CN103254143B - 4-[4-(2-diethylin kharophen) anilino]-6-substituted quinazoline compounds and Synthesis and applications - Google Patents

Abstract

The invention discloses a 4-[4-(2-diethylaminoacetamido)anilino]-6-(substituted methoxy)formamidoquinazoline compound and its preparation and application. The compound has The following general structural formula (I), in the general structural formula (I), R is isopropyl or cyclohexyl. The 4-[4-(2-diethylaminoacetamido)anilino]-6-(substituted methoxy)formamidoquinazoline compounds of the present invention can be used for the preparation of prevention or treatment of human lung cancer or human breast cancer Drugs for diseases with good anticancer activity.

Description

4-[4-(2-Diethylaminoacetamido)anilino]-6-substituted quinazoline compounds and their preparation and application

(1) Technical field

The present invention relates to 4-[4-(2-diethylaminoacetamido)anilino]-6-(substituted methoxy)formamidoquinazoline compounds——4-[4-(2-diethylamino Acetylamino)anilino]-6-isobutoxycarboxamidoquinazoline and 4-[4-(2-diethylaminoacetamido)anilino]-6-cyclohexylmethoxycarboxamidoquinazoline Phenoline and its preparation method, and the application of the two compounds in the preparation of drugs 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 4-anilinoquinazolines compound. 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 kind of novel 4-[4-(2-diethylaminoacetamido) anilino base]-6-(substituted methoxy) formamidoquinazoline compound and its anticancer activity Preparation method and application, this type of compound has a good inhibitory rate on human lung cancer cell line A-549 or human breast cancer cell line MCF-7 at a certain dose; and the preparation method of this type of compound is simple, easy to operate, and the raw materials are easy to obtain , and the production cost is low, suitable for industrial application.

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

The present invention provides a kind of 4-[4-(2-diethylaminoacetamido)anilino]-6-(substituted methoxy)formamidoquinazoline compound, which has the following general structural formula (I) :

In the general structural formula (I), R is isopropyl or cyclohexyl.

The present invention also provides two intermediates for the preparation of the 4-[4-(2-diethylaminoacetamido)anilino]-6-(substituted methoxy)formamidoquinazoline compounds, namely the structure 4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazoline as shown in formula (IV) and 4-[4-(2) as shown in formula (Ⅴ) -Diethylaminoacetamido)anilino]-6-aminoquinazoline:

The invention provides a method for preparing the 4-[4-(2-diethylaminoacetamido)anilino]-6-(substituted methoxy)formamidoquinazoline compounds, the preparation Methods include:

(1) 2-diethylamino-N-(4-aminophenyl) acetamide shown in formula (II) and 4-chloro-6-nitroquinazoline shown in formula (Ⅲ) in organic solvent A1 4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazoline is reacted under the effect of basic catalyst B1 to prepare formula (IV); the basic Catalyst B1 is selected from one of the following: pyridine, diethylamine, triethylamine, quinoline, N,N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate; the organic solvent A1 is selected from one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N,N-dimethylformamide;

(2) 4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazoline shown in formula (Ⅳ) is reacted under the action of reducing agent B2 in organic solvent A2 to prepare the formula (Ⅴ) 4-[4-(2-diethylaminoacetamido)anilino]-6-aminoquinazoline; the reducing agent B2 is one of the following: iron powder/concentrated hydrochloric acid, iron powder/ Acetic acid, palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate; the organic solvent A2 is one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N,N-dimethylformyl ;

(3) 4-[4-(2-diethylaminoacetamido)anilino]-6-aminoquinazoline shown in formula (Ⅴ) and isobutyl chloroformate or cyclohexylmethyl chloroformate in an organic solvent In A3, 4-[4-(2-diethylaminoacetamido)anilino]-6-(substituted methoxy)formylaminoquinazoles shown in formula (I) are reacted under the action of basic catalyst B3 Phenyl compounds; the basic catalyst B3 is one of the following: pyridine, diethylamine, triethylamine, quinoline, N,N-xylidine, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate; the organic solvent A3 is one of the following: THF, methylene chloride, chloroform, ethyl acetate, ether, acetonitrile, toluene or benzene;

In the formula (I), R is isopropyl or cyclohexyl.

