CN101260075B - 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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CN101260075B
CN101260075B CN2007100378744A CN200710037874A CN101260075B CN 101260075 B CN101260075 B CN 101260075B CN 2007100378744 A CN2007100378744 A CN 2007100378744A CN 200710037874 A CN200710037874 A CN 200710037874A CN 101260075 B CN101260075 B CN 101260075B
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phenacyl
piperidines
piperidines alcohol
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benzyl
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CN101260075A (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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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 S07137874420070322D000021
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 S07137874420070322D000022
Or
Ar 2Representative:
Figure S07137874420070322D000024
Or
Figure S07137874420070322D000025
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-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
IX-7 N-((4 '-morpholinyl) phenylethyl)-4-phenacyl-4-Chloperastine
The particular chemical formula is as shown in table 1:
Table 1
Figure S07137874420070322D000061
Wherein, further preferred compound comprises:
III-5 N-PAB-4-phenacyl-4-piperidines alcohol
III-7 N-diphenyl-methyl-4-phenacyl-4-piperidines alcohol
III-15 N-is to methoxy-benzyl-4-phenacyl-4-piperidines alcohol
V-3 N-diphenyl-methyl-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol
IX-1 N-p-methoxyphenyl ethyl-4-phenacyl-4-fluorine piperidines
Compound of the present invention can adopt following method to synthesize:
Synthetic route one:
a:CeCl 3/NaI/THF；
Figure S07137874420070322D000082
b:CF 3COOH/CH 2Cl 2
c：Et 3N/CH 2Cl 2?or?K 2CO 3/KI/CH 3COCH 3；
Figure S07137874420070322D000083
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:
Figure S07137874420070322D000084
c：Et 3N/CH 2Cl 2?or?K 2CO 3/KI/CH 3COCH 3；
Figure S07137874420070322D000085
a:CeCl 3/NaI/THF；
Figure S07137874420070322D000086
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 S07137874420070322D000091
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:
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 S07137874420070322D000101
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 mol ratio 1:1 such as employing reaction, yield is the highest.
This method adopts Cerium II Chloride-sodium iodide system, CeCl 3The mol ratio of/NaI wherein adopts 1:3 within the scope of 1:1～1:5, 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 (3x20ml) merges organic phase, water (1x10ml) washing, saturated aqueous common salt water (1x10ml) washing, 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 (6x20ml), merge organic phase, use saturated aqueous common salt water (1x20ml) washing again, the ethyl acetate solution anhydrous sodium sulfate drying filters, and is concentrated into 20ml, uses HCl/C 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, uses AcOEt
Figure S07137874420070322D000121
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 (3x20ml) merges organic phase, water (1x10ml) washing, saturated aqueous common salt water (1x10ml) 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 (2x20ml), 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.The cooling reaction solution is to room temperature, with saturated sodium bicarbonate aqueous solution (2x20ml) washing, water washing (1x20ml), saturated common salt water washing (1x20ml), 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 (1x20ml), saturated common salt water washing (1x20ml), 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 extracts (4x30ml), merges organic phase, with saturated common salt water washing (1x30ml), drying, concentrate, and column chromatography for separation, the petrol ether/ethyl acetate wash-out gets 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 (4x30ml) merges organic phase, with saturated common salt water washing (1x30ml), drying, is concentrated into driedly, and residuum is through HCl/C 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-1 N-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:
Figure S07137874420070322D000131
(theoretical value %:C66.01, H7.20, N3.85, Cl9.74 experimental value %:C65.83, H7.07, N3.96, Cl9.82)
Figure S07137874420070322D000132
(theoretical value %:C58.83, H6.42, N3.43, Br19.57 experimental value %:C58.63, H6.57, N3.65, Br19.82)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000133
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-NHCl), 7.20-8.10 (m, 10H, ArH), 9.5-12.0 (2B, 1H, piperidines-OH).
