CN108295076B - Application of propionyl-amino-dimethoxy-benzo [ d ] aza-quinazoline in preparation of drugs for treating lung cancer - Google Patents
Application of propionyl-amino-dimethoxy-benzo [ d ] aza-quinazoline in preparation of drugs for treating lung cancer Download PDFInfo
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Abstract
The invention discloses propionyl amino dimethoxy benzo [ d]Aza derivatives
Description
(I) technical field
The invention relates to propionyl amino dimethoxy benzo [ d]Aza derivatives
The application of the fluoroquinazoline compound in preparing the medicine for preventing or treating human lung cancer diseases.
(II) background of the invention
The quinazoline compounds have a plurality of good biological activities and are widely applied in the field of medicine, particularly, some quinazoline derivatives with special structures have obvious antiviral activity, antibacterial activity, antitumor activity and the like, and the quinazoline compounds are marketed as antitumor drugs. For example, Gefitinib (Gefitinib) and Erlotinib (Erlotinib) are marketed for the treatment of lung cancer, and Lapatinib (Lapatinib) is marketed for the treatment of breast cancer, both of which belong to the quinazoline class of compounds. Novel quinazoline compounds and their biological activities are also commonly reported in the literature (see y. -y. ke, h. -y. shiao, y. c. hsu, c. -y. chu, w. -c. wang, y. -c. lee, w. -h. lin, c. -h. chen, j. t. a. hsu, c. -w. chang, c. -w. lin, t. -k. yeh, y. -s. chao, m.s. coumar, h. -p. hsieh, chemed chem 2013,8, 136-148; a.garofalo, a.farce, s.ravez, a.lemoine, p.six, p.vachatte, l.gos, p.depenux, j.chem. 1204, d. chem. 1189). Of course most quinazoline compounds do not have anti-tumor activity.
Disclosure of the invention
The invention aims to provide a novel quinazoline compound-propionyl-amino dimethoxy benzo [ d]Aza derivatives
The application of the quinazoline compounds in preparing medicaments for preventing or treating lung cancer has obvious inhibition rate on human lung cancer cell strain A-549 under certain dosage; the preparation method of the compound is simple and convenient, easy to operate, easily available in raw materials and low in production costLow cost and is suitable for industrial application.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides propionyl amino dimethoxy benzo [ d ] shown as a formula (I)]Aza derivatives
The application of the fluoroquinazoline compound in preparing medicaments for preventing or treating tumor diseases, in particular the application in preparing medicaments for preventing or treating human lung cancer;
preferably, the medicament is a medicament for inhibiting the activity of a human lung cancer cell strain A-549.
The invention provides propionylamino dimethoxy benzo [ d ] shown as a formula (I)]Aza derivatives
The preparation method of the fluoroquinazoline compound comprises the following steps: (1) mixing a compound shown as a formula (II) and a compound shown as a formula (III), reacting at 25-120 ℃ in an organic solvent A under the action of a basic catalyst B (TLC tracking monitoring is carried out, a developing agent is ethyl acetate/petroleum ether which is 1: 3(v/v), and preferably 40-100 ℃ for 0.5-12 h), and after the reaction is completed, separating and purifying a reaction solution to obtain a compound shown as a formula (IV); the organic solvent A is selected from one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the basic catalyst B is selected from one of the following: pyridine, diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate (preferably pyridine, diethylamine, triethylamine, N-dimethylaniline or 4-dimethylaminopyridine);
(2) dissolving the compound shown in the formula (IV) obtained in the step (1) in an organic solvent D, completely reacting at 25-100 ℃ under the action of a reducing agent E (TLC tracking monitoring, a developing agent is ethyl acetate/petroleum ether ═ 1: 1(v/v), preferably reacting at 40-80 ℃ for 0.5-12 h), filtering a reaction solution, concentrating a filtrate under reduced pressure, and drying a concentrate (preferably drying at 25 ℃ in vacuum) to obtain the compound shown in the formula (V); the organic solvent D is one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the reducing agent E is one of the following: iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium on carbon/ammonium formate or palladium on carbon/hydrazine hydrate; the iron powder/concentrated hydrochloric acid refers to the mixing of iron powder and concentrated hydrochloric acid in any proportion, the iron powder/acetic acid refers to the mixing of iron powder and acetic acid in any proportion, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate in any proportion, and the palladium carbon/hydrazine hydrate refers to the mixing of palladium carbon and hydrazine hydrate in any proportion;
(3) mixing the compound shown in the formula (V) obtained in the step (2) with propionyl chloride or propionic anhydride, reacting completely at-10-50 ℃ in an organic solvent G under the action of an alkaline catalyst F (TLC tracking monitoring, a developing agent is ethyl acetate/petroleum ether which is 1: 1(v/v), preferably reacting for 3-12 h at-10-50 ℃), and carrying out aftertreatment on a reaction solution to obtain the compound shown in the formula (I); the organic solvent G is one of the following: tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, diethyl ether, acetonitrile, toluene or benzene; the alkaline catalyst F is one of the following: pyridine, diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate;
further, in the step (1), the ratio of the amount of the compound represented by the formula (III) to the amount of the compound represented by the formula (II) and the amount of the substance charged as the basic catalyst B is 1.0: 0.8 to 1.2: 1.0 to 8.0.
