hours.Post-processing operation by logical method three obtains white crystal 0.65g, yield 34.6%.
Ultimate analysis: C 24H 30N 2O 2
Figure A20071003787400321
2HCl
Figure A20071003787400322
H 2(theoretical value %:C 61.40, and H 7.30, and N 5.97, Cl15.10 for O; Experimental value %:C 61.56, H 7.51, and N 6.17, Cl 15.32)
1HNMR (DMSO-d 6):
Figure A20071003787400323
1.65-2.10 (m, 8H), 2.85-3.20 (m, 8H), 3.15 (s, 2H, CH 2CO), 4.03 (s, 2H, PhCH 2), 4.98 (s, 1H), 6.80-8.10 (m, 9H, ArH), 9.6-11.0 (2B, 1H, piperidines-OH).
MS：m/z 379(M+1)
Embodiment 36
III-36N-benzyl-4-(4 '-morpholinyl phenacyl)-4-piperidines alcohol hydrochloride
With anhydrous cerium chloride (0.99g, 4.0mmol) and sodium iodide (1.8g 12.0mmol) joins in the 10ml anhydrous tetrahydro furan solvent, forms suspension liquid.2-bromo-1-(4 '-pyrrolidyl phenyl)-ethyl ketone 1.07g (4.0mmol) and N-benzyl-4-piperidone 0.76g (4.0mmol) is dissolved in the 10ml anhydrous tetrahydro furan, this drips of solution is added in the above-mentioned suspension liquid room temperature reaction 2 hours.Post-processing operation by logical method three obtains white crystal 0.69g, yield 34.3%.
Ultimate analysis: C 24H 30N 2O 3
Figure A20071003787400324
2HCl
Figure A20071003787400325
2H 2(theoretical value %:C 57.26, and H 7.21, and N 5.56, and Cl 14.08 for O; Experimental value %:C 57.46, H 7.38, and N 5.77, Cl 14.26)
1HNMR (DMSO-d 6): 1.70-2.10 (m, 4H), 2.80-3.80 (m, 12H), 3.16 (s, 2H, CH 2CO), 4.02 (s, 2H, PhCH 2), 4.99 (s, 1H), 6.80-8.10 (m, 9H, ArH), 9.6-11.0 (2B, 1H, piperidines-OH).
MS：m/z 395(M+1)
Embodiment 37
III-37 N-benzyl-4-((5-indolinyl) formyl methyl)-4-piperidines alcohol hydrochloride
With anhydrous cerium chloride (0.99g, 4.0mmol) and sodium iodide (1.8g 12.0mmol) joins in the 10ml anhydrous tetrahydro furan solvent, forms suspension liquid.2-bromo-1-(5-indolinyl)-ethyl ketone 0.96g (4.0mmol) and N-benzyl-4-piperidone 0.76g (4.0mmol) is dissolved in the 10ml anhydrous tetrahydro furan, this drips of solution is added in the above-mentioned suspension liquid room temperature reaction 2 hours.Post-processing operation by logical method three obtains white crystal 0.64g, yield 36.2%.
Ultimate analysis: C 22H 26N 2O 2
Figure A20071003787400327
2HCl
Figure A20071003787400328
H 2(theoretical value %:C 59.86, and H 6.85, and N 6.35, Cl16.06 for O; Experimental value %:C 59.67, H 6.57, and N 6.19, Cl 16.33)
1HNMR (DMSO-d 6):
Figure A20071003787400329
1.80-2.10 (m, 4H, piperidines-H), 2.80-3.20 (m, 6H), 3.16 (s, 2H, CH 2CO), 3.40-3.50 (m, 2H), 4.03 (s, 2H), 4.98 (s, 1H, piperidines-N HCl), and 6.90-8.10 (m, 8H, ArH), 9.6-11.0 (2B, 1H, piperidines-OH).
MS：m/z 351(M+1)
Embodiment 38
III-38N-benzyl-4-(3 ', 4 '-methylene-dioxy benzoyl methyl)-4-piperidines alcohol hydrochloride
With anhydrous cerium chloride (0.99g, 4.0mmol) and sodium iodide (1.8g 12.0mmol) joins in the 10ml anhydrous tetrahydro furan solvent, forms suspension liquid.2-bromo-1-(3 ', 4 '-methylenedioxyphenyl)-ethyl ketone 0.97g (4.0mmol) and N-benzyl-4-piperidone 0.76g (4.0mmol) is dissolved in the 10ml anhydrous tetrahydro furan, this drips of solution is added in the above-mentioned suspension liquid room temperature reaction 2 hours.Post-processing operation by logical method three obtains white crystal 0.70g, yield 42.9%.
Ultimate analysis: C 22H 26N 2O 2
Figure A20071003787400331
HCl H 2(theoretical value %:C 61.84, and H 6.42, and N 3.43, and Cl 8.69 for O; Experimental value %:C 61.57, H 6.71, and N 3.52, Cl 8.87)
1HNMR (DMSO-d 6):
Figure A20071003787400333
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.13 (s, 2H, CH 2CO), 4.25 (s, 2H), 5.02 (s, 1H, piperidines-N HCl), 5.92 (s, 2H), 6.90-8.10 (m, 8H, ArH), 9.6-11.0 (2B, 1H, piperidines-OH).
MS：m/z 354(M+1)
Embodiment 39
III-39N-benzyl-4-(1-benzoyl ethyl)-4-piperidines alcohol hydrochloride
With anhydrous cerium chloride (0.99g, 4.0mmol) and sodium iodide (1.8g 12.0mmol) joins in the 10ml anhydrous tetrahydro furan solvent, forms suspension liquid.2-bromo-1-Propiophenone 0.85g (4.0mmol) and N-benzyl-4-piperidone 0.76g (4.0mmol) is dissolved in the 10ml anhydrous tetrahydro furan, this drips of solution is added in the above-mentioned suspension liquid room temperature reaction 2 hours.Post-processing operation by logical method three obtains white crystal 0.46g, yield 30.5%.
Ultimate analysis: C 21H 25NO 2
Figure A20071003787400334
HCl
Figure A20071003787400335
H 2(theoretical value %:C 66.74, and H 7.47, and N 3.71, and Cl 9.38 for O; Experimental value %:C 66.54, H 7.61, and N 3.94, Cl 9.55)
1HNMR (DMSO-d 6):
Figure A20071003787400336
1.37 (d, 3H), 1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.12 (m, 1H ,-CHCO), 4.11 (s, 2H), 5.01 (s, 1H, piperidines-N HCl), and 7.10-8.10 (m, 10H, ArH), 9.6-11.0 (2B, 1H, piperidines-OH).
