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CN1696115B - Synthetic building block 4-substituent-4-amino-piperidine derivative, its preparation method and use - Google Patents

  • ️Wed Jun 09 2010
Synthetic building block 4-substituent-4-amino-piperidine derivative, its preparation method and use Download PDF

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Publication number
CN1696115B
CN1696115B CN2004100182307A CN200410018230A CN1696115B CN 1696115 B CN1696115 B CN 1696115B CN 2004100182307 A CN2004100182307 A CN 2004100182307A CN 200410018230 A CN200410018230 A CN 200410018230A CN 1696115 B CN1696115 B CN 1696115B Authority
CN
China
Prior art keywords
amino
piperidines
preparation
substituted
building block
Prior art date
2004-05-11
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN2004100182307A
Other languages
Chinese (zh)
Other versions
CN1696115A (en
Inventor
龙亚秋
姜晓华
宋艳丽
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Materia Medica of CAS
Original Assignee
Shanghai Institute of Materia Medica of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
2004-05-11
Filing date
2004-05-11
Publication date
2010-06-09
2004-05-11 Application filed by Shanghai Institute of Materia Medica of CAS filed Critical Shanghai Institute of Materia Medica of CAS
2004-05-11 Priority to CN2004100182307A priority Critical patent/CN1696115B/en
2005-11-16 Publication of CN1696115A publication Critical patent/CN1696115A/en
2010-06-09 Application granted granted Critical
2010-06-09 Publication of CN1696115B publication Critical patent/CN1696115B/en
2024-05-11 Anticipated expiration legal-status Critical
Status Expired - Fee Related legal-status Critical Current

Links

  • 238000002360 preparation method Methods 0.000 title claims abstract description 21
  • 150000001875 compounds Chemical class 0.000 claims abstract description 20
  • SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical class OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 claims abstract description 11
  • 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
  • 238000006969 Curtius rearrangement reaction Methods 0.000 claims abstract description 5
  • 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 5
  • 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 5
  • 125000001424 substituent group Chemical group 0.000 claims abstract description 4
  • -1 4-substituted-4-amino-piperidines Chemical class 0.000 claims description 25
  • 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 10
  • 238000000034 method Methods 0.000 claims description 9
  • 125000003118 aryl group Chemical group 0.000 claims description 7
  • 230000007062 hydrolysis Effects 0.000 claims description 6
  • 238000006460 hydrolysis reaction Methods 0.000 claims description 6
  • 239000002994 raw material Substances 0.000 claims description 6
  • SNOFKGQEUYMNCE-UHFFFAOYSA-N 2,2,2-trifluoro-1-$l^{1}-oxidanylethanone Chemical compound [O]C(=O)C(F)(F)F SNOFKGQEUYMNCE-UHFFFAOYSA-N 0.000 claims description 5
  • 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
  • 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims description 5
  • 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
  • YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 4
  • UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
  • 125000000623 heterocyclic group Chemical group 0.000 claims description 4
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  • 229910052739 hydrogen Inorganic materials 0.000 claims description 4
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  • PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 claims 1
  • 239000002184 metal Substances 0.000 claims 1
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  • QQKDTTWZXHEGAQ-UHFFFAOYSA-N propyl carbonochloridate Chemical compound CCCOC(Cl)=O QQKDTTWZXHEGAQ-UHFFFAOYSA-N 0.000 claims 1
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  • BCIIMDOZSUCSEN-UHFFFAOYSA-N piperidin-4-amine Chemical class NC1CCNCC1 BCIIMDOZSUCSEN-UHFFFAOYSA-N 0.000 abstract 1
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  • 230000000975 bioactive effect Effects 0.000 description 5
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  • 239000002253 acid Substances 0.000 description 4
  • LMRCKXYHPYNEJV-UHFFFAOYSA-N piperazine;piperidine Chemical compound C1CCNCC1.C1CNCCN1 LMRCKXYHPYNEJV-UHFFFAOYSA-N 0.000 description 4
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  • 238000005984 hydrogenation reaction Methods 0.000 description 1
  • 150000002466 imines Chemical class 0.000 description 1
  • INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
  • XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 1
  • 239000002547 new drug Substances 0.000 description 1
  • 238000005935 nucleophilic addition reaction Methods 0.000 description 1
  • 239000003921 oil Substances 0.000 description 1
  • 239000003402 opiate agonist Substances 0.000 description 1
  • 150000007530 organic bases Chemical class 0.000 description 1
  • 239000012071 phase Substances 0.000 description 1
  • XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
  • 230000003389 potentiating effect Effects 0.000 description 1
  • GGOZGYRTNQBSSA-UHFFFAOYSA-N pyridine-2,3-diol Chemical compound OC1=CC=CN=C1O GGOZGYRTNQBSSA-UHFFFAOYSA-N 0.000 description 1
  • VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
  • 239000000376 reactant Substances 0.000 description 1
  • 238000006462 rearrangement reaction Methods 0.000 description 1
  • RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
  • 238000002390 rotary evaporation Methods 0.000 description 1
  • 239000002904 solvent Substances 0.000 description 1
  • 238000001228 spectrum Methods 0.000 description 1
  • 208000018556 stomach disease Diseases 0.000 description 1
  • 208000011580 syndromic disease Diseases 0.000 description 1
  • 238000004809 thin layer chromatography Methods 0.000 description 1

