CN1696115B - Synthesized building block of derivative of 4-substituent-4-amido-piperidine, preparation method and application - Google Patents
Synthesized building block of derivative of 4-substituent-4-amido-piperidine, preparation method and application Download PDFInfo
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Abstract
A synthetic building block 4-substituent-4-amino-piperidine derivative used as intermediate to synthesize different active moleculae, such as CCR5 depressant, muscarin M3 receptor antagon, etc is prepared from 4-piperidylformic acid through amino and carboxy protection, alkylation, and Curtius reforming reaction.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field; be specifically related to a kind of new synthetic building block 4-substituting group-4-amino-piperadine derivatives and the preparation method of simple and effective wide spectrum thereof; the 4-piperidine carboxylic acid ester of the amino due care of the 1-that more specifically says so can be at 4 substituting groups of introducing different structure neatly by nucleophilic substitution reaction under alkaline condition, again through the synthetic building block of the various 4-substituted-4-amino-piperidine derivative of Curtius rearrangement reaction high-yield quick rate ground preparation structure under condition as mild as a dove as a series of bioactive molecules.
Background technology
4-substituted-4-amino-piperidines is the important synthetic building block of a class, and it is the important structure unit of a series of active compounds.As have fentanyl compounds (1.Bagley, a J.R. of extremely strong analgesic activity; Thomas, S.A.; Rudo, F.G.; Spencer, H.K.; Doorley, B.M.; Ossipov, M.H.; Jerussi, T.P.; Benvenga, M.J.; Spaulding, T.J.Med.Chem.1991,34,827-841.2.
I.V.;
M.D.; Vuckovic, S.M.; Prostran, M.
L.;
V.D.Bioorg.Med.Chem.Lett.2000,10,2011-2014.), have deep malicious alkali M3 receptor antagonist (Ogino, a Y. of treatment respiratory tract obstruction and urethra disorder disease; Ohtake, N.; Kobayashi, K.; Kimura, T.; Fujikawa, T.; Hasegawa, T.; Noguchi, K.; Mase, T.Bioorg.Med.Chem.Lett.2003,13,2167-2172.) and to respiratory tract and disease of stomach have the neurokinine-1 of result of treatment and part (1.Albert, the J.S. of neurokinin-2 acceptor; Aharony, D.; Andisik, D.; Barthlow, H.; Bernstein, P.R.; Bialecki, R.A.; Dedinas, R.; Et.al.J.Med.Chem.2002,45,3972-3983.2.Bleicher, K.H.; W ü thrich, Y.; De Boni, M.; Kolczewski, S.; Hoffmann, T.; Sleight, A.J.Bioorg.Med.Chem.Lett.2002,12,2519-2522.) all contain 4-substituting group-4-substituted-amino-piperidines drug effect unit.Recently, a kind of new drug CCR5 inhibitor that is rich in the treatment acquired immune deficiency syndrome (AIDS) of prospect also is to be pharmacophoric group (Kazmierski, W. with this class formation; Bifulco, N.; Yang, H.; Boone, L.; DeAnda, F.; Watson, C.; Kenakin, T.Bioorg.Med.Chem.2003,11,2663-2676.).Two of U.S. Schering-Plough institute exploitation is that the selectivity CCR5 inhibitor of core texture enters the clinical I phase as anti-acquired immunodeficiency syndrome drug and studies (Borman, S.Promising Drugs.Chemical ﹠amp with piperidines-piperidines and piperazine-piperidine; Engineering News, May 26,2003, pp29-31.).Schering-Plough institute has used improved Strecker reaction (Tagat, J.R. when making up piperidines-piperidines or piperazine-piperidine pharmacophore; Steensma, R.W.; McCombie, S.W.; Nazareno, D.V.; Lin, S.-I.; Neustadt, B.R.; Cox, K.; Xu, S.; Wojcik, L.; Murray, M.G.; Vantuno, N.; Baroudy, B.M.; Strizki, J.M.J.Med.Chem.2001,44,3343-3346), need poisonous reagent diethyl cyano group aluminium, and reactions steps is long.We can just can make up corresponding pharmacophoric group through single step reaction with 4-substituting group-4-amino-piperadine as synthetic building block under normal condition.Therefore, 4-substituted-4-amino-piperidines is the key intermediate that makes up the active structure with important biomolecule medicinal use.
