CN109369497B - A kind of synthetic method of N-pyrrolyl piperidine compounds - Google Patents
A kind of synthetic method of N-pyrrolyl piperidine compounds Download PDFInfo
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- CN109369497B CN109369497B CN201811414675.5A CN201811414675A CN109369497B CN 109369497 B CN109369497 B CN 109369497B CN 201811414675 A CN201811414675 A CN 201811414675A CN 109369497 B CN109369497 B CN 109369497B
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- pyrrolylpiperidine
- ethyl acetate
- piperidine
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- FYNZLNTWHGFUEV-UHFFFAOYSA-N 1-(1h-pyrrol-2-yl)piperidine Chemical class C1CCCCN1C1=CC=CN1 FYNZLNTWHGFUEV-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 238000010189 synthetic method Methods 0.000 title claims description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 74
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 68
- 238000000034 method Methods 0.000 claims abstract description 37
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims abstract description 32
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000001301 oxygen Substances 0.000 claims abstract description 29
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 29
- -1 N-substituted piperidine Chemical class 0.000 claims abstract description 22
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 17
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 9
- 239000000654 additive Substances 0.000 claims abstract description 7
- 229940125782 compound 2 Drugs 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- 229950000077 iodol Drugs 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 150000001879 copper Chemical class 0.000 claims abstract description 5
- VJOVAKSZILJDBB-UHFFFAOYSA-N iodol Chemical compound IC=1NC(I)=C(I)C=1I VJOVAKSZILJDBB-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229940126214 compound 3 Drugs 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 75
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical class [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 27
- 229910052740 iodine Inorganic materials 0.000 claims description 27
- 239000011630 iodine Substances 0.000 claims description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 15
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical group [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 230000000996 additive effect Effects 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 239000003446 ligand Substances 0.000 claims description 4
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical group [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 claims description 3
- 229910001511 metal iodide Chemical class 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical group I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims 1
- 229940045803 cuprous chloride Drugs 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 13
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000000758 substrate Substances 0.000 abstract description 3
- 238000005899 aromatization reaction Methods 0.000 abstract description 2
- 238000005859 coupling reaction Methods 0.000 abstract description 2
- 230000006324 decarbonylation Effects 0.000 abstract description 2
- 238000006606 decarbonylation reaction Methods 0.000 abstract description 2
- 238000006356 dehydrogenation reaction Methods 0.000 abstract description 2
- 230000001590 oxidative effect Effects 0.000 abstract description 2
- GNEDCDOSYXWZDO-UHFFFAOYSA-N 2-iodo-1h-pyrrole Chemical class IC1=CC=CN1 GNEDCDOSYXWZDO-UHFFFAOYSA-N 0.000 abstract 1
- 125000002346 iodo group Chemical group I* 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 162
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 64
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
- 238000001035 drying Methods 0.000 description 27
- 238000001914 filtration Methods 0.000 description 27
- 239000012074 organic phase Substances 0.000 description 27
- 238000000926 separation method Methods 0.000 description 27
- 239000000741 silica gel Substances 0.000 description 27
- 229910002027 silica gel Inorganic materials 0.000 description 27
