CN108129461B - Benzoylaminobenzo [ d ] aza-quinazoline compound, preparation and application thereof - Google Patents
Benzoylaminobenzo [ d ] aza-quinazoline compound, preparation and application thereof Download PDFInfo
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- CN108129461B CN108129461B CN201810069196.8A CN201810069196A CN108129461B CN 108129461 B CN108129461 B CN 108129461B CN 201810069196 A CN201810069196 A CN 201810069196A CN 108129461 B CN108129461 B CN 108129461B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 17
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 12
- 230000000694 effects Effects 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 180
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 100
- 150000001875 compounds Chemical class 0.000 claims description 79
- 239000000243 solution Substances 0.000 claims description 56
- 239000003208 petroleum Substances 0.000 claims description 49
- 239000002904 solvent Substances 0.000 claims description 48
- 239000012141 concentrate Substances 0.000 claims description 46
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 44
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- 229910002027 silica gel Inorganic materials 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 43
- 239000003960 organic solvent Substances 0.000 claims description 43
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- 238000002156 mixing Methods 0.000 claims description 33
- 238000001704 evaporation Methods 0.000 claims description 31
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- 238000004440 column chromatography Methods 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 29
- 238000001035 drying Methods 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 21
- 239000003480 eluent Substances 0.000 claims description 21
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 239000011259 mixed solution Substances 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 238000011049 filling Methods 0.000 claims description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 14
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- 239000003638 chemical reducing agent Substances 0.000 claims description 13
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 13
- 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 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 239000012295 chemical reaction liquid Substances 0.000 claims description 12
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 12
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 10
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 7
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 7
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 claims description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 1
- -1 quinazoline compound Chemical class 0.000 abstract description 17
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 12
- 201000005202 lung cancer Diseases 0.000 abstract description 12
- 208000020816 lung neoplasm Diseases 0.000 abstract description 12
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000001514 detection method Methods 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 24
- 150000003246 quinazolines Chemical class 0.000 description 21
- 239000003795 chemical substances by application Substances 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 238000002844 melting Methods 0.000 description 16
- 230000008018 melting Effects 0.000 description 16
- 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 15
- 238000003756 stirring Methods 0.000 description 15
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 13
- 239000012265 solid product Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
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- 230000005907 cancer growth Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- GVRRXASZZAKBMN-UHFFFAOYSA-N 4-chloroquinazoline Chemical compound C1=CC=C2C(Cl)=NC=NC2=C1 GVRRXASZZAKBMN-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
- 238000004113 cell culture Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000009982 effect on human Effects 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
- 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
- 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
- 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
- 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
- VDDAVZWCRBHDLQ-UHFFFAOYSA-N 2-phenylquinazoline Chemical compound C1=CC=CC=C1C1=NC=C(C=CC=C2)C2=N1 VDDAVZWCRBHDLQ-UHFFFAOYSA-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
- NJAKCIUOTIPYED-UHFFFAOYSA-N 4-iodobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(I)C=C1 NJAKCIUOTIPYED-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 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
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011081 inoculation Methods 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
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229940049954 penicillin Drugs 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
- 238000010898 silica gel chromatography Methods 0.000 description 1
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- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a benzoylaminobenzo [ d]Aza derivatives
A quinazoline compound, a preparation method and an application thereof. The invention provides benzamidobenzo [ d]Aza derivatives
The quinazoline compound has obvious inhibition activity on human breast cancer cell strains MCF-7 and human lung cancer cell strains A-549, and is expected to be applied to preparation of medicaments for preventing or treating human breast cancer and human lung cancer. The present invention provides such benzoylaminobenzo [ d]Aza derivatives
Description
(I) technical field
The invention relates to a quinazoline compound and application thereof, in particular to benzamidobenzo [ d]Aza derivatives
A quinazoline compound, a preparation method thereof and application of the compound in preparing medicaments for preventing or treating tumor diseases.
