CN108276384B - acetaminobenzo [ d ] azepinyl quinazoline compound and preparation and application thereof - Google Patents
acetaminobenzo [ d ] azepinyl quinazoline compound and preparation and application thereof Download PDFInfo
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Abstract
Description
(I) technical field
The invention relates to an acetamidobenzo [ d ] aza-quinazoline compound, a preparation method thereof and application of the compound in preparation of a medicament 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. source, 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 an acetamidobenzo [ d ] aza-based quinazoline compound with anti-tumor activity, which has obvious inhibition rate on human lung cancer cell strains A-549 and human breast cancer cell strains 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.
The technical scheme adopted by the invention is as follows:
In a first aspect, the invention provides an acetamidobenzo [ d ] azaquinazoline compound of formula (I),
In a second aspect, the present invention provides a method for preparing an acetamidobenzo [ d ] azaquinazoline compound represented by formula (i), wherein the method comprises: (1) mixing a compound shown as a formula (II) and a compound shown as a formula (III), reacting at 25-120 ℃ in an organic solvent A under the action of a basic catalyst B (TLC tracking monitoring is carried out, a developing agent is ethyl acetate/petroleum ether which is 1: 3(v/v), and preferably 40-100 ℃ for 0.5-12 h), and after the reaction is completed, separating and purifying a reaction solution to obtain a compound shown as a formula (IV); the organic solvent A is selected from one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the basic catalyst B is selected from one of the following: pyridine, diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate (preferably pyridine, diethylamine, triethylamine, N-dimethylaniline or 4-dimethylaminopyridine);
(2) 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 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 organic solvent D is one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide;
(3) Mixing a compound shown as a formula (V) with acetyl chloride or acetic 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 at-10-50 ℃ for 3-12 h), and separating and purifying 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 in an organic solvent C to obtain a dissolved solution, adding column chromatography silica gel (preferably 300-400 mesh coarse pore (zcx.II) type column chromatography silica gel) in an amount which is 1.0-2.0 times the weight of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture 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), the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, and the feeding mass ratio of the compound shown in the formula (IV) to the iron powder, the concentrated hydrochloric acid or the acetic acid in the reducing agent E is 1.0: 1.0-3.0: 0.2-1.0; in the invention, the mass concentration of the concentrated hydrochloric acid is 36-38%, and the acetic acid is glacial acetic acid.
Further, in the step (2), 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 acetyl chloride or acetic anhydride and the basic catalyst F 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 acetyl chloride or acetic anhydride in the organic solvent G solution of the compound shown in the formula (V) and the basic catalyst F or the organic solvent G solution of the compound shown in the formula (V) and the basic catalyst F at-10 ℃, reacting for 3-12 hours at-10-50 ℃, and separating and purifying the obtained reaction liquid to obtain the compound shown in the formula (I); the volume consumption of the organic solvent for dissolving acetyl chloride or acetic anhydride has no influence on the invention, 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), and the total consumption of the organic solvent G refers to the total volume of the organic solvent for dissolving the catalyst and the compound shown in the formula (V) and the organic solvent for dissolving acetyl chloride or acetic anhydride.
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 (preferably 300-400 mesh coarse pore (zcx.II) type column chromatography silica gel) into the dissolved solution in an amount which is 1.0-2.0 times the weight of the concentrate, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, packing the mixture into a column, and then mixing the mixture with the silica gel in a volume ratio of 1: taking a mixed solution of petroleum ether and ethyl acetate of 0.1-10 as an eluent, collecting an effluent containing a target component (preferably, ethyl acetate/petroleum ether is 1: 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 provides application of the acetamidobenzo [ d ] aza-quinazoline compound shown in the formula (I) in preparing a medicament for preventing or treating tumors, in particular application in preparing a medicament for preventing or treating human breast cancer or human lung cancer.
Preferably, the medicament is a medicament for inhibiting the activity of the human breast cancer cell strain MCF-7. The acetamidobenzo [ d ] azahetero quinazoline (I) has obvious inhibiting effect on human breast cancer cell strains MCF-7.
The acetamidobenzo [ d ] aza-quinazoline compound (I) 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) provides a novel quinazoline compound with good anti-cancer (especially human breast cancer or lung cancer) activity, and is expected to be applied to the preparation of medicaments for preventing or treating human breast cancer or lung cancer; (2) the preparation method of the acetamidobenzo [ d ] aza-quinazoline compound (I) provided by the invention is simple and easy to operate, the raw materials are easy to obtain, the production cost is low, and the preparation method is suitable for practical use.
(IV) detailed description of the preferred embodiments
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
The compound (II) can be prepared by the method described in Weinstock, J.et al.J.Med.chem.,1986, 29(11), 2315-2325. 4-chloro-6-nitroquinazoline (III) prepared by 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 nitrobenzo [ d ] azahetero 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 the TLC detection, concentrating the collected eluent, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 85.1%, and the melting point is 164-166 ℃.1H NMR (500MHz, CDCl3) δ: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 ═ 8.6, 2H),7.93(d, J ═ 8.7H, 7.93(d, 1H), 7.96 (d, 8.7H), 1H), 7.96 (dd, 8.7H, 1H), 1H), 7.96 (dd, 8.7H). IR (KBr, cm-1) v: 2917,2848,1616,1580,1510,1463,1355,1327,1249,1038,847.
Example 2: preparation of nitrobenzo [ d ] azahetero 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 eluent, 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 nitrobenzo [ d ] azahetero quinazolines (IV)
Sequentially adding 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 into a 100ml three-neck flask, heating to 60 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(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 by using 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 eluent, 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 nitrobenzo [ d ] azahetero 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: the petroleum ether/ethyl acetate mixed solution of 1 is used as an eluent to elute, follow-up detection is carried out by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), eluent containing the compound shown in the formula (IV) is collected according to TLC detection (the Rf value is 0.5), the collected eluent is concentrated, and drying is carried out 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 nitrobenzo [ d ] azahetero 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: the petroleum ether/ethyl acetate mixed solution of 1 is used as an eluent to elute, follow-up detection is carried out by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), eluent containing the compound shown in the formula (IV) is collected according to TLC detection (the Rf value is 0.5), the collected eluent is concentrated, and drying is carried out 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 nitrobenzo [ d ] azahetero 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 a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected eluent, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 78.3%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 7: preparation of aminobenzo [ d ] azahetero-based quinazolines (V)
0.40 g (0.77mmol) of nitrobenzo [ d ] azaquinazoline (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 are sequentially added into a reaction bottle, stirred at room temperature and 25 ℃, followed by TLC detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), reacted for 12 hours, filtered, concentrated, and dried in vacuum at 25 ℃ to obtain a light yellow solid product of aminobenzo [ d ] azaquinazoline (V), the yield is 98.2%, and the melting point is 122-126 ℃.1H NMR (500MHz, CDCl3) δ: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 ═ 8.9, 1H), 8.50H (s, 1H). IR (KBr, cm-1) v 3368,3215,2932,2825,1628, 1566,1512,1487,1353,1248,1036, 834.
Example 8: preparation of aminobenzo [ d ] azahetero-based quinazolines (V)
0.40 g (0.77mmol) of nitrobenzo [ d ] azaheteroylquinazoline (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 of 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-1: 1(v/v)), stirred for 0.5 hour, cooled and filtered, and concentrated, and vacuum-dried at 25 ℃ to obtain a light yellow solid product of aminobenzo [ d ] azaheteroylquinazoline (V), wherein the yield is 100.0%, and the melting point is 122-126 ℃.1H NMR and IR were the same as in example 7.
Example 9: preparation of aminobenzo [ d ] azahetero-based quinazolines (V)
0.40 g (0.77mmol) of nitrobenzo [ d ] azaquinazoline (IV) prepared in the method of example 3, 0.08 g of concentrated hydrochloric acid (the mass concentration is 36-38%), 0.40 g of iron powder and 20.0 ml of methanol are sequentially added into a 50ml reaction bottle, the mixture is heated to 40 ℃, TLC tracking detection is carried out (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), the mixture is stirred for 8 hours, cooled and filtered, the filtrate is concentrated, and vacuum drying is carried out at 25 ℃ to obtain a light yellow solid product of aminobenzo [ d ] azaquinazoline (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 aminobenzo [ d ] azahetero-based quinazolines (V)
0.40 g (0.77mmol) of nitrobenzo [ d ] azaheteroylquinazoline (IV), 0.40 g of acetic acid, 1.20 g of iron powder and 20.0 ml of isopropanol prepared in the method of example 4 are sequentially added into a 50ml reaction bottle, heated to 80 ℃, subjected to TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirred for 3 hours, cooled, filtered, concentrated, and dried in vacuum at 25 ℃ to obtain a light yellow solid product, namely aminobenzo [ d ] azaylquinazoline (V), 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 acetamidobenzo [ d ] azahetero-ylquinazolines (I)
0.27 g (0.55mmol) of aminobenzo [ d ] azaquinazoline (v), 0.13 g (1.64mmol) of pyridine and 3 ml of tetrahydrofuran prepared in the method of example 7 are sequentially added into a reaction flask, 0.345 g (4.39mmol) of acetyl chloride is dropwise added under the stirring condition at-10 ℃, the dropwise addition is finished, TLC tracking detection is carried out (a developing agent is ethyl acetate/petroleum ether is 1: 1), the reaction is carried out for 12 hours under the condition of 10 ℃, the filtration is carried out, the solvent is removed by evaporation from the filtrate, 10 ml of ethyl acetate is added into the concentrate to be dissolved, a dissolved solution is obtained, 0.60 g of silica gel column chromatography (300-400 mesh silica gel) is added into the dissolved solution, the mixture is uniformly mixed, the solvent is removed by evaporation, a mixture of dried concentrate and silica gel is obtained, the mixture is packed into a column, and then the volume ratio is 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 the collected eluent, and drying at 50 ℃ to obtain an acetamidobenzo [ d ] azaquinazoline white solid shown in the formula (I), wherein the yield is 67.6%, and the melting point is 190-194 ℃.1H NMR (500MHz, CDCl3) δ:2.27(s,3H),3.26-3.33(m, 1H),3.52(dt, J ═ 15.3,3.6Hz,1H),3.75(s,3H),3.79-3.84(m,7H),3.95-4.07(m, 2H),4.65(dd, J ═ 7.9,14.1Hz,1H),5.24(t, J ═ 8.7Hz,1H),6.65(s,1H),6.88(d, J ═ 8.7Hz,2H),7.08(d, J ═ 8.7Hz,2H),7.48(d, J ═ 8.9Hz,1H),7.65(s,1H), 7.81(d, J ═ 8.9, 1H), 1H, 57.70H, 1H), 1H, and 1H. IR (KBr, cm-1) v 3274,2936, 1682,1562,1525,1509,1450,1350,1245,1034, 837.
Example 12: preparation of acetamidobenzo [ d ] azahetero-ylquinazolines (I)
0.27 g (0.55mmol) of aminobenzo [ d ] azaquinazoline (v), 0.04 g (0.55mmol) of diethylamine, and 10.0 ml of chloroform prepared in example 8 were sequentially added to a 50ml reaction flask, a mixed solution of 0.043 g (0.55mmol) of acetyl chloride and 5.0 ml of chloroform was added dropwise under stirring at 10 ℃, after completion of the addition, followed by TLC detection (developing solvent is ethyl acetate/petroleum ether ═ 1: 1(v/v)), and reacted at 10 ℃ for 8 hours, the filtrate was filtered, the solvent was evaporated, the concentrate was dissolved by adding 20 ml of ethanol to obtain a dissolved solution, 0.26 g of column chromatography silica gel (300 to 400 mesh column chromatography silica gel) was added to the dissolved solution, and after the mixing, the solvent was evaporated to obtain a mixture of dried concentrate and silica gel, the mixture was packed into a column, and then: 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: 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 the collected eluent, and drying at 50 ℃ to obtain an acetamidobenzo [ d ] azaquinazoline white solid shown in the formula (I), wherein the yield is 82.3%, and the melting point is 190-194 ℃.1H NMR and IR were the same as in example 11.
Example 13: preparation of acetamidobenzo [ d ] azahetero-ylquinazolines (I)
0.27 g (0.55mmol) of aminobenzo [ d ] azaquinazoline (v), 0.111 g (1.10mmol) of triethylamine and 10.0 ml of ethyl acetate prepared in example 9 were sequentially added to a 50ml reaction flask, 0.086 g (1.10mmol) of acetyl chloride and 5.0 ml of ethyl acetate were added dropwise with stirring at 0 ℃, followed by TLC (ethyl acetate/petroleum ether as a developing solvent) for reaction at 25 ℃ for 6 hours, filtration was performed, the solvent was distilled off from the filtrate, the concentrate was dissolved by adding 20 ml of chloroform to obtain a dissolved solution, 0.30 g of silica gel (300-400 mesh column chromatography silica gel) was added to the dissolved solution, after mixing, the solvent was distilled off to obtain a mixture of dried concentrate and silica gel, the mixture was packed into a column, and then the volume ratio of the mixture was 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 the collected eluent, and drying at 50 ℃ to obtain an acetamidobenzo [ d ] azaquinazoline white solid shown in the formula (I), wherein the yield is 88.7%, and the melting point is 190-194 ℃.1H NMR and IR were the same as in example 11.
Example 14: preparation of acetamidobenzo [ d ] azahetero-ylquinazolines (I)
0.27 g (0.55mmol) of aminobenzo [ d ] azaquinazoline (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 0.224 g (2.19mmol) of acetic anhydride and 7.0 ml of toluene is added dropwise under stirring at 5 ℃, the mixture is heated to 50 ℃, TLC tracking detection (the developing agent is ethyl acetate/petroleum ether is 1: 1), reaction is carried out for 3 hours, filtration is carried out, the solvent is distilled off from the filtrate, 20 ml of tetrahydrofuran is added to the concentrate to be dissolved to obtain a dissolved solution, 0.40 g of column chromatography 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 a dried concentrate and silica gel, the mixture is loaded into a column, and then the volume ratio of the mixture is 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 the collected eluent, and drying at 50 ℃ to obtain an acetamidobenzo [ d ] azaquinazoline white solid shown in the formula (I), wherein the yield is 74.2%, and the melting point is 190-194 ℃.1H NMR and IR were the same as in example 11.
example 15: preparation of acetamidobenzo [ d ] azahetero-ylquinazolines (I)
0.27 g (0.55mmol) of aminobenzo [ d ] azaquinazoline (v), 0.213 g (1.65mmol) of quinoline and 15.0 ml of benzene prepared by the method of example 10 are sequentially added to a 50ml reaction flask, a solution of 0.173 g (2.20mmol) of acetyl chloride and 5.0 ml of benzene is added dropwise under stirring at-10 ℃, dropwise addition and TLC follow-up detection (developing solvent is ethyl acetate/petroleum ether ═ 1: 1), reaction is carried out at 10 ℃ for 12 hours, filtration is carried out, the solvent is distilled off from the filtrate, 20 ml of tetrahydrofuran is added to the concentrate to dissolve the concentrate 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 packed into a column, and then the volume ratio of the mixture is 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 the collected eluent, and drying at 50 ℃ to obtain an acetamidobenzo [ d ] azaquinazoline white solid shown in the formula (I), wherein the yield is 62.5% and the melting point is 190-194 ℃.1H NMR and IR were the same as in example 11.
Example 16: preparation of acetamidobenzo [ d ] azahetero-ylquinazolines (I)
0.27 g (0.55mmol) of aminobenzo [ d ] azaquinazoline (v), 0.164 g (1.10mmol) of 4-pyrrolidinylpyridine prepared in example 9 and 15.0 ml of dichloromethane were sequentially added to a 50ml reaction flask, 0.086 g (1.10mmol) of acetyl chloride and 5.0 ml of dichloromethane were added dropwise with stirring at 10 ℃, followed by TLC (ethyl acetate/petroleum ether as a developing solvent) detection, the mixture was reacted at 10 ℃ for 8 hours, the filtrate was filtered, the solvent was evaporated, the concentrate was dissolved by adding 20 ml of ethanol to obtain a solution, 0.50 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) was added to the solution, and after mixing, the solvent was evaporated to obtain a mixture of dried concentrate and silica gel, the mixture was packed into a column, and then the volume ratio of the mixture was 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 the collected eluent, and drying at 50 ℃ to obtain an acetamidobenzo [ d ] azaquinazoline white solid shown in the formula (I), wherein the yield is 79.8%, and the melting point is 190-194 ℃.1H NMR and IR were the same as in example 11.
Example 17: in vitro test for anti-cancer Activity
(1) And (3) carrying out biological activity tests on the prepared compounds (I) and (IV) on 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 line A-549 and human breast cancer cell line MCF-7, which were 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 medium (Gibco) contains 80 ten thousand units of penicillin, 1.0g of streptomycin and 10% inactivated fetal bovine serum.
② culturing cells: inoculating the tumor cells into a culture medium, culturing in a 5% CO2 incubator at 37 ℃, and carrying out passage for 3-5 d.
Measuring the inhibition of the sample on the growth of tumor cells
The 10 th generation cells were digested with EDTA-trypsin digestion solution, diluted to 1X 106/mL with the medium, added to a 96-well cell culture plate at 100. mu.L per well, and cultured in a 5% CO2 incubator at 37 ℃.24 h after inoculation, 100. mu.g/mL, 10. mu.g/mL and 1. mu.g/mL samples diluted with medium were added, 100. mu.L per well, 3 wells per concentration, incubated at 37 ℃, 5% CO2 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 to completely solubilize the formazan, and colorimetric at 570nm using a microplate reader. The IC50 of the samples on tumor cell growth was calculated using cells cultured in medium without sample and with the same concentration of DMSO as a control under the same conditions.
The results of the tests are shown in tables 1 and 2:
TABLE 1 inhibitory Effect of Compounds (I) and (IV) on the growth of Lung cancer cell line A-549
TABLE 2 inhibitory Effect of Compounds (I) and (IV) on the growth of Breast cancer cell line MCF-7
(2) quinazoline compounds (a), (b) and (c) were synthesized according to example 11 by substituting acetyl chloride with 4-iodobenzoyl chloride, 3-methoxybenzoyl chloride and cinnamoyl chloride, respectively, and following the following structures:
the prepared quinazoline compounds (a), (b) and (c) are subjected to biological activity tests on a human lung cancer cell line A-549 and a human breast cancer cell line MCF-7 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 line A-549 and the human breast cancer cell line MCF-7, and the compounds (a), (b) and (c) have far lower anticancer activity than the compound (I) on the human lung cancer cell line A-549 and the human breast cancer cell line MCF-7. The specific results are shown in tables 3 and 4:
TABLE 3 inhibitory Effect of Compounds (a), (b) and (c) on the growth of Lung cancer cell line A-549
TABLE 4 inhibitory Effect of Compounds (a), (b) and (c) on the growth of Breast 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 a human lung cancer cell strain A-549 and a human breast cancer cell strain MCF-7. The compound (I) has obvious inhibition effect on the growth of a human lung cancer cell strain A-549 and a human breast cancer cell strain MCF-7, and is obviously superior to the compounds (a), (b) and (c).
(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 biological activity tests on a human lung cancer cell strain A-549 and a human breast cancer cell strain MCF-7 according to the method, and the test result shows that the quinazoline compound (d) has far lower anticancer activity than the compound (I) on the human lung cancer cell strain A-549 and the human breast cancer cell strain MCF-7. The specific results are shown in tables 5 and 6:
TABLE 5 inhibitory Effect of Compound (d) on the growth of cancer cell line A-549
TABLE 6 inhibitory Effect of Compound (d) on growth of cancer cell line MCF-7
(4) Quinazoline compounds (e), (f), (g) and (h) were synthesized according to example 11 by substituting acetyl chloride with benzoyl chloride, butyryl chloride, propionyl chloride or chloroacetyl chloride, respectively, and following the same procedure as in example 11, respectively, and have the following structures:
The prepared quinazoline compounds (e), (f), (g) and (h) are subjected to a biological activity test of a human lung cancer cell strain A-549 according to the method, and the test result shows that the quinazoline compounds (e), (f), (g) and (h) have inferior anticancer activity to the human lung cancer cell strain A-549 to the anticancer activity of the compound (I). The prepared quinazoline compounds (e), (f) and (g) are 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 compounds (e), (f) and (g) have inferior anticancer activity to the human breast cancer cell line MCF-7 compared with the compound (I). The specific results are shown in tables 7 and 8:
TABLE 7 inhibitory Effect of Compounds (e), (f), (g) and (h) on the growth of cancer cell line A-549
TABLE 8 inhibitory Effect of Compounds (e), (f) and (g) on the growth of cancer cell line MCF-7
Claims (10)
1. an acetamidobenzo [ d ] aza-quinazoline compound shown as a formula (I),
2. a process for the preparation of an acetamidobenzo [ d ] azaquinazolines compound according to claim 1, characterized in that said process comprises: (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 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 organic solvent D is one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide;
(3) Mixing a compound shown as a formula (V) with acetyl chloride or acetic anhydride, completely reacting in an organic solvent G at-10-50 ℃ under the action of a basic catalyst F, and separating and purifying reaction liquid 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 process according to claim 2, wherein the amount of the compound of formula (III) to the compound of formula (II) and the basic catalyst B to be charged in step (1) is 1.0: 0.8 to 1.2: 1.0 to 8.0, and the amount of the organic solvent A is 10 to 50mL/g based on the mass of the compound of formula (III).
4. The method according to claim 2, wherein the reaction solution in step (1) is separated and purified by: 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 according to 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 represented by the formula (IV) to the iron powder, concentrated hydrochloric acid or acetic acid in the reducing agent E is 1.0: 1.0-3.0: 0.2-1.0; 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 palladium-carbon, ammonium formate or hydrazine hydrate in the reducing agent E is 1.0: 0.1-0.5: 1.0-3.0; the dosage of the organic solvent D is 10-50 mL/g based on the mass of the compound shown in the formula (IV).
6. The process according to claim 2, wherein the ratio of the amount of the compound of formula (V) to the amount of the acetyl chloride or acetic anhydride and the basic catalyst F fed in step (3) is 1: 1.0 to 8.0: 1.0 to 3.0, and the amount of the organic solvent G is 11 to 100mL/G based on the mass of the compound of formula (V).
7. The method of claim 2, wherein step (3) is performed as follows: and (2) at-10 ℃, dropwise adding acetyl chloride or acetic anhydride in the organic solvent G solution of the compound shown in the formula (V) and the basic catalyst F or in the organic solvent G solution of 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 liquid to obtain the compound shown in the formula (I).
8. The method according to claim 2 or 7, wherein the reaction solution in the step (3) is separated and purified by: 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, 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. Use of the acetamidobenzo [ d ] azaquinazoline compound of claim 1 in the preparation of a medicament for the prevention or treatment of 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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