Further, in the step (1), the amount of the organic solvent A is 10-50 mL/g based on the mass of the compound represented by the formula (III).
Further, the method for separating and purifying the reaction solution in the step (1) of the present invention comprises: after the reaction is completed, evaporating the solvent from the reaction solution, dissolving the concentrate with an organic solvent C to obtain a dissolved solution, adding column chromatography silica gel (preferably 300-400 mesh coarse pore (zcx.II) type column chromatography silica gel) in an amount which is 1.0-2.0 times the weight of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, packing the mixture into a column, and then mixing the mixture with the silica gel in a volume ratio of 1: taking a mixed solution of petroleum ether and ethyl acetate of 0.1-10 as an eluent, collecting an effluent containing a target component (preferably, ethyl acetate/petroleum ether is 1: 3(v/v) is taken as a developing agent for tracking detection, collecting the target component, preferably, collecting a component with an Rf value of 0.5), concentrating under reduced pressure, and drying (preferably, drying at 50 ℃) to obtain 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), the reducing agent E is palladium on carbon/ammonium formate or palladium on carbon/hydrazine hydrate, and the feeding mass ratio of the compound represented by the formula (iv) to the palladium on carbon, ammonium formate or hydrazine hydrate in the reducing agent E is 1.0: 0.1 to 0.5: 1.0 to 3.0. The mass loading amount of palladium in the palladium-carbon applicable to the invention is 2-10%, preferably 5%, and the mass concentration of hydrazine hydrate is 40-80%, preferably 80%.
Further, in the step (2), the amount of the organic solvent D is 10-50 mL/g based on the mass of the compound represented by the formula (IV).
Further, in the step (3), the ratio of the compound represented by the formula (v) to the amounts of the propionyl chloride or the propionic anhydride and the basic catalyst F to be charged is 1: 1.0 to 8.0: 1.0 to 3.0.
Further, in the step (3), the amount of the organic solvent G is 11 to 100mL/G based on the mass of the compound represented by the formula (V).
Further, the step (3) is carried out according to the following method: dropwise adding a propionyl chloride or propionic anhydride organic solvent G solution into the compound shown in the formula (V) and the alkaline catalyst F organic solvent G solution or the compound shown in the formula (V) and the alkaline catalyst F at-10 ℃, 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); the volume dosage of the organic solvent for dissolving propionyl chloride or propionic anhydride has no influence on the invention, and the total dosage of the organic solvent G is 11-100 mL/G based on the mass of the compound shown in the formula (V). The total amount of the organic solvent G is the total volume of the organic solvent G in which the basic catalyst F and the compound represented by the formula (V) are dissolved and the organic solvent G in which propionyl chloride or propionic anhydride is dissolved.
Further, the post-treatment method of the reaction solution in the step (3) of the present invention comprises: filtering the reaction solution, evaporating the solvent from the filtrate, dissolving the concentrate 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) in an amount which is 1.0-2.0 times the weight of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, packing the mixture into a column, and then mixing the mixture with the silica gel in a volume ratio of 1: taking a mixed solution of petroleum ether and ethyl acetate of 0.1-10 as an eluent, collecting an effluent containing a target component (preferably, ethyl acetate/petroleum ether is 1: 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.
