CN112645887A - Preparation method of quinazolinone derivative - Google Patents
Preparation method of quinazolinone derivative Download PDFInfo
- Publication number
- CN112645887A CN112645887A CN202011521464.9A CN202011521464A CN112645887A CN 112645887 A CN112645887 A CN 112645887A CN 202011521464 A CN202011521464 A CN 202011521464A CN 112645887 A CN112645887 A CN 112645887A
- Authority
- CN
- China
- Prior art keywords
- solvent
- producing
- derivative according
- quinazolinone
- water
- 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.)
- Granted
Links
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class 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 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 50
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims abstract description 44
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 239000002904 solvent Substances 0.000 claims abstract description 34
- 239000012043 crude product Substances 0.000 claims abstract description 26
- 229910000024 caesium carbonate Inorganic materials 0.000 claims abstract description 25
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims abstract description 24
- 238000000926 separation method Methods 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 20
- 150000001299 aldehydes Chemical class 0.000 claims abstract description 11
- HLCPWBZNUKCSBN-UHFFFAOYSA-N 2-aminobenzonitrile Chemical class NC1=CC=CC=C1C#N HLCPWBZNUKCSBN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003446 ligand Substances 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- 150000002576 ketones Chemical class 0.000 claims abstract 6
- -1 phenyl,Methylphenyl Chemical group 0.000 claims description 26
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 24
- 238000004440 column chromatography Methods 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 23
- 238000005406 washing Methods 0.000 claims description 23
- 229910021592 Copper(II) chloride Inorganic materials 0.000 claims description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 5
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 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
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 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
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000012065 filter cake Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000005059 halophenyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- IYRGXJIJGHOCFS-UHFFFAOYSA-N neocuproine Chemical compound C1=C(C)N=C2C3=NC(C)=CC=C3C=CC2=C1 IYRGXJIJGHOCFS-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 abstract description 5
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 238000011065 in-situ storage Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 72
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- 239000000203 mixture Substances 0.000 description 42
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 23
- 239000000047 product Substances 0.000 description 23
- 239000012074 organic phase Substances 0.000 description 22
- 238000002390 rotary evaporation Methods 0.000 description 22
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 18
- RWZYAGGXGHYGMB-UHFFFAOYSA-N o-aminobenzenecarboxylic acid Natural products NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 13
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 6
- 239000002994 raw material Substances 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 2
- DTUQWGWMVIHBKE-UHFFFAOYSA-N phenylacetaldehyde Chemical compound O=CCC1=CC=CC=C1 DTUQWGWMVIHBKE-UHFFFAOYSA-N 0.000 description 2
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 description 1
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 1
