CN112457260B - N-杂环芳基喹唑啉-4-胺化合物及其制备方法 - Google Patents
N-杂环芳基喹唑啉-4-胺化合物及其制备方法 Download PDFInfo
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- CN112457260B CN112457260B CN202011421165.8A CN202011421165A CN112457260B CN 112457260 B CN112457260 B CN 112457260B CN 202011421165 A CN202011421165 A CN 202011421165A CN 112457260 B CN112457260 B CN 112457260B
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- 238000002360 preparation method Methods 0.000 title abstract description 37
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 24
- -1 heterocyclic arylamine Chemical class 0.000 claims abstract description 19
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical class COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 235000019253 formic acid Nutrition 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 7
- HLCPWBZNUKCSBN-UHFFFAOYSA-N 2-aminobenzonitrile Chemical class NC1=CC=CC=C1C#N HLCPWBZNUKCSBN-UHFFFAOYSA-N 0.000 claims abstract description 5
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims abstract description 5
- RWZYAGGXGHYGMB-UHFFFAOYSA-N o-aminobenzenecarboxylic acid Natural products NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 6
- 238000004821 distillation Methods 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 17
- 239000010949 copper Substances 0.000 abstract description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 abstract description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 abstract description 4
- 230000005494 condensation Effects 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 238000006482 condensation reaction Methods 0.000 abstract description 2
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 abstract description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- DBGFGNCFYUNXLD-UHFFFAOYSA-N 4-chloropyrimidin-2-amine Chemical compound NC1=NC=CC(Cl)=N1 DBGFGNCFYUNXLD-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 16
- PPJAGCBNZHJIOE-UHFFFAOYSA-N FC1=CC=C2C(NC3=NC=CC(Cl)=N3)=NC=NC2=C1 Chemical compound FC1=CC=C2C(NC3=NC=CC(Cl)=N3)=NC=NC2=C1 PPJAGCBNZHJIOE-UHFFFAOYSA-N 0.000 description 15
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical class C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 description 8
- CBXKVIFVKCNVGJ-UHFFFAOYSA-N 2-amino-4-fluorobenzonitrile Chemical compound NC1=CC(F)=CC=C1C#N CBXKVIFVKCNVGJ-UHFFFAOYSA-N 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 5
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 5