The invention has the following beneficial effects: provides the application of a novel quinazoline compound in preparing a medicament for preventing or treating human lung cancer, and the compound has obvious inhibitory activity on a human lung cancer cell strain A-549.
(IV) detailed description of the preferred embodiments
The invention is further illustrated by reference to specific examples, which are intended to illustrate the invention, but not to limit it in any way. The compound (II) can be prepared by the method described in Weinstock, J.et al.J.Med.chem.,1986, 29(11), 2315-2325. 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: nitrobenzo [ d]Aza derivatives
Preparation of the quinazolines (IV)
Sequentially adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 2.39 g (6.87mmol) of compound (II), 3.62 g (45.76mmol) of pyridine and 12 ml of chloroform into a 50ml reaction bottle, heating to 40 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for 10 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 10 ml of ethyl acetate into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 3.0 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of a dried concentrate and the silica gel, filling the mixture into a column, and then performing column chromatography by using a volume ratio of 1: eluting with a mixed solution of petroleum ether and ethyl acetate as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 85.1%, and the melting point is 164-166 ℃.1H NMR(500MHz,CDCl3)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。
Example 2: nitrobenzo [ d]Aza derivatives
Preparation of the quinazolines (IV)
Sequentially adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 1.59 g (4.57mmol) of compound (II), 1.67 g (22.83mmol) of diethylamine and 60 ml of toluene into a 100ml three-neck flask, heating to 100 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for 2 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of ethanol into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 2.5 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography by using a volume ratio of 1: eluting with a petroleum ether/ethyl acetate mixed solution of 5 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 72.6%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 3: nitrobenzo [ d]Aza derivatives
Preparation of the quinazolines (IV)
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 in sequence, 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 (300.73 mmol) into the dissolved solutionAbout 400 mesh column chromatography silica gel), mixing uniformly, evaporating the solvent to obtain a mixture of a dry concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture by a volume ratio of 10: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 77.2%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 4: nitrobenzo [ d]Aza derivatives
Preparation of the quinazolines (IV)
Adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 2.20 g (6.32mmol) of compound (II), 1.40 g (11.46mmol) of 4-dimethylaminopyridine and 60 ml of isopropanol into a 100ml three-neck flask, stirring at room temperature and 25 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether ═ 1: 3(v/v)), reacting for 12 hours, closing the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of tetrahydrofuran into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 4.0 g of column chromatography silica gel (300-400 mesh silica gel) into the dissolved solution, mixing uniformly, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography on the mixture in a volume ratio of 5: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 80.2%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 5: nitrobenzo [ d]Aza derivatives
Preparation of the quinazolines (IV)
1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 1.79 g in this orderAdding 1.04 g (5.15mmol) of the 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 (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring and reacting for 0.5 hour, closing the reaction, evaporating the reaction solution to remove the solvent, adding 20 ml of tetrahydrofuran into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 5.0 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating to remove the solvent to obtain a mixture of a dried concentrate and the silica gel, filling the mixture into a column, and then performing column chromatography according to a volume ratio of 1: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 89.6%, and the melting point is 164-166 ℃.1HNMR and IR were the same as in example 1.