The report that does not also have the identical compound of the synthetic block structure of this designed class of appearance and the present invention in the document.But for synthesizing of similar structures, the method of bibliographical information is mainly from the 4-piperidone of amido protecting, at first generate imine intermediate with the amine reaction, carry out the piperidines that nucleophilic addition(Adn) just can obtain 4-substituting group-4-substituted-amino with lithium reagent or Grignard reagent again, but productive rate is lower, and the structure kind of 4 bit substituents very limited (1.Cossy, J.; Poitevin, C.; Pardo, D.G.; Pegion, J.-L.; Dessinges, A.Tetrahedron Lett.1998,39,2965-2968.2.Cossy.J.; Poitevin, C.; Pardo, D.G.; Peglion, J.-L.; Dessinges, A.J.Org.Chem.1998,63,4554-4557.).Another kind of route of synthesis also is the 4-piperidone from amido protecting, but will use the poisonous reagent sodium cyanide, does not have practical value (1.Wysong, C.L.; Yokum, T.S.; Morales, G.A.; Gundry, R.L.; McLaughlin, M.L.and Hammer, R.P.J.Org.Chem.1996,61,7650-7651.2.Albert, J.S.; Aharony, D.; Andisik, D.; Barthlow, H.; Bernstein, P.R.; Bialecki, R.A.; Dedinas, R.; Et.al.J.Med.Chem.2002,45,3972-3983.).Also mentioning with the 4-piperidone in the document is raw material, generates 4-substituting group-4-ethanamide-piperidine derivative (Taylor, G.M. by grignard reaction and Ritter reaction; Baker, S.J.; Gedney, A.; Pearson, D.J.and Sibley, E.M.Tetrahedron Lett.1996,37,1297-1300.), the latter is hydrolyzed to our target compound again.But this method need be used a large amount of strong acid (the vitriol oil and the used concentrated hydrochloric acid of amide hydrolysis that the Ritter reaction is used); make the amino of piperidinyl-1 position can only select for use, prepare the range of application of the various bioactive molecules of structure thereby limited 4-substituting group-synthetic building block of 4-amino-piperadine derivatives conduct to the high stability protecting group of acid.
The present invention is a raw material with 4-piperidine carboxylic acid ester cheap and easy to get, can introduce different substituting groups neatly 4 of piperidines by nucleophilic substitution reaction, rearrangement reaction is converted into the 4-piperylhydrazine with the 4-piperidine carboxylic acid through Curtius again, thereby high-yield quick rate ground prepares the various 4-substituted-4-amino-piperidine derivative of structure under condition as mild as a dove.And the isocyanic ester that the Curtius rearrangement reaction produces can be hydrolyzed to free amine group under acidity or alkaline condition; therefore this method can prepare the 4-substituted-4-amino-piperidine derivative with different 1-bit amino protecting groups, to be applicable to the synthesis strategy of different activities molecule.The efficient preparation method easily of this important synthetic building block will go far towards the CCR5 inhibitor of different structure, deep malicious alkali M3 receptor antagonist, fentanyl class-opioid receptor agonist, and the acquisition and the structure activity study of the part of neurokinine-1/neurokinin-2 acceptor, have very application prospects.
Summary of the invention
An object of the present invention is to provide a kind of be used for synthetic all contain the bioactive molecules of 4-substituting group-4-substituted-amino-piperidines unit or 4-substituting group-piperidines-piperazine core texture.
Another object of the present invention provides the preparation method of above-mentioned synthetic building block.
A further object of the present invention provides the synthetic purposes of building block in pharmacy and chemical industry of such compound.
The invention provides the 4-substituted-4-amino-piperidines that has as shown in the formula (1) structure
In the formula:
R=hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heterocycle;
R '=tertbutyloxycarbonyl, carbobenzoxy-(Cbz), trifluoroacetyl oxygen base, acetoxyl group, benzyl, fluorenylmethyloxycarbonyl.
The present invention also provides the method that is prepared as follows with formula (1) structure 4-substituted-4-amino-piperidines:
1. be raw material with 4-piperidine carboxylic acid ester, under alkaline condition, introduce different substituting groups neatly 4 of piperidines by nucleophilic substitution reaction;
2. hydrolysis obtains corresponding 4-replacement-4-piperidine carboxylic acid;
3. obtain target compound through the 4 steps reaction (isobutyl chlorocarbonate activation, sodiumazide nucleophilic substitution, Curtius reset and be isocyanic ester, acid or basic hydrolysis) for the treatment of different things alike.