In step (1) of the present invention, the organic solvent A1 is preferably one of the following: chloroform, toluene, methanol or isopropanol. The indicated basic catalyst B1 is preferably one of the following: pyridine, diethylamine, triethylamine or 4-dimethylaminopyridine. The molar ratio of the 4-chloro-6-nitroquinazoline, 2-diethylamino-N-(4-aminophenyl)acetamide and basic catalyst B1 is 1.0:0.8～1.2:1.0～8.0 , the amount of the organic solvent A1 is 10-50 mL/g based on the mass of 4-chloro-6-nitroquinazoline (III). The reaction in step (1) is carried out at a temperature of 25-120°C, preferably at a temperature of 40-100°C, and the end point of the reaction can be monitored by methods such as TLC, and the reaction time is generally 0.5-12 hours.

The present invention specifically recommends that the step (1) be carried out as follows: combine 2-diethylamino-N-(4-aminophenyl)acetamide shown in formula (II) with 4-chloro -6-nitroquinazoline is reacted at 25-120°C under the action of basic catalyst B1 in organic solvent A1, after the reaction is completed, it is allowed to stand overnight, filtered and dried to obtain 4- [4-(2-Diethylaminoacetamido)anilino]-6-nitroquinazoline.

In step (2) of the present invention, the organic solvent A2 is preferably one of the following: chloroform, toluene, methanol or isopropanol. In step (2), when the reducing agent B2 is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, 4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazole The mass ratio of morphine (IV) to iron powder, concentrated hydrochloric acid or acetic acid in reducing agent B2 is 1.0:1.0～3.0:0.2～1.0; when the reducing agent B2 is palladium carbon/ammonium formate or palladium carbon/hydration In the case of hydrazine, the mass ratio of 4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazoline (Ⅳ) to palladium carbon, ammonium formate or hydrazine hydrate in reducing agent B2 is 1.0: 0.1～0.5: 1.0～3.0, the amount of the organic solvent A2 is calculated as 10～50mL/g. The reaction in step (2) is carried out at a temperature of 25-100°C, preferably at a temperature of 40-80°C. The end point of the reaction can be monitored by TLC and other methods, and the reaction time is generally 0.5-12 hours.

The present invention specifically recommends that step (2) be carried out as follows: 4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazoline shown in formula (IV), reducing agent B2 is added to the organic solvent A2, fully reacted at 25-100°C, filtered, the filtrate is concentrated to precipitate a solid, filtered, and dried to obtain 4-[4-(2-diethylaminoacetamido)anilino represented by formula (Ⅴ) ]-6-aminoquinazoline.

In step (3) of the present invention, the organic solvent A3 is preferably one of the following: tetrahydrofuran, chloroform, ethyl acetate or toluene. The basic catalyst B3 is preferably one of the following: pyridine, diethylamine, triethylamine or 4-dimethylaminopyridine. Feeding of the 4-[4-(2-diethylaminoacetamido)anilino]-6-aminoquinazoline (V), isobutyl chloroformate or cyclohexylmethyl chloroformate, basic catalyst B3 The molar ratio is 1:1.0～8.0:1.0～3.0, the amount of the organic solvent A3 is based on the mass of 4-[4-(2-diethylaminoacetamido)anilino]-6-aminoquinazoline (V) Calculated as 10-95mL/g. The reaction in step (3) is carried out at a temperature of -10-50° C., and the end point of the reaction can be monitored by methods such as TLC. The reaction time is generally 3-12 hours.

The present invention specifically recommends that the step (3) be carried out as follows: 4-[4-(2-diethylaminoacetamido)anilino]-6-aminoquinazoline shown in formula (Ⅴ), basic catalyst Add B3 to the organic solvent A3, and add dropwise the organic solvent A3 solution of isobutyl chloroformate or cyclohexyl methyl chloroformate at -10 to 10°C, and react at -10 to 50°C for 3 to 12 hours. Filtration, the filtrate was evaporated to remove the solvent, and the residue column chromatography obtained the corresponding 4-[4-(2-diethylaminoacetamido)anilino]-6-(substituted methoxy)formamidoquinazoline compounds ( I).