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 1
- JDEJRLXMWUYMSS-UHFFFAOYSA-N 2-(2-phenylethenyl)-1h-quinazolin-4-one Chemical class N1C2=CC=CC=C2C(=O)N=C1C=CC1=CC=CC=C1 JDEJRLXMWUYMSS-UHFFFAOYSA-N 0.000 description 1
- ZZFIIOFXVHZVGK-UHFFFAOYSA-N 2-(3,4-dimethylphenyl)-1h-quinazolin-4-one Chemical compound C1=C(C)C(C)=CC=C1C1=NC2=CC=CC=C2C(=O)N1 ZZFIIOFXVHZVGK-UHFFFAOYSA-N 0.000 description 1
- AKHUKZJZNGHOJU-UHFFFAOYSA-N 2-(4-chlorophenyl)-1h-quinazolin-4-one Chemical compound C1=CC(Cl)=CC=C1C1=NC(=O)C2=CC=CC=C2N1 AKHUKZJZNGHOJU-UHFFFAOYSA-N 0.000 description 1
- IXMXCFSRQIHRHB-UHFFFAOYSA-N 2-(4-fluorophenyl)-1h-quinazolin-4-one Chemical compound C1=CC(F)=CC=C1C1=NC(=O)C2=CC=CC=C2N1 IXMXCFSRQIHRHB-UHFFFAOYSA-N 0.000 description 1
- HETSSARHFAGODR-UHFFFAOYSA-N 2-(4-methoxyphenyl)-1H-quinazolin-4-one Chemical compound C1=CC(OC)=CC=C1C1=NC(=O)C2=CC=CC=C2N1 HETSSARHFAGODR-UHFFFAOYSA-N 0.000 description 1
- UTEHUKGJDLVHIH-UHFFFAOYSA-N 2-(4-methylphenyl)-1h-quinazolin-4-one Chemical compound C1=CC(C)=CC=C1C1=NC(=O)C2=CC=CC=C2N1 UTEHUKGJDLVHIH-UHFFFAOYSA-N 0.000 description 1
- OATYCBHROMXWJO-UHFFFAOYSA-N 2-amino-5-bromobenzonitrile Chemical compound NC1=CC=C(Br)C=C1C#N OATYCBHROMXWJO-UHFFFAOYSA-N 0.000 description 1
- QYRDWARBHMCOAG-UHFFFAOYSA-N 2-amino-5-chlorobenzonitrile Chemical compound NC1=CC=C(Cl)C=C1C#N QYRDWARBHMCOAG-UHFFFAOYSA-N 0.000 description 1
- SRWMPAZUWXLIPG-UHFFFAOYSA-N 2-amino-5-methoxybenzonitrile Chemical compound COC1=CC=C(N)C(C#N)=C1 SRWMPAZUWXLIPG-UHFFFAOYSA-N 0.000 description 1
- OZLMBXPYRDASTP-UHFFFAOYSA-N 2-amino-5-methylbenzonitrile Chemical compound CC1=CC=C(N)C(C#N)=C1 OZLMBXPYRDASTP-UHFFFAOYSA-N 0.000 description 1
- MGCGMYPNXAFGFA-UHFFFAOYSA-N 2-amino-5-nitrobenzonitrile Chemical compound NC1=CC=C([N+]([O-])=O)C=C1C#N MGCGMYPNXAFGFA-UHFFFAOYSA-N 0.000 description 1
- MEJVTQKBWPYBFG-UHFFFAOYSA-N 2-amino-6-chlorobenzonitrile Chemical compound NC1=CC=CC(Cl)=C1C#N MEJVTQKBWPYBFG-UHFFFAOYSA-N 0.000 description 1
- 239000001431 2-methylbenzaldehyde Substances 0.000 description 1
- PWLHUQRFCZDOQK-UHFFFAOYSA-N 2-naphthalen-1-yl-1h-quinazolin-4-one Chemical compound C1=CC=C2C(C3=NC(C4=CC=CC=C4N3)=O)=CC=CC2=C1 PWLHUQRFCZDOQK-UHFFFAOYSA-N 0.000 description 1
- VDULOAUXSMYUMG-UHFFFAOYSA-N 2-phenyl-1h-quinazolin-4-one Chemical class N=1C2=CC=CC=C2C(O)=NC=1C1=CC=CC=C1 VDULOAUXSMYUMG-UHFFFAOYSA-N 0.000 description 1
- MFAZKHYKVSPPIB-UHFFFAOYSA-N 2-propyl-1h-quinazolin-4-one Chemical class C1=CC=C2NC(CCC)=NC(=O)C2=C1 MFAZKHYKVSPPIB-UHFFFAOYSA-N 0.000 description 1
- SVVNZCGMBNAQFW-UHFFFAOYSA-N 2-thiophen-2-yl-1h-quinazolin-4-one Chemical class N1C2=CC=CC=C2C(=O)N=C1C1=CC=CS1 SVVNZCGMBNAQFW-UHFFFAOYSA-N 0.000 description 1
- POQJHLBMLVTHAU-UHFFFAOYSA-N 3,4-Dimethylbenzaldehyde Chemical compound CC1=CC=C(C=O)C=C1C POQJHLBMLVTHAU-UHFFFAOYSA-N 0.000 description 1
- BEOBZEOPTQQELP-UHFFFAOYSA-N 4-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=C(C=O)C=C1 BEOBZEOPTQQELP-UHFFFAOYSA-N 0.000 description 1
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
- PIMQQGJMDMAZGT-UHFFFAOYSA-N 4-methylthiobenzaldehyde Chemical compound CC1=CC=C(C=S)C=C1 PIMQQGJMDMAZGT-UHFFFAOYSA-N 0.000 description 1
- XZNVPUBSOYWXPY-UHFFFAOYSA-N 5-chloro-2-phenyl-3H-quinazolin-4-one Chemical compound ClC1=C2C(NC(=NC2=CC=C1)C1=CC=CC=C1)=O XZNVPUBSOYWXPY-UHFFFAOYSA-N 0.000 description 1
- NXSZVAPNPHKIKA-UHFFFAOYSA-N 6-bromo-2-phenyl-1h-quinazolin-4-one Chemical compound N1C(=O)C2=CC(Br)=CC=C2N=C1C1=CC=CC=C1 NXSZVAPNPHKIKA-UHFFFAOYSA-N 0.000 description 1
- PGMBDCKPRFLKLG-UHFFFAOYSA-N 6-chloro-2-phenyl-1h-quinazolin-4-one Chemical compound N=1C(=O)C2=CC(Cl)=CC=C2NC=1C1=CC=CC=C1 PGMBDCKPRFLKLG-UHFFFAOYSA-N 0.000 description 1