- CWUMAUMHRXFDTR-UHFFFAOYSA-N COC(C=C(C1=C2)N=CN=C1NC1=NC=CC(Cl)=N1)=C2[N+]([O-])=O Chemical compound COC(C=C(C1=C2)N=CN=C1NC1=NC=CC(Cl)=N1)=C2[N+]([O-])=O CWUMAUMHRXFDTR-UHFFFAOYSA-N 0.000 description 4
- BLANPFMTILUJJW-UHFFFAOYSA-N COC1=CC(Cl)=NC(NC2=NC=NC3=CC(F)=CC=C23)=N1 Chemical compound COC1=CC(Cl)=NC(NC2=NC=NC3=CC(F)=CC=C23)=N1 BLANPFMTILUJJW-UHFFFAOYSA-N 0.000 description 4
- ZNQGBPAKWVDBLM-UHFFFAOYSA-N COC1=CC=C2C(NC3=NC=CC(Cl)=N3)=NC=NC2=C1 Chemical compound COC1=CC=C2C(NC3=NC=CC(Cl)=N3)=NC=NC2=C1 ZNQGBPAKWVDBLM-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- OHXRDHXNJFGKMA-UHFFFAOYSA-N FC1=CC=C2C(NC3=NC(Cl)=CC(Cl)=N3)=NC=NC2=C1 Chemical compound FC1=CC=C2C(NC3=NC(Cl)=CC(Cl)=N3)=NC=NC2=C1 OHXRDHXNJFGKMA-UHFFFAOYSA-N 0.000 description 4
- HMHWUSKOMBUIPF-UHFFFAOYSA-N FC1=CC=C2C(NC3=NC(Cl)=NC(Cl)=C3)=NC=NC2=C1 Chemical compound FC1=CC=C2C(NC3=NC(Cl)=NC(Cl)=C3)=NC=NC2=C1 HMHWUSKOMBUIPF-UHFFFAOYSA-N 0.000 description 4
- MWNAXMIANPVTIW-UHFFFAOYSA-N FC1=CC=C2C(NC3=NC(N4CCOCC4)=CC(Cl)=N3)=NC=NC2=C1 Chemical compound FC1=CC=C2C(NC3=NC(N4CCOCC4)=CC(Cl)=N3)=NC=NC2=C1 MWNAXMIANPVTIW-UHFFFAOYSA-N 0.000 description 4
- CWAFKSKZQGEZFY-UHFFFAOYSA-N FC1=CC=C2C(NC3=NC(N4CCOCC4)=CC(N4CCOCC4)=N3)=NC=NC2=C1 Chemical compound FC1=CC=C2C(NC3=NC(N4CCOCC4)=CC(N4CCOCC4)=N3)=NC=NC2=C1 CWAFKSKZQGEZFY-UHFFFAOYSA-N 0.000 description 4
- AUHNOPHWQBUZOE-UHFFFAOYSA-N FC1=CC=C2C(NC3=NC=CC(Cl)=C3)=NC=NC2=C1 Chemical compound FC1=CC=C2C(NC3=NC=CC(Cl)=C3)=NC=NC2=C1 AUHNOPHWQBUZOE-UHFFFAOYSA-N 0.000 description 4
- XLKLWGJLCWQNPF-UHFFFAOYSA-N FC1=CC=C2C(NC3=NC=CC(N4CCOCC4)=C3)=NC=NC2=C1 Chemical compound FC1=CC=C2C(NC3=NC=CC(N4CCOCC4)=C3)=NC=NC2=C1 XLKLWGJLCWQNPF-UHFFFAOYSA-N 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- SMPFVORBOQSDCH-UHFFFAOYSA-N [O-][N+](C(C=C1C(NC2=NC=CC(Cl)=N2)=NC=NC1=C1)=C1F)=O Chemical compound [O-][N+](C(C=C1C(NC2=NC=CC(Cl)=N2)=NC=NC1=C1)=C1F)=O SMPFVORBOQSDCH-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YQNRGPHLSFQTHM-UHFFFAOYSA-N FC1=CC=C2C(NC3=NC=CC(N4CCOCC4)=N3)=NC=NC2=C1 Chemical compound FC1=CC=C2C(NC3=NC=CC(N4CCOCC4)=N3)=NC=NC2=C1 YQNRGPHLSFQTHM-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 2
- DRGLHMZTIPPDDJ-UHFFFAOYSA-N COC1=NC(NC2=NC=NC3=CC(F)=CC=C23)=NC(N2CCOCC2)=C1 Chemical compound COC1=NC(NC2=NC=NC3=CC(F)=CC=C23)=NC(N2CCOCC2)=C1 DRGLHMZTIPPDDJ-UHFFFAOYSA-N 0.000 description 2
- CJDINHVXZXQLFM-UHFFFAOYSA-N FC1=CC=C2C(NC3=CC(Cl)=NC=C3)=NC=NC2=C1 Chemical compound FC1=CC=C2C(NC3=CC(Cl)=NC=C3)=NC=NC2=C1 CJDINHVXZXQLFM-UHFFFAOYSA-N 0.000 description 2
