CN117209437A - Preparation method of aminoquinazolinone derivative - Google Patents
Preparation method of aminoquinazolinone derivative Download PDFInfo
- Publication number
- CN117209437A CN117209437A CN202311137304.8A CN202311137304A CN117209437A CN 117209437 A CN117209437 A CN 117209437A CN 202311137304 A CN202311137304 A CN 202311137304A CN 117209437 A CN117209437 A CN 117209437A
- Authority
- CN
- China
- Prior art keywords
- cyanamide
- aminoquinazolinone
- potassium
- reaction
- cupric
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- NXBWFXMEJVOABP-UHFFFAOYSA-N 4-amino-1h-quinazolin-2-one Chemical class C1=CC=C2C(N)=NC(=O)NC2=C1 NXBWFXMEJVOABP-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 15
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000001879 copper Chemical class 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 238000006555 catalytic 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 45
- 238000006243 chemical reaction Methods 0.000 claims description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
- -1 amino, carboxyl Chemical group 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 8
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- MVXMNHYVCLMLDD-UHFFFAOYSA-N 4-methoxynaphthalene-1-carbaldehyde Chemical compound C1=CC=C2C(OC)=CC=C(C=O)C2=C1 MVXMNHYVCLMLDD-UHFFFAOYSA-N 0.000 claims description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- VIKGLBAPRKOUCY-UHFFFAOYSA-N N#CN.[Li] Chemical compound N#CN.[Li] VIKGLBAPRKOUCY-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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- YEOCHZFPBYUXMC-UHFFFAOYSA-L copper benzoate Chemical compound [Cu+2].[O-]C(=O)C1=CC=CC=C1.[O-]C(=O)C1=CC=CC=C1 YEOCHZFPBYUXMC-UHFFFAOYSA-L 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 4
- XPQRZQHNWFOKMS-UHFFFAOYSA-N cyanamide;potassium Chemical compound [K].NC#N XPQRZQHNWFOKMS-UHFFFAOYSA-N 0.000 claims description 4
- JWEKFMCYIRVOQZ-UHFFFAOYSA-N cyanamide;sodium Chemical compound [Na].NC#N JWEKFMCYIRVOQZ-UHFFFAOYSA-N 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 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
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000004280 Sodium formate Substances 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000012300 argon atmosphere Substances 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- HFDWIMBEIXDNQS-UHFFFAOYSA-L copper;diformate Chemical compound [Cu+2].[O-]C=O.[O-]C=O HFDWIMBEIXDNQS-UHFFFAOYSA-L 0.000 claims description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 2
- 229940076286 cupric acetate Drugs 0.000 claims description 2
- 229960003280 cupric chloride Drugs 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- ZMMDPCMYTCRWFF-UHFFFAOYSA-J dicopper;carbonate;dihydroxide Chemical compound [OH-].[OH-].[Cu+2].[Cu+2].[O-]C([O-])=O ZMMDPCMYTCRWFF-UHFFFAOYSA-J 0.000 claims description 2
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- ZFSLODLOARCGLH-UHFFFAOYSA-N isocyanuric acid Chemical compound OC1=NC(O)=NC(O)=N1 ZFSLODLOARCGLH-UHFFFAOYSA-N 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 2
- 235000019254 sodium formate Nutrition 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 abstract description 13
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000003054 catalyst Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000012043 crude product Substances 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 229940125898 compound 5 Drugs 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 229920001971 elastomer Polymers 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 3
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical class C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 3
- JNJDRRFUFIPRIJ-UHFFFAOYSA-N 2-amino-3-phenylquinazolin-4-one Chemical compound NC1=NC2=CC=CC=C2C(=O)N1C1=CC=CC=C1 JNJDRRFUFIPRIJ-UHFFFAOYSA-N 0.000 description 2