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 27
- 239000003208 petroleum Substances 0.000 description 25
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 15
- 238000012512 characterization method Methods 0.000 description 15
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 229930182821 L-proline Natural products 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 229960002429 proline Drugs 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- QRDAPCMJAOQZSU-KQQUZDAGSA-N (e)-3-[4-[(e)-3-(3-fluorophenyl)-3-oxoprop-1-enyl]-1-methylpyrrol-2-yl]-n-hydroxyprop-2-enamide Chemical compound C1=C(\C=C\C(=O)NO)N(C)C=C1\C=C\C(=O)C1=CC=CC(F)=C1 QRDAPCMJAOQZSU-KQQUZDAGSA-N 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- REDUQXCPUSNJOL-UHFFFAOYSA-N C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O Chemical compound C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O REDUQXCPUSNJOL-UHFFFAOYSA-N 0.000 description 2
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 2
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 2
- KSCRVOKQPYZBHZ-IXPOFIJOSA-N benzyl n-[(2s)-1-[[(2s)-1-[[(2s)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@H]1C(NCC1)=O)C(=O)C=1SC2=CC=CC=C2N=1)C(C)C)C(=O)OCC1=CC=CC=C1 KSCRVOKQPYZBHZ-IXPOFIJOSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- VPMIAOSOTOODMY-KJAPKAAFSA-N (4r)-6-[(e)-2-[6-tert-butyl-4-(4-fluorophenyl)-2-propan-2-ylpyridin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1/C=C/C=1C(C(C)C)=NC(C(C)(C)C)=CC=1C1=CC=C(F)C=C1 VPMIAOSOTOODMY-KJAPKAAFSA-N 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- DKNPRRRKHAEUMW-UHFFFAOYSA-N Iodine aqueous Chemical compound [K+].I[I-]I DKNPRRRKHAEUMW-UHFFFAOYSA-N 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- BGDKAVGWHJFAGW-UHFFFAOYSA-N Tropicamide Chemical compound C=1C=CC=CC=1C(CO)C(=O)N(CC)CC1=CC=NC=C1 BGDKAVGWHJFAGW-UHFFFAOYSA-N 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- 229960004791 tropicamide Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了一种N‑吡咯基哌啶类化合物的合成方法，属于有机合成技术领域。N‑取代哌啶1加入溶剂中，在醋酸铜、4‑二甲氨基吡啶和添加剂存在下，在氧气中加热反应得到碘代吡咯类化合物2；第二步、将化合物2、铜盐、配体、碱和哌啶混和，加热反应得到N‑吡咯基哌啶类化合物3。该方法通过N‑取代哌啶类化合物的氧化缩环、脱羰、脱氢、芳构化和β位碘代等一系列串联反应合成碘代吡咯类化合物，然后通过碘代吡咯与哌啶的偶联反应得到N‑吡咯基哌啶类化合物，具有原料简单、操作简便、条件温和、底物适用范围广等优点，为N‑吡咯基哌啶类化合物的合成提供了一种经济实用且绿色环保的新方法。The invention discloses a method for synthesizing N-pyrrolylpiperidine compounds, and belongs to the technical field of organic synthesis. N-substituted piperidine 1 is added to a solvent, and in the presence of copper acetate, 4-dimethylaminopyridine and additives, the reaction is heated in oxygen to obtain iodopyrrole compound 2; in the second step, compound 2, copper salt, compound The compound, base and piperidine are mixed, and the N-pyrrolylpiperidine compound 3 is obtained by heating reaction. In this method, iodopyrrole compounds are synthesized through a series of series reactions such as oxidative ring condensation, decarbonylation, dehydrogenation, aromatization and β-position iodo of N-substituted piperidine compounds, and then through the synthesis of iodopyrrole and piperidine. The coupling reaction obtains N-pyrrolylpiperidine compounds, which has the advantages of simple raw materials, simple operation, mild conditions, and wide application range of substrates, and provides an economical, practical and green method for the synthesis of N-pyrrolylpiperidine compounds. A new way to be environmentally friendly.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of an N-pyrrolylpiperidine compound.
Background
Pyrrole and piperidine, two important nitrogen-containing heterocyclic structural units, are ubiquitous in natural products and are effective components of many Chinese herbal medicines. In addition, many artificially designed and synthesized pyrrole and piperidine derivatives have become widely used drugs (such as tolmetin, sunitinib, atorvastatin, tropicamide and irinotecan) in clinic, and make important contributions to human health and civilization progress. Therefore, the synthesis and application research of pyrrole and piperidine compounds is an important research content in the fields of synthetic chemistry, pharmaceutical chemistry, biochemistry and the like.
