CN106957273A - 一种喹唑啉酮及其衍生物的制备方法 - Google Patents
一种喹唑啉酮及其衍生物的制备方法 Download PDFInfo
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- CN106957273A CN106957273A CN201710191427.8A CN201710191427A CN106957273A CN 106957273 A CN106957273 A CN 106957273A CN 201710191427 A CN201710191427 A CN 201710191427A CN 106957273 A CN106957273 A CN 106957273A
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- China
- Prior art keywords
- derivative
- preparation
- copper
- quinazolinone
- halobenzoyl
- Prior art date
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Links
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- -1 nitrile compounds Chemical class 0.000 claims abstract description 18
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 18
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 239000003208 petroleum Substances 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 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
- 150000007529 inorganic bases Chemical class 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 3
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 3
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 150000001879 copper Chemical class 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- 229960004643 cupric oxide Drugs 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000001119 stannous chloride Substances 0.000 claims description 3
- 235000011150 stannous chloride Nutrition 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- 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 description 2
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical group [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 2
- 229940112669 cuprous oxide Drugs 0.000 claims description 2
- 230000000694 effects Effects 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
- 229910052740 iodine Chemical group 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 229910052792 caesium Inorganic materials 0.000 claims 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 4
- 206010020772 Hypertension Diseases 0.000 abstract description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 3
- 230000000975 bioactive effect Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 201000005202 lung cancer Diseases 0.000 abstract description 3
- 208000020816 lung neoplasm Diseases 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- 208000019901 Anxiety disease Diseases 0.000 abstract description 2
- 230000003750 conditioning effect Effects 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 10
- 239000003480 eluent Substances 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 239000012299 nitrogen atmosphere Substances 0.000 description 10
- 239000012265 solid product Substances 0.000 description 10
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 9