MS：m/z 324(M+1)
Embodiment 40
V-1 N-is to methoxy-benzyl-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol hydrochloride
Prepare N-to methoxy-benzyl-4-phenacyl-4-piperidines alcohol (III-15) by the synthetic and post-treating method among the embodiment 12 earlier, getting N-is dissolved in the 30ml ethanolic soln methoxy-benzyl-4-phenacyl-4-piperidines alcohol 1.36g (4.0mmol), add sodium borohydride 0.17g (4.4mmol) in batches, mix the back stirring at room to reacting completely.Post-processing operation by logical method four obtains white crystal 1.07g, yield 78.4%.
Ultimate analysis: C 21H 27NO 3 HCl
Figure A20071003787400338
H 2(theoretical value %:C 63.71, and H 7.64, and N 3.54, Cl, 8.95 for O; Experimental value %:C 63.54, H 7.87, N 3.76, Cl, 9.06)
1HNMR (DMSO-d 6):
Figure A20071003787400339
1.70-2.10 (m, 6H), 3.00-3.30 (m, 5H), 3.79 (s, 3H), 4.01-4.10 (m, 2H, PhCH 2), 4.85-4.90 (m, 1H), 5.01 (s, 1H, piperidines-N HCl), and 7.00-8.20 (m, 9H, ArH), 11.5-12.5 (B, 1H, piperidines-OH).
MS：m/z 342(M+1)。
Embodiment 41
V-2N-acetparaminosalol benzyl-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol hydrochloride
Prepare N-to acetamido benzyl-4-phenacyl-4-piperidines alcohol (III-6) by the synthetic and post-treating method among the embodiment 6 earlier, getting N-is dissolved in the 30ml ethanolic soln acetamido benzyl-4-phenacyl-4-piperidines alcohol 1.47g (4.0mmol), add sodium borohydride 0.17g (4.4mmol) in batches, mix the back stirring at room to reacting completely.Post-processing operation by logical method four obtains white crystal 1.08g, yield 63.9%.
Ultimate analysis: C 22H 28N 2O 3 HCl
Figure A20071003787400342
H 2(theoretical value %:C 62.48, and H 7.39, and N 6.62, Cl, 8.38 for O; Experimental value %:C 62.71, H 7.15, N 6.94, Cl, 8.63)
1HNMR (DMSO-d 6):
Figure A20071003787400343
1.70-2.10 (m, 6H), 2.02 (s, 3H), 3.00-3.30 (m, 5H), 4.01-4.10 (m, 2H, PhCH 2), 4.85-4.90 (m, 1H), 5.02 (s, 1H, piperidines-N HCl), and 7.00-8.20 (m, 9H, ArH), 9.80-10.2 (B, 1H), 11.5-12.5 (B, 1H, piperidines-OH).
MS：m/z 369(M+1)。
Embodiment 42
V-3N-diphenyl-methyl-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol hydrochloride
Prepare N-diphenyl-methyl-4-phenacyl-4-piperidines alcohol (III-7) by the synthetic and post-treating method among the embodiment 7 earlier, getting N-diphenyl-methyl-4-phenacyl-4-piperidines alcohol 1.54g (4.0mmol) is dissolved in the 30ml ethanolic soln, add sodium borohydride 0.17g (4.4mmol) in batches, mix the back stirring at room to reacting completely.Post-processing operation by logical method four obtains white crystal 1.28g, yield 75.5%.
Ultimate analysis: C 26H 29NO 2
Figure A20071003787400344
(theoretical value %:C 73.65, and H 7.13, and N 3.30, Cl, 8.36 for HCl; Experimental value %:C73.51, H 7.03, N 3.17, Cl, 8.27)
1HNMR (DMSO-d 6):
Figure A20071003787400345
1.70-2.10 (m, 6H), 3.00-3.30 (m, 5H), 4.76 (s, H, Ph 2CH), and 4.85-4.90 (m, 1H), 5.01 (s, 1H, piperidines-N HCl), and 7.00-8.20 (m, 15H, ArH), 10.5-12.0 (B, 1H, piperidines-OH).
MS：m/z 388(M+1)。
Embodiment 43
V-4N-(3 ', 4 '-methylenedioxy benzyl)-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol hydrochloride
Prepare N-(3 ' by the synthetic and post-treating method among the embodiment 13 earlier, 4 '-methylenedioxy benzyl)-4-phenacyl-4-piperidines alcohol (III-13), get N-(3 ', 4 '-methylenedioxy benzyl)-4-phenacyl-4-piperidines alcohol 1.41g (4.0mmol) is dissolved in the 30ml ethanolic soln, add sodium borohydride 0.17g (4.4mmol) in batches, mix the back stirring at room to reacting completely.Post-processing operation by logical method four obtains white crystal 1.12g, yield 68.3%.
Ultimate analysis: C 21H 25NO 4
Figure A20071003787400346
HCl
Figure A20071003787400347
H 2(theoretical value %:C 61.53, and H 6.89, and N 3.42, and Cl 8.65 for O; Experimental value %:C 61.14, H 7.07, N 3.73, Cl, 8.46)
1HNMR (DMSO-d 6):
Figure A20071003787400351
1.70-2.10 (m, 6H), 3.00-3.30 (m, 5H), 4.02-4.10 (m, 2H, PhCH 2), 4.85-4.90 (m, 1H), 5.01 (s, 1H, piperidines-N HCl), 5.93 (s, 2H), 6.90-8.10 (m, 8H, ArH), 10.5-12.0 (B, 1H, piperidines-OH).
MS：m/z 356(M+1)。
Embodiment 44
V-5N-(2 '-p-methoxy-phenyl)-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol hydrochloride
Prepare N-(2-p-methoxy-phenyl)-4-phenacyl-4-piperidines alcohol (III-15) by the synthetic and post-treating method among the embodiment 15 earlier, getting N-(2-p-methoxy-phenyl)-4-phenacyl-4-piperidines alcohol 1.30g (4.0mmol) is dissolved in the 30ml ethanolic soln, add sodium borohydride 0.17g (4.4mmol) in batches, mix the back stirring at room to reacting completely.Post-processing operation by logical method four obtains white crystal 1.06g, yield 69.3%.