Example 6: nitrobenzo [ d]Aza derivatives
Preparation of the quinazolines (IV)
Adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 2.39 g (6.87mmol) of compound (II), 3.62 g (45.76mmol) of pyridine and 20 ml of propanol into a 50ml reaction bottle, heating to 40 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for 10 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of ethyl acetate into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 3.5 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography by using a volume ratio of 1: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, tracking and detecting by TLC (ethyl acetate/petroleum ether is 1: 3(v/v)) to collect eluate containing compound shown in formula (IV) (Rf value is 0.5) according to TLC detection, concentrating the collected solution, drying at 50 deg.C to obtain light yellow solid product shown in formula (IV) with yield of 78.3%,the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 7: aminobenzo [ d ] s]Aza derivatives
Preparation of the quinazolines (V)
0.40 g (0.77mmol) of nitrobenzo [ d ] prepared by the method of example 1 are successively introduced]Aza derivatives
The phenyl quinazoline (IV), 0.40 g (6.34mmol) ammonium formate, 0.04 g 5% Pd/C, 4.0 ml chloroform into a reaction bottle, stirring at room temperature of 25 ℃, detecting by TLC (a developing agent is ethyl acetate/petroleum ether-1: 1(v/v)), reacting for 12 hours, filtering, concentrating the filtrate, and drying in vacuum at 25 ℃ to obtain a light yellow solid product aminobenzo [ d]Aza derivatives
The yield of the quinazoline (V) is 98.2 percent, and the melting point is 122-126 ℃.1H NMR(500MHz,CDCl3)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。
Example 8: aminobenzo [ d ] s]Aza derivatives
Preparation of the quinazolines (V)
0.40 g (0.77mmol) of nitrobenzo [ d ] prepared by the method of example 2 are successively introduced]Aza derivatives
The quinazoline (IV), 1.20 g (19.18mmol)80 wt% hydrazine hydrate, 0.20 g 5% Pd/C, 20.0 ml toluene were added to a 50ml reaction flask, heated to 100 deg.C, and monitored by TLC (developing solvent ethyl acetate/petroleum)Ether 1: 1(v/v)), stirring for reaction for 0.5 hour, cooling, filtering, concentrating the filtrate, and vacuum drying at 25 ℃ to obtain a light yellow solid product aminobenzo [ d]Aza derivatives
The yield of the quinazoline (V) is 100.0 percent, and the melting point is 122-126 ℃.1H NMR and IR were the same as in example 7.
Example 9: aminobenzo [ d ] s]Aza derivatives
Preparation of the quinazolines (V)
0.40 g (0.77mmol) of nitrobenzo [ d ] prepared by the method of example 3 are successively reacted]Aza derivatives
Adding 0.08 g of concentrated hydrochloric acid (mass concentration is 36-38%), 0.40 g of iron powder and 20.0 ml of methanol into a 50ml reaction bottle, heating to 40 ℃, carrying out TLC tracking detection (ethyl acetate/petroleum ether is used as a developing agent: 1(v/v)), stirring for 8 hours, cooling, filtering, concentrating the filtrate, and carrying out vacuum drying at 25 ℃ to obtain a light yellow solid product aminobenzo [ d]Aza derivatives
The yield of the quinazoline (V) is 94.1 percent, and the melting point is 122-126 ℃.1HNMR and IR were the same as in example 7.
Example 10: aminobenzo [ d ] s]Aza derivatives
Preparation of the quinazolines (V)
0.40 g (0.77mmol) of nitrobenzo [ d ] prepared by the method of example 4 are successively reacted]Aza derivatives
The quinazoline (IV), 0.40 g acetic acid, 1.20 g iron powder and 20.0 ml isopropanol are added into a 50ml reaction bottle, heated to 80 ℃, detected by TLC (a developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), and stirred and reactedCooling and filtering the mixture for 3 hours, concentrating the filtrate, and drying the concentrated filtrate in vacuum at 25 ℃ to obtain a light yellow solid product, namely aminobenzo [ d]Aza derivatives
The yield of the quinazoline (V) is 97.5 percent, and the melting point is 122-126 ℃.1H NMR and IR were the same as in example 7.