The present invention also provides 4-substituted-4-amino-piperidine derivatives shown in the formula (1) to synthesize the application of building block in pharmacy and chemical industry.
The bioactive molecules that application 4-substituting group-4-amino-piperadine derivatives contains 4-substituting group-4-amino piperidine-piperazine core as synthetic building block preparation has reaction efficiency height, Atom economy and reaches advantages such as environmentally friendly by force, has avoided the use of poisonous reagent diethyl cyano group aluminium in the bibliographical information method.
Describe the present invention below.
Following flow preparation is pressed in the synthetic building block of 4-substituted-4-amino-piperidine derivatives shown in the formula of the present invention (1):
R=hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heterocycle
R '=tertbutyloxycarbonyl, carbobenzoxy-(Cbz), trifluoroacetyl oxygen base, acetoxyl group, benzyl, fluorenylmethyloxycarbonyl
R "=C
1～C
6Alkyl, the alkyl that aryl or heteroatoms replace, aryl
The embodiment of above-mentioned flow process is listed below:
1,4-piperidine carboxylic acid ester in the presence of 1.5 normal diisopropylamine lithiums with the halohydrocarbon generation nucleophilic substitution reaction of 2.0 equivalent different structures, introduce corresponding substituting group in its 4-position;
2, hydrolysis gets corresponding 4-replacement-4-piperidine carboxylic acid in the methanol solution of 2 mol lithium hydroxides or sodium hydroxide;
3, the 4 steps reaction (isobutyl chlorocarbonate activation, sodiumazide nucleophilic substitution, Curtius reset be isocyanic ester, acid or basic hydrolysis) of 4-replacement-4-piperidine carboxylic acid through treating different things alike obtains target product.
Below introduce 4-substituting group-4-amino-piperadine derivatives is used to prepare the bioactive molecules that contains the piperazine-piperidine core as synthetic building block method.
Potent, oral absorbable aryl piperazines-piperidine amide compound is synthetic, as follows as the CCR5 antagonist:
Reagent and reaction conditions: (a) chloroacetyl chloride, 1, the 2-ethylene dichloride refluxes; (b) 1, diisopropyl ethyl amine, methyl alcohol refluxes; (c) (i) trifluoroacetic acid, methylene dichloride, room temperature; (ii) sodium borohydride, boron trifluoride diethyl etherate, glycol dimethyl ether refluxes; (d) phenylformic acid, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, I-hydroxybenzotriazole, diisopropyl ethyl amine, methylene dichloride, room temperature.
The amino of compound 5 obtains compound 6 through the acetylize of chloroacetyl chloride high productivity, and this is that we use synthetic building block and carry out another fragment of integrated type synthetic.Compound 6 mixes with synthetic building block 1, in the presence of organic bases such as diisopropyl ethyl amine, adds the 2 hydroxy pyrimidine of catalytic amount, is solvent with methyl alcohol or acetonitrile or toluene, but reflux just high productivity generate the core skeleton of pharmacophore.This shows, above-mentioned reaction is a key intermediate with 4-methyl-4-amino piperidine, utilize nucleophilic substitution reaction and one step of intramolecularly amidate action to make up the piperazine-piperidine core skeleton, efficient and succinct, do not use any poisonous reagent, have at aspects such as productive rate, step, operations previous method the superiority that can not compare.
Embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment never are any limitation of the invention.
The preparation of embodiment 14-amino-4-methyl-piperidines-1-carboxylic acid tert-butyl ester 1a
Step 1:N-tertbutyloxycarbonyl-4-piperidine methyl formate (compound 2)
With 4-nipecotic acid methyl ester hydrochloride (8.85g 49.3mmol) is dissolved in 1,4-dioxane (70.0mL)/water (24.0mL), (13.76mL 96.8mmol), stirred 15 minutes, in batches adding (Boc) to add triethylamine in the time of 0 ℃
2(11.3g 51.77mmol), is warming up to room temperature and continues to stir 6 hours O, concentrating under reduced pressure, remove 1,4-dioxane, resistates ethyl acetate extraction, merge organic phase, saturated sodium bicarbonate solution is washed, saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure gets colorless oil product 2 (11.98g, 100%).