Ultimate analysis: C 20H 25NO 3 HCl
Figure A20071003787400353
H 2(theoretical value %:C 62.90, and H 7.39, and N 3.67, Cl, 9.28 for O; Experimental value %:C 63.04, H 7.57, N 3.96, Cl, 9.60)
1HNMR (DMSO-d 6):
Figure A20071003787400354
1.70-2.10 (m, 6H), 3.00-3.30 (m, 5H), 4.76 (s, 3H), 4.85-4.90 (m, 1H), 5.01 (s, 1H, piperidines-N HCl), and 6.90-8.10 (m, 9H, ArH), 10.5-12.0 (B, 1H, piperidines-OH).MS：m/z 328(M+1)。
Embodiment 45
V-6N-(5-indolinyl) methyl-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol hydrochloride
Prepare N-(5-indolinyl) methyl-4-phenacyl-4-piperidines alcohol (III-30) by the synthetic and post-treating method among the embodiment 30 earlier, getting N-(5-indolinyl) methyl-4-phenacyl-4-piperidines alcohol 0.85g (4.0mmol) is dissolved in the 30ml ethanolic soln, add sodium borohydride 0.17g (4.4mmol) in batches, mix the back stirring at room to reacting completely.Post-processing operation by logical method four obtains white crystal 1.37g, yield 71.8%.
Ultimate analysis: C 22H 26N 2O 2 2HCl 3H 2(theoretical value %:C 55.35, and H 7.18, and N 5.87, Cl, 14.85 for O; Experimental value %:C 55.74, H 7.03, N 5.56, Cl, 15.08)
1HNMR (DMSO-d 6):
Figure A20071003787400357
1.70-2.10 (m, 6H), 2.80-3.30 (m, 7H), 3.40-3.50 (m, 2H), 4.02-4.15 (m, 3H), 4.85-4.90 (m, 1H), 5.01 (s, 1H, piperidines-N HCl), and 6.90-8.10 (m, 8H, ArH), 10.5-12.0 (B, 1H, piperidines-OH).
MS：m/z 353(M+1)。
Embodiment 46
V-7N-((4 '-pyrrolidyl) phenylethyl)-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol hydrochloride
Prepare N-(4 '-pyrrolidyl benzyl)-4-phenacyl-4-piperidines alcohol (III-24) by the synthetic and post-treating method among the embodiment 24 earlier, getting N-(4 '-pyrrolidyl benzyl)-4-phenacyl-4-piperidines alcohol 1.51g (4.0mmol) is dissolved in the 30ml ethanolic soln, add sodium borohydride 0.17g (4.4mmol) in batches, mix the back stirring at room to reacting completely.Post-processing operation by logical method four obtains white crystal 1.31g, yield 69.3%.
Ultimate analysis: C 24H 32N 2O 2
Figure A20071003787400361
2HCl H 2(theoretical value %:C 61.14, and H 7.70, and N 5.94, Cl, 15.04 for O; Experimental value %:C 61.55, H 7.97, N 5.76, Cl, 15.20)
1HNMR (DMSO-d 6):
Figure A20071003787400363
1.37 (d, 3H, CH 3), 1.70-2.10 (m, 10H), 2.80-3.30 (m, 9H), 4.02-4.09 (m, 1H), 4.85-4.90 (m, 1H), 5.01 (s, 1H, piperidines-N HCl), and 6.80-8.10 (m, 9H, ArH), 10.5-12.0 (B, 1H, piperidines-OH).
MS：m/z 381(M+1)。
Embodiment 47
V-8N-((4 '-morpholinyl) phenylethyl)-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol hydrochloride
Prepare N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-piperidines alcohol (III-27) by the synthetic and post-treating method among the embodiment 12 earlier, getting N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-piperidines alcohol 1.63g (4.0mmol) is dissolved in the 30ml ethanolic soln, add sodium borohydride (4.4mmol) in batches, mix the back stirring at room to reacting completely.Post-processing operation by logical method four obtains white crystal 1.24g, yield 62.0%.
Ultimate analysis: C 25H 34N 2O 3
Figure A20071003787400364
2HCl
Figure A20071003787400365
H 2(theoretical value %:C 59.88, and H 7.64, and N 5.59, Cl, 14.14 for O; Experimental value %:C 59.74, H 7.37, and N 5.77, Cl 14.62)
1HNMR (DMSO-d 6):
Figure A20071003787400366
1.37 (d, 3H, CH 3), 1.70-2.10 (m, 6H), 2.80-3.30 (m, 13H), 4.01-4.10 (m, 1H), 4.85-4.90 (m, 1H), 5.01 (s, 1H, piperidines-N HCl), and 6.80-8.10 (m, 9H, ArH), 10.5-12.0 (B, 1H, piperidines-OH).
MS：m/z 411(M+1)。
Embodiment 48
VIII-1N-acetparaminosalol benzyl-4-phenacyl-4-methoxyl group piperidine hydrochlorate
Prepare N-acetparaminosalol benzyl-4-phenacyl-4-piperidines alcohol (III-6) by the synthetic and post-treating method among the embodiment 6 earlier; get N-acetparaminosalol benzyl-4-phenacyl-4-piperidines alcohol 1.47g (4.0mmol) by the method protection ketone carbonyl in the logical method five; it is dissolved in the 20ml benzene then; the NaH0.16g (4.0mmol) of slow adding 60%; stirred 0.5 hour; (5.0mmol, 5ml), stirring at room is to reacting completely for the benzole soln of dropping methyl iodide in reaction solution.By aftertreatment in the logical method five and deprotection method operation, get white crystal 0.71g, total recovery 40.8%.
Ultimate analysis: C 23H 28N 2O 3
Figure A20071003787400367
HCl H 2(theoretical value %:C 63.51, and H 7.18, and N 6.44, Cl, 8.15 for O; Experimental value %:C 63.44, H 7.43, and N 6.67, Cl 8.47)
1HNMR (DMSO-d 6):
Figure A20071003787400369
1.80-2.10 (m, 4H, piperidines-H), 2.02 (s, 3H), 3.00-3.20 (m, 4H, piperidines-H), 3.13 (s, 2H, CH 2CO), 3.49 (s, 3H), 4.03-4.10 (m, 2H, PhCH 2), 5.01 (s, 1H, piperidines-N HCl), and 7.20-8.10 (m, 9H, ArH), 9.80-10.20 (s, broad peak, 1H).
MS：m/z 381(M+1)。
Embodiment 49
VIII-2N-p-methoxyphenyl ethyl-4-phenacyl-4-methoxyl group piperidine hydrochlorate
Prepare N-(p-methoxyphenyl ethyl)-4-phenacyl-4-piperidines alcohol (III-19) by the synthetic and post-treating method among the embodiment 19 earlier; get N-(p-methoxyphenyl ethyl)-4-phenacyl-4-piperidines alcohol 1.41g (4.0mmol) by the method protection ketone carbonyl in the logical method five; it is dissolved in the 20ml benzene then; the NaH0.16g (4.0mmol) of slow adding 60%; stirred 0.5 hour; in reaction solution, drip the benzole soln (5.0mmol of methyl iodide; 5ml), stirring at room is to reacting completely.By aftertreatment in the logical method five and deprotection method operation, get white crystal 0.72g, total recovery 42.7%.