- UHSQXWSTFPABAF-UHFFFAOYSA-N 6-methoxy-2-phenyl-1h-quinazolin-4-one Chemical compound N=1C(=O)C2=CC(OC)=CC=C2NC=1C1=CC=CC=C1 UHSQXWSTFPABAF-UHFFFAOYSA-N 0.000 description 1
- YAEHYTHSAFRMPM-UHFFFAOYSA-N 6-methyl-2-phenyl-1h-quinazolin-4-one Chemical compound N=1C(=O)C2=CC(C)=CC=C2NC=1C1=CC=CC=C1 YAEHYTHSAFRMPM-UHFFFAOYSA-N 0.000 description 1
- DIMUSFUWBLFMSV-UHFFFAOYSA-N 6-nitro-2-phenyl-1h-quinazolin-4-one Chemical class N1C(=O)C2=CC([N+](=O)[O-])=CC=C2N=C1C1=CC=CC=C1 DIMUSFUWBLFMSV-UHFFFAOYSA-N 0.000 description 1
- SDYPYHJQLJZTJH-UHFFFAOYSA-N CC(SC=C1)=C1C(N1)=NC2=CC=CC=C2C1=O Chemical compound CC(SC=C1)=C1C(N1)=NC2=CC=CC=C2C1=O SDYPYHJQLJZTJH-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- ZDUVLDCZFKNYHH-UHFFFAOYSA-N Glycosminine Chemical class N1C2=CC=CC=C2C(=O)N=C1CC1=CC=CC=C1 ZDUVLDCZFKNYHH-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- AXMVYSVVTMKQSL-UHFFFAOYSA-N UNPD142122 Natural products OC1=CC=C(C=CC=O)C=C1O AXMVYSVVTMKQSL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 229940117916 cinnamic aldehyde Drugs 0.000 description 1
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229940100595 phenylacetaldehyde Drugs 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a preparation method of a quinazolinone derivative, which comprises the following steps: dissolving the o-aminobenzonitrile compounds shown in the formula I and aldehydes shown in the formula II in a solvent, and heating to react under the combined action of a catalyst, a ligand and alkali to generate quinazoline-4 (3) shown in the formula IIIH) A ketone derivative, after the reaction is finished, quinazoline-4 (3) is obtained by separationH) A crude product of the ketone derivative, which is purified to obtain quinazoline-4 (3)H) -pure ketone derivative; according to the invention, o-aminobenzonitrile and aldehyde which are easily obtained are used as starting materials, under the combined action of copper chloride and cesium carbonate, the o-aminobenzonitrile is hydrolyzed in situ to generate o-aminobenzamide, and then the o-aminobenzamide reacts with the aldehyde, so that the quinazolinone derivative is obtained by a one-pot method, and the reaction takes water as a solvent, so that the method is green and environment-friendly and has wide application prospects.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a quinazolinone derivative.
Background
Quinazolinone is a nitrogen-containing heterocyclic compound with good biological medical activity, and most of important natural alkaloids and synthetic drugs contain quinazolinone skeleton structures. Due to the wide pharmacological activity of the quinazolinone compound, the quinazolinone compound shows good activity in the aspects of antianaphylaxis, anticancer, antitumor, anti-inflammation, antihypertensive, insecticidal sterilization and the like. Therefore, the synthesis method has been receiving a lot of attention, and in recent years, different synthesis methods have been reported in succession, but most of them use aldehydes, acid anhydrides, acid chlorides, amidines, etc. and anthranilamides as raw materials, and these conventional synthesis methods have some disadvantages such as low yield, difficulty in obtaining raw materials, and use of equivalent or excessive amounts of oxidizing agents such as: KMnO4, MnO2, DDQ, t-BuOOH, PhI (OAo)2, etc., produce a large amount of by-products and severely pollute the environment (Eur.J.Med.chem.,2010,45, 4904-.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a preparation method of a quinazolinone derivative. The method takes aldehyde and o-aminobenzonitrile as initial raw materials, takes green water as a solvent, has mild reaction conditions, simple post-treatment and higher yield, and realizes the preparation of the quinazolinone derivative by a one-pot method.