On the other hand, different kinds of heterocycles such as pyrrole are introduced to the piperidine ring, that is, a hybrid of two or more nitrogen-containing heterocycles is synthesized, and the improvement and adjustment of the biological activity and the luminescence property of the original parent heterocyclic compound are finally realized through introducing a new dominant structure and changing the polarity, the electrical property and the solubility property of the original heterocycle. In addition, the introduction of a new heterocyclic ring can provide a new reaction site, so that the reaction performance of the piperidine compound is further enriched. It should be noted that although N-pyrrolylpiperidine compounds have important application value, the current methods for synthesizing the compounds are very limited, and the methods often have the problems of poor regioselectivity, complicated operation, use of expensive metal catalysts and the like. Therefore, research and development of a novel method for synthesizing the N-pyrrolylpiperidine compound by using a simple and easily available reagent as a raw material through relatively simple and convenient operation steps have important theoretical significance and important application value.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a synthesis method of an N-pyrrolylpiperidine compound, which comprises the steps of synthesizing an iodopyrrole compound through a series of series reactions of oxidative ring shrinkage, decarbonylation, dehydrogenation, aromatization, beta-position iodine substitution and the like of an N-substituted piperidine compound, and obtaining the N-pyrrolylpiperidine compound through the coupling reaction of iodopyrrole and piperidine. Has the advantages of simple and convenient operation, mild condition, wide substrate application range and the like, and is suitable for industrial production.
The invention adopts the following technical scheme for solving the technical problems, and the synthesis method of the N-pyrrolylpiperidine compound is characterized by comprising the following steps:
firstly, adding N-substituted piperidine 1 into a solvent, and heating in oxygen in the presence of copper acetate, 4-Dimethylaminopyridine (DMAP) and an additive to react to generate iodopyrrole compound 2. The reaction equation is:
and secondly, mixing the compound 2, copper salt, ligand, alkali and piperidine, and heating for reaction to obtain the N-pyrrolylpiperidine compound 3. The reaction equation is:
wherein: r1Is phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is fluorine, chlorine, bromine or C1-4One or more of alkyl or alkoxy, R2Is hydrogen, phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is fluorine, chlorine, bromine or C1-4One or more of alkyl or alkoxy.
Further, in the first step, the solvent for the reaction serves to dissolve the raw materials, and acetonitrile, dichloroethane, 1, 4-dioxane, N-dimethylformamide, or dimethylsulfoxide is preferable.
Further, in the first step, the additive is elemental iodine or an iodinated metal salt. The metal iodide salt is lithium iodide, sodium iodide or potassium iodide. Elemental iodine and potassium iodide are preferred.
Further, in the first step, the reaction is carried out under an oxygen atmosphere of 1 to 2 atm.
Further, in the first step and the second step, the reaction temperature is 40-100 ℃.
Further, in the first step, the ratio of the amount of the N-substituted piperidine 1, the copper acetate, the additive and the 4-dimethylamino pyridine is 1:1-2:0.25-1: 0.5-2.
Further, in the second step, the copper salt is CuI, CuBr or CuCl. The ligand is L-proline.
Further, in the second step, the reaction is carried out in a solvent selected from DMF, DMSO or 1, 4-dioxane.
Further, in the second step, the base is cesium fluoride or cesium carbonate.
Compared with the prior art, the invention has the following advantages: (1) the synthesis process is simple and efficient; (2) the raw materials are simple, cheap and easily available; (3) the reaction condition is mild, and the operation is simple and convenient; (4) the application range of the substrate is wide. Therefore, the invention provides a novel method which is economical, practical, green and environment-friendly for the synthesis of the N-pyrrolylpiperidine compound.