MS：m/z?310(M+1)
Embodiment 2
III-2 N-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:
Figure S07137874420070322D000141
(theoretical value %:C60.31, H6.33, N3.52, Cl17.80 experimental value %:C60.42, H6.15, N3.30, Cl17.96)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000142
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, IH, piperidines-NHCl), 7.20-8.10 (m, 9H, ArH), 10.5-11.5 (2B, 1H, piperidines-OH).
MS：m/z?344(M +)
Embodiment 3
III-3 N-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:
Figure S07137874420070322D000143
(theoretical value %:C62.90, H6.60, N3.67, Cl9.28 experimental value %:C60.87, H6.45, N3.39, Cl9.56)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000144
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, IH, piperidines-NHCl), 7.20-8.10 (m, 9H, ArH), 10.6-11.2 (2B, 1H, piperidines-OH).
MS：m/z?328(M +)
Embodiment 4
III-4 N-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:
Figure S07137874420070322D000145
(theoretical value %:C58.75, H6.16, N6.85, Cl8.67; Experimental value %:C58.52, H6.28, N7.04, Cl8.95)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000151
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-5 N-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 (4x20ml), merge organic phase, saturated common salt water washing (1x20ml), anhydrous MgSO4 drying, merge organic phase, saturated common salt water washing (1x20ml), anhydrous MgSO4 drying is filtered, 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: (theoretical value %:C55.43, H6.98, N6.46, Cl16.36; Experimental value %:C55.56, H6.72, N6.18, Cl16.69)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000153
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-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-6 N-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 (4x20ml), merge organic phase, saturated common salt water washing (1x20ml), 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:
Figure S07137874420070322D000154
(theoretical value %:C62.77, H6.94, N6.66, Cl8.42; Experimental value %:C62.56, H7.08, N6.92, Cl8.84)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000155
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-NHCl), 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-7 N-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: (theoretical value %:C74.01, H6.69, N3.32, Cl8.40; Experimental value %:C74.12, H6.89, N3.51, Cl8.80)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000162
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-NHCl), 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/z286(M+1)。
Embodiment 8
III-8 N-(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:
Figure S07137874420070322D000163
(theoretical value %:C56.86, H6.53, N6.98, Cl17.67; Experimental value %:C56.68, H6.77, N6.83, Cl17.84)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000164
1.80-2.10 (m, 4H, piperidines-H), 3.00-3.20 (m, 4H, piperidines-H), 3.16 (s, 2H, CH 2CO), 4.06-4.13 (m, 2H), 4.97 (s, H, piperidines-NHCl), 7.20-8.60 (m, 9H), 9.6-10.2 (2B, 1H, piperidines-OH).
MS：m/z311(M+1)
Embodiment 9
III-9 N-(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: (theoretical value %:C58.03, H6.30, N11.94, Cl10.08; Experimental value %:C58.27, H6.49, N11.78, Cl10.22)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000171
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-NHCl), 7.20-8.70 (m, 8H), 9.6-10.2 (2B, 1H, piperidines-OH).
MS：m/z312(M+1)
Embodiment 10
III-10 N-(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:
Figure S07137874420070322D000172
(theoretical value %:C59.09, H6.61, N11.49, Cl9.69; Experimental value %:C59.27, H6.89, N11.68, Cl10.02)
1HNMR (DMSO-d 6): 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-NHCl), 7.20-8.70 (m, 8H), 9.6-10.2 (2B, 1H, piperidines-OH).
MS：m/z?324(M+1)
Embodiment 11
III-11 N-(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:
Figure S07137874420070322D000174
(theoretical value %:C60.42, H5.99, N6.41, Cl16.21; Experimental value %:C60.65, H6.12, N6.24, Cl16.01)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000175
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-NHCl), 7.20-8.50 (m, 11H), 9.6-10.2 (2B, 1H, piperidines-OH).
MS：m/z?347(M+1)。
Embodiment 12
III-12 N-(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: (theoretical value %:C66.38, H6.69, N3.87, Cl9.80; Experimental value %:C66.16, H6.81, N4.18, Cl10.02)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000182
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-13 N-(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 4HClH 2O (theoretical value %:C61.84, H6.42, N3.43, Cl8.69; Experimental value %:C61.62, H6.27, N3.73, Cl8.86)
1HNMR (DMSO-d 6): 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-14 N-(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:
Figure S07137874420070322D000184
(theoretical value %:C60.85, H7.11, N3.09, Cl7.81; Experimental value %:C61.03, H7.40, N3.21, Cl8.04)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000185
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-NHCl), 6.10-8.05 (m, 7H, ArH), 9.5-12.0 (2B, 1H, piperidines-OH).
