CN104177298B - 4,4-二取代-4,5-二氢-1h–咪唑-5-酮、衍生物及其合成方法 - Google Patents
4,4-二取代-4,5-二氢-1h–咪唑-5-酮、衍生物及其合成方法 Download PDFInfo
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- CN104177298B CN104177298B CN201410478433.8A CN201410478433A CN104177298B CN 104177298 B CN104177298 B CN 104177298B CN 201410478433 A CN201410478433 A CN 201410478433A CN 104177298 B CN104177298 B CN 104177298B
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- Prior art keywords
- ketone
- aryl
- substituted
- branch
- cyclic alkyl
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- 238000006467 substitution reaction Methods 0.000 title claims abstract description 32
- 238000010189 synthetic method Methods 0.000 title claims abstract description 20
- -1 amidine compound Chemical class 0.000 claims abstract description 83
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 46
- 239000001301 oxygen Substances 0.000 claims abstract description 46
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 46
- 150000002576 ketones Chemical class 0.000 claims abstract description 40
- 239000003513 alkali Substances 0.000 claims abstract description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000007800 oxidant agent Substances 0.000 claims abstract description 22
- 230000001590 oxidative effect Effects 0.000 claims abstract description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 18
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 17
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 16
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 8
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims abstract 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 40
- 125000000623 heterocyclic group Chemical group 0.000 claims description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 35
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 30
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- QXAITBQSYVNQDR-ZIOPAAQOSA-N amitraz Chemical compound C=1C=C(C)C=C(C)C=1/N=C/N(C)\C=N\C1=CC=C(C)C=C1C QXAITBQSYVNQDR-ZIOPAAQOSA-N 0.000 claims description 11
- 229960002587 amitraz Drugs 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 claims description 6
- HCFAJYNVAYBARA-UHFFFAOYSA-N 4-heptanone Chemical compound CCCC(=O)CCC HCFAJYNVAYBARA-UHFFFAOYSA-N 0.000 claims description 6
- CATSNJVOTSVZJV-UHFFFAOYSA-N heptan-2-one Chemical compound CCCCCC(C)=O CATSNJVOTSVZJV-UHFFFAOYSA-N 0.000 claims description 6
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims description 6
- 229930192474 thiophene Natural products 0.000 claims description 5
- BQVJCMMLDJPBFZ-UHFFFAOYSA-N [amino(phenyl)methylidene]azanium;chloride;hydrate Chemical compound O.Cl.NC(=N)C1=CC=CC=C1 BQVJCMMLDJPBFZ-UHFFFAOYSA-N 0.000 claims description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical class BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 4
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 4
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 4
- MTDUPZAXNYELOU-UHFFFAOYSA-N hydron;4-methylbenzenecarboximidamide;chloride Chemical compound Cl.CC1=CC=C(C(N)=N)C=C1 MTDUPZAXNYELOU-UHFFFAOYSA-N 0.000 claims description 4
- VKCYHJWLYTUGCC-UHFFFAOYSA-N nonan-2-one Chemical compound CCCCCCCC(C)=O VKCYHJWLYTUGCC-UHFFFAOYSA-N 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 4
- GEWWCWZGHNIUBW-UHFFFAOYSA-N 1-(4-nitrophenyl)propan-2-one Chemical compound CC(=O)CC1=CC=C([N+]([O-])=O)C=C1 GEWWCWZGHNIUBW-UHFFFAOYSA-N 0.000 claims description 3
- ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 2-octanone Chemical compound CCCCCCC(C)=O ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 0.000 claims description 3
- DCSKAMGZSIRJAQ-UHFFFAOYSA-N 4-(2-methylbutan-2-yl)cyclohexan-1-one Chemical class CCC(C)(C)C1CCC(=O)CC1 DCSKAMGZSIRJAQ-UHFFFAOYSA-N 0.000 claims description 3
- OKSDJGWHKXFVME-UHFFFAOYSA-N 4-ethylcyclohexan-1-one Chemical class CCC1CCC(=O)CC1 OKSDJGWHKXFVME-UHFFFAOYSA-N 0.000 claims description 3
- VGVHNLRUAMRIEW-UHFFFAOYSA-N 4-methylcyclohexan-1-one Chemical group CC1CCC(=O)CC1 VGVHNLRUAMRIEW-UHFFFAOYSA-N 0.000 claims description 3