The invention is realized by the following technical scheme:
a method for preparing a quinazolinone derivative, comprising the steps of:
dissolving an anthranilic nitrile compound shown in a formula I and an aldehyde shown in a formula II in a solvent, heating to react under the combined action of a catalyst, a ligand and alkali to generate a quinazoline-4 (3H) -ketone derivative shown in a formula III, separating after the reaction is finished to obtain a crude product of the quinazoline-4 (3H) -ketone derivative, and purifying the crude product to obtain a pure product of the quinazoline-4 (3H) -ketone derivative;
wherein R is1Is hydrogen, methyl, methoxy, halogen or nitro; r2Is C3-C8Alkyl, benzyl, phenyl, methylphenyl, methoxyphenyl, halophenyl, trifluoromethylphenyl, nitrophenyl, mercaptophenyl, cinnamyl, naphthyl, thienyl, furyl or pyridyl.
The invention further improves the scheme as follows:
the catalyst is CuXnWherein X is Cl, Br, I, OAc, OTf or SO4And n is 1 or 2.
Preferably, the catalyst is CuCl2。
Further, the ligand is one or a mixture of more than two of 2,2' -bipyridyl, 4' -dimethyl-2, 2' -bipyridyl, triphenylphosphine, tricyclohexylphosphine, triphenylphosphine, 2, 9-dimethyl-1, 10-phenanthroline and 1, 10-phenanthroline.
Preferably, the ligand is 1, 10-phenanthroline.
Further, the alkali is one or more of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, potassium methoxide, sodium bicarbonate, potassium carbonate or cesium carbonate.
Preferably, the base is cesium carbonate.
Furthermore, the solvent is one or more than two of toluene, dimethyl sulfoxide DMSO, DMF, tert-butyl alcohol, water or 1, 4-dioxane.
Preferably, the solvent is water.
Further, the reaction temperature is 60-80 ℃, the reaction time is 10-12 h, and in the reaction process, the thin-layer chromatography is used for tracking the reaction until the raw materials disappear, namely the reaction is finished; the separation process comprises the steps of cooling the reaction liquid to room temperature, filtering, washing a filter cake and drying; the purification method is column chromatography or recrystallization.
Further, the solvent of the column chromatography is petroleum ether/ethyl acetate with the volume ratio of 3:1, and the solvent of the recrystallization is methanol.
Further, the molar ratio of the o-aminobenzonitrile compound to the aldehyde to the catalyst to the ligand to the base is 1: 1-1.5: 0.08-0.12: 0.8-1.2.
Compared with the prior art, the invention has the beneficial effects that:
according to the invention, o-aminobenzonitrile and aldehyde which are easily obtained are used as starting materials, under the combined action of copper chloride and cesium carbonate, the o-aminobenzonitrile is hydrolyzed in situ to generate o-aminobenzamide, and then the o-aminobenzamide reacts with the aldehyde, so that the quinazolinone derivative is obtained by a one-pot method, and the reaction takes water as a solvent, so that the method is green and environment-friendly and has wide application prospects.
Detailed Description
Example 1: 2-phenylquinazolin-4 (3H) -ones
Anthranilic acid nitrile (1mmol), benzaldehyde (1.2mmol), CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 92%.
1H NMR(500MHz,DMSO-d6):δ＝12.57(br s,1H),8.21–8.17(m,3H),7.85(t,J＝7.6Hz,1H),7.76(d,J＝8.0Hz,1H),7.62–7.52(m,4H)；13C NMR(125MHz,DMSO-d6):δ162.4,152.4,148.9,134.7,132.9,131.5,128.7,127.9,127.6,126.7,126.0,121.1.
Example 2: 2-p-methylphenyl quinazolin-4 (3H) -one
Anthranilic acid nitrile (1mmol), 4-methylbenzaldehyde (1.2mmol), CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 95%.
1H NMR(500MHz,DMSO-d6):δ＝12.48(br s,1H),8.16(d,J＝7.8Hz,1H),8.11(d,J＝8.2Hz,2H),7.87–7.80(m,1H),7.74(d,J＝8.0Hz,1H),7.52(t,J＝7.4Hz,1H),7.36(d,J＝8.1Hz,2H),2.40(s,3H)；13C NMR(125MHz,DMSO-d6):δ＝162.4,152.4,149.0,141.6,134.7,130.1,129.4,127.9,127.6,126.6,126.0,121.1,21.2.