- LQAPAVUPOABRBC-UHFFFAOYSA-N FC1=CC=C2C(NC3=CC(N4CCOCC4)=NC=C3)=NC=NC2=C1 Chemical compound FC1=CC=C2C(NC3=CC(N4CCOCC4)=NC=C3)=NC=NC2=C1 LQAPAVUPOABRBC-UHFFFAOYSA-N 0.000 description 2
- JRHXPOCMUQVANX-UHFFFAOYSA-N FC1=CC=C2C(NC3=NC(Cl)=NC(N4CCOCC4)=C3)=NC=NC2=C1 Chemical compound FC1=CC=C2C(NC3=NC(Cl)=NC(N4CCOCC4)=C3)=NC=NC2=C1 JRHXPOCMUQVANX-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical class 0.000 description 2
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- UPVBKNZVOJNQKE-UHFFFAOYSA-N 2,6-dichloropyrimidin-4-amine Chemical group NC1=CC(Cl)=NC(Cl)=N1 UPVBKNZVOJNQKE-UHFFFAOYSA-N 0.000 description 1
- LYDXIVHSGDCURB-UHFFFAOYSA-N 2-amino-4-methoxy-5-nitrobenzonitrile Chemical group COC1=CC(N)=C(C#N)C=C1[N+]([O-])=O LYDXIVHSGDCURB-UHFFFAOYSA-N 0.000 description 1
- WLKYODIBWNIWDK-UHFFFAOYSA-N 2-amino-4-nitrobenzonitrile Chemical group NC1=CC([N+]([O-])=O)=CC=C1C#N WLKYODIBWNIWDK-UHFFFAOYSA-N 0.000 description 1
- AFMPMSCZPVNPEM-UHFFFAOYSA-N 2-bromobenzonitrile Chemical compound BrC1=CC=CC=C1C#N AFMPMSCZPVNPEM-UHFFFAOYSA-N 0.000 description 1
- FZGYHUPILYKVDN-UHFFFAOYSA-N 2-chloro-6-morpholin-4-ylpyrimidin-4-amine Chemical group ClC1=NC(N)=CC(N2CCOCC2)=N1 FZGYHUPILYKVDN-UHFFFAOYSA-N 0.000 description 1
- ZSXQDGMZXKOADT-UHFFFAOYSA-N 2-morpholin-4-ylpyridin-4-amine Chemical group NC1=CC=NC(N2CCOCC2)=C1 ZSXQDGMZXKOADT-UHFFFAOYSA-N 0.000 description 1
- JPZOAVGMSDSWSW-UHFFFAOYSA-N 4,6-dichloropyrimidin-2-amine Chemical group NC1=NC(Cl)=CC(Cl)=N1 JPZOAVGMSDSWSW-UHFFFAOYSA-N 0.000 description 1
- RRWUHIBMUBKKAY-UHFFFAOYSA-N 4,6-dimorpholin-4-ylpyrimidin-2-amine Chemical group N=1C(N)=NC(N2CCOCC2)=CC=1N1CCOCC1 RRWUHIBMUBKKAY-UHFFFAOYSA-N 0.000 description 1
- BLBDTBCGPHPIJK-UHFFFAOYSA-N 4-Amino-2-chloropyridine Chemical group NC1=CC=NC(Cl)=C1 BLBDTBCGPHPIJK-UHFFFAOYSA-N 0.000 description 1
- VFEYBTFCBZMBAU-UHFFFAOYSA-N 4-chloro-6-methoxypyrimidin-2-amine Chemical group COC1=CC(Cl)=NC(N)=N1 VFEYBTFCBZMBAU-UHFFFAOYSA-N 0.000 description 1
- CWKCJXZYXLANTB-UHFFFAOYSA-N 4-chloro-6-morpholin-4-ylpyrimidin-2-amine Chemical group NC1=NC(Cl)=CC(N2CCOCC2)=N1 CWKCJXZYXLANTB-UHFFFAOYSA-N 0.000 description 1
- RQMWVVBHJMUJNZ-UHFFFAOYSA-N 4-chloropyridin-2-amine Chemical group NC1=CC(Cl)=CC=N1 RQMWVVBHJMUJNZ-UHFFFAOYSA-N 0.000 description 1
- GVRRXASZZAKBMN-UHFFFAOYSA-N 4-chloroquinazoline Chemical compound C1=CC=C2C(Cl)=NC=NC2=C1 GVRRXASZZAKBMN-UHFFFAOYSA-N 0.000 description 1
- CJBPWORQCZUZID-UHFFFAOYSA-N 4-methoxy-6-morpholin-4-ylpyrimidin-2-amine Chemical group COc1cc(nc(N)n1)N1CCOCC1 CJBPWORQCZUZID-UHFFFAOYSA-N 0.000 description 1