Classifications

    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Landscapes

  • Hydrogenated Pyridines (AREA)

Abstract

本发明揭示了一种新的合成砌块，即具有不同结构4位取代基的4-氨基-哌啶衍生物以及它的便捷实用的制备方法和用途。价廉易得的4-哌啶甲酸经氨基和羧基保护后经烷基化反应能得到4-位不同结构取代基的4-哌啶甲酸衍生物，再经过Curtius重排反应高产率地制备4-取代基-4-氨基-哌啶衍生物。这一合成砌块是制备许多活性化合物的关键中间体。我们发明的这一高效温和的制备方法应用于范围广泛的4-取代基-4-氨基-哌啶，而且哌啶1-位氨基的保护基可选用与合成途径相适应的任何基团，通式中的R代表烷基、烷氧基或含杂原子的取代烷基；取代芳基；杂环取代基等。这一合成砌块可用于诸多活性分子，如CCR5抑制剂、覃毒碱M3受体拮抗剂、芬太尼类μ-阿片受体激动剂，以及神经激肽-1受体的配体的合成。The invention discloses a new synthetic building block, that is, 4-amino-piperidine derivatives with different structural 4-position substituents, as well as its convenient and practical preparation method and application. 4-piperidinecarboxylic acid derivatives with different structural substituents at the 4-position can be obtained by alkylation reaction after protecting the amino and carboxyl groups of cheap and easy-to-obtain 4-piperidinecarboxylic acid derivatives, and then prepare 4-piperidinecarboxylic acid derivatives with high yield through Curtius rearrangement reaction - Substituents - 4-amino-piperidine derivatives. This synthetic building block is a key intermediate for the preparation of many active compounds. This efficient and mild preparation method invented by us is applicable to a wide range of 4-substituents-4-amino-piperidines, and the protecting group of the 1-amino group of piperidines can be selected from any group that is compatible with the synthetic route. R in the formula represents an alkyl group, an alkoxy group or a substituted alkyl group containing a heteroatom; a substituted aryl group; a heterocyclic substituent, etc. This synthetic building block can be used in the synthesis of many active molecules, such as CCR5 inhibitors, murine M3 receptor antagonists, fentanyl-like μ-opioid receptor agonists, and ligands for neurokinin-1 receptors .

Description

Synthetic building block 4-substituting group-4-amino-piperadine derivatives, Preparation Method And The Use

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.

Figure G2004100182307D00011

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):

Figure G2004100182307D00051

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:

Figure G2004100182307D00052

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%.

Figure G2004100182307D00111

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%.

Figure G2004100182307D00122

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

Figure G2004100182307D00123

(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

Figure G2004100182307D00141

(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),

Figure F2004100182307C00011

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):

Figure F2004100182307C00012

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,

Figure F2004100182307C00021

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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