CN108014113B - Application of butyrylamidodimethoxybenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating cervical cancer - Google Patents
Application of butyrylamidodimethoxybenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating cervical cancer Download PDFInfo
- Publication number
- CN108014113B CN108014113B CN201810069784.1A CN201810069784A CN108014113B CN 108014113 B CN108014113 B CN 108014113B CN 201810069784 A CN201810069784 A CN 201810069784A CN 108014113 B CN108014113 B CN 108014113B
- Authority
- CN
- China
- Prior art keywords
- ethyl acetate
- formula
- petroleum ether
- silica gel
- solvent
- 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.)
- Active
Links
- 206010008342 Cervix carcinoma Diseases 0.000 title claims abstract description 19
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 title claims abstract description 19
- 201000010881 cervical cancer Diseases 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 title claims abstract description 13
- -1 quinazoline compound Chemical class 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title description 23
- 229940079593 drug Drugs 0.000 title description 2
- 230000000694 effects Effects 0.000 claims abstract description 7
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 165
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 91
- 150000001875 compounds Chemical class 0.000 description 56
- 239000000243 solution Substances 0.000 description 49
- 239000003208 petroleum Substances 0.000 description 47
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 41
- 239000012141 concentrate Substances 0.000 description 41
- 239000000741 silica gel Substances 0.000 description 41
- 229910002027 silica gel Inorganic materials 0.000 description 41
- 239000002904 solvent Substances 0.000 description 41
- 239000000203 mixture Substances 0.000 description 35
- 238000004440 column chromatography Methods 0.000 description 28
- 238000001514 detection method Methods 0.000 description 28
- 238000001704 evaporation Methods 0.000 description 28
- 239000003960 organic solvent Substances 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- 238000002156 mixing Methods 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
- 238000001035 drying Methods 0.000 description 20
- 239000003480 eluent Substances 0.000 description 20
- 239000003795 chemical substances by application Substances 0.000 description 19
- 238000000034 method Methods 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000002844 melting Methods 0.000 description 16
- 230000008018 melting Effects 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000011259 mixed solution Substances 0.000 description 15
- LZOSFEDULGODDH-UHFFFAOYSA-N 4-chloro-6-nitroquinazoline Chemical compound N1=CN=C(Cl)C2=CC([N+](=O)[O-])=CC=C21 LZOSFEDULGODDH-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 150000003246 quinazolines Chemical class 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- 238000011049 filling Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 239000012265 solid product Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 7
- 239000003638 chemical reducing agent Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 7
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 6
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000011068 loading method Methods 0.000 description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000005907 cancer growth Effects 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- VDDAVZWCRBHDLQ-UHFFFAOYSA-N 2-phenylquinazoline Chemical compound C1=CC=CC=C1C1=NC=C(C=CC=C2)C2=N1 VDDAVZWCRBHDLQ-UHFFFAOYSA-N 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 208000019065 cervical carcinoma Diseases 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 229960004891 lapatinib Drugs 0.000 description 2
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- WOGITNXCNOTRLK-VOTSOKGWSA-N (e)-3-phenylprop-2-enoyl chloride Chemical compound ClC(=O)\C=C\C1=CC=CC=C1 WOGITNXCNOTRLK-VOTSOKGWSA-N 0.000 description 1
- RUQIUASLAXJZIE-UHFFFAOYSA-N 3-methoxybenzoyl chloride Chemical compound COC1=CC=CC(C(Cl)=O)=C1 RUQIUASLAXJZIE-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical group N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AOQONNCNKUWWRI-UHFFFAOYSA-N cyclohexylmethyl carbonochloridate Chemical compound ClC(=O)OCC1CCCCC1 AOQONNCNKUWWRI-UHFFFAOYSA-N 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses butyrylamino dimethoxy benzo [ d]Aza derivatives
Description
(I) technical field
The invention relates to butyrylamino dimethoxy benzo [ d]Aza derivatives
The application of the quinazoline compound in preparing the medicine for preventing or treating human cervical carcinoma.
(II) background of the invention
The quinazoline compounds have a plurality of good biological activities and are widely applied in the field of medicine, particularly, some quinazoline derivatives with special structures have obvious antiviral activity, antibacterial activity, antitumor activity and the like, and the quinazoline compounds are marketed as antitumor drugs. For example, Gefitinib (Gefitinib) and Erlotinib (Erlotinib) are marketed for the treatment of lung cancer, and Lapatinib (Lapatinib) is marketed for the treatment of breast cancer, both of which belong to the quinazoline class of compounds. Novel quinazoline compounds and their biological activities are also commonly reported in the literature (see y. -y. ke, h. -y. shiao, y. c. hsu, c. -y. chu, w. -c. wang, y. -c. lee, w. -h. lin, c. -h. chen, j. t. a. hsu, c. -w. chang, c. -w. lin, t. -k. yeh, y. -s. chao, m.s. coumar, h. -p. hsieh, chemed chem 2013,8, 136-148; a.garofalo, a.farce, s.ravez, a.lemoine, p.six, p.vachatte, l.gos, p.depenux, j.chem. 1204, d. chem. 1189). Of course most quinazoline compounds do not have anti-tumor activity.