Ultimate analysis: C 23H 29NO 3
Figure A20071003787400371
HCl
Figure A20071003787400372
H 2(theoretical value %:C 65.47, and H 7.64, and N 3.32, Cl, 8.40 for O; Experimental value %:C 65.54, H 7.41, and N 3.47, Cl 8.66)
1HNMR (DMSO-d 6):
Figure A20071003787400373
1.34 (d, 3H, CH 3), 1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.17 (s, 2H, CH 2CO), 3.45 (s, 3H), 3.82 (s, 3H), 4.03-4.10 (m, 1H), 5.01 (s, 1H, piperidines-N HCl), and 7.00-8.10 (m, 9H, ArH).
MS：m/z 368(M+1)。
Embodiment 50
VIII-3N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-methoxyl group piperidine hydrochlorate
Prepare N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-piperidines alcohol (III-27) by the synthetic and post-treating method among the embodiment 19 earlier; get N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-piperidines alcohol 1.63g (4.0mmol) by the method protection ketone carbonyl in the logical method five; it is dissolved in the 20ml benzene then; the NaH0.16g (4.0mmol) of slow adding 60%; stirred 0.5 hour; in reaction solution, drip the benzole soln (5.0mmol of methyl iodide; 5ml), stirring at room is to reacting completely.By aftertreatment in the logical method five and deprotection method operation, get white crystal 0.91g, total recovery 44.4%.
Ultimate analysis: C 26H 34N 2O 3
Figure A20071003787400374
2HCl
Figure A20071003787400375
H 2(theoretical value %:C 60.81, and H 7.46, and N 5.46, Cl, 13.81 for O; Experimental value %:C 60.67, H 7.63, and N 5.57, Cl 14.06)
1HNMR (DMSO-d 6):
Figure A20071003787400376
1.34 (d, 3H, CH 3), 1.75-2.10 (m, 4H), 2.80-3.80 (m, 12H), 3.17 (s, 2H, CH 2CO), 3.45 (s, 3H), 4.03-4.10 (m, 1H), 5.02 (s, 1H, piperidines-N HCl), and 6.90-8.20 (m, 9H, ArH).
MS：m/z 423(M+1)。
Embodiment 51
IX-1N-p-methoxyphenyl ethyl-4-phenacyl-4-fluorine piperidine hydrochlorate
Prepare N-p-methoxyphenyl ethyl-4-phenacyl-4-piperidines alcohol (III-19) by the synthetic and post-treating method among the embodiment 19 earlier; getting N-p-methoxyphenyl ethyl-4-phenacyl-4-piperidines alcohol 1.41g (4.0mmol) is dissolved in the exsiccant 20ml methylene dichloride; the dry ice-propanone cooling; temperature control＜-70 ℃; the dichloromethane solution of dropping DAST in the nitrogen protection downhill reaction liquid (8mol, 25ml).After being added dropwise to complete, keep-75 ℃ of reactions 1 hour, slowly heat up, keep-10 ℃ of reactions 2 hours.Then, the post-treating method operation by in the logical method six gets white crystals 0.57g, yield 34.8%.
Ultimate analysis: C 22H 26FNO 2
Figure A20071003787400381
HCl
Figure A20071003787400382
H 2(theoretical value %:C 64.46, and H 7.13, and N 3.42, Cl, 8.65 for O; Experimental value %:C 64.74, H 7.44, and N 3.57, Cl 8.86)
1HNMR (DMSO-d 6):
Figure A20071003787400383
1.35 (d, 3H, CH 3), 1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.16 (s, 2H, CH 2CO), 3.78 (s, 3H ,-OCH 3), 4.03-4.10 (m, 1H, PhCH), 4.99 (s, 1H, piperidines-N HCl), and 7.00-8.10 (m, 9H, ArH).
MS：m/z 356(M+1)。
Embodiment 52
IX-2N-(3 ', 4 '-methylenedioxy benzyl)-4-phenacyl-4-fluorine piperidine hydrochlorate
Prepare N-(3 ' by the synthetic and post-treating method among the embodiment 13 earlier; 4 '-methylenedioxy benzyl)-4-phenacyl-4-piperidines alcohol (III-13); get N-(3 '; 4 '-methylenedioxy benzyl)-4-phenacyl-4-piperidines alcohol 1.41g (4.0mmol) is dissolved in the exsiccant 20ml methylene dichloride; the dry ice-propanone cooling; temperature control＜-70 ℃, drip in the nitrogen protection downhill reaction liquid DAST dichloromethane solution (8mol, 25ml).After being added dropwise to complete, keep-75 ℃ of reactions 1 hour, slowly heat up, keep-10 ℃ of reactions 2 hours.Then, the post-treating method operation by in the logical method six gets white crystals 0.61g, yield 37.2%.
Ultimate analysis: C 21H 22FNO 3 HCl
Figure A20071003787400385
H 2(theoretical value %:C 64.54, and H 6.15, and N 3.42, Cl, 8.65 for O; Experimental value %:C 64.69, H 6.43, and N 3.60, Cl 8.75)
1HNMR (DMSO-d 6):
Figure A20071003787400386
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.15 (s, 2H, CH 2CO), 4.02-4.10 (m, 2H, PhCH 2), 5.01 (s, 1H, piperidines-N HCl), 5.93 (s, 2H), 7.00-8.10 (m, 8H, ArH).
MS：m/z 356(M+1)。
Embodiment 53
IX-3N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-fluorine piperidine hydrochlorate
Prepare N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-piperidines alcohol (III-27) by the synthetic and post-treating method among the embodiment 27 earlier; getting N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-piperidines alcohol 1.63g (4.0mmol) is dissolved in the exsiccant 20ml methylene dichloride; the dry ice-propanone cooling; temperature control＜-70 ℃; the dichloromethane solution of dropping DAST in the nitrogen protection downhill reaction liquid (8mol, 25ml).After being added dropwise to complete, keep-75 ℃ of reactions 1 hour, slowly heat up, keep-10 ℃ of reactions 2 hours.Then, the post-treating method operation by in the logical method six gets white crystals 0.81g, yield 40.5%.
Ultimate analysis: C 25H 31FN 2O 2 2HCl H 2(theoretical value %:C 59.88, and H 7.04, and N 5.59, Cl, 14.14 for O; Experimental value %:C 59.67, H 7.33, and N 5.67, Cl 14.45)
1HNMR (DMSO-d 6): 1.34 (d, 3H, CH 3), 1.75-2.10 (m, 4H), 2.80-3.80 (m, 12H), 3.17 (s, 2H, CH 2CO), and 4.03-4.10 (m, 1H), 5.02 (s, 1H, piperidines-N HCl), and 6.90-8.20 (m, 9H, ArH).