- BHHGABOCAHPYMA-UHFFFAOYSA-N 2-bromo-N-phenylbenzamide Chemical compound BrC1=CC=CC=C1C(=O)NC1=CC=CC=C1 BHHGABOCAHPYMA-UHFFFAOYSA-N 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- 102000007339 Nerve Growth Factor Receptors Human genes 0.000 description 2
- 108010032605 Nerve Growth Factor Receptors Proteins 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000000410 anti-febrile effect Effects 0.000 description 2
- MYFXBBAEXORJNB-UHFFFAOYSA-N calcium cyanamide Chemical compound [Ca+2].[N-]=C=[N-] MYFXBBAEXORJNB-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 2
- KYZSFZRRZVYDDA-UHFFFAOYSA-N 1,5-dimethylcyclohexa-2,4-dien-1-amine Chemical compound CC1(N)CC(=CC=C1)C KYZSFZRRZVYDDA-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- ORQHHLPTMSGMQT-UHFFFAOYSA-N 2-[4-(5-fluoropyridin-2-yl)piperazin-1-yl]-n-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)acetamide Chemical compound N1=CC(F)=CC=C1N1CCN(CC(=O)NC=2SC=3CCCCC=3N=2)CC1 ORQHHLPTMSGMQT-UHFFFAOYSA-N 0.000 description 1
- XVWHGSIKTVUHFT-UHFFFAOYSA-N 2-amino-3-(4-methoxyphenyl)quinazolin-4-one Chemical compound C1=CC(OC)=CC=C1N1C(=O)C2=CC=CC=C2N=C1N XVWHGSIKTVUHFT-UHFFFAOYSA-N 0.000 description 1
- FNDKKMGLSIFSIA-UHFFFAOYSA-N 2-amino-3-(4-methylphenyl)quinazolin-4-one Chemical compound C1=CC(C)=CC=C1N1C(=O)C2=CC=CC=C2N=C1N FNDKKMGLSIFSIA-UHFFFAOYSA-N 0.000 description 1
- XDCOYBQVEVSNNB-UHFFFAOYSA-N 4-[(7-naphthalen-2-yl-1-benzothiophen-2-yl)methylamino]butanoic acid Chemical compound OC(=O)CCCNCc1cc2cccc(-c3ccc4ccccc4c3)c2s1 XDCOYBQVEVSNNB-UHFFFAOYSA-N 0.000 description 1
- RLLNOZZVLWEBBI-UHFFFAOYSA-N 4-methyl-3h-quinazolin-2-one Chemical compound C1=CC=CC2=C(C)NC(=O)N=C21 RLLNOZZVLWEBBI-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 241001643730 Hydrangea sect. Dichroa Species 0.000 description 1
- 241000334154 Isatis tinctoria Species 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 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 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- SGEVKYATLFKDRR-UHFFFAOYSA-N n-(2-bromo-4-methylphenyl)benzamide Chemical compound BrC1=CC(C)=CC=C1NC(=O)C1=CC=CC=C1 SGEVKYATLFKDRR-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940126680 traditional chinese medicines Drugs 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention is applicable to the technical field of organic synthesis, and provides a preparation method of an aminoquinazolinone derivative, which comprises the following steps: under the catalysis of copper salt and alkali, cyanamide and o-halogen benzamide are reacted to obtain the amino quinazolinone derivative. According to the invention, the copper salt catalyst is introduced into the o-halogen benzamide in a matching manner to promote the formation of carbon-nitrogen bonds, and is separated under the action of alkali to obtain the quinazolinone derivative, so that the raw materials and the catalyst are easy to obtain, the synthesis is simple, the production cost can be effectively reduced, the yield and the chemical selectivity are improved, and the method can be conveniently applied to the preparation of each amino quinazolinone derivative.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an aminoquinazolinone derivative.
Background
Quinazolinone and its derivatives are core structures of many tenib natural medicines, are also basic structural units of traditional Chinese medicine antifebrile, are mainly existing in traditional Chinese medicines such as antifebrile dichroa and dyers woad leaf, have important biological activity, have inhibitory activity on Epidermal Growth Factor Receptor (EGFR) or tyrosine kinase (EGFR-TK) thereof, vascular Endothelial Growth Factor Receptor (VEGFR), nerve Growth Factor Receptor (NGFR) and other multiple action targets, and play various pharmacological actions such as anticancer and antiviral.