- NHNAEZDWNCRWRW-UHFFFAOYSA-N 2-bromobenzamide Chemical class NC(=O)C1=CC=CC=C1Br NHNAEZDWNCRWRW-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000006073 displacement reaction Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 3
- 0 *C1=CI=CC=C1C(N)=O Chemical compound *C1=CI=CC=C1C(N)=O 0.000 description 2
- SIQZJFKTROUNPI-UHFFFAOYSA-N 1-(hydroxymethyl)-5,5-dimethylhydantoin Chemical compound CC1(C)N(CO)C(=O)NC1=O SIQZJFKTROUNPI-UHFFFAOYSA-N 0.000 description 2
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 238000010719 annulation reaction Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- QMGHHBHPDDAGGO-IIWOMYBWSA-N (2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[5-bromo-4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]pyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide Chemical compound CN(CCCNC1=NC(NC2=CC=C(OCCCOCCCCOCCCOCC(=O)N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)NCC3=CC=C(C=C3)C3=C(C)N=CS3)C(C)(C)C)C=C2)=NC=C1Br)C(=O)C1CCC1 QMGHHBHPDDAGGO-IIWOMYBWSA-N 0.000 description 1
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BVCOJESIQPNOIF-UHFFFAOYSA-N 2-(2-bromophenyl)acetonitrile Chemical class BrC1=CC=CC=C1CC#N BVCOJESIQPNOIF-UHFFFAOYSA-N 0.000 description 1
- QLVGHFBUSGYCCG-UHFFFAOYSA-N 2-amino-n-(1-cyano-2-phenylethyl)acetamide Chemical compound NCC(=O)NC(C#N)CC1=CC=CC=C1 QLVGHFBUSGYCCG-UHFFFAOYSA-N 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229940126650 Compound 3f Drugs 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- KGPGFQWBCSZGEL-ZDUSSCGKSA-N GSK690693 Chemical compound C=12N(CC)C(C=3C(=NON=3)N)=NC2=C(C#CC(C)(C)O)N=CC=1OC[C@H]1CCCNC1 KGPGFQWBCSZGEL-ZDUSSCGKSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940125796 compound 3d Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- MUTCAPXLKRYEPR-ITWZMISCSA-N methyl (e,3r,5s)-7-[4-bromo-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\N1C(C(C)C)=C(Br)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 MUTCAPXLKRYEPR-ITWZMISCSA-N 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000007704 transition Effects 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
- C07D239/88—Oxygen atoms
- C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
-
- 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
- C07D239/88—Oxygen atoms
- C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明属于医药化工中间体及相关化学技术领域,提供了一种喹唑啉酮及其衍生物制备方法。以2‑卤代苯甲酰胺和腈类化合物为原料,以铜盐作为催化剂,在无机碱性条件作用下发生环合反应,合成一系列喹唑啉酮及其衍生物。喹唑啉酮及其衍生物是一类重要的生物活性分子,其骨架结构频繁出现于天然分子和药物分子中,对高血压、肺癌以及焦虑症都有较好的治疗效果,在有机合成及药物化学等领域有着重要的应用。该方法的合成路线短、条件温和、操作简单、有望实现工业化生产。本发明具有较大的使用价值和社会经济效益。
Description
技术领域
本发明属于医药化工中间体及相关化学技术领域,涉及到一种喹唑啉酮及其衍生物制备方法。
背景技术
喹唑啉酮及其衍生物是一类重要的具有生物活性分子,其骨架结构频繁出现于天然分子和药物分子中,对高血压、肺癌以及焦虑症都有较好的治疗效果,在有机合成及药物化学等领域有着重要的应用。
关于喹唑啉酮类化合物的合成,通常采用如下两种方法:
(1)过渡金属催化的邻氯芳基酰胺与醛和氨水的成环反应
该方法的反应条件复杂,原子经济性差,产率较低,不适合工业化生产。[参见:(a)Guo,S.;Li,Y.;Tao,L.;Zhang,W.;Fan,X.RSC Adv.2014,4,59289-59296.(b)Xu,W.;Jin,Y.;Liu,H.;Jiang,Y.;Fu,H.Org.Lett.2011,13,1274-1277.(c)Xu,W.;Fu,H.J.Org.Chem.2011,76,3846-3852.]