Disclosure of the invention
The invention aims to provide a novel quinazoline compound, butyrylamidodimethoxybenzo [ d]Aza derivatives
Radical-quinazoline compoundsThe compounds have obvious inhibition rate on human cervical cancer cell strains Siha under certain dosage; and the preparation method of the compound is simple and convenient, easy to operate, easy to obtain raw materials, low in production cost and suitable for industrial application.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides butyrylamino dimethoxy benzo [ d ] shown as a formula (I)]Aza derivatives
The application of the quinazoline compounds in preparing medicaments for preventing or treating tumors, in particular to the application in preparing medicaments for preventing or treating human cervical carcinoma:
preferably, the medicament is a medicament capable of inhibiting the activity of the human cervical cancer cell line Siha.
The invention provides butyrylamino dimethoxy benzo [ d ] shown as a formula (I)]Aza derivatives
The preparation method of the fluoroquinazoline compound comprises the following steps: (1) mixing a compound shown as a formula (II) and a compound shown as a formula (III), reacting at 25-120 ℃ in an organic solvent A under the action of a basic catalyst B (TLC tracking monitoring is carried out, a developing agent is ethyl acetate/petroleum ether which is 1: 3(v/v), and preferably 40-100 ℃ for 0.5-12 h), and after the reaction is completed, separating and purifying a reaction solution to obtain a compound shown as a formula (IV); the organic solvent A is selected from one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the basic catalyst B is selected from one of the following: pyridine, diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate (preferably pyridine, diethylamine, triethylamine, N-dimethylaniline or 4-dimethylaminopyridine);
(2) dissolving the compound shown in the formula (IV) obtained in the step (1) in an organic solvent D, completely reacting at 25-100 ℃ under the action of a reducing agent E (TLC tracking monitoring, a developing agent is ethyl acetate/petroleum ether ═ 1: 1(v/v), preferably reacting at 40-80 ℃ for 0.5-12 h), filtering a reaction solution, concentrating a filtrate under reduced pressure, and drying a concentrate (preferably drying at 25 ℃ in vacuum) to obtain the compound shown in the formula (V); the organic solvent D is one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the reducing agent E is one of the following: iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium on carbon/ammonium formate or palladium on carbon/hydrazine hydrate; the iron powder/concentrated hydrochloric acid refers to the mixing of iron powder and concentrated hydrochloric acid in any proportion, the iron powder/acetic acid refers to the mixing of iron powder and acetic acid in any proportion, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate in any proportion, and the palladium carbon/hydrazine hydrate refers to the mixing of palladium carbon and hydrazine hydrate in any proportion;
(3) mixing the compound shown in the formula (V) obtained in the step (2) with butyryl chloride or butyric anhydride, completely reacting in an organic solvent G at-10-50 ℃ under the action of an alkaline catalyst F (tracking and monitoring by TLC, a developing agent is ethyl acetate/petroleum ether which is 1: 1(v/v), preferably reacting for 3-12 h at-10-50 ℃), and carrying out aftertreatment on a reaction solution to obtain the compound shown in the formula (I); the organic solvent G is one of the following: tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, diethyl ether, acetonitrile, toluene or benzene; the alkaline catalyst F is one of the following: pyridine, diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate;
further, in the step (1), the ratio of the amount of the compound represented by the formula (iii) to the amount of the compound represented by the formula (II) to the amount of the basic catalyst B to be charged is 1.0: 0.8 to 1.2: 1.0 to 8.0.
Further, in the step (1), the amount of the organic solvent A is 10-50 mL/g based on the mass of the compound represented by the formula (III).
Further, the method for separating and purifying the reaction solution in the step (1) of the present invention comprises: after the reaction is completed, evaporating the solvent from the reaction solution, dissolving the concentrate with an organic solvent C to obtain a dissolved solution, adding column chromatography silica gel (preferably 300-400 mesh coarse pore (zcx.II) type column chromatography silica gel) in an amount which is 1.0-2.0 times the weight of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, packing the mixture into a column, and then mixing the mixture with the silica gel in a volume ratio of 1: taking a mixed solution of petroleum ether and ethyl acetate of 0.1-10 as an eluent, collecting an effluent containing a target component (preferably, ethyl acetate/petroleum ether is 1: 3(v/v) is taken as a developing agent for tracking detection, collecting the target component, preferably, collecting a component with an Rf value of 0.5), concentrating under reduced pressure, and drying (preferably, drying at 50 ℃) to obtain the compound shown in the formula (IV); the organic solvent C is one of the following solvents: ethanol, chloroform, tetrahydrofuran or ethyl acetate. The organic solvent C is used in an amount capable of dissolving the residue.
Further, in the step (2), the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, and the charging mass ratio of the compound represented by the formula (IV) to the iron powder, concentrated hydrochloric acid or acetic acid in the reducing agent E is 1.0: 1.0-3.0: 0.2-1.0. In the invention, the mass concentration of the concentrated hydrochloric acid is 36-38%, and the acetic acid is glacial acetic acid.