(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, namely benzoylaminobenzo [ d]Aza derivatives
The quinazoline compound has obvious inhibition rate on a human lung cancer cell strain A-549 or a human breast cancer cell strain MCF-7 under a 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:
in a first aspect, the present invention provides a benzoylaminobenzo [ d ] of formula (I)]Aza derivatives
Fluoroquinazoline compounds:
in a second aspect, the present invention provides a benzoylaminobenzo [ d ] of 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), and reacting in an organic solvent A at 25-120 ℃ under the action of a basic catalyst B (TLC tracking monitoring, a developing agent of ethyl acetate/petroleum ether is 1: 3(v/v), preferably 40 ℃. (v/v)Reacting at 100 ℃ for 0.5-12 h), and after the reaction is completed, separating and purifying the reaction liquid to obtain a compound shown in 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) completely reacting a compound shown in a formula (IV) in an organic solvent D under the action of a reducing agent E at 25-100 ℃ (TLC tracking monitoring, a developing agent is ethyl acetate/petroleum ether which is 1: 1(v/v), and preferably reacting for 0.5-12 h at 40-80 ℃), filtering a reaction solution, concentrating a filtrate under reduced pressure, and drying a concentrate (preferably drying at 25 ℃ in vacuum) to obtain a compound shown in a 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 a compound shown as a formula (V) with benzoyl chloride or benzoic anhydride, completely reacting in an organic solvent G at-10-50 ℃ under the action of a basic catalyst F (TLC tracking monitoring, a developing agent is ethyl acetate/petroleum ether-1: 1(v/v), preferably reacting for 3-12 h at-10-50 ℃), and carrying out aftertreatment on a reaction solution to obtain a compound shown as a formula (I); the alkaline catalyst F is one of the following: pyridine, diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate; the organic solvent G is one of the following: tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, diethyl ether, acetonitrile, toluene or benzene;
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) and the amount of the substance charged as the basic catalyst B 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 of which the weight is 1.0-2.0 times that of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture with the organic solvent C 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 a compound shown in a 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), when the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, 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 to 3.0: 0.2 to 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), when the reducing agent E is palladium on carbon/ammonium formate or palladium on carbon/hydrazine hydrate, the feeding mass ratio of the compound represented by the formula (iv) to 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 10-50 mL/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 benzoyl chloride or benzoic 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 benzoyl chloride or benzoic anhydride into a compound shown in the formula (V) and an organic solvent G solution of a basic catalyst F or into the compound shown in the formula (V) and the basic catalyst F at-10 ℃, reacting for 3-12 hours at-10-50 ℃, and carrying out aftertreatment on the obtained reaction liquid to obtain a compound shown in the formula (I); the volume dosage of the organic solvent for dissolving benzoyl chloride or benzoic anhydride has no influence on 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 benzoyl chloride or benzoic anhydride is dissolved.
Further, the method for post-treating the reaction solution in the step (3) of the present invention comprises: after the reaction is completed, filtering the reaction solution, evaporating the solvent from the filtrate, dissolving the concentrate with an organic solvent H to obtain a dissolved solution, adding column chromatography silica gel of which the weight is 1.0-2.0 times that of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture with the organic solvent H according to 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: 1(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 (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.
In a third aspect, the invention also relates to benzoylaminobenzo [ d ] s of formula (I)]Aza derivatives
The application of the fluoroquinazoline compound in preparing the medicaments for preventing or treating tumors is particularly suitable for preparing the medicaments for preventing or treating human breast cancer.
Preferably, the medicament is a medicament for inhibiting the activity of the human breast cancer cell line MCF-7. The compound provided by the invention has a good inhibition effect on a human breast cancer cell strain MCF-7.
The benzamidobenzo [ d ] compounds of formula (I) according to the invention]Aza derivatives
The quinazoline compound also has a remarkable inhibiting effect on a human lung cancer cell strain A-549, and can be applied to preparation of medicaments for preventing or treating human lung cancer.
The invention has the following beneficial effects: (1) a novel benzoylaminobenzo [ d ] having excellent antitumor activity, particularly against human breast cancer or human lung cancer is provided]Aza derivatives
The quinazoline compound (I) is expected to be applied to the preparation of medicaments for preventing or treating tumor diseases, in particular to human breast cancer or human lung cancer; (2) the invention provides benzamidobenzo [ d]Aza derivatives
The preparation method of the quinazoline compound (I) is simple and easy to operate, the raw materials are easy to obtain, the production cost is lower,is suitable for practical use.