- UKLNPJDLSPMJMQ-UHFFFAOYSA-N 4-pentylcyclohexan-1-one Chemical compound CCCCCC1CCC(=O)CC1 UKLNPJDLSPMJMQ-UHFFFAOYSA-N 0.000 claims description 3
- YKAYMASDSHFOGI-UHFFFAOYSA-N 4-phenylcyclohexan-1-one Chemical class C1CC(=O)CCC1C1=CC=CC=C1 YKAYMASDSHFOGI-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910004373 HOAc Inorganic materials 0.000 claims description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 claims description 3
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical class ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000003997 cyclic ketones Chemical class 0.000 claims description 3
- CGZZMOTZOONQIA-UHFFFAOYSA-N cycloheptanone Chemical compound O=C1CCCCCC1 CGZZMOTZOONQIA-UHFFFAOYSA-N 0.000 claims description 3
- IIRFCWANHMSDCG-UHFFFAOYSA-N cyclooctanone Chemical compound O=C1CCCCCCC1 IIRFCWANHMSDCG-UHFFFAOYSA-N 0.000 claims description 3
- ZAJNGDIORYACQU-UHFFFAOYSA-N decan-2-one Chemical class CCCCCCCCC(C)=O ZAJNGDIORYACQU-UHFFFAOYSA-N 0.000 claims description 3
- WCQOBLXWLRDEQA-UHFFFAOYSA-N ethanimidamide;hydrochloride Chemical compound Cl.CC(N)=N WCQOBLXWLRDEQA-UHFFFAOYSA-N 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 3
- WSGCRAOTEDLMFQ-UHFFFAOYSA-N nonan-5-one Chemical compound CCCCC(=O)CCCC WSGCRAOTEDLMFQ-UHFFFAOYSA-N 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- SXVPOSFURRDKBO-UHFFFAOYSA-N Cyclododecanone Chemical compound O=C1CCCCCCCCCCC1 SXVPOSFURRDKBO-UHFFFAOYSA-N 0.000 claims 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical class FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims 1
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical compound C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 claims 1
- UXJMXERXJQAWSP-UHFFFAOYSA-N 2-pentylcyclohexan-1-one Chemical compound CCCCCC1CCCCC1=O UXJMXERXJQAWSP-UHFFFAOYSA-N 0.000 claims 1
- ZYOUNOPGEAAOFI-UHFFFAOYSA-N CC(C)C(C)CCCC1CCCCC1=O Chemical class CC(C)C(C)CCCC1CCCCC1=O ZYOUNOPGEAAOFI-UHFFFAOYSA-N 0.000 claims 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims 1
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- ATQXMSAPMLWHBZ-UHFFFAOYSA-N chlorobenzene;propan-2-one Chemical compound CC(C)=O.ClC1=CC=CC=C1 ATQXMSAPMLWHBZ-UHFFFAOYSA-N 0.000 claims 1
- FXFPOKGPAPEJNE-UHFFFAOYSA-N cyclopropanecarboximidamide Chemical class NC(=N)C1CC1 FXFPOKGPAPEJNE-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- CAAMSDWKXXPUJR-UHFFFAOYSA-N 3,5-dihydro-4H-imidazol-4-one Chemical compound O=C1CNC=N1 CAAMSDWKXXPUJR-UHFFFAOYSA-N 0.000 abstract description 14
- 239000000463 material Substances 0.000 abstract description 9
- WZELXJBMMZFDDU-UHFFFAOYSA-N Imidazol-2-one Chemical class O=C1N=CC=N1 WZELXJBMMZFDDU-UHFFFAOYSA-N 0.000 abstract description 8
- 239000003054 catalyst Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 229910052751 metal Inorganic materials 0.000 abstract description 7
- 239000002184 metal Substances 0.000 abstract description 7
- 150000002978 peroxides Chemical class 0.000 abstract description 6
- 229940000201 avapro Drugs 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- YOSHYTLCDANDAN-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2NN=NN=2)C(CCCC)=NC21CCCC2 YOSHYTLCDANDAN-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003863 metallic catalyst Substances 0.000 abstract description 3
- 206010020772 Hypertension Diseases 0.000 abstract description 2
- 150000002460 imidazoles Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 108
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 35
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 31
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- 125000003003 spiro group Chemical group 0.000 description 23
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 230000005311 nuclear magnetism Effects 0.000 description 12
- 239000000126 substance Substances 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical class ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 230000001766 physiological effect Effects 0.000 description 3
- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical class C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 description 2
- KFPLPFVPPOJDFF-UHFFFAOYSA-N 1-chloro-1-phenylpropan-2-one Chemical compound CC(=O)C(Cl)C1=CC=CC=C1 KFPLPFVPPOJDFF-UHFFFAOYSA-N 0.000 description 2