- KEQRMEXRBFYCCN-UHFFFAOYSA-N 4-morpholin-4-ylpyridin-2-amine Chemical group C1=NC(N)=CC(N2CCOCC2)=C1 KEQRMEXRBFYCCN-UHFFFAOYSA-N 0.000 description 1
- UMUSFEOPXQLLAG-UHFFFAOYSA-N 4-morpholin-4-ylpyrimidin-2-amine Chemical group NC1=NC=CC(N2CCOCC2)=N1 UMUSFEOPXQLLAG-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 238000006088 Dimroth rearrangement reaction Methods 0.000 description 1
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical class NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- LWOVBHWWFDZQLG-UHFFFAOYSA-N NC1=C(C#N)C=C(C(=C1)F)[N+](=O)[O-] Chemical group NC1=C(C#N)C=C(C(=C1)F)[N+](=O)[O-] LWOVBHWWFDZQLG-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 229960001686 afatinib Drugs 0.000 description 1
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000003937 benzamidines Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- UZVFDUCTYXQQJJ-UHFFFAOYSA-N quinazolin-4-yl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC1=NC=NC2=CC=CC=C12 UZVFDUCTYXQQJJ-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种N‑杂环芳基喹唑啉‑4‑胺化合物及其制备方法,用三氟甲磺酸铜(Cu(OTf)3)催化取代邻氨基苯甲腈、杂环芳胺和甲酸发生串联的加成/缩合/环化反应得到N‑杂环芳基喹唑啉‑4‑胺化合物(式1),其中,X、Y、Z各自独立地为N或CH,R1为H或NO2,R2为F或OCH3,R3、R4各自独立地为H、Cl、OCH3或4‑吗啉基。本发明方法合成路线短,反应条件温和,目标产物收率高,操作安全简便,避免使用有毒有害的氯化亚砜和三氯氧磷,对环境友好,为合成N‑芳基喹唑啉‑4‑胺化合物提供了一种高效简便的绿色方法,具有潜在的工业化应用前景。
Description
技术领域
本发明涉及喹唑啉-4-胺化合物的合成,具体涉及一种取代邻氨基苯甲腈、杂环芳胺和甲酸发生三组分串联反应制备N-杂环芳基喹唑啉-4-胺化合物的方法,属于有机合成技术领域。
背景技术
4-氨基喹唑啉类化合物是一种特异性激酶抑制剂,被用作肿瘤生长抑制剂,对肺癌、乳腺癌、肝癌、结肠癌、前列腺癌、膀胱癌等细胞具有抑制活性,目前美国食品药品管理局(FDA)已经批准了多种以4-氨基喹唑啉为母核的抗肿瘤药物,如吉非替尼, 厄洛替尼,阿法替尼, 达克替尼, 妥卡替尼和拉帕替尼等(式1)。此外,4-氨基喹唑啉类化合物还具有抗病毒、抗菌、抗炎、抗结核、抗疟原虫、抗心血管疾病、抗帕金森氏病等生物活性,现已成为靶向药物创制的研究热点之一。
式1 FDA批准的4-氨基喹唑啉类抗肿瘤药物。
4-氨基喹唑啉化合物的经典合成方法(式2)主要有:(1)以邻氨基苯甲酸或其酯为原料,首先与乙酸甲脒或甲酰胺缩合环化得到喹唑啉-4(3H)-酮化合物,然后氯化或酯化得到4-氯喹唑啉或喹唑啉-4-基对甲苯磺酸酯,最后与胺进行芳香亲核取代(SNAr)反应合成4-氨基喹唑林化合物(Teng Y, Li X, Ren S, et al. Eur J Med Chem, 2020, 208,112865; Zhuo L S, Wu F X, Wang M S, et al.Eur J Med Chem, 2020, 208, 112785;Mularski J, Malarz K, Pacholczyk M, et al. Eur J Med Chem, 2019, 163, 610-625);或者喹唑啉-4(3H)-酮与苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)、1,8-二氮杂二环十一碳-7-烯(DBU)和胺直接“一锅”合成4-氨基喹唑啉化合物(WanZ K, Wacharasindhu S, Levins C G, et al. J Org Chem, 2007, 72(26): 10194-10210)。(2)以邻氨基苯甲腈为原料,三氯化铝催化下与胺加成得到N-取代苯甲脒,接着与甲酸缩合环化合成4-氨基喹唑啉化合物(Szczepankiewicz W, Suwiński J, Bujok R.Tetrahedron, 2000, 56(47): 9343-9349);或者与N,N-二甲基甲酰胺二甲基缩醛缩合得到N-取代甲脒,再与胺发生Dimroth重排合成4-氨基喹唑啉化合物(Schmitt J, Huang S,Goodfellow E, et al. J Med Chem, 2020, 63(11): 5752-5762)。(3)以邻溴苯甲腈为原料,CuI催化下与胺加成得到N-取代苯甲脒,然后在CuI催化下与甲酰胺缩合环化合成4-氨基喹唑啉化合物(刘长春,顾言语, 梁恩.精细化工, 2019, 36(04): 776-780)。这些合成方法反应步骤多,目标产物收率低,反应条件苛刻,后处理困难,对环境不友好,不利于工业化生产。因此,开发一种制备N-杂环芳基喹唑啉-4-胺的高效简便绿色方法具有重要的研究意义。