(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 the 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-carbon (Pd/C) model D5H5A used in the embodiment of the invention is purchased from Shaanxi Rui New Material Co., Ltd.
Example 1: nitrobenzo [ d]Aza derivatives
Preparation of the quinazolines (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 liquid, 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 quinazolines (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 (a 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, adding 20 ml of ethanol into the obtained concentrate to dissolve the 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, and then performing column chromatography by using a volume ratio of 1: eluting with a petroleum ether/ethyl acetate mixed solution of 5 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 liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 72.6%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 3: nitrobenzo [ d]Aza derivatives
Preparation of the quinazolines (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 are added into a 100ml three-neck flask in sequence, the mixture is heated to 60 ℃, TLC tracking detection is carried out (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), the reaction is stirred for 8 hours, the reaction is stopped, the solvent is distilled off from the reaction liquid, and 20 ml of chlorine is added into the obtained concentrateDissolving the mixture 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 to remove 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 on the mixture in a volume ratio of 10: 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 liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 77.2%, 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 quinazolines (IV)
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 tracking detection (a developing agent is ethyl acetate/petroleum ether ═ 1: 3(v/v)), 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, mixing uniformly, 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 in a volume ratio of 5: 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 liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 80.2%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 5: nitrobenzo [ d]Aza derivatives
Preparation of the quinazolines (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 a 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 liquid, 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 ℃.1HNMR and IR were the same as in example 1.
Example 6: nitrobenzo [ d]Aza derivatives
Preparation of the quinazolines (IV)
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: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, tracking by TLC (developing solvent ethyl acetate/petroleum ether is 1: 3(v/v)), collecting eluate containing compound shown in formula (IV) (Rf value is 0.5) by TLC detection, collecting the eluate, and collecting eluateConcentrating, 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 phenyl quinazoline (IV), 0.40 g (6.34mmol) ammonium formate, 0.04 g 5% Pd/C, 4.0 ml chloroform into a reaction bottle, stirring at room temperature of 25 ℃, detecting by TLC (a developing agent is ethyl acetate/petroleum ether-1: 1(v/v)), reacting for 12 hours, filtering, concentrating the filtrate, and drying in vacuum at 25 ℃ to obtain a light yellow solid product aminobenzo [ d]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
Basyquinazoline (IV), 1.20 g (19.18mmol)80 wt% hydrazine hydrate, 0.20 g 5% Pd/C, 20.0 mL toluene was added to 50mLHeating to 100 deg.C in a reaction flask, detecting by TLC (developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirring for 0.5 hr, cooling, filtering, concentrating the filtrate, and vacuum drying at 25 deg.C to obtain light yellow solid product aminobenzo [ d]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
The quinazoline (IV), 0.40 g acetic acid, 1.20 g iron powder, 20.0 ml isopropanol were added to a 50ml reaction flask and heated to 80 deg.CAnd TLC (ethyl acetate/petroleum ether as developing solvent) for stirring reaction for 3 hr, cooling, filtering, concentrating the filtrate, and vacuum drying at 25 deg.C to obtain light yellow solid product 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: benzoylaminobenzo [ d]Aza derivatives
Preparation of a quiazoline (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 0.618 g (4.40mmol) of benzoyl 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 to dissolve 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, tracking and detecting by TLC (developing solvent is 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 benzoylaminobenzo [ d ] shown in formula (I)]Aza derivatives
The quinazoline is off-white solid, the yield is 55.4%, and the melting point is 152-153 ℃.1H NMR(500MHz,CDCl3)1H NMR(500MHz,CDCl3):3.28-3.34(m,1H),3.56(dt,J＝3.6,15.4Hz,1H),3.74(s,3H),3.81-3.84(m,7H),4.00-4.10(m,2H),4.68(dd,J＝8.3,14.4Hz,1H),5.31(t,J＝8.7Hz,1H),6.70(s,1H),6.88(d,J＝8.7Hz,2H),7.10(d,J＝8.7Hz,2H),7.54-7.63(m,4H),7.85(d,J＝8.9Hz,1H),7.95(d,J＝7.3Hz,2H),8.13(s,1H),8.60(s,1H),8.86(s,1H)。HRMS-ESI m/z:595.2107[M+H]+。IR(KBr,cm-1)ν:2996,2935,2825,1668,1599,1550,1523,1488,1463,1349,1249,1108,1037,837。