- USHZYUPZIKQYMI-UHFFFAOYSA-N 2-methylbenzenecarboximidamide;hydrochloride Chemical compound Cl.CC1=CC=CC=C1C(N)=N USHZYUPZIKQYMI-UHFFFAOYSA-N 0.000 description 2
- OCJLPZCBZSCVCO-UHFFFAOYSA-N 2-propylcyclohexan-1-one Chemical compound CCCC1CCCCC1=O OCJLPZCBZSCVCO-UHFFFAOYSA-N 0.000 description 2
- 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- LZCZIHQBSCVGRD-UHFFFAOYSA-N benzenecarboximidamide;hydron;chloride Chemical compound [Cl-].NC(=[NH2+])C1=CC=CC=C1 LZCZIHQBSCVGRD-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- JRYOZJIRAVZGMV-UHFFFAOYSA-N cyclopropanecarboximidamide;hydron;chloride Chemical compound Cl.NC(=N)C1CC1 JRYOZJIRAVZGMV-UHFFFAOYSA-N 0.000 description 2
- 125000005594 diketone group Chemical group 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 239000005864 Sulphur Chemical group 0.000 description 1
- LHZWIAPUJMCNIT-UHFFFAOYSA-N acetic acid;pyridine-2-carboximidamide Chemical compound CC(O)=O.NC(=N)C1=CC=CC=N1 LHZWIAPUJMCNIT-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- ZKJQFTYIIXRKEW-UHFFFAOYSA-N benzenecarboximidamide;nitric acid Chemical compound O[N+]([O-])=O.NC(=N)C1=CC=CC=C1 ZKJQFTYIIXRKEW-UHFFFAOYSA-N 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- GAPYKZAARZMMGP-UHFFFAOYSA-N pyridin-1-ium;acetate Chemical compound CC(O)=O.C1=CC=NC=C1 GAPYKZAARZMMGP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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Abstract
一种4,4‑二取代‑4,5‑二氢‑1H–咪唑‑5‑酮、衍生物及其合成方法,它首次采用不需要使用催化剂,只在碱的作用下,用空气或氧气作为氧化剂,用吡啶、喹啉、三乙胺、NMP、DMA、DMSO、1,4‑二氧六环、甲苯等作有机溶剂,将脒类化合物和酮转化为咪唑酮及衍生物的技术方案。它克服了现有咪唑酮类化合物的合成方法存在合成步骤复杂,需要采取多步合成工艺才能完成,还需要使用金属催化剂、化学当量的金属氧化剂或者过氧化物的困难。它适合作多种功能材料;特别适合用于制造治疗高血压药物Avapro的重要原料。
Description
技术领域
本发明涉及一种咪唑酮类化合物及其合成方法,特别是一种4,4-二取代-4,5-二氢-1H–咪唑-5-酮、衍生物及其合成方法。
背景技术
咪唑酮类化合物用途很广,是制造多种功能材料、药物的重要原料,其中治疗高血压的药物Avapro就是一种4,4-二取代-4,5-二氢-1H–咪唑-5-酮的衍生物。而此类化合物的合成方法少有公开,且公开的文献中大部分方法都需要多步合成。例如J.HeterocyclicChem.,2010,47,1356-1360;Org.Lett.,2004,6,735-738;Tetrahedron Letters,2007,48,3109-3113;US6162923(2000)中曾报道了一些合成这类物质的方法。这些方法都是采取多步合成工艺完成,其中,需要用金属催化剂,还要加入化学当量的金属氧化剂或者过氧化物。
发明内容
针对上述情况,本发明的目的是提供一种4,4-二取代-4,5-二氢-1H–咪唑-5-酮及衍生物,它分子结构稳定、化学性质优良,它既是重要的分子切块,又是含生理活性和药理活性的化合物片段。
本发明的又一目的是提供一种合成4,4-二取代-4,5-二氢-1H–咪唑-5-酮及衍生物的方法,它工艺科学、合理,操作容易,反应步骤少,所需设备简单,所用原料廉价易得且不需要进行预处理,该反应不需要使用催化剂、金属氧化剂或者过氧化物,反应能极大限度地保持原子经济性,投入低产出高,易于工业化生产和普及推广。
为了实现上述目的,一种4,4-二取代-4,5-二氢-1H–咪唑-5-酮及衍生物,它的通式为式Ⅰ:
其中
n为0或2-7的整数
R选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基;
R1选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基;
R2、R3选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基。
为了实现上述另一目的,一种合成4,4-二取代-4,5-二氢-1H–咪唑-5-酮及衍生物的方法,在碱和氧化剂的作用下,将脒类化合物、酮和有机溶剂混合进行反应、纯化得到产物。
为了提高本发明的综合性能,实现结构、效果优化,其进一步的措施是:
所述的碱选自KHCO3、K2CO3、Na2CO3、K3PO4、K2HPO4、KOH、NaOH、CsOH、叔丁醇钾、叔丁醇钠、乙醇钠、甲醇钠的一种或数种;所述的碱为NaOH。
所述的氧化剂为空气或氧气。
所述的有机溶剂为吡啶、喹啉、三乙胺、NMP、DMA、DMSO、1,4-二氧六环、甲苯。
所述的脒类化合物、酮和碱的摩尔比为1:1.1-6:1.1-10,反应温度为20℃-200℃。
所述的酮类化合物选自C6-C12的环状酮或C4-C30的链状酮,其通式为式Ⅱ:
其中
n为0或2-7的整数
R选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基;
R1选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基;
R2、R3选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基。
式Ⅱ中的环状酮或链状酮进一步选自环己酮,4-甲基环己酮,4-乙基环己酮,4-异丙基环己酮,4-正戊基环己酮,4-叔戊基环己酮,4-环丙基环己酮,4-苯基环己酮,4-(3-噻吩基)环己酮,4-(3-(5-氯噻吩基))环己酮,4-(4-硝基苯基)环己酮,环庚酮,环辛酮,环十二酮,2-戊酮,2-己酮,4-甲基-2-戊酮,2-庚酮,2-辛酮,2-壬酮,2-癸酮,2-二十酮,3-戊酮,4-庚酮,5-壬酮,8-十五酮,苯丙酮,对甲基苯丙酮,对氯苯丙酮,对硝基苯丙酮,1,2-二苯基乙酮,1,2-双(4-异丙基苯基)乙酮,1,2-双(4-溴苯基)乙酮,1,2-双(4-氨基苯基)乙酮。
所述的脒类化合物通式为式Ⅲ:
其中
m为1-3的整数,
x为0-6,
M为HF、HCl、HBr、HI、HNO3、HOAc、H2SO4、H3PO4;
R选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基。
所述脒类化合物进一步选自苯甲脒盐酸盐一水合物、4-甲基苯甲脒盐酸盐、4-氯苯甲脒盐酸盐、4-溴苯甲脒盐酸盐、4-三氟甲基苯甲脒盐酸盐、4-硝基苯甲脒磷酸盐、4-氨基苯甲脒硝酸盐、2-甲基苯甲脒氢碘酸盐、2-氯苯甲脒硫酸盐、3-甲脒基吡啶盐酸盐、4-甲脒基吡啶醋酸盐、醋酸甲脒、盐酸乙脒、环丙甲脒盐酸盐、4-异丙基苯甲脒硝酸盐、4-环丙基苯甲脒氢氟酸盐、3-噻吩甲脒氢溴酸盐、3-呋喃甲脒盐酸盐、3-(5-氯噻吩基)甲脒盐酸盐。
本发明一种4,4-二取代-4,5-二氢-1H–咪唑-5-酮、衍生物及其合成方法,它首次采用不需要使用催化剂,只在碱的作用下,用空气或氧气作为氧化剂,用吡啶、喹啉、三乙胺、NMP、DMA、DMSO、1,4-二氧六环、甲苯等作有机溶剂,将脒类化合物和酮转化为咪唑酮及其衍生物的技术方案;它克服了现有咪唑酮类化合物的合成方法存在合成步骤复杂,需要采取多步合成工艺才能完成,还需要使用催化剂、化学当量的金属氧化剂或者过氧化物等缺陷;它极大限度地保持了原子经济性;它具有分子结构稳定、化学性质优良,分子切块和化合物片段包含丰富的生物活性和药理活性内容;它还具有反应体系简单、反应条件温和、反应设备较少、实验操作简便、用料来源广泛、用户和应用易于扩展、产品利用价值较高、市场商业化前景可以预期等特点。
本发明相比现有技术所产生的有益效果:
(Ⅰ)本发明采用首次在碱的作用下,用空气或氧气作为氧化剂,将脒类化合物和酮转化为咪唑酮及其衍生物的技术方案,制得分子结构稳定,化学性质优良的产品及其附加产品;
(Ⅱ)本发明采用首次在碱的作用下,用空气或氧气作为氧化剂,将脒类化合物和酮转化为咪唑酮的技术方案,反应原料廉价易得,且不需要经过预处理,反应的原子经济性高;
(Ⅲ)本发明采用首次在碱的作用下,用空气或氧气作为氧化剂,将脒类化合物和酮转化为咪唑酮的技术方案,反应不需要使用催化剂,金属氧化剂或过氧化物,只需要用碱和绿色氧化剂空气或氧气,减少了环境污染,节约了原材料,减少了反应成本;
(Ⅳ)本发明采用首次在碱的作用下,用空气或氧气作为氧化剂,将脒类化合物和酮转化为咪唑酮的技术方案,采用一锅直接合成产物且收率高,克服了现有多步合成方法带来的人、财、物巨大浪费的困境,节约了大量的研制时间与生产周期;
(Ⅴ)本发明采用首次在碱的作用下,用空气或氧气作为氧化剂,将脒类化合物和酮转化为咪唑酮的技术方案,克服了现有多步合成方法带来的产品实施成本较高的困境,从而使产品的实际应用大大地提前进入,为提早工业化生产创造了基础条件;
(Ⅵ)本发明采用首次在碱的作用下,用空气或氧气作为氧化剂,将脒类化合物和酮转化为咪唑酮的技术方案,反应所需温度大大低于现有多步合成法所需温度,节约大量的能源消耗;
(Ⅶ)本发明采用首次在碱的作用下,用空气或氧气作为氧化剂,将脒类化合物和酮转化为咪唑酮的技术方案,它工艺科学、合理,操作容易,反应步骤少,所需设备少;
(Ⅷ)本发明采用首次在碱的作用下,用空气或氧气作为氧化剂,将脒类化合物和酮转化为咪唑酮的技术方案,它具有原料广泛,低投入、高产出,易于进一步大批量生产和普及推广;
(Ⅸ)本发明采用首次在碱的作用下,用空气或氧气作为氧化剂,将脒类化合物和酮转化为咪唑酮的技术方案,它具有反应体系简单、反应条件温和、反应设备较少、实验操作简便、用料来源广泛、用户和应用易于扩展、产品利用价值较高、市场商业化前景可以预期等特点。
本发明适合作多种功能材料原料;特别适用于制造治疗高血压药物Avapro的重要原料。
下面结合附图和实施例对本发明作进一步详细说明。
附图说明
图1本发明化合物的合成路线图。
图2-1实施例1产物的核磁氢谱图。
图2-2实施例1产物的核磁碳谱图。
图3-1实施例3产物的核磁氢谱图。
图3-2实施例3产物的核磁碳谱图。
图4-1实施例25产物的核磁氢谱图。
图4-2实施例25产物的核磁碳谱图。
图5-1实施例35产物的核磁氢谱图。
图5-2实施例35产物的核磁碳谱图。
图6-1实施例50产物的核磁氢谱图。
图6-2实施例50产物的核磁碳谱图。
具体实施方式
结合本发明化合物的合成路线,4,4-二取代-4,5-二氢-1H-咪唑-5-酮、衍生物及其合成原理,如附图1所示:它包括首次采用不需要使用催化剂,只在碱的作用下,用空气或氧气作为氧化剂,用吡啶、喹啉、三乙胺、NMP、DMA、DMSO、1,4-二氧六环、甲苯等作有机溶剂,将脒类化合物和酮转化为咪唑酮及其衍生物的技术方案;它克服了现有咪唑酮类化合物的合成方法存在合成步骤复杂,需要采取多步合成工艺才能完成,还需要用金属催化剂、化学当量的金属氧化剂或者过氧化物的困难;它极大限度地保持了原子经济性;它具有分子结构稳定、化学性质优良,分子切块和化合物片段包含丰富的生物活性和药理活性内容;它还具有反应体系简单、反应条件温和、反应设备较少、实验操作简便、用料来源广泛、用户和应用易于扩展、产品利用价值较高、市场商业化前景可以预期等特点。
结合附图,一种4,4-二取代-4,5-二氢-1H–咪唑-5-酮及衍生物,它的通式为式Ⅰ:
其中
n为0或2-7的整数
R选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基;
R1选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基;
R2、R3选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基。
为了实现合成4,4-二取代-4,5-二氢-1H–咪唑-5-酮及衍生物的方法,在碱和氧化剂的作用下,将脒类化合物、酮和有机溶剂混合进行反应、纯化得到产物。
为了提高本发明的综合性能,实现结构、效果优化,其进一步的措施是:
所述的碱选自KHCO3、K2CO3、Na2CO3、K3PO4、K2HPO4、KOH、NaOH、CsOH、叔丁醇钾、叔丁醇钠、乙醇钠、甲醇钠的一种或数种;所述的碱为NaOH,所述的氧化剂为空气或氧气,所述的有机溶剂为吡啶、喹啉、三乙胺、NMP、DMA、DMSO、1,4-二氧六环、甲苯,所述的脒类化合物、酮和碱的摩尔比为1:1.1-6:1.1-10,反应温度为20℃-200℃。
所述的酮类化合物选自C6-C12的环状酮或C4-C30的链状酮,其通式为式Ⅱ:
其中
n为0或2-7的整数
R选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基;
R1选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基;
R2、R3选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基。
式Ⅱ中的环状酮或链状酮进一步选自环己酮,4-甲基环己酮,4-乙基环己酮,4-异丙基环己酮,4-正戊基环己酮,4-叔戊基环己酮,4-环丙基环己酮,4-苯基环己酮,4-(3-噻吩基)环己酮,4-(3-(5-氯噻吩基))环己酮,4-(4-硝基苯基)环己酮,环庚酮,环辛酮,环十二酮,2-戊酮,2-己酮,4-甲基-2-戊酮,2-庚酮,2-辛酮,2-壬酮,2-癸酮,2-二十酮,3-戊酮,4-庚酮,5-壬酮,8-十五酮,苯丙酮,对甲基苯丙酮,对氯苯丙酮,对硝基苯丙酮,1,2-二苯基乙酮,1,2-双(4-异丙基苯基)乙酮,1,2-双(4-溴苯基)乙酮,1,2-双(4-氨基苯基)乙酮。
所述的脒类化合物,其通式为式Ⅲ:
其中
m为1-3的整数,
x为0-6,
M为HF、HCl、HBr、HI、HNO3、HOAc、H2SO4、H3PO4;
R选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的C3-C10杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基。
脒类化合物进一步选自苯甲脒盐酸盐一水合物、4-甲基苯甲脒盐酸盐、4-氯苯甲脒盐酸盐、4-溴苯甲脒盐酸盐、4-三氟甲基苯甲脒盐酸盐、4-硝基苯甲脒磷酸盐、4-氨基苯甲脒硝酸盐、2-甲基苯甲脒氢碘酸盐、2-氯苯甲脒硫酸盐、3-甲脒基吡啶盐酸盐、4-甲脒基吡啶醋酸盐、醋酸甲脒、盐酸乙脒、环丙甲脒盐酸盐、4-异丙基苯甲脒硝酸盐、4-环丙基苯甲脒氢氟酸盐、3-噻吩甲脒氢溴酸盐、3-呋喃甲脒盐酸盐、3-(5-氯噻吩基)甲脒盐酸盐。
由式Ⅰ、Ⅱ、Ⅲ构成4,4-二取代-4,5-二氢-1H–咪唑-5-酮及其衍生物合成本发明的反应体系通式,如:
包括以下步骤
⑴加入碱、脒类化合物、酮和有机溶剂;
⑵将反应物充分混合,充入1atm O2加热反应;
⑶纯化得产物;
其中,有机溶剂为吡啶、喹啉、三乙胺、NMP、DMA、DMSO、1,4-二氧六环、甲苯;
优选吡啶;
氧化剂为空气或者氧气;
优选氧气,氧化剂为1atm的氧气;
为了达到更好的合成效果,优选脒类化合物,酮和碱的摩尔比为1:1.1-6:1.1-10,最佳方案优选1:1.5:4.5;
所用碱是KHCO3、K2CO3、Na2CO3、K3PO4、K2HPO4、KOH、NaOH、CsOH、叔丁醇钾、叔丁醇钠、乙醇钠、甲醇钠中的一种或数种;
特别优选NaOH;
反应的温度优选为20℃-200℃;
更优选为80℃。
从上述本发明化合物的合成反应体系过程中可以得出,4,4-二取代-4,5-二氢-1H-咪唑-5-酮及其衍生物,它首次在不需要使用催化剂,只需要碱的条件下,用空气或氧气作为氧化剂,将脒类化合物和酮反应转化为咪唑酮。
上述式Ⅰ化合物作为一种重要的分子切块,它分子结构稳定、化学性质优良,其本身具有一定的生理活性,还可通过对官能团的转换进一步合成很多含有咪唑酮结构的化合物片段,该含有咪唑酮结构的化合物都有很强的生理活性和药理活性;比如,一种咪唑酮衍生物-Avapro,它已成为当下全球销量领先的降压药。
Avapro结构式
总之,本发明化合物具有反应原料廉价易得且不需要进行预处理;反应不需要使用催化剂以及金属氧化剂或过氧化物;只需要使用碱作为促进剂,使用的氧化剂是绿色廉价的空气或氧气;反应为一锅直接合成等特点;它解决了现有采用多步合成方法带来的成本较高等难题;它反应条件温和,反应所需温度大大低于以往多步合成的反应温度;合成的一系列咪唑酮类化合物具有相当高的潜在应用价值。
参照附图,实施例1-41如下:
实施例12-苯基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮的合成
取一反应管,氧气保护下加入0.9mmol(36mg)氢氧化钠、0.2mmol(35.6mg)苯甲脒盐酸盐一水合物、0.3mmol(31.2μL)环己酮、0.8mL吡啶,80℃下反应24小时,常规处理得到纯品36.8mg,产率86%。
实施例1产物的核磁及质谱数据如下:
1H NMR(400MHz,CDCl3,ppm)δ10.02(br,1H),7.92(d,J=6.8Hz,2H),7.54-7.49(m,3H),2.07-1.97(m,8H);13C NMR(100MHz,DMSO-d6,ppm)δ187.8,157.0,131.0,128.2,127.9,126.2,76.9,36.5,25.0;MS(EI)m/z(%)214,171,104(100),83,54.