式2 4-氨基喹唑啉化合物的经典合成路线
发明内容
本发明解决的技术问题是提供N-杂环芳基喹唑啉-4-胺的制备方法,该制备方法以取代邻氨基苯甲腈、芳胺和甲酸为原料通过发生串联的加成/缩合/环化反应得到结构多样的N-杂环芳基喹唑啉-4-胺化合物。
本发明另一要解决的技术问题是提供由该制备方法得到的N-杂环芳基喹唑啉-4-胺化合物。
本发明通过以下技术方案实现:
一种N-杂环芳基喹唑啉-4-胺化合物,其特征在于具有以下结构式:
其中,X、Y、Z各自独立地为N或CH,R1为H或NO2,R2为F或OCH3,R3、R4各自独立地为H、Cl、OCH3或4-吗啉基。
N-杂环芳基喹唑啉-4-胺化合物(3a~3p)的具体示例如下:
上述N-杂环芳基喹唑啉-4-胺化合物的制备方法,包括以下步骤:
在单口烧瓶中加入取代邻氨基苯甲腈(1a~1d)、杂环芳胺(2a~2m)、甲酸和催化剂,搅拌反应至完全。反应液冷却至室温后,减压蒸馏除去剩余甲酸,残留物中加入饱和碳酸氢钠溶液,用乙酸乙酯萃取,有机相用无水硫酸钠干燥,过滤并减压蒸除溶剂,残留物用无水乙醇重结晶,40℃真空干燥24 h,得到N-杂环芳基喹唑啉-4-胺化合物(3a~3p)。
具体化学反应式描述如下:
所述N-杂环芳基喹唑啉-4-胺化合物的制备方法中,取代邻氨基苯甲腈与杂环芳胺的物质的量比为1:1~1:1.5,优选为1:1.2;取代邻氨基苯甲腈为以下化合物1a~1d中的一种:
杂环芳胺为以下化合物2a~2m中的一种:
所述N-杂环芳基喹唑啉-4-胺化合物的制备方法中,甲酸的用量为1~3ml/mmol取代邻氨基苯甲腈,优选为2ml/mmol取代邻氨基苯甲腈;所用的催化剂为三氟甲磺酸铜(Cu(OTf)3)、或氯化铜,优选为三氟甲磺酸铜;催化剂的用量为0.05~0.2mmol/mmol取代邻氨基苯甲腈,优选为0.1mmol/mmol取代邻氨基苯甲腈;反应温度为80~110℃,优选为110℃;反应时间为8~16h,优选为12h。
本发明中,首先使用CuCl或CuI为催化剂,甲酸既作为反应物也作为溶剂,与底物1a和2a在110℃反应12 h,可以得到预期产物(3a),但是收率较低。接着使用Cu(Ⅱ)盐为催化剂,预期产物(3a)的收率得到明显的提高,其中Cu(OTf)2作为催化剂时,反应可以基本转化完全,预期产物(3a)的收率最高。其它的三氟甲磺酸盐不能更好地催化反应进行,预期产物(3a)的收率很低。Cu(OTf)2用量为10%(摩尔分数,以底物1a计)时,对反应的催化效果最好;减少Cu(OTf)2用量,预期产物(3a)的收率明显降低;增加Cu(OTf)2用量,预期产物(3a)的收率没有改变。对其它的反应溶剂进行筛选,发现甲苯和二氧六环作为溶剂时,并不能得到更高的收率;DMF作为溶剂时,没有生成预期产物(3a)。
本发明中,底物2a过量对反应有利,当底物1a和2a的物质的量比达到1:1.2后,预期产物(3a)的收率无显著增加。反应在110℃下能顺利进行完全,降低反应温度对反应不利,预期产物(3a)的收率明显下降。随着反应时间的延长,反应能逐渐转化完全;当反应时间达到12 h后,预期产物(3a)的收率不再增加。
与现有技术相比,本发明的合成路线短,反应条件温和,目标产物收率高,操作安全简便,避免使用有毒有害的氯化亚砜和三氯氧磷,对环境友好,为合成N-芳基喹唑啉-4-胺化合物提供了一种高效简便的绿色方法,具有潜在的工业化应用前景。
具体实施方式
以下结合实施例对本发明作进一步的阐述,实施例仅用于解释本发明,而不能理解为对本发明的限制。
实施例1
N-(4-氯嘧啶-2-基)-7-氟喹唑啉-4-胺(3a)的制备
在单口烧瓶中加入2-氨基-4-氟苯甲腈(1a)5mmol,2-氨基-4-氯嘧啶(2a)6mmol,甲酸20ml,三氟甲磺酸铜0.05mmol,110℃搅拌反应12h。反应液冷却至室温后,减压蒸馏除去剩余甲酸,残留物中加入饱和碳酸氢钠溶液100ml,用乙酸乙酯萃取(100ml×3),有机相用无水硫酸钠干燥,过滤并减压蒸除溶剂,残留物用无水乙醇重结晶,40℃真空干燥24 h,得到白色固体N-(4-氯嘧啶-2-基)-7-氟喹唑啉-4-胺(3a)1.17g,收率85%;
1HNMR(400MHz,DMSO-d6),δ:9.39(s, 1H), 8.73(s, 1H), 8.21(d, J=7.5Hz,1H), 8.18-8.14(m, 1H), 7.58-7.56(m, 1H), 7.26-7.22(m, 1H), 6.72(d, J=7.5Hz,1H);13CNMR(100MHz,DMSO-d6),δ:162.78, 159.77, 157.66, 157.48, 154.29, 153.37,149.62, 125.96, 115.11, 112.27, 112.20, 111.72。
实施例2
N-(4-吗啉基嘧啶-2-基)-7-氟喹唑啉-4-胺(3b)的制备
按照实施例1的制备方法,将2-氨基-4-氯嘧啶(2a)替换成2-氨基-4-吗啉基嘧啶(2b),得到白色固体N-(4-氯嘧啶-2-基)-7-氟喹唑啉-4-胺(3b)1.43g,收率88%。
1HNMR(400MHz,DMSO-d6),δ:9.26(s, 1H), 8.70(s, 1H), 8.26-8.23(m, 1H),8.15(d, J=7.5Hz, 1H), 7.47-7.45(m, 1H), 7.27-7.22(m, 1H), 6.23(d, J=7.5Hz,1H), 3.79-3.71(m, 4H), 3.70-3.61(m, 4H);13CNMR(100MHz,DMSO-d6),δ:161.53,161.04, 156.75, 156.04, 154.29, 153.34, 150.37, 125.90, 114.97, 112.20,111.27, 94.75, 66.63(2C), 46.90(2C)。