Further, in the step (2), the reducing agent E is palladium on carbon/ammonium formate or palladium on carbon/hydrazine hydrate, and the feeding mass ratio of the compound represented by the formula (IV) to the palladium on carbon, ammonium formate or hydrazine hydrate in the reducing agent E is 1.0: 0.1 to 0.5: 1.0 to 3.0. The mass loading amount of palladium in the palladium-carbon applicable to the invention is 2-10%, preferably 5%, and the mass concentration of hydrazine hydrate is 40-80%, preferably 80%.
Further, in the step (2), the amount of the organic solvent D is 10 to 50mL/g based on the mass of the compound represented by the formula (IV).
Further, in the step (3), the ratio of the compound represented by the formula (V) to the amounts of the butyryl chloride or butyric anhydride and the basic catalyst F to be charged is 1: 1.0 to 8.0: 1.0 to 3.0.
Further, in the step (3), the amount of the organic solvent G is 11 to 100mL/G based on the mass of the compound represented by the formula (V).
Further, the step (3) is carried out according to the following method: dropwise adding an organic solvent G solution of butyryl chloride or butyric anhydride into a compound shown in a formula (V) and an organic solvent G solution of a basic catalyst F at-10 ℃, reacting for 3-12 hours at-10-50 ℃, and carrying out post-treatment on the obtained reaction solution to obtain a compound shown in a formula (I); the volume dosage of the organic solvent for dissolving the butyryl chloride or the butyric anhydride does not influence the invention, and the total dosage of the organic solvent G is 11-100 mL/G based on the mass of the compound shown in the formula (V). The total amount of the organic solvent G used is the total volume of the organic solvent G in which the basic catalyst F and the compound represented by the formula (V) are dissolved and the organic solvent G in which the butyryl chloride or the butyric anhydride is dissolved.
Further, the post-treatment method of the reaction solution in the step (3) of the present invention comprises: filtering the reaction solution, evaporating the solvent from the filtrate, dissolving the concentrate in an organic solvent H to obtain a dissolved solution, adding column chromatography silica gel (preferably 300-400 mesh coarse pore (zcx.II) type column chromatography silica gel) in an amount which is 1.0-2.0 times the weight of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, loading the mixture into a column, collecting an effluent containing a target component (preferably tracking detection by using ethyl acetate/petroleum ether ═ 1: 1(v/v) as a developing agent, collecting the target component, preferably collecting a component with an Rf value of 0.5) by using a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 1: 0.1-10 as an eluent), concentrating under reduced pressure, and drying (preferably drying at 50 ℃) to obtain the compound represented by the formula (I); the organic solvent H is one of the following: ethanol, chloroform, tetrahydrofuran or ethyl acetate. The organic solvent H is used in an amount capable of dissolving the residue.
The organic solvents A, C, D, G and H are organic solvents, so that the organic solvents used for distinguishing different steps are named for convenience, and letters have no meanings; the catalyst B, the reducing agent E and the catalyst F are all catalysts, are named for the convenience of distinguishing the catalysts used in different steps, and have no meaning by letters per se.
The invention has the following beneficial effects: provides the application of a novel quinazoline compound in preparing a medicament for preventing or treating human cervical cancer, and the compound has obvious inhibitory activity on human cervical cancer cell strain Siha.
(IV) detailed description of the preferred embodiments
The invention is further illustrated by reference to specific examples, which are intended to illustrate the invention, but not to limit it in any way.
The compound (II) can be prepared by a method described in Weinstock, J.et al.J.Med.chem.,1986, 29(11), 2315-2325. Preparation of 4-chloro-6-nitroquinazoline (III) according to the method of Fernandes, C.et al bioorg.Med.chem.,2007,15(12), 3974-3980.
The palladium on carbon (Pd/C) type used in the embodiment of the invention: D5H5A, manufacturer: shaanxi Rui Material Ltd
Example 1: nitrobenzo [ d]Aza derivatives
Preparation of the fluoroquinazolines (IV)
Sequentially adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 2.39 g (6.87mmol) of compound (II), 3.62 g (45.76mmol) of pyridine and 12 ml of chloroform into a 50ml reaction bottle, heating to 40 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for 10 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 10 ml of ethyl acetate into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 3.0 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of a dried concentrate and the silica gel, filling the mixture into a column, and then performing column chromatography by using a volume ratio of 1: eluting with a mixed solution of petroleum ether and ethyl acetate as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected eluent, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 85.1%, and the melting point is 164-166 ℃.1H NMR(500MHz,CDCl3):3.32-3.38(m,1H),3.63(dt,J＝3.4,15.5Hz,1H),3.75(s,3H),3.82(s,6H),3.91(dd,J＝8.1,14.3Hz,1H),4.03(td,J＝4.1,11.7Hz,1H),4.15(d,J＝11.5Hz,1H),4.72(dd,J＝8.3,14.2Hz,1H),5.14(t,J＝8.9Hz,1H),6.60(s,1H),6.90(d,J＝8.7Hz,2H),7.08(d,J＝8.6Hz,2H),7.93(d,J＝9.1Hz,1H),8.48(dd,J＝2.4,9.2Hz,1H),8.71(s,1H),8.96(d,J＝2.4Hz,1H)。IR(KBr,cm-1)ν:2917,2848,1616,1580,1510,1463,1355,1327,1249,1038,847。
Example 2: nitrobenzo [ d]Aza derivatives
Preparation of the fluoroquinazolines (IV)
Sequentially adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 1.59 g (4.57mmol) of compound (II), 1.67 g (22.83mmol) of diethylamine and 60 ml of toluene into a 100ml three-neck flask, heating to 100 ℃, performing TLC tracking detection (developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for 2 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, dissolving the obtained concentrate by adding 20 ml of ethanol into the obtained concentrate to obtain a dissolved solution, adding 2.5 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, eluting by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 1: 5 as an eluent, eluting, performing TLC tracking detection (developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting eluate containing the compound shown in formula (IV) according to TLC detection (Rf value is 0.5), concentrating the collected eluate, and drying at 50 deg.C to obtain light yellow solid product shown in formula (IV), with yield of 72.6% and melting point of 164-166 deg.C.1H NMR and IR were the same as in example 1.