Because the medicaments have excellent pharmacological activity, derivative research based on a quinazolinone mother nucleus becomes a hotspot, and particularly a simple and efficient method for synthesizing the quinazolinone derivative is established for the structural synthesis and modification of the 4-quinazolinone derivative, and the currently reported synthesis methods of the quinazolinone compound mainly comprise the following steps:
an intermediate similar to isatoic anhydride (compound B) is synthesized by anthranilic acid (compound A) under the condition of acetic anhydride or triethoxyethyl ether, and then methyl quinazolinone (compound C) is synthesized by the intermediate and amine under the condition of acetic acid, so that a target product (J MED CHEM,2016,59 (10): 5011-5021.);
cyclizing the anthranilamide derivative (compound D) under the condition of copper triflate and ligand to generate a target product (ORG BIOMOL CHEM,2017,15 (34): 7140-7146.);
reacting anthranilamide (compound E) with aldehyde (compound F) to generate quinazolinone (compound G), and carrying out N-alkylation reaction on the quinazolinone and bromide (compound H) to obtain a target product (BIOORG MED CHEM LETT,2017,27 (15): 3529-3533.; EUR J MED CHEM,2021, 212:112996.);
reacting anthranilamide (compound E) with amine (compound I) to generate quinazolinone (compound K), and performing a quinazolinone re-derivatization reaction to obtain a target product (chemistry select,2017,2 (17): 4963-4968.);
reacting anthranilamide (compound E) with pyruvic acid (compound J) to obtain a compound K, and closing the ring of the compound K under alkaline conditions to obtain quinazolinone (molecular, 2023,28 (10): 4240.);
furthermore, quinazolinones were constructed by reacting anthranilic acid amine (compound E) with carboxylic acid (compound L) (EUR J MED CHEM,2021,212:112996., 2023:101597.), and with alcohol (compound M) (Organometallics, 2021,40 (6): 725-734.).
Although the reaction can simply and efficiently synthesize the quinazolinone compound, the application range of the substrate is wide, the problems that the anthranilic acid is a first type of easy-to-poison chemical, the substrate is difficult to synthesize, noble metal catalysis is needed for synthesis and the like still exist.
Disclosure of Invention
The embodiment of the invention aims to provide a preparation method of an aminoquinazolinone derivative, which aims to solve the problems in the background art.
The embodiment of the invention is realized in such a way that the preparation method of the aminoquinazolinone derivative comprises the following steps: under the catalysis of copper salt and alkali, cyanamide and o-halogen benzamide are reacted to obtain aminoquinazolinone derivatives, wherein the reaction formula is as follows:
preferably, the cyanamide is one of calcium cyanamide (lime nitrogen), lithium cyanamide, sodium cyanamide, potassium cyanamide, cyanamide and dicyandiamide.
Preferably, the cyanamide is calcium cyanamide or cyanamide.
Preferably, the L group in the o-halobenzamide is one of fluorine, chlorine, bromine, iodine and amino, and the X group is oxygen or sulfur.
Preferably, the L group is chlorine, bromine or iodine.
Preferably, R in the o-halobenzamide and aminoquinazolinone derivatives 1 、R 2 、R 3 、R 4 And R is 5 Each radical is independently selected from hydrogen, halogen, substituted or unsubstituted C 1～10 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 1～10 Alkoxy, substituted or unsubstituted amino, carboxyl, ester, acyl, cyano, nitro, hydroxyl, azido.
Preferably, the molar ratio of the cyanmine to the o-halobenzamide is 1:0.9-3.0, the molar ratio of the copper salt to the o-halobenzamide is 1:0.05-0.5, and the molar ratio of the alkali to the o-halobenzamide is 1:0.5-3.5.
Preferably, the molar ratio of the cyanuric acid to the o-halobenzamide is 1:1.0-20, the molar ratio of the copper salt to the o-halobenzamide is 1:0.05-0.5, and the molar ratio of the alkali to the o-halobenzamide is 1:1.5-3.0.