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
Example 1
1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and 4-dimethylaminopyridine (DMAP,0.5mmol,61mg) were added in this order to a 10mL Schlenk's tube, and after vacuum and oxygen charging (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (87mg, 65%). 2a (0.3mmol,81mg), CuI (0.03mmol,5.7mg), L-proline (0.03mmol,3.5mg) and cesium fluoride (0.6mmol,91mg) were placed in a 10mL Schlenk tube, evacuated and charged with nitrogen, then piperidine (0.6mmol,51mg) and DMSO (3mL) were added to the system, warmed to 50 ℃ and reacted for 24 h. The reaction system was worked up to give the desired product 3a (43mg, 63%). Characterization data for compound 2a are as follows:1H NMR(400MHz,CDCl3)δ6.42(t,J＝1.2Hz,1H),6.96(t,J＝2.0Hz,1H),7.13(t,J＝2.0Hz,1H),7.28(t,J＝7.2Hz,1H),7.34(d,J＝7.6Hz,2H),7.43(t,J＝7.6Hz,2H).13C NMR(100MHz,CDCl3)δ62.0,117.6,120.6,121.2,124.2,126.4,129.7,139.9.MS(EI):269[M]+.
example 2
1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine simple substance (0.125mmol,32mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum-charging oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (34mg, 25%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 3
1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine simple substance (0.25mmol,64mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum-charging oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (69mg, 51%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 4
1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine simple substance (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum-charging oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (61mg, 45%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 5
To a 10mL Schlenk tube were added 1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), potassium iodide (0.5mmol,83mg) and DMAP (0.25mmol,31mg) in this order, and after evacuation and charging with oxygen (1atm), the mixture was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (41mg, 30%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 6
To a 10mL Schlenk tube were added 1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), potassium iodide (0.5mmol,83mg) and DMAP (0.5mmol,61mg) in this order, and after evacuation and charging with oxygen (1atm), the mixture was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (54mg, 40%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 7
To a 10mL Schlenk tube were added 1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), potassium iodide (0.5mmol,83mg) and DMAP (1mmol,122mg) in this order, and after applying vacuum and charging oxygen (1atm), the mixture was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (53mg, 39%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 8
1a (0.5mmol,81mg), dichloroethane (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine simple substance (0.25mmol,64mg) and DMAP (0.5mmol,61mg) were sequentially added to a 10mL Schlenk's tube, and after vacuum-pumping and oxygen-charging (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (17mg, 13%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 9
1a (0.5mmol,81mg), 1, 4-dioxane (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine simple substance (0.25mmol,64mg) and DMAP (0.5mmol,61mg) were sequentially added to a 10mL Schlenk's tube, and after vacuum evacuation and oxygen charging (1atm), it was placed in an 80 ℃ oil bath and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (20mg, 15%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 10
1a (0.5mmol,81mg), N-dimethylformamide (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine simple substance (0.25mmol,64mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk's tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (23mg, 17%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 11
1a (0.5mmol,81mg), dimethyl sulfoxide (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine simple substance (0.25mmol,64mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum evacuation and oxygen charging (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (23mg, 17%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 12
To a 10mL Schlenk tube, 1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine (0.25mmol,64mg) and DMAP (0.5mmol,61mg) were added in this order, and after evacuation and charging of oxygen (1atm), they were placed in a 40 ℃ oil bath and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (11mg, 8%).
Example 13
To a 10mL Schlenk tube, 1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine (0.25mmol,64mg) and DMAP (0.5mmol,61mg) were added in this order, and after vacuum-charging oxygen (1atm), the mixture was placed in a 100 ℃ oil bath and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (15mg, 11%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 14
To a 10mL Schlenk tube, 1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine (0.25mmol,64mg) and DMAP (0.5mmol,61mg) were added in this order, and after vacuum and nitrogen gas charging, they were placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (17mg, 13%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 15
1b (0.5mmol,90mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petrol ether/ethyl acetate 100/1) gave product 2b as a brown solid (95mg, 66%). According to the method of example 1, 2b can be converted to 3b in 60% yield. Characterization data for compound 2b are as follows:1H NMR(400MHz,CDCl3)δ6.33(d,J＝1.6Hz,1H),6.80(t,J＝2.4Hz,1H),6.97(s,1H),7.02-7.06(m,2H),7.20-7.23(m,2H).13C NMR(150MHz,CDCl3)δ62.0,116.5(d,2JC-F＝23.1Hz),117.7,121.5,122.5(d,3JC-F＝8.9Hz),124.5,136.3(d,4JC-F＝2.3Hz),161.0(d,1JC-F＝245.1Hz).19F NMR(376MHz,CDCl3)δ-115.78.MS(EI):287[M]+.