Example 3: nitrobenzo [ d]Aza derivatives
Preparation of the fluoroquinazolines (IV)
1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 1.99 g (5.72mmol) of compound (II), 0.58 g (5.73mmol) of triethylamine and 60 ml of ethanol were added in this order to 100ml ofHeating to 60 deg.C in a three-neck flask, performing TLC tracking detection (developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for 8 hr, stopping reaction, evaporating solvent from reaction solution, dissolving the obtained concentrate with 20 ml chloroform to obtain solution, adding 2.5 g column chromatography silica gel (300-400 mesh column chromatography silica gel) into solution, mixing, evaporating solvent to obtain mixture of dried concentrate and silica gel, loading the mixture into column, eluting with petroleum ether/ethyl acetate mixed solution at volume ratio of 10: 1 as eluent, performing TLC tracking detection (developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting eluate containing compound shown in formula (IV) (Rf value is 0.5), concentrating the collected eluate, drying at 50 deg.C to obtain light yellow solid product shown in formula (IV), the yield is 77.2 percent, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 4: nitrobenzo [ d]Aza derivatives
Preparation of the fluoroquinazolines (IV)
Sequentially adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 2.20 g (6.32mmol) of compound (II), 1.40 g (11.46mmol) of 4-dimethylaminopyridine and 60 ml of isopropanol into a 100ml three-neck flask, stirring at room temperature and 25 ℃, performing TLC (ethyl acetate/petroleum ether-1: 3(v/v)) tracking detection (developing agent), reacting for 12 hours, closing the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of tetrahydrofuran into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 4.0 g of column chromatography silica gel (300-400 mesh silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, eluting by using a mixed solution of petroleum ether/ethyl acetate with a volume ratio of 5: 1 as an eluent, performing TLC tracking detection (ethyl acetate/petroleum ether-1: 3(v/v)), collecting eluate containing the compound shown in formula (IV) according to TLC detection (Rf value is 0.5), concentrating the collected eluate, and drying at 50 deg.C to obtain light yellow solid product shown in formula (IV) with yield of 80.2% and melting point of 164-166 deg.C.1HNMR and IR were the same as in example 1.
Example 5: nitrobenzo [ d]Aza derivatives
Preparation of the fluoroquinazolines (IV)
Adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 1.79 g (5.15mmol) of compound (II), 1.04 g (8.58mmol) of N, N-dimethylaniline and 12 ml of N, N-dimethylformamide into a 50ml reaction bottle, heating to 120 ℃, performing TLC tracking detection (ethyl acetate/petroleum ether is 1: 3(v/v)) and stirring for 0.5 hour, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of tetrahydrofuran into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 5.0 g of silica gel (300-400 mesh silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of the dried concentrate and the silica gel, filling the mixture into a column, and then filling the mixture into the column according to the volume ratio of 1: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected eluent, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 89.6%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 6: nitrobenzo [ d]Aza derivatives
Preparation of the fluoroquinazolines (IV)
Sequentially adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 2.39 g (6.87mmol) of compound (II), 3.62 g (45.76mmol) of pyridine and 20 ml of propanol into a 50ml reaction bottle, heating to 40 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for 10 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of ethyl acetate into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 3.5 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography by using a volume ratio of 1: 1Eluting with the mixed solution of petroleum ether and ethyl acetate as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected eluent, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 78.3%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 7: aminobenzo [ d ] s]Aza derivatives
Preparation of the quinazolines (V)
0.40 g (0.77mmol) of nitrobenzo [ d ] prepared by the method of example 1 are successively introduced]Aza derivatives
The reaction flask was charged with phenylquinazoline (IV), 0.40 g (6.34mmol) ammonium formate, 0.04 g 5% Pd/C, 4.0 ml chloroform, stirred at 25 ℃ and monitored by TLC (developing solvent ethyl acetate/petroleum ether ═ 1: 1(v/v)), reacted for 12 hours, filtered, the filtrate was concentrated and dried in vacuo at 25 ℃ to give aminobenzo [ d ] as a pale yellow solid product]Aza derivatives
The yield of the quinazoline (V) is 98.2 percent, and the melting point is 122-126 ℃.1H NMR(500MHz,CDCl3):3.40-3.48(m,2H),3.71(s,3H),3.82(s,3H),3.83(s,3H),3.87-3.98(m,5H),4.45(dd,J＝6.3,13.8Hz,1H),4.95(dd,J＝6.5,9.2Hz,1H),6.47(s,1H),6.90(d,J＝8.7Hz,2H),6.95(d,J＝2.5Hz,1H),7.11(d,J＝8.6Hz,2H),7.15(dd,J＝8.9,2.5Hz,1H),7.69(d,J＝8.9Hz,1H),8.50(s,1H)。IR(KBr,cm-1)ν:3368,3215,2932,2825,1628,1566,1512,1487,1353,1248,1036,834。
Example 8: aminobenzo [ d ] s]Aza derivatives
Preparation of the quinazolines (V)
0.40 g (0.77mmol) of nitrobenzo [ d ] prepared by the method of example 2 are successively introduced]Aza derivatives
The phenyl quinazoline (IV), 1.20 g (19.18mmol)80 wt% hydrazine hydrate, 0.20 g 5% Pd/C, 20.0 ml toluene were added into a 50ml reaction bottle, heated to 100 deg.C, monitored by TLC (developing solvent ethyl acetate/petroleum ether-1: 1(v/v)), stirred for 0.5 hours, cooled and filtered, the filtrate was concentrated, and vacuum dried at 25 deg.C to obtain aminobenzo [ d ] as a light yellow solid product]Aza derivatives
The yield of the quinazoline (V) is 100.0 percent, and the melting point is 122-126 ℃.1H NMR and IR were the same as in example 7.