Example 12: benzoylaminobenzo [ d]Aza derivatives
Preparation of a quiazoline (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 0.077 g (0.55mmol) of benzoyl chloride and 5.0 ml of chloroform under the stirring condition at 10 ℃, carrying out TLC tracking detection (ethyl acetate/petroleum ether is used as a developing agent: 1(v/v)), reacting for 8 hours at 10 ℃, filtering, evaporating the filtrate to remove the solvent, dissolving the concentrate in 20 ml of ethanol 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 the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then filling the mixture in a volume ratio of 1: eluting with petroleum ether/ethyl acetate mixed solution of 5 as eluent, tracking and detecting by TLC (developing solvent is 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 benzoylaminobenzo [ d ] shown in formula (I)]Aza derivatives
The quinazoline is off-white solid, the yield is 53.8%, and the melting point is 152-153 ℃.1H NMR and IR were the same as in example 11.
Example 13: benzoylaminobenzo [ d]Aza derivatives
Preparation of a quiazoline (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 and 10.0 ml of ethyl acetate into a 50ml reaction bottle, dropwise adding 0.155 g (1.10mmol) of benzoyl 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 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 the volume ratio of 10: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, tracking and detecting by TLC (developing solvent is 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 benzoylaminobenzo [ d ] shown in formula (I)]Aza derivatives
The quinazoline is off-white solid, the yield is 64.8%, and the melting point is 152-153 ℃.1H NMR and IR were the same as in example 11.
Example 14: benzoylaminobenzo [ d]Aza derivatives
Preparation of a quiazoline (I)
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 10 are successively reacted]Aza derivatives
3.067 g (0.55mmol) of 4-dimethylaminopyridine, 20.0 ml of toluene were added to 50 mmol of the above quinazoline (V)Adding a solution of 0.498 g (2.20mmol) of benzoic anhydride and 7.0 ml of toluene dropwise into a reaction bottle at 5 ℃ under stirring, heating to 50 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1), reacting for 3 hours, filtering, evaporating a filtrate to remove a solvent, adding 20 ml of tetrahydrofuran into a 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, mixing uniformly, evaporating the solvent to obtain a mixture of a dried concentrate and silica gel, loading the mixture into a column, and then performing reaction at a volume ratio of 5: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, tracking and detecting by TLC (developing solvent is 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 benzoylaminobenzo [ d ] shown in formula (I)]Aza derivatives
The quinazoline is off-white solid, the yield is 45.2%, and the melting point is 152-153 ℃.1H NMR and IR were the same as in example 11.
Example 15: benzoylaminobenzo [ d]Aza derivatives
Preparation of a quiazoline (I)
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 7 are successively reacted]Aza derivatives
Adding 0.213 g (1.65mmol) of quinoline and 15.0 ml of benzene into a 50ml reaction bottle, dropwise adding a solution of 0.309 g (2.20mmol) of benzoyl chloride and 5.0 ml of benzene under the stirring condition at-10 ℃, after finishing dropping, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1), reacting for 12 hours at 10 ℃, filtering, evaporating the filtrate to remove the solvent, 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,then, mixing the raw materials in a volume ratio of 1: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, tracking and detecting by TLC (developing solvent is 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 benzoylaminobenzo [ d ] shown in formula (I)]Aza derivatives
The quinazoline is off-white solid, the yield is 63.7%, and the melting point is 152-153 ℃.1H NMR and IR were the same as in example 11.
Example 16: benzoylaminobenzo [ d]Aza derivatives
Preparation of a quiazoline (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 0.155 g (1.10mmol) of benzoyl 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, 1: 1), reacting for 8 hours at 10 ℃, filtering, evaporating the solvent from the filtrate, dissolving the concentrate with 20 ml of ethanol 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, loading the mixture into a column, and carrying out reaction in a volume ratio of 10: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, tracking and detecting by TLC (developing solvent is 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 benzoylaminobenzo [ d ] shown in formula (I)]Aza derivatives
Quinazoline baseOff-white solid, yield 66.1%, melting point 152-153 ℃.1H NMR and IR were the same as in example 11.
