CN108017621B - Morpholinyl acetamido dimethoxy benzo [ d ] aza-based quinazoline compound and preparation and application thereof - Google Patents
Morpholinyl acetamido dimethoxy benzo [ d ] aza-based quinazoline compound and preparation and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- -1 quinazoline compound Chemical class 0.000 title claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 128
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- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 21
- 230000000694 effects Effects 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 258
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 148
- 239000000243 solution Substances 0.000 claims description 83
- 239000000203 mixture Substances 0.000 claims description 81
- 239000003208 petroleum Substances 0.000 claims description 71
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- 239000000741 silica gel Substances 0.000 claims description 69
- 229910002027 silica gel Inorganic materials 0.000 claims description 69
- 239000012141 concentrate Substances 0.000 claims description 68
- 239000002904 solvent Substances 0.000 claims description 66
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 54
- 239000003960 organic solvent Substances 0.000 claims description 53
- 238000002156 mixing Methods 0.000 claims description 47
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 44
- 238000004440 column chromatography Methods 0.000 claims description 43
- 238000001704 evaporation Methods 0.000 claims description 43
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- 239000003480 eluent Substances 0.000 claims description 39
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- 238000001035 drying Methods 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 36
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- 239000003054 catalyst Substances 0.000 claims description 26
- 238000011049 filling Methods 0.000 claims description 26
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- 239000011259 mixed solution Substances 0.000 claims description 24
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 22
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- 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
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 12
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- 238000011282 treatment Methods 0.000 claims description 9
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- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 7
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- 239000000126 substance Substances 0.000 claims description 4
- 230000005764 inhibitory process Effects 0.000 abstract description 20
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- 201000005202 lung cancer Diseases 0.000 abstract description 18
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- 238000012360 testing method Methods 0.000 description 31
- 150000003246 quinazolines Chemical class 0.000 description 30
- 239000003795 chemical substances by application Substances 0.000 description 29
- RPTKRGHYKSBDJL-UHFFFAOYSA-N 6-nitroquinazoline Chemical compound N1=CN=CC2=CC([N+](=O)[O-])=CC=C21 RPTKRGHYKSBDJL-UHFFFAOYSA-N 0.000 description 28
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- 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 16
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- XFGPXURFKAUHQR-UHFFFAOYSA-N quinazolin-6-amine Chemical class N1=CN=CC2=CC(N)=CC=C21 XFGPXURFKAUHQR-UHFFFAOYSA-N 0.000 description 14
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- DOLQYFPDPKPQSS-UHFFFAOYSA-N 3,4-dimethylaniline Chemical compound CC1=CC=C(N)C=C1C DOLQYFPDPKPQSS-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
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- LGDHZCLREKIGKJ-UHFFFAOYSA-N 3,4-dimethoxyaniline Chemical compound COC1=CC=C(N)C=C1OC LGDHZCLREKIGKJ-UHFFFAOYSA-N 0.000 description 4
- RUQIUASLAXJZIE-UHFFFAOYSA-N 3-methoxybenzoyl chloride Chemical compound COC1=CC=CC(C(Cl)=O)=C1 RUQIUASLAXJZIE-UHFFFAOYSA-N 0.000 description 4
- GVRRXASZZAKBMN-UHFFFAOYSA-N 4-chloroquinazoline Chemical compound C1=CC=C2C(Cl)=NC=NC2=C1 GVRRXASZZAKBMN-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 229930182555 Penicillin Natural products 0.000 description 4
- 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 4
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 4
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- 238000011081 inoculation Methods 0.000 description 4
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 4
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- 230000004565 tumor cell growth Effects 0.000 description 4
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- NJAKCIUOTIPYED-UHFFFAOYSA-N 4-iodobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(I)C=C1 NJAKCIUOTIPYED-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
- 201000011510 cancer Diseases 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
- 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
- 229960002584 gefitinib Drugs 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
- 238000011068 loading method Methods 0.000 description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 2
- 125000003368 amide group Chemical group 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
- 238000001816 cooling Methods 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000001291 vacuum drying Methods 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
Abstract
The invention discloses morpholinyl acetamido dimethoxy benzo [ d ]]Aza derivatives
A quinazoline compound, a preparation method and an application thereof. The invention provides morpholinyl acetamido dimethoxy benzo [ d ]]Aza derivatives
Description
(I) technical field
The invention relates to a quinazoline compound and application thereof, in particular to morpholinyl acetamido dimethoxy benzo [ 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-morpholinyl acetamido dimethoxy benzo [ d ] with anticancer activity]Aza derivatives
The quinazoline compound has good inhibition effect on a human lung cancer cell strain A-549, a human breast cancer cell strain MCF-7, a human promyelocytic leukemia cell strain HL-60 or a human cervical cancer cell strain Siha 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 morpholinoacetamidodimethoxybenzo [ d ] of formula (I)]Aza derivatives
The quinazoline compound is a quinazoline compound which is a quinazoline compound,
in a second aspect, the present invention provides a morpholinoacetamidodimethoxybenzo [ 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), in an organic solvent A under the action of a basic catalyst B,carrying out a reaction at 25-120 ℃ (TLC tracking monitoring, wherein a developing agent is ethyl acetate/petroleum ether which is 1: 3(v/v), preferably reacting for 0.5-12 h at 40-100 ℃), 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) 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 chloroacetyl chloride or chloroacetic anhydride, completely reacting at-10-50 ℃ in an organic solvent G under the action of an alkaline catalyst F (tracking and monitoring by TLC, wherein a developing agent is ethyl acetate/petroleum ether (1: 1(v/v), preferably reacting at-10-50 ℃ for 3-12 h), and carrying out aftertreatment A on a reaction solution to obtain a compound shown as a formula (VI); 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;
(4) mixing a compound shown as a formula (VI) with morpholine, reacting at 25-120 ℃ in an organic solvent J under the action of a basic catalyst K (TLC tracking monitoring is carried out, a developing agent is ethyl acetate/petroleum ether which is 1: 1(v/v), and preferably, the reaction is carried out at 40-100 ℃ for 0.5-36 h), and after the reaction is completed, carrying out post-treatment on a reaction solution B to obtain a compound shown as a formula (I); the organic solvent J is selected from one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the basic catalyst K is selected from one of the following: pyridine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate (preferably pyridine, quinoline, triethylamine, N-dimethylaniline or 4-dimethylaminopyridine).
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).
In the step (3), the ratio of the compound of the formula (v) to the amount of chloroacetyl chloride or chloroacetic anhydride and the basic catalyst F to be fed 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 specific recommended step (3) of the present invention is performed as follows: dropwise adding chloroacetyl chloride or chloroacetic anhydride organic solvent G solution into the compound shown in the formula (V) and the organic solvent G solution of the basic catalyst F at-10 ℃ or the compound shown in the formula (V) and the basic catalyst F, reacting for 3-12 hours at-10-50 ℃, and carrying out aftertreatment on the obtained reaction solution A to obtain the compound shown in the formula (VI); the volume consumption of the organic solvent for dissolving the chloroacetyl chloride or the chloroacetic anhydride does not influence the invention, and the total consumption 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 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 chloroacetyl chloride or chloroacetic anhydride is dissolved.
Further, the method for separating and purifying 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 a compound shown in a formula (VI); 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.
Further, in the step (4), the ratio of the compound represented by the formula (VI) to the charged substances of morpholine and the basic catalyst K is 1.0: 0.8 to 8.0: 1.0 to 8.0.
Further, in the step (4), the amount of the organic solvent J is 10-60 mL/g based on the mass of the compound represented by the formula (VI).
Further, the method for post-treating the reaction solution B in the step (4) of the present invention comprises: after the reaction is completed, evaporating the solvent from the reaction solution, dissolving the concentrate with an organic solvent M 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 M 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: 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 M is one of the following: ethanol, chloroform, tetrahydrofuran or ethyl acetate. The organic solvent M is used in an amount capable of dissolving the residue.
In a third aspect, the invention also relates to morpholinyl acetamido-dimethoxybenzo [ d ] 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 (I) provided by the invention has a good inhibition effect on human breast cancer cell strain MCF-7.
The morpholinyl acetamido-dimethoxybenzo [ d ] of the formula (I)]Aza derivatives
The quinazoline compound also has obvious inhibition effect on a human lung cancer cell strain A-549, a human promyelocytic leukemia cell strain HL-60 or a human cervical cancer cell strain Siha, and can be applied to preparation of medicaments for preventing or treating human lung cancer, human leukemia or human cervical cancer.
The organic solvents A, C, D, G, H, J and M 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, the catalyst F and the catalyst K are all catalysts, so that the catalysts used in different steps are named for convenience of distinguishing, and letters have no meanings; the post-treatment A and the post-treatment B are both post-treatments, so that the post-treatments used for distinguishing different steps are named for convenience, and the letters have no meanings.
The invention has the following beneficial effects: (1) the morpholinyl acetamido-dimethoxybenzo [ d ] of the invention]Aza derivatives
The fluoroquinazoline compound (I) has good resistanceThe cancer activity is expected to be applied to the preparation of medicaments for preventing or treating tumor diseases, in particular to the application of medicaments for preventing and treating human breast cancer, human lung cancer, human leukemia or human cervical cancer; (2) the invention provides morpholinyl acetamido dimethoxy benzo [ 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 low, and the quinazoline compound (I) 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: preparation of 6-nitroquinazoline (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 10 mixed solution of petroleum ether and ethyl acetate as eluent, tracking by TLC (developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting eluate containing compound shown in formula (IV) (Rf value is 0.5) according to TLC detection, concentrating the collected solutionCondensing and drying at 50 ℃ to obtain a light yellow solid product shown in a 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: preparation of 6-nitroquinazoline (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 60ml 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: preparation of 6-nitroquinazoline (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 60ml 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 the obtained concentrated solution is obtainedAnd (2) adding 20 ml of chloroform into the condensate to dissolve the condensate 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 a dried 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 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: preparation of 6-nitroquinazoline (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 60ml 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: preparation of 6-nitroquinazoline (IV)
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 are added in sequence to a 50ml reaction flask, heated to 120 ℃ and detected by TLC (developing solvent is ethyl acetate)Petroleum ether is 1: 3(v/v)), stirring for reacting for 0.5 hour, closing the reaction, evaporating the reaction solution to remove the solvent, adding 20 ml of tetrahydrofuran into the obtained concentrate to dissolve the tetrahydrofuran to obtain a dissolved solution, adding 5.0 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 the 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 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 ℃.1H NMR and IR were the same as in example 1.
Example 6: preparation of 6-nitroquinazoline (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 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 78.3%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 7: preparation of 6-aminoquinazolines (V)
0.40 g (0.77mmol) of 6-nitroquinazoline (IV), 0.40 g (6.34mmol) of ammonium formate, 0.04 g of 5% Pd/C and 4.0 ml of chloroform prepared by the method of example 1 were sequentially added to a reaction flaskStirring at room temperature of 25 ℃, carrying out TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), reacting for 12 hours, filtering, concentrating the filtrate, and carrying out vacuum drying at 25 ℃ to obtain a light yellow solid product, namely 6-aminoquinazoline (V), wherein the yield is 98.2%, 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: preparation of 6-aminoquinazolines (V)
0.40 g (0.77mmol) of 6-nitroquinazoline (IV), 1.20 g (19.18mmol) of 80 wt% hydrazine hydrate, 0.20 g of 5% Pd/C and 20.0 ml of toluene prepared by the method in example 2 are sequentially added into a 50ml reaction bottle, heated to 100 ℃, subjected to TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirred for 0.5 hour, cooled and filtered, the filtrate is concentrated, and vacuum-dried at 25 ℃ to obtain a light yellow solid product, namely 6-aminoquinazoline (V), with the yield of 100.0% and the melting point of 122-126 ℃.1H NMR and IR were the same as in example 7.
Example 9: preparation of 6-aminoquinazolines (V)
0.40 g (0.77mmol) of 6-nitroquinazoline (IV), 0.08 g of concentrated hydrochloric acid (mass concentration is 36-38%), 0.40 g of iron powder and 20.0 ml of methanol which are prepared by the method in example 3 are sequentially added into a 50ml reaction bottle, heated to 40 ℃, subjected to TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirred and reacted for 8 hours, cooled and filtered, and the filtrate is concentrated and dried in vacuum at 25 ℃ to obtain a light yellow solid product, namely 6-aminoquinazoline (V), the yield is 94.1% and the melting point is 122-126 ℃.1H NMR and IR were the same as in example 7.
Example 10: preparation of 6-aminoquinazolines (V)
0.40 g (0.77mmol) of 6-nitroquinazoline (IV) prepared by the method of example 4, 0.40 g of acetic acid, 1.20 g of iron powder and 20.0 ml of isopropanol were added to 50ml of the mixture in this orderHeating the mixture to 80 ℃ in a reaction bottle, carrying out TLC tracking detection (the developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirring the mixture for reaction for 3 hours, cooling and filtering the mixture, concentrating the filtrate, and drying the concentrated filtrate in vacuum at 25 ℃ to obtain a light yellow solid product, namely 6-aminoquinazoline (V), wherein the yield is 97.5%, and the melting point is 122-126 ℃.1H NMR and IR were the same as in example 7.
Example 11: preparation of chloroacetamidoquinazoline (VI)
Adding 0.27 g (0.55mmol) of 6-aminoquinazoline (V), 0.13 g (1.64mmol) of pyridine and 3 ml of tetrahydrofuran prepared in the method of example 7 into a reaction bottle, dropwise adding 0.497 g (4.40mmol) of chloroacetyl chloride under the condition of stirring at-10 ℃, after dropwise adding, performing TLC tracking detection (the 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 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 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 in a volume ratio of 1: eluting by using a petroleum ether/ethyl acetate mixed solution of 10 as an eluent, tracking and detecting by TLC (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (VI) according to TLC detection (the Rf value is 0.5), concentrating the collected liquid, and drying at 50 ℃ to obtain the chloracetyl amido quinazoline yellow solid shown in the formula (VI), wherein the yield is 95.6%, and the melting point is 255-258 ℃.1H NMR(500MHz,CDCl3):3.26-3.33(m,1H),3.54(dt,J＝3.7,15.4Hz,1H),3.74(s,3H),3.81-3.82(m,7H),3.95-4.05(m,2H),4.28(s,2H),4.64(dd,J＝8.2,14.4Hz,1H),5.24(t,J＝8.8Hz,1H).6.64(s,1H),6.88(d,J＝8.8Hz,2H),7.07(d,J＝8.7Hz,2H),7.53(dd,J＝2.3,9.0Hz,1H),7.83(d,J＝9.0Hz,1H),8.54(s,1H),8.60(s,1H),8.69(d,J＝2.2Hz,1H)。IR(KBr,cm-1)ν:3396,2998,2937,2835,1694,1557,1525,1510,1489,1463,1349,1249,1179,1036,840。
Example 12: preparation of chloroacetamidoquinazoline (VI)
0.27 g (0.55mmol) of 6-aminoquinazoline (V) prepared in example 8, 0.04 g (0.55mmol) of diethylamine, and 10.0 ml of chloroform were added to 50 mmol of chloroform in this orderAdding 0.07 g (0.55mmol) of chloroacetyl chloride and 5.0 ml of chloroform into a reaction bottle under the condition of stirring at 10 ℃, 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 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 column chromatography on the mixture according to the volume ratio of 1: and (3) eluting by using a petroleum ether/ethyl acetate mixed solution of 5 as an eluent, tracking and detecting by TLC (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent (the Rf value is 0.5) containing the compound shown in the formula (VI) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a chloroacetylamidoquinazoline yellow solid shown in the formula (VI), wherein the yield is 83.4%, and the melting point is 255-258 ℃.1H NMR and IR were the same as in example 11.
Example 13: preparation of chloroacetamidoquinazoline (VI)
Adding 0.27 g (0.55mmol) of 6-aminoquinazoline (V), 0.111 g (1.10mmol) of triethylamine and 10.0 ml of ethyl acetate prepared in the method of example 9 into a 50ml reaction bottle, dropwise adding 0.14 g (1.09mmol) of chloroacetyl chloride and 5.0 ml of ethyl acetate solution under the condition of stirring at 0 ℃, after dropwise adding, performing TLC tracking detection (the developing agent is ethyl acetate/petroleum ether is 1: 1), 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 silica gel (300-400 mesh silica gel) into the dissolved solution, mixing uniformly, evaporating to remove the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then filling the mixture into the column at a volume ratio of 10: eluting by using a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (VI) according to TLC detection (the Rf value is 0.5), concentrating the collected liquid, and drying at 50 ℃ to obtain a chloroacetylamidoquinazoline yellow solid shown in the formula (VI), wherein the yield is 70.5%, and the melting point is 255-258 ℃.1H NMR and IR were the same as in example 11.
Example 14: preparation of chloroacetamidoquinazoline (VI)
0.27 g (0.55mmol) of 6-aminoquinazoline (v), 0.067 g (0.55mmol) of 4-dimethylaminopyridine and 20.0 ml of toluene prepared in example 10 are sequentially added to a 50ml reaction flask, a solution of 0.376 g (2.20mmol) of chloroacetic anhydride and 7.0 ml of toluene is added dropwise under stirring at 5 ℃, the mixture is heated to 50 ℃, TLC tracking detection is carried out (the developing agent is ethyl acetate/petroleum ether is 1: 1), the mixture reacts for 3 hours, the filtrate is filtered, the solvent is distilled off, the concentrate is dissolved by adding 20 ml of tetrahydrofuran to obtain a dissolved solution, 0.40 g of silica gel (300-400 mesh column chromatography silica gel) is added to the dissolved solution, the mixture is uniformly mixed, the solvent is distilled off to obtain a mixture of dried concentrate and silica gel, the mixture is filled into a column, and then the volume ratio of the mixture is 5: eluting by using a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (VI) according to TLC detection (the Rf value is 0.5), concentrating the collected liquid, and drying at 50 ℃ to obtain a chloroacetylamidoquinazoline yellow solid shown in the formula (VI), wherein the yield is 85.3%, and the melting point is 255-258 ℃.1H NMR and IR were the same as in example 11.
Example 15: preparation of chloroacetamidoquinazoline (VI)
Adding 0.27 g (0.55mmol) of 6-aminoquinazoline (V), 0.213 g (1.65mmol) of quinoline and 15.0 ml of benzene prepared in the method of example 7 into a 50ml reaction bottle, dropwise adding a solution of 0.28 g (2.19mmol) of chloroacetyl chloride and 5.0 ml of benzene 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), reacting at-10 ℃ for 12 hours, 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 silica gel (300-400 mesh silica gel) into the dissolved solution, mixing uniformly, evaporating to remove the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then filling the mixture into the column at a volume ratio of 1: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, detecting by TLC (developing solvent is ethyl acetate/petroleum ether ═ 1: 1(v/v)), and collecting eluate containing compound shown in formula (VI) according to TLC detectionAnd (3) concentrating the collected liquid (the Rf value is 0.5), and drying at 50 ℃ to obtain a yellow chloroacetylamidoquinazoline solid shown in the formula (VI), wherein the yield is 82.1%, and the melting point is 255-258 ℃.1H NMR and IR were the same as in example 11.
Example 16: preparation of chloroacetamidoquinazoline (VI)
Adding 0.27 g (0.55mmol) of 6-aminoquinazoline (V), 0.164 g (1.10mmol) of 4-pyrrolidinylpyridine and 15.0 ml of dichloromethane prepared in the method of example 7 into a 50ml reaction bottle, dropwise adding 00.14 g (1.09mmol) of chloroacetyl chloride and 5.0 ml of dichloromethane solution under the condition of stirring at 10 ℃, after dropwise adding, performing 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, adding 20 ml of ethanol into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.50 g of silica gel (300-400 mesh silica gel) into the dissolved solution for column chromatography, mixing uniformly, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then filling the mixture into the column at a volume ratio of 10: eluting by using a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (VI) according to TLC detection (the Rf value is 0.5), concentrating the collected liquid, and drying at 50 ℃ to obtain a chloroacetylamidoquinazoline yellow solid shown in the formula (VI), wherein the yield is 90.2%, and the melting point is 255-258 ℃.1H NMR and IR were the same as in example 11.
Example 17: morpholinoacetamidodimethoxybenzo [ d ]]Aza derivatives
Preparation of a quiazoline (I)
3.25 g (5.73mmol) of chloroacetamidoquinazoline (VI) prepared in example 11, 0.598 g (6.86mmol) of morpholine, 3.626 g (45.84mmol) of pyridine and 32.5 ml of methanol were sequentially added to a 50ml reaction flask, heated to 40 ℃, followed by TLC detection (developing solvent ethyl acetate/petroleum ether is 1: 1(v/v)), stirred for 10 hours, the reaction was stopped, the solvent was distilled off from the reaction solution, 10 ml of ethyl acetate was added to the obtained concentrate to dissolve it, a solution was obtained, and then the solution was added to the solutionAdding 1.5 g of column chromatography silica gel (300-400 mesh column chromatography silica gel), 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 mixing the mixture according to 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: 1(v/v)), collecting an eluent containing the compound shown in the formula (I) (the Rf value is 0.5) according to TLC detection, concentrating a collected solution, and drying at 50 ℃ to obtain an off-white solid product shown in the formula (I), wherein the yield is 65.4%, and the melting point is 122-125 ℃.1H NMR(500MHz,CDCl3):2.65-2.72(m,4H),3.19(s,2H),3.30(m,1H),3.54(d,J＝15.3Hz,1H),3.74(s,3H),3.81-3.84(m,11H),3.99-4.01(m,2H),4.64(dd,J＝8.2.14.2Hz,1H),5.27(t,J＝8.6Hz,1H),6.67(s,1H),6.87(d,J＝8.6Hz,2H),7.07(d,J＝8.6Hz,2H),7.40(dd,J＝2.0,8.9Hz,1H),7.81(d,J＝8.9Hz,1H),8.58(s,1H),8.84(s,1H),9.29(s,1H)。HRMS-ESI m/z:618.2477[M+H]+。IR(KBr,cm-1)ν:2933,2833,1692,1609,1523,1568,1523,1488,1461,1348,1248,1116,1035,838。
Example 18: morpholinoacetamidodimethoxybenzo [ d ]]Aza derivatives
Preparation of a quiazoline (I)
Sequentially adding 3.25 g (5.73mmol) of chloroacetamidoquinazoline (VI) prepared in example 12, 0.398 g (4.57mmol) of morpholine, 2.95 g (22.84mmol) of quinoline and 80 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: 1(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 on the mixture in a volume ratio of 1: eluting with petroleum ether/ethyl acetate mixed solution of 5 as eluent, tracking by TLC (developing solvent is ethyl acetate/petroleum ether ═ 1: 1(v/v)), and collecting eluate containing compound shown in formula (I) according to TLC detection(Rf value is 0.5), the collected liquid is concentrated and dried at 50 ℃ to obtain an off-white solid product shown in the formula (I), the yield is 61.6%, and the melting point is 122-125 ℃.1H NMR and IR were the same as in example 17.
Example 19: morpholinoacetamidodimethoxybenzo [ d ]]Aza derivatives
Preparation of a quiazoline (I)
Sequentially adding 3.25 g (5.73mmol) of chloroacetamidoquinazoline (VI) prepared in example 13, 0.499 g (5.73mmol) of morpholine, 0.58 g (5.73mmol) of triethylamine and 80 ml of ethanol into a 100ml three-neck flask, heating to 60 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirring for 8 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of chloroform 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 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: 1(v/v)), collecting an eluent containing the compound shown in the formula (I) (the Rf value is 0.5) according to TLC detection, concentrating a collected solution, and drying at 50 ℃ to obtain an off-white solid product shown in the formula (I), wherein the yield is 57.7%, and the melting point is 122-125 ℃.1H NMR and IR were the same as in example 17.
Example 20: morpholinoacetamidodimethoxybenzo [ d ]]Aza derivatives
Preparation of a quiazoline (I)
3.25 g (5.73mmol) of chloroacetamidoquinazoline (VI) prepared in example 14, 1.997 g (22.92mmol) of morpholine, 1.40 g (11.46mmol) of 4-dimethylaminopyridine and 60ml of isopropanol were added in this order to a 100ml three-necked flask, stirred at room temperature of 25 ℃, followed by TLC detection (developing solvent ethyl acetate/petroleum ether ═ 1: 1(v/v)), reacted for 36 hours, the reaction was stopped, and the reaction solution was distilled offDissolving the obtained concentrate with 20 ml of tetrahydrofuran 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 the dried 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 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: 1(v/v)), collecting an eluent containing the compound shown in the formula (I) (the Rf value is 0.5) according to TLC detection, concentrating a collected solution, and drying at 50 ℃ to obtain an off-white solid product shown in the formula (I), wherein the yield is 71.3%, and the melting point is 122-125 ℃.1H NMR and IR were the same as in example 17.
Example 21: morpholinoacetamidodimethoxybenzo [ d ]]Aza derivatives
Preparation of a quiazoline (I)
Sequentially adding 3.25 g (5.73mmol) of chloroacetamidoquinazoline (VI) prepared in example 15, 0.449 g (5.15mmol) of morpholine, 1.04 g (8.58mmol) of N, N-dimethylaniline and 33 ml of N, N-dimethylformamide into a 50ml reaction flask, heating to 120 ℃, performing TLC tracking detection (ethyl acetate/petroleum ether is 1: 1(v/v)) and stirring for reaction for 0.5 hour, stopping the reaction, evaporating the reaction solution 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 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 filling the mixture into the column at a 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: 1(v/v)), collecting an eluent containing the compound shown in the formula (I) (the Rf value is 0.5) according to TLC detection, concentrating a collected solution, and drying at 50 ℃ to obtain an off-white solid product shown in the formula (I), wherein the yield is 55.2%, and the melting point is 122-125 ℃.1H NMR and IR were the same as in example 17.
Example 22: morpholinoacetamidodimethoxybenzo [ d ]]Aza derivatives
Preparation of a quiazoline (I)
Sequentially adding 3.25 g (5.73mmol) of chloroacetamidoquinazoline (VI) prepared in example 16, 3.994 g (45.84mmol) of morpholine, 3.626 g (45.84mmol) of pyridine and 195 ml of propanol into a 500 ml reaction bottle, heating to 40 ℃, performing TLC tracking detection (developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirring for 10 hours, stopping the reaction, evaporating the reaction solution to remove the solvent, adding 20 ml of ethyl acetate into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 6.0 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 dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography on the mixture in a 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: 1(v/v)), collecting an eluent containing the compound shown in the formula (I) (the Rf value is 0.5) according to TLC detection, concentrating a collecting solution, and drying at 50 ℃ to obtain an off-white solid product shown in the formula (I), wherein the yield is 75.7%, and the melting point is 122-125 ℃.1H NMR and IR were the same as in example 17.
Example 23: in vitro test for anti-cancer Activity
(1) The prepared compounds (I), (IV), (V) and (VI) are subjected to a human breast cancer cell strain MCF-7 bioactivity test.
The test method comprises the following steps: tetrazolium salt reduction (MTT process).
Cell lines: 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.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% 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 the 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 Compounds (I), (IV), (V) and (VI) on the growth of cancer cell line MCF-7
(2) Quinazoline compounds (a), (b) and (c) were synthesized according to example 11 by substituting chloroacetyl 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 a biological activity test on a human breast cancer cell line MCF-7 according to the method, and the test results show that the quinazoline compounds (a), (b) and (c) have no obvious inhibition effect on the human breast cancer cell line MCF-7, and the compounds (a), (b) and (c) have far lower anticancer activity on the human breast cancer cell line MCF-7 than the compound (I). The specific results are shown in table 2:
TABLE 2 inhibitory Effect of Compounds (a), (b) and (c) on the growth of cancer cell line MCF-7
The anti-cancer activity in vitro test experiment shows that: the other 3 compounds (a), (b) and (c) with similar structures have no obvious inhibition effect on the growth of the human breast cancer cell strain MCF-7. The compound (I) has obvious inhibition effect on the growth of human breast cancer cell strains MCF-7, and is obviously superior to the compounds (a), (b) and (c).
(3) Quinazoline compounds (d), (e) and (f) were synthesized according to example 17 by substituting morpholine with 3, 4-dimethylaniline, 3, 4-dimethoxyaniline or di-n-propylamine, respectively, and following the following structures:
the prepared quinazoline compounds (d), (e) and (f) are subjected to a biological activity test of a human breast cancer cell line MCF-7 according to the method, and the results show that the quinazoline compounds (d), (e) and (f) have far lower anticancer activity than the compound (I) on the human breast cancer cell line MCF-7. Specific results are shown in table 3:
TABLE 3 inhibitory Effect of Compounds (d), (e) and (f) on the growth of cancer cell line MCF-7
(4) Referring to the literature (Rao, G. -W.et al. ChemMedChem,2013,8(6),928-933), 4-chloroquinazoline was prepared, 4-chloro-6-nitroquinazoline was substituted with 4-chloroquinazoline according to example 1, and the other operations were the same as in example 1 to synthesize a quinazoline compound (g) having the following structure:
the prepared quinazoline compound (g) 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 (g) has far lower anticancer activity on the human breast cancer cell line MCF-7 than the compound (I). Specific results are shown in table 4:
TABLE 4 inhibitory Effect of Compound (g) on the growth of cancer cell line MCF-7
Example 24: in vitro test for anti-cancer Activity
(1) The prepared compounds (I), (IV) and (VI) are tested for the biological activity of a human lung cancer cell strain A-549.
The test method comprises the following steps: tetrazolium salt reduction (MTT process).
Cell lines: human lung cancer cell strain A-549. 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 2 nd 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% 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 test are shown in table 5:
TABLE 5 inhibitory Effect of Compounds (I), (IV) and (VI) on the growth of cancer cell line A-549
(2) Quinazoline compounds (a), (b) and (c) were synthesized according to example 11 by substituting chloroacetyl 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 a biological activity test of a human lung cancer cell strain A-549 according to the method, and test results show that the quinazoline compounds (a), (b) and (c) have no obvious inhibition effect on the human lung cancer cell strain A-549, and the compounds (a), (b) and (c) have far lower anti-cancer activity than the compound (I) on the human lung cancer cell strain A-549. Specific results are shown in table 6:
TABLE 6 inhibitory Effect of Compounds (a), (b) and (c) on the growth of cancer cell line A-549
The anti-cancer activity in vitro test experiment shows that: the other 3 compounds (a), (b) and (c) with similar structures have no obvious inhibition effect on the growth of the human lung cancer cell strain A-549. The compound (I) has obvious inhibition effect on the growth of a human lung cancer cell strain A-549, and is obviously superior to the compounds (a), (b) and (c).
(3) Quinazoline compounds (d), (e) and (f) were synthesized according to example 17 by substituting morpholine with 3, 4-dimethylaniline, 3, 4-dimethoxyaniline or di-n-propylamine, respectively, and following the following structures:
the prepared quinazoline compounds (d), (e) and (f) are subjected to a biological activity test of a human lung cancer cell strain A-549 according to the method, and the results show that the anticancer activity of the quinazoline compounds (d), (e) and (f) on the human lung cancer cell strain A-549 is far lower than that of the compound (I). Specific results are shown in table 7:
TABLE 7 inhibitory Effect of Compounds (d), (e) and (f) on the growth of cancer cell line A-549
(4) Referring to the literature (Rao, G. -W.et al. ChemMedChem,2013,8(6),928-933), 4-chloroquinazoline was prepared, 4-chloro-6-nitroquinazoline was substituted with 4-chloroquinazoline according to example 1, and the other operations were the same as in example 1 to synthesize a quinazoline compound (g) having the following structure:
the prepared quinazoline compound (g) is subjected to a biological activity test of a human lung cancer cell strain A-549 according to the method, and a test result shows that the anticancer activity of the quinazoline compound (g) on the human lung cancer cell strain A-549 is far lower than that of the compound (I). Specific results are shown in table 8:
TABLE 8 inhibitory Effect of Compound (g) on the growth of cancer cell line A-549
Example 25: in vitro test for anti-cancer Activity
(1) The prepared compound (I) is subjected to biological activity test of a human promyelocytic leukemia cell strain HL-60.
The test method comprises the following steps: tetrazolium salt reduction (MTT process).
Cell lines: human promyelocytic leukemia cell line HL-60. 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 2 nd 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% 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 testing are shown in table 9:
TABLE 9 inhibitory Effect of Compound (I) on the growth of cancer cell line HL-60
(2) Quinazoline compounds (b) and (c) were synthesized according to example 11 by substituting chloroacetyl chloride with 3-methoxybenzoyl chloride or cinnamoyl chloride, respectively, and following structures as shown in the following, in the same manner as in example 11:
the prepared quinazoline compounds (b) and (c) are subjected to a biological activity test of a human promyelocytic leukemia cell line HL-60 according to the method, and test results show that the quinazoline compounds (b) and (c) have no obvious inhibition effect on the human promyelocytic leukemia cell line HL-60, and the anticancer activities of the compounds (b) and (c) on the human promyelocytic leukemia cell line HL-60 are far lower than that of the compound (I). Specific results are shown in table 10:
TABLE 10 inhibitory Effect of Compounds (b) and (c) on the growth of cancer cell line HL-60
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 promyelocytic leukemia cell line HL-60. The compound (I) has obvious inhibition effect on the growth of human promyelocytic leukemia cell strain HL-60, and is obviously superior to the compounds (b) and (c).
(3) Quinazoline compounds (d), (e) and (f) were synthesized according to example 17 by substituting morpholine with 3, 4-dimethylaniline, 3, 4-dimethoxyaniline or di-n-propylamine, respectively, and following the following structures:
the biological activity of the quinazoline compounds (d), (e) and (f) prepared by the method in a human promyelocytic leukemia cell line HL-60 test proves that the anticancer activity of the quinazoline compounds (d), (e) and (f) in the human promyelocytic leukemia cell line HL-60 is far lower than that of the compound (I). Specific results are shown in table 11:
TABLE 11 inhibitory Effect of Compounds (d), (e) and (f) on the growth of cancer cell line HL-60
Example 26: in vitro test for anti-cancer Activity
(1) The prepared compound (I) is subjected to a biological activity test of a human cervical cancer cell strain Siha.
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 2 nd 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% 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 testing are shown in table 12:
TABLE 12 inhibition of growth of cancer cell lines Siha by Compound (I)
(2) Quinazoline compounds (b) and (c) were synthesized according to example 11 by substituting chloroacetyl chloride with 3-methoxybenzoyl chloride or cinnamoyl chloride, respectively, and following structures as shown in the following, in the same manner as in example 11:
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). Specific results are shown in table 13:
TABLE 13 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) Quinazoline compounds (d), (e) and (f) were synthesized according to example 17 by substituting morpholine with 3, 4-dimethylaniline, 3, 4-dimethoxyaniline or di-n-propylamine, respectively, and following the following structures:
the prepared quinazoline compounds (d), (e) and (f) are subjected to a biological activity test on human cervical cancer cell lines Siha according to the method, and the results show that the anticancer activity of the quinazoline compounds (d), (e) and (f) on the human cervical cancer cell lines Siha is far lower than that of the compound (I). Specific results are shown in table 14:
TABLE 14 inhibitory Effect of Compounds (d), (e) and (f) on growth of cancer cell line Siha
Claims (10)
1. A morpholinyl acetylamino dimethoxybenzo [ d ] as shown in formula (I)]Aza derivatives
Fluoroquinazoline compounds:
2. a morpholinoacetamidodimethoxybenzo [ 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) 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 ℃, filtering a reaction solution, and drying a concentrate obtained by concentrating a filtrate under reduced pressure 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 in a formula (V) with chloroacetyl chloride or chloroacetic anhydride, completely reacting in an organic solvent G at-10-50 ℃ under the action of an alkaline catalyst F, and carrying out post-treatment on a reaction solution A to obtain a compound shown in a formula (VI); 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;
(4) mixing a compound shown as a formula (VI) with morpholine, reacting in an organic solvent J at 25-120 ℃ under the action of a basic catalyst K, and after the reaction is completed, carrying out post-treatment B on a reaction liquid to obtain a compound shown as a formula (I); the organic solvent J is selected from one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the basic catalyst K is selected from one of the following: pyridine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate.
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 ratio of the compound of the formula (V) to chloroacetyl chloride or chloroacetic anhydride and the basic catalyst F in the feeding substances in the step (3) is 1: 1.0-8.0: 1.0-3.0; the dosage of the organic solvent G is 11-100 mL/G based on the mass of the compound shown in the formula (V).
7. The method of claim 2, wherein: the method for post-treating the reaction solution A 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.
8. The method of claim 2, wherein: in the step (4), the ratio of the compound represented by the formula (VI) to the amount of morpholine to the amount of alkaline catalyst K to be fed is 1.0: 0.8 to 8.0: 1.0 to 8.0; the dosage of the organic solvent J is 10-60 mL/g based on the mass of the compound shown in the formula (VI);
the method for post-treating the reaction solution B comprises the following steps: after the reaction is completed, evaporating the solvent from the reaction solution, dissolving the concentrate with an organic solvent M 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 M 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 M is one of the following: ethanol, chloroform, tetrahydrofuran or ethyl acetate.
9. Morpholinoacetamidodimethoxybenzo [ 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 |
| CN106831725A (en) * | 2016-08-09 | 2017-06-13 | 江西科技师范大学 | The quinazoline compounds and its application of quinoline containing indoline and similar structures |
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| GB9508565D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quiazoline derivative |
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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 |
| CN106831725A (en) * | 2016-08-09 | 2017-06-13 | 江西科技师范大学 | The quinazoline compounds and its application of quinoline containing indoline and similar structures |
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