The residue column chromatography described in the step (3) of the present invention can be carried out as follows: take the residue after the solvent has been evaporated and put it in a one-necked bottle, add an organic solvent C to dissolve it, obtain a solution, and then add the solution to the solution Add 1.0 to 2.0 times the amount of the residue mass of column chromatography silica gel, mix well, evaporate the solvent to obtain a mixture of dry residue and silica gel, put the mixture on the column, and then use the volume ratio of 1:12 to 0 (1:12, 1:8, 1:4, 1:2, 1:1, 1:0) mixed solution of ethyl acetate and petroleum ether as the eluent, gradient elution, and the collected eluent is ethyl acetate Fraction of ester/petroleum ether (1:4, 1:2, 1:1 or 1:0), the collected solution was concentrated and dried to obtain 4-[4-(2-diethylaminoacetyl) represented by formula (I) Amino)anilino]-6-(substituted methoxy)formamidoquinazolines. The organic solvent C is one of the following: ethanol, chloroform, tetrahydrofuran or ethyl acetate.

The 4-[4-(2-diethylaminoacetamido)anilino]-6-(substituted methoxy)formamidoquinazoline compound (I) of the present invention can be applied to the preparation of tumor prevention or treatment Medicines for diseases, especially for the preparation of medicines for preventing or treating human lung cancer or human breast cancer. The compound provided by the invention has good inhibitory rate to human lung cancer cell line A-549 or human breast cancer cell line MCF-7. Effects of 4-[4-(2-diethylaminoacetamido)anilino]-6-isobutoxycarboxamidoquinazoline (Ⅰ-1) on human lung cancer cell line A-549 and human breast cancer cell line MCF The _IC50s of -7 were 16.9 μM and 7.83 μM, respectively. Effects of 4-[4-(2-diethylaminoacetamido)anilino]-6-cyclohexylmethoxycarboxamidoquinazoline (Ⅰ-2) on human lung cancer cell line A-549 and human breast cancer cell line The IC ₅₀ of MCF-7 were 5.38 μM and 4.18 μM, respectively.

The beneficial effects of the present invention are mainly reflected in: (1) 4-[4-(2-diethylaminoacetamido)anilino]-6-(substituted methoxy)formamidoquinazolines of the present invention 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; (2) the 4-[4-(2-diethylaminoacetamido) of the present invention provided by the present invention The preparation method of anilino]-6-(substituted methoxy)formamidoquinazoline compound (I) is simple and easy to operate, the raw materials are readily available, and the production cost is relatively low, which 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.

References for the preparation of 4-chloro-6-nitroquinazoline (Ⅲ) (C.Fernandes, C.Oliveira, L.Gano, A.Bourkoula, I.Pirmettis, I.Santos, Bioorg.Med.Chem.2007 , 15,3974-3980) prepared by the method. 2-diethylamino-N-(4-aminophenyl) acetamide (Ⅱ) is prepared according to the following reaction scheme (a) with reference to literature (A.D.Moorhouse, A.M.Santos, M.Gunaratnam, M.Moore, S.Neidle, J.E.Moses, J.Am.Chem.Soc.2006,128,15972-15973) method prepared,

Embodiment 1: Preparation of 2-diethylamino-N-(4-aminophenyl)acetamide (Ⅱ)

(1) Add 5.00 g (23.30 mmol) of the compound 2-chloro-N-(4-nitrophenyl) acetamide, 30.0 ml of absolute ethanol, and 4.50 g (61.53 mmol) of diethylamine to 100 ml of three ports In the flask, heated to 50°C for 20 h, evaporated the reaction solution to dryness, dissolved ethyl acetate and washed with water, dried the organic phase over anhydrous magnesium sulfate, concentrated to obtain 2.95 g of light yellow product 2-(diethylamino)-N- (4-nitrophenyl) acetamide, yield 50.4%. IR (film): v=3205, 2968, 1694 cm ^-1 .

(2) Compound 2-(diethylamino)-N-(4-nitrophenyl)acetamide 2.80g (11.14mmol), anhydrous methanol 30.0ml, ammonium formate 4.20g (66.60mmol), 5% Add 0.28 g of Pd/C into a 100 ml three-neck flask, heat to 50°C for 4 hours, evaporate the reaction liquid to dryness, dissolve ethyl acetate and wash with water, dry the organic phase with anhydrous magnesium sulfate, and concentrate to obtain 2.15 g of a brown product 2-Diethylamino-N-(4-aminophenyl)acetamide (Ⅱ), yield 87.2%. IR (film): v=3334, 2968, 1663 cm ^-1 .

Example 2: Preparation of 4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazoline (IV)

1.20 grams (5.73 mmol) of 4-chloro-6-nitroquinazoline (Ⅲ) and 1.52 grams (6.87 mmol) of 2-diethylamino-N-(4-aminophenyl) acetamide (Ⅱ) were successively added, Add 3.62 g (45.76 mmol) of pyridine and 60 ml of chloroform into a 100 ml three-neck flask, heat to 40°C, perform TLC tracking detection (developing solvent is ethyl acetate/petroleum ether = 1:1), stir for 10 hours, and close the reaction , left to stand overnight, filtered, and dried to obtain 1.89 grams of 4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazoline yellow solid shown in formula (IV), yield 83.7% , melting point 235 ~ 238 ℃. ¹ H NMR(500MHz,[D6]DMSO):δ=1.05(t,J=7.1Hz,6H),2.63(q,J=7.1Hz,4H),3.17(s,2H),7.70-7.71(m ,2H),7.77(d,J=9.0Hz,2H),7.93(d,J=9.2Hz,1H),8.56(dd,J=2.4,9.2Hz,1H),8.69(s,1H),9.67 (d,J=2.5Hz,1H),9.69(s,1H),10.45ppm(s,1H);IR(KBr):v=3308,3209,2971,2938,1661,1628,1604,675cm ^-1 .

Example 3: Preparation of 4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazoline (IV)

1.20 grams (5.73 mmol) of 4-chloro-6-nitroquinazoline (Ⅲ) and 1.01 grams (4.56 mmol) of 2-diethylamino-N-(4-aminophenyl) acetamide (Ⅱ) were added successively, Add 1.67 g (22.83 mmol) of diethylamine and 60 ml of toluene into a 100 ml three-neck flask, heat to 100 degrees, and perform TLC tracking detection (developing solvent: ethyl acetate/petroleum ether = 1:1), and stir for 2 hours. Close the reaction, let it stand overnight, filter, and dry to obtain 1.22 grams of 4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazoline yellow solid shown in formula (IV). 67.8%, melting point 235-238°C. ¹ H NMR(500MHz,[D6]DMSO):δ=1.05(t,J=7.1Hz,6H),2.63(q,J=7.1Hz,4H),3.17(s,2H),7.70-7.71(m ,2H),7.77(d,J=9.0Hz,2H),7.93(d,J=9.2Hz,1H),8.56(dd,J=2.4,9.2Hz,1H),8.69(s,1H),9.67 (d,J=2.5Hz,1H),9.69(s,1H),10.45ppm(s,1H);IR(KBr):v=3308,3209,2971,2938,1661,1628,1604,675cm ^-1 .

Example 4: Preparation of 4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazoline (IV)

1.20 grams (5.73 mmol) of 4-chloro-6-nitroquinazoline (Ⅲ) and 1.27 grams (5.74 mmol) of 2-diethylamino-N-(4-aminophenyl) acetamide (Ⅱ) were added successively, Add 0.58 g (5.73 mmol) of triethylamine and 60 ml of methanol into a 100 ml three-neck flask, heat to 60°C, perform TLC tracking detection (developing solvent is ethyl acetate/petroleum ether = 1:1), and stir for 8 hours. Close the reaction, let it stand overnight, filter, and dry to obtain 1.65 grams of