Example 3: 2-p-methoxyphenyl quinazolin-4 (3H) -one
O-aminobenzonitrile (1mmol), 4-methoxybenzaldehyde (1.2mmol), CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 96%.
1H NMR(500MHz,DMSO-d6):δ＝12.42(br s,1H),8.21(d,J＝8.9Hz,2H),8.14(d,J＝6.9Hz,1H),7.82(t,J＝7.6Hz,1H),7.71(d,J＝8.0Hz,1H),7.49(t,J＝7.7Hz,1H),7.10(d,J＝8.9Hz,2H),3.86(s,3H)；13C NMR(125MHz,DMSO-d6):δ＝162.5,162.0,152.0,149.1,134.7,129.6,127.5,126.3126.0,125.0,120.9,114.2,55.6.
Example 4: 2- (3, 4-dimethylphenyl) quinazolin-4 (3H) -one
O-aminobenzonitrile (1mmol), 3, 4-dimethylbenzaldehyde (1.2mmol) and CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 96%.
1H NMR(500MHz,DMSO-d6)δ＝12.36(br s,1H),8.11(d,J＝7.9Hz,1H),7.98(s,1H),7.89(d,J＝9.3Hz,1H),7.79(t,J＝8.3Hz,1H),7.70(d,J＝7.9Hz,1H),7.47(t,J＝7.9Hz,1H),7.27(d,J＝7.9Hz,1H),2.29(s,3H),2.27(s,3H)；13C NMR(125MHz,DMSO-d6)δ＝162.64,152.72,149.30,140.65,137.01,134.97,130.57,130.11,129.04,127.82,126.75,126.26,125.59,121.33,19.82,19.80.
Example 5: 2-p-fluorophenyl quinazolin-4 (3H) -one
Anthranilic acid nitrile (1mmol), 4-fluorobenzaldehyde (1.2mmol) and CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 84%.
1H NMR(500MHz,DMSO-d6):δ＝12.58(br s,1H),8.32–8.21(m,2H),8.16(d,J＝7.8Hz,1H),7.85(t,J＝7.4Hz,1H),7.74(d,J＝8.0Hz,1H),7.53(t,J＝7.3Hz,1H),7.40(t,J＝8.5Hz,2H)；13C NMR(125MHz,DMSO-d6):δ＝164.2(d,J＝249.4Hz),162.4,151.6,148.8,134.8,130.5(d,J＝7.7Hz),129.4,127.6,126.8,126.0,121.0,115.8(d,J＝21.9Hz).
Example 6: 2- (4-chlorophenyl) quinazolin-4 (3H) -one
Anthranilic acid nitrile (1mmol), 4-chlorobenzaldehyde (1.2mmol), CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 86%.
1H NMR(500MHz,DMSO-d6):δ＝12.62(br s,1H),8.28–8.10(m,3H),7.85(d,J＝6.9Hz,1H),7.75(d,J＝7.6Hz,1H),7.63(d,J＝7.7Hz,2H),7.54(t,J＝6.7Hz,1H)；13C NMR(125MHz,DMSO-d6):δ＝162.3,151.5,148.8,136.5,134.8,131.7,129.8,128.9,127.7,127.0,126.0,121.2.
Example 7: 2-P-trifluoromethylphenylquinazolin-4 (3H) -one
Anthranilic acid nitrile (1mmol), 4-trifluoromethylbenzaldehyde (1.2mmol), CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then diluted and extracted by ethyl acetate, washed by water for three times, and then the organic phase is separated and anhydrousDrying the magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; separating by column chromatography to obtain pure product with yield of 78%
1H NMR(500MHz,DMSO-d6):δ＝12.75(br s,1H),8.38(d,J＝7.1Hz,2H),8.19(d,J＝7.0Hz,1H),7.90(m,3H),7.79(d,J＝7.3Hz,1H),7.57(s,1H)；13C NMR(125MHz,DMSO-d6):δ＝162.5,151.6,148.9,137.1,135.1,131.7(q,JC-F＝31.7),129.2,128.1,127.6,126.3,125.9(q,JC-F＝3.2Hz),124.4(q,JC-F＝271.5Hz),121.7.