MS：m/z 411(M+1)。
Embodiment 54
IX-4N-((4 '-pyrrolidyl) phenylethyl)-4-phenacyl-4-fluorine piperidine hydrochlorate
Prepare N-((4 '-pyrrolidyl) phenylethyl)-4-phenacyl-4-piperidines alcohol (III-25) by the synthetic and post-treating method among the embodiment 25 earlier; getting N-((4 '-pyrrolidyl) phenylethyl)-4-phenacyl-4-piperidines alcohol 1.57g (4.0mmol) is dissolved in the exsiccant 20ml methylene dichloride; the dry ice-propanone cooling; temperature control＜-70 ℃; the dichloromethane solution of dropping DAST in the nitrogen protection downhill reaction liquid (8mol, 25ml).After being added dropwise to complete, keep-75 ℃ of reactions 1 hour, slowly heat up, keep-10 ℃ of reactions 2 hours.Then, the post-treating method operation by in the logical method six gets white crystals 0.78g, yield 40.2%.
Ultimate analysis: C 25H 31FN 2O 2HCl H 2(theoretical value %:C 61.85, and H 7.27, and N 5.77, Cl, 14.61 for O; Experimental value %:C 61.77, H 7.43, and N 5.89, Cl 14.91)
1HNMR(DMSO-d 6)：
Figure A20071003787400396
1.37(d，3H，CH 3)，1.75-2.20(m，8H)，2.88-3.20(m，8H)，3.15(s，2H，CH 2CO)，4.02-4.10(m，1H)，5.00(s，1H)，6.80-8.10(m，9H，ArH)。
MS：m/z 395(M+1)。
Embodiment 55
IX-5N-p-methoxyphenyl ethyl-4-phenacyl-4-Chloperastine hydrochloride
Prepare N-p-methoxyphenyl ethyl-4-phenacyl-4-piperidines alcohol (III-19) by the synthetic and post-treating method among the embodiment 19 earlier, getting N-p-methoxyphenyl ethyl-4-phenacyl-4-piperidines alcohol 1.41g (4.0mmol) is dissolved in the exsiccant 20ml methylene dichloride, the frozen water cooling, 0 ℃ of temperature control drips SOCl in reaction solution 2Dichloromethane solution (8mol, 25ml).After being added dropwise to complete, slowly be warming up to room temperature reaction 1 hour.Then, the post-treating method operation by in the logical method seven gets white crystals 0.68g, yield 39.9%.
Ultimate analysis: C 22H 26ClNO 2
Figure A20071003787400397
HCl
Figure A20071003787400398
H 2(theoretical value %:C 61.97, and H 6.86, and N 3.29, Cl, 16.63 for O; Experimental value %:C 62.05, H 7.03, and N 3.58, Cl 16.86)
1HNMR (DMSO-d 6): 1.35 (d, 3H, CH 3), 1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.17 (s, 2H, CH 2CO), 3.79 (s, 3H ,-OCH 3), 4.03-4.10 (m, 1H, PhCH), 4.99 (s, 1H, piperidines-N HCl), and 7.00-8.10 (m, 9H, ArH).
MS：m/z 372(M+1)。
Embodiment 56
IX-6N-(3 ', 4 '-methylenedioxy benzyl)-4-phenacyl-4-Chloperastine hydrochloride
Prepare N-(3 ' by the synthetic and post-treating method among the embodiment 13 earlier, 4 '-methylenedioxy benzyl)-4-phenacyl-4-piperidines alcohol (III-13), get N-(3 ', 4 '-methylenedioxy benzyl)-4-phenacyl-4-piperidines alcohol 1.41g (4.0mmol) is dissolved in the exsiccant 20ml methylene dichloride, the frozen water cooling, 0 ℃ of temperature control drips SOCl in reaction solution 2Dichloromethane solution (8mol, 25ml).After being added dropwise to complete, slowly be warming up to room temperature reaction 1 hour.Then, the post-treating method operation by in the logical method seven gets white crystals 0.65g, yield 38.1%.
Ultimate analysis: C 21H 22ClNO 3
Figure A20071003787400401
HCl
Figure A20071003787400402
H 2(theoretical value %:C 59.16, and H 5.91, and N 3.29, Cl, 16.63 for O; Experimental value %:C 59.35, H 6.10, and N 3.55, Cl 16.92)
1HNMR (DMSO-d 6):
Figure A20071003787400403
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.15 (s, 2H, CH 2CO), 4.02-4.10 (m, 2H, PhCH 2), 5.01 (s, 1H, piperidines-N HCl), 5.93 (s, 2H), 7.00-8.10 (m, 8H, ArH).
MS：m/z 372(M+1)。
Embodiment 57
IX-7N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-Chloperastine hydrochloride
Prepare N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-piperidines alcohol (III-27) by the synthetic and post-treating method among the embodiment 27 earlier, getting N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-piperidines alcohol 1.63g (4.0mmol) is dissolved in the exsiccant 20ml methylene dichloride, the frozen water cooling, 0 ℃ of temperature control drips SOCl in reaction solution 2Dichloromethane solution (8mol, 25ml).After being added dropwise to complete, slowly be warming up to room temperature reaction 1 hour.Then, the post-treating method operation by in the logical method seven gets white crystals 0.76g, yield 36.8%.
Ultimate analysis: C 25H 31ClN 2O 2
Figure A20071003787400404
2HCl
Figure A20071003787400405
H 2(theoretical value %:C 57.98, and H 6.81, and N 5.41, Cl, 20.54 for O; Experimental value %:C 57.75, H 6.69, and N 5.54, Cl 20.82)
1HNMR (DMSO-d 6):
Figure A20071003787400406
1.34 (d, 3H, CH 3), 1.75-2.10 (m, 4H), 2.80-3.80 (m, 12H), 3.17 (s, 2H, CH 2CO), and 4.03-4.10 (m, 1H), 5.01 (s, 1H, piperidines-N HCl), and 6.90-8.20 (m, 9H, ArH).
MS：m/z 427(M+1)。
Embodiment 58
Tablet: derivative 25mg of the present invention
Sucrose 155mg
W-Gum 65mg
Magnesium Stearate 5mg
The preparation method: activeconstituents is mixed with sucrose, W-Gum, and it is moistening to add water, stirs, and drying, crushing screening adds Magnesium Stearate, mixes compressing tablet.Every heavy 250mg, active component content is 25mg.
Embodiment 59
Injection: derivative 10mg of the present invention
Water for injection 90mg
The preparation method: activeconstituents is dissolved in water for injection, mixes, filter, the solution that is obtained is sub-packed in the ampoule under aseptic condition, every bottle of 10mg, active component content are the 1mg/ bottle.
Embodiment 60
Analgesia and sedative effect in the chemical combination object
1, laboratory animal:
Kunming mouse, cleaning level KM mouse is raised in the conventional environment available from Shanghai Si Laike laboratory animal company.