实施例3
N-(4,6-二氯嘧啶-2-基)-7-氟喹唑啉-4-胺(3c)的制备
按照实施例1的制备方法,将2-氨基-4-氯嘧啶(3a)替换成2-氨基-4,6-二氯嘧啶(3c),得到黄色固体N-(4,6-二氯嘧啶-2-基)-7-氟喹唑啉-4-胺(3c)1.18g,收率76%。
1HNMR(400MHz,DMSO-d6),δ:9.48(s, 1H), 8.70(s, 1H), 8.23-8.20(m, 1H),7.55-7.53(m, 1H), 7.24-7.20(m, 1H), 6.62(s, 1H);13CNMR(100MHz,DMSO-d6),δ:162.75, 157.88, 157.70(2C), 154.13, 153.36, 148.94, 125.88, 115.08, 112.27,112.14, 111.89。
实施例4
N-(4-氯-6-吗啉基嘧啶-2-基)-7-氟喹唑啉-4-胺(3d)的制备
按照实施例1的制备方法,将2-氨基-4-氯嘧啶(2a)替换成2-氨基-4-氯-6-吗啉基嘧啶(2d),得到白色固体N-(4-氯-6-吗啉基嘧啶-2-基)-7-氟喹唑啉-4-胺(3d)1.44g,收率80%。
1HNMR(400MHz,DMSO-d6),δ:9.26(s, 1H), 8.74(s, 1H), 8.28-8.24(m, 1H),7.49-7.46(m, 1H), 7.26-7.22(m, 1H), 5.97(s, 1H), 3.75(t, J=7.1Hz, 4H), 3.55(t, J=7.1Hz, 4H);13CNMR(100MHz,DMSO-d6),δ:162.67, 161.52, 157.36, 156.19,154.16, 153.36, 150.47, 125.93, 115.06, 112.26, 112.23, 95.40, 66.63(2C),46.72(2C)。
实施例5
N-(4,6-二吗啉基嘧啶-2-基)-7-氟喹唑啉-4-胺(3e)的制备
按照实施例1的制备方法,将2-氨基-4-氯嘧啶(2a)替换成2-氨基-4,6-二吗啉基嘧啶(2e),得到白色固体N-(4,6-二吗啉基嘧啶-2-基)-7-氟喹唑啉-4-胺(3e)1.87g,收率91%。
1HNMR(400MHz,DMSO-d6),δ:9.59(s, 1H), 8.75(s, 1H), 8.22(dd, J=7.5,5.0Hz, 1H), 7.50(dd, J=8.0, 1.6Hz, 1H), 7.29(td, J=7.8, 1.5Hz, 1H), 5.35(s,1H), 3.75(t, J=7.3Hz, 8H), 3.62(t, J=6.8Hz, 8H);13CNMR(100 MHz,DMSO-d6),δ:162.82(2C), 162.15, 157.95, 154.12, 153.34, 150.21, 126.17, 114.54, 112.29,111.22, 76.82, 66.63(4C), 46.63(4C)。
实施例6
N-(4-氯-6-甲氧基嘧啶-2-基)-7-氟喹唑啉-4-胺(3f)的制备
按照实施例1的制备方法,将2-氨基-4-氯嘧啶(2a)替换成2-氨基-4-氯-6-甲氧基嘧啶(2f),得到白色固体N-(4-氯-6-甲氧基嘧啶-2-基)-7-氟喹唑啉-4-胺(3f)1.29g,收率84%。
1HNMR(400MHz,DMSO-d6),δ:9.82(s, 1H), 8.70(s, 1H), 8.26(dd, J=7.5,5.0Hz, 1H), 7.53(dd, J=8.0, 1.5Hz, 1H), 7.22(td, J=7.7, 1.5Hz, 1H), 6.55(s,1H), 3.93(s, 3H);13CNMR(100 MHz,DMSO-d6),δ:170.01, 162.55, 158.44, 156.36,154.04, 153.35, 149.32, 125.88, 115.08, 112.20, 112.19, 96.27, 53.87。
实施例7
N-[4-甲氧基-6-(4-吗啉基)嘧啶-2-基]-7-氟喹唑啉-4-胺(3g)的制备
按照实施例1的制备方法,将2-氨基-4-氯嘧啶(2a)替换成2-氨基-4-甲氧基-6-(4-吗啉基)嘧啶(2g),得到白色固体N-[4-甲氧基-6-(4-吗啉基)嘧啶-2-基]-7-氟喹唑啉-4-胺(3g)1.60g,收率90%。
1HNMR(400MHz,DMSO-d6),δ:9.32(s, 1H), 8.74(s, 1H), 8.25(dd, J=7.5,5.0Hz, 1H), 7.49(dd, J=8.0, 1.5Hz, 1H), 7.28(td, J=7.7, 1.5Hz, 1H), 5.59(s,1H), 3.90(s, 3H), 3.72~3.64(m, 4H), 3.55(t, J=6.8Hz, 4H);13CNMR(100 MHz,DMSO-d6),δ:168.02, 162.75, 161.49, 160.24, 158.47, 154.41, 153.37, 150.34, 125.93,115.14, 112.27, 112.23, 80.56, 66.63(2C), 53.88, 46.70(2C)。
实施例8
N-(2,6-二氯嘧啶-4-基)-7-氟喹唑啉-4-胺(3h)的制备
按照实施例1的制备方法,将2-氨基-4-氯嘧啶(2a)替换成4-氨基-2,6-二氯嘧啶(2h),得到黄色固体N-(2,6-二氯嘧啶-4-基)-7-氟喹唑啉-4-胺(3h)1.22g,收率79%。