MS：m/z400(M+1)
Embodiment 15
III-15 N-is to methoxy-benzyl-4-phenacyl-4-piperidines alcohol hydrochloride
Reach each 4-phenacyl of post-treating method system-4-piperidines alcohol (II) by synthesizing of logical method one earlier, again will be to methoxyl group bromobenzyl 1.77g (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 1.93g, yield 61.3%.
Ultimate analysis: C 21H 25NO 3HClH 2O (theoretical value %:C64.03, H7.16, N3.56, Cl9.00; Experimental value %:C64.32, H7.33, N3.80, Cl9.27)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000191
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-NHCl), 7.20-8.10 (m, 9H, ArH), 9.5-12.0 (2B, 1H, piperidines-OH).
MS：m/z?340(M+1)。
Embodiment 16
III-16 N-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:
Figure S07137874420070322D000192
(theoretical value %:C66.74, H7.47, N3.71, Cl9.38; Experimental value %:C66.98, H7.67, N3.83, Cl9.52)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000193
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), 4.03-4.10 (m, 1H, PhCH), 4.95 (s, 1H, piperidines-NHCl), 7.20-8.10 (m, 10H, ArH), 9.6-10.2 (2B, 1H, piperidines-OH).
MS：m/z?324(M+1)
Embodiment 17
III-17 N-(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:
Figure S07137874420070322D000194
(theoretical value %:C66.74, H7.47, N3.71, Cl9.38; Experimental value %:C66.98, H7.67, N3.83, Cl9.52)
MS:m/z?324(M+1)
Embodiment 18
III-18 N-(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:
Figure S07137874420070322D000201
(theoretical value %:C66.74, H7.47, N3.71, Cl9.38; Experimental value %:C66.98, H7.67, N3.83, Cl9.52)
MS：m/z?324(M+1)
Embodiment 19
III-19 N-(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:
Figure S07137874420070322D000202
(theoretical value %:C64.77, H7.41, N3.43, Cl8.69; Experimental value %:C64.99, H7.52, N3.31, Cl8.92)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000203
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-NHCl), 7.00-8.10 (m, 9H, ArH), 9.6-11.2 (2B, 1H, piperidines-OH).
MS：m/z?354(M+1)
Embodiment 20
III-20 N-(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:
Figure S07137874420070322D000204
(theoretical value %:C63.71, H6.87, N3.54, Cl8.96; Experimental value %:C63.96, H6.65, N3.32, Cl9.12)
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), 3.16 (s, 2H, CH 2CO), 4.03-4.10 (m, 1H, PhCH), 5.01 (s, 1H, piperidines-NHCl), 7.20-8.10 (m, 9H, ArH), 9.6-10.2 (2B, 1H, piperidines-OH).
MS：m/z?342(M+1)
Embodiment 21
III-21 N-(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 (4x20ml), merge organic phase, saturated common salt water washing (1x20ml), anhydrous MgSO4 drying, merge organic phase, saturated common salt water washing (1x20ml), anhydrous MgSO4 drying is filtered, 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: (theoretical value %:C58.74, H7.04, N6.52, Cl16.51; Experimental value %:C58.91, H6.86, N6.50, Cl16.83)
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), 4.03-4.10 (m, 1H, PhCH), 4.99 (s, 1H, piperidines-NHCl), 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-22 N-(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:
Figure S07137874420070322D000214
(theoretical value %:C62.63, H6.69, N3.32, Cl8.40; Experimental value %:C62.74, H6.85, N3.52, Cl8.69)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000215
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), 4.03-4.10 (m, 1H, PhCH), 4.97 (s, 1H, piperidines-NHCl), 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-23 N-(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:
Figure S07137874420070322D000221
(theoretical value %:C71.67, H6.98, N3.34, Cl8.46; Experimental value %:C71.28, H7.06, N3.12, Cl8.59)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000222
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-NHCl), 7.10-8.20 (m, 12H, ArH), 9.9-11.5 (2B, 1H, piperidines-OH).