2, experiment administering mode:
Compound is mixed with 4mg/ml, 2mg/ml, 1mg/ml solution with water for injection, and control group and administration group all adopt animal via neck subcutaneous injection administration.
3, experiment dosage:
The administration group adopts three kinds of various dose administrations, is respectively: 10mg/kg, 20mg/kg, 40mg/kg.
4, experimental technique:
With the positive control drug of Asprin, adopt the acetic acid twisting method to experimentize.
5, concrete experimental implementation:
Get 30 of mouse, male and female half and half, body weight is between the 18-23 gram.It is divided into five groups, is respectively: negative control group, positive controls, low dose group, middle dosage group and high dose group, specific as follows:
Negative control group physiological saline 0.2ml
Positive controls Asprin 0.2mg
Low dose group is subjected to reagent thing 1mg/ml 0.2ml
Middle dosage group is subjected to reagent thing 2mg/ml 0.2ml
High dose group is subjected to reagent thing 4mg/ml 0.2ml
Mouse is earlier through neck subcutaneous injection specimen solution (10mg/kg, 20mg/kg, 40mg/kg), negative control group oral normal saline (20ml/kg), positive controls oral aspirin (20ml/kg), respectively organize mouse ip 0.7% acetate 10ml/kg respectively after 1 hour, the writhing response number of times that mouse occurs respectively organized in record behind the 5min in 15min at interval, calculates the writhing response inhibiting rate of each administration group by following formula.
Figure A20071003787400411
6, sedative effect adopts alternating current pipe record spontaneous activity in mice.
7, the analgesic activity and the sedative effect of single dose (20mg/kg) administration test compounds see table 2 for details
Table 2
Analgesia Calm Analgesia Calm Analgesia Calm
III-1 62 43 III-21 57 70.8 V-2 80 39.6
III-2 14 44 III-22 43 73 V-3 84 43
III-3 76 35 III-23 74 32 V-4 76 99
III-4 100 91 III-24 62 97 V-5 72 86
III-5 100 65 III-25 80 93 V-6 69 51
III-6 45 75 III-26 64 65 V-7 79 93
III-7 45 60 III-27 92 81 V-8 77 84
III-8 77 96 III-28 64 47 VIII-1 64 48
III-9 57 74 III-29 45 7 VIII-2 76 90.1
III-10 51 99 III-30 42 35 VIII-3 60 72
III-11 44 0 III-31 42 4 IX-1 76 26
III-12 21 52 III-32 49 32 IX-2 45 0
III-13 37 66 III-33 26 56 IX-3 64 42
III-14 54 20 III-34 75 92 IX-4 64 84
III-15 96 54 III-35 64 61 IX-5 68 88
III-16 33 64 III-36 41 27 IX-6 59 90.1
III-17 66 52 III-37 52 36 IX-7 72 55
III-18 84 20 III-38 46 45
III-19 91 52 III-39 56 32
III-20 37 67 V-1 76 56
8, part of compounds multiple dose administration experimental result: see table 3 for details
Table 3
Figure A20071003787400421
Annotate: *Expression P value＜0.05, *Expression P value＜0.01
Embodiment 61
The mouse hot plate method is measured analgesic activity in the chemical combination object
1, laboratory animal:
Kunming mouse, cleaning level KM mouse is raised in the conventional environment available from Shanghai Si Laike laboratory animal company.
2, experiment administering mode:
Compound is mixed with 4mg/ml, 2mg/ml, 1mg/ml solution with water for injection, and control group and administration group all adopt animal via neck subcutaneous injection administration.
3, experiment dosage:
The administration group adopts three kinds of various dose administrations, is respectively: 10mg/kg, 20mg/kg, 40mg/kg.
4, experimental technique:
With the positive control drug of morphine, adopt hot plate method to experimentize.
5, concrete experimental implementation:
Get 30～40 of mouse, male and female half and half, body weight is between the 18-23 gram.At first, respectively mouse is placed on 55.5 ℃ the hot plate and test basic threshold of pain 2～3 times, basic threshold of pain 5～30s is qualified, eliminates underproof mouse.Get 30 qualified mouse it is divided into five groups, be respectively: negative control group, positive controls, low dose group, middle dosage group and high dose group, specific as follows:
Negative control group is directly tested basic threshold of pain
Positive controls morphine 0.2mg/ml 0.2ml
Low dose group is subjected to reagent thing 1mg/ml 0.2ml
Middle dosage group is subjected to reagent thing 2mg/ml 0.2ml
High dose group is subjected to reagent thing 4mg/ml 0.2ml
Mouse through neck subcutaneous injection specimen solution (10mg/kg, 20mg/kg, 40mg/kg), positive controls subcutaneous injection morphine (2mg/kg), respectively organize after 1 hour mouse survey respectively threshold of pain as administration after threshold of pain.Calculate threshold of pain raising rate by following formula:
Figure A20071003787400431
6, part of compounds experimental result: see table 4 for details
Table 4
Figure A20071003787400441
Annotate: *Expression P value＜0.05, *Expression P value＜0.01
Embodiment 62
The drug dependence experiment of compound III-15
1, preliminary resistance research:
With the hot plate method test, the analgesic activity that mouse gavaging III-15 (60mg/kg) produces is not naloxone (1mg/kg, ip) upset.But (bucinnazine hydrochloride, Fortanodyn) analgesic activity of Chan Shenging is all overturn by naloxone for morphine and Fortanodyn.Continuous 8 days of mouse gavages III-15 (60mg/kg) every day, and 15min surveys the variation of mouse pain valve with hot plate method after each administration.III-15 pain valve under the continuous use condition is not seen and is weakened.(10mg/kg, PO) in administration after second day, analgesic activity weakens the positive control drug morphine gradually, presents obvious resistance.Many medications of prompting III-15
After do not show resistance.
2, preliminary habituation test (naloxone roll-over test):
With mouse jump and conditioned place preference, physical dependence and the drug dependence effect of test I II-15 respectively.Mouse was pressed ascending-dose in 2 days (20-120mg/kg PO) gives III-15 seven dosage, and behind the dosage 3 hours the last time, intravenous injection naloxone 2mg/kg did not observe mouse and hopping response occurs again, and obvious hopping response then appears in morphine group mouse.Mouse gavages III-1560mg/kg every day, and successive administration was tested after 6 days, and mouse is Conditions position preference not, and the morphine mouse obvious condition bit offset then occurs and likes.Results suggest, III-15 is different from morphine, is not repeatedly producing habituation after the medication.
Embodiment 63
The acute toxicity preliminary experiment of III-15:
With Bliss method statistics, the mouse single gavages the LD of III-15 50Be 452mg/kg.The rat single gavages the LD of III-15 50Be 524mg/kg.