Example 9: aminobenzo [ d ] s]Aza derivatives
Preparation of the quinazolines (V)
0.40 g (0.77mmol) of nitrobenzo [ d ] prepared by the method of example 3 are successively reacted]Aza derivatives
Adding 0.08 g of concentrated hydrochloric acid (mass concentration is 36-38%), 0.40 g of iron powder and 20.0 ml of methanol into a 50ml reaction bottle, heating to 40 ℃, carrying out TLC tracking detection (ethyl acetate/petroleum ether is used as a developing agent: 1(v/v)), stirring for 8 hours, cooling, filtering, concentrating the filtrate, and carrying out vacuum drying at 25 ℃ to obtain a light yellow solid product aminobenzo [ d]Aza derivatives
The yield of the quinazoline (V) is 94.1 percent, and the melting point is 122-126 ℃.1HNMR and IR were the same as in example 7.
Example 10: aminobenzo [ d ] s]Aza derivatives
Preparation of the quinazolines (V)
0.40 g (0.77mmol) of nitrobenzo [ d ] prepared by the method of example 4 are successively reacted]Aza derivatives
Adding the quinazoline (IV), 0.40 g acetic acid, 1.20 g iron powder and 20.0 ml isopropanol into a 50ml reaction bottle, heating to 80 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirring for reacting for 3 hours, cooling, filtering, concentrating the filtrate, and performing vacuum drying at 25 ℃ to obtain a light yellow solid product, namely aminobenzo [ d]Aza derivatives
The yield of the quinazoline (V) is 97.5 percent, and the melting point is 122-126 ℃.1H NMR and IR were the same as in example 7.
Example 11: butyrylamiodoxybenzo [ d ]]Aza derivatives
Preparation of the quiazolidines (I)
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 7 are successively reacted]Aza derivatives
Adding 0.13 g (1.64mmol) of pyridine and 3 ml of tetrahydrofuran into a reaction bottle, dropwise adding 0.469 g (4.40mmol) of butyryl chloride under the stirring condition at-10 ℃, after dropwise adding, performing TLC tracking detection (the developing agent is ethyl acetate/petroleum ether is 1: 1), reacting for 12 hours under the condition of 10 ℃, filtering, evaporating the solvent from the filtrate, adding 10 ml of ethyl acetate into the concentrate, dissolving the concentrate to obtain a dissolved solution, adding 0.60 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, loading the mixture into a column, and then performing volume ratio of the mixture to 1: eluting with 10 mixed solution of petroleum ether and ethyl acetate as eluent, detecting by TLC (developing solvent ethyl acetate/petroleum ether is 1: 1(v/v)), collecting eluate containing compound shown in formula (I) (Rf value is 0.5) according to TLC detection, concentrating the collected solution, and drying at 50 deg.C to obtain butyrylamidomethoxybenzo [ d ] shown in formula (I)]Aza derivatives
The quinazoline is an off-white solid, the yield is 47.2%, and the melting point is 216-217 ℃.1H NMR(500MHz,CDCl3):1.02(t,J＝7.4Hz,3H)；1.76-1.83(m,2H)；2.41-2.51(m,2H)；3.24-3.30(m,1H),3.54(dt,J＝3.6,15.1Hz,1H),3.74(s,3H),3.81-3.82(m,7H),3.98-4.09(m,2H),4.66(dd,J＝8.3,14.2Hz,1H),5.27(t,J＝8.8Hz,1H).6.67(s,1H),6.88(d,J＝8.8Hz,2H),7.07(d,J＝8.7Hz,2H),7.61(dd,J＝2.0,9.0Hz,1H),7.80(d,J＝8.9Hz,1H),8.40(s,1H),8.53(s,1H),8.85(d,J＝1.8Hz,1H)。HRMS-ESI m/z:561.2265[M+H]+。IR(KBr,cm-1)ν:2960,2933,2870,2835,1692,1562,1523,1511,1488,1463,1349,1250,1035,836。
Example 12: butyrylamiodoxybenzo [ d ]]Aza derivatives
Preparation of the quiazolidines (I)
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 8 are successively reacted]Aza derivatives
Adding 0.04 g (0.55mmol) of diethylamine and 10.0 ml of chloroform into a 50ml reaction bottle, dropwise adding a mixed solution of 0.059 g (0.55mmol) of butyryl chloride and 5.0 ml of chloroform under the condition of stirring at 10 ℃, after dropwise adding, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), reacting for 8 hours at 10 ℃, filtering, evaporating the filtrate to remove the solvent, adding 20 ml of ethanol into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.26 g of column chromatography silica gel (300-400 mesh silica gel column chromatography) into the dissolved solution, uniformly mixing, evaporating to remove the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography on the mixture according to the volume ratio of 1: eluting with petroleum ether/ethyl acetate mixed solution of 5 as eluent, detecting by TLC (developing solvent ethyl acetate/petroleum ether is 1: 1(v/v)), collecting eluate containing compound shown in formula (I) (Rf value is 0.5) according to TLC detection, concentrating the collected solution, and drying at 50 deg.C to obtain butyrylamidomethoxybenzo [ d ] shown in formula (I)]Aza derivatives
The quinazoline is an off-white solid, the yield is 32.9%, and the melting point is 216-217 ℃.1H NMR and IR were the same as in example 11.