MS：m/z?374(M+1)
Embodiment 24
III-24 N-(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:
Figure S07137874420070322D000223
(theoretical value %:C61.40, H7.30, N5.97, Cl15.10; Experimental value %:C61.28, H7.45, N6.07, Cl15.34)
1HNMR (DMSO-d 6): 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-25 N-((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:
Figure S07137874420070322D000231
(theoretical value %:C62.11, H7.51, N5.79, Cl14.67; Experimental value %:C61.34, H7.24, N6.03, Cl15.01)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000232
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-26 N-(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:
Figure S07137874420070322D000233
(theoretical value %:C57.26, H7.21, N5.56, Cl14.08; Experimental value %:C57.57, H7.32, N5.81, Cl14.35)
1HNMR (DMSO-d 6): 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-27 N-((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:
Figure S07137874420070322D000235
(theoretical value %:C58.02, H7.40, N5.41, Cl13.70; Experimental value %:C59.27, H7.55, N5.67, Cl14.01)
1HNMR (DMSO-d 6): 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:
Figure S07137874420070322D000241
(theoretical value %:C62.11, H7.51, N5.79, Cl14.67; Experimental value %:C62.28, H7.76, N6.07, Cl14.84)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000242
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-29 N-(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:
Figure S07137874420070322D000243
(theoretical value %:C63.08, H6.50, N6.69, Cl8.46; Experimental value %:C63.25, H6.86, N6.47, Cl8.77)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000244
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-NHCl), 6.90-8.10 (m, 8H, ArH), 9.5-11.8 (3B, 2H).
MS：m/z?365(M+1)
Embodiment 30
III-30 N-(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:
Figure S07137874420070322D000245
(theoretical value %:C59.86, H6.85, N6.35, Cl16.06; Experimental value %:C59.55, H6.96, N6.45, Cl16.03)
1HNMR (DMSO-d 6): 1.80-2.10 (m, 4H, piperidines-H), 2.80-3.20 (m, 6H), 3.15 (s, 2H, CH 2CO), 3.40-3.50 (m, 2H), 4.02-4.15 (m, 3H), 5.03 (s, 1H, piperidines-NHCl), 6.90-8.10 (m, 8H, ArH), 9.5-11.0 (2B, 1H, piperidines-OH).
MS：m/z?351(M+1)
Embodiment 31
III-31 N-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:
Figure S07137874420070322D000252
(theoretical value %:C56.35, H5.91, N3.29, Br18.74 experimental value %:C56.62, H5.83, N3.46, Br18.57)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000253
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-NHBr), 7.20-8.10 (m, 9H, ArH), 9.6-11.2 (2B, 1H, piperidines-OH).
MS：m/z?328(M+1)
Embodiment 32
III-32 N-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 3HBrH 2O (theoretical value %:C57.54, H6.44, N3.20, Br18.23; Experimental value %:C57.33, H6.53, N3.39, Cl18.41)
1HNMR (DMSO-d 6): 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-NHBr), 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: (theoretical value %:C54.25, H5.69, N6.18, Cl8.01, Br18.05; Experimental value %:C54.27, H5.77, N6.37, Cl8.13, Br18.26)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000262
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-NHBr), 7.20-8.10 (m, 9H, ArH), 9.8-11.0 (2B, 1H, piperidines-OH).
MS：m/z?344(M+1)
Embodiment 34
III-34 N-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:
Figure S07137874420070322D000263
(theoretical value %:C55.75, H6.16, N6.84, Br19.52; Experimental value %:C55.81, H6.32, N6.57, Br19.801)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000264
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-NHBr), 7.20-8.60 (m, 9H), 9.6-11.0 (2B, 1H, piperidines-OH).