1H?NMR(400MHz，CDCl
3)：δ4.03(dt，2H，J＝13.6，3.6Hz)；3.70(s，3H)；2.84(ddd，2H，J＝13.6，11.6，3.2Hz)；2.46(tt，1H，J＝11.2，4.0Hz)；1.91-1.86(m，2H)；1.68-1.58(m，2H)；1.48(s，9H).
Step 2:4-methyl-l-piperidines-1, the 4-dicarboxylic acid 1-tert-butyl ester-4-ethyl ester (compound 3a)
Under nitrogen protection, (11.06mL 78.88mmol) is dissolved in tetrahydrofuran (THF) (40.0mL) with diisopropylamine; cryosel is bathed and to be chilled to-15 ℃, and (46.0mL 73.6mmol) slowly drops in the system with the n-Butyl Lithium of 1.6 mol;-15 ℃ were stirred 1 hour, and made lithium diisopropyl amido.
Under nitrogen protection; with compound N-tertbutyloxycarbonyl-4-piperidine ethyl formate (12.59g; 49.0mmol) be dissolved in tetrahydrofuran (THF) (75.0mL), be cooled to-50 ℃, slowly drop to the lithium diisopropyl amido of above-mentioned preparation in the system;-50 ℃--40 ℃ were stirred after 1 hour; be cooled to-78 ℃, with methyl iodide (6.10mL, tetrahydrofuran (THF) 98.0mmol) (50.0mL) solution slowly drops in the system;-78 ℃ were stirred 1 hour; naturally be warming up to room temperature, thin-layer chromatography point plate is followed the tracks of to react to raw material and is all disappeared, and will react cancellation with the hydrochloric acid of 1 mol; concentrating under reduced pressure; remove tetrahydrofuran (THF), the resistates extracted with diethyl ether merges organic phase; the saturated common salt washing; anhydrous sodium sulfate drying concentrates column chromatography (petrol ether/ethyl acetate=10: 1); get colorless oil 3a (11.42g), productive rate 86.0%.
Step 3:4-methyl-l-piperidines-1, the 4-dicarboxylic acid list tert-butyl ester (compound 4a)
(5.77g 22.4mmol) is dissolved in methyl alcohol (20.0mL), under the room temperature condition with compound 3a, the lithium hydroxide solution (28.0mL) of 2 mol is dropped in the system stirring at room 1 hour, concentrating under reduced pressure, remove methyl alcohol, the resistates extracted with diethyl ether, organic phase is abandoned it, water is transferred pH to 3 with the hydrochloric acid of 1 mol, and dichloromethane extraction merges organic phase, the saturated common salt washing, anhydrous sodium sulfate drying concentrates, get white solid compound 4a (4.79g), productive rate 88.0%.
1H?NMR(400MHz，CDCl
3)：δ3.84-3.76(m，2H)；3.08-2.98(m，2H)；2.07(m，2H)；1.49(s，9H)；1.42-1.35(m，2H)；1.27(s，3H).EI-MS(M/Z，％)：243(M
+)；186(9.0)；170(13.0)；142(16.0)；57(100.0).IR(KBr)：3427，2976，1653，1443，1282，1173，1088，874，764cm
-1.
Step 4:4-amino-4-methyl-piperidines-1-carboxylic acid tert-butyl ester (compound 1a)
Compound 4a (1.215g, 5.0mmol) be dissolved in tetrahydrofuran (THF) (25.0mL), be cooled to-15 ℃, in system, drip N-methylmorpholine (0.58mL, 5.25mmol),-15 ℃ were stirred 15 minutes, and the dropping isobutyl chlorocarbonate (0.69mL, 5.25mmol),-15 ℃ were stirred 1 hour, (0 ℃ was stirred after 1.5 hours 0 ℃ of dropping sodiumazide for 0.488g, water 7.5mmol) (4.0mL) solution, reactant is poured in the frozen water, extracted with diethyl ether merges organic phase, and saturated sodium bicarbonate solution is washed, the saturated common salt washing, anhydrous sodium sulfate drying, under the room temperature condition, concentrating under reduced pressure obtains the oily trinitride.The crude product trinitride is dissolved in dry toluene (25.0mL), and 90 ℃ were stirred 1 hour, and concentrating under reduced pressure is removed toluene, obtains the oily isocyanic ester.Isocyanic ester is dissolved in the tetrahydrofuran (THF)/water (10mL/10mL) of ice, potassium hydroxide solution with 10 ice-cold mol in the time of 0 ℃ drops in the system, 0 ℃ was stirred 0.5 hour, the reaction solution rotary evaporation, resistates concentrates with methyl alcohol and washed with dichloromethane, organic phase, column chromatography (methylene chloride=30: 1), obtain white solid compound 1a (1.899g, 89.0%).