Example 11: propionyl amino dimethoxy benzo [ d]Aza derivatives
Preparation of a quiazoline (I)
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 7 are successively reacted]Aza derivatives
Adding 0.13 g (1.64mmol) of pyridine and 3 ml of tetrahydrofuran into a reaction bottle, dropwise adding 0.407 g (4.40mmol) of propionyl chloride under the condition of stirring at 10 ℃, after dropwise adding, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1), reacting for 12 hours at 10 ℃, filtering, evaporating the solvent from the filtrate, adding 10 ml of ethyl acetate into the concentrate, dissolving the concentrate to obtain a dissolved solution, adding 0.60 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, loading the mixture into a column, and then performing column chromatography by using a volume ratio of 1: eluting with 10 mixed solution of petroleum ether and ethyl acetate as eluent, detecting by TLC (developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting eluate containing compound shown in formula (I) (Rf value is 0.5) according to TLC detection, concentrating the collected solution, and drying at 50 deg.C to obtain propionylaminodimethoxybenzo [ d ] shown in formula (I)]Aza derivatives
The quinazoline is an off-white solid, the yield is 63.2%, and the melting point is 125-129 ℃.1H NMR(500MHz,CDCl3)δ:1.30(t,J＝7.6Hz,3H),2.44-2.53(m,2H),3.26-3.32(m,1H),3.57–3.49(m,1H),3.75(s,3H),3.76-3.82(m,7H),3.95-4.06(m,2H),4.64(dd,J＝8.2,14.3Hz,1H),5.27(t,J＝8.6Hz,1H),6.69(s,1H),6.88(d,J＝8.7Hz,2H),7.08(d,J＝8.6Hz,2H),7.44-7.48(m,2H),7.78(d,J＝8.9Hz,1H),8.57(s,1H),8.72(s,1H)。HRMS-ESI m/z:547.2107[M+H]+。IR(KBr,cm-1)ν:2936,2831,1690,1557,1523,1511,1460,1351,1247,1037,840。
Example 12: propionyl amino dimethoxy benzo [ d]Aza derivatives
Preparation of a quiazoline (I)
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 8 are successively reacted]Aza derivatives
Adding 0.04 g (0.55mmol) of diethylamine and 10.0 ml of chloroform into a 50ml reaction bottle, dropwise adding a mixed solution of 0.051 g (0.55mmol) of propionyl chloride and 5.0 ml of chloroform under the condition of stirring at 10 ℃, carrying out TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), reacting for 8 hours at 10 ℃, filtering, evaporating the filtrate to remove the solvent, dissolving the concentrate in 20 ml of ethanol to obtain a dissolved solution, adding 0.26 g of column chromatography silica gel (300-400 mesh silica gel column chromatography) into the dissolved solution, mixing uniformly, evaporating to remove the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then filling the mixture in a volume ratio of 1: eluting with petroleum ether/ethyl acetate mixed solution of 5 as eluent, detecting by TLC (developing solvent is ethyl acetate/petroleum ether ═ 1: 1(v/v)), collecting eluate containing compound shown in formula (I) (Rf value is 0.5) according to TLC detection, concentrating the collected solution, and drying at 50 deg.C to obtain propionylaminodimethoxybenzo [ d ] shown in formula (I)]Aza derivatives
The quinazoline is an off-white solid, the yield is 62.0%, and the melting point is 125-129 ℃.1H NMR and IR were the same as in example 11.
Example 13: propionyl amino dimethoxy benzo [ d]Aza derivatives
Preparation of a quiazoline (I)
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 9 are successively reacted]Aza derivatives
Adding 0.111 g (1.10mmol) of triethylamine and 10.0 ml of ethyl acetate into a 50ml reaction bottle, dropwise adding 0.102 g (1.10mmol) of propionyl chloride and 5.0 ml of ethyl acetate solution under the condition of stirring at 0 ℃, after dropwise adding, performing TLC tracking detection (ethyl acetate/petroleum ether is used as a developing agent), reacting for 6 hours at 25 ℃, filtering, evaporating the filtrate to remove the solvent, adding 20 ml of chloroform into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.30 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating to remove the solvent to obtain a mixture of dried concentrate and silica gel, loading the mixture into a column, and then performing volume ratio of 10: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, detecting by TLC (developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting eluate containing compound shown in formula (I) (Rf value is 0.5) according to TLC detection, concentrating the collected solution, and drying at 50 deg.C to obtain propionylaminodimethoxybenzo [ d ] shown in formula (I)]Aza derivatives
The quinazoline is an off-white solid, the yield is 58.8%, and the melting point is 125-129 ℃.1H NMR and IR were the same as in example 11.