MS：m/z?311(M+1)
Embodiment 35
III-35 N-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:
Figure S07137874420070322D000271
(theoretical value %:C61.40, H7.30, N5.97, Cl15.10; Experimental value %:C61.56, H7.51, N6.17, Cl15.32)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000272
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-36 N-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:
Figure S07137874420070322D000273
(theoretical value %:C57.26, H7.21, N5.56, Cl14.08; Experimental value %:C57.46, H7.38, N5.77, Cl14.26)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000274
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, IH, 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:
Figure S07137874420070322D000275
(theoretical value %:C59.86, H6.85, N6.35, Cl16.06; Experimental value %:C59.67, H6.57, N6.19, Cl16.33)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000276
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-NHCl), 6.90-8.10 (m, 8H, ArH), 9.6-11.0 (2B, 1H, piperidines-OH).
MS：m/z?351(M+1)
Embodiment 38
III-38 N-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:
Figure S07137874420070322D000281
(theoretical value %:C61.84, H6.42, N3.43, Cl8.69; Experimental value %:C61.57, H6.71, N3.52, Cl8.87)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000282
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-NHCl), 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-39 N-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:
Figure S07137874420070322D000283
(theoretical value %:C66.74, H7.47, N3.71, Cl9.38; Experimental value %:C66.54, H7.61, N3.94, Cl9.55)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000284
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-NHCl), 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:
Figure S07137874420070322D000285
(theoretical value %:C63.71, H7.64, N3.54, Cl, 8.95; Experimental value %:C63.54, H7.87, N3.76, Cl, 9.06)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000286
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-NHCl), 7.00-8.20 (m, 9H, ArH), 11.5-12.5 (B, 1H, piperidines-OH).
MS:m/z?342(M+1)。
Embodiment 41
V-2 N-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:
Figure S07137874420070322D000291
(theoretical value %:C62.48, H7.39, N6.62, Cl, 8.38; Experimental value %:C62.71, H7.15, N6.94, Cl, 8.63)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000292
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-NHCl), 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-3 N-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:
Figure S07137874420070322D000293
(theoretical value %:C73.65, H7.13, N3.30, Cl, 8.36; Experimental value %:C73.51, H7.03, N3.17, Cl, 8.27)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000294
1.70-2.10 (m, 6H), 3.00-3.30 (m, 5H), 4.76 (s, H, Ph 2CH), 4.85-4.90 (m, 1H), 5.01 (s, 1H, piperidines-NHCl), 7.00-8.20 (m, 15H, ArH), 10.5-12.0 (B, 1H, piperidines-OH).
MS：m/z?388(M+1)。
Embodiment 43
V-4 N-(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:
Figure S07137874420070322D000295
(theoretical value %:C61.53, H6.89, N3.42, Cl8.65; Experimental value %:C61.14, H7.07, N3.73, Cl, 8.46)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000301
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-NHCl), 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-5 N-(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:
Figure S07137874420070322D000302
(theoretical value %:C62.90, H7.39, N3.67, Cl, 9.28; Experimental value %:C63.04, H7.57, N3.96, Cl, 9.60)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000303
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-NHCl), 6.90-8.10 (m, 9H, ArH), 10.5-12.0 (B, IH, piperidines-OH).
MS：m/z?328(M+1)。
Embodiment 45
V-6 N-(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:
Figure S07137874420070322D000304
(theoretical value %:C55.35, H7.18, N5.87, Cl, 14.85; Experimental value %:C55.74, H7.03, N5.56, Cl, 15.08)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000305
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-NHCl), 6.90-8.10 (m, 8H, ArH), 10.5-12.0 (B, 1H, piperidines-OH).
MS：m/z?353(M+1)。
Embodiment 46
V-7 N-((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:
Figure S07137874420070322D000311
(theoretical value %:C61.14, H7.70, N5.94, Cl, 15.04; Experimental value %:C61.55, H7.97, N5.76, CI, 15.20)
1HNMR (DMSO-d 6): 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-NHCl), 6.80-8.10 (m, 9H, ArH), 10.5-12.0 (B, IH, piperidines-OH).