example 16
1c (0.5mmol,98g), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and column separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2c (103mg, 68%). 2c can be converted to 3c according to the method of example 1. Characterization data for compound 2c are as follows:1H NMR(600MHz,CDCl3)δ6.42(d,J＝0.6Hz,1H),6.91(t,J＝2.4Hz,1H),7.08(s,1H),7.27(d,J＝8.4Hz,2H),7.39(d,J＝9.0Hz,2H).13C NMR(150MHz,CDCl3)δ62.5,118.0,121.1,121.7,124.1,129.8,131.9,138.4.
example 17
1d (0.5mmol,120mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtering, and carrying out spin-drying,separation on silica gel column (petroleum ether/ethyl acetate 100/1) gave compound 2d (106mg, 61%). 2d can be converted to 3d according to the method of example 1. Characterization data for compound 2d are as follows:1H NMR(600MHz,CDCl3)δ6.42(s,1H),6.91(s,1H),7.09(s,1H),7.21(d,J＝7.2Hz,2H),7.54(d,J＝7.8Hz,2H).13C NMR(100MHz,CDCl3)δ62.6,118.1,119.5,121.0,122.0,124.0,132.8,138.8.
example 18
1e (0.5mmol,88mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2e (83mg, 59%). 2e (0.5mmol,141mg), CuI (0.05mmol,9.5mg), L-proline (0.05mmol,5.8mg) and cesium fluoride (1mmol,152mg) were placed in a 10mL Schlenk tube, evacuated and charged with nitrogen, then piperidine (1mmol,85mg) and DMSO (5mL) were added to the system, warmed to 50 ℃ and reacted for 24 h. The reaction system was worked up to give the desired product 3e (73mg, 61%). Characterization data for compound 2e are as follows:1H NMR(600MHz,CDCl3)δ2.37(s,3H),6.39(dd,J1＝3.0Hz,J2＝1.2Hz,1H),6.91(t,J＝2.4Hz,1H),7.08(d,J＝1.8Hz,1H),7.22(s,4H).13C NMR(100MHz,CDCl3) δ 20.9,61.5,117.3,120.5,121.3,124.2,130.2,136.2,137.6 characterization data for compound 3e are as follows:1H NMR(600MHz,CDCl3)δ1.45-1.49(m,2H),1.63-1.67(m,4H),2.27(s,3H),2.88(t,J＝5.4Hz,4H),6.02(t,J＝2.4Hz,1H),6.46(t,J＝1.8Hz,1H),6.85(t,J＝2.4Hz,1H),7.10(d,J＝8.4Hz,2H),7.15(d,J＝8.4Hz,2H).13C NMR(150MHz,CDCl3)δ20.8,24.2,25.7,52.1,101.9,103.4,118.1,119.4,130.0,134.3,138.7,142.5.HRMS calcd for C16H20N2Na:263.1519[M+Na]+,found:263.1521.
example 19
1f (0.5mmol,95mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2f (92mg, 62%). 2f can be converted to 3f according to the methods of example 1 and example 18. Characterization data for compound 2f are as follows:1H NMR(600MHz,CDCl3)δ1.25(t,J＝7.8Hz,3H),2.67(q,J＝7.8Hz,2H),6.40(t,J＝1.8Hz,1H),6.92(d,J＝2.4Hz,1H),7.09(s,1H),7.24(s,4H).13C NMR(150MHz,CDCl3)δ15.6,28.3,61.5,117.3,120.7,121.3,124.3,129.0,137.8,142.6.