Preferably, the reaction is carried out in the presence of a solvent, which is one or more of water, methanol, ethanol, acetonitrile, benzene, toluene, tetrahydrofuran, 1, 4-dioxane, dimethyl sulfoxide, N-dimethylformamide, ethylene glycol, polyethylene glycol (PEG-200-600);
the copper salt includes, but is not limited to, one or more of cuprous chloride, cuprous bromide, cuprous iodide, cupric chloride, cupric bromide, cupric iodide, basic cupric carbonate, cupric acetate, cupric formate, cupric benzoate, cupric triflate, and cuprous triflate;
the base includes, but is not limited to, one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium formate, potassium formate, sodium acetate, potassium acetate, sodium tert-butoxide, potassium phosphate, DBU.
Preferably, the reaction temperature is 60-140 ℃ and the reaction time is 1-24 h.
Preferably, the reaction temperature is 80-130 ℃ and the reaction time is 4-12 h.
Preferably, the reaction is carried out under air or an inert atmosphere, which is a nitrogen atmosphere or an argon atmosphere.
Preferably, the cyanamide is one of calcium cyanamide, lithium cyanamide, sodium cyanamide and potassium cyanamide, water is added as a cocatalyst, and the molar ratio of water to o-halobenzamide is 1:0.5-3.
Preferably, after the reaction is finished, the reaction solution is extracted by ethyl acetate, washed by an organic phase for a plurality of times and dried by anhydrous magnesium sulfate, and finally the organic phase is concentrated to obtain the aminoquinazolinone derivative.
Preferably, the concentration is one of atmospheric distillation, vacuum distillation, rotary evaporation.
Preferably, the post-treatment can be performed by column chromatography purification using 200-300 mesh silica gel as a separation resin, wherein the eluent is at least one of petroleum ether, n-hexane, dichloromethane, water, acetonitrile, methanol, and ethyl acetate.
Preferably, the quinazolinone derivative has the following structural formula:
according to the preparation method of the amino quinazolinone derivative, the copper salt catalyst is introduced into the o-halogen benzamide in a matching manner to promote the formation of carbon-nitrogen bonds, and is separated under the action of alkali to obtain the quinazolinone derivative, so that the raw materials and the catalyst are more easily obtained, the production cost can be effectively reduced, the yield and the chemical selectivity can be improved, and the preparation method can be conveniently applied to the preparation of all the quinazolinone derivatives.
Drawings
FIG. 1 is a nuclear magnetic resonance 1H NMR spectrum of compound 5a provided in example 1 of the present invention;
FIG. 2 is a nuclear magnetic 13C NMR carbon spectrum of compound 5a prepared in example 1 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Specific implementations of the invention are described in detail below in connection with specific embodiments.
Example 1
A preparation method of an aminoquinazolinone derivative (a compound 5 a), which comprises the following steps:
the method comprises the following steps:
the method comprises the following specific steps: weighing cyanamide (1.5 mmol,63 mg), potassium tert-butoxide (2 mmol,224 mg), bromobenzanilide (1 mmol,275 mg), cuprous iodide (0.1 mmol,19 mg) in a 25mL round bottom flask, adding a magneton, plugging a rubber stopper, replacing three times with high-purity nitrogen, adding DMSO (2 mL) into the flask under the protection of nitrogen, transferring the flask into an oil bath pot at 110 ℃ and stirring, reacting overnight, detecting and tracking the reaction by TLC, cooling the flask to room temperature after the reaction is finished, adding 10mL saturated saline into the system, and stirring; extraction with ethyl acetate (10 ml×3), combining the organic phases, and removal of the solvent with a rotary evaporator gives the crude product; the crude product is loaded by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=1:1, pure 2-amino-3-phenylquinazolin-4 (3H) -one was obtained as a white solid with an isolated yield of 83.2%.