Embodiment 64
The Ames test of III-15
Bacterial classification: mouse Salmonellas Histidine nutrient defect mutation strain TA 97, TA 98, TA 100And TA 102
The result: experiment comprises-S 9With+S 9Two parts are at no S 9TA in the test macro 98With add S 9TA in the test macro 97
Figure A20071003787400451
Ware has bacteriostatic action.Other dosage does not all have bacteriostatic action to all bacterial strains, and the growth background is good.No matter all proof loads are at no S 9Or add S 9In the experimental system, do not cause that all any bacterium colony returns parameter and obviously increases, the Salmonella reversion test feminine gender.
The above results shows that III-15 has obvious analgesic activity, and oral absorption is better.Do not show resistance after many medications of III-15, the pharmacological dependence begetting power is very low, the Salmonella reversion test feminine gender, and therapeutic index is bigger, possesses the potential value as the novel non-habituation analgesic agent research and development of a class.

Claims (11)

1. an aralkyl piperidine piperidine derivatives is characterized in that, is free alkali or the salt with following structure general formula:
Figure A2007100378740002C1
Wherein:
A representative: OH, F, Cl, Br, (C 1-C 4) alkoxyl group, wherein (C 1-C 4) moieties of alkoxyl group can choose wantonly to be replaced and can also choose wantonly by amino or hydroxyl substituent by 1-3 fluorine atom and replace;
When B when adjacent carbon is connected with singly-bound, B represents OH;
When B when adjacent carbon is connected with two keys, B represents O or S;
Ar 1Representative:
Figure A2007100378740002C2
Or
Figure A2007100378740002C3
Ar 2Representative:
Figure A2007100378740002C4
Or
Figure A2007100378740002C5
X, Y are independent respectively to represent C, CH, N;
The Z representative contains N, O, S heteroatomic five yuan or hexa-atomic saturated or undersaturated aliphatic heterocycle or aromatic heterocycle, and wherein the heteroatoms sum is less than or equal to 3;
R 1, R 2Independent respectively hydrogen, the C of representing 1-C 4Alkyl, C 5Or C 6Cycloaliphatic ring, benzene and substituted-phenyl, hydroxyl, (C 1-C 4) a kind of in alkoxyl group, amino and substituted-amino, halogen, carboxylic acid and carboxylicesters, nitro or the acetonitrile, wherein C 1-C 4Alkyl, (C 1-C 4) alkoxyl group and C 5Or C 6Cycloaliphatic ring on moieties can choose wantonly to be replaced and can also choose wantonly and replace by amino or hydroxyl substituent by 1-3 fluorine atom;
R 3, R 4, R 5Independent respectively hydrogen, the C of representing 1-C 4Alkyl, C 5Or C 6Cycloaliphatic ring, five yuan or hexa-atomic one or two N, O, the heteroatomic saturated or undersaturated cycloaliphatic ring of S, benzene and substituted-phenyl, the hydroxyl, (C of containing 1-C 4) a kind of in alkoxyl group, amino and substituted-amino, halogen, carboxylic acid and carboxylicesters, nitro or the acetonitrile, wherein C 1-C 4Alkyl, (C 1-C 4) alkoxyl group and C 5Or C 6Cycloaliphatic ring on moieties can choose wantonly to be replaced and can also choose wantonly and replace by amino or hydroxyl substituent by 1-3 fluorine atom;
R 6, R 7, R 8Independent respectively hydrogen, the C of representing 1-C 4Alkyl, C 5Or C 6Cycloaliphatic ring, five yuan or hexa-atomic one or two N, O, the heteroatomic saturated or undersaturated cycloaliphatic ring of S, benzene and substituted-phenyl, the hydroxyl, (C of containing 1-C 4) a kind of in alkoxyl group, halogen, carboxylic acid and carboxylicesters, nitro or the acetonitrile etc., wherein C 1-C 4Alkyl, (C 1-C 4) alkoxyl group and C 5Or C 6Cycloaliphatic ring on moieties can choose wantonly to be replaced and can also choose wantonly and replace by amino or hydroxyl substituent by 1-3 fluorine atom;
N=0,1,2,3; M=1,2,3; Work as n, m=2,, substituent R at 3 o'clock 1And R 2Can directly link to each other with any one or more carbon on the carbochain.
2. aralkyl piperidine piperidine derivatives according to claim 1 is characterized in that, A is: OH, a kind of among F or the Cl.
3. aralkyl piperidine piperidine derivatives according to claim 1 is characterized in that R 1, R 2For: hydrogen, C 1-C 4Alkyl or benzene and substituted-phenyl in a kind of.
4. aralkyl piperidine piperidine derivatives according to claim 1 is characterized in that R 3, R 4, R 5For: hydrogen, C 1-C 4Alkyl, hydroxyl, first, oxyethyl group, amino and substituted-amino, morpholine, tetramethyleneimine, piperidines, a kind of in halogen or the nitro.
5. aralkyl piperidine piperidine derivatives according to claim 1 is characterized in that R 6, R 7, R 8For: hydrogen, C 1-C 4Alkyl, hydroxyl, first, oxyethyl group, halogen, morpholine, a kind of in tetramethyleneimine or the piperidines.
6. aralkyl piperidine piperidine derivatives according to claim 1 is characterized in that, said salt is hydrochloride, hydrogen bromide salt, vitriol, trifluoroacetate or mesylate.
7. aralkyl piperidine piperidine derivatives according to claim 6 is characterized in that, salt is hydrochloride, hydrogen bromide salt.
8. aralkyl piperidine piperidine derivatives according to claim 7 is characterized in that said salt contains the crystal water of 0.5-3 molecule.