1H?NMR(400MHz，CDCl
3)：δ3.42(m，4H)；2.25(s，2H)；1.54-1.41(m，4H)；1.44(s，9H)；1.23(s，3H).EI-MS(m/z，％)：214(M
+，1.0)；197(6.0)；157(18.0)；141(56.0)；126(30.0)；57(100).HR-MS(EI)calcd?for?C
11H
22N
2O
2：214.1681，found?214.1686.
Target compound 1b-1d makes with similar approach.
The preparation of embodiment 2:4-amino-4-ethyl-piperidines-1-carboxylic acid tert-butyl ester 1b
Compound 3b, white solid, productive rate 83.0%.
1H?NMR(400MHz，CDCl
3)：δ3.85(m，2H)；3.70(s，3H)；2.83(m，2H)；2.07(m，2H)；1.52(q，2H，J＝7.6Hz)；1.42(s，9H)；1.34-1.26(dt，2H，J
1＝13.6，2.4Hz)；0.78(t，3H，J＝7.6Hz).EI-MS(m/z，％)：228(M
+)；214(31.0)；198(9.0)；170(23.0)；156(20.0)；140(3.0)；112(18.0)；57(100.0).IR(KBr)：3432，2964，1726，1682，1421，1367，1144，1020，866，771cm
-1.
Compound 4b, white solid, productive rate 85.0%.
1H?NMR(400MHz，CDCl
3)：δ3.90-3.86(m，2H)；2.97-2.90(m，2H)；2.1(m，2H)；1.60(q，2H，J＝7.6Hz)；1.44(s，9H)；1.38-1.32(m，2H)；0.9(t，3H，J＝7.6Hz).EI-MS(m/z，％)：257(M
+)；200(13.0)；184(15.0)；156(18.0)；112(11.0)；57(100.0).IR(KBr)：3432，2963，1686，1481，1279，1147，1014，860，731cm
-1.
Compound 1b, colorless oil, productive rate 79%.
1H?NMR(400MHz，CDCl
3)：δ3.59(br，2H)；3.2(m，2H)；1.47-1.44(m，2H)；1.41(s，9H)；1.36(q，2H，J＝7.6Hz)；1.31-1.25(m，2H)；1.12(br，2H)；0.87(t，3H，J＝7.6Hz).EI-MS(m/z，％)：228(M
+)；171(27.0)；155(72.0)；126(53.0)；110(12.0)；82(76.0)；57(100.0).IR(film)：3369，2966，2931，1689，1423，1245，1022，865，769cm
-1.Anal.calcd?for?C
12H
24N
2O
2·0.1H
2O：C?62.63，H10.60，N?12.17；Found?C?62.75，H?0.48，N?11.91.
The preparation of embodiment 3:4-amino-4-allyl group-piperidines-1-carboxylic acid tert-butyl ester 1c
Compound 3c, colorless oil, productive rate 91.0%.
1H?NMR(400MHz，CDCl
3)：δ5.74-5.64(m，1H)；5.11-5.04(m，2H)；3.89(dt，2H，J＝14.0，3.2Hz)；3.72(s，3H)；2.95-2.88(m，2H)；2.29(d，2H，J＝7.2Hz)；2.12-2.09(m，2H)；1.47(s，9H)；1.46-1.38(m，2H).EI-MS(m/z，％)：283(M
+，3.0)；227(17.0)；226(16.0)；210(12.0)；182(18.0)；168(100)；124(61.0)；57(84.0).IR(KBr)：2976，2868，1732，1693，1421，1217，918cm
-1.
Compound 4c, white solid, productive rate 91.0%.
1H?NMR(400MHz，CDCl
3)：δ5.71(ddt，1H，J＝17.2，10.0，7.6Hz)；5.10-5.05(m，2H)；3.89-3.85(m，2H)；2.99-2.92(m，2H)；2.31(d，2H，J＝7.6Hz)；2.08-2.04(m，2H)；1.44(s，9H)；1.42-1.35(m，2H).EI-MS(m/z，％)：269(M
+，10.0)；213(19.0)；226(16.0)；168(67.0)；124(45.0)；57(100.0).IR(KBr)：3421，2980，1718，1639，1448，1367，1170，865，740cm
-1.