(2)邻氨基苯甲酰胺参与成环反应
该方法的反应条件非常苛刻,需高温操作,多步反应收率低,也不适合工业化生产[参见:(a)Connolly,D.J.;Cusack,D.;O’Sullivan,T.P.;Guiry,P.J.Tetrahedron 2005,61,10153-10202.(b)Mitobe,Y.;Ito,S.;Mizutani,T.;Nagase,T.;Sato,N.;Tokita,S.Bioorg.Med.Chem.Lett.2009,19,4075-4078.(c)Zhan,D.;Li,T.;Wei,H.;Weng,W.;Ghandi,K.;Zeng,Q.RSC Adv.2013,3,9325-9329.]
发明内容
本发明提供了一种喹唑啉酮及其衍生物的制备方法,以2-卤代苯甲酰胺和腈类化合物为原料,以铜盐作为催化剂,在无机碱性条件作用下发生环合反应合成一系列喹唑啉酮及其衍生物。
本发明的技术方案:
一种喹唑啉酮及其衍生物的制备方法,步骤如下:
以2-卤代苯甲酰胺类化合物的和腈类化合物为原料,以铜盐作为催化剂,在无机碱性条件作用下发生环合反应,合成一系列喹唑啉酮及其衍生物;合成路线如下:
其中:X为溴或碘;
R1选自氢、烷基和烷氧基;
R2选自烷基、苯基、烷基苯基、烷氧基、苯基、氯和溴。
所述的铜盐催化剂为氧化亚铜、碘化亚铜、溴化亚铜、氯化亚铜、三氟甲基磺酸亚铜、氧化铜、溴化铜、氯化铜、三氟甲基磺酸铜、醋酸铜中的一种或两种以上混合,铜盐催化剂的加入量为2-卤代苯甲酰胺类化合物的1-50mol%。
所述的无机碱为叔丁醇钾、碳酸铯、氢氧化钠、叔丁醇钠、氢氧化钾、碳酸钠、碳酸钾中的一种或两种以上混合,无机碱的加入量为2-卤代苯甲酰胺类化合物的100-300mol%。
所述的有机溶剂为苯、甲苯、1,4-二氧六环、二甲基亚砜、N,N-二甲基甲酰胺、甲醇、乙醇、异丙醇、正丁醇、二氯甲烷、三氯甲烷、正丁醚、四氯化碳、乙酸乙酯、石油醚、甲基叔丁基醚、四氢呋喃、丙酮、乙腈中的一种或两种以上混合,有机溶剂的加入量为2-卤代苯甲酰胺类化合物重量的2-100倍。
在上述合成方法的反应中,反应温度在30~120℃。
本发明的方法合成路线短、条件温和、操作简单和收率较高。喹唑啉酮类化合物广泛应用于化学领域的多个方面,具有广阔的市场前景。例如喹唑啉酮及其衍生物是一类重要的生物活性分子,其骨架结构频繁出现于天然分子和药物分子中,对高血压、肺癌以及焦虑症都有较好的治疗效果,在有机合成及药物化学等领域有着重要的应用。
附图说明
图1是实施例1中化合物3a的1H核磁谱图。
图2是实施例2中化合物3b的1H核磁谱图。
图3是实施例3中化合物3c的1H核磁谱图。
图4是实施例4中化合物3d的1H核磁谱图。
图5是实施例5中化合物3e的1H核磁谱图。
图6是实施例6中化合物3f的1H核磁谱图。
图7是实施例7中化合物3g的1H核磁谱图。
图8是实施例8中化合物3h的1H核磁谱图。
图9是实施例9中化合物3i的1H核磁谱图。
图10是实施例10中化合物3n的1H核磁谱图。
具体实施方式
以下结合附图和技术方案,进一步说明本发明的具体实施方式。
实施例1:3-苯基喹唑啉酮(3a)的合成
将2-溴苯甲酰胺(100.0mg,0.5mmol)、醋酸铜(1.0mg,0.01mmol)、叔丁醇钾(56.0mg,0.5mmol)、苯甲腈(51.6mg,0.5mmol)依次加入到Schlenk反应瓶中,真空、氮气置换3次后,在氮气气氛中,加入甲苯0.2mL,30℃反应4小时,反应结束后,减压除去溶剂,柱层析分离(洗脱剂为石油醚:乙酸乙酯=20:1,V:V),得到淡黄色固体产物0.089g,收率为80%。Mp 235–236℃.1H NMR(400MHz,CDCl3)δ7.49–7.53(m,1H),7.58–7.60(m,3H),7.78–7.86(m,2H),8.25–8.28(m,2H),8.32–8.35(m,1H),11.67(s,1H).
实施例2:3-对甲苯基喹唑啉酮(3b)的合成
将2-溴苯甲酰胺(100.0mg,0.5mmol)、醋酸铜(9.1mg,0.1mmol)、叔丁醇钾(56.0mg,0.5mmol)、4-甲基苯甲腈(117.1mg,1.0mmol)依次加入到Schlenk反应瓶中,真空、氮气置换3次后,在氮气气氛中,加入甲醇1.0mL,50℃反应5小时,反应结束后,减压除去溶剂,柱层析分离(洗脱剂为石油醚:乙酸乙酯=20:1,V:V),得到白色固体产物0.105g,收率为89%。Mp 240–241℃.1H NMR(400MHz,CDCl3)δ2.40(s,3H),7.36(d,J=8.0Hz,2H),7.49–7.53(m,1H),7.74(d,J=8.0Hz,1H),7.81–7.86(m,1H),8.11(d,J=8.0Hz,2H),8.16(dd,J=12.0,4.0Hz,1H),12.48(s,1H).
实施例3:3-(4-甲氧基苯基)喹唑啉酮(3c)的合成
将2-溴苯甲酰胺(100mg,0.5mmol)、醋酸铜(18.2mg,0.2mmol)、叔丁醇钾(84.0mg,1.0mmol)、4-甲氧基苯甲酰胺(99.9mg,0.75mmol)依次加入到Schlenk反应瓶中,真空、氮气置换3次后,在氮气气氛中,加入乙二醇二甲醚0.5mL,60℃反应6小时,反应结束后,减压除去溶剂,柱层析分离(洗脱剂为石油醚:乙酸乙酯=20:1,V:V),得到白色固体产物0.107g,收率为85%;Mp 249–250℃.1H NMR(400MHz,DMSO-d6)δ3.84(s,3H),7.07–7.09(d,J=8.0Hz,2H),7.46–7.50(m,1H),7.70(d,1H),7.78–7.83(m,1H),8.13(d,J=8.0Hz,1H),8.19(d,J=8.0Hz,2H),12.42(s,1H).
实施例4:3-(2-甲基苯基)喹唑啉酮(3d)的合成
将2-溴苯甲酰胺(100.0mg,0.5mmol)、醋酸铜(1.0mg,0.005mmol)、碳酸钾(69.0mg,0.5mmol)、2-甲基苯甲腈(117.1mg,1.0mmol)依次加入到Schlenk反应瓶中,真空、氮气置换3次后,在氮气气氛中,加入乙醇2.0mL,90℃反应9小时,反应结束后,减压除去溶剂,柱层析分离(洗脱剂为石油醚:乙酸乙酯=20:1,V:V),得到白色固体产物0.106g,收率为90%;Mp 221–222℃.1H NMR(400MHz,CDCl3)δ2.53(s,3H),7.33–7.36(m,2H),7.41–7.45(m,1H),7.49–7.53(m,1H),7.56–7.59(m,1H),7.79–7.80(d,J=4.0Hz,2H),8.25–8.27(d,J=8.0Hz,1H),10.56(s,1H).