1HNMR(400MHz,DMSO-d6),δ:9.93(s, 1H), 8.77(s, 1H), 8.27(dd, J=7.5,5.0Hz, 1H), 7.55(dd, J=8.0, 1.5Hz, 1H), 7.22(td, J=7.8, 1.6Hz, 1H), 6.50(s,1H);13CNMR(100 MHz,DMSO-d6),δ:162.75, 159.61, 158.60, 157.63, 154.37, 153.19,150.08, 125.88, 114.60, 112.29, 112.20, 105.97。
实施例9
N-(2-氯-6-吗啉基嘧啶-4-基)-7-氟喹唑啉-4-胺(3i)的制备
按照实施例1的制备方法,将2-氨基-4-氯嘧啶(2a)替换成4-氨基-2-氯-6-(4-吗啉基)嘧啶(2i),得到白色固体N-(2-氯-6-吗啉基嘧啶-4-基)-7-氟喹唑啉-4-胺(3i)1.50g,收率83%。
1HNMR(400MHz,DMSO-d6),δ:9.78(s, 1H), 8.75(s, 1H), 8.27(dd, J=7.5,5.0Hz, 1H), 7.49(dd, J=7.9, 1.6Hz, 1H), 7.25(td, J=7.7, 1.5Hz, 1H), 6.86(s,1H), 3.75(t, J=7.1Hz, 4H), 3.54(t, J=7.1Hz, 4H);13CNMR(100 MHz,DMSO-d6),δ:162.45, 161.52, 157.73, 157.52, 154.39, 153.04, 150.22, 125.93, 114.84,112.23, 111.21, 87.43, 66.63(2C), 46.72(2C)。
实施例10
N-(4-氯吡啶-2-基)-7-氟喹唑啉-4-胺(3j)的制备
按照实施例1的制备方法,将2-氨基-4-氯嘧啶(2a)替换成2-氨基-4-氯吡啶(2j),得到白色固体N-(4-氯吡啶-2-基)-7-氟喹唑啉-4-胺(3j)1.13g,收率82%。
1HNMR(400MHz,DMSO-d6),δ:10.01(s, 1H), 8.77(s, 1H), 8.25~8.15(m, 2H),7.57(dd, J=8.1, 1.5Hz, 1H), 7.20(td, J=7.8, 1.5Hz, 1H), 7.06(dd, J=7.5,1.5Hz, 1H), 6.94(d, J=1.6Hz, 1H);13CNMR(100 MHz,DMSO-d6),δ:162.78, 154.97,154.64, 153.43, 149.78, 147.71, 137.69, 125.96, 115.93, 114.60, 113.02,112.20, 109.86。
实施例11
N-(4-吗啉基吡啶-2-基)-7-氟喹唑啉-4-胺(3k)的制备
按照实施例1的制备方法,将2-氨基-4-氯嘧啶(2a)替换成2-氨基-4-吗啉基吡啶(2k),得到白色固体N-(4-吗啉基吡啶-2-基)-7-氟喹唑啉-4-胺(3k)1.43g,收率88%。
1HNMR(400MHz,DMSO-d6),δ:9.83(s, 1H), 8.75(s, 1H), 8.24(dd, J=7.5,5.0Hz, 1H), 7.96(d, J=7.5Hz, 1H), 7.46(dd, J=8.0, 1.5Hz, 1H), 7.15(td, J=7.8,1.5Hz, 1H), 7.03(d, J=1.6Hz, 1H), 6.24(dd, J=7.5, 1.5Hz, 1H), 3.75(t, J=7.1Hz, 4H), 3.39(t, J=7.1Hz, 4H);13CNMR(100 MHz,DMSO-d6),δ:161.53, 156.83,154.52, 154.37, 153.83, 150.41, 147.09, 125.90, 114.64, 112.33, 112.20,97.96, 96.65, 66.63(2C), 48.42(2C)。
实施例12
N-(2-氯吡啶-4-基)-7-氟喹唑啉-4-胺(3l)的制备
按照实施例1的制备方法,将2-氨基-4-氯嘧啶(2a)替换成4-氨基-2-氯吡啶(2l),得到白色固体N-(2-氯吡啶-4-基)-7-氟喹唑啉-4-胺(3l)1.16g,收率85%。
1HNMR(400MHz,DMSO-d6),δ:9.69(s, 1H), 8.67(s, 1H), 8.25~8.15(m, 2H),7.56~7.50(m, 2H), 7.22~7.12(m, 2H);13CNMR(100 MHz,DMSO-d6),δ:162.78, 153.71,153.57, 150.81, 149.64, 148.37, 145.48, 125.89, 115.11, 113.08, 112.20,112.06, 110.57。
实施例13
N-(2-吗啉基吡啶-4-基)-7-氟喹唑啉-4-胺(3m)的制备
按照实施例1的制备方法,将2-氨基-4-氯嘧啶(2a)替换成4-氨基-2-吗啉基吡啶(2m),得到白色固体N-(2-吗啉基吡啶-4-基)-7-氟喹唑啉-4-胺(3m)1.50g,收率92%。
1HNMR(400MHz,DMSO-d6),δ:9.78(s, 1H), 8.64(s, 1H), 8.26(dd, J=7.5,5.0Hz, 1H), 8.02(d, J=7.5Hz, 1H), 7.50~7.44(m, 2H), 7.15(td, J=7.8, 1.5Hz,1H), 7.04(d, J=1.5Hz, 1H), 3.77(t, J=7.4Hz, 4H), 3.64(t, J=6.8Hz, 4H);13CNMR(100 MHz,DMSO-d6),δ:161.53, 158.26, 153.42, 153.39, 150.48, 147.49, 145.86,125.96, 114.92, 112.20, 112.03, 107.78, 100.88, 66.63(2C), 46.74(2C)。
实施例14
N-(4-氯嘧啶-2-基)-7-甲氧基喹唑啉-4-胺(3n)的制备
按照实施例1的制备方法,将2-氨基-4-氟苯甲腈(1a)替换成2-氨基-4-硝基苯甲腈(1b),得到黄色固体N-(4-氯嘧啶-2-基)-7-甲氧基喹唑啉-4-胺(3n)1.31g,收率87%。