Example 14: propionyl amino dimethoxy benzo [ d]Aza derivatives
Preparation of a quiazoline (I)
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 10 are successively reacted]Aza derivatives
3.067 g (0.55mmol) of 4-dimethylaminopyridine and 20.0 ml of toluene were added to a 50ml reaction flask, and 0.286 g (2.20mmol) of propionic anhydride and 7.0 ml of toluene were added dropwise with stirring at 5 deg.CAfter the solution of toluene is dripped, heating to 50 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1), reacting for 3 hours, filtering, evaporating a filtrate to remove a solvent, adding 20 ml of tetrahydrofuran into a concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.40 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating to remove the solvent to obtain a mixture of a dried concentrate and the silica gel, filling the mixture into a column, and then performing TLC tracking detection on the mixture according to a volume ratio of 5: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, detecting by TLC (developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting eluate containing compound shown in formula (I) (Rf value is 0.5) according to TLC detection, concentrating the collected solution, and drying at 50 deg.C to obtain propionylaminodimethoxybenzo [ d ] shown in formula (I)]Aza derivatives
The quinazoline is an off-white solid, and the yield is 54.5%, and the melting point is 125-129 ℃.1HNMR and IR were the same as in example 11.
Example 15: propionyl amino dimethoxy benzo [ d]Aza derivatives
Preparation of a quiazoline (I)
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 7 are successively reacted]Aza derivatives
Adding 0.213 g (1.65mmol) of quinoline and 15.0 ml of benzene into a 50ml reaction bottle, dropwise adding a solution of 0.204 g (2.20mmol) of propionyl chloride and 5.0 ml of benzene under the stirring condition at-10 ℃, after finishing dropping, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1), reacting for 12 hours at 10 ℃, filtering, evaporating the filtrate to remove the solvent, adding 20 ml of tetrahydrofuran into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.40 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, mixing uniformly, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, loading the mixture into a column, and then performing column chromatography by using a volume ratio of 1: 1 petroleum ether/ethyl acetate mixed solution is used as eluent,eluting, detecting by TLC (ethyl acetate/petroleum ether as developing solvent) 1: 1(v/v)), collecting eluate containing compound shown in formula (I) (Rf value is 0.5) according to TLC detection, concentrating the collected solution, and drying at 50 deg.C to obtain propionylaminodimethoxybenzo [ d ] shown in formula (I)]Aza derivatives
The quinazoline is an off-white solid, the yield is 72.1%, and the melting point is 125-129 ℃.1H NMR and IR were the same as in example 11.
Example 16: propionyl amino dimethoxy benzo [ d]Aza derivatives
Preparation of a quiazoline (I)
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 7 are successively reacted]Aza derivatives
Adding 0.164 g (1.10mmol) of 4-pyrrolidinyl pyridine and 15.0 ml of dichloromethane into a 50ml reaction bottle, dropwise adding 0.102 g (1.10mmol) of propionyl chloride and 5.0 ml of dichloromethane solution under the condition of stirring at 10 ℃, carrying out TLC tracking detection (ethyl acetate/petroleum ether is used as a developing agent, reacting for 8 hours at 10 ℃, filtering, evaporating the filtrate to remove the solvent, adding 20 ml of ethanol into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.50 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, mixing uniformly, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, loading the mixture into a column, and then carrying out reaction in a volume ratio of 10: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, detecting by TLC (developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting eluate containing compound shown in formula (I) (Rf value is 0.5) according to TLC detection, concentrating the collected solution, and drying at 50 deg.C to obtain propionylaminodimethoxybenzo [ d ] shown in formula (I)]Aza derivatives
The quinazoline is an off-white solid, the yield is 57.8%, and the melting point is 125-129 ℃.1H NMR and IR were the same as in example 11.
Example 17: in vitro test for anti-cancer Activity
(1) The prepared compounds (I) and (IV) are subjected to a biological activity test of a human lung cancer cell strain A-549.
The test method comprises the following steps: tetrazolium salt reduction (MTT process).
Cell lines: human lung cancer cell strain A-549. The tumor cell strain is purchased from cell banks of Shanghai Life sciences of Chinese academy of sciences.
The experimental procedure was as follows:
(a) preparation of samples: for soluble samples, each 1mg was dissolved in 40. mu.L DMSO, 2. mu.L was diluted with 1000. mu.L of medium to a concentration of 100. mu.g/mL, and then serially diluted with the culture medium to the use concentration.
(b) Culture of cells
① preparation of culture Medium Each 1000mL of DMEM medium (Gibco) contained 80 million units of penicillin, 1.0g of streptomycin, and 10% inactivated fetal bovine serum.