实施例5:3-(2-氯苯基)喹唑啉酮(3e)的合成
将2-溴苯甲酰胺(100.0mg,0.5mmol)、溴化铜(2.2mg,0.01mmol)、叔丁醇钾(78.5mg,1.0mmol)、2-氯苯甲腈(137.6mg,1.0mmol)依次加入到Schlenk反应瓶中,真空、氮气置换3次后,在氮气气氛中,加入乙醇3.0mL,50℃反应10小时,反应结束后,减压除去溶剂,柱层析分离(洗脱剂为石油醚:乙酸乙酯=20:1,V:V),得到淡黄色固体产物0.193g,收率为65%;Mp176–178℃.1H NMR(400MHz,DMSO-d6)δ7.47–7.63(m,4H),7.66–7.73(m,2H),7.83–7.87(m,1H),8.17-8.20(d,J=8.0Hz,1H),12.64(s,1H);
实施例6:3-(2-溴苯基)喹唑啉酮(3f)的合成
将2-溴苯甲酰胺(100.0mg,0.5mmol)、氧化铜(8.0mg,0.1mmol)、叔丁醇钾(78.5mg,1.0mmol)、2-溴苯甲腈(61.0mg,0.5mmol)依次加入到Schlenk反应瓶中,真空、氮气置换3次后,在氮气气氛中,加入乙二醇二甲醚3.0mL,50℃反应12小时,反应结束后,减压除去溶剂,柱层析分离(洗脱剂为石油醚:乙酸乙酯=20:1,V:V),得到白色固体产物0.108g,收率为72%;Mp175–177℃.1H NMR(400MHz,DMSO-d6)δ7.46–7.59(m,3H),7.62–7.66(m,1H),7.74(dd,J=24.0,8.0Hz,2H),7.83–7.88(m,1H),8.18(d,J=7.9Hz,2H),12.61(s,1H).
实施例7:3-甲基喹唑啉酮(3g)的合成
将2-溴苯甲酰胺(100.0mg,0.5mmol)、三氟甲基磺酸亚铜(0.8mg,0.005mmol)、碳酸钠(106.0mg,1.0mmol)、乙腈(41.5mg,1.0mmol)依次加入到Schlenk反应瓶中,真空、氮气置换3次后,在氮气气氛中,加入四氢呋喃1.0mL,50℃反应12小时,反应结束后,减压除去溶剂,柱层析分离(洗脱剂为石油醚:乙酸乙酯=20:1,V:V),得到白色固体产物0.064g,收率为80%;Mp 234–235℃.1H NMR(400MHz,DMSO-d6)δ2.34(s,3H),7.44(t,J=8.0Hz,1H),7.56(d,J=4.0Hz,1H),7.73–7.78(m,1H),8.06(dd,J=8.0,4.0Hz,1H),12.19(s,1H).
实施例8:3-正丁基喹唑啉酮(3h)的合成
将2-溴苯甲酰胺(100.0mg,0.5mmol)、氯化亚铜(2.0mg,0.02mmol)、氢氧化钾(112.0mg,1.0mmol)、正己腈(97.1mg,1.0mmol)依次加入到Schlenk反应瓶中,真空、氮气置换3次后,在氮气气氛中,加入乙腈4.0mL,30℃反应12小时,反应结束后,减压除去溶剂,柱层析分离(洗脱剂为石油醚:乙酸乙酯=20:1,V:V),得到白色固体产物0.131g,收率为75%;Mp 109–110℃.1H NMR(400MHz,CDCl3)δ1.01(t,J=8.0Hz,3H),1.52(q,J=4.0Hz,2H),1.86–1.94(m,2H),2.83(t,J=8.0Hz,2H),7.47(t,J=8.0Hz,1H),7.70–7.80(m,2H),8.29(d,J=4.0Hz,2H),12.21(s,1H).