example 20
To a 10mL Schlenk tube were added 1g (0.5mmol,96mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) in this order, and after evacuation and charging of oxygen (1atm), the mixture was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave 2g (75mg, 50%). According to the method of example 1 and example 18, 2g can be converted to 3g with a yield of 58%. Characterization data for compound 2g is as follows:1H NMR(600MHz,CDCl3)δ3.76(s,3H),6.32(dd,J1＝3.0Hz,J2＝1.2Hz,1H),6.79(t,J＝2.4Hz,1H),6.87(dd,J1＝6.6Hz,J2＝1.8Hz,2H),6.96(t,J＝1.8Hz,1H),7.18(d,J＝6.6Hz,2H).13C NMR(100MHz,CDCl3)δ55.6,61.1,114.7,117.1,121.6,122.3,124.5,133.6,158.2.
example 21
To a 10mL Schlenk tube were added 1h (0.5mmol,90mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) in this order, and after evacuation and charging of oxygen (1atm), the mixture was placed in an oil bath at 80 ℃ and stirred for reaction for 10 h. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petrol ether/ethyl acetate 100/1) gave compound 2h (85mg, 59%). In accordance with the methods of example 1 and example 18, 2h can be converted to 3 h. Characterization data for compound 2h are as follows:1H NMR(600MHz,CDCl3)δ6.43(s,1H),6.95-6.99(m,2H),7.06(d,J＝9.6Hz,1H),7.13-7.14(m,2H),7.37-7.41(m,1H).13C NMR(150MHz,CDCl3)δ62.7,107.9(d,2JC-F＝25.2Hz),113.1(d,2JC-F＝20.9Hz),115.8(d,4JC-F＝3.3Hz),118.1,121.0,124.1,131.0(d,3JC-F＝9.9Hz),141.2(d,3JC-F＝9.9Hz),163.3(d,1JC-F＝246.0Hz).19F NMR(376MHz,CDCl3)δ-110.55.
example 22
To a 10mL Schlenk tube were added 1i (0.5mmol,120mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), elemental iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) in this order, followed by vacuum extractionAfter being charged with oxygen (1atm), the mixture was placed in an oil bath at 80 ℃ and stirred for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and column separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2i (104mg, 60%). In accordance with the methods of example 1 and example 18, 2i can be converted to 3 i. Characterization data for compound 2i are as follows:1H NMR(400MHz,CDCl3)δ6.35(s,1H),6.86(t,J＝2.4Hz,1H),7.04(s,1H),7.19-7.23(m,2H),7.32-7.34(m,1H),7.44(s,1H).13C NMR(100MHz,CDCl3)δ62.8,118.2,118.9,121.0,123.2,123.6,124.0,129.3,131.0,140.9.
example 23
1j (0.5mmol,88mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2j (89mg, 63%). 2j can be converted to 3j according to the methods of example 1 and example 18. Characterization data for compound 2j are as follows:1H NMR(400MHz,CDCl3)δ2.31(s,3H),6.32(s,1H),6.85(s,1H),7.00(d,J＝7.2Hz,1H),7.03-7.06(m,3H),7.21(t,J＝7.6Hz,1H).13C NMR(100MHz,CDCl3)δ21.5,61.8,117.4,117.7,121.2,121.3,124.2,127.1,129.5,139.8,139.9.
example 24
To a 10mL Schlenk tube were added 1k (0.5mmol,88mg), acetonitrile (5mL), anhydrous copper acetate in that order(1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg), which were placed in an oil bath at 80 ℃ for stirring reaction for 10 hours after vacuum charging with oxygen (1 atm). Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2k (85mg, 60%). Following the procedures of example 1 and example 18, 2k can be converted to 3k in 55% yield. Characterization data for compound 2k are as follows:1H NMR(400MHz,CDCl3)δ2.13(s,3H),6.31(t,J＝2.4Hz,1H),6.59(t,J＝2.4Hz,1H),6.76(t,J＝2.0Hz,1H),7.12-7.13(m,1H),7.15-7.23(m,3H).13C NMR(150MHz,CDCl3)δ17.7,60.1,116.2,123.9,126.6,126.7,128.1,131.2,133.8,139.7.