The second method is as follows:
the method comprises the following specific steps: lime nitrogen (1.8 mmol,148 mg), potassium t-butoxide (2 mmol,224 mg), bromobenzanilide (1 mmol,275 mg), cuprous iodide (0.1 mmol,19 mg) were weighed into a 25mL round bottom flask, a magnet was added, a rubber stopper was plugged, after three substitutions with high purity nitrogen, DMSO (2 mL) was added to the flask under nitrogen protection, water (3.6 mmol,65 mg) was added, and the mixture was transferred into an oil bath pot at 110℃and stirred, reacted overnight, the reaction was followed by TLC detection, and after the reaction was completed, the flask was cooled to room temperature. 10mL of saturated saline solution is added into the system and stirred; extraction with ethyl acetate (10 ml×3), combining the organic phases, and removal of the solvent with a rotary evaporator gives the crude product; the crude product is loaded by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=1:1, pure 2-amino-3-phenylquinazolin-4 (3H) -one was obtained as a white solid with an isolated yield of 46.5%.
Structural identification of compound 5 a:
nuclear magnetic resonance data:
1 H NMR(400MHz,DMSO-d 6 )δ7.937(dd,J＝7.9,1.6Hz,1H),7.668-7.485(m,4H),7.397(d,J＝7.2,2H),7.304(d,J＝8.2Hz,1H),7.197-7.051(m,1H),6.468(s,1H).
13 C NMR(100MHz,DMSO-d 6 )δ162.34,152.21,150.48,135.94,134.87,130.45,129.66,129.34,127.02,124.38,122.04,117.30.
compound 5a 1 H NMR、 13 The C NMR is shown in FIG. 1 and FIG. 2, and the analysis results show that the obtained target product is correct.
Example 2
A preparation method of an aminoquinazolinone derivative (a compound 5 b), which comprises the following steps:
the method comprises the following specific steps: cyanamide (1.5 mmol,63 mg), potassium t-butoxide (2 mmol,224 mg), o-bromobenzoyl-p-methoxyaniline (1 mmol,305 mg), cuprous iodide (0.1 mmol,19 mg) were weighed into a 25mL round bottom flask, a magnet was added, a rubber stopper was plugged, and after three substitutions with high purity nitrogen, DMSO (2 mL) was added to the flask under nitrogen protection, and the flask was transferred into an oil bath at 110℃and stirred, and reacted overnight. The reaction was followed by TLC, after the completion of the reaction, the flask was cooled to room temperature, 10mL of saturated brine was added to the system, and the mixture was stirred; extraction with ethyl acetate (10 ml×3), combining the organic phases, and removal of the solvent with a rotary evaporator gives the crude product; the crude product is loaded by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=1:1, pure 2-amino-3-p-methoxyphenyl quinazolin-4 (3H) -one was obtained as a white solid with an isolated yield of 88.4%.
Structural identification of compound 5 b:
nuclear magnetic resonance data:
1 H NMR(500MHz,DMSO-d 6 )δ7.903(dd,J＝7.9,1.6Hz,1H),7.618-7.584(m,1H),7.292-7.249(m,3H),7.132-7.090(m,3H),6.333(s,2H),3.832(s,3H).
13 C NMR(125MHz,DMSO-d 6 )δ162.02,159.50,152.09,150.07,134.28,129.91,127.85,126.51,123.87,121.39,116.80,115.16,55.37.
compound 5b 1 H NMR、 13 Analysis of the C NMR data shows that the target product was obtained correctly.
Example 3
A preparation method of an aminoquinazolinone derivative (a compound 5 c), which comprises the following steps:
the method comprises the following specific steps: cyanamide (1.5 mmol,63 mg), potassium t-butoxide (2 mmol,224 mg), o-bromobenzoyl-p-methylaniline (1 mmol,299 mg), cuprous iodide (0.1 mmol,19 mg) were weighed into a 25mL round bottom flask, a magnet was added, a rubber stopper was plugged, after three substitutions with high purity nitrogen gas, DMSO (2 mL) was added to the flask under nitrogen protection, and the flask was transferred into an oil bath at 110℃and stirred, and reacted overnight. The reaction was followed by TLC, after the completion of the reaction, the flask was cooled to room temperature, 10mL of saturated brine was added to the system, and the mixture was stirred; extraction with ethyl acetate (10 ml×3), combining the organic phases, and removal of the solvent with a rotary evaporator gives the crude product; the crude product is loaded by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=1:1, pure 2-amino-3-p-methylphenyl quinazolin-4 (3H) -one was obtained as a white solid with an isolated yield of 87.3%.