实施例9:4-甲氧基-3-苯基喹唑啉酮(3i)的合成
将2-溴-5-甲氧基苯甲酰胺(115.0mg,0.5mmol)、溴化亚铜(1.4mg,0.01mmol)、叔丁醇钠(96.1mg,1.0mmol)、苯甲腈(103.1mg,1.0mmol)依次加入到Schlenk反应瓶中,真空、氮气置换3次后,在氮气气氛中,加入正己烷4.0mL,50℃反应12小时,反应结束后,减压除去溶剂,柱层析分离(洗脱剂为石油醚:乙酸乙酯=20:1,V:V),得到白色固体产物0.098g,收率为78%;Mp 247–248℃.1H NMR(400MHz,CDCl3)δ3.96(s,3H),7.39–7.42(m,1H),7.56–7.57(m,3H),7.69(d,J=4.0Hz,1H),7.77(d,J=8.0Hz,1H),10.57(s,1H).
实施例10:6-甲基-3-苯基喹唑啉酮(3n)的合成
将4-甲基2-溴苯甲酰胺(107.0mg,0.5mmol)、碘化亚铜(18.9mg,0.1mmol)、碳酸钾(60.0mg,1.5mmol)、苯甲腈(77.3mg,0.75mmol)依次加入到Schlenk反应瓶中,真空、氮气置换3次后,在氮气气氛中,加入甲苯4.0mL,120℃反应12小时,反应结束后,减压除去溶剂,柱层析分离(洗脱剂为石油醚:乙酸乙酯=20:1,V:V),得到白色固体产物0.112g,收率为95%;Mp 240–241℃.1H NMR(400MHz,CDCl3)δ2.46(s,3H),7.33(d,J=8.0Hz,1H),7.52–7.68(m,4H),8.03(d,J=8.0Hz,1H),8.17(d,J=8.0Hz,1H),12.44(s,1H).
Claims (5)
1.一种喹唑啉酮及其衍生物的制备方法,其特征在于,步骤如下:
以2-卤代苯甲酰胺类化合物和腈类化合物为原料,以铜盐作为催化剂,在无机碱性条件作用下发生环合反应,合成一系列喹唑啉酮及其衍生物;合成路线如下:
其中:X为溴或碘;
R1选自氢、烷基和烷氧基;
R2选自烷基、苯基、烷基苯基、烷氧基、苯基、氯和溴;
所述的铜盐催化剂的加入量为2-卤代苯甲酰胺类化合物的1-50mol%;
所述的无机碱的加入量为2-卤代苯甲酰胺类化合物的100-300mol%;
所述的有机溶剂的加入量为2-卤代苯甲酰胺类化合物重量的2-100倍;
反应温度在30~120℃。
2.根据权利要求1所述的制备方法,其特征在于,所述的铜盐催化剂为氧化亚铜、碘化亚铜、溴化亚铜、氯化亚铜、三氟甲基磺酸亚铜、氧化铜、溴化铜、氯化铜、三氟甲基磺酸铜、醋酸铜中的一种或两种以上混合。
3.根据权利要求1或2所述的制备方法,其特征在于,所述的无机碱为叔丁醇钾、碳酸铯、氢氧化钠、叔丁醇钠、氢氧化钾、碳酸钠、碳酸钾中的一种或两种以上混合。
4.根据权利要求1或2所述的制备方法,其特征在于,所述的有机溶剂为苯、甲苯、1,4-二氧六环、二甲基亚砜、N,N-二甲基甲酰胺、甲醇、乙醇、异丙醇、正丁醇、二氯甲烷、三氯甲烷、正丁醚、四氯化碳、乙酸乙酯、石油醚、甲基叔丁基醚、四氢呋喃、丙酮、乙腈中的一种或两种以上混合。
5.根据权利要求3所述的制备方法,其特征在于,所述的有机溶剂为苯、甲苯、1,4-二氧六环、二甲基亚砜、N,N-二甲基甲酰胺、甲醇、乙醇、异丙醇、正丁醇、二氯甲烷、三氯甲烷、正丁醚、四氯化碳、乙酸乙酯、石油醚、甲基叔丁基醚、四氢呋喃、丙酮、乙腈中的一种或两种以上混合。
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CN111471023A (zh) * | 2020-05-26 | 2020-07-31 | 河南大学 | 光催化条件下合成喹唑啉酮类化合物的方法 |
CN112645887A (zh) * | 2020-12-21 | 2021-04-13 | 淮阴工学院 | 一种喹唑啉酮衍生物的制备方法 |
CN114230526A (zh) * | 2021-12-26 | 2022-03-25 | 重庆医科大学 | 一种4-3(h)喹唑啉酮及其衍生物的合成方法 |
CN114230526B (zh) * | 2021-12-26 | 2023-06-23 | 重庆医科大学 | 一种4-3(h)喹唑啉酮及其衍生物的合成方法 |
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