MS：m/z?381(M+1)。
Embodiment 47
V-8 N-((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:
Figure S07137874420070322D000313
(theoretical value %:C59.88, H7.64, N5.59, Cl, 14.14; Experimental value %:C59.74, H7.37, N5.77, Cl14.62)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000314
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-NHCl), 6.80-8.10 (m, 9H, ArH), 10.5-12.0 (B, 1H, piperidines-OH).
MS：m/z?411(M+1)。
Embodiment 48
VIII-1 N-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: (theoretical value %:C63.51, H7.18, N6.44, Cl, 8.15; Experimental value %:C63.44, H7.43, N6.67, Cl8.47)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000316
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-NHCl), 7.20-8.10 (m, 9H, ArH), 9.80-10.20 (s, broad peak, 1H).
MS：m/z?381(M+1)。
Embodiment 49
VIII-2 N-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:
Figure S07137874420070322D000321
(theoretical value %:C65.47, H7.64, N3.32, Cl, 8.40; Experimental value %:C65.54, H7.41, N3.47, Cl8.66)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000322
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-NHCl), 7.00-8.10 (m, 9H, ArH).
MS：m/z?368(M+1)。
Embodiment 50
VIII-3 N-((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:
Figure S07137874420070322D000323
(theoretical value %:C60.81, H7.46, N5.46, Cl, 13.81; Experimental value %:C60.67, H7.63, N5.57, Cl14.06)
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), 3.45 (s, 3H), 4.03-4.10 (m, IH), 5.02 (s, 1H, piperidines-NHCl), 6.90-8.20 (m, 9H, ArH).
MS：m/z?423(M+1)。
Embodiment 51
IX-1 N-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:
Figure S07137874420070322D000331
(theoretical value %:C64.46, H7.13, N3.42, Cl, 8.65; Experimental value %:C64.74, H7.44, N3.57, Cl8.86)
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), 3.16 (s, 2H, CH 2CO), 3.78 (s, 3H ,-OCH 3), 4.03-4.10 (m, IH, PhCH), 4.99 (s, 1H, piperidines-NHCl), 7.00-8.10 (m, 9H, ArH).
MS：m/z?356(M+1)。
Embodiment 52
IX-2 N-(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:
Figure S07137874420070322D000333
(theoretical value %:C64.54, H6.15, N3.42, Cl, 8.65; Experimental value %:C64.69, H6.43, N3.60, Cl8.75)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000334
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-NHCl), 5.93 (s, 2H), 7.00-8.10 (m, 8H, ArH).
MS：m/z?356(M+1)。
Embodiment 53
IX-3 N-((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:
Figure S07137874420070322D000341
(theoretical value %:C59.88, H7.04, N5.59, Cl, 14.14; Experimental value %:C59.67, H7.33, N5.67, Cl14.45)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000342
1.34 (d, 3H, CH 3), 1.75-2.10 (m, 4H), 2.80-3.80 (m, 12H), 3.17 (s, 2H, CH 2CO), 4.03-4.10 (m, 1H), 5.02 (s, 1H, piperidines-NHCl), 6.90-8.20 (m, 9H, ArH).
MS：m/z?411(M+1)。
Embodiment 54
IX-4 N-((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: (theoretical value %:C61.85, H7.27, N5.77, Cl, 14.61; Experimental value %:C61.77, H7.43, N5.89, Cl14.91)
1HNMR(DMSO-d 6)：
Figure S07137874420070322D000344
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-5 N-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:
Figure S07137874420070322D000345
(theoretical value %:C61.97, H6.86, N3.29, Cl, 16.63; Experimental value %:C62.05, H7.03, N3.58, Cl16.86)
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-NHCl), 7.00-8.10 (m, 9H, ArH).
MS：m/z?372(M+1)。
Embodiment 56
IX-6 N-(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: (theoretical value %:C59.16, H5.91, N3.29, Cl, 16.63; Experimental value %:C59.35, H6.10, N3.55, Cl16.92)
1HNMR (DMSO-d 6): 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-NHCl), 5.93 (s, 2H), 7.00-8.10 (m, 8H, ArH).