Example 17: in vitro test for anti-cancer Activity
(1) The compound (i) prepared in the examples was tested for biological activity in human lung cancer and human breast cancer.
The test method comprises the following steps: tetrazolium salt reduction (MTT process).
Cell lines: human lung cancer cell strain A-549 and human breast cancer cell strain MCF-7. 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.g/mL, 10. mu.g/mL and 1. mu.g/mL samples diluted with medium were added to each well at 3 concentrations and placed at 37 ℃ in 5% CO2The culture was performed in an incubator, 5mg/mL MTT was added to the cell culture wells after 72h, 10. mu.L per well, incubated at 37 ℃ for 3h, DMSO was added, 150. mu.L per well, shaken with a shaker, and formazan was completely solubilized 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 tests are shown in tables 1 and 2:
TABLE 1 inhibitory Effect of Compound (I) on the growth of cancer cell line A-549
TABLE 2 inhibitory Effect of Compound (I) on the growth of cancer cell line MCF-7
(2) Quinazoline compounds (a), (b) and (c) were synthesized according to example 11 by substituting benzoyl chloride with 4-iodobenzoyl chloride, 3-methoxybenzoyl chloride or cinnamoyl chloride, respectively, and following the following structures:
the prepared quinazoline compounds (a), (b) and (c) are subjected to biological activity tests on human breast cancer cell strains MCF-7 and human lung cancer cell strains A-549 according to the method, and the results show that the quinazoline compounds (a), (b) and (c) have no obvious inhibition effect on human breast cancer cell strains MCF-7, the quinazoline compounds (b) and (c) have no obvious inhibition effect on human lung cancer cell strains A-549, and the anticancer activity of the quinazoline compounds (a), (b) and (c) is far less than that of benzoylaminobenzo [ d-549]Aza derivatives
A quinazoline (I). The specific results are shown in tables 3 and 4:
TABLE 3 inhibitory Effect of Compounds (a), (b) and (c) on the growth of cancer cell line MCF-7
TABLE 4 inhibitory Effect of Compounds (b) and (c) on the growth of cancer cell line A-549
(3) 4-chloroquinazoline was prepared according to the method of the reference (Rao, G. -W.et al. ChemMedChem,2013,8(6),928-933), 4-chloro-6-nitroquinazoline was substituted with 4-chloroquinazoline according to example 1, and the quinazoline compound (d) was synthesized according to the same procedure as in example 1, and the structure thereof is as follows:
the prepared quinazoline compound (d) is subjected to a biological activity test of a human breast cancer cell line MCF-7 according to the method, and the test result shows that the quinazoline compound (d) has far lower anticancer activity on the human breast cancer cell line MCF-7 than the compound (I). Specific results are shown in table 5:
TABLE 5 inhibitory Effect of Compound (d) on growth of cancer cell line MCF-7
Claims (10)
1. A benzoylaminobenzo [ d ] of formula (I)]Aza derivatives
Fluoroquinazoline compounds:
2. a benzamidobenzo [ d ] of formula (i) as defined in claim 1]Aza derivatives
The preparation method of the fluoroquinazoline compound is characterized by comprising the following steps:
(1) mixing a compound shown as a formula (II) and a compound shown as a formula (III), reacting in an organic solvent A at 25-120 ℃ under the action of a basic catalyst B, and after the reaction is completed, separating and purifying a reaction liquid 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;
(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, filtering reaction liquid, and drying a concentrate obtained by concentrating a filtrate under reduced pressure to obtain a 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 a compound shown as a formula (V) with benzoyl chloride or benzoic anhydride, completely reacting in an organic solvent G at-10-50 ℃ under the action of a basic catalyst F, and carrying out aftertreatment on a reaction solution to obtain a compound shown as a formula (I); the alkaline catalyst F is one of the following: pyridine, diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate; the organic solvent G is one of the following: tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, diethyl ether, acetonitrile, toluene or benzene;
3. the method of claim 2, wherein: the ratio of the compound represented by the formula (III) to the compound represented by the formula (II) and the amount of the charged substance of the basic catalyst B in the step (1) is 1.0: 0.8 to 1.2: 1.0 to 8.0; the dosage of the organic solvent A is 10-50 mL/g based on the mass of the compound shown in the formula (III).
