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CN1316994A - Piperidine derivatives - Google Patents

Piperidine derivatives Download PDF

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Publication number
CN1316994A
CN1316994A CN99810642A CN99810642A CN1316994A CN 1316994 A CN1316994 A CN 1316994A CN 99810642 A CN99810642 A CN 99810642A CN 99810642 A CN99810642 A CN 99810642A CN 1316994 A CN1316994 A CN 1316994A
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Prior art keywords
phenyl
piperidines
alcohol
ether
solution
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CN99810642A
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Inventor
A·塞苏尔
T·霍弗曼
S·罗维尔
J·维啻曼
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/42—Oxygen atoms attached in position 3 or 5
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4

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Abstract

The invention relates to compounds of general formula and to their use with pharmaceutically acceptable acidsAddition salts of (2), wherein R1Is tetrahydronaphthyl; or- (CH)2)n－C6H5－R4Wherein n is 0-4 and R4Is H, lower alkyl or lower alkoxy; or C unsubstituted or substituted by lower alkyl5－C12A cycloalkyl group; r2H, OH, lower alkoxy, lower alkenyloxy or lower alkyl; r3Is unsubstituted or substituted by a substituent C5－C7Cycloalkyl or phenyl, said substituents being OH, halogen, lower alkoxy, lower alkenyloxy, lower alkyl or-O- (CH)2)n－C6H5Wherein n is 0 to 3. The compounds of formula are suitable for the treatment of memory and attention deficits, psychiatric, neurological and physiological disorders such as anxiety and stress disorders, depression, memory loss due to Alzheimer's disease or other dementias such as vascular dementia and AIDS dementia complex, Parkinson's disease, epilepsy and convulsions, acute and/or chronic pain disorders, withdrawal symptoms and reduction of abuse/craving of addictive drugs, control of water balance, Na+Voiding and arterial blood pressure diseases and metabolic diseases such as obesity.

Description

Piperidine derivative
The present invention relates to new formula I compound and pharmaceutically acceptable acid additive salt thereof
Figure A9981064200051
Wherein:
R 1Be tetralyl;
Or-(CH 2) n-C 6H 5-R 4, wherein n is 0-4 and R 4Be H, low alkyl group or lower alkoxy;
Or the C that does not replace or replace by low alkyl group 5-C 12Cycloalkyl;
R 2Be H, OH, lower alkoxy, rudimentary alkenyloxy or low alkyl group;
R 3Be C unsubstituted or that replace by substituting group 5-C 7Cycloalkyl or phenyl, described substituting group be OH, halogen, lower alkoxy, rudimentary alkenyloxy, low alkyl group or-O-(CH 2) n-C 6H 5, wherein n is 0-3.
Formula I compound and salt thereof are to be feature with its valuable therapeutic property.Be surprised to find that The compounds of this invention is the agonist/antagonist of OFQ acceptor.Therefore, they will be used for the treatment of memory and attention deficiency, psychiatry, neurological and physiology disease, particularly include, but are not limited to improve the symptom of following disease, described disease such as anxiety and nervous disease, depressed, by the dull-witted memory loss that causes as vascular dementia and AIDS dementia syndrome of presenile dementia or other, Parkinson's disease, epilepsy and tic, acute and/or chronic pain disease, the Withrawal symptom of addictive drug and its abuse/sensual desires of minimizing, the controlled levels weighing apparatus, Na +Drain and arteriotony disease and metabolic disease such as obesity.
A kind ofly separated from the mouse brain by 17 amino acids formed peptides (F-G-G-F-T-G-A-R-K-S-A-R-K-L-A-N-Q) Orphanin FQ (OFQ), it is the native ligand of G-protein linked receptor (OFQ-R), and its content in cerebral tissue is higher.
OFQ shows the activity of exciting OFQ-R in vitro and in vivo.
Julius (Nature 377,476, [1995]) has discussed the discovery of OFQ, and the result notices that this peptide and a kind of dynorphin A that has been defined as endogenous opiate (opioid) receptors ligand have maximum sequence similarity.OFQ is suppressing CHO (LC132 +) in the culturing cell adenylate cyclase and when giving mouse, induce hyperpathia by Intraventricular.The result shows, this 17 peptide is that it seems that endogenous LC132 receptor stimulant and it have short nociceptive character.The someone describes, when giving mouse by intracerebral ventricle injection, OFQ slow down the motion and induce hyperpathia, according to inferring, OFQ may regulate nociception behavior and motor behavior as brain neurotransmitter.
Preferred compound is as shown in the formula I compound, wherein R 1Be C unsubstituted or that replace by low alkyl group 5-C 12Cycloalkyl, for example following compounds:
(3RS, 4RS)-1-ring nonyl-4-(2-hydroxyl-phenyl) piperidines-3-alcohol hydrochloride (1: 1);
1-encircles decyl-4-(2-methoxyl group-phenyl)-piperidine hydrochlorate (1: 1);
(3RS, 4RS)-1-ring decyl-4-(2-sec.-propyl-phenyl) piperidines-3-alcohol hydrochloride (1: 1);
(3RS, 4RS)-4-(2-hydroxyl-phenyl)-1-(suitable-and (trans-4-isopropyl cyclohexyl)-piperidines-3-alcohol hydrochloride (1: 1);
2-(1-encircles decyl-piperidin-4-yl)-phenolate hydrochlorate (1: 1);
(3RS, 4RS)-1-encircles decyl-4-(2-methoxyl group-phenyl)-piperidines-3-alcohol hydrochloride (1: 1);
1-encircles decyl-4-cyclohexyl-piperidine hydrochlorate (1: 1);
(3RS, 4RS)-1-encircles nonyl-4-(2-methoxyl group-phenyl)-piperidines-3-alcohol hydrochloride (1: 1);
(3RS, 4RS)-4-(2-allyloxy-phenyl)-1-encircles decyl-piperidines-3-alcohol hydrochloride (1: 1);
1-encircles decyl-4-phenyl-piperidine hydrochlorate (1: 1);
(3RS, 4RS)-1-encircles nonyl-4-(2-sec.-propyl-phenyl)-piperidines-3-alcohol hydrochloride (1: 1); With
(3RS, 4RS)-1-encircles decyl-4-(2-hydroxyl-phenyl)-piperidines-3-alcohol hydrochloride (1: 1).
Target of the present invention is new formula I compound itself and pharmaceutically acceptable acid additive salt thereof, racemic mixture and corresponding enantiomer thereof, the preparation of above-claimed cpd, comprise they medicine and production and above-claimed cpd in the control of particularly previously mentioned disease of disease or morbid state or the application in the prevention.
The generic term of no matter using in this manual is independent or unite appearance, and following definition all is suitable for.
Term used herein " low alkyl group " is meant the straight or branched alkyl that comprises 1-6 carbon atom, methyl for example, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, 2-butyl, the tertiary butyl.
Formula I compound and pharmaceutically acceptable acid additive salt thereof can pass through methods known in the art, and for example by hereinafter described method preparation, it comprises formula II compound With formula IV compound Carry out reductive amination, wherein R 1, R 2And R 3As mentioned above.
Described amination took place by two steps, wherein at first formed the intermediate imines, and in the presence of reductive agent such as sodium cyanoborohydride, molecular hydrogen or nickel, this intermediate imines further reduces then.
Can for example, begin to prepare the amination reagent II by known method from formula III compound by the method for hydrogenation:
R wherein 2And R 3As mentioned above and work as R 3Serve as reasons-O-CH 2-C 6H 5When cycloalkyl that replaces or phenyl, generation-CH in reaction process 2-C 6H 5The disconnection of base.
This is reflected at hydrogen and there is generation down in suitable hydrogenation catalyst such as palladium carbon.
For example, by in the presence of inert solvent such as anhydrous tetrahydro furan, with haloalkane, haloolefin, benzene alkylogen or lower alcohol reaction, can be with R wherein 2Be hydroxyl and/or R 3For the cycloalkyl that replaced by hydroxyl or halogen or the formula I compound of phenyl are converted into wherein R 2Be lower alkoxy, rudimentary alkenyloxy or low alkyl group and/or R 3For by lower alkoxy, rudimentary alkenyloxy, low alkyl group or-O-(CH 2) n-C 6H 5The cycloalkyl that replaces or the formula I compound of phenyl.
Can according to the method for document (Juan C.Jean and Lawrence D.Wise for example, J.Heterocyclic Chem.1987,24,1317-1319) obtain formula III compound.
If desired, formula I compound can be converted into its pharmaceutically acceptable acid additive salt.Described salt can be at room temperature, and is known and be the method acquisition that any technician in this area is familiar with itself.Not only comprise the salt with mineral acid, and comprise and organic acid salt.Hydrochloride, hydrobromate, vitriol, nitrate, Citrate trianion, acetate, maleate, succinate, mesylate, tosilate etc. all are the examples of described salt.
As mentioned above, formula I compound and pharmaceutically acceptable acid additive salt thereof have valuable pharmacodynamic profiles.Have been found that, The compounds of this invention is the agonist/antagonist of OFQ acceptor and in memory and attention deficiency, psychiatry, neurological and physiology disease are as anxiety and nervous disease, depressed, by the dull-witted memory loss that causes as vascular dementia and AIDS dementia syndrome of presenile dementia or other, Parkinson's disease, epilepsy and tic, the symptom of acute and/or chronic pain disease, the Withrawal symptom of addictive drug and its abuse/sensual desires of minimizing, controlled levels weighing apparatus, Na +Has effect in the animal model of drainage and arteriotony disease and metabolic disease such as obesity.
Described compound is studied according to the test that is hereinafter provided.OFQ-R is in conjunction with method for measuring
Cell cultures
In being added with the HL substratum of 2%FBS, cultivate the HEK-293 cell (293s) that is suitable for suspension growth.With rat OFQ receptor cdna (LC132) transfectional cell (FEBS Lett.347,284-288,1994), described cDNA uses lipofection agent (Life Technologies, Bethesda, MD USA) is cloned in expression vector pCEP4 (Invitrogen, SanDiego, CA, USA) in.(USA) there is selection cells transfected down in CA for Calbiochem, SanDiego at Totomycin (1000U/ml).(Amersham PLC, Buckinghamshire England) express in conjunction with the OFQ-R that measures collected resistant cell by [3H]-OFQ.These cells (293s-OFQ-R) amplification is used for large-scale the cultivation and membrane prepare.
Membrane prepare
By centrifugal collection 293s-OFQ-R cell,, be suspended in buffer A (50mM Tris-HCl, pH7.8,5mM MgCl then again with phosphate-buffered saline (PBS) washing 3 times 2, 1mMEGTA) in and with tissue homogenizer fragmentation (30 seconds, 4 retainings, Pt 20, Kinematica, Krlens-Lucern, Switzerland).By at 4 ℃ of total film components of the centrifugal acquisition of the rotating speed with 49000 * g.This process repeats twice and will precipitate again to be suspended in the buffer A.Under-70 ℃ of temperature, store aliquots containig and use BCA TM(Pierce, Rockford IL) measure proteinic concentration by the method for manufacturer recommendation to protein determination reagent.