9. aralkyl piperidine piperidine derivatives according to claim 1 is characterized in that, said compound comprises:
III-1 N-benzyl-4-phenacyl-4-piperidines alcohol
III-2 N-p-chlorobenzyl-4-phenacyl-4-piperidines alcohol
III-3 N-is to luorobenzyl-4-phenacyl-4-piperidines alcohol
III-4 N-is to nitrobenzyl-4-phenacyl-4-piperidines alcohol
III-5 N-PAB-4-phenacyl-4-piperidines alcohol
III-6 N-acetparaminosalol benzyl-4-phenacyl-4-piperidines alcohol
III-7 N-diphenyl-methyl-4-phenacyl-4-piperidines alcohol
III-8 N-(2-pyridyl) methyl-4-phenacyl-4-piperidines alcohol
III-9 N-(2-pyrimidyl)-4-phenacyl-4-piperidines alcohol
III-10 N-(2-pyrimidyl) methyl-4-phenacyl-4-piperidines alcohol
III-11 N-(2-quinolyl)-4-phenacyl-4-piperidines alcohol
III-12 N-(2 '-p-methoxy-phenyl)-4-phenacyl-4-piperidines alcohol
III-13 N-(3 ', 4 '-methylenedioxy benzyl)-4-phenacyl-4-piperidines alcohol
III-14 N-(3 ', 4 ', 5 '-trimethoxy benzyl)-4-phenacyl-4-piperidines alcohol
III-15 N-is to methoxy-benzyl-4-phenacyl-4-piperidines alcohol
III-16 N-styroyl-4-phenacyl-4-piperidines alcohol
III-17 N-(1R-phenylethyl)-4-phenacyl-4-piperidines alcohol
III-18 N-(1S-phenylethyl)-4-phenacyl-4-piperidines alcohol
III-19 N-(p-methoxyphenyl ethyl)-4-phenacyl-4-piperidines alcohol
III-20 N-(to the fluorophenyl ethyl)-4-phenacyl-4-piperidines alcohol
III-21 N-(p-aminophenyl ethyl)-4-phenacyl-4-piperidines alcohol
III-22 N-(3 ', 4 '-methylenedioxyphenyl ethyl)-4-phenacyl-4-piperidines alcohol
III-23 N-(α-menaphthyl)-4-phenacyl-4-piperidines alcohol
III-24 N-(4 '-pyrrolidyl benzyl)-4-phenacyl-4-piperidines alcohol
III-25 N-((4 '-pyrrolidyl) phenylethyl)-4-phenacyl-4-piperidines alcohol
III-26 N-(4 '-morpholinyl benzyl)-4-phenacyl-4-piperidines alcohol
III-27 N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-piperidines alcohol
III-28 N-(4 '-piperidyl benzyl)-4-phenacyl-4-piperidines alcohol
III-29 N-(5-(2-oxoindoline base)) methyl-4-phenacyl-4-piperidines alcohol
III-30 N-(5-indolinyl) methyl-4-phenacyl-4-piperidines alcohol
III-31 N-benzyl-4-(to the fluorobenzoyl methyl)-4-piperidines alcohol
III-32 N-benzyl-4-(to the methoxybenzoyl methyl)-4-piperidines alcohol
III-33 N-benzyl-4-(to the chlorobenzoyl methyl)-4-piperidines alcohol
III-34 N-benzyl-4-(2-pyridine formyl methyl)-4-piperidines alcohol
III-35 N-benzyl-4-(4-pyrrolidyl phenacyl)-4-piperidines alcohol
III-36 N-benzyl-4-(4 '-morpholinyl phenacyl)-4-piperidines alcohol
III-37 N-benzyl-4-((5-indolinyl) formyl methyl)-4-piperidines alcohol
III-38 N-benzyl-4-(3 ', 4 '-methylene-dioxy benzoyl methyl)-4-piperidines alcohol
III-39 N-benzyl-4-(1 '-benzoyl ethyl)-4-piperidines alcohol
V-1 N-is to methoxy-benzyl-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
V-2 N-acetparaminosalol benzyl-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
V-3 N-diphenyl-methyl-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
V-4 N-(3 ', 4 '-methylenedioxy benzyl)-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
V-5 N-(2 '-p-methoxy-phenyl)-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
V-6 N-(5-indolinyl) methyl-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
V-7 N-((4 '-pyrrolidyl) phenylethyl)-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
V-8 N-((4 '-morpholinyl) phenylethyl)-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
VIII-1 N-acetparaminosalol benzyl-4-phenacyl-4-methoxyl group piperidines
VIII-2 N-p-methoxyphenyl ethyl-4-phenacyl-4-methoxyl group piperidines
VIII-3 N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-methoxyl group piperidines
IX-1 N-p-methoxyphenyl ethyl-4-phenacyl-4-fluorine piperidines
IX-2 N-(3 ', 4 '-methylenedioxy benzyl)-4-phenacyl-4-fluorine piperidines
IX-3 N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-fluorine piperidines
IX-4 N-((4 '-pyrrolidyl) phenylethyl)-4-phenacyl-4-fluorine piperidines
IX-5 N-p-methoxyphenyl ethyl-4-phenacyl-4-Chloperastine
IX-6 N-(3 ', 4 '-methylenedioxy benzyl)-4-phenacyl-4-Chloperastine or
IX-7 N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-Chloperastine.
10. a pharmaceutical composition comprises claim 1～9 each the described aralkyl piperidine piperidine derivatives and the medically acceptable carrier for the treatment of significant quantity.
11. the application of each described aralkyl piperidine piperidine derivatives of claim 1～9 in preparation analgesia, downern.
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WO2009152647A1 (en) * 2008-06-20 2009-12-23 江苏恩华药业股份有限公司 Aralkyl piperidine derivatives and their uses as antalgic or ataractic agent
CN103360305A (en) * 2012-04-09 2013-10-23 江苏恩华药业股份有限公司 Substituted aryl piperazine aralkyl ketone derivative and application of derivative in preparing analgesic
CN103420898A (en) * 2012-05-17 2013-12-04 上海医药工业研究院 Diaryl piperidine derivatives and applications thereof as multiple-target-point antidepressants
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CA2324330A1 (en) * 1999-11-08 2001-05-08 Ssp Co., Ltd. 4-hydroxy-4-phenylpiperidine derivatives and pharmaceuticals containing the same
CN1150176C (en) * 2002-05-22 2004-05-19 上海医药工业研究院 Aralkylone pipeazine derivative and its application
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WO2009152647A1 (en) * 2008-06-20 2009-12-23 江苏恩华药业股份有限公司 Aralkyl piperidine derivatives and their uses as antalgic or ataractic agent
US8501778B2 (en) 2008-06-20 2013-08-06 Nhwa Pharma. Corporation Aralkyl piperidine derivatives and their uses as antalgic or ataractic agent
CN103360305A (en) * 2012-04-09 2013-10-23 江苏恩华药业股份有限公司 Substituted aryl piperazine aralkyl ketone derivative and application of derivative in preparing analgesic
CN103360305B (en) * 2012-04-09 2015-12-16 江苏恩华药业股份有限公司 Substituted aryl piperazine aralkyl ketone derivatives and preparing the application in analgesic
CN103420898A (en) * 2012-05-17 2013-12-04 上海医药工业研究院 Diaryl piperidine derivatives and applications thereof as multiple-target-point antidepressants
CN103420898B (en) * 2012-05-17 2015-10-28 上海医药工业研究院 Diaryl piperidines analog derivative and the application as Mutiple Targets anti-depression drug thereof
CN113214140A (en) * 2020-02-03 2021-08-06 江苏谛奇医药科技有限公司 Piperidine amide derivative, pharmaceutical composition and application thereof

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