Compound 1c, colorless oil, productive rate 65.0%.
1H?NMR(400MHz，CDCl
3)：δ5.82(ddt，1H，J＝16.8，10.0，7.6Hz)；5.16-5.07(m，2H)；5.63(br，2H)；3.26(ddd，2H，J＝13.6，10.0，3.6Hz)；2.12(d，2H，J＝7.6Hz)；1.47(s，9H)；1.55-1.33(m，6H).EI-MS(m/z，％)：241(M
+，2.0)；199(45.0)；167(15.0)；143(100.0)；126(13.0)；57(67.0).IR(film)：3365，3074，2976，2929，1689，1425，1365，1277，1247，1161，916，864，769cm
-1.Anal.calcd?for?C
13H
24N
2O
2·0.2H
2O：C?64.01，H?10.08，N?11.48；Found?C?63.95，H9.97，N?11.32.
The preparation of embodiment 4:4-amino-4-benzyl-piperidines-1-carboxylic acid tert-butyl ester 1d
Compound 3d, colorless oil, productive rate 97.0%.
1H?NMR(400MHz，CDCl
3)：δ7.28-7.19(m，3H)；7.03-7.00(m，2H)；3.92(dt，2H，J＝13.6，3.6Hz)；3.63(s，3H)；2.83-2.76(m，2H)；2.81(s，2H)；2.09-2.06(m，2H)；1.48-1.39(m，2H)；1.4(s，9H).EI-MS(M/Z，％)：333(M
+，1.0)；276(33.0)；233(37.0)；174(22.0)；91(24.0)；57(100).IR(KBr)：2974，1732，1693，1425，1172，743，702cm
-1.
Compound 4d, white solid, productive rate 84.0%.
1H?NMR(400MHz，CDCl
3)：δ7.28-7.24(m，3H)；7.12-7.10(m，2H)；3.97-3.94(m，2H)；2.91-2.85(m，4H)；2.08-2.05(m，2H)；1.50-1.41(m，2H)；1.46(s，9H).EI-MS(m/z，％)：319(M
+，2.0)；263(12.0)；262(6.0)；219(21.0)；218(13.0)；199(29.0)；143(58.0)；91(34.0)；57(100).IR(KBr)：3427，2978，1722，1635，1448，1167，860，704cm
-1.
Compound 1d, colorless oil, productive rate 85.0%.
1H?NMR(400MHz，CDCl
3)：δ7.32-7.23(m，3H)；7.17-7.15(m，2H)；3.75(br，2H)；3.20(m，2H)；2.67(s，2H)；1.61-1.48(m，2H)；1.45(s，9H)；1.16-1.13(m，2H)；1.12(br，2H).EI-MS(m/z，％)：291(M
++1，2.0)；233(1.0)；217(10.0)；199(100.0)；173(38.0)；106(82.0).IR(film)：3367，2976，2931，1682，1423，1246，766，704cm
-1.Anal.calcd?for?C
17H
26N
2O
2：C?70.31，H?9.02，N?9.65；Found?C?70.01，H?9.09，N?9.46.
The preparation of embodiment 5:4-amino-piperadine-1-carboxylic acid tert-butyl ester 1e
(1.99g 10.0mmol) and palladium/carbon of 10% (0.2g), adds saturated ammonia/methyl alcohol (20.0mL), and normal pressure hydrogenation obtains target compound 1e (1.671g, 84.0%) to add 4-piperidone-1-carboxylic acid tert-butyl ester in the single neck bottle of exsiccant 50mL.
1H?NMR(300MHz，CDCl
3)：δ4.04(br，2H)；2.84-2.74(m，3H)；1.46(s，9H)；1.45-1.38(s，3H)；1.30-1.21(m，2H).EI-MS(m/z，％)：200(M
+，4.0)；183(12.0)；143(34.0)；127(75.0)；57(100).HR-MS(EI)calcd?for?C
10H
20N
2O
2：200.1525，found?200.1520.