Structural identification of compound 5 c:
nuclear magnetic resonance data:
1 H NMR(400MHz,DMSO-d 6 )δ7.903(dd,J＝7.9,1.6Hz,1H),7.633-7.590(m,1H),7.377(d,J＝8.2Hz,2H),7.280-7.222(m,2H),7.144-7.105(m,1H),6.373(s,2H),2.403(s,3H).
13 C NMR(125MHz,DMSO-d 6 )δ162.32,152.30,150.33,139.05,134.84,133.25,130.97,129.00,127.00,124.26,121.99,117.26,21.32.
compound 5c 1 H NMR、 13 Analysis of the C NMR data shows that the target product was obtained correctly.
Example 4
A preparation method of an aminoquinazolinone derivative (compound 5 k) comprises the following steps:
the method comprises the following specific steps: cyanamide (1.5 mmol,63 mg), potassium t-butoxide (2 mmol,224 mg), o-bromobenzoyl para-trifluoromethoxy aniline (1 mmol,416 mg), cuprous iodide (0.1 mmol,19 mg) were weighed into a 25mL round bottom flask, a magnet was added, a rubber stopper was plugged, and after three substitutions with high purity nitrogen, DMSO (2 mL) was added to the flask under nitrogen protection, and the flask was transferred into an oil bath at 110℃and stirred, and reacted overnight. The reaction was followed by TLC, after the completion of the reaction, the flask was cooled to room temperature, 10mL of saturated brine was added to the system, and the mixture was stirred; extraction with ethyl acetate (10 ml×3), combining the organic phases, and removal of the solvent with a rotary evaporator gives the crude product; the crude product is loaded by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=1:1, pure 2-amino-3-p-trifluoromethoxyphenyl quinazolin-4 (3H) -one was obtained as a white solid with an isolation yield of 76.2%.
Structural identification of compound 5 k:
nuclear magnetic resonance data:
1 H NMR(400MHz,CDCl 3 )δ8.129(d,J＝7.9Hz,1H),7.695-7.601(m,1H),7.524-7.371(m,4H),7.319(d,J＝8.3Hz,1H),7.234(t,J＝7.6Hz,1H),5.085(s,2H).
13 C NMR(100MHz,CDCl 3 )δ162.12,150.42,150.08,148.30,135.20,133.10,130.42,127.51,123.89,123.52,122.83,121.63,119.06,117.38.
compound 5k 1 HNMR、 13 Analysis of the C NMR data shows that the target product was obtained correctly.
Example 5
A preparation method of an aminoquinazolinone derivative (compound 5 u) comprises the following steps:
the method comprises the following specific steps: cyanamide (1.5 mmol,63 mg), potassium t-butoxide (2 mmol,224 mg), m-dimethylaniline (1 mmol,304 mg), cuprous iodide (0.1 mmol,19 mg) were weighed into a 25mL round bottom flask, a magnet was added, a rubber stopper was plugged, and after three substitutions with high purity nitrogen, DMSO (2 mL) was added to the flask under nitrogen protection, and the flask was transferred into an oil bath at 110℃and stirred, and reacted overnight. The reaction was followed by TLC, after the completion of the reaction, the flask was cooled to room temperature, 10mL of saturated brine was added to the system, and the mixture was stirred; extraction with ethyl acetate (10 ml×3), combining the organic phases, and removal of the solvent with a rotary evaporator gives the crude product; the crude product is loaded by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=1:1, pure 2-amino-3- (3, 5-dimethyl) phenylquinazolin-4 (3H) -thione was obtained in the form of a white solid with an isolated yield of 76.1%.