Example 13: butyrylamiodoxybenzo [ d ]]Aza derivatives
Preparation of the quiazolidines (I)
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 9 are successively reacted]Aza derivatives
Adding 0.111 g (1.10mmol) of triethylamine, 10.0 ml of ethyl acetate into a 50ml reaction bottle, dropwise adding 0.117 g (1.10mmol) of butyryl chloride and 5.0 ml of ethyl acetate solution under the condition of stirring at 0 ℃, after dropwise adding, performing TLC tracking detection (ethyl acetate/petroleum ether is used as a developing agent), reacting for 6 hours at 25 ℃, filtering, evaporating the filtrate to remove the solvent, adding 20 ml of chloroform into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.30 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating to remove the solvent to obtain a mixture of dried concentrate and silica gel, loading the mixture into a column, and then performing volume ratio of 10: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, detecting by TLC (developing solvent ethyl acetate/petroleum ether is 1: 1(v/v)), collecting eluate containing compound shown in formula (I) (Rf value is 0.5) according to TLC detection, concentrating the collected solution, and drying at 50 deg.C to obtain butyrylamidomethoxybenzo [ d ] shown in formula (I)]Aza derivatives
The yield of the quinazoline is 46.6%, and the melting point is 216-217 ℃.1H NMR and IR were the same as in example 11.
Example 14: butyrylamiodoxybenzo [ d ]]Aza derivatives
Preparation of the quiazolidines (I)
Example in turn0.27 g (0.55mmol) of aminobenzo [ d ] prepared by method 10]Aza derivatives
Adding 0.067 g (0.55mmol) of 4-dimethylaminopyridine and 20.0 ml of toluene into a 50ml reaction bottle, dropwise adding a solution of 0.348 g (2.20mmol) of butyric anhydride and 7.0 ml of toluene under the stirring condition at 5 ℃, heating to 50 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1), reacting for 3 hours, filtering, evaporating the solvent from the filtrate, dissolving the concentrate by adding 20 ml of tetrahydrofuran to obtain a dissolved solution, adding 0.40 g of column chromatography silica gel (300-400 mesh silica gel column chromatography) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography on the mixture according to the volume ratio of 5: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, detecting by TLC (developing solvent ethyl acetate/petroleum ether is 1: 1(v/v)), collecting eluate containing compound shown in formula (I) (Rf value is 0.5) according to TLC detection, concentrating the collected solution, and drying at 50 deg.C to obtain butyrylamidomethoxybenzo [ d ] shown in formula (I)]Aza derivatives
The quinazoline is an off-white solid, the yield is 50.7%, and the melting point is 216-217 ℃.1H NMR and IR were the same as in example 11.
Example 15: butyrylamiodoxybenzo [ d ]]Aza derivatives
Preparation of the quiazolidines (I)
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 7 are successively reacted]Aza derivatives
The quinazoline (V), 0.213 g (1.65mmol) quinoline, 15.0 ml benzene into a 50ml reaction bottle, dripping a solution of 0.234 g (2.20mmol) butyryl chloride and 5.0 ml benzene under stirring at-10 ℃, and detecting by TLC (ethyl acetate/petroleum ether as a developing solvent is 1: 1) at-10 DEG CAnd (2) filtering for 12 hours, evaporating the solvent from the filtrate, adding 20 ml of tetrahydrofuran into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.40 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of a dried concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture in a volume ratio of 1: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, detecting by TLC (developing solvent ethyl acetate/petroleum ether is 1: 1(v/v)), collecting eluate containing compound shown in formula (I) (Rf value is 0.5) according to TLC detection, concentrating the collected solution, and drying at 50 deg.C to obtain butyrylamidomethoxybenzo [ d ] shown in formula (I)]Aza derivatives
The quinazoline is off-white solid, the yield is 51.4%, and the melting point is 216-217 ℃.1H NMR and IR were the same as in example 11.