Example 8: 2-methylthiophenylquinazolin-4 (3H) -one
O-aminobenzonitrile (1mmol), 4-methylthiobenzaldehyde (1.2mmol), CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; separating by column chromatography to obtain pure product with yield of 78%
1H NMR(500MHz,DMSO-d6)δ＝12.44(s,1H),8.18–8.04(m,3H),7.78(t,J＝7.6Hz,1H),7.68(d,J＝8.0Hz,1H),7.46(t,J＝7.5Hz,1H),7.35(d,J＝8.5Hz,2H),2.51(s,3H)；13C NMR(125MHz,DMSO-d6)δ＝162.41,151.95,148.98,143.21,134.73,128.83,128.23,127.56,126.54,126.02,125.28,121.07,14.27.
Example 9: 2-styryl-quinazolin-4 (3H) -ones
Anthranilic acid nitrile (1mmol), cinnamic aldehyde (1.2mmol), CuCl2(10 mol%) and 1, 10-phenanthroline (1)0mol％)，Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 80%.
1H NMR(500MHz,DMSO-d6):δ＝12.34(br s,1H),8.12(d,J＝7.7Hz,1H),7.96(d,J＝16.2Hz,1H),7.82(t,J＝7.4Hz,1H),7.68(t,J＝7.7Hz,3H),7.50-7.42(m,4H),7.02(d,J＝16.2Hz,1H)；13C NMR(125MHz,DMSO-d6):δ＝161.9,151.6,149.2,138.4,135.2,134.7,130.0,129.3,127.8,127.3,126.4,126.0,121.3.
Example 10: 2- (2-thienyl) quinazolin-4 (3H) -ones
Anthranilic acid nitrile (1mmol), 2-thiophenecarboxaldehyde (1.2mmol) and CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 82%.
1H NMR(500MHz,DMSO-d6):δ＝12.66(br s,1H),8.25(d,J＝4.6Hz,1H),8.14(d,J＝7.9Hz,1H),7.88(d,J＝5.0Hz,1H),7.81(t,J＝7.7Hz,1H),7.67(d,J＝8.0Hz,1H),7.50(t,J＝7.9Hz,1H),7.27–7.23(m,1H)；13C NMR(125MHz,DMSO-d6):δ＝162.0,148.8,148.0,137.5,134.9,132.3,129.6,128.7,127.1,126.5,126.2,121.1
Example 11: 2-Benzylquinazolin-4 (3H) -ones
Anthranilic acid nitrile (1mmol), phenylacetaldehyde (1.2mmol) and CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 74 percent.
1H NMR(500MHz,DMSO-d6):δ＝12.41(br s,1H),8.08(d,J＝7.8Hz,1H),7.78(t,J＝7.7Hz,1H),7.61(d,J＝8.1Hz,1H),7.47(t,J＝7.5Hz,1H),7.38(d,J＝7.4Hz,2H),7.32(t,J＝7.5Hz,2H),7.24(t,J＝7.3Hz,1H),3.94(s,2H)；13C NMR(125MHz,DMSO-d6):δ＝162.0,156.1,149.1,136.7,134.6,129.0,128.7,127.1,127.0,126.4,125.9,120.9,41.0.
Example 12: 2- (1-naphthyl) quinazolin-4 (3H) -one
Anthranilic acid nitrile (1mmol), 1-naphthaldehyde (1.2mmol) and CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 74 percent.
1H NMR(500MHz,DMSO-d6):δ＝12.67(br s,1H),8.23(d,J＝7.8Hz,1H),8.18(d,J＝7.7Hz,1H),8.13(d,J＝8.2Hz,1H),8.05(d,J＝8.4Hz,1H),7.87(t,J＝7.6Hz,1H),7.80(d,J＝7.0Hz,1H),7.74(d,J＝8.1Hz,1H),7.65(t,J＝7.7Hz,1H),7.57-7.62(m,3H)；13C NMR(125MHz,DMSO-d6):δ＝162.1,153.9,148.9,134.7,133.3,131.9,130.6,130.4,128.5,127.9,127.7,127.3,127.0,126.5,126.0,125.4,125.2,121.4.
Example 13: 2-propylquinazolin-4 (3H) -ones
Anthranilic acid nitrile (1mmol), n-butyraldehyde (1.2mmol) and CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 70%.