实施例22-(对甲基苯基)-1,3-二氮杂螺[4,4]壬-1-烯-4-酮的合成
取一反应管,氧气保护下加入0.9mmol(36mg)氢氧化钠、0.2mmol(34.1mg)4-甲基苯甲脒盐酸盐、0.3mmol(31.2μL)环己酮、0.8mL喹啉,40℃下反应48小时。常规处理得到纯品39.7mg,产率87%。
实施例2产物的核磁及质谱数据如下:
1H NMR(500MHz,CDCl3,ppm)δ10.14(br,1H),7.80(d,J=8.0Hz,2H),7.31(d,J=8.1Hz,2H),2.42(s,3H),2.07-1.94(m,8H);13C NMR(125MHz,DMSO-d6,ppm)δ187.3,156.1,135.7,128.3,128.0,126.2,77.0,36.5,25.0,20.5;MS(EI)m/z(%)228,185,118(100),83,65;HRMS calcd.for:C14H17ON2[M+H]+229.1335,found229.1333.
实施例32-(4-氯苯基)-1,3-二氮杂螺[4,4]壬-1-烯-4-酮的合成
取一反应管,氧气保护下加入0.9mmol(36mg)氢氧化钠、0.2mmol(38.2mg)4-氯苯甲脒盐酸盐、0.3mmol(31.2μL)环己酮、0.8mL甲苯,150℃下反应12小时。
常规处理得到纯品25.3mg,产率51%。
实施例3产物的核磁及质谱数据如下:
1H NMR(400MHz,CDCl3,ppm)δ10.02(br,1H),7.86(d,J=7.7Hz,2H),7.49(d,J=8.2Hz,2H),2.06-1.94(m,8H);13C NMR(125MHz,DMSO-d6,ppm)δ187.4,156.2,135.7,128.4,128.0,127.2,77.1,36.5,25.0;MS(EI)m/z(%)248,138(100),83,75,54;HRMS calcd.for:C13H14ON2Cl[M+H]+249.0789,found 249.0787.
实施例42-(4-溴苯基)-1,3-二氮杂螺[4,4]壬-1-烯-4-酮的合成
取一反应管,氧气保护下加入0.9mmol(36mg)氢氧化钠、0.2mmol(47.1mg)4-溴苯甲脒盐酸盐、0.3mmol(31.2μL)环己酮、0.8mL DMSO,120℃下反应24小时。常规处理得到纯品36.2mg,产率62%。
实施例4产物的核磁及质谱数据如下:
1H NMR(500MHz,CDCl3,ppm)δ9.98(br,1H),7.78(d,J=8.2Hz,2H),7.65(d,J=8.5Hz,2H),2.11-1.94(m,8H);13C NMR(125MHz,DMSO-d6,ppm)δ187.4,156.3,131.3,128.2,127.5,124.7,77.1,36.5,25.0;MS(EI)m/z(%)292,184,83(100),76,54;HRMS calcd.for:C13H14ON2Br[M+H]+293.0284,found 293.0282.
实施例52-(4-三氟甲基苯基)-1,3-二氮杂螺[4,4]壬-1-烯-4-酮的合成
取一反应管,氧气保护下加入0.9mmol(36mg)氢氧化钠、0.2mmol(44.9mg)4-三氟甲基苯甲脒盐酸盐、31.2μL环己酮、0.8mL NMP,80℃下反应24小时。常规处理得到纯品39.5mg,产率70%。
实施例5产物的核磁及质谱数据如下:
1H NMR(500MHz,CDCl3,ppm)δ10.81(br,1H),8.09(d,J=8.2Hz,2H),7.79(d,J=8.3Hz,2H),2.14-1.94(m,8H);13C NMR(125MHz,DMSO-d6,ppm)δ187.2,156.2,132.1,130.8(q,J=33.6Hz),127.1,125.5(q,J=274.5Hz),125.1,77.3,36.5,25.0;MS(EI)m/z(%)282,239,172(100),145,54;HRMS calcd.for:C14H14ON2F3[M+H]+283.1053,found283.1049.
实施例62-(2-甲基苯基)-1,3-二氮杂螺[4,4]壬-1-烯-4-酮的合成
取一反应管,氧气保护下加入0.9mmol(36mg)氢氧化钠、0.2mmol(34.1mg)2-甲基苯甲脒盐酸盐、0.3mmol(31.2μL)环己酮、0.8mL DMA,100℃下反应24小时。常规处理得到纯品34.2mg,产率75%。
实施例6产物的核磁及质谱数据如下:
1H NMR(500MHz,CDCl3,ppm)δ8.86(br,1H),7.50-7.48(m,1H),7.39-7.36(m,1H),7.30-7.28(m,2H),2.52(s,3H),2.08-1.92(m,8H);13C NMR(125MHz,CDCl3,ppm)δ189.6,158.3,137.2,131.2,130.4,128.8,128.4,125.9,78.6,37.5,26.0,20.4;MS(EI)m/z(%)228,158,118(100),83,54;HRMS calcd.for:C14H17ON2[M+H]+229.1335,found 229.1333.
按照实施例1所述的操作方法,本发明合成了以下化合物:
下面给出了本发明部分实施例化合物的核磁、质谱等表针数据:
实施例112-硝基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮
1H NMR(500MHz,CDCl3,ppm)δ10.86(br,1H),8.38(d,J=8.8Hz,2H),8.15(d,J=8.7Hz,2H),2.14-1.95(m,8H);13C NMR(125MHz,DMSO-d6,ppm)δ187.2,155.9,148.6,133.9,127.6,123.4,77.5,36.5,25.0;MS(EI)m/z(%)259,149,103,83(100),54;HRMScalcd.for:C13H14O3N3[M+H]+260.1030,found 260.1033.实施例122-氨基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮
MS(EI)m/z(%)229,200,119(100),84,65;HRMS calcd.for:C14H17ON2[M+H]+230.1288,found 230.1291.
实施例132-(2-甲基苯基)-1,3-二氮杂螺[4,4]壬-1-烯-4-酮的合成
1H NMR(500MHz,CDCl3,ppm)δ8.86(br,1H),7.50-7.48(m,1H),7.39-7.36(m,1H),7.30-7.28(m,2H),2.52(s,3H),2.08-1.92(m,8H);13C NMR(125MHz,CDCl3,ppm)δ189.6,158.3,137.2,131.2,130.4,128.8,128.4,125.9,78.6,37.5,26.0,20.4;MS(EI)m/z(%)228,158,118(100),83,54;HRMS calcd.for:C14H17ON2[M+H]+229.1335,found 229.1333.
实施例142-(2-氯苯基)-1,3-二氮杂螺[4,4]壬-1-烯-4-酮
1H NMR(500MHz,CDCl3,ppm)δ8.68(br,1H),7.92(d,J=7.4Hz,1H),7.46-7.45(m,2H),7.41-7.37(m,1H),2.07-1.94(m,8H);13C NMR(125MHz,DMSO-d6,ppm)δ187.4,156.8,131.5,130.2,129.4,128.7,126.8,126.2,77.1,36.2,25.0;MS(EI)m/z(%)248,185,138(100),83,54.