1HNMR(400MHz,DMSO-d6),δ:9.38(s, 1H), 8.72(d, J=1.6Hz, 1H), 8.64(s,1H), 8.28(dd, J=7.5, 1.5Hz, 1H), 8.20(d, J=7.5Hz, 1H), 7.87(d, J=7.5Hz, 1H),6.72(d, J=7.5Hz, 1H);13CNMR(100 MHz,DMSO-d6),δ:159.59, 157.93, 157.30, 154.10,153.93, 152.61, 146.06, 127.23, 126.83, 120.33, 113.60, 111.72。
实施例15
N-(4-氯嘧啶-2-基)-7-氟-6-硝基喹唑啉-4-胺(3o)的制备
按照实施例1的制备方法,将2-氨基-4-氟苯甲腈(1a)替换成2-氨基-4-氟-5-硝基苯甲腈(1c),得到橙红色固体N-(4-氯嘧啶-2-基)-7-氟-6-硝基喹唑啉-4-胺(3o)1.47g,收率92%。
1HNMR(400MHz,DMSO-d6),δ:9.53(s, 1H), 8.70(s, 1H), 8.62(d, J=5.0Hz,1H), 8.20(d, J=7.5Hz, 1H), 7.72(d, J=8.0Hz, 1H), 6.74(d, J=7.5Hz, 1H);13CNMR(100 MHz,DMSO-d6),δ:159.53, 158.44, 157.92, 157.29, 153.94, 153.31, 149.95,135.05, 123.68, 114.18, 112.00, 111.50。
实施例16
N-(4-氯嘧啶-2-基)-7-甲氧基-6-硝基喹唑啉-4-胺(3p)的制备
按照实施例1的制备方法,将2-氨基-4-氟苯甲腈(1a)替换成2-氨基-4-甲氧基-5-硝基苯甲腈(1d),得到土黄色固体N-(4-氯嘧啶-2-基)-7-甲氧基-6-硝基喹唑啉-4-胺(3p)1.34g,收率81%。
1HNMR(400MHz,DMSO-d6),δ:9.32(s, 1H), 8.87(s, 1H), 8.74(s, 1H), 8.20(d,J=7.5Hz, 1H), 7.39(s, 1H), 6.73(d, J=7.5Hz, 1H), 4.01(s, 3H);13CNMR(100 MHz,DMSO-d6),δ:159.53, 157.39, 157.30, 155.53, 154.32, 153.19, 151.32, 137.21,122.99, 112.15, 110.95, 106.48, 56.94。
Claims (1)
1.一种N-杂环芳基喹唑啉-4-胺化合物的制备方法,其特征在于包括以下步骤:
在单口烧瓶中加入物质的量比为1:1.2的取代邻氨基苯甲腈和杂环芳胺,三氟甲磺酸铜0.1mmol/mmol取代邻氨基苯甲腈,甲酸2ml/mmol取代邻氨基苯甲腈,110℃搅拌反应12h,反应液冷却至室温后,减压蒸馏除去剩余甲酸,残留物中加入饱和碳酸氢钠溶液,用乙酸乙酯萃取,有机相用无水硫酸钠干燥,过滤并减压蒸除溶剂,残留物用无水乙醇重结晶,40℃真空干燥24 h,得到N-杂环芳基喹唑啉-4-胺化合物;
其中,取代邻氨基苯甲腈为以下化合物1a~1d中的一种:
杂环芳胺为以下化合物2a~2m中的一种:
N-杂环芳基喹唑啉-4-胺化合物的结构式如下:
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101190899A (zh) * | 2007-12-26 | 2008-06-04 | 北京理工大学 | 一种合成1,2-二氢喹唑啉-4(3h)-酮类化合物的方法 |
CN103237801A (zh) * | 2010-08-31 | 2013-08-07 | 韩美科学株式会社 | 对细胞有凋亡诱导活性的喹啉或喹唑啉衍生物 |
CN108912059A (zh) * | 2018-06-14 | 2018-11-30 | 温州医科大学附属第医院 | 一种含氮杂环炎症抑制化合物的合成方法 |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101190899A (zh) * | 2007-12-26 | 2008-06-04 | 北京理工大学 | 一种合成1,2-二氢喹唑啉-4(3h)-酮类化合物的方法 |
CN103237801A (zh) * | 2010-08-31 | 2013-08-07 | 韩美科学株式会社 | 对细胞有凋亡诱导活性的喹啉或喹唑啉衍生物 |
CN108912059A (zh) * | 2018-06-14 | 2018-11-30 | 温州医科大学附属第医院 | 一种含氮杂环炎症抑制化合物的合成方法 |
Non-Patent Citations (2)
Title |
---|
Palladium(II)-Catalyzed Three-Component Tandem Cyclization Reaction for the One-Pot Assembly of 4-Arylquinazolines;Zijuan Wang et al.;《Synthesis》;20201019;第52卷;第1-9页 * |
Synthesis of 4-Arylaminoquinazolines and 2-Aryl-4-arylaminoquinazolines from 2-Aminobenzonitrile, Anilines and Formic Acid or Benzaldehydes;Wojciech Szczepankiewicz et al.;《Tetrahedron》;20001117;第56卷;第9343-9349页 * |
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