MS：m/z?372(M+1)。
Embodiment 57
IX-7 N-((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:
Figure S07137874420070322D000353
(theoretical value %:C57.98, H6.81, N5.41, Cl, 20.54; Experimental value %:C57.75, H6.69, N5.54, Cl20.82)
1HNMR (DMSO-d 6):
Figure S07137874420070322D000354
1.34 (d, 3H, CH 3), 1.75-2.10 (m, 4H), 2.80-3.80 (m, 12H), 3.17 (s, 2H, CH 2CO), 4.03-4.10 (m, 1H), 5.01 (s, 1H, piperidines-NHCl), 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 ip0.7% 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.
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 S07137874420070322D000371
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 S07137874420070322D000381
6, part of compounds experimental result: see table 4 for details
Table 4
Figure S07137874420070322D000391
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, P0) in administration after second day, analgesic activity weakens the positive control drug morphine gradually, presents obvious resistance.Do not show resistance after many medications of prompting III-15.
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 P0) 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 975000 ↘ g/ wares have 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 (16)

1. an aralkyl piperidine piperidine derivatives is characterized in that, is free alkali or the salt with following structure general formula:
Wherein:
A representative: OH, F, Cl, OCH 3
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 FSB00000349788500012
Ar 2Representative:
Figure FSB00000349788500013
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, phenyl in a kind of;
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, phenyl, the hydroxyl, (C of containing 1-C 4) a kind of in alkoxyl group, amino, halogen, carboxylic acid group and carboxylic acid ester groups, nitro or the acetonitrile-base, 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, five yuan or hexa-atomic one or two N, O, the heteroatomic saturated or undersaturated cycloaliphatic ring of the S, (C of containing of representing 1-C 4) a kind of in the alkoxyl group, halogen;
n＝0，1；m＝1。
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: a kind of in hydrogen, the methyl or phenyl.
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, methoxyl group, oxyethyl group, amino, morpholinyl, pyrrolidyl, piperidyl, 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 8Be hydrogen, methoxyl group, oxyethyl group, halogen, morpholinyl, a kind of in pyrrolidyl or the piperidyl.
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-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-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-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-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. aralkyl piperidine piperidine derivatives, it is N-acetparaminosalol benzyl-4-phenacyl-4-piperidines alcohol.
11. an aralkyl piperidine piperidine derivatives, it is N-acetparaminosalol benzyl-4-(2-hydroxyl-2-phenylethyl)-4-piperidines alcohol.
12. an aralkyl piperidine piperidine derivatives, it is N-acetparaminosalol benzyl-4-phenacyl-4-methoxyl group piperidines.
13. an aralkyl piperidine piperidine derivatives, it is N-benzyl-4-((5-indolinyl) formyl methyl)-4-piperidines alcohol.
14. an aralkyl piperidine piperidine derivatives, it is N-benzyl-4-(3 ', 4 '-methylene-dioxy benzoyl methyl)-4-piperidines alcohol.
15. a pharmaceutical composition comprises claim 1～14 each the described aralkyl piperidine piperidine derivatives and the medically acceptable carrier for the treatment of significant quantity.
16. the application of each described aralkyl piperidine piperidine derivatives of claim 1～14 in preparation analgesia, downern.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1304929A (en) * 1999-11-08 2001-07-25 Ss制药株式会社 4-hydroxy-4-phenyl piperidine derivative and medicine containing said derivative
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CN1884262A (en) * 2005-06-24 2006-12-27 中国人民解放军军事医学科学院毒物药物研究所 4-amino piperidine compounds and their pharmaceutical use

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1304929A (en) * 1999-11-08 2001-07-25 Ss制药株式会社 4-hydroxy-4-phenyl piperidine derivative and medicine containing said derivative
CN1381449A (en) * 2002-05-22 2002-11-27 上海医药工业研究院 Aralkylone pipeazine derivative and its application
CN1884262A (en) * 2005-06-24 2006-12-27 中国人民解放军军事医学科学院毒物药物研究所 4-amino piperidine compounds and their pharmaceutical use

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