Structural identification of compound 5 u:
nuclear magnetic resonance data:
1 H NMR(400MHz,DMSO-d 6 )δ7.021(dd,J＝8.0,1.6Hz,1H),6.699-6.657(m,1H),6.384(d,J＝8Hz,1H),6.220-6.183(m,2H),6.059(s,2H),5.572(s,2H),1.424(s,6H).
13 C NMR(125MHz,DMSO-d 6 )δ162.28,152.18,150.53,139.67,135.71,134.79,131.09,126.94,126.61,124.40,121.96,117.29,21.26.
compound 5u 1 H NMR、 13 Analysis of the C NMR data shows that the target product was obtained correctly.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (10)
1. A method for preparing an aminoquinazolinone derivative, comprising the steps of: under the catalysis of copper salt and alkali, cyanamide and o-halogen benzamide are reacted to obtain aminoquinazolinone derivatives, wherein the reaction formula is as follows:
2. the method for producing an aminoquinazolinone derivative according to claim 1, wherein said cyanamide is one of calcium cyanamide, lithium cyanamide, sodium cyanamide, potassium cyanamide, mono-cyanamide and dicyandiamide.
3. The method for preparing aminoquinazolinone derivative according to claim 1, wherein the L group in o-halobenzamide is one of fluorine, chlorine, bromine, iodine and amino, and the X group is oxygen or sulfur.
4. The method for producing aminoquinazolinone derivative according to claim 1, wherein R in said anthranilamide and aminoquinazolinone derivative is 1 、R 2 、R 3 、R 4 And R is 5 Each radical is independently selected from hydrogen, halogen, substituted or unsubstituted C 1～10 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 1～10 Alkoxy, substituted or unsubstituted amino, carboxyl, ester, acyl, cyano, nitro, hydroxyl, azido.
5. The method for preparing aminoquinazolinone derivative according to claim 1, wherein the molar ratio of cyanuric acid to o-halobenzamide is 1:0.9-3.0, the molar ratio of copper salt to o-halobenzamide is 1:0.05-0.5, and the molar ratio of alkali to o-halobenzamide is 1:0.5-3.5.
6. The method for preparing the aminoquinazolinone derivative according to claim 1, wherein said reaction is performed in the presence of a solvent, said solvent being one or more of water, methanol, ethanol, acetonitrile, benzene, toluene, tetrahydrofuran, 1, 4-dioxane, dimethyl sulfoxide, N-dimethylformamide, ethylene glycol, polyethylene glycol;
the copper salt is one or more of cuprous chloride, cuprous bromide, cuprous iodide, cupric chloride, cupric bromide, cupric iodide, basic cupric carbonate, cupric acetate, cupric formate, cupric benzoate, cupric triflate and cuprous triflate;
the alkali is one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium formate, potassium formate, sodium acetate, potassium acetate, sodium tert-butoxide, potassium phosphate and DBU.
7. The method for producing an aminoquinazolinone derivative according to claim 1, wherein said reaction temperature is 60 to 140 ℃ and said reaction time is 1 to 24 hours.
8. The method for producing an aminoquinazolinone derivative according to claim 1, wherein said reaction is performed under air or an inert atmosphere, and said inert atmosphere is a nitrogen atmosphere or an argon atmosphere.
9. The preparation method of the aminoquinazolinone derivative according to claim 1, wherein the cyanamide is one of calcium cyanamide, lithium cyanamide, sodium cyanamide and potassium cyanamide, water is added as a cocatalyst, and the molar ratio of water to o-halobenzamide is 1:0.5-3.
10. The method for preparing aminoquinazolinone derivative according to claim 1, wherein after the reaction is finished, extracting the reaction solution with ethyl acetate, washing the reaction solution with an organic phase for a plurality of times, drying the reaction solution with anhydrous magnesium sulfate, and concentrating the organic phase to obtain the aminoquinazolinone derivative.
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