实施例152-(3-吡啶基)-1,3-二氮杂螺[4,4]壬-1-烯-4-酮
1H NMR(500MHz,CDCl3,ppm)δ10.98(br,1H),9.20(d,J=1.6Hz,1H),8.79-8.78(m,1H),8.32-8.29(m,1H),7.48-7.46(m,1H),2,13-1.93(m,8H);13C NMR(125MHz,CDCl3,ppm)δ190.6,155.7,152.0,150.0,134.5,125.0,123.7,78.8,37.5,26.1;MS(EI)m/z(%)215,172,105(100),78,54;HRMS calcd.for:C12H14ON3[M+H]+216.1131,found 216.1130.
实施例162-(4-吡啶基)-1,3-二氮杂螺[4,4]壬-1-烯-4-酮
1H NMR(500MHz,CDCl3,ppm)δ10.89(br,1H),8.82(d,J=5.1Hz,2H),7.83(d,J=6.0Hz,2H),2,14-1.93(m,8H);13C NMR(125MHz,CDCl3,ppm)δ190.8,155.9,150.6,136.1,120.7,79.5,37.6,26.2;MS(EI)m/z(%)215,172,105(100),83,54;HRMS calcd.for:C12H14ON3[M+H]+216.1131,found 216.1135.
实施例182-甲基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮
MS(EI)m/z(%)152,104,82(100),51;HRMS calcd.for:C8H12ON2[M+H]+153.1335,found 153.1333.
实施例192-环丙基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮
MS(EI)m/z(%)178,156,104(100),82,51;HRMS calcd.for:C10H15ON2[M+H]+179.1181,found 179.1179.
实施例257-甲基-2-苯基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮
1H NMR(500MHz,CDCl3,mixture,ppm)δ10.27(br,0.5H),10.19(br,0.5H),7.92(d,J=7.6Hz,2H),7.55-7.49(m,3H),2.61-2.53(m,0.5H),2.48-2.40(m,0.5H),2.22-1.93(m,4H),1.75-1.54(m,2H),1.15(t,J=7.0Hz,3H);13C NMR(125MHz,CDCl3,mixture,ppm)δ191.2,190.6,157.3,131.6,128.8,128.6,126.9,79.2,78.6,46.1,44.8,37.6,36.7,35.4,35.1,35.0,34.5,19.9,19.6;MS(EI)m/z(%)228,185,104(100),82,51;HRMS calcd.for:C14H17ON2[M+H]+229.1335,found 229.1334.
实施例267-乙基-2-苯基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮
1H NMR(500MHz,CDCl3,mixture,ppm)δ10.15(br,0.5H),10.05(br,0.5H),7.92-7.90(m,2H),7.55-7.48(m,3H),2.43-1.92(m,5H),1.76-1.47(m,4H),0.97-0.94(m,3H);13CNMR(125MHz,CDCl3,mixture,ppm)δ191.1,190.5,157.3,131.6,128.8,128.7,126.9,78.9,78.3,44.1,42.8,42.6,42.3,37.4,36.4,32.7,32.1,28.4,28.2,13.0,12.9;MS(EI)m/z(%)242,173,104(100),82,54;HRMS calcd.for:C15H19ON2[M+H]+243.1492,found243.1489.
实施例277-异丙基-2-苯基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮
1H NMR(500MHz,CDCl3,mixture,ppm)δ10.12(br,0.5H),9.99(br,0.5H),7.92-7.90(t,J=6.1Hz,2H),7.55-7.48(m,3H),2.18-1.58(m,8H),0.98-0.97(m,3H),0.94-0.92(m,3H);13C NMR(125MHz,CDCl3,mixture,ppm)δ191.1,190.6,157.3,131.6,128.8,128.7,128.66,126.9,126.88,78.9,78.3,48.3,47.9,42.8,41.4,37.4,36.3,33.4,33.3,31.3,30.6,21.6,21.56,21.55,21.5;MS(EI)m/z(%)256,228,173,104(100),82;HRMScalcd.for:C16H21ON2[M+H]+257.1648,found 257.1649.
实施例287-正戊基-2-苯基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮
1H NMR(500MHz,CDCl3,mixture,ppm)δ10.14(br,0.5H),10.04(br,0.5H),7.92-7.90(m,2H),7.55-7.49(m,3H),2.49-2.28(m,1H),2.22-1.92(m,4H),1.76-1.25(m,10H),0.89(t,J=6.8Hz,3H);13C NMR(125MHz,CDCl3,mixture,ppm)δ191.1,190.6,157.2,131.6,128.8,128.7,126.9,78.9,78.3,44.5,43.1,40.8,40.5,37.4,36.4,35.5,35.3,33.1,32.5,32.0,31.9,29.7,28.34,28.31,22.63,22.62,14.1;MS(EI)m/z(%)284,173,104(100),82,55;HRMS calcd.for:C18H25ON2[M+H]+285.1961,found 285.1958.
实施例297-叔戊基-2-苯基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮
1H NMR(500MHz,CDCl3,ppm)δ9.97(br,1H),7.92(d,J=5.2Hz,2H),7.56-7.48(m,3H),2.38-2.31(m,1H),2.02-1.82(m,6H),1.32-1.27(q,J=7.5Hz,2H),0.90-0.85(m,9H);13C NMR(125MHz,CDCl3,mixture,ppm)δ191.3,190.7,157.4,157.35,131.5,128.7,128.66,128.62,126.9,126.87,78.6,77.9,49.0,48.8,38.9,37.7,36.8,36.3,34.4,34.2,33.8,33.7,27.2,26.5,23.9,23.8,23.75,23.70,8.3,8.2;MS(EI)m/z(%)284,255,173(100),82,55;HRMS calcd.for:C18H25ON2[M+H]+285.1961,found 285.1957.
实施例312,7-二苯基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮
1H NMR(400MHz,CDCl3,mixture,ppm)δ10.18(br,0.5H),10.03(br,0.5H),7.96(d,J=6.4Hz,2H),7.57-7.52(m,3H),7.41-7.32(m,4H),7.23-7.22(m,1H),3.75-3.71(m,0.5H),3.60-3.56(m,0.5H),2.52-2.07(m,6H);13C NMR(125MHz,CDCl3,mixture,ppm)δ190.7,190.3,157.7,157.6,144.2,144.0,131.8,131.7,128.92,128.91,128.7,128.4,127.3,127.2,126.92,126.90,126.3,126.2,78.7,78.2,46.0,45.6,45.4,44.3,37.6,36.6,35.2,34.3;MS(EI)m/z(%)290,173(100),104,77,51;HRMS calcd.for:C19H19ON2[M+H]+291.1492,found 291.1491.