1H NMR(500MHz,DMSO-d6):δ＝12.16(br s,1H),8.08(d,J＝7.8Hz,1H),7.80–7.74(m,1H),7.59(d,J＝8.1Hz,1H),7.46(t,J＝7.5Hz,1H),2.58(t,J＝7.5Hz,2H),1.79–1.71(m,2H),0.94(t,J＝7.4Hz,3H)；13C NMR(125MHz,DMSO-d6):δ＝162.0,157.5,149.1,134.4,127.0,126.1,125.8,121.0,36.5,20.4,13.7
Example 14: 6-methoxy-2-phenylquinazolin-4 (3H) -one
2-amino-5-methoxybenzonitrile (148mg,1mmol), benzaldehyde (1.2mmol), CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 82%.
1H NMR(500MHz,DMSO-d6)；δ＝12.52(br s,1H),8.17(d,J＝7.0Hz,2H),7.71(d,J＝8.9Hz,1H),7.59–7.52(m,4H),7.45(dd,J＝8.9,2.8Hz,1H),3.90(s,3H)；13C NMR(125MHz,DMSO-d6):δ＝162.2,157.9,150.3,143.4,133.0,131.2,129.4,128.8,127.7,124.3,122.0,106.1,55.8.
Example 15: 6-methyl-2-phenylquinazolin-4 (3H) -one
2-amino-5-methylbenzonitrile (132mg,1mmol), benzaldehyde (1.2mmol), CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 84%.
1H NMR(500MHz,DMSO-d6)δ＝12.42(s,1H),8.12(d,J＝7.0Hz,2H),7.91(s,1H),7.64–7.59(m,2H),7.55–7.47(m,3H),2.41(s,3H)；13C NMR(125MHz,DMSO-d6)δ＝162.31,151.63,146.93,136.45,136.02,132.97,131.38,128.74,127.80,127.55,125.41,120.91,21.01.
Example 16: 5-chloro-2-phenylquinazolin-4 (3H) -one
2-amino-6-chlorobenzonitrile (152mg,1mmol), benzaldehyde (1.2mmol), CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; layer of warp columnThe pure product can be obtained after separation, and the yield is 76%.
1H NMR(500MHz,DMSO-d6)δ＝12.48(s,1H),8.13(d,J＝7.4Hz,2H),7.69(t,J＝7.9Hz,1H),7.63(d,J＝8.0Hz,1H),7.55(d,J＝6.9Hz,1H),7.50(t,J＝7.3Hz,2H),7.46(d,J＝7.4Hz,1H)；13C NMR(125MHz,DMSO-d6)δ＝160.53,153.15,151.46,134.50,132.68,132.30,131.84,129.09,128.77,128.01,128.01,127.26,118.12.
Example 17: 6-chloro-2-phenylquinazolin-4 (3H) -one
2-amino-5-chlorobenzonitrile (152mg,1mmol), benzaldehyde (1.2mmol), CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 75%.
1H NMR(500MHz,DMSO-d6):δ＝12.71(br s,1H),8.18(d,J＝6.4Hz,2H),8.09(s,1H),7.86(d,J＝7.5Hz,1H),7.77(d,J＝8.2Hz,1H),7.64-7.52(m,3H)；13C NMR(125MHz,DMSO-d6):δ＝161.5,153.0,147.7,134.9,132.6,131.8,130.9,129.9,128.8,128.0,125.1,122.4.
Example 18: 6-bromo-2-phenylquinazolin-4 (3H) -one
2-amino-5-bromobenzonitrile (197mg,1mmol), benzaldehyde (1.2mmol), CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water were sequentially added to a 25mL reaction tube, and the mixture was reacted at 80 ℃ for 12 hoursCooling to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 78%.
1H NMR(500MHz,DMSO-d6):δ＝12.74(br s,1H),8.23(s,1H),8.18(d,J＝7.4Hz,2H),7.98(d,J＝10.0Hz,1H),7.70(d,J＝8.6Hz,1H),7.64–7.50(m,3H)；13C NMR(125MHz,DMSO-d6):δ＝161.4,153.1,147.9,137.6,132.6,131.8,130.0,128.8,128.2,128.0,122.8,119.1.
Example 19: 6-nitro-2-phenylquinazolin-4 (3H) -ones
2-amino-5-nitrobenzonitrile (163mg,1mmol), benzyl alcohol (108mg, 1mmol), Fe (NO)3)3·9H2O (40.4mg,0.10mmol), TEMPO (15.6mg,0.10mmol), t-BuOK (224mg,2equiv) and toluene 2mL were added to a 25mL reaction tube in that order, the mixture was reacted at reflux for 12h, cooled to room temperature; adding ethyl acetate to dilute the reaction solution, washing with water for three times, separating an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 65%.