Example 16: butyrylamiodoxybenzo [ d ]]Aza derivatives
Preparation of the quiazolidines (I)
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 7 are successively reacted]Aza derivatives
Adding 0.164 g (1.10mmol) of 4-pyrrolidinyl pyridine and 15.0 ml of dichloromethane into a 50ml reaction bottle, dropwise adding 0.117 g (1.10mmol) of butyryl chloride and 5.0 ml of dichloromethane solution under the condition of stirring at 10 ℃, carrying out TLC tracking detection (ethyl acetate/petroleum ether is used as a developing agent) and reacting for 8 hours at 10 ℃, filtering, evaporating the filtrate to remove the solvent, adding 20 ml of ethanol into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.50 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, mixing uniformly, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then carrying out column chromatography according to the volume ratio of 10: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, and detecting by TLC (developing solvent ethyl acetate/petroleum ether ═ 1: 1(v/v)), according to TLCCollecting eluate containing compound shown in formula (I) (Rf value is 0.5), concentrating the collected solution, and drying at 50 deg.C to obtain butyrylamidomethoxybenzo [ d ] shown in formula (I)]Aza derivatives
The quinazoline is an off-white solid, the yield is 43.7%, and the melting point is 216-217 ℃.1H NMR and IR were the same as in example 11.
Example 17: in vitro test for anti-cancer Activity
(1) The prepared compound (I) is subjected to a human cervical cancer cell line Siha bioactivity test.
The test method comprises the following steps: tetrazolium salt reduction (MTT process).
Cell lines: human cervical cancer cell line Siha. The tumor cell strain is purchased from cell banks of Shanghai Life sciences of Chinese academy of sciences.
The experimental procedure was as follows:
(a) preparation of samples: for soluble samples, each 1mg was dissolved in 40. mu.L DMSO, 2. mu.L was diluted with 1000. mu.L of medium to a concentration of 100. mu.g/mL, and then serially diluted with the culture medium to the use concentration.
(b) Culture of cells
Preparation of culture medium, each 1000mL of DMEM culture medium (Gibco) contains 80 ten thousand units of penicillin, 1.0g of streptomycin and 10% inactivated fetal bovine serum.
② cultivation of cells, inoculating tumor cells into culture medium, standing at 37 deg.C and 5% CO2Culturing in an incubator, and carrying out passage for 3-5 days.
Measuring the inhibition of the sample on the growth of tumor cells
The 10 th generation cells were digested with EDTA-pancreatin digest and diluted to 1 × 10 with medium6Perml, 100. mu.L/well in 96-well cell culture plates, 37 ℃ 5% CO2Culturing in an incubator. After 24h of inoculation, 100. mu.L of 100. mu.L/well, 10. mu.g/mL and 1. mu.g/mL samples diluted with medium were added to each well at 3 concentrations, and the mixture was incubated at 37 ℃ with 5% CO2Culturing in incubator, adding 5mg/mL MTT into cell culture well after 72h, incubating at 37 deg.C for 3h, adding DMSO, and incubating at 15 deg.C0 μ L, shaken with a shaker, resulted in complete solubilization of the formazan and colorimetric with a microplate reader at a wavelength of 570 nm. Using cells cultured in the same DMSO concentration medium without sample under the same conditions as a control, the IC of the sample on tumor cell growth was calculated50。
The results of the test are shown in table 1:
TABLE 1 inhibitory Effect of Compound (I) on growth of cancer cell line Siha
(2) Quinazoline compounds (b) and (c) were synthesized according to example 11 by substituting butyryl chloride with 3-methoxybenzoyl chloride or cinnamoyl chloride, respectively, and following structures as shown in example 11, respectively:
the prepared quinazoline compounds (b) and (c) are subjected to a human cervical cancer cell line Siha bioactivity test according to the method, and test results show that the quinazoline compounds (b) and (c) have no obvious inhibition effect on the human cervical cancer cell line Siha, and the anticancer activities of the compounds (b) and (c) on the human cervical cancer cell line Siha are far lower than that of the compound (I). The specific results are shown in table 2:
TABLE 2 inhibitory Effect of Compounds (b) and (c) on growth of cancer cell lines Siha
The anti-cancer activity in vitro test experiment shows that: the other 2 compounds (b) and (c) with similar structures have no obvious inhibition effect on the growth of the human cervical cancer cell strain Siha. The compound (I) has obvious inhibition effect on the growth of human cervical cancer cell strains Siha, and is obviously superior to the compounds (b) and (c).