example 25
1l (0.5mmol,96mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave 2l (76mg, 51%). In accordance with the methods of example 1 and example 18, 2l can be converted to 3 l. Characterization data for compound 2l are as follows:1H NMR(600MHz,CDCl3)δ3.77(s,3H),6.30(s,1H),6.79(t,J＝2.4Hz,1H),6.92-6.96(m,3H),7.16-7.18(m,1H),7.20-7.23(m,1H).13C NMR(100MHz,CDCl3)δ55.8,60.4,112.3,116.1,121.0,123.9,125.6,126.7,128.1,129.3,152.6.
example 26
1m (0.5mmol,95mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2m (81mg, 54%). In accordance with the methods of example 1 and example 18, 2m can be converted to 3 m. Characterization data for compound 2m are as follows:1H NMR(600MHz,CDCl3)δ2.35(s,6H),6.39(s,1H),6.91-6.95(m,4H),7.10(s,1H).13C NMR(100MHz,CDCl3)δ21.4,61.5,117.2,118.4,121.2,124.2,128.0,139.5,139.9.
example 27
1n (0.5mmol,119mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were sequentially added to a 10mL Schlenk tube, and after vacuum charging (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2n (83mg, 48%). 2n can be converted to 3n according to the methods of example 1 and example 18. Characterization data for compound 2n are as follows:1H NMR(400MHz,CDCl3)δ6.55(d,J＝3.2Hz,1H),7.16(d,J＝3.2Hz,1H),7.27-7.32(m,1H),7.39-7.51(m,7H),7.60-7.63(m,2H).13C NMR(100MHz,CDCl3)δ70.9,111.6,126.57,126.62,127.4,128.16,128.24,128.5,128.9,132.1,136.4,141.3。
the foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (6)
1. A synthetic method of an N-pyrrolylpiperidine compound is characterized by comprising the following steps: firstly, adding N-substituted piperidine 1 into a solvent, and heating in oxygen in the presence of copper acetate, 4-dimethylaminopyridine and an additive to react to obtain an iodopyrrole compound 2; secondly, mixing the compound 2, copper salt, ligand, alkali and piperidine, and heating for reaction to obtain an N-pyrrolylpiperidine compound 3, wherein the reaction equation is as follows:
wherein: r1Is phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is fluorine, chlorine, bromine or C1-4One or more of alkyl or alkoxy, R2Is hydrogen, phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is fluorine, chlorine, bromine or C1-4One or more of alkyl or alkoxy; in the first step, the additive is selected from elementary iodine or metal iodide salt; the metal iodide salt is lithium iodide, sodium iodide or potassium iodide; in the second step, the copper salt is selected from cuprous iodide, cuprous bromide or cuprous chloride; the ligand is selected from L-proline; the base is selected from cesium fluoride or cesium carbonate.
2. The method for synthesizing an N-pyrrolylpiperidine compound according to claim 1, wherein: the first-step reaction solvent is selected from acetonitrile, dichloroethane, 1, 4-dioxane, N-dimethylformamide or dimethyl sulfoxide.
3. The method for synthesizing an N-pyrrolylpiperidine compound according to claim 1, wherein: the first step reaction is carried out under 1-2atm of oxygen atmosphere.
4. The method for synthesizing an N-pyrrolylpiperidine compound according to claim 1, wherein: in the first step and the second step, the heating reaction temperature is selected from 40-100 ℃.
5. The method for synthesizing an N-pyrrolylpiperidine compound according to any one of claims 1 to 4, wherein: in the first step, the ratio of the amount of N-substituted piperidine 1, copper acetate, additive and 4-dimethylamino pyridine is 1:1-2:0.25-1: 0.5-2.
6. The method for synthesizing an N-pyrrolylpiperidine compound according to claim 1, wherein: in the second step, the reaction is carried out in a solvent selected from DMF, DMSO or 1, 4-dioxane.
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| WO2015128334A1 (en) * | 2014-02-27 | 2015-09-03 | Laboratoire Biodim | 3h-thieno[3,4]pyrimidin-4-oneand pyrrolopyrimid-4-one as gram-positive antibacterial agents |
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