Comparative example 1
The copper salt in this comparative example was copper nitrate and the procedure was otherwise the same as in example 1.
Anthranilic acid nitrile (1mmol), benzaldehyde (1.2mmol), Cu (NO)3)2(10 mol%) and 1, 10-phenanthroline (10 mol%), Cs2CO3(1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at the temperature of 80 ℃, and the mixture is cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 40%.
Comparative example 2
The base in this comparative example was KOH and the procedure was otherwise the same as in example 1.
Anthranilic acid nitrile (1mmol), benzaldehyde (1.2mmol), CuCl2(10 mol%) and 1, 10-phenanthroline (10 mol%), KOH (1equiv) and 2mL of water are sequentially added into a 25mL reaction tube, the mixture reacts for 12h at 80 ℃, and the mixture is cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 60%.
Comparative example 3
The ligand in this comparative example was 2,2' -bipyridine, and the other operations were the same as in example 1.
Anthranilic acid nitrile (1mmol), benzaldehyde (1.2mmol), CuCl2(10 mol%) and 2,2' -bipyridine (10 mol%), KOH (1equiv) and 2mL of water were sequentially added to a 25mL reaction tube, and the mixture was reacted at 80 ℃ for 12 hours and cooled to room temperature; then dilute extracting with ethyl acetate, washing with water for three times, separating out an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product; the pure product can be obtained by column chromatography separation, and the yield is 36%.
Claims (10)
1. A preparation method of quinazolinone derivatives is characterized by comprising the following steps:
dissolving the o-aminobenzonitrile compounds shown in the formula I and aldehydes shown in the formula II in a solvent, and heating to react under the combined action of a catalyst, a ligand and alkali to generate quinazoline-4 (3) shown in the formula IIIH) A ketone derivative, after the reaction is finished, quinazoline-4 (3) is obtained by separationH) A crude product of the ketone derivative, which is purified to obtain quinazoline-4 (3)H) -pure ketone derivative;
wherein R is1Is hydrogen, methyl, methoxy, halogen or nitro; r2Is C3-C8Alkyl, benzyl, phenyl,Methylphenyl, methoxyphenyl, halophenyl, trifluoromethylphenyl, nitrophenyl, mercaptophenyl, cinnamyl, naphthyl, thienyl, furyl or pyridyl;
the catalyst is CuXnWherein X is Cl, Br, I, OAc, OTf or SO4And n is 1 or 2.
2. The process for producing a quinazolinone derivative according to claim 1, wherein: the catalyst is CuCl2。
3. The process for producing a quinazolinone derivative according to claim 1, wherein: the ligand is one or more than two of 2,2' -bipyridyl, 4' -dimethyl-2, 2' -bipyridyl, triphenylphosphine, tricyclohexylphosphine, triphenylphosphine, 2, 9-dimethyl-1, 10-phenanthroline or 1, 10-phenanthroline.
4. The process for producing a quinazolinone derivative according to claim 3, wherein: the ligand is 1, 10-phenanthroline.
5. The process for producing a quinazolinone derivative according to claim 1, wherein: the alkali is one or more of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, potassium methoxide, sodium bicarbonate, potassium carbonate or cesium carbonate.
6. The method for preparing a quinazolinone derivative according to claim 5, wherein: the base is cesium carbonate.
7. The process for producing a quinazolinone derivative according to claim 1, wherein: the solvent is one or more than two of toluene, dimethyl sulfoxide DMSO, DMF, tert-butanol, water or 1, 4-dioxane.
8. The process for producing a quinazolinone derivative according to claim 7, wherein: the solvent is water.
9. The process for producing a quinazolinone derivative according to claim 1, wherein: the reaction temperature is 60-80 ℃, and the reaction time is 10-12 h; the separation process comprises the steps of cooling the reaction liquid to room temperature, filtering, washing a filter cake and drying; the purification method is column chromatography or recrystallization.
10. The process for producing a quinazolinone derivative according to claim 1, wherein: the molar ratio of the o-aminobenzonitrile compound to the aldehyde to the catalyst to the ligand to the alkali is 1: 1-1.5: 0.08-0.12: 0.8-1.2.
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Application publication date: 20210413 Assignee: Hubei Moco Biotechnology Co.,Ltd. Assignor: HUAIYIN INSTITUTE OF TECHNOLOGY Contract record no.: X2024980005312 Denomination of invention: A Preparation Method of Quinazolinone Derivatives Granted publication date: 20230113 License type: Common License Record date: 20240507 |