(3) In the same manner as in example 11 except for using cyclohexylmethylchloroformate instead of butyryl chloride in example 11, a quinazoline compound (k) having the following structure was synthesized:
the prepared quinazoline compound (k) is subjected to a biological activity test on a human cervical cancer cell line Siha according to the method, and the test result shows that the anticancer activity of the compound (k) on the human cervical cancer cell line Siha is far lower than that of the compound (I). Specific results are shown in table 3:
TABLE 3 inhibitory Effect of Compound (k) on growth of cancer cell line Siha
Claims (2)
1. Butyrylamino dimethoxy benzo [ d ] shown in formula (I)]Aza derivatives
The application of the quinazoline compound in preparing the medicine for preventing or treating the cervical cancer of the human:
2. the use of claim 1, wherein: the medicine is a medicine with the activity of inhibiting the Siha of a human cervical cancer cell strain.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810069784.1A CN108014113B (en) | 2018-01-24 | 2018-01-24 | Application of butyrylamidodimethoxybenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating cervical cancer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810069784.1A CN108014113B (en) | 2018-01-24 | 2018-01-24 | Application of butyrylamidodimethoxybenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating cervical cancer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108014113A CN108014113A (en) | 2018-05-11 |
| CN108014113B true CN108014113B (en) | 2020-10-09 |
Family
ID=62074841
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810069784.1A Active CN108014113B (en) | 2018-01-24 | 2018-01-24 | Application of butyrylamidodimethoxybenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating cervical cancer |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108014113B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111973602B (en) * | 2019-05-21 | 2022-02-11 | 浙江工业大学 | Application of morpholinyl acetamido quinazoline compound as EGFR (epidermal growth factor receptor) inhibitor |
| CN111973601B (en) * | 2019-05-21 | 2022-02-11 | 浙江工业大学 | Application of cinnamyl amino quinazoline compound as EGFR (epidermal growth factor receptor) inhibitor in preparation of medicines |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995023141A1 (en) * | 1994-02-23 | 1995-08-31 | Pfizer Inc. | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2074867T3 (en) * | 1990-11-06 | 1995-09-16 | Pfizer | QUINAZOLINE DERIVATIVES TO PROMOTE ANTITUMORAL ACTIVITY. |
-
2018
- 2018-01-24 CN CN201810069784.1A patent/CN108014113B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995023141A1 (en) * | 1994-02-23 | 1995-08-31 | Pfizer Inc. | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108014113A (en) | 2018-05-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108014113B (en) | Application of butyrylamidodimethoxybenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating cervical cancer | |
| CN109251196B (en) | Aminobenzo [ d ] aza-quinazoline compound and preparation method and application thereof | |
| CN108017621B (en) | Morpholinyl acetamido dimethoxy benzo [ d ] aza-based quinazoline compound and preparation and application thereof | |
| CN108078994B (en) | Application of 6- (2-morpholinyl acetamido) quinazoline compound in preparation of medicine for treating lung cancer | |
| CN108042546B (en) | Application of morpholinyl acetamidobenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating cervical cancer | |
| CN108125961B (en) | Application of morpholinyl acetamido methoxyphenyl benzazepinyl quinazoline compound in preparation of drugs for treating leukemia | |
| CN108329299B (en) | Butyrylamino chloro benzo [ d ] aza-based quinazoline compound, preparation and application thereof | |
| CN108129461B (en) | Benzoylaminobenzo [ d ] aza-quinazoline compound, preparation and application thereof | |
| CN108309984B (en) | Application of propionyl aminoquinazoline compound in preparation of medicine for treating cervical cancer | |
| CN108324717B (en) | Application of pivaloylchlorobenzo [ d ] aza-quinazoline compound in preparation of drugs for treating cervical cancer | |
| CN108295076B (en) | Application of propionyl-amino-dimethoxy-benzo [ d ] aza-quinazoline in preparation of drugs for treating lung cancer | |
| CN108324718B (en) | Application of cyclohexyl methoxy formyl amino chloro benzo aza group quinazoline compound in leukemia treatment drug | |
| CN108117542B (en) | Propionyl amino methoxyphenyl benzo [ d ] nitrogen hetero-pinyl quinazoline compound, preparation and application | |
| CN108324719B (en) | Application of o-toluidino-acetamido-methoxy-phenyl benzazepinyl-quinazoline compound in preparation of cervical cancer treatment drug | |
| CN108014112B (en) | Application of o-toluidine amino acetamido benzo [ d ] aza-based quinazoline compound in preparation of drugs for treating lung cancer | |
| CN108276384B (en) | acetaminobenzo [ d ] azepinyl quinazoline compound and preparation and application thereof | |
| CN108125962B (en) | Application of benzo [ d ] aza-quinazoline compound in preparation of drugs for treating lung cancer | |
| CN108329300B (en) | Nitrobenzo [ d ] aza-quinazoline compound and preparation method and application thereof | |
| CN108078992B (en) | Application of pivaloyl-amino-dimethoxy-benzo [ d ] aza-quinazoline compound in preparation of drugs for treating leukemia | |
| CN108143736B (en) | Application of butyrylaminobenzo [ d ] aza-based quinazoline in preparation of drugs for treating lung cancer | |
| CN108186649B (en) | Application of propionyl amino chloro benzo [ d ] aza-quinazoline in preparing medicament for treating leukemia | |
| CN108014116B (en) | Application of aminodimethoxybenzo [ d ] aza-quinazoline compound in preparation of drugs for treating lung cancer | |
| CN108164510B (en) | Chloroacetamidobenzo [ d ] aza-based quinazoline compound and preparation method and application thereof | |
| CN108125960B (en) | Application of isobutyrylaminobenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating lung cancer | |
| CN108014114B (en) | Application of chloroacetylamidoquinazoline compounds in preparation of drugs for treating lung cancer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |