CN108084162A - Dimethoxy benzene aminoacetylamino benzo [d] azepine * bases quinazoline compounds and preparation and application - Google Patents

Abstract

The invention discloses a kind of dimethoxy benzene aminoacetylamino benzo [d] azepinesBase quinazoline compounds and preparation and application.Dimethoxy benzene aminoacetylamino benzo [d] azepine provided by the inventionBase quinazoline compounds are expected to be applied to prepare treatment human breast carcinoma, human lung cancer, human promyelocytic leukemia, the drug of human cervical carcinoma's drug for being respectively provided with significant inhibitory activity to Breast cancer lines MCF 7, human lung carcinoma cell line A 549, people in loop strain HL 60, human cervical carcinoma cell lines Siha.The present invention provides dimethoxy benzene aminoacetylamino benzo [d] azepines

Description

Dimethoxyanilinoacetamidobenzo[d]aza*ylquinazolines and preparation and application

(1) Technical field

The invention relates to a quinazoline compound and its application, in particular to a dimethoxyanilinoacetamidobenzo[d]azepine A quinazoline compound, a preparation method thereof, and an application of the compound in the preparation of a drug for preventing or treating tumor diseases.

(2) Background technology

Quinazoline compounds have many good biological activities and are widely used in the field of medicine, especially some quinazoline derivatives with special structures have obvious antiviral activity, antibacterial activity, antitumor activity, etc., quinazoline Some compounds have been listed as antitumor drugs. For example, Gefitinib and Erlotinib, which are marketed for the treatment of lung cancer, and Lapatinib, which are used for the treatment of breast cancer, all belong to quinazoline 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, ChemMedChem 2013, 8, 136-148; A. Garofalo, A. Farce, S. Ravez, A. Lemoine, P. Six, P. Chavatte, L. Goossens, P. Depreux, J . Med. Chem. 2012, 55, 1189-1204). Of course, most quinazoline compounds do not have antitumor activity.

(3) Contents of the invention

The object of the present invention is to provide a novel quinazoline compound with anticancer activity—dimethoxyanilinoacetamidobenzo[d]azepine Quinazoline compound and its preparation method and application, the compound has the effect on human lung cancer cell line A-549, human breast cancer cell line MCF-7, human promyelocytic leukemia cell line HL-60 or human The cervical cancer cell line Siha has a good inhibitory effect; and the preparation method of this compound is simple, easy to operate, the raw material is easy to obtain, and the production cost is low, so it is suitable for industrial application.

In order to realize the above-mentioned purpose of the invention, the present invention adopts following technical scheme:

In the first aspect, the present invention provides a dimethoxyanilinoacetamidobenzo[d]azepine represented by formula (I) base quinazoline compounds,

In a second aspect, the present invention provides a dimethoxyanilinoacetamidobenzo[d]azepine represented by formula (I) The preparation method of quinazoline compound, described method is: (1) compound shown in formula (II) and formula (III) are mixed, in organic solvent A, in the effect of basic catalyst B 25～120℃ for reaction (TLC tracking monitoring, developer is ethyl acetate/petroleum ether=1:3 (v/v), preferably 40～100℃ for 0.5～12h), after the reaction is complete, the reaction solution Separation and purification to obtain the compound shown in 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,N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or carbonic acid Sodium (preferably pyridine, diethylamine, triethylamine, N,N-dimethylaniline or 4-dimethylaminopyridine);

(2) The compound represented by formula (Ⅳ) reacts completely in organic solvent D under the action of reducing agent E at 25-100°C (TLC tracking monitoring, developer is ethyl acetate/petroleum ether=1:1( v/v), preferably at 40-80°C for 0.5-12h), the reaction solution is filtered, the filtrate is concentrated under reduced pressure and the concentrate is dried (preferably vacuum-dried at 25°C), to obtain the compound shown in 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 carbon/ammonium formate or palladium carbon/hydrazine hydrate; said iron powder/concentrated hydrochloric acid refers to the mixing of iron powder and concentrated hydrochloric acid in any proportion, and iron powder/acetic acid refers to the mixture of iron powder and acetic acid in any Mixing, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate in any proportion, and the palladium carbon/hydrazine hydrate is a mixture of palladium carbon and hydrazine hydrate in any proportion;

(3) Mix the compound shown in formula (Ⅴ) with chloroacetyl chloride or chloroacetic anhydride, under the action of basic catalyst F, in organic solvent G, the reaction is complete at -10～50°C (TLC tracking monitoring, developing agent is Ethyl acetate/petroleum ether=1:1 (v/v), preferably -10～50°C for 3～12h), the reaction solution is post-treated A to obtain the compound shown in formula (VI); the base The catalyst F is one of the following: pyridine, diethylamine, triethylamine, quinoline, N,N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate; the organic solvent G is one of the following: tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ether, acetonitrile, toluene or benzene;

(4) Mix the compound shown in formula (Ⅵ) with 3,4-dimethoxyaniline, in organic solvent J, under the effect of basic catalyst K, react at 25～120°C (TLC tracking monitoring, developing The agent is ethyl acetate/petroleum ether=1:1 (v/v), preferably at 40-100°C for 0.5-36h), after the reaction is complete, the reaction solution is subjected to post-treatment B to obtain the compound represented by 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 the following One: pyridine, triethylamine, quinoline, N,N-xylidine, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate (preferably pyridine, quinoline, triethylamine, N,N- xylidine or 4-dimethylaminopyridine).

Further, in step (1), the ratio of the amount of the compound represented by the formula (III) to the compound represented by the formula (II) and the basic catalyst B is 1.0:0.8-1.2:1.0-8.0.

Further, in step (1), the amount of the organic solvent A used is 10-50 mL/g based on the mass of the compound represented by formula (III).

Further, the method for separating and purifying the reaction solution in step (1) of the present invention is: after the reaction is complete, the reaction solution is evaporated to remove the solvent, and the concentrate is dissolved with an organic solvent C to obtain a solution, and then the solution is added to the solution Add 1.0 to 2.0 times the weight of the concentrate for column chromatography silica gel, mix well, evaporate the solvent, and dry to obtain a mixture of the concentrate and silica gel, put the mixture into a column, and then use petroleum ether with a volume ratio of 1:0.1 to 10 Mix the solution with ethyl acetate as eluent, collect the effluent containing the target component (preferably use ethyl acetate/petroleum ether=1:3 (v/v) as the developing agent for tracking detection, collect the target component, preferably collect The component whose Rf value is 0.5), concentrated under reduced pressure, dried (preferably 50 ℃ dried), obtains the compound shown in formula (IV); The organic solvent C is one of the following: ethanol, chloroform, tetrahydrofuran or ethyl acetate . The amount of the organic solvent C can be used to dissolve the residue.

Further, in step (2), when the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, the compound shown in formula (IV) and the iron powder in reducing agent E, concentrated hydrochloric acid or acetic acid The feeding mass ratio is 1.0:1.0~3.0:0.2~1.0. In the present invention, the concentrated hydrochloric acid has a mass concentration of 36% to 38%, and the acetic acid is glacial acetic acid.

Further, in step (2), when the reducing agent E is palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate, the compound shown in formula (IV) and palladium carbon in reducing agent E, ammonium formate or hydrate The feed mass ratio of hydrazine is 1.0:0.1~0.5:1.0~3.0. The palladium-on-carbon applicable in the present invention has a mass loading capacity of palladium of 2-10%, preferably 5%, and a mass concentration of hydrazine hydrate of 40-80%, preferably 80%.

Further, in step (2), the amount of the organic solvent D used is 10-50 mL/g based on the mass of the compound represented by formula (IV).

Further, in step (3), the ratio of the amount of the compound represented by the formula (V) to chloroacetyl chloride or chloroacetic anhydride, and the basic catalyst F is 1:1.0-8.0:1.0-3.0.

Further, in step (3), the amount of the organic solvent G used is 11-100 mL/g based on the mass of the compound represented by formula (V).

Further, the present invention specifically recommends step (3) to be carried out according to the following method: under the condition of -10～10°C, add the compound represented by formula (Ⅴ) and the organic solvent G solution of basic catalyst F or to the organic solvent G solution represented by formula (Ⅴ). Add the organic solvent G solution of chloroacetyl chloride or chloroacetic anhydride dropwise to the compound shown and the basic catalyst F, dropwise, and react at -10 to 50°C for 3 to 12 hours, and the resulting reaction solution is post-treated A to obtain the compound of formula (Ⅵ). Show compound; The organic solvent volume consumption of dissolving chloroacetyl chloride or chloroacetic anhydride has no influence on the present invention, and the total consumption of described organic solvent G is calculated as 11～100mL/g by the quality of the compound shown in formula (Ⅴ). The total consumption of organic solvent G refers to the total volume of the organic solvent G that dissolves the basic catalyst F and the compound shown in formula (V) and the organic solvent G that dissolves chloroacetyl chloride or chloroacetic anhydride.

Further, the method for separating and purifying the reaction liquid in step (3) of the present invention is: after the reaction is complete, filter the reaction liquid, evaporate the filtrate to remove the solvent, take the concentrate and dissolve it with an organic solvent H to obtain a solution, and then to dissolve Add 1.0 to 2.0 times the weight of the concentrate to the column chromatography silica gel, mix well, evaporate the solvent, and dry to obtain a mixture of the concentrate and silica gel, put the mixture on a column, and then use a volume ratio of 1:0.1 to 10 The mixed solution of petroleum ether and ethyl acetate is used as the eluent, and the effluent containing the target component is collected (preferably ethyl acetate/petroleum ether=1:1 (v/v) is used as the developing agent for tracking detection, and the target component is collected. Preferably collect the component whose Rf value is 0.5), concentrate under reduced pressure, dry (preferably 50 ℃ dry), obtain the compound shown in formula (VI); The organic solvent H is one of the following: ethanol, chloroform, tetrahydrofuran or acetic acid ethyl ester. The amount of the organic solvent H is enough to dissolve the residue.

Further, in step (4), the ratio of the amount of the compound represented by the formula (VI) to 3,4-dimethoxyaniline and basic catalyst K is 1.0:0.8-8.0:1.0-8.0.

Further, in step (4), the amount of the organic solvent J used is 10-60 mL/g based on the mass of the compound represented by formula (VI).

Further, the method for post-processing B of the reaction solution described in the step (4) of the present invention is: after the reaction is complete, the reaction solution is evaporated to remove the solvent, and the concentrate is dissolved with an organic solvent M to obtain a solution, and then to the solution Add 1.0 to 2.0 times the weight of the concentrate to the column chromatography silica gel, mix well, evaporate the solvent, and dry to obtain a mixture of the concentrate and silica gel. The mixture is packed into a column, and then the volume ratio is 1:0.1 to 10 petroleum The mixed solution of ether and ethyl acetate is used as the eluent, and the effluent containing the target component is collected (preferably ethyl acetate/petroleum ether=1:1 (v/v) is used as the developing agent for tracking detection, and the target component is collected, preferably Collect components with an Rf value of 0.5), concentrate under reduced pressure, and dry (preferably 50°C drying) to obtain the compound shown in formula (I); the organic solvent M is one of the following: ethanol, chloroform, tetrahydrofuran or ethyl acetate ester. The organic solvent M can be used in an amount capable of dissolving the residue.

In the third aspect, the present invention also relates to dimethoxyanilinoacetamidobenzo[d]azepine represented by formula (I) The application of quinazoline compounds in the preparation of medicaments for preventing or treating tumors is particularly suitable for the preparation of medicaments for preventing or treating human breast cancer.

Preferably, the drug is a drug capable of inhibiting the activity of human breast cancer cell line MCF-7. The compound (I) provided by the invention has better inhibitory effect on human breast cancer cell line MCF-7.

Dimethoxyanilinoacetamidobenzo[d]azepine represented by formula (I) of the present invention Quinazoline compounds also have significant inhibitory effect on human lung cancer cell line A-549, human promyelocytic leukemia cell line HL-60 or human cervical cancer cell line Siha, and can be applied to the preparation of prevention or treatment of human lung cancer, human Drugs for leukemia or human cervical cancer.

The organic solvents A, C, D, G, H, J and M of the present invention are all organic solvents, which are named for the convenience of different organic solvents used in different steps, and the letters themselves have no meaning; the catalyst B, reducing agent E, Catalyst F and Catalyst K are both catalysts, named for the convenience of different catalysts used in different steps, and the letters themselves have no meaning; the post-treatment A and post-treatment B are all post-treatments, named for the convenience of different post-treatments used in different steps , the letters themselves have no meaning.

The beneficial effects of the present invention are mainly reflected in: (1) the dimethoxyanilinoacetamidobenzo[d]azepine described in the present invention The quinazoline compound (I) has good anticancer activity and is expected to be used in the preparation of drugs for the prevention or treatment of tumor diseases, especially the application in drugs for human breast cancer, human lung cancer, human leukemia or human cervical cancer; ( 2) Dimethoxyanilinoacetamidobenzo[d]azepine provided by the present invention The preparation method of the quinazoline compound (I) is simple and easy to operate, the raw materials are readily available, and the production cost is relatively low, so it is suitable for practical use.

(4) Specific implementation methods

The present invention is further described in conjunction with specific examples, and the following examples illustrate the present invention, rather than limit the present invention in any way.

Compound (II) was prepared according to the method in the literature (Weinstock, J. et al. J. Med. Chem., 1986, 29(11), 2315-2325). 4-Chloro-6-nitroquinazoline (Ⅲ) was prepared by referring to the method in the literature (Fernandes, C.etal.Bioorg.Med.Chem., 2007, 15(12), 3974-3980).

The palladium carbon (Pd/C) model D5H5A used in the embodiment of the present invention was purchased from Shaanxi Ruike New Material Co., Ltd.

Embodiment 1: the preparation of 6-nitroquinazoline (IV)

1.20 grams (5.73mmol) of 4-chloro-6-nitroquinazoline (Ⅲ) and 2.39 grams (6.87mmol) of compound (Ⅱ), 3.62 grams (45.76mmol) of pyridine, and 12 milliliters of chloroform were added to 50 milliliters of the reaction In the bottle, heated to 40°C, followed by TLC detection (developing solvent: ethyl acetate/petroleum ether = 1:3 (v/v)), stirred for 10 hours, closed the reaction, evaporated the reaction solution to remove the solvent, and obtained the concentrate 10 milliliters of ethyl acetate was added to dissolve it to obtain a solution, and 3.0 grams 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 dry concentrate The mixture with silica gel, the mixture was packed into a column, and then the mixed solution of petroleum ether/ethyl acetate with a volume ratio of 1:10 was used as the eluent for elution, and TLC tracking detection (developing solvent was ethyl acetate/petroleum ether=1 : 3 (v/v)), according to TLC detection, collect the eluate containing the compound shown in formula (IV) (Rf value is 0.5), the collected solution is concentrated, and dried at 50°C to obtain the light yellow compound shown in formula (IV). The solid product has a yield of 85.1% and a melting point of 164-166°C. ¹ H NMR (500MHz, CDCl ₃ ) 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=8.6Hz,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.

Embodiment 2: the preparation of 6-nitroquinazoline (IV)

1.20 grams (5.73 mmol) of 4-chloro-6-nitroquinazoline (Ⅲ) and 1.59 grams (4.57 mmol) of compound (Ⅱ), 1.67 grams (22.83 mmol) of diethylamine, and 60 milliliters of toluene were added to 100 milliliters successively. In a three-necked flask, heated to 100°C, followed by TLC detection (developing agent: ethyl acetate/petroleum ether = 1:3 (v/v)), stirred for 2 hours, closed the reaction, evaporated the reaction solution to remove the solvent, and obtained Add 20 ml of ethanol to the concentrate to dissolve it to obtain a solution, add 2.5 grams of column chromatography silica gel (300-400 mesh column chromatography silica gel) to the solution, mix well, and evaporate the solvent to obtain a dry concentrate The mixture with silica gel, the mixture was packed into a column, and then the mixed solution of petroleum ether/ethyl acetate with a volume ratio of 1:5 was used as the eluent for elution, and TLC tracking detection (developing solvent was ethyl acetate/petroleum ether=1 : 3 (v/v)), according to TLC detection, collect the eluate containing the compound shown in formula (IV) (Rf value is 0.5), the collected solution is concentrated, and dried at 50°C to obtain the light yellow compound shown in formula (IV). The solid product has a yield of 72.6% and a melting point of 164-166°C. ¹ H NMR and IR are the same as in Example 1.

Embodiment 3: the preparation of 6-nitroquinazoline (IV)

1.20 grams (5.73 mmol) of 4-chloro-6-nitroquinazoline (Ⅲ) and 1.99 grams (5.72 mmol) of compound (Ⅱ), 0.58 grams (5.73 mmol) of triethylamine, and 60 milliliters of ethanol were added to 100 milliliters of In a three-necked flask, heated to 60°C, followed by TLC detection (developing solvent: ethyl acetate/petroleum ether = 1:3 (v/v)), stirred for 8 hours, closed the reaction, and evaporated the solvent from the reaction solution to obtain Add 20 ml of chloroform to the concentrate to dissolve it to obtain a solution, add 2.5 grams of column chromatography silica gel (300-400 mesh column chromatography silica gel) to the solution, mix well, and evaporate the solvent to obtain a dry concentrate The mixture with silica gel, the mixture was packed into a column, and then the mixed solution of petroleum ether/ethyl acetate with a volume ratio of 10:1 was used as the eluent for elution, and TLC tracking detection (developing solvent was ethyl acetate/petroleum ether=1 : 3 (v/v)), according to TLC detection, collect the eluate containing the compound shown in formula (IV) (Rf value is 0.5), the collected solution is concentrated, and dried at 50°C to obtain the light yellow compound shown in formula (IV). The solid product has a yield of 77.2%, and a melting point of 164-166°C. ¹ H NMR and IR are the same as in Example 1.

Embodiment 4: the preparation of 6-nitroquinazoline (IV)

1.20 grams (5.73mmol) of 4-chloro-6-nitroquinazoline (Ⅲ) and 2.20 grams (6.32mmol) of compound (Ⅱ), 1.40 grams (11.46mmol) of 4-dimethylaminopyridine, and 60 milliliters of isoquinazoline were successively Add propanol to a 100 ml three-neck flask, stir at room temperature 25°C, track and detect with TLC (developing solvent is ethyl acetate/petroleum ether = 1:3 (v/v)), react for 12 hours, close the reaction, and evaporate the reaction liquid Solvent, add 20 milliliters of tetrahydrofuran to the obtained concentrate to dissolve it, obtain a solution, add 4.0 grams of column chromatography silica gel (300 ~ 400 mesh column chromatography silica gel) to the solution, after mixing, evaporate the solvent to obtain The mixture of the dried concentrate and silica gel was packed into a column, and then the mixed solution of petroleum ether/ethyl acetate with a volume ratio of 5:1 was used as an eluent for elution, and TLC tracking detection (developing solvent was ethyl acetate/ethyl acetate) Petroleum ether=1:3 (v/v)), according to TLC detection, collect the eluate containing the compound shown in formula (IV) (Rf value is 0.5), collect the solution and concentrate, dry at 50 ℃ to obtain the compound of formula (IV) The pale yellow solid product shown, the yield is 80.2%, and the melting point is 164-166°C. ¹ H NMR and IR are the same as in Example 1.

Embodiment 5: the preparation of 6-nitroquinazoline (IV)

1.20 grams (5.73mmol) of 4-chloro-6-nitroquinazoline (Ⅲ) and 1.79 grams (5.15mmol) of compound (Ⅱ), 1.04 grams (8.58mmol) of N,N-xylidine, 12 ml Add N,N-dimethylformamide into a 50ml reaction bottle, heat to 120°C, TLC tracking detection (developing solvent: ethyl acetate/petroleum ether = 1:3 (v/v)), and stir for 0.5 hours , close the reaction, the reaction solution is evaporated to remove the solvent, and 20 milliliters of tetrahydrofuran is added to the obtained concentrate to dissolve it to obtain a solution, and 5.0 grams of column chromatography silica gel (300-400 mesh column chromatography silica gel) are added to the solution, and mixed After homogenization, the solvent was evaporated to obtain a mixture of the dry concentrate and silica gel, and the mixture was packed into a column, and then the mixed solution of petroleum ether/ethyl acetate with a volume ratio of 1:1 was used as the eluent for elution, and TLC tracking detection (The developing solvent is ethyl acetate/petroleum ether=1:3 (v/v)), and the eluate containing the compound shown in formula (IV) is collected according to TLC detection (Rf value is 0.5), and the collected solution is concentrated, 50 Dry at °C to obtain a pale yellow solid product represented by formula (IV), with a yield of 89.6% and a melting point of 164-166 °C. ¹ HNMR and IR are the same as in Example 1.

Embodiment 6: the preparation of 6-nitroquinazoline (IV)

1.20 grams (5.73mmol) of 4-chloro-6-nitroquinazoline (Ⅲ) and 2.39 grams (6.87mmol) of compound (Ⅱ), 3.62 grams (45.76mmol) of pyridine, and 20 milliliters of propanol were added to 50 milliliters of In the reaction flask, heated to 40°C, followed by TLC detection (developing solvent: ethyl acetate/petroleum ether = 1:3 (v/v)), stirred for 10 hours, closed the reaction, evaporated the reaction solution to remove the solvent, and concentrated 20 milliliters of ethyl acetate was added to the mixture to dissolve it to obtain a solution, and 3.5 grams 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 dry concentrated The mixture of compound and silica gel, the mixture was packed into a column, and then the mixed solution of petroleum ether/ethyl acetate with a volume ratio of 1:1 was used as eluent, eluted, and TLC tracking detection (developing solvent was ethyl acetate/petroleum ether = 1:3 (v/v)), the eluate containing the compound represented by formula (IV) was collected according to TLC detection (Rf value was 0.5), the collected liquid was concentrated, and dried at 50°C to obtain the light compound represented by formula (IV). Yellow solid product, yield 78.3%, melting point 164-166°C. ¹ H NMR and IR are the same as in Example 1.

Embodiment 7: the preparation of 6-aminoquinazoline (V)

0.40 grams (0.77mmol) of 6-nitroquinazoline (Ⅳ) prepared by the method of Example 1, 0.40 grams (6.34 mmol) of ammonium formate, 0.04 grams of 5% Pd/C, and 4.0 milliliters of chloroform were added to the reaction flask , stirred at room temperature 25°C, followed by TLC detection (developing solvent: ethyl acetate/petroleum ether = 1:1 (v/v)), reacted for 12 hours, filtered, concentrated the filtrate, and dried in vacuo at 25°C to obtain a light yellow solid product 6- Aminoquinazoline (V), yield 98.2%, melting point 122-126°C. ¹ H NMR (500MHz, CDCl ₃ )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=8.9Hz,1H),8.50(s ,1H). IR (KBr, cm ^-1 ) ν: 3368, 3215, 2932, 2825, 1628, 1566, 1512, 1487, 1353, 1248, 1036, 834.

Embodiment 8: the preparation of 6-aminoquinazoline (V)

0.40 gram (0.77mmol) 6-nitroquinazoline (Ⅳ) prepared by the method of Example 2, 1.20 gram (19.18mmol) 80wt% hydrazine hydrate, 0.20 gram 5% Pd/C, 20.0 milliliters of toluene were added to 50 In a ml reaction bottle, heat to 100°C, TLC tracking detection (developing solvent: ethyl acetate/petroleum ether = 1:1 (v/v)), stir for 0.5 hours, cool and filter, concentrate the filtrate, and vacuum dry at 25°C The light yellow solid product 6-aminoquinazoline (V) was obtained with a yield of 100.0% and a melting point of 122-126°C. ¹ H NMR and IR are the same

Example 7.

Embodiment 9: the preparation of 6-aminoquinazoline (V)

0.40 gram (0.77mmol) of 6-nitroquinazoline (Ⅳ) prepared by the method of Example 3, 0.08 gram of concentrated hydrochloric acid (mass concentration 36～38%), 0.40 gram of iron powder, and 20.0 milliliters of methanol were added to 50 milliliters of In a reaction flask, heated to 40°C, followed by TLC detection (developer: ethyl acetate/petroleum ether = 1:1 (v/v)), stirred for 8 hours, cooled and filtered, the filtrate was concentrated, and vacuum-dried at 25°C to obtain The light yellow solid product 6-aminoquinazoline (Ⅴ) has a yield of 94.1% and a melting point of 122-126°C. ¹ H NMR and IR are the same as in Example 7.

Embodiment 10: the preparation of 6-aminoquinazoline (V)

0.40 gram (0.77mmol) 6-nitroquinazoline (Ⅳ) that embodiment 4 method is prepared successively, 0.40 gram acetic acid, 1.20 gram iron powder, 20.0 milliliters of isopropanols join in the reaction bottle of 50 milliliters, heat to 80°C, TLC tracking detection (developing solvent: ethyl acetate/petroleum ether = 1:1 (v/v)), stirred for 3 hours, cooled and filtered, the filtrate was concentrated, and vacuum-dried at 25°C to obtain a light yellow solid product 6-amino Quinazoline (Ⅴ), yield 97.5%, melting point 122-126°C. ¹ H NMR and IR are the same as in Example 7.

Embodiment 11: the preparation of chloroacetamidoquinazoline (Ⅵ)

0.27 grams (0.55 mmol) of 6-aminoquinazoline (Ⅴ), 0.13 grams (1.64 mmol) of pyridine, and 3 milliliters of tetrahydrofuran prepared by the method of Example 7 were successively added to the reaction flask, and 0.497 Gram (4.40mmol) chloroacetyl chloride, dropwise, TLC follow-up detection (developer: ethyl acetate/petroleum ether = 1:1), react at -10°C for 12 hours, filter, distill the filtrate to remove the solvent, and add the concentrate to 10 milliliters of ethyl acetate was dissolved to obtain a solution, and 0.60 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 dry concentrate and silica gel. The mixture was packed into a column, and then the mixed solution of petroleum ether/ethyl acetate with a volume ratio of 1:10 was used as the eluent for elution, and TLC tracking detection (developing solvent was ethyl acetate/petroleum ether=1:1 (v/v)), detect and collect the eluate (Rf value is 0.5) containing the compound shown in formula (VI) according to TLC, collect liquid and concentrate, dry at 50 ℃ to obtain the chloroacetamidoquinone shown in formula (VI) Azoline yellow solid, yield 95.6%, melting point 255-258°C. ¹ H NMR (500MHz, CDCl ₃ ) δ: 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.

Embodiment 12: the preparation of chloroacetamidoquinazoline (Ⅵ)

0.27 grams (0.55 mmol) of 6-aminoquinazoline (Ⅴ) prepared by the method of Example 8, 0.04 grams (0.55 mmol) of diethylamine, and 10.0 milliliters of chloroform were added to a 50 milliliter reaction flask successively, and stirred at 10°C Add dropwise a mixed solution of 0.07 g (0.55 mmol) chloroacetyl chloride and 5.0 ml chloroform, after the drop is complete, TLC tracking detection (developing solvent is ethyl acetate/petroleum ether=1:1 (v/v)), under the condition of 10°C React for 8 hours, filter, evaporate the solvent from the filtrate, add 20 ml of ethanol to the concentrate to dissolve it to obtain a solution, add 0.26 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) to the solution, and mix well , evaporate the solvent to obtain a mixture of the dry concentrate and silica gel, the mixture is packed into a column, and then a mixed solution of petroleum ether/ethyl acetate with a volume ratio of 1:5 is used as an eluent for elution, and TLC tracking detection (developed The reagent is ethyl acetate/petroleum ether=1:1 (v/v)), and the eluate containing the compound shown in formula (VI) is collected according to TLC detection (Rf value is 0.5), the collected solution is concentrated, and dried at 50°C The chloroacetamidoquinazoline yellow solid represented by the formula (VI) was obtained with a yield of 83.4% and a melting point of 255-258°C. ¹ H NMR and IR are the same as in Example 11.

Embodiment 13: Preparation of chloroacetamidoquinazoline (Ⅵ)

0.27 grams (0.55 mmol) of 6-aminoquinazoline (Ⅴ) prepared by the method of Example 9, 0.111 grams (1.10 mmol) of triethylamine, and 10.0 milliliters of ethyl acetate were added to a 50 milliliter reaction flask successively at 0° C. Add dropwise 0.14 g (1.09 mmol) of chloroacetyl chloride and 5.0 ml of ethyl acetate solution under stirring condition, after dropping, TLC tracking detection (developing solvent is ethyl acetate/petroleum ether = 1:1), react 6 at 25°C hour, filter, the filtrate is evaporated to remove the solvent, and the concentrate is dissolved by adding 20 milliliters of chloroform to obtain a solution, and 0.30 gram of column chromatography silica gel (300-400 mesh column chromatography silica gel) is added to the solution, after mixing, evaporate The solvent was removed to obtain a mixture of dry concentrate and silica gel, the mixture was packed into a column, and then a mixed solution of petroleum ether/ethyl acetate with a volume ratio of 10:1 was used as an eluent for elution, and TLC tracking detection (developing agent was Ethyl acetate/petroleum ether=1:1 (v/v)), collect the eluate containing the compound shown in formula (VI) according to TLC detection (Rf value is 0.5), concentrate the collected solution, and dry at 50°C to obtain the formula The chloroacetamidoquinazoline shown in (VI) is a yellow solid with a yield of 70.5% and a melting point of 255-258°C. ¹ H NMR and IR are the same as in Example 11.

Embodiment 14: Preparation of chloroacetamidoquinazoline (Ⅵ)

0.27 gram (0.55mmol) 6-aminoquinazoline (Ⅴ) prepared by embodiment 10 method successively, 0.067 gram (0.55mmol) 4-dimethylaminopyridine, 20.0 milliliters of toluene joins in the reaction flask of 50 milliliters, 5 Add dropwise a solution of 0.376 g (2.20 mmol) of chloroacetic anhydride and 7.0 ml of toluene under stirring at °C, after the drop is complete, heat to 50 °C, and perform TLC tracking detection (developing solvent is ethyl acetate/petroleum ether=1:1), and the reaction 3 hours, filtered, the filtrate was evaporated to remove the solvent, the concentrate was dissolved by adding 20 ml of tetrahydrofuran to obtain a solution, and 0.40 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) was added to the solution. After mixing, The solvent was evaporated to obtain a mixture of the dry concentrate and silica gel, the mixture was packed into a column, and then a mixed solution of petroleum ether/ethyl acetate with a volume ratio of 5:1 was used as an eluent for elution, and TLC tracking detection (developing solvent Ethyl acetate/petroleum ether=1:1 (v/v)), the eluate containing the compound represented by formula (VI) was collected according to TLC detection (Rf value 0.5), the collected solution was concentrated, and dried at 50°C to obtain Chloroacetamidoquinazoline represented by formula (VI) is a yellow solid with a yield of 85.3% and a melting point of 255-258°C. ¹ H NMR and IR are the same as in Example 11.

Embodiment 15: Preparation of chloroacetamidoquinazoline (Ⅵ)

0.27 grams (0.55 mmol) of 6-aminoquinazoline (Ⅴ) prepared by the method of Example 7, 0.213 grams (1.65 mmol) of quinoline, and 15.0 milliliters of benzene were added to a 50 milliliter reaction flask successively, and stirred at -10°C A solution of 0.28 g (2.19 mmol) of chloroacetyl chloride and 5.0 ml of benzene was added dropwise, and the drop was completed, followed by TLC detection (developing solvent: ethyl acetate/petroleum ether = 1:1), and reacted at -10°C for 12 hours. Filtrate, evaporate the solvent from the filtrate, add 20 ml of tetrahydrofuran to the concentrate to dissolve it, and obtain a solution, add 0.40 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) to the solution, mix well, and evaporate the solvent , to obtain the mixture of the dry concentrate and silica gel, the mixture is packed into a column, and then the petroleum ether/ethyl acetate mixed solution with a volume ratio of 1:1 is used as the eluent for elution, and TLC tracking detection (developing agent is ethyl acetate Ester/petroleum ether=1:1 (v/v)), the eluate containing the compound shown in formula (VI) was collected according to TLC detection (Rf value is 0.5), the collected solution was concentrated, and dried at 50°C to obtain formula (VI) ) as a yellow solid of chloroacetamidoquinazoline with a yield of 82.1% and a melting point of 255-258°C. ¹ H NMR and IR are the same as in Example 11.

Embodiment 16: Preparation of chloroacetamidoquinazoline (Ⅵ)

0.27 grams (0.55 mmol) of 6-aminoquinazoline (Ⅴ) prepared by the method of Example 7, 0.164 grams (1.10 mmol) of 4-pyrrolidinyl pyridine, and 15.0 milliliters of dichloromethane were added to a 50 milliliter reaction flask , 00.14 g (1.09 mmol) of chloroacetyl chloride and 5.0 ml of dichloromethane solution were added dropwise under stirring at 10°C. React for 8 hours, filter, evaporate the solvent from the filtrate, add 20 ml of ethanol to the concentrate to dissolve it, and obtain a solution, add 0.50 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) to the solution, and mix Afterwards, the solvent was evaporated to obtain a mixture of the dry concentrate and silica gel, the mixture was packed into a column, and then the petroleum ether/ethyl acetate mixed solution with a volume ratio of 10:1 was used as an eluent for elution, and TLC tracking detection ( The developer is ethyl acetate/petroleum ether=1:1 (v/v)), and the eluate containing the compound represented by formula (VI) is collected according to TLC detection (Rf value is 0.5), and the collected solution is concentrated and stored at 50°C After drying, the yellow solid of chloroacetamidoquinazoline represented by formula (VI) was obtained with a yield of 90.2% and a melting point of 255-258°C. ¹ H NMR and IR are the same as in Example 11.

Example 17: Dimethoxyanilinoacetamidobenzo[d]azepine Preparation of quinazoline (Ⅰ)

3.25 grams (5.73 mmol) of chloroacetamidoquinazoline (VI) and 1.053 grams (6.87 mmol) of 3,4-dimethoxyaniline prepared by the method of Example 11, 3.626 grams (45.84 mmol) of pyridine, and 32.5 ml Add methanol into a 50 ml reaction bottle, heat to 40°C, track and detect with TLC (developer: ethyl acetate/petroleum ether = 1:1 (v/v)), stir for 10 hours, close the reaction, and evaporate the reaction solution Solvent, add 10 milliliters of ethyl acetate in the obtained concentrate and dissolve it, obtain the solution, add 1.5 grams of column chromatography silica gel (300～400 mesh column chromatography silica gel) to the solution, after mixing, evaporate the solvent , to obtain the mixture of the dry concentrate and silica gel, the mixture is packed into a column, and then the petroleum ether/ethyl acetate mixed solution with a volume ratio of 1:10 is used as the eluent for elution, and TLC tracking detection (developing agent is ethyl acetate Ester/petroleum ether=1:1 (v/v)), collect the eluate containing the compound represented by formula (I) according to TLC detection (Rf value is 0.5), concentrate the collected solution, and dry at 50°C to obtain formula (I) ) as a yellow solid product with a yield of 52.7% and a melting point of 124-127°C. ¹ HNMR(500MHz,[D ₆ ]DMSO)δ:3.14-3.20(m,1H),3.33-3.39(m,1H),3,61(s,6H),3,68(s,3H),3 ,70(s,3H),3,72(s,3H),3.75-3.82(m,1H),3.84-3.93(m,4H),4.52(dd,J＝8.5,14.4Hz,1H),5.28 (t,J=8.4Hz,1H),5.74(s,1H),6.08(dd,J=2.6,8.8Hz,1H),6.40(d,J=7.6Hz,1H),6.72(d,J= 8.6Hz, 1H), 6.86-6.88(m, 3H), 7.02(d, J＝8.7Hz, 2H), 7.70-7.72(m, 1H), 7.75-7.77(m, 1H), 8.45(s, 1H ), 8.72(s,1H), 10.38(s,1H). HRMS-ESI m/z: 684.2589 [M+H] ⁺ . IR (KBr, cm ^-1 ) ν: 3324, 2933, 2832, 1688, 1595, 1513, 1462, 1349, 1232, 1032, 837.

Example 18: Dimethoxyanilinoacetamidobenzo[d]azepine Preparation of quinazoline (Ⅰ)

3.25 grams (5.73 mmol) of chloroacetamidoquinazoline (VI) and 0.702 grams (4.58 mmol) of 3,4-dimethoxyaniline prepared by the method of Example 12, 2.95 grams (22.84 mmol) of quinoline, 80 Add one milliliter of toluene into a 100-milliliter three-neck flask, heat to 100°C, track and detect with TLC (developing solvent is ethyl acetate/petroleum ether=1:1 (v/v)), stir and react for 2 hours, close the reaction, and evaporate the reaction solution to Remove solvent, add 20 milliliters of ethanols in the concentrate that obtains and dissolve it, obtain solution, add 2.5 grams of column chromatography silica gel (300～400 mesh column chromatography silica gel) to solution, after mixing, evaporate solvent, Obtain the mixture of the dry concentrate and silica gel, the mixture is packed into a column, and then the petroleum ether/ethyl acetate mixed solution with a volume ratio of 1:5 is used as eluent for elution, and TLC tracking detection (developing agent is ethyl acetate /petroleum ether=1:1 (v/v)), according to TLC detection, collect the eluate containing the compound represented by formula (I) (Rf value is 0.5), concentrate the collected solution, and dry at 50°C to obtain formula (I) The yellow solid product shown has a yield of 41.1% and a melting point of 124-127°C. ¹ HNMR and IR are the same as in Example 17.

Example 19: Dimethoxyanilinoacetamidobenzo[d]azepine Preparation of quinazoline (Ⅰ)

3.25 grams (5.73 mmol) of chloroacetamidoquinazoline (VI) and 0.878 grams (5.73 mmol) of 3,4-dimethoxyaniline prepared by the method of Example 13, 0.58 grams (5.73 mmol) of triethylamine, Add 80 milliliters of ethanol into a 100 milliliter three-neck flask, heat to 60°C, track and detect with TLC (developing solvent is ethyl acetate/petroleum ether=1:1 (v/v)), stir for 8 hours, close the reaction, and the reaction liquid Evaporate the solvent, add 20 milliliters of chloroform to the obtained concentrate to dissolve it, and obtain a solution, add 2.5 grams of column chromatography silica gel (300-400 mesh column chromatography silica gel) to the solution, mix well, and evaporate the solvent , to obtain the mixture of the dry concentrate and silica gel, the mixture is packed into a column, and then the petroleum ether/ethyl acetate mixed solution with a volume ratio of 10:1 is used as the eluent for elution, and TLC tracking detection (developing agent is ethyl acetate Ester/petroleum ether=1:1 (v/v)), collect the eluate containing the compound represented by formula (I) according to TLC detection (Rf value is 0.5), concentrate the collected solution, and dry at 50°C to obtain formula (I) ) as a yellow solid product with a yield of 46.4% and a melting point of 124-127°C. ¹ HNMR and IR are the same as in Example 17.

Example 20: Dimethoxyanilinoacetamidobenzo[d]azepine Preparation of quinazoline (Ⅰ)

3.25 grams (5.73 mmol) of chloroacetamidoquinazoline (VI) and 3.511 grams (22.92 mmol) of 3,4-dimethoxyaniline prepared by the method of Example 14, 1.40 grams (11.46 mmol) of 4-dimethyl Add aminopyridine and 60 ml of isopropanol to a 100 ml three-neck flask, stir at room temperature 25°C, track and detect with TLC (developing solvent is ethyl acetate/petroleum ether = 1:1 (v/v)), react for 36 hours, close reaction, the reaction solution was evaporated to remove the solvent, and 20 milliliters of tetrahydrofuran was added to the obtained concentrate to dissolve it to obtain a solution, and 3.0 grams of column chromatography silica gel (300-400 mesh column chromatography silica gel) was added to the solution, and after mixing, , evaporate the solvent to obtain a mixture of dry concentrate and silica gel, the mixture is packed into a column, and then a mixed solution of petroleum ether/ethyl acetate with a volume ratio of 5:1 is used as an eluent for elution, and TLC tracking detection (developed The reagent is ethyl acetate/petroleum ether=1:1 (v/v)), and the eluate containing the compound represented by formula (I) is collected according to TLC detection (Rf value is 0.5), the collected solution is concentrated, and dried at 50°C The yellow solid product represented by formula (I) was obtained with a yield of 58.1% and a melting point of 124-127°C. ¹ H NMR and IR are the same as in Example 17.

Example 21: Dimethoxyanilinoacetamidobenzo[d]azepine Preparation of quinazoline (Ⅰ)

3.25 grams (5.73 mmol) of chloroacetamidoquinazoline (VI) and 0.790 grams (5.16 mmol) of 3,4-dimethoxyaniline prepared by the method of Example 15, 1.04 grams (8.58 mmol) of N, N- Add xylidine and 33 ml of N,N-dimethylformamide into a 50 ml reaction flask, heat to 120°C, and perform TLC tracking detection (developing solvent is ethyl acetate/petroleum ether=1:1 (v/v) ), stirred and reacted for 0.5 hour, closed the reaction, evaporated the solvent from the reaction solution, added 20 milliliters of tetrahydrofuran (THF) to the obtained concentrate and dissolved it to obtain a solution, and added 4.0 grams of column chromatography silica gel (300 to 400 mesh column Chromatographic silica gel), after mixing, evaporate the solvent to obtain a mixture of dry concentrate and silica gel, the mixture is packed into a column, and then the mixed solution of petroleum ether/ethyl acetate with a volume ratio of 1:1 is used as the eluent. Elution, TLC follow-up detection (developing solvent is ethyl acetate/petroleum ether=1:1 (v/v)), and the eluate containing the compound shown in formula (I) is collected according to TLC detection (Rf value is 0.5) , the collected solution was concentrated, and dried at 50°C to obtain a yellow solid product represented by formula (I), with a yield of 32.8% and a melting point of 124-127°C. ¹ H NMR and IR are the same as in Example 17.

Example 22: Dimethoxyanilinoacetamidobenzo[d]azepine Preparation of quinazoline (Ⅰ)

3.25 grams (5.73 mmol) of chloroacetamidoquinazoline (VI) and 7.022 grams (45.84 mmol) of 3,4-dimethoxyaniline prepared by the method of Example 16, 3.626 grams (45.84 mmol) of pyridine, 195 milliliters Propanol was added to a 500 ml reaction flask, heated to 40°C, followed by TLC detection (developing solvent: ethyl acetate/petroleum ether = 1:1 (v/v)), stirred for 10 hours, the reaction was closed, and the reaction solution was evaporated. In addition to the solvent, 20 milliliters of ethyl acetate was added to the obtained concentrate to dissolve it, and to obtain a solution, 6.0 grams of column chromatography silica gel (300-400 mesh column chromatography silica gel) was added to the solution, and after mixing, the solution was evaporated. Solvent, the mixture of dry concentrate and silica gel is obtained, the mixture is packed into a column, and then the mixed solution of petroleum ether/ethyl acetate with a volume ratio of 1:1 is used as eluent, eluted, and TLC tracking detection (developing agent is acetic acid Ethyl ester/petroleum ether=1:1 (v/v)), according to TLC detection, collect the eluate containing the compound shown in formula (I) (Rf value is 0.5), collect liquid concentration, dry at 50 ℃ to obtain formula ( The yellow solid product shown in I) has a yield of 54.5% and a melting point of 124-127°C. ¹ H NMR and IR are the same as in Example 17.

Example 23: In vitro test of anticancer activity

(1) The compound (I) prepared in the embodiment was subjected to human lung cancer cell line A-549, human breast cancer cell line MCF-7, human promyelocytic leukemia cell line HL-60 and human cervical cancer cell line Siha Biological activity test.

Test method: tetrazolium salt reduction method (MTT method).

Cell lines: human lung cancer cell line A-549, human breast cancer cell line MCF-7, human promyelocytic leukemia cell line HL-60 and human cervical cancer cell line Siha. The above tumor cell lines were purchased from the Cell Bank of Shanghai Institute of Biological Sciences, Chinese Academy of Sciences.

The experimental steps are as follows:

(a) Sample preparation: For soluble samples, dissolve each 1 mg with 40 μL DMSO, take 2 μL and dilute with 1000 μL medium to make the concentration 100 μg/mL, and then serially dilute with culture medium to the use concentration.

(b) Culture of cells

① Preparation of culture medium: Each 1000 mL DMEM medium (Gibco) contains 800,000 units of penicillin, 1.0 g of streptomycin, and 10% inactivated fetal bovine serum.

②Cultivation of cells: Inoculate the tumor cells in the culture medium, culture them in a 37°C, 5% CO ₂ incubator, and passage them for 3-5 days.

③ Determination of the inhibitory effect of samples on tumor cell growth

The 10th passage cells were digested with EDTA-trypsin digestion solution, diluted with medium to 1×10 ⁶ /mL, added to a 96-well cell culture plate, 100 μL per well, and placed in a 37°C, 5% CO ₂ incubator nourish. 24 hours after inoculation, add 100 μg/mL, 10 μg/mL and 1 μg/mL samples diluted with culture medium, 100 μL per well, add 3 wells for each concentration, culture in 37 °C, 5% _CO2 incubator, and after 72 h Add 5 mg/mL MTT to the cell culture wells, 10 μL per well, incubate at 37 °C for 3 h, add DMSO, 150 μL per well, shake with an oscillator to completely dissolve formazan, and use a microplate reader to perform colorimetry at a wavelength of 570 nm. The cells cultured in the medium containing no sample and the same concentration of DMSO under the same conditions were used as a control, and the IC ₅₀ of the sample on tumor cell growth was calculated.

The test results are shown in Table 1, Table 2, Table 3, and Table 4:

Table 1. The inhibitory effect of compound (Ⅰ) on the growth of cancer cell line MCF-7

Table 2. Inhibitory effect of compound (I) on the growth of cancer cell line A-549

Table 3. Inhibitory effect of compound (I) on the growth of cancer cell line HL-60

Table 4. Inhibitory effect of compound (Ⅰ) on the growth of cancer cell line Siha

(2) According to embodiment 11, chloroacetyl chloride is replaced with 4-iodobenzoyl chloride, 3-methoxybenzoyl chloride or cinnamoyl chloride respectively, and other operations are with embodiment 11, synthesized respectively quinazoline compound ( a), (b) and (c), the structure is as follows:

The quinazoline compounds (a), (b) and (c) prepared according to the above method have been tested for human breast cancer cell line MCF-7 biological activity, and the test results show that the quinazoline compounds (a), ( b) and (c) have no obvious inhibitory effect on human breast cancer cell line MCF-7, and compound (a), (b) and (c) are far less effective than compound ( I). The quinazoline compounds (b) and (c) prepared according to the above method have been tested for human promyelocytic leukemia cell line HL-60 biological activity, and the test results show that the quinazoline compounds (b) and (c) The inhibitory effect on human promyelocytic leukemia cell line HL-60 is not obvious, and the anticancer activity of compounds (b) and (c) on human promyelocytic leukemia cell line HL-60 is far inferior to that of compound (I).

The specific results are shown in Table 5 and Table 6:

Table 5. Compounds (a), (b) and (c) inhibit the growth of cancer cell line MCF-7

Table 6. Compounds (b) and (c) inhibit the growth of cancer cell line HL-60

(3) According to Example 17, 3,4-dimethoxyaniline is replaced with 3,4-xylaniline or di-n-propylamine respectively, other operations are the same as Example 17, and quinazoline compounds (d ) and (f), the structure is as follows:

The quinazoline compounds (d) and (f) prepared according to the above method were tested for the biological activity of human breast cancer cell line MCF-7 and human promyelocytic leukemia cell line HL-60, and the results showed that quinazoline compounds The anticancer activity of compounds (d) and (f) on human breast cancer cell line MCF-7 and human promyelocytic leukemia cell line HL-60 is inferior to that of compound (I). The specific results are shown in Table 7 and Table 8:

Table 7. Compounds (d) and (f) inhibit the growth of cancer cell line MCF-7

Table 8. Compounds (d) and (f) inhibit the growth of cancer cell line HL-60

(4) 4-chloroquinazoline was prepared by referring to the method of literature (Rao, G.-W.et al.ChemMedChem, 2013, 8(6), 928-933), and then according to Example 1, 4-chloro- 6-nitroquinazoline is replaced with 4-chloroquinazoline, and other operation is with embodiment 1, has synthesized quinazoline compound (g), and structure is as follows:

The quinazoline compounds (g) prepared according to the method described above have carried out the human breast cancer cell line MCF-7 bioactivity test, and the test results show that the quinazoline compounds (g) have an effect on the human breast cancer cell line MCF-7. The anticancer activity is far inferior to that of compound (I). The specific results are shown in Table 9:

Table 9. The inhibitory effect of compound (g) on the growth of cancer cell line MCF-7

Claims (10)

1. a kind of dimethoxy benzene aminoacetylamino benzo [d] azepine shown in formula (I)Base quinazoline compounds：

2. a kind of dimethoxy benzene aminoacetylamino benzo [d] azepine shown in formula as described in claim 1 (I)Base quinoline The preparation method of oxazoline compound, it is characterised in that the method is：

(1) compound shown in formula (II) is mixed with compound shown in formula (III), in organic solvent A, in basic catalyst B's Under effect, 25~120 DEG C are reacted, and after the reaction was complete, reaction solution is isolated and purified, and compound shown in formula (IV) is made；Institute Organic solvent A is stated selected from one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N- dimethyl formyl Amine；The basic catalyst B is selected from one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4- diformazans Aminopyridine, 4- pyrollidinopyridines or sodium carbonate；

(2) formula (IV) compound represented is in organic solvent D, and under reducing agent E effects, at 25~100 DEG C, the reaction was complete, instead Liquid is answered to filter, formula (V) compound represented is made in the concentrate drying (preferably 25 DEG C vacuum drying) after filtrate decompression concentration； The organic solvent D is one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N- dimethyl formyl Amine；The reducing agent E is one of following：Iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate；It is described Iron powder/concentrated hydrochloric acid refers to that the mixing of iron powder and concentrated hydrochloric acid arbitrary proportion, iron powder/acetic acid refer to the mixed of iron powder and acetic acid arbitrary proportion It closes, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate arbitrary proportion, and the palladium carbon/hydrazine hydrate is palladium carbon and hydration The mixture of hydrazine arbitrary proportion；

(3) compound shown in formula (V) is mixed with chloracetyl chloride or chloroacetic anhydride, under basic catalyst F effects, in organic In solvent G, -10~50 DEG C the reaction was complete, the post-treated A of reaction solution, and formula (VI) compound represented is made；The alkalescence is urged Agent F is one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrrolidines Yl pyridines or sodium carbonate；The organic solvent G is one of following：Tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ether, Acetonitrile, toluene or benzene；

(4) compound shown in formula (VI) and 3,4- dimethoxyanilines are mixed, in organic solvent J, in basic catalyst K's Under effect, 25~120 DEG C are reacted, and after the reaction was complete, by the post-treated B of reaction solution, compound shown in formula (I) is made；Institute Organic solvent J is stated selected from one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N- dimethyl formyl Amine；The basic catalyst K is selected from one of following：Pyridine, triethylamine, quinoline, N, N- dimethylanilines, 4- dimethylamino pyrroles Pyridine, 4- pyrollidinopyridines or sodium carbonate.

3. method as claimed in claim 2, it is characterised in that：Compound shown in formula (III) described in step (1) and formula (II) The ratio between shown compound, amount for the substance that feeds intake of basic catalyst B are 1.0 ﹕, 0.8~1.2 ﹕ 1.0~8.0；The organic solvent A Dosage 10~50mL/g is calculated as with the quality of compound shown in formula (III)..

4. method as claimed in claim 2, it is characterised in that：The method that reaction solution isolates and purifies described in step (1) is：Instead After answering completely, solvent is evaporated off in reaction solution, concentrate is taken to be dissolved with organic solvent C, lysate is obtained, then to lysate The middle column chromatography silica gel for adding in 1.0~2.0 times of weight of concentrate, after mixing, is evaporated off solvent, dry, obtains concentrate and silica gel Mixture, mixture is filled into column, then using volume ratio as 1：0.1~10 petroleum ether is elution with ethyl acetate mixture Agent collects the efflux containing target components, is concentrated under reduced pressure, dry, obtains formula (IV) compound represented；The organic solvent C To be one of following：Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.

5. method as claimed in claim 2, it is characterised in that：In step (2), when the reducing agent E is iron powder/concentrated hydrochloric acid Or iron powder/acetic acid, formula (IV) compound represented are with iron powder, the mass ratio that feeds intake of concentrated hydrochloric acid or acetic acid in reducing agent E 1.0 ﹕, 1.0~3.0 ﹕ 0.2~1.0；When the reducing agent E be palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate, shown in formula (IV) The mass ratio that feeds intake of palladium carbon, ammonium formate or hydrazine hydrate in compound and reducing agent E is 1.0 ﹕, 0.1~0.5 ﹕ 1.0~3.0.

6. method as claimed in claim 2, it is characterised in that：Compound and chloroethene shown in formula (V) described in step (3) Acyl chlorides or chloroacetic anhydride, the ratio between the amount for the substance that feeds intake of basic catalyst F are 1 ﹕, 1.0~8.0 ﹕ 1.0~3.0；It is described organic molten The dosage of agent G is calculated as 11~100mL/g with the quality of compound shown in formula (V).

7. method as claimed in claim 2, it is characterised in that：The method of step (3) reaction solution post processing A is：It will be anti- Liquid is answered to filter, filtrate steaming removal solvent takes concentrate to be dissolved with organic solvent H, obtains lysate, then adds into lysate Enter the column chromatography silica gel of 1.0~2.0 times of weight of concentrate, after mixing, solvent is evaporated off, it is dry, obtain the mixed of concentrate and silica gel Object is closed, mixture is filled into column, then using volume ratio as 1：0.1~10 petroleum ether is eluant, eluent with ethyl acetate mixture, The efflux containing target components is collected, is concentrated under reduced pressure, it is dry, obtain formula (VI) compound represented；Under the organic solvent H is One of row：Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.

8. method as claimed in claim 2, it is characterised in that：In step (4), compound shown in the formula (VI) and 3,4- bis- Aminoanisole, the ratio between the amount for the substance that feeds intake of basic catalyst K are 1.0 ﹕, 0.8~8.0 ﹕ 1.0~8.0；The organic solvent J Dosage 10~60mL/g is calculated as with the quality of compound shown in formula (VI)；

The method of reaction solution post processing B is：After the reaction was complete, solvent is evaporated off in reaction solution, takes concentrate organic solvent M It is dissolved, obtains lysate, the column chromatography silica gel of 1.0~2.0 times of weight of concentrate, mixing are then added in into lysate Afterwards, solvent is evaporated off, it is dry, the mixture of concentrate and silica gel is obtained, mixture is filled into column, then using volume ratio as 1：0.1~ 10 petroleum ether is eluant, eluent with ethyl acetate mixture, collects the efflux containing target components, is concentrated under reduced pressure, dry, is obtained Obtain formula (I) compound represented；The organic solvent M is one of following：Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.

9. dimethoxy benzene aminoacetylamino benzo [d] azepine shown in formula (I) as described in claim 1Base quinazoline Application of the class compound in prevention or treatment human breast carcinoma drug is prepared.

10. application as claimed in claim 9, it is characterised in that the drug is with inhibition MCF-7 cell strainHJ2mm The drug of activity.