Embodiment 6:CCR5 inhibitor Sch-350634's is synthetic
Compound 6
In the single neck bottle of exsiccant 50mL, add compound 5 (0.479g, 1.74mmol) and anhydrous 1, adding chloroacetyl chloride under the 2-ethylene dichloride (15mL), room temperature condition (2.78mL, 34.8mmol), be warming up to 90 ℃, refluxed 1.5 hours, after reaction system concentrating under reduced pressure, resistates dilute with ether, the saturated sodium hydrogen carbonate solution that adds ice, the water extracted with diethyl ether merges organic phase, and saturated sodium bicarbonate solution is washed, the saturated common salt washing, anhydrous sodium sulfate drying concentrates column chromatography (petrol ether/ethyl acetate=3.5: 1), get white solid 6 (0.589g), productive rate 96.0%.
[α]
D 20＝-105(c＝0.55，CHCl
3).
1H?NMR(400MHz，CDCl
3)：δ7.65(m，4H)；5.28(q，1H，J＝7.2Hz)；4.19(q
AB，2H，J＝12.4Hz)；3.57(s，3H)；3.49(q，1H，J＝7.2Hz)；1.77(d，3H，J＝7.2Hz)；1.56(d，3H，J＝7.2Hz).EI-MS(M/Z，％)：353(M
++2，0.3)；351(M
+，1.0)；274(28.0)；266(12.0)；264(36.0)；173(100.0)；153(14.0).IR(KBr)：3467，3037，2958，1741，1633，1437，1329，1242，1121，1068，841，613cm
-1.
Compound 7
In the single neck bottle of exsiccant 25mL, add compound 6 (0.261g, 0.74mmol), synthetic building block 1a (0.179g, 0.84mmol) and anhydrous acetonitrile (5mL), under the room temperature condition, the adding diisopropyl ethyl amine (0.167mL, 0.96mmol), backflow is spent the night, concentrate, resistates is dissolved in dry toluene (1.5mL), adds dihydroxy-pyridine (0.18g), 90 ℃ were reacted 6 hours, system concentrates, column chromatography (petrol ether/ethyl acetate=1: 1) gets white solid foam 7 (0.244g), productive rate 67.0%.
[α]
D 20＝-19(c＝0.565，CHCl
3).
1H?NMR(400MHz，CDCl
3)：δ7.60(d，2H，J＝8.0Hz)；7.36(d，2H，J＝8.0Hz)；5.82(q，1H，J＝7.2Hz)；4.06(d，1H，J＝16.4Hz)；3.91(d，1H，J＝16.4Hz)；3.64(q，1H，J＝7.2Hz)；3.59-3.48(m，2H)；3.26-3.11(m，2H)；2.44-2.39(m，1H)；2.26-2.21(m，1H)；1.79-1.68(m，2H)；1.66-1.62(m，3H)；1.48(d，3H，J＝7.2Hz)；1.47(s，9H)；1.36(s，3H).EI-MS(m/z，％)：497(M
+)；441(56.0)；424(11.0)；301(23.0)；173(18.0)；96(100).IR(KBr)：3400，2980，2862，1684，1653，1414，1327，1140，1173cm
-1.
Compound 8
(0.146g 0.29mmol) is dissolved in methylene dichloride (3.0mL), adds trifluoroacetic acid (3.0mL) during room temperature with compound 7, stirring at room 2 hours, system concentrates, after resistates dilutes with ethyl acetate, the sodium hydroxide that adds 2 mol, the water ethyl acetate extraction merges organic phase, saturated sodium bicarbonate is washed, the saturated salt washing, anhydrous sodium sulfate drying concentrates, not purified, directly next step reaction.(0.117g 0.29mmol) is dissolved in glycol dimethyl ether (5mL), adds sodium borohydride (0.111g with the crude product piperidone, 2.94mmol), (0.23mL 1.76mmol), refluxes after 3 hours to add boron trifluoride diethyl etherate during room temperature, be cooled to 0 ℃, slowly add methyl alcohol (3.6mL) and concentrated hydrochloric acid (2.1mL) in system, stirring at room 15 minutes refluxed 45 minutes then, concentrating under reduced pressure is removed methyl alcohol, resistates is transferred alkalescence with the sodium hydroxide of 6 mol, and the water ethyl acetate extraction merges organic phase, the saturated salt washing, anhydrous sodium sulfate drying concentrates, and obtains compound 8, not purified, directly next step reaction.
Compound S ch-350634
Crude product compound 8 (0.107g, 0.29mmol), 2,4-dimethyl nicotinic acid-N-oxide compound (0.073g, 0.44mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.084g, 0.44mmol), I-hydroxybenzotriazole (0.059g, 0.44mmol) and diisopropyl ethyl amine (0.51mL) add in the single neck bottle of 25mL, add anhydrous methylene chloride (5.0mL), stirred overnight at room temperature concentrates column chromatography (methylene chloride=30: 1), get white solid foam Sch-350634 (0.085g), three step yields 64%.