实施例352-苯基-1,3-二氮杂螺[4,4]癸-1-烯-4-酮
1H NMR(500MHz,CDCl3,ppm)δ10.24(br,1H),7.95-7.93(m,2H),7.55-7.49(m,3H),1.91-1.50(m,10H);13C NMR(125MHz,CDCl3,ppm)δ190.7,157.2,131.5,128.8,128.7,127.0,72.1,33.2,25.3,21.6;MS(EI)m/z(%)228,173,104(100),97,54.实施例362-苯基-1,3-二氮杂螺[4,4]十一-1-烯-4-酮
1H NMR(500MHz,CDCl3,ppm)δ10.11(br,1H),7.93(d,J=6.9Hz,2H),7.56-7.49(m,3H),1.92-1.68(m,12H);13C NMR(100MHz,DMSO-d6,ppm)δ188.4,156.7,131.0,128.2,128.0,126.3,72.5,35.4,29.1,22.0;MS(EI)m/z(%)242,173,104(100),83,54;HRMScalcd.for:C15H19ON2[M+H]+243.1492,found 243.1490.
实施例384-甲基-4-乙基-2-苯基-1H-咪唑-5-酮
1H NMR(400MHz,CDCl3,ppm)δ10.23(br,1H),7.94(d,J=7.0Hz,2H),7.57-7.51(m,3H),1.92(q,J=7.0Hz,2H),1.47(s,3H),0.84(t,J=7.4Hz,3H);13C NMR(125MHz,CDCl3,ppm)δ190.1,158.1,131.7,128.8,128.4,126.9,73.0,30.9,22.9,8.2;MS(EI)m/z(%)202,173,104(100),77,51;HRMS calcd.for:C12H15ON2[M+H]+203.1179,found 203.1176.
实施例394-甲基-4-正丙基-2-苯基-1H-咪唑-5-酮
1H NMR(400MHz,CDCl3,ppm)δ10.16(br,1H),7.94(d,J=6.6Hz,2H),7.57-7.50(m,3H),1.86(t,J=8.4Hz,2H),1.46(s,3H),1.34-1.14(m,2H),0.88(t,J=7.2Hz,3H);13C NMR(125MHz,CDCl3,ppm)δ190.2,157.9,131.7,128.8,128.4,126.9,72.7,39.9,23.3,17.1,14.0;MS(EI)m/z(%)216,173,104(100),77,51;HRMS calcd.for:C13H17ON2[M+H]+217.1335,found 217.1334.
实施例404-甲基-4-异丙基-2-苯基-1H-咪唑-5-酮
1H NMR(500MHz,CDCl3,ppm)δ10.23(br,1H),7.94(d,J=7.1Hz,2H),7.56-7.50(m,3H),2.16-2.10(m,1H),1.45(s,3H),1.08(d,J=6.8Hz,3H),0.92(d,J=6.8Hz,3H);13C NMR(125MHz,CDCl3,ppm)δ190.3,158.0,131.7,128.9,128.5,126.9,75.2,34.9,21.2,16.9,16.8;MS(EI)m/z(%)216,174,104(100),77,51;HRMS calcd.for:C13H17ON2[M+H]+217.1335,found 217.1337.
实施例414-甲基-4-正丁基-2-苯基-1H-咪唑-5-酮
1H NMR(500MHz,CDCl3,ppm)δ10.29(br,1H),7.94(d,J=7.1Hz,2H),7.58-7.51(m,3H),1.87(t,J=8.1Hz,2H),1.46(s,3H),1.31-1.10(m,4H),0.84(t,J=7.2Hz,3H);13C NMR(125MHz,CDCl3,ppm)δ190.3,158.0,131.7,128.8,128.4,126.9,72.5,37.6,25.8,23.3,22.6,13.8;MS(EI)m/z(%)230,144,104(100),77,57;HRMS calcd.for:C14H19ON2[M+H]+231.1492,found 231.1491.
实施例424-甲基-4-正戊基-2-苯基-1H-咪唑-5-酮
1H NMR(500MHz,CDCl3,ppm)δ10.16(br,1H),7.94(d,J=7.3Hz,2H),7.58-7.50(m,3H),1.87(t,J=8.0Hz,2H),1.46(s,3H),1.28-1.11(m,6H),0.82(t,J=6.9Hz,3H);13C NMR(125MHz,CDCl3,ppm)δ190.3,157.9,131.7,128.8,128.4,126.9,72.7,37.8,31.7,23.4,23.3,22.3,13.9;MS(EI)m/z(%)244,174,104(100),77,51;HRMS calcd.for:C15H21ON2[M+H]+245.1648,found 245.1646.
实施例434-甲基-4-正己基-2-苯基-1H-咪唑-5-酮
1H NMR(500MHz,CDCl3,ppm)δ10.30(br,1H),7.95(d,J=7.2Hz,2H),7.58-7.51(m,3H),1.87(t,J=7.7Hz,2H),1.47(s,3H),1.25-1.12(m,8H),0.82(t,J=6.9Hz,3H);13C NMR(125MHz,CDCl3,ppm)δ190.2,157.8,131.7,128.8,128.4,126.9,72.7,37.9,31.6,29.3,23.7,23.4,22.5,14.0;MS(EI)m/z(%)258,187,104(100),77,57;HRMS calcd.for:C16H23ON2[M+H]+259.1805,found 259.1803.
实施例444-甲基-4-正庚基-2-苯基-1H-咪唑-5-酮
1H NMR(500MHz,CDCl3,ppm)δ10.00(br,1H),7.95(d,J=5.2Hz,2H),7.59-7.51(m,3H),1.88(t,J=7.3Hz,2H),1.47(s,3H),1.25-1.12(m,10H),0.83(t,J=7.0Hz,3H);13CNMR(125MHz,CDCl3,ppm)δ190.3,157.9,131.7,128.8,128.4,126.9,72.7,37.9,31.7,29.5,29.0,23.8,23.3,22.5,14.0;MS(EI)m/z(%)272,174,104(100),77,57;HRMScalcd.for:C17H25ON2[M+H]+273.1961,found 273.1959.
实施例464-甲基-4-乙基-2-苯基-1H-咪唑-5-酮
1H NMR(400MHz,CDCl3,ppm)δ10.23(br,1H),7.94(d,J=7.0Hz,2H),7.57-7.51(m,3H),1.92(q,J=7.0Hz,2H),1.47(s,3H),0.84(t,J=7.4Hz,3H);13C NMR(125MHz,CDCl3,ppm)δ190.1,158.1,131.7,128.8,128.4,126.9,73.0,30.9,22.9,8.2;MS(EI)m/z(%)202,173,104(100),77,51;HRMS calcd.for:C12H15ON2[M+H]+203.1179,found 203.1176.
实施例474-乙基-4-丙基-2-苯基-1H-咪唑-5-酮
1H NMR(500MHz,CDCl3,ppm)δ10.11(br,1H),7.93(d,J=7.1Hz,2H),7.58-7.50(m,3H),1.96-1.81(m,4H),1.31-1.13(m,2H),0.87(t,J=7.3Hz,3H),0.81(t,J=7.4Hz,3H);13C NMR(125MHz,CDCl3,ppm)δ189.7,158.4,131.7,128.8,128.3,126.9,77.2,39.2,30.3,16.9,14.1,7.9;MS(EI)m/z(%)230,187,104(100),77,51;HRMS calcd.for:C14H19ON2[M+H]+231.1492,found 231.1491.