4. The method of claim 2, wherein: the method for separating and purifying the reaction liquid in the step (1) comprises the following steps: 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 of which the weight is 1.0-2.0 times that of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture with the organic solvent C 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, concentrating under reduced pressure, and drying to obtain a compound shown as a formula (IV); the organic solvent C is one of the following solvents: ethanol, chloroform, tetrahydrofuran or ethyl acetate.
5. The method of claim 2, wherein: in the step (2), when the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, the feeding mass ratio of the compound shown in 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; when the reducing agent E is palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate, the feeding mass ratio of the compound shown in the formula (IV) to the palladium carbon, ammonium formate or hydrazine hydrate in the reducing agent E is 1.0: 0.1-0.5: 1.0-3.0.
6. The method of claim 2, wherein: the step (3) is carried out according to the following method: dropwise adding an organic solvent G solution of benzoyl chloride or benzoic anhydride into a compound shown in the formula (V) and an organic solvent G solution of a basic catalyst F or into the compound shown in the formula (V) and the basic catalyst F at-10 ℃, reacting for 3-12 hours at-10-50 ℃, and carrying out aftertreatment on the obtained reaction liquid to obtain a compound shown in the formula (I); 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).
7. The method of claim 2, wherein: the ratio of the compound represented by the formula (V) to the fed materials of benzoyl chloride or benzoic anhydride and the basic catalyst F in the step (3) is 1: 1.0 to 8.0: 1.0 to 3.0; the dosage of the organic solvent G is 11-100 mL/G based on the mass of the compound shown in the formula (V).
8. The method of claim 2, wherein: the post-treatment method of the reaction solution in the step (3) comprises the following steps: filtering the reaction solution, evaporating the solvent from the filtrate, dissolving the concentrate with an organic solvent H to obtain a dissolved solution, adding column chromatography silica gel of which the weight is 1.0-2.0 times that of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, filling 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, concentrating under reduced pressure, and drying to obtain a compound shown in a formula (I); the organic solvent H is one of the following: ethanol, chloroform, tetrahydrofuran or ethyl acetate.
9. Benzamidobenzo [ d ] of formula (I) as claimed in claim 1]Aza derivatives
Application of the fluoroquinazoline compound in preparing medicaments for preventing or treating human breast cancer.
10. The use according to claim 9, wherein the medicament is a medicament having the activity of inhibiting the activity of human breast cancer cell line MCF-7.
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| CN1061411A (en) * | 1990-11-06 | 1992-05-27 | 美国辉瑞有限公司 | Be used to strengthen the active quinazoline derivant of antineoplastic agent |
| CN1141633A (en) * | 1994-02-23 | 1997-01-29 | 辉瑞大药厂 | 4-heterocyclyl-substituted Quinazoline derivatives, method for prepn. of same and the use as anti-cancer agent |
| CN103275018A (en) * | 2013-04-26 | 2013-09-04 | 浙江工业大学 | 4-(3-chloro-4-substituted anilino)-6-substituted carbamonyl quinazoline compounds, and preparation method and applications thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1061411A (en) * | 1990-11-06 | 1992-05-27 | 美国辉瑞有限公司 | Be used to strengthen the active quinazoline derivant of antineoplastic agent |
| CN1141633A (en) * | 1994-02-23 | 1997-01-29 | 辉瑞大药厂 | 4-heterocyclyl-substituted Quinazoline derivatives, method for prepn. of same and the use as anti-cancer agent |
| CN103275018A (en) * | 2013-04-26 | 2013-09-04 | 浙江工业大学 | 4-(3-chloro-4-substituted anilino)-6-substituted carbamonyl quinazoline compounds, and preparation method and applications thereof |
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