In conjunction with measuring
At room temperature, use 77 μ g membrane proteins to add 0.1%BSA with the buffer A of 0.5ml final volume and 0.01% bacitracin (Boehringer-Mannheim, Mannheim, Germany) carry out [ 3H]-OFQ competes research, and the time is 1 hour.Use the unlabelled OFQ of 50nM to determine non-specific binding.Through Whatman GF/C filter membrane (Unifilter-96, CanberraPackard S.A., Zurich, Switzerland) filter to stop measure, before this, filter membrane is with 0.3% polymine (Sigma, ST.Louis, MO, USA) and 0.1%BSA (Sigma) pre-treatment 1 hour.Filter membrane washs 6 times with the ice-cooled 50mM Tris-HCl pH7.5 of 1ml.After adding 40 μ l Microscint 40 (Canberra Packard), with the radioactivity of Packard Top-Count microplate scintillometer record reservation.Use at least 6 concentration to measure the effect of compounds with three parts and measure twice.Determine IC by fitting of a curve 50Value, and use the method for Cheng and Prusoff (Blochem.Pharmacol., 22,3099,1973) that these values are converted into the Ki value.
With pKi represent to the avidity of OFQ-acceptor in the 6.0-8.0 scope, for example the pKi of the compound of hereinafter being mentioned is as follows:
Embodiment ????OFQ?pKi
????4 ????7.5
????36 ????7.0
????19 ????6.5
4 (3RS, 4RS)-1-ring nonyl-4-(2-hydroxyl-phenyl)-piperidines-3-alcohol hydrochloride (1: 1) 36 (3RS, 4RS)-1-encircles decyl-4-(2,6-dimethoxy-phenyl)-piperidines-3-alcohol hydrochloride (1: 1)
19 (3RS, 4RS)-4-(2-methoxyl group-phenyl)-1-(suitable-and the mixture of (trans-4-isopropyl-cyclohexyl)-piperidines-3-alcohol hydrochloride (1: 1)
Formula I compound and pharmaceutically acceptable acid additive salt thereof can be used as medicine with the form of for example pharmaceutical preparation.Pharmaceutical preparation can for example pass through orally give with tablet, coated tablet, dragee, form hard and Gelseal, solution, emulsion or suspension.Yet, also can be for example give by rectum or for example give by parenteral route with the form of injection liquid with the form of suppository.
Inorganic or organic excipients machining type I compound of available pharmaceutical inert and pharmaceutically acceptable acid additive salt thereof are produced tablet, coated tablet, dragee and hard-gelatin capsules.Lactose, W-Gum or derivatives thereof, talcum powder, stearic acid or its salt etc. can be used as for example vehicle of tablet, dragee and hard-gelatin capsules.
The vehicle of suitable Gelseal is for example vegetables oil, wax, fat, semisolid and liquid polyol etc.
Be suitable for the vehicle of producing solution and syrup and for example be water, polyvalent alcohol, sucrose, inertia sugar, glucose etc.
The vehicle of suitable preparation injection liquid is for example water, alcohol, polyvalent alcohol, glycerine, plant wet goods.The vehicle that is suitable for suppository is for example natural oil or winterized stearin, wax, fat, semi liquid state or liquid polyol etc.
In addition, pharmaceutical preparation can comprise salt, buffer reagent, sequestering agent or the antioxidant of sanitas, solubilizing agent, stablizer, wetting agent, emulsifying agent, sweeting agent, tinting material, correctives, change osmotic pressure.They also can further comprise the material that other have therapeutic value again.
Dosage can change and should meet certainly requirement individual under each particular disease states in the scope of broad.Usually, under the oral administration situation, the dosage that is approximately the 10-1000mg generalformula everyone every day should suit, although also can surpass the above-mentioned upper limit when needs.
The following example illustrates but does not limit the present invention in any way.
Embodiment 12-(1-encircles decyl-piperidin-4-yl)-phenolate hydrochlorate (1: 1) a), 1-benzyl-4-(2-benzyloxy-phenyl)-1,2,3, the 6-tetrahydropyridine
According to literature method (Juan C.Jean and Lawrence D.Wise, J.Heterocyclic Chem.1987,24,1317-1319), by two the step begin to replace to begin to have prepared title compound from 2-benzyloxy bromobenzene with comparable productive rate from 2-bromine anisole.The product that obtains is a light brown oily thing.
MS?m/e(％):356(M+H +,100)。B), 2-piperidin-4-yl-phenol
7.0g 10% palladium carbon is added to 37.3g (0.105mol) 1-benzyl-4-(2-benzyloxy-phenyl)-1,2,3, in the solution of 6-tetrahydropyridine in 380ml methyl alcohol.With the hydrogen (approximately 20h) of this reaction mixture hydrogenation (room temperature, 5 crust) until the consumption theoretical amount.Catalyzer filtered and with methanol wash (3 * 50ml).With filtrate vacuum-evaporation and obtain the light brown foam thing of 14.8g (80%) title compound by flash chromatography.
MS?m/e(％):177(M +,100)。C), 2-(1-encircles decyl-piperidin-4-yl)-phenol
8.0g (28mmol) original four-isopropyl titanate is added in the suspension of 1.0g (5.64mmol) 2-piperidin-4-yl phenol in 870mg (5.64mmol) ring decanone.After at room temperature stirring 4 days, obtain viscosity oily matter.In 3-4 minute, drip the solution of 250mg (3.95mmol) sodium cyanoborohydride in 4ml ethanol.Continuously stirring 2h and add the cholamine solution of 10ml 2.5M at room temperature.Evaporate with sedimentation and filtration and with filtrate.Residue is obtained the weak yellow foam thing of 1.37g (77%) title compound by the flash chromatography purifying.
MS?m/e(％):316(M+H +,100)。D), 2-(1-encircles decyl-piperidin-4-yl)-phenolate hydrochlorate (1: 1)
The diethyl ether solution of 1ml 2.3N spirit of salt is added in 100mg (0.32mmol) 2-(1-encircles decyl-piperidin-4-yl)-solution of phenol in the 20ml ether.Stir after 30 minutes, vacuum is removed excessive spirit of salt and ether and residue is resuspended in the 10ml ether.Throw out is filtered and obtains with the ether washing white powder of 101mg (91%) title compound.
MS?m/e(％):316(M+H +,100)。
Embodiment 21-encircles decyl-4-(2-methoxyl group-phenyl)-piperidine hydrochlorate (1: 1)
Under 0 ℃, 76mg (0.38mmol) two (trimethyl silyl) potassium amide is added in 100mg (0.32mmol) 2-(1-encircles decyl-piperidin-4-yl)-solution of phenol (embodiment 1c) in the 1ml anhydrous tetrahydro furan.Under this temperature, continue to stir 1h and add 55mg (0.38mmol) methyl iodide.After stirring 30 minutes under 0 ℃, remove ice bath and allow reaction mixture be warmed to ambient temperature overnight.
Remove solvent and residue flash chromatography purifying is obtained 74mg oily matter.With this amine solvent in the 5ml ether and drip the diethyl ether solution of 1ml 2.3M spirit of salt.With sedimentation and filtration, obtain the white powder of 42mg (36%) title compound with ether washing and vacuum-drying.
MS?m/e(％):330(M+H +,100)。
Embodiment 34-(2-allyloxy-phenyl)-1-encircles decyl-piperidine hydrochlorate (1: 1)
Under 0 ℃, 152mg (0.76mmol) two (trimethyl silyl) potassium amide is added in 200mg (0.64mmol) 2-(1-encircles decyl-piperidin-4-yl)-solution of phenol (embodiment 1c) in the 2ml anhydrous tetrahydro furan.Continuously stirring 1h and add 92mg (0.76mmol) allyl bromide 98 under this temperature.After stirring 30 minutes under 0 ℃, remove ice bath and allow reaction mixture be warmed to ambient temperature overnight.
Remove solvent and residue flash chromatography purifying is obtained 164mg oily matter.With this amine solvent in the 10ml ether and drip the diethyl ether solution of 1ml 2.3M spirit of salt.With sedimentation and filtration, obtain the white powder of 138mg (55%) title compound with ether washing and vacuum-drying.
MS?m/e(％):356(M+H +,100)。
Embodiment 4 (3RS, 4RS)-1-ring nonyl-4-(2-hydroxyl-phenyl)-piperidines-3-alcohol hydrochloride (1: 1) a), (3RS, 4RS)-1-benzyl-4-(2-benzyloxy-phenyl)-piperidines-3-alcohol hydrochloride (1: 1)
According to literature method (Juan C.Jean and Lawrence D.Wise, J.Heterocyclic Chem.1987,24,1317-1319), by three the step begin to replace to begin to have prepared title compound from 2-benzyloxy bromobenzene with comparable yield from 2-bromine anisole.The product that obtains is a white crystals.
MS?m/e(％):374(M+H +,100)。B), (3RS, 4RS)-4-(2-hydroxyl-phenyl)-piperidines-3-alcohol hydrochloride (1: 1)
With 8.5g 10% palladium carbon be added to 46.5g (0.11mol) (3RS, 4RS)-1-benzyl-4-(2-benzyloxy-phenyl)-piperidines-solution of 3-alcohol hydrochloride (1: 1) in 1100ml methyl alcohol in.With the hydrogen (approximately 20h) of this reaction mixture hydrogenation (room temperature, 5 crust) until the consumption theoretical amount.Catalyzer filtered and with methanol wash (3 * 100ml).With filtrate vacuum-evaporation and obtain the white powder of 21.0g (99%) title compound by flash chromatography.
MS?m/e(％):193(M +,78),164(58),44(100)。C), (3RS, 4RS)-4-(2-hydroxyl-phenyl)-piperidines-3-alcohol
With 1.5g yellow soda ash be added to 3.17g (1.38mmol) (3RS, 4RS)-4-(2-hydroxyl-phenyl)-piperidines-solution of 3-alcohol hydrochloride (1: 1) in 30ml methyl alcohol in.After at room temperature stirring 1h, sodium salt is filtered and uses the 10ml washing with alcohol.With filtrate concentrate, with alcohol dilution and refilter.The filtrate evaporation is obtained the white solid of 2.7g (quantitatively) title compound.
MS?m/e(％):194(M+H +,100)。D), (3RS, 4RS)-1-encircles nonyl-4-(2-hydroxyl-phenyl)-piperidines-3-alcohol
With 3.80g (13mmol) original four-isopropyl titanate be added to 520mg (2.69mmol) (3RS, 4RS)-suspension of 4-(2-hydroxyl-phenyl)-piperidines-3-alcohol in 380mg (1.55mmol) cyclononanone in.After at room temperature stirring 2 days, obtain heavy-gravity oily matter.In 3-4 minute, drip the solution of 120mg (1.9mmol) sodium cyanoborohydride in 1ml ethanol.Continuously stirring 6h and add the ethanolic soln of 2ml 2.5M ammonia at room temperature.Evaporate with sedimentation and filtration and with filtrate.Residue is obtained the weak yellow foam thing of 435mg (51%) title compound by the flash chromatography purifying.
MS?m/e(％):318(M+H +,100)。E), (3RS, 4RS)-1-encircles nonyl-4-(2-hydroxyl-phenyl)-piperidines-3-alcohol hydrochloride (1: 1)
With the diethyl ether solution of 1ml 2.3N spirit of salt be added to 100mg (0.32mmol) (3RS, 4RS)-1-ring nonyl-4-(2-hydroxyl-phenyl)-piperidines-solution of 3-alcohol in the 10ml ether in.Stir after 30 minutes, vacuum is removed excessive spirit of salt and ether and residue is resuspended in the 10ml ether.Throw out is filtered and obtains with the ether washing white powder of 98mg (88%) title compound.
MS?m/e(％):318(M+H +,100)。
Embodiment 5 (3RS, 4RS)-1-encircles nonyl-4-(2-methoxyl group-phenyl)-piperidines-3-alcohol hydrochloride (1: 1)
Under 0 ℃, with 85mg (0.42mmol) two (trimethyl silyl) potassium amide be added to 110mg (0.35mmo1) (3RS, 4RS)-1-ring nonyl-4-(2-hydroxyl-phenyl)-solution of piperidines-3-alcohol (embodiment 4d) in the 1ml anhydrous tetrahydro furan in.Continuously stirring 1h and add 59mg (0.42mmol) methyl iodide under this temperature.After stirring 30 minutes under 0 ℃, remove ice bath and allow reaction mixture be warmed to ambient temperature overnight.
Remove solvent and residue flash chromatography purifying is obtained 74mg oily matter.With this amine solvent in the 5ml ether and drip the diethyl ether solution of 1ml 2.3M spirit of salt.With sedimentation and filtration, obtain the white powder of 70mg (54%) title compound with ether washing and vacuum-drying.
MS?m/e(％):332(M+H +,100)。
Embodiment 6 (3RS, 4RS)-1-encircles nonyl-4-(2-hydroxyl-phenyl)-piperidines-3-alcohol hydrochloride (1: 1)
With 4.58g (16.1mmol) original four-isopropyl titanate be added to 2.5g (12.9mmol) (3RS, 4RS)-suspension of 4-(2-hydroxyl-phenyl)-piperidines-3-alcohol (embodiment 4c) in 2.00g (12.9mmol) ring decanone in.After at room temperature stirring is spent the night, obtain heavy-gravity oily matter.The solution of Dropwise 5 70mg (9mmol) sodium cyanoborohydride in 10ml ethanol in 1 minute.At room temperature continuously stirring is spent the night and is added 50ml 1N hydrochloric acid soln.After 30 minutes, wash the light brown foam thing that obtains 2.81g (59%) title compound with sedimentation and filtration and with the 1N hydrochloric acid soln.MS?m/e(％):332(M+H +,100)。
Embodiment 7
(3RS, 4RS)-1-ring decyl-4-(2-oxyethyl group-phenyl)-piperidines-3-alcohol hydrochloride (1: 1) a), (3RS, 4RS)-1-encircles decyl-4-(2-hydroxyl-phenyl)-piperidines-3-alcohol
With 1.5g yellow soda ash be added to 570mg (1.55mmol) (3RS, 4RS)-1-ring decyl-4-(2-hydroxyl-phenyl)-piperidines-solution of 3-alcohol hydrochloride (1: 1) (embodiment 6) in 20ml ethanol in.After at room temperature stirring 1h, sodium salt is filtered and uses the 10ml washing with alcohol.The filtrate evaporation is obtained the white solid of 510mg (quantitatively) title compound.
MS?m/e(％):332(M+H +,100)。B), (3RS, 4RS)-1-encircles decyl-4-(2-oxyethyl group-phenyl)-piperidines-3-alcohol
Under 0 ℃, with 147mg (0.74mmol) two (trimethyl silyl) potassium amide be added to 204mg (0.62mmol) (3RS, 4RS)-1-ring decyl-4-(2-hydroxyl-phenyl)-piperidines-solution of 3-alcohol in the 1ml anhydrous tetrahydro furan in.Continuously stirring 1h and add 74mg (0.68mmol) monobromethane under this temperature.After stirring 30 minutes under 0 ℃, remove ice bath and allow reaction mixture be warmed to ambient temperature overnight.
Remove solvent and residue flash chromatography purifying is obtained the colorless oil of 51mg (23%) title compound.
MS?m/e(％):360(M+H +,100)。C), (3RS, 4RS)-1-encircles decyl-4-(2-oxyethyl group-phenyl)-piperidines-3-alcohol hydrochloride (1: 1)
With the diethyl ether solution of 0.2ml 2.5N spirit of salt be added to 7mg (0.02mmol) (3RS, 4RS)-1-ring decyl-4-(2-oxyethyl group-phenyl)-piperidines-solution of 3-alcohol in the 1ml ether in.Stir after 30 minutes, vacuum is removed excessive spirit of salt and ether and residue is resuspended in the 2ml ether.Throw out is filtered and obtains with the ether washing white crystals of 7mg (quantitatively) title compound.
MS?m/e(％):360(M+H +,100)。
Embodiment 8 (3RS, 4RS)-1-ring decyl-3-oxyethyl group-4-(2-oxyethyl group-phenyl)-piperidine hydrochlorate (1: 1) a), (3RS, 4RS)-1-encircles decyl-3-oxyethyl group-4-(2-oxyethyl group-phenyl)-piperidines
Separate and purifying (3RS, 4RS)-1-encircles in the process of decyl-4-(2-oxyethyl group-phenyl)-piperidines-3-alcohol (embodiment 7b), obtains the title compound as byproduct.Obtain the light brown oily thing of 93mg (38mg) title compound behind the flash chromatography.
MS?m/e(％):388(M+H +,100)。B), (3RS, 4RS)-1-encircles decyl-3-oxyethyl group-4-(2-oxyethyl group-phenyl)-piperidine hydrochlorate (1: 1)
With the diethyl ether solution of 0.2ml 2.5N spirit of salt be added to 10mg (0.025mmol) (3RS, 4RS)-1-ring decyl-3-oxyethyl group-4-(2-oxyethyl group-phenyl)-solution of piperidines in the 1ml ether in.Stir after 30 minutes, vacuum is removed excessive spirit of salt and ether and residue is resuspended in the 2ml ether.Throw out is filtered and obtains with the ether washing white crystals of 10mg (quantitatively) title compound.
MS?m/e(％):388(M+H +,100)。
Embodiment 9 (3RS, 4RS)-4-(2-allyloxy-phenyl)-1-ring decyl-piperidines-3-alcohol hydrochloride (1: 1) a), (3RS, 4RS)-4-(2-allyloxy-phenyl)-1-encircles decyl-piperidines-3-alcohol
With 298mg (2.15mmol) salt of wormwood and 260mg (2.15mmol) allyl bromide 98 be added to 645mg (1.96mmol) (3RS, 4RS)-1-ring decyl-4-(2-hydroxyl-phenyl)-solution of piperidines-3-alcohol (embodiment 7a) in the 6ml anhydrous propanone in.Stir down at 60 ℃ and to spend the night, with product with ethyl acetate extraction (3 * 10ml), use the salt water washing, dry (sal epsom) also evaporates.Residue is obtained the white powder of 557mg (76%) title compound by the flash chromatography purifying.
MS?m/e(％):372(M+H +,100)。B), (3RS, 4RS)-4-(2-allyloxy-phenyl)-1-encircles decyl-piperidines-3-alcohol hydrochloride (1: 1)
With the hydrobromic diethyl ether solution of 2ml 2.5N be added to 133mg (0.36mmol) (3RS, 4RS)-4-(2-allyloxy-phenyl)-the 1-ring decyl-piperidines-solution of 3-alcohol in the 2.5ml tetrahydrofuran (THF) in.Stir after 30 minutes, vacuum is removed excessive Hydrogen bromide and ether and residue is resuspended in the 10ml ether.Throw out is filtered and obtains with the ether washing white crystals of 100mg (68%) title compound.
MS?m/e(％):372(M+H +,100)。
Embodiment 10 (3RS, 4RS)-4-(2-allyloxy-phenyl)-1-encircles decyl-3-methoxyl group-piperidine hydrochlorate (1: 1)
Under 0 ℃, with 85mg (0.43mmol) two (trimethyl silyl) potassium amide be added to 133mg (0.36mmol) (3RS, 4RS)-4-(2-allyloxy-phenyl)-solution of 1-ring decyl-piperidines-3-alcohol (embodiment 9a) in the 1.5ml anhydrous tetrahydro furan in.Continuously stirring 1h and add 61mg (0.43mmol) methyl iodide under this temperature.After stirring 30 minutes under 0 ℃, remove ice bath and allow reaction mixture be warmed to ambient temperature overnight.
After adding 2ml water, (3 * 10ml), dry (sal epsom) also evaporates product with ether extraction.Residue is obtained 77mg oily matter by the flash chromatography purifying.With amine solvent in the 10ml ether and drip the diethyl ether solution of 1ml 2.3M spirit of salt.With sedimentation and filtration, obtain the white powder of 67mg (44%) title compound with ether washing and vacuum-drying.
MS?m/e(％):386(M+H +,100)。
Embodiment 11 (3RS, 4RS)-1-encircles decyl-3-methoxyl group-4-(2-propoxy--phenyl)-piperidine hydrochlorate (1: 1)
With 10mg 10% palladium carbon be added to 30mg (0.07mol) (3RS, 4RS)-4-(2-allyloxy-phenyl)-the 1-ring decyl-solution of 3-methoxyl group-piperidine hydrochlorate (1: 1) (embodiment 10) in 1.5ml methyl alcohol in.This reaction mixture hydrogenation (room temperature, 1 crust) is spent the night.Catalyzer filtered and with methanol wash (3 * 1ml).Filtrate vacuum-evaporation is obtained the white powder of 23mg (77%) title compound.
MS?m/e(％):388(M +,100)。
Embodiment 12 (3RS, 4RS)-4-(2-benzyloxy-phenyl)-1-encircles decyl-piperidines-3-alcohol hydrochloride (1: 1)
With 810mg (5.88mmol) salt of wormwood and 370mg (2.16mmol) bromotoluene be added to 721mg (1.96mmol) (3RS, 4RS)-1-ring decyl-4-(2-hydroxyl-phenyl)-piperidines-solution of 3-alcohol hydrochloride (1: 1) (embodiment 6) in the 3ml anhydrous dimethyl formamide in.After 60 ℃ stirring was spent the night down, (3 * 10ml) extracted, and use the salt water washing, and dry (sal epsom) also evaporates with ethyl acetate with product.Residue is obtained the 90mg faint yellow solid by the flash chromatography purifying.With amine solvent in the 10ml ether and drip the diethyl ether solution of 1ml 2.3M spirit of salt.With sedimentation and filtration, obtain the white powder of 63mg (7%) title compound with ether washing and vacuum-drying.MS?m/e(％):422(M+H +,100)。
Embodiment 13 (3RS, 4RS)-1-ring undecyl-4-(2-hydroxyl-phenyl)-piperidines-3-alcohol hydrochloride (1: 1) a), (3RS, 4RS)-1-encircles undecyl-4-(2-hydroxyl-phenyl)-piperidines-3-alcohol
With 2.20g (7.8mmol) original four-isopropyl titanate be added to 300mg (1.55mmol) (3RS, 4RS)-4-(2-hydroxyl-phenyl)-suspension of piperidines-3-alcohol (embodiment 4c) in 260mg (1.55mmol) cycloundecanone in.After at room temperature stirring 6 days, obtain heavy-gravity oily matter.In 3-4 minute, drip the solution of 70mg (1.1mmol) sodium cyanoborohydride in 1ml ethanol.Continuation is at room temperature stirred 6h and is added the ethanolic soln of 2ml 2.5M ammonia.Evaporate with sedimentation and filtration and with filtrate.Residue is obtained the weak yellow foam thing of 138mg (26%) title compound by the flash chromatography purifying.
MS?m/e(％):346(M+H +,100)。B), (3RS, 4RS)-1-encircles undecyl-4-(2-hydroxyl-phenyl)-piperidines-3-alcohol hydrochloride (1: 1)
With the diethyl ether solution of 0.2ml 2.3N spirit of salt be added to 7mg (0.02mmol) (3RS, 4RS)-1-ring undecyl-4-(2-hydroxyl-phenyl)-piperidines-solution of 3-alcohol in the 1ml ether in.Stir after 30 minutes, vacuum is removed excessive spirit of salt and ether and residue is resuspended in the 1ml ether.Throw out is filtered and obtains with the ether washing white powder of 7mg (quantitatively) title compound.
MS?m/e(％):346(M+H +,100)。
Embodiment 14 (3RS, 4RS)-1-encircles undecyl-4-(2-methoxyl group-phenyl)-piperidines-3-alcohol hydrochloride (1: 1)
Under 0 ℃, with 65mg (0.34mmol) two (trimethyl silyl) potassium amide be added to 110mg (0.31mmol) (3RS, 4RS)-1-ring undecyl-4-(2-hydroxyl-phenyl)-solution of piperidines-3-alcohol (embodiment 13a) in the 1ml anhydrous tetrahydro furan in.Continuously stirring 1h and add 48mg (0.34mmol) methyl iodide under this temperature.After stirring 30 minutes under 0 ℃, remove ice bath and allow reaction mixture be warmed to ambient temperature overnight.
After adding 2ml water, (3 * 10ml) extract, dry (sal epsom) and evaporation with ether with product.Residue is obtained 70mg oily matter by the flash chromatography purifying.With amine solvent in the 5ml ether and drip the diethyl ether solution of 1ml 2.3M spirit of salt.With sedimentation and filtration, obtain the white powder of 65mg (55%) title compound with ether washing and vacuum-drying.
MS?m/e(％):360(M+H +,100)。
Embodiment 15 (3RS, 4RS)-and (3SR, 4SR)-and 4-(2-hydroxyl-phenyl)-1-[(RS)-1,2,3,4-tetrahydrochysene-naphthalene-2-yl]-mixture of piperidines-3-alcohol hydrochloride (1: 1) a), (3RS, 4RS)-and (3SR, 4SR)-4-(2-hydroxyl-phenyl)-1-[(RS)-1,2,3,4-tetrahydrochysene-naphthalene-2-yl]-mixture of piperidines-3-alcohol
With 2.20g (7.8mmol) original four-isopropyl titanate be added to 300mg (1.55mmol) (3RS, 4RS)-mixture of 4-(2-hydroxyl-phenyl)-piperidines-3-alcohol (embodiment 4c) and 230mg (1.55mmol) beta-tetrahydro naphthalenone in.After at room temperature stirring 5 days, obtain heavy-gravity oily matter.In 3-4 minute, drip the solution of 70mg (1.1mmol) sodium cyanoborohydride in 1ml ethanol.Continuation is at room temperature stirred 6h and is added the ethanolic soln of 2ml 2.5M ammonia.Evaporate with sedimentation and filtration and with filtrate.Residue is obtained the light brown foam thing of 100mg (20%) title compound by the flash chromatography purifying.
MS?m/e(％):324(M+H +,100)。B), (3RS, 4RS)-and (3SR, 4SR)-4-(2-hydroxyl-phenyl)-1-[(RS)-1,2,3,4-tetrahydrochysene-naphthalene-2-yl]-mixture of piperidines-3-alcohol hydrochloride (1: 1)
With the diethyl ether solution of 0.2ml 2.3N spirit of salt be added to 7mg (0.02mmol) (3RS, 4RS)-and (3SR, 4SR)-4-(2-hydroxyl-phenyl)-1-[(RS)-1,2,3,4-tetrahydrochysene-naphthalene-2-yl]-piperidines-solution of 3-alcohol in the 1ml ether in.Stir after 30 minutes, vacuum is removed excessive spirit of salt and ether and residue is resuspended in the 1ml ether.Throw out is filtered and obtains with the ether washing white powder of 7mg (quantitatively) title compound.
MS?m/e(％):324(M+H +,100)。
Embodiment 16 (3RS, 4RS)-and (3SR, 4SR)-4-(2-methoxyl group-phenyl)-1-[(RS)-1,2,3,4-tetrahydrochysene-naphthalene-2-yl]-mixture of piperidines-3-alcohol hydrochloride (1: 1)
Under 0 ℃, 55mg (0.27mmol) two (trimethyl silyl) potassium amide is added to 78mg (0.24mmol) (3RS, 4RS)-and (3SR, 4SR)-4-(2-hydroxyl-phenyl)-1-[(RS)-1,2,3,4-tetrahydrochysene-naphthalene-2-yl]-solution of piperidines-3-alcohol (embodiment 15a) mixture in the 0.8ml anhydrous tetrahydro furan in.Continuously stirring 1h and add 38mg (0.27mmol) methyl iodide under this temperature.After stirring 30 minutes under 0 ℃, remove ice bath and allow reaction mixture be warmed to ambient temperature overnight.
After adding 2ml water, (3 * 10ml) extract, dry (sal epsom) and evaporation with ether with product.Residue is obtained 38mg foam thing by the flash chromatography purifying.With amine solvent in the 3ml ether and drip the diethyl ether solution of 1ml 2.3M spirit of salt.With sedimentation and filtration, obtain the light brown powder of 40mg (44%) title compound with ether washing and vacuum-drying.
MS?m/e(％):338(M+H +,100)。
Embodiment 17 (3RS, 4RS)-and (3SR, 4SR)-and 4-(2-hydroxyl-phenyl)-1-[(RS)-1,2,3,4-tetrahydrochysene-naphthalene-1-yl]-mixture of piperidines-3-alcohol hydrochloride (1: 1) a), (3RS, 4RS)-and (3SR, 4SR)-4-(2-hydroxyl-phenyl)-1-[(RS)-1,2,3,4-tetrahydrochysene-naphthalene-1-yl]-mixture of piperidines-3-alcohol
With 2.20g (7.8mmol) original four-isopropyl titanate be added to 300mg (1.55mmol) (3RS, 4RS)-mixture of 4-(2-hydroxyl-phenyl)-piperidines-3-alcohol (embodiment 4c) and 230mg (1.55mmol) α-Tetralone an intermediate of Sertraline in.After at room temperature stirring 5 days, obtain heavy-gravity oily matter.In 3-4 minute, drip the solution of 70mg (1.1mmol) sodium cyanoborohydride in 1ml ethanol.Continuously stirring 6h and add the ethanolic soln of 2ml 2.5M ammonia at room temperature.Evaporate with sedimentation and filtration and with filtrate.Residue is obtained the light brown foam thing of 29mg (6%) title compound by the flash chromatography purifying.
MS?m/e(％):324(M+H +,100)。B), (3RS, 4RS)-and (3SR, 4SR)-4-(2-hydroxyl-phenyl)-1-[(RS)-1,2,3,4-tetrahydrochysene-naphthalene-1-yl]-mixture of piperidines-3-alcohol hydrochloride (1: 1)
With the diethyl ether solution of 0.2ml 2.3N spirit of salt be added to 4mg (0.01mmol) (3RS, 4RS)-and (3SR, 4SR)-4-(2-hydroxyl-phenyl)-1-[(RS)-1,2,3,4-tetrahydrochysene-naphthalene-1-yl]-piperidines-solution of 3-alcohol in the 1ml ether in.Stir after 30 minutes, vacuum is removed excessive hydrochloric acid and ether and residue is resuspended in the 1ml ether.Throw out is filtered and obtains with the ether washing white powder of 4mg (quantitatively) title compound.
MS?m/e(％):324(M+H +,100)。
Embodiment 18 (3RS, 4RS)-4-(2-hydroxyl-phenyl)-1-(suitable-and the mixture of (trans-4-isopropyl-cyclohexyl)-piperidines-3-alcohol hydrochloride (1: 1) a), (3RS, 4RS)-4-(2-hydroxyl-phenyl)-1-is (suitable-and the mixture of (trans-4-isopropyl-cyclohexyl)-piperidines-3-alcohol
With 9.16g (32.2mmol) original four-isopropyl titanate be added to 2.5g (12.9mmol) (3RS, 4RS)-suspension of 4-(2-hydroxyl-phenyl)-piperidines-3-alcohol (embodiment 4c) in 1.88g (12.9mmol) 4-sec.-propyl pimelinketone in.After at room temperature stirring is spent the night, obtain heavy-gravity oily matter.The solution of Dropwise 5 70mg (9mmol) sodium cyanoborohydride in 10ml ethanol in 1 minute.At room temperature continuously stirring is spent the night and is added 50ml 1M hydrochloric acid soln.After 30 minutes, obtain the 1.51g white solid with sedimentation and filtration and with the washing of 1N hydrochloric acid soln.Mother liquor is merged with dichloromethane extraction and with extract and primary precipitation.Obtain the white solid of 1.90g (46%) title compound by the flash chromatography purifying.
MS?m/e(％):318(M+H +,100)。B), (3RS, 4RS)-4-(2-hydroxyl-phenyl)-1-(suitable-and the mixture of (trans-4-isopropyl-cyclohexyl)-piperidines-3-alcohol hydrochloride (1: 1)
With the diethyl ether solution of 0.2ml 2.5N spirit of salt be added to 10mg (0.03mmol) (3RS, 4RS)--4-(2-hydroxyl-phenyl)-1-(suitable-and (trans-4-isopropyl-cyclohexyl)-piperidines-solution of 3-alcohol in the 1ml ether in.Stir after 30 minutes, vacuum is removed excessive spirit of salt and ether and residue is resuspended in the 1ml ether.Throw out is filtered and obtains with the ether washing white powder of 10mg (quantitatively) title compound.
MS?m/e(％):318(M+H +,100)。
Embodiment 19 (3RS, 4RS)-4-(2-methoxyl group-phenyl)-1-(suitable-and the mixture of (trans-4-isopropyl-cyclohexyl)-piperidines-3-alcohol hydrochloride (1: 1)
Under 0 ℃, with 103mg (0.52mmol) two (trimethyl silyl) potassium amide be added to 75mg (0.24mmol) (3RS, 4RS)-4-(2-hydroxyl-phenyl)-1-(suitable-and the solution of (trans-4-isopropyl-cyclohexyl)-piperidines-3-alcohol (embodiment 18a) in the 1ml anhydrous tetrahydro furan in.Continuously stirring 1h and add 70mg (0.49mmol) methyl iodide under this temperature.After stirring 30 minutes under 0 ℃, remove ice bath and allow reaction mixture be warmed to ambient temperature overnight.
Remove solvent and residue is obtained 7mg oily matter by the flash chromatography purifying.With amine solvent in the 1ml ether and drip the diethyl ether solution of 0.2ml 2.3M spirit of salt.With sedimentation and filtration, obtain the white powder of 7mg (8%) title compound with ether washing and vacuum-drying.
MS?m/e(％):332(M+H +,100)。
Embodiment 20 (3RS, 4RS)-4-(2-allyloxy-phenyl)-1-(suitable-and the mixture of (trans-4-isopropyl-cyclohexyl)-piperidines-3-alcohol hydrochloride (1: 1) a), (3RS, 4RS)-4-(2-allyloxy-phenyl)-1-is (suitable-and the mixture of (trans-4-isopropyl-cyclohexyl)-piperidines-3-alcohol
With 610mg (4.4mmol) salt of wormwood and 320mg (2.64mmol) allyl bromide 98 be added to 700mg (2.2mmol) (3RS, 4RS)-4-(2-hydroxyl-phenyl)-1-(suitable-and the solution of (trans-4-isopropyl-cyclohexyl)-piperidines-3-alcohol (embodiment 18a) in the 3ml anhydrous dimethyl formamide in.Stir down at 60 ℃ and to spend the night, remove solvent and residue is obtained the colourless foam thing of 125mg (16%) title compound by the flash chromatography purifying.
MS?m/e(％):358(M+H +,100)。B), (3RS, 4RS)-4-(2-allyloxy-phenyl)-1-(suitable-and the mixture of (trans-4-isopropyl-cyclohexyl)-piperidines-3-alcohol hydrochloride (1: 1)
With the diethyl ether solution of 0.2ml 2.3N spirit of salt be added to 5mg (0.014mmol) (3RS, 4RS)-4-(2-allyloxy-phenyl)-1-(suitable-and (trans-4-isopropyl-cyclohexyl)-piperidines-solution of 3-alcohol in the 1ml ether in.Stir after 30 minutes, vacuum is removed excessive spirit of salt and ether and residue is resuspended in the 1ml ether.Throw out is filtered and obtains with the ether washing white powder of 5mg (quantitatively) title compound.
MS?m/e(％):358(M+H +,100)。
Embodiment 21 (3RS, 4RS)-4-(2-allyloxy-phenyl)-1-(suitable-and the mixture of (trans-4-isopropyl-cyclohexyl)-3-methoxyl group-piperidine hydrochlorate (1: 1)
Under 0 ℃, with 33mg (0.17mmol) two (trimethyl silyl) potassium amide be added to 50mg (0.14mmol) (3RS, 4RS)-4-(2-allyloxy-phenyl)-1-(suitable-and the solution of (trans-4-isopropyl-cyclohexyl)-piperidines-3-alcohol mixture (embodiment 20a) in the 0.5ml anhydrous tetrahydro furan in.Continuously stirring 1h and add 24mg (0.17mmol) methyl iodide under this temperature.After stirring 30 minutes under 0 ℃, remove ice bath and allow reaction mixture be warmed to ambient temperature overnight.
After adding 2ml water, (3 * 10ml) extract, dry (sal epsom) and evaporation with ether with product.Residue is obtained 30mg oily matter by the flash chromatography purifying.With amine solvent in the 2ml ether and drip the diethyl ether solution of 0.5ml 2.3M spirit of salt.With sedimentation and filtration, obtain the white powder of 32mg (56%) title compound with ether washing and vacuum-drying.
MS?m/e(％):372(M+H +,100)。
Embodiment 22 (3RS, 4RS)-4-(2-benzyloxy-phenyl)-1-(suitable-and the mixture of (trans-4-isopropyl-cyclohexyl)-piperidines-3-alcohol hydrochloride (1: 1) a), (3RS, 4RS)-4-(2-benzyloxy-phenyl)-1-is (suitable-and the mixture of (trans-4-isopropyl-cyclohexyl)-piperidines-3-alcohol
With 912mg (6.6mmol) salt of wormwood and 450mg (2.64mmol) bromotoluene be added to 397mg (1.25mmol) (3RS, 4RS)-4-(2-hydroxyl-phenyl)-1-(suitable-and the solution of (trans-4-isopropyl-cyclohexyl)-piperidines-3-alcohol mixture (embodiment 18a) in the 3ml anhydrous dimethyl formamide in.Stir down at 60 ℃ and to spend the night, remove solvent and residue is obtained the colourless foam thing of 228mg (45%) title compound by the flash chromatography purifying.
MS?m/e(％):408(M+H +,100)。B), (3RS, 4RS)-4-(2-benzyloxy-phenyl)-1-(suitable-and the mixture of (trans-4-isopropyl-cyclohexyl)-piperidines-3-alcohol hydrochloride (1: 1)
With the diethyl ether solution of 0.2ml 2.3N spirit of salt be added to 7mg (0.017mmol) (3RS, 4RS)-4-(2-benzyloxy-phenyl)-1-(suitable-and (trans-4-isopropyl-cyclohexyl)-piperidines-solution of 3-alcohol in the 1ml ether in.Stir after 30 minutes, vacuum is removed excessive spirit of salt and ether and residue is resuspended in the 1ml ether.Throw out is filtered and obtains with the ether washing white powder of 7mg (quantitatively) title compound.
MS?m/e(％):408(M+H +,100)。
Embodiment 23 (3RS, 4RS)-1-benzyl-3-methoxyl group-4-(2-methoxyl group-phenyl)-piperidine hydrochlorate (1: 1) a), (3RS, 4RS)-1-benzyl-4-(2-methoxyl group-phenyl)-piperidines-3-alcohol
According to literature method (Juan C.Jean and Lawrence D.Wise, J.Heterocyclic Chem.1987,24,1317-1319), by three the step begin to have prepared title compound from 2-bromine anisole with comparable yield.Obtain the white powder product.
MS?m/e(％):298(M+H +,100)。B), (3RS, 4RS)-1-benzyl-3-methoxyl group-4-(2-methoxyl group-phenyl)-piperidine hydrochlorate (1: 1)
Under 0 ℃, with 126mg (0.6mmol) two (trimethyl silyl) potassium amide be added to 149mg (0.5mmol) (3RS, 4RS)-1-benzyl-4-(2-methoxyl group-phenyl)-piperidines-solution of 3-alcohol in the 1.5ml anhydrous tetrahydro furan in.Continuously stirring 1h and add 85mg (0.6mmol) methyl iodide under this temperature.After stirring 30 minutes under 0 ℃, remove ice bath and allow reaction mixture be warmed to ambient temperature overnight.
After adding 2ml water, (3 * 10ml) extract, dry (sal epsom) and evaporation with ether with product.Residue is obtained 128mg oily matter by the flash chromatography purifying.With amine solvent in the 10ml ether and drip the diethyl ether solution of 1ml 2.3M spirit of salt.With sedimentation and filtration, obtain the white powder of 130mg (75%) title compound with ether washing and vacuum-drying.
MS?m/e(％):312(M+H +,100)。
Embodiment 24 (3RS, 4RS)-3-methoxyl group-1-(2-methoxyl group-phenyl)-4-(2-methoxyl group-phenyl) piperidine hydrochlorate (1: 1) a), (3RS, 4RS)-3-methoxyl group-4-(2-methoxyl group-phenyl)-piperidines
With 1.0g 10% palladium carbon be added to 4.03g (11.6mol) (3RS, 4RS)-1-benzyl-3-methoxyl group-4-(2-methoxyl group-phenyl)-solution of piperidine hydrochlorate (1: 1) (embodiment 23b) in 100ml methyl alcohol in.With this reaction mixture hydrogenation (room temperature, 1 crust) 20h.Catalyzer filtered and with methanol wash (3 * 10ml).Filtrate is concentrated into the about 50ml of cumulative volume and adds 1.3g yellow soda ash.Behind this suspension restir 2h, decompression is removed solvent and residue is resuspended in the 50ml methylene dichloride.Inorganic salt are filtered and the filtrate evaporation are obtained the faint yellow oily thing of 2.20g (74%) title compound.
MS?m/e(％):221(M +,17),189(100),178(62)。B), (3RS, 4RS)-3-methoxyl group-1-(2-methoxyl group-benzyl)-4-(2-methoxyl group-phenyl)-piperidine hydrochlorate (1: 1)
With 75mg (0.55mmol) 2-methoxybenzaldehyde be added to 111mg (0.5mmol) (3RS, 4RS)-3-methoxyl group-4-(2-methoxyl group-phenyl)-solution of piperidines in 1.5ml methyl alcohol in.This reaction mixture was at room temperature stirred 5 minutes and dripped 63mg (1.0mmol) sodium cyanoborohydride.After reaction is spent the night, add the methanol solution of 1ml 2.3M spirit of salt.With this reaction mixture evaporation, be dissolved in again in the 5ml water and and wash with ether.By adding solid potassium hydroxide the aqueous solution is transferred to pH10 and use dichloromethane extraction, dry (sal epsom) evaporates and obtains 100mg oily matter by the flash chromatography purifying.With amine solvent in the 10ml ether and drip the diethyl ether solution of 1ml 2.3M spirit of salt.With sedimentation and filtration, wash also vacuum-evaporation to the dried white powder that obtains 70mg (35%) title compound with ether.
MS?m/e(％):342(M+H +,100)。
Embodiment 25 (3RS, 4RS)-3-methoxyl group-4-(2-methoxyl group-phenyl)-1-(3-phenyl-propyl group) piperidine hydrochlorate (1: 1)
With 74mg (0.55mmol) 3-phenylpropyl aldehyde be added to 111mg (0.5mmol) (3RS, 4RS)-3-methoxyl group-4-(2-methoxyl group-phenyl)-solution of piperidines (embodiment 24a) in 1.5ml methyl alcohol in.This reaction mixture at room temperature stirred 5 minutes and add 63mg (1.0mmol) sodium cyanoborohydride.After reaction is spent the night, add the methanol solution of 1ml 2.3M spirit of salt.With this reaction mixture evaporation, be dissolved in again in the 5ml water and and wash with ether.By adding solid potassium hydroxide the aqueous solution is transferred to pH 10 and uses dichloromethane extraction, dry (sal epsom) and evaporation obtain 155mg oily matter.With amine solvent in the 10ml ether and drip the diethyl ether solution of 1ml 2.3M spirit of salt.With sedimentation and filtration, wash also vacuum-evaporation to the dried white powder that obtains 150mg (80%) title compound with ether.
MS?m/e(％):340(M+H +,100)。
Embodiment 26 (3RS, 4RS)-1-(the 4-tertiary butyl-benzyl)-3-methoxyl group-4-(2-methoxyl group-phenyl) piperidine hydrochlorate (1: 1)
With 89mg (0.55mmol) 4-tert.-butylbenzene formaldehyde be added to 111mg (0.5mmol) (3RS, 4RS)-3-methoxyl group-4-(2-methoxyl group-phenyl)-solution of piperidines (embodiment 24a) in 1.5ml methyl alcohol in.This reaction mixture at room temperature stirred 5 minutes and add 63mg (1.0mmol) sodium cyanoborohydride.After reaction is spent the night, add the methanol solution of 1ml 2.3M spirit of salt.With this reaction mixture evaporation, be dissolved in again in the 5ml water and and wash with ether.By adding solid potassium hydroxide the aqueous solution is transferred to pH 10 and uses dichloromethane extraction, dry (sal epsom) and evaporation obtain 100mg oily matter.With amine solvent in the 10ml ether and drip the diethyl ether solution of 1ml 2.3M spirit of salt.With sedimentation and filtration, wash also vacuum-evaporation to the dried white powder that obtains 110mg (55%) title compound with ether.
MS?m/e(％):368(M+H +,100)。
Embodiment 27 (3RS, 4RS)-3-allyloxy-1-benzyl-4-(2-methoxyl group-phenyl)-piperidine hydrochlorate (1: 1)
Under 0 ℃, with 126mg (0.6mmol) two (trimethyl silyl) potassium amide be added to 149mg (0.5mmol) (3RS, 4RS)-1-benzyl-4-(2-methoxyl group-phenyl)-solution of piperidines-3-alcohol (embodiment 23a) in the 1.5ml anhydrous tetrahydro furan in.Continuously stirring 1h and add 73mg (0.6mmol) allyl bromide 98 under this temperature.After stirring 30 minutes under 0 ℃, remove ice bath and allow reaction mixture be warmed to ambient temperature overnight.
After adding 2ml water, (3 * 10ml) extract, dry (sal epsom) and evaporation with ether with product.Residue is obtained 149mg oily matter by the flash chromatography purifying.With amine solvent in the 10ml ether and drip the diethyl ether solution of 1ml 2.3M spirit of salt.With sedimentation and filtration, obtain the white powder of 150mg (80%) title compound with ether washing and vacuum-drying.
MS?m/e(％):338(M+H +,100)。
Embodiment 28 (3RS, 4RS)-1-ring decyl-4-(2-methoxyl group-phenyl)-piperidines-3-alcohol hydrochloride (1: 1) a), (3RS, 4RS)-4-(2-methoxyl group-phenyl)-piperidines-3-alcohol hydrochloride (1: 1)
With 5.95g (20mmol) (3RS, 4RS)-1-benzyl-4-(2-methoxyl group-phenyl)-solution stirring of piperidines-3-alcohol (embodiment 23a) in the ethanolic soln of 100ml 1N spirit of salt 30 minutes.Vacuum is removed solvent and excessive spirit of salt.Be dissolved in residue in the 100ml methyl alcohol and add 1.5g 10% palladium carbon.With this reaction mixture hydrogenation (room temperature, 1 crust) 20h.Catalyzer filtered and with methanol wash (3 * 10ml).Filtrate vacuum-evaporation is obtained the white powder of 4.7g (96%) title compound.
MS?m/e(％):207(M +,19),178(100)。
B), (3RS, 4RS)-4-(2-methoxyl group-phenyl)-piperidines-3-alcohol
With 2.1g yellow soda ash be added to 4.7g (20mmol) (3RS, 4RS)-4-(2-methoxyl group-phenyl)-piperidines-solution of 3-alcohol hydrochloride (1: 1) in 40ml methyl alcohol in.After at room temperature stirring 1h, sodium salt is filtered and uses the 10ml methanol wash.Filtrate is concentrated, dilutes and refilter with the 2-propyl alcohol.The filtrate evaporation is obtained the white solid of 4.10g (quantitatively) title compound.
MS?m/e(％):208(M+H +,100)。C), (3RS, 4RS)-1-encircles decyl-4-(2-methoxyl group-phenyl)-piperidines-3-alcohol
With 7.12g (25mmol) original four-isopropyl titanate be added to 4.14g (20mmol) (3RS, 4RS)-suspension of 4-(2-methoxyl group-phenyl)-piperidines-3-alcohol in 3.09g (20mmol) ring decanone in.After at room temperature stirring is spent the night, obtain heavy-gravity oily matter.In 3-4 minute, drip the 20ml ethanolic soln of 880mg (14mmol) sodium cyanoborohydride.Continuously stirring 48h and add the hydrochloric acid of 10ml 25% at room temperature.After 30 minutes, with sedimentation and filtration and add the ethanolic soln of 200ml2.5M ammonia.Precipitation is refiltered and filtrate is evaporated.Residue is obtained the faint yellow oily thing of 5.40g (78%), crystallization when at room temperature placing by the flash chromatography purifying.
MS?m/e(％):346(M+H +,100)。D), (3RS, 4RS)-1-encircles decyl-4-(2-methoxyl group-phenyl)-piperidines-3-alcohol hydrochloride (1: 1)
With the diethyl ether solution of 2ml 2.5N spirit of salt be added to 270mg (0.78mmol) (3RS, 4RS)-ether (10ml) solution of 1-ring decyl-4-(2-methoxyl group-phenyl)-piperidines-3-alcohol in.Stir after 30 minutes, vacuum is removed excessive spirit of salt and ether and residue is resuspended in the 20ml ether.Throw out is filtered and obtains with the ether washing white powder of 298mg (quantitatively) title compound.
MS?m/e(％):346(M+H +,100)。
Embodiment 29 (3RS, 4RS)-3-methoxyl group-1-encircles decyl-4-(2-methoxyl group-phenyl)-piperidine hydrochlorate (1: 1)
Under 0 ℃, with 126mg (0.6mmol) two (trimethyl silyl) potassium amide be added to 173mg (0.5mmol) (3RS, 4RS)-anhydrous tetrahydro furan (1.5ml) solution of 1-ring decyl-4-(2-methoxyl group-phenyl)-piperidines-3-alcohol (embodiment 28c) in.Continuously stirring 1h and add 85mg (0.6mmol) methyl iodide under this temperature.After stirring 30 minutes under 0 ℃, remove ice bath and allow reaction mixture be warmed to ambient temperature overnight.
After adding 2ml water, (3 * 10ml) extract, dry (sal epsom) and evaporation with ether with product.Residue is obtained 120mg oily matter by the flash chromatography purifying.With amine solvent in the 10ml ether and drip the diethyl ether solution of 1ml 2.3M spirit of salt.With sedimentation and filtration, obtain the white powder of 133mg (67%) title compound with ether washing and vacuum-drying.
MS?m/e(％):360(M+H +,100)。
Embodiment 30 (3RS, 4RS)-the 3-allyloxy-1-ring decyl-4-(2-methoxyl group-phenyl)-piperidine hydrochlorate (1: 1) a), (3RS, 4RS)-3-allyloxy-1-encircles decyl-4-(2-methoxyl group-phenyl)-piperidines
Under 0 ℃, with 256mg (1.2mmol) two (trimethyl silyl) potassium amide be added to 146mg (1.0mmol) (3RS, 4RS)-anhydrous tetrahydro furan (3.0ml) solution of 1-ring decyl-4-(2-methoxyl group-phenyl)-piperidines-3-alcohol (embodiment 28c) in.Continuously stirring 1h and add 145mg (1.2mmol) allyl bromide 98 under this temperature.After stirring 30 minutes under 0 ℃, remove ice bath and allow reaction mixture be warmed to ambient temperature overnight.
After adding 4ml water, (3 * 20ml) extract, dry (sal epsom) and evaporation with ether with product.Residue is obtained the colorless oil of 280mg (73%) title compound by the flash chromatography purifying.
MS?m/e(％):386(M+H +,100)。B), (3RS, 4RS)-3-allyloxy-1-encircles decyl-4-(2-methoxyl group-phenyl)-piperidine hydrochlorate (1: 1)
With the diethyl ether solution of 1ml 2.3M spirit of salt be added to 100mg (0.26mmol) (3RS, 4RS)-ether (10ml) solution of 3-allyloxy-1-ring decyl-4-(2-methoxyl group-phenyl)-piperidines in.Throw out is filtered, obtain the white powder of 109mg (quantitatively) title compound with ether washing and vacuum-drying.
MS?m/e(％):386(M+H +,100)。
Embodiment 31 (3RS, 4RS)-1-encircles decyl-4-(2-methoxyl group-phenyl)-3-propoxy--piperidine hydrochlorate (1: 1)
With 40mg 10% palladium carbon be added to 77mg (0.2mol) (3RS, 4RS)-the 3-allyloxy-1-ring decyl-4-(2-methoxyl group-phenyl)-solution of piperidines (embodiment 30a) in the 10ml ethyl acetate in.With this reaction mixture hydrogenation (room temperature, 1 crust) 20h.Wash (3 * 1ml) with the catalyzer filtration and with ethyl acetate.Filtrate vacuum-evaporation is obtained 78mg oily matter.With amine solvent in the 10ml ether and drip the diethyl ether solution of 1ml 2.3M spirit of salt.With sedimentation and filtration, obtain the white powder of 85mg (quantitatively) title compound with ether washing and vacuum-drying.
MS?m/e(％):388(M +,100)。
Embodiment 32 (3RS, 4RS)-1-ring decyl-4-(2-sec.-propyl-phenyl)-piperidines-3-alcohol hydrochloride (1: 1) a), (3RS, 4RS)-1-benzyl-4-(2-sec.-propyl-phenyl)-piperidines-3-alcohol
According to literature method (Juan C.Jean and Lawrence D.Wise, J.Heterocyclic Chem.1987,24,1317-1319), begin replacement by three steps from 2-bromine isopropyl benzene and begin to have prepared title compound with comparable yield from 2-bromine anisole.Obtain the white solid product.
MS?m/e(％):310(M+H +,100)。B), (3RS, 4RS)-4-(2-sec.-propyl-phenyl)-piperidines-3-alcohol hydrochloride (1: 1)
With 10.9g (32mmol) (3RS, 4RS)-solution stirring of 1-benzyl-4-(2-sec.-propyl-phenyl)-piperidines-3-alcohol in 100ml 1N spirit of salt ethanolic soln 30 minutes.Vacuum is removed solvent and excessive spirit of salt.Be dissolved in residue in the 300ml methyl alcohol and add 2.4g 10% palladium carbon.With this reaction mixture hydrogenation (room temperature, 5 crust) 20h.Catalyzer filtered and with methanol wash (3 * 50ml).Filtrate vacuum-evaporation is obtained the white powder of 5.9g (74%) title compound.
MS?m/e(％):219(M +,17),202(21),190(39),172(42),44(100)。C), (3RS, 4RS)-4-(2-sec.-propyl-phenyl)-piperidines-3-alcohol
With 3.6g yellow soda ash be added to 5.75g (22.6mmol) (3RS, 4RS)-ethanol (150ml) suspension of 4-(2-sec.-propyl-phenyl)-piperidines-3-alcohol hydrochloride (1: 1) in.After at room temperature stirring 2h, sodium salt is filtered and uses the 10ml washing with alcohol.Filtrate is concentrated, dilutes and refilter with the 2-propyl alcohol.The filtrate evaporation is obtained the white solid of 4.93g (quantitatively) title compound.
MS?m/e(％):220(M+H +,100)。D), (3RS, 4RS)-1-encircles decyl-4-(2-sec.-propyl-phenyl)-piperidines-3-alcohol
With 3.24g (11.4mmol) original four-isopropyl titanate be added to 500mg (2.28mmol) (3RS, 4RS)-suspension of 4-(2-sec.-propyl-phenyl)-piperidines-3-alcohol in 350mg (2.28mmol) ring decanone in.After at room temperature stirring 5 days, obtain heavy-gravity oily matter.In 3-4 minute, drip ethanol (2ml) solution of 100mg (1.59mmol) sodium cyanoborohydride.Continuously stirring 4h and add 25ml 2.3N spirit of salt ethanolic soln at room temperature.Behind heating 3h under 60 ℃, solution is transferred to pH 8 and filtration by adding 25% sodium hydroxide solution.Filtrate is used ethyl acetate extraction, with organic phase salt water washing, dry (sal epsom) and evaporation.Residue is obtained the white solid of 415mg (51%) title compound by the flash chromatography purifying.
MS?m/e(％):358(M+H +,100)。E), (3RS, 4RS)-1-encircles decyl-4-(2-sec.-propyl-phenyl)-piperidines-3-alcohol hydrochloride (1: 1)
With the ethanolic soln of 0.3ml 2.3M spirit of salt be added to 30mg (0.08mmol) (3RS, 4RS)-1-ring decyl-4-(2-sec.-propyl-phenyl)-piperidines-solution of 3-alcohol in 3ml ethanol in.Solution was at room temperature stirred 30 minutes and evaporation.Be suspended in residue in the ether and stir 1h.With sedimentation and filtration, obtain the white powder of 23mg (70%) title compound with ether washing and vacuum-drying.
MS?m/e(％):358(M+H +,100)。
Embodiment 33 (3RS, 4RS)-1-encircles decyl-4-(2-sec.-propyl-phenyl)-3-methoxyl group-piperidine hydrochlorate (1: 1)
Under 0 ℃, with 134mg (0.67mmol) two (trimethyl silyl) potassium amide be added to 200mg (0.56mmol) (3RS, 4RS)-1-ring decyl-4-(2-sec.-propyl-phenyl)-solution of piperidines-3-alcohol (embodiment 32d) in the 2ml anhydrous tetrahydro furan in.Continuously stirring 1h and add 80mg (0.56mmol) methyl iodide under this temperature.After stirring 30 minutes under 0 ℃, remove ice bath and allow reaction mixture be warmed to ambient temperature overnight.
After adding 2ml water, (3 * 10ml) extract, dry (sal epsom) and evaporation with ether with product.Residue is obtained 50mg oily matter by the flash chromatography purifying.With amine solvent in the 10ml ether and drip the diethyl ether solution of 1ml 2.3M spirit of salt.With sedimentation and filtration, obtain the white powder of 34mg (15%) title compound with ether washing and vacuum-drying.
MS?m/e(％):372(M+H +,100)。
Embodiment 34 (3RS, 4RS)-1-encircles nonyl-4-(2-sec.-propyl-phenyl)-piperidines-3-alcohol hydrochloride (1: 1)
With 1.29g (4.56mmol) original four-isopropyl titanate be added to 200mg (0.91mmol) (3RS, 4RS)-4-(2-sec.-propyl-phenyl)-suspension of piperidines-3-alcohol (embodiment 32c) in 160mg (1.14mmol) cyclononanone in.After at room temperature stirring 6 days, obtain heavy-gravity oily matter.In 3-4 minute, drip ethanol (2ml) solution of 24mg (0.64mmol) sodium borohydride.Continuously stirring 1h and add the ethanolic soln of 10ml 2.3N spirit of salt at room temperature.Behind heating 4h under 60 ℃, solution is transferred to pH 8 and filtration by adding 25% sodium hydroxide solution.Filtrate is used ethyl acetate extraction, with organic phase salt water washing, dry (sal epsom) and evaporation.Residue is obtained the faint yellow oily thing of 160mg by the flash chromatography purifying.With amine solvent in 10ml ethanol and drip the ethanolic soln of 1ml 2.3M spirit of salt.Solution was at room temperature stirred 30 minutes and evaporation, be suspended in resistates in the ether and stirred 1 hour.With sedimentation and filtration, obtain the white powder of 175mg (51%) title compound with ether washing and vacuum-drying.
MS?m/e(％):344(M+H +,100)。
Embodiment 351-ring decyl-4-(2,6-dimethoxy-phenyl)-piperidine hydrochlorate (1: 1) a), 1-benzyl-4-(2,6-dimethoxy-phenyl)-1,2,3,6-tetrahydrochysene-piperidines
According to literature method (Juan C.Jean and Lawrence D.Wise, J.Heterocyclic Chem.1987,24,1317-1319), by two steps from 1,2-dimethoxy benzene-2-base magnesium bromide begins to replace beginning to have prepared title compound with comparable yield from 2-p-methoxy-phenyl magnesium bromide.Obtain product as white needles.
MS?m/e(％):310(M+H +,100)。B), 4-(2,6-dimethoxy-phenyl)-piperidines
With 3.4g (11mmol) 1-benzyl-4-(2,6-dimethoxy-phenyl)-1,2,3, the solution stirring of 6-tetrahydrochysene-piperidines in 100ml 1N spirit of salt ethanolic soln 30 minutes.Vacuum is removed solvent and excessive spirit of salt.Be dissolved in residue in the 110ml methyl alcohol and add 0.9g 10% palladium carbon.With this reaction mixture hydrogenation (room temperature, 5 crust) 20h.Catalyzer filtered and with methanol wash (3 * 50ml).With filtrate vacuum-evaporation and product is obtained the white powder of 1.34g (57%) title compound by the flash chromatography purifying.
MS?m/e(％):222(M+H +,100)。C), 1-ring decyl-4-(2,6-dimethoxy-phenyl)-piperidine hydrochlorate (1: 1)
1.28g (4.52mmol) original four-isopropyl titanate is added in the suspension of 200mg (0.9mmol) 4-(2,6-dimethoxy-phenyl)-piperidines in 140mg (0.9mmol) ring decanone.After at room temperature stirring 4 days, obtain heavy-gravity oily matter.In 3-4 minute, drip the solution of 40mg (0.63mmol) sodium cyanoborohydride in 1ml ethanol.Continuously stirring 5h and add the ethanolic soln of 10ml 2.3N spirit of salt at room temperature.Behind heating 3h under 60 ℃, solution is transferred to pH 8 and filtration by adding 25% sodium hydroxide solution.Filtrate is used ethyl acetate extraction, with organic phase salt water washing, dry (sal epsom) and evaporation.Residue is obtained the 18mg white crystals by the flash chromatography purifying.With amine solvent in the 10ml ether and drip the diethyl ether solution of 1ml 2.3M hydrochloric acid.Solution was at room temperature stirred 30 minutes and evaporation.Residue is resuspended in the ether and vacuum-drying obtains the white powder of 20mg (6%) title compound.
MS?m/e(％):360(M+H +,100)。
Embodiment 36 (3RS, 4RS)-1-ring decyl-4-(2,6-dimethoxy-phenyl)-piperidines-3-alcohol hydrochloride (1: 1) a), (3RS, 4RS)-1-benzyl-4-(2,6-dimethoxy-phenyl)-piperidines-3-alcohol hydrochloride (1: 1)
According to literature method (Juan C.Jean and Lawrence D.Wise, J.Heterocyclic Chem.1987,24,1317-1319), by three steps from 1,3-anisole-2-base magnesium bromide begins to replace beginning to have prepared title compound with comparable productive rate from 2-p-methoxy-phenyl magnesium bromide.Obtain white crystals shape product.
MS?m/e(％):328(M+H +,100)。B), (3RS, 4RS)-4-(2,6-dimethoxy-phenyl)-piperidines-3-alcohol hydrochloride (1: 1)
With 600mg 10% palladium carbon be added to 2.9g (8mmol) (3RS, 4RS)-methyl alcohol (80ml) solution of 1-benzyl-4-(2,6-dimethoxy-phenyl)-piperidines-3-alcohol hydrochloride (1: 1) in.With the hydrogen (approximately 20h) of this reaction mixture hydrogenation (room temperature, 5 crust) until the consumption theoretical amount.Catalyzer filtered and with methanol wash (3 * 20ml).Filtrate vacuum-evaporation is obtained the pale yellow powder of 1.88g (87%) title compound.
MS?m/e(％):237(M +,27),208(100)。C), (3RS, 4RS)-4-(2,6-dimethoxy-phenyl)-piperidines-3-alcohol
With 1.0g yellow soda ash be added to 1.78g (6.53mmol) (3RS, 4RS)-4-(2, the 6-dimethoxy-phenyl)-piperidines-solution of 3-alcohol hydrochloride (1: 1) in 25ml ethanol in.After at room temperature stirring 2h, sodium salt is filtered and uses the 10ml washing with alcohol.Filtrate is concentrated, dilutes and refilter with the 2-propyl alcohol.The filtrate evaporation is obtained the faint yellow solid of 1.46g (quantitatively) title compound.
MS?m/e(％):238(M+H +,100)。D), (3RS, 4RS)-1-encircles decyl-4-(2,6-dimethyl-phenyl)-piperidines-3-alcohol
With 3.0g (10.5mmol) original four-isopropyl titanate be added to 500mg (2.1mmol) (3RS, 4RS)-suspension of 4-(2,6-dimethoxy-phenyl)-piperidines-3-alcohol in 325mg (2.1mmol) ring decanone in.After at room temperature stirring 4 days, obtain heavy-gravity oily matter.In 3-4 minute, drip the solution of 93mg (1.5mmol) sodium cyanoborohydride in 1.5ml ethanol.Continuously stirring 2h and add the ethanolic soln of 25ml 2.3N spirit of salt at room temperature.Behind heating 2h under 60 ℃, transfer to pH 8 and filtration by adding 25% sodium hydroxide solution.Filtrate is used ethyl acetate extraction, with organic phase salt water washing, dry (sal epsom) and evaporation.Residue is obtained the yellow oil of 218mg (27%) title compound by the flash chromatography purifying.
MS?m/e(％)：376(M+H +,100)。E), (3RS, 4RS)-1-encircles decyl-4-(2,6-dimethoxy-phenyl)-piperidines-3-alcohol hydrochloride (1: 1)
To 30mg (0.08mmol) (3RS, 4RS)-drip 0.3ml 2.3M spirit of salt ethanolic soln in 1-ring decyl-4-(2, the 6-Dimethoxyphenyl)-piperidines-solution of 3-alcohol in 3ml ethanol.Stirring at room solution 30 minutes and evaporation.Be suspended in resistates in the ether and stirred 1 hour.The filtering precipitation is washed and vacuum-drying with ether, obtains 21mg (61%) white powder title compound.
MS?m/e(％):376(M+H +,100)。
Embodiment 371-encircles decyl-4-phenyl-piperidine hydrochlorate (1: 1)
1.76g (6.2mmol) original four-isopropyl titanate is added in the suspension of 200mg (1.24mmol) 4-Phenylpiperidine in 230mg (1.49mmol) ring decanone.After at room temperature stirring 5 days, obtain heavy-gravity oily matter.In 3-4 minute, drip the solution of 235mg (6.2mmol) sodium borohydride in 10ml ethanol.Continuously stirring 2h and add the 10ml liquor ammoniae fortis at room temperature.Inorganic sediment is removed by filter and uses washed with dichloromethane.Filtrate is used dichloromethane extraction, with organic phase salt water washing, dry (sal epsom) and evaporation.Residue is obtained the 270mg yellow solid by the flash chromatography purifying.With amine solvent in 10ml ethanol and drip the ethanolic soln of 1ml 2.3M spirit of salt.Solution was at room temperature stirred 30 minutes and evaporation.Be resuspended in residue in the ether and stir 1h.With sedimentation and filtration, obtain the white powder of 200mg (48%) title compound with ether washing and vacuum-drying.
MS?m/e(％):300(M+H +,100)。
Embodiment 381-encircles decyl-4-cyclohexyl-piperidine hydrochlorate (1: 1)
1.67g (6.0mmol) original four-isopropyl titanate is added in the suspension of 200mg (1.12mmol) 4-cyclohexyl piperidines in 220mg (1.43mmol) ring decanone.After at room temperature stirring 5 days, obtain heavy-gravity oily matter.In 3-4 minute, drip the solution of 225mg (6.0mmol) sodium borohydride in 10ml ethanol.Continuously stirring 2h and add the 10ml liquor ammoniae fortis at room temperature.Inorganic sediment is filtered and uses washed with dichloromethane.Filtrate is used dichloromethane extraction, with organic phase salt water washing, dry (sal epsom) and evaporation.Residue is obtained the 80mg faint yellow solid by the flash chromatography purifying.With amine solvent in 10ml ethanol and drip the ethanolic soln of 1ml 2.3M spirit of salt.Solution was at room temperature stirred 30 minutes and evaporation.Be resuspended in residue in the ether and stir 1h.With sedimentation and filtration, obtain the white powder of 78mg (19%) title compound with ether washing and vacuum-drying.
MS?m/e(％):305(M +,18),206(100)。

Claims (11)

1、通式Ⅰ化合物及其与可药用酸的加成盐
Figure A9981064200021
其中：1. Compounds of general formula I and their addition salts with pharmaceutically acceptable acids
Figure A9981064200021
in: R1为四氢萘基；R 1 is tetrahydronaphthyl; 或-(CH2)n-C6H5-R4，其中n为0-4并且R4为H、低级烷基或低级烷氧基；Or -(CH 2 ) n -C 6 H 5 -R 4 , wherein n is 0-4 and R 4 is H, lower alkyl or lower alkoxy; 或未取代或由低级烷基取代的C5-C12环烷基；Or C 5 -C 12 cycloalkyl unsubstituted or substituted by lower alkyl; R2为H、OH、低级烷氧基、低级链烯氧基或低级烷基；R 2 is H, OH, lower alkoxy, lower alkenyloxy or lower alkyl; R3为未取代或由取代基取代的C5-C7环烷基或苯基，所述取代基为OH、卤素、低级烷氧基、低级链烯氧基、低级烷基或-O-(CH2)n-C6H5，其中n为0-3。R 3 is C 5 -C 7 cycloalkyl or phenyl which is unsubstituted or substituted by a substituent, and the substituent is OH, halogen, lower alkoxy, lower alkenyloxy, lower alkyl or -O- (CH 2 ) n -C 6 H 5 , wherein n is 0-3. 2、权利要求1的化合物，其中R1是可被低级烷基取代或不取代的C5-C12环烷基。2. The compound of claim 1, wherein R 1 is C 5 -C 12 cycloalkyl which may be substituted or not substituted by lower alkyl. 3、权利要求2的化合物，其为3. The compound of claim 2 which is (3RS,4RS)-1-环壬基-4-(2-羟基-苯基)哌啶-3-醇；(3RS,4RS)-1-cyclononyl-4-(2-hydroxy-phenyl)piperidin-3-ol; 1-环癸基-4-(2-甲氧基-苯基)-哌啶；1-cyclodecyl-4-(2-methoxy-phenyl)-piperidine; (3RS,4RS)-1-环癸基-4-(2-异丙基-苯基)哌啶-3-醇；(3RS,4RS)-1-cyclodecyl-4-(2-isopropyl-phenyl)piperidin-3-ol; (3RS,4RS)-4-(2-羟基-苯基)-1-(顺-和(反-4-异丙基环己基)-哌啶-3-醇；(3RS,4RS)-4-(2-Hydroxy-phenyl)-1-(cis- and (trans-4-isopropylcyclohexyl)-piperidin-3-ol; 2-(1-环癸基-哌啶-4-基)-苯酚；2-(1-cyclodecyl-piperidin-4-yl)-phenol; (3RS,4RS)-1-环癸基-4-(2-甲氧基-苯基)-哌啶-3-醇；(3RS,4RS)-1-cyclodecyl-4-(2-methoxy-phenyl)-piperidin-3-ol; 1-环癸基-4-环己基-哌啶；1-cyclodecyl-4-cyclohexyl-piperidine; (3RS,4RS)-1-环壬基-4-(2-甲氧基-苯基)-哌啶-3-醇；(3RS,4RS)-1-cyclononyl-4-(2-methoxy-phenyl)-piperidin-3-ol; (3RS,4RS)-4-(2-烯丙氧基-苯基)-1-环癸基-哌啶-3-醇；(3RS,4RS)-4-(2-allyloxy-phenyl)-1-cyclodecyl-piperidin-3-ol; 1-环癸基-4-苯基-哌啶；1-cyclodecyl-4-phenyl-piperidine; (3RS,4RS)-1-环壬基-4-(2-异丙基-苯基)-哌啶-3-醇；和(3RS,4RS)-1-cyclononyl-4-(2-isopropyl-phenyl)-piperidin-3-ol; and (3RS,4RS)-1-环癸基-4-(2-羟基-苯基)-哌啶-3-醇。(3RS,4RS)-1-Cyclodecyl-4-(2-hydroxy-phenyl)-piperidin-3-ol. 4、权利要求1-3任一项的化合物，用作治疗活性物质，特别是用于治疗记忆力和注意力不足，精神病学、神经病学和生理学疾病，如焦虑和紧张疾病，抑郁，由早老性痴呆或其他痴呆如血管性痴呆和AIDS性痴呆综合征引起的记忆力丧失，帕金森病，癫痫和抽搐，急性和/或慢性疼痛性疾病，成瘾性药物的戒断症状和减少其滥用/嗜欲，控制水平衡，Na+排泄和动脉血压疾病和代谢性疾病如肥胖。4. Compounds according to any one of claims 1-3, for use as therapeutically active substances, in particular for the treatment of memory and attention deficits, psychiatric, neurological and physiological diseases such as anxiety and stress disorders, depression, caused by premature aging Memory loss due to dementia or other dementias such as vascular dementia and AIDS dementia syndrome, Parkinson's disease, epilepsy and convulsions, acute and/or chronic painful disorders, withdrawal symptoms of addictive drugs and reduction of their abuse/craving , control of water balance, Na + excretion and arterial blood pressure diseases and metabolic diseases such as obesity. 5、含有一种或多种权利要求1-3任一项的化合物或其可药用盐的药物。5. A medicament containing one or more compounds according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof. 6、权利要求5的药物，其用于治疗Orphanin FQ(OFQ)受体相关疾病，所述疾病包括记忆力和注意力不足，精神病学、神经病学和生理学疾病，如焦虑和紧张疾病，抑郁，由早老性痴呆或其他痴呆如血管性痴呆和AIDS性痴呆综合征引起的记忆力丧失，帕金森病，癫痫和抽搐，急性和/或慢性疼痛性疾病，成瘾性药物的戒断症状和减少其滥用/嗜欲，控制水平衡，Na+排泄和动脉血压疾病和代谢性疾病如肥胖。6. The medicament of claim 5 for the treatment of Orphanin FQ (OFQ) receptor related diseases, said diseases include memory and attention deficit, psychiatric, neurological and physiological diseases such as anxiety and stress disorders, depression, by Memory loss in Alzheimer's disease or other dementias such as vascular dementia and AIDS-related dementia syndrome, Parkinson's disease, epilepsy and convulsions, acute and/or chronic pain disorders, withdrawal symptoms of addictive drugs and reduction of their abuse / Appetite, control of water balance, Na + excretion and arterial blood pressure diseases and metabolic diseases such as obesity. 7、权利要求1所定义的式Ⅰ化合物的制备方法，该方法括将式Ⅱ化合物
Figure A9981064200031
用式Ⅳ化合物
Figure A9981064200032
进行还原性胺化，其中R1、R2和R3定义同权利要求1。7. The preparation method of the compound of formula I defined in claim 1, which method comprises the compound of formula II
Figure A9981064200031
With formula Ⅳ compound
Figure A9981064200032
Reductive amination is carried out, wherein R 1 , R 2 and R 3 are as defined in claim 1. 8、权利要求1-3的一种或多种化合物或其可药用盐在制备药物中的用途。8. Use of one or more compounds according to claims 1-3 or a pharmaceutically acceptable salt thereof for the preparation of a medicament. 9、权利要求8的用途，其为用于制备治疗下列疾病的药物：记忆力和注意力不足，精神病学、神经病学和生理学疾病，如焦虑和紧张疾病，抑郁，由早老性痴呆或其他痴呆如血管性痴呆和AIDS性痴呆综合征引起的记忆力丧失，帕金森病，癫痫和抽搐，急性和/或慢性疼痛性疾病，成瘾性药物的戒断症状和减少其滥用/嗜欲，控制水平衡，Na+排泄和动脉血压疾病和代谢性疾病如肥胖。9. The use of claim 8 for the preparation of a medicament for the treatment of memory and attention deficits, psychiatric, neurological and physiological diseases such as anxiety and tension disorders, depression, caused by Alzheimer's disease or other dementias such as Memory loss due to vascular dementia and AIDS dementia syndrome, Parkinson's disease, epilepsy and convulsions, acute and/or chronic painful disorders, withdrawal symptoms of addictive drugs and reduction of their abuse/craving, control of water balance, Na + excretion and arterial blood pressure diseases and metabolic diseases such as obesity. 10、通过权利要求7的方法或相当方法获得的通式Ⅰ的化合物。10. Compounds of general formula I obtainable by the process of claim 7 or equivalents. 11、基本上按本文所描述的发明。11. The invention substantially as herein described.
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