[α]
D 20＝+9.08(c＝0.93，CHCl
3).
1H?NMR(300MHz，CDCl
3)：δ8.16(d，1H，J＝6.6Hz)；7.53(m，4H)；7.00(d，1H，J＝6.9Hz)；4.22(brt，1H)；3.98(brs，1H)；3.40(m，2H)；2.99(m，2H)；2.67-2.57(m，1H)；2.46(d，3H，J＝9.9Hz)；2.41-2.27(m，4H)；2.26(d，3H，J＝9.0Hz)；2.01(brt，1H)；1.82-1.72(m，2H)；1.46-1.25(m，2H)；1.29(d，3H，J＝6.9Hz)；1.14(d，3H，J＝6.3Hz)；0.93(s，3H).EI-MS(M/Z，％)：518(M
+，0.5)；516(2.0)；502(44.0)；501(100.0)；487(12.0)；328(62.0)；271(46.0)；260(38.0)；231(60.0)；173(36.0)；134(68.0).
Claims (5)
1. the preparation method of 4-substituted-4-amino-piperidines as the formula (1),
In the formula:
R=hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heterocycle;
R '=tertbutyloxycarbonyl, carbobenzoxy-(Cbz), trifluoroacetyl oxygen base, acetoxyl group, benzyl, fluorenylmethyloxycarbonyl;
It is characterized in that: with 4-piperidine carboxylic acid ester is raw material, and nucleo philic substitution reaction obtains the substituent 4-piperidinecarboxylatderivatives derivatives of 4-position different structure, makes the synthetic building block of 4-substituting group-4-amino-piperadine derivatives through Curtius rearrangement reaction and hydrolysis again.
2. according to the preparation method of the described 4-substituted-4-amino-piperidines of claim 1, the general formula of the raw material 4-piperidine carboxylic acid ester that it adopts is as shown in the formula shown in (2):
Wherein:
R ' is a tertbutyloxycarbonyl, carbobenzoxy-(Cbz), trifluoroacetyl oxygen base, acetoxyl group, benzyl, fluorenylmethyloxycarbonyl;
R " be C
1～C
6Alkyl.
3. according to the preparation method of the described 4-substituted-4-amino-piperidines of claim 1, wherein 4-piperidine carboxylic acid ester carries out the condition of nucleophilic substitution reaction for alkaline.
4. according to the preparation method of the described 4-substituted-4-amino-piperidines of claim 1; before carrying out the Curtius reaction, the following treatment step of process: methyl-chloroformate, Vinyl chloroformate, propyl chloroformate, isopropyl chlorocarbonate, butyl chlorocarbonate or isobutyl chlorocarbonate activation, azide metal salt nucleophilic substitution form acyl azide.
5. 4-substituting group shown in the formula (the 1)-application of the synthetic building block of 4-amino-piperadine derivatives conduct in synthesizing the compound that contains piperidines-piperazine twin nuclei,
In the formula:
R=hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heterocycle;
R '=tertbutyloxycarbonyl, carbobenzoxy-(Cbz), trifluoroacetyl oxygen base, acetoxyl group, benzyl, fluorenylmethyloxycarbonyl.
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2004
- 2004-05-11 CN CN2004100182307A patent/CN1696115B/en not_active Expired - Fee Related
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| DE4405140A1 (en) * | 1994-02-18 | 1995-08-24 | Hoechst Ag | Complexing agent for nuclides that can be used in nuclear medicine, process for producing the complexes, and diagnostic agent containing these complexes |
| WO2000075137A1 (en) * | 1999-06-02 | 2000-12-14 | Janssen Pharmaceutica N.V. | Pyrrolidinyl, piperidinyl or homopiperidinyl substituted (benzodioxan, benzofuran or benzopyran) derivatives |
| WO2002048117A1 (en) * | 2000-12-11 | 2002-06-20 | Fujisawa Pharmaceutical Co., Ltd. | Quinazolinone derivatives |
| WO2002051836A1 (en) * | 2000-12-27 | 2002-07-04 | Kyowa Hakko Kogyo Co., Ltd. | Dipeptidyl peptidase iv inhibitor |
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