② cultivation of cells, inoculating tumor cells into culture medium, standing at 37 deg.C and 5% CO2Culturing in an incubator, and carrying out passage for 3-5 days.
③ determination of the inhibitory Effect of a sample on tumor cell growth
The 10 th generation cells were digested with EDTA-pancreatin and diluted to 1X 10 with medium6Perml, 100. mu.L/well in 96-well cell culture plates, 37 ℃ 5% CO2Culturing in an incubator. After 24h of inoculation, 100. mu.L of 100. mu.L/well, 10. mu.g/mL and 1. mu.g/mL samples diluted with medium were added to each well at 3 concentrations, and the mixture was incubated at 37 ℃ with 5% CO2The culture was performed in an incubator, 5mg/mL MTT was added to the cell culture wells after 72h, 10. mu.L per well, incubated at 37 ℃ for 3h, DMSO was added, 150. mu.L per well, shaken with a shaker, and formazan was completely solubilized and colorimetric with a microplate reader at a wavelength of 570 nm. Using cells cultured in the same DMSO concentration medium without sample under the same conditions as a control, the IC of the sample on tumor cell growth was calculated50。
The results of the test are shown in table 1:
TABLE 1 inhibitory Effect of Compounds (I) and (IV) on the growth of cancer cell line A-549
(2) The quinazoline compounds (a), (b) and (c) were synthesized according to example 11 by substituting propionyl chloride with 4-iodobenzoyl chloride, 3-methoxybenzoyl chloride or cinnamoyl chloride, respectively, and otherwise performing the same procedures as in example 11, and the structures thereof were as follows:
the prepared quinazoline compounds (a), (b) and (c) are subjected to a biological activity test of a human lung cancer cell strain A-549 according to the method, and test results show that the quinazoline compounds (a), (b) and (c) have no obvious inhibition effect on the human lung cancer cell strain A-549, and the compounds (a), (b) and (c) have far lower anti-cancer activity than the compound (I) on the human lung cancer cell strain A-549. The specific results are shown in table 2:
TABLE 2 inhibitory Effect of Compounds (a), (b) and (c) on the growth of cancer cell line A-549
The anti-cancer activity in vitro test experiment shows that: the other 3 compounds (a), (b) and (c) with similar structures have no obvious inhibition effect on the growth of the human lung cancer cell strain A-549. The compound (I) has obvious inhibition effect on the growth of a human lung cancer cell strain A-549, and is obviously superior to the compounds (a), (b) and (c).
(3) 4-chloroquinazoline was prepared according to the method of the reference (Rao, G. -W.et al. ChemMedChem,2013,8(6),928-933), 4-chloro-6-nitroquinazoline was substituted with 4-chloroquinazoline according to example 1, and the quinazoline compound (d) was synthesized according to the same procedure as in example 1, and the structure thereof is as follows:
the prepared quinazoline compound (d) is subjected to a biological activity test of a human lung cancer cell strain A-549 according to the method, and a test result shows that the anticancer activity of the quinazoline compound (d) on the human lung cancer cell strain A-549 is far lower than that of the compound (I). Specific results are shown in table 3:
TABLE 3 inhibitory Effect of Compound (d) on the growth of cancer cell line A-549
(4) Quinazoline compounds (e), (g) and (h) were synthesized according to example 11 by substituting propionyl chloride with benzoyl chloride, chloroacetyl chloride or isobutyryl chloride, respectively, and following the same procedure as in example 11, respectively, and have the following structures:
the prepared quinazoline compounds (e), (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), (g) and (h) have inferior anticancer activity to the human lung cancer cell strain A-549 than the compound (I). Specific results are shown in table 4:
TABLE 4 inhibitory Effect of Compounds (e), (g) and (h) on the growth of cancer cell line A-549
Claims (2)
1. Propionyl amino dimethoxy benzo [ d ] shown in formula (I)]Aza derivatives
The application of the fluoroquinazoline compound in preparing the medicaments for preventing or treating the lung cancer of the human body;
2. the use of claim 1, wherein: the medicine is a medicine with the activity of inhibiting a human lung cancer cell strain A-549.
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