实施例484-丙基-4-丁基-2-苯基-1H-咪唑-5-酮
1H NMR(500MHz,CDCl3,ppm)δ9.98(br,1H),7.94(d,J=4.7Hz,2H),7.59-7.51(m,3H),1.93-1.8(m,4H),1.32-1.09(m,6H),0.86(t,J=7.3Hz,3H),0.82(t,J=7.2Hz,3H);13CNMR(125MHz,CDCl3,ppm)δ189.7,158.3,131.7,128.7,128.3,126.9,76.2,39.5,37.1,25.5,22.6,16.8,14.0,13.8;MS(EI)m/z(%)258,187,104(100),77,57;HRMS calcd.for:C16H23ON2[M+H]+259.1805,found 259.1804.
实施例504-甲基-2,4-二苯基-1H-咪唑-5-酮
1H NMR(400MHz,CDCl3,ppm)δ10.14(br,1H),8.01(d,J=7.0Hz,2H),7.65(d,J=7.6Hz,2H),7.61-7.52(m,3H),7.38-7.27(m,3H),1.84(s,3H);13C NMR(125MHz,CDCl3,ppm)δ188.7,158.9,139.5,132.0,128.8,128.4,128.2,127.7,127.1,125.7,73.5,25.4;MS(EI)m/z(%)250,180,104(100),77,51;HRMS calcd.for:C16H15ON2[M+H]+251.1179,found251.1178.
实施例542,4,4-三苯基-1H-咪唑-5-酮
1H NMR(400MHz,CDCl3,ppm)δ10.05(br,1H),8.01(d,J=7.2Hz,2H),7.62-7.49(m,7H),7.35-7.27(m,6H);13C NMR(100MHz,CDCl3,ppm)δ185.9,158.2,140.3,132.1,129.2,128.9,128.4,127.8,127.4,127.2,84.1;MS(EI)m/z(%)312,269,180(100),104,51.
实施例584-甲基-2-环丙基-4-苯基-1H-咪唑-5-酮
MS(EI)m/z(%)214,180,104(100),77,51;HRMS calcd.for:C16H15ON2[M+H]+215.1138,found 215.1136.
实施例597-甲基-2-(4-氯苯基)-1,3-二氮杂螺[4,4]壬-1-烯-4-酮
MS(EI)m/z(%)262,180,104(100),77,51;HRMS calcd.for:C16H15ON2[M+H]+263.1337,found 263.1334.
实施例604-甲基-4-正丁基-2-(4-氯苯基)-1H-咪唑-5-酮
MS(EI)m/z(%)264,180,104(100),77,51;HRMS calcd.for:C16H15ON2[M+H]+265.1428,found 265.1426.
Claims (7)
1.一种合成4,4-二取代-4,5-二氢-1H–咪唑-5-酮、衍生物的方法,其特征在于在碱和氧化剂的作用下,将脒类化合物、酮和有机溶剂混合进行反应、纯化得到产物;
构成4,4-二取代-4,5-二氢-1H–咪唑-5-酮及其衍生物为
式Ⅰ,
其中
n为0或2-7的整数
R选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基;
R1选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基;
R2、R3选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基;
酮为式Ⅱ,
其中
n为0或2-7的整数
R1选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或未取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基;
R2、R3选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或非取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基;
脒类化合物为式Ⅲ,
其中
m为1-3的整数,
x为0-6,
M为HF、HCl、HBr、HI、HNO3、HOAc、H2SO4、H3PO4;
R选自氢原子;C1-C10的直链、支链、环状烷基;取代或非取代的C6-C20芳基;取代或非取代的含有氮、氧、硫原子的杂环基团;其中芳基或者杂环基团的取代基选自C1-C10的直链、支链、环状烷基,卤素基,硝基,氨基;
所述4,4-二取代-4,5-二氢-1H–咪唑-5-酮、衍生物的合成,它在碱和氧化剂的作用下,将脒类化合物、酮和有机溶剂混合进行反应、纯化得到产物;
包括以下步骤,
⑴加入碱、脒类化合物、酮和有机溶剂;
⑵将反应物充分混合,充入1 atm O2加热反应;
⑶纯化得产物。
2.根据权利要求1所述的合成方法,其特征在于式Ⅱ中的环状酮或链状酮选自环己酮,4-甲基环己酮,4-乙基环己酮,4-异丙基环己酮,4-正戊基环己酮,4-叔戊基环己酮,4-环丙基环己酮,4-苯基环己酮,4-(3-噻吩基)环己酮,4-(3-(5-氯噻吩基))环己酮,4-(4-硝基苯基)环己酮,环庚酮,环辛酮,环十二酮,2-戊酮,2-己酮,4-甲基-2-戊酮,2-庚酮,2-辛酮,2-壬酮,2-癸酮,2-二十酮,3-戊酮,4-庚酮,5-壬酮,8-十五酮,苯丙酮,对甲基苯丙酮,对氯苯丙酮,对硝基苯丙酮,1,2-二苯基乙酮,1,2-双(4-异丙基苯基)乙酮,1,2-双(4-溴苯基)乙酮,1,2-双(4-氨基苯基)乙酮。
3.根据权利要求1所述的合成方法,其特征在于式Ⅲ中的脒类化合物选自苯甲脒盐酸盐一水合物、4-甲基苯甲脒盐酸盐、4-氯苯甲脒盐酸盐、4-溴苯甲脒盐酸盐、4-三氟甲基苯甲脒盐酸盐、4-硝基苯甲脒磷酸盐、4-氨基苯甲脒硝酸盐、2-甲基苯甲脒氢碘酸盐、2-氯苯甲脒硫酸盐、3-甲脒基吡啶盐酸盐、4-甲脒基吡啶醋酸盐、醋酸甲脒、盐酸乙脒、环丙甲脒盐酸盐、4-异丙基苯甲脒硝酸盐、4-环丙基苯甲脒氢氟酸盐、3-噻吩甲脒氢溴酸盐、3-呋喃甲脒盐酸盐、3-(5-氯噻吩基)甲脒盐酸盐。
4.根据权利要求1所述的合成方法,其特征在于所用碱是KHCO3、K2CO3、Na2CO3、K3PO4、K2HPO4、KOH、NaOH、CsOH、叔丁醇钾、叔丁醇钠、乙醇钠、甲醇钠中的一种或数种。
5.根据权利要求1所述的合成方法,其特征在于所用有机溶剂为吡啶、喹啉、三乙胺、NMP、DMA、DMSO、1,4-二氧六环、甲苯。
6.根据权利要求1所述的合成方法,其特征在于所用脒类化合物,酮和碱的摩尔比为1:1.1~6:1.1~10。
7.根据权利要求1所述的合成方法,其特征在于所述反应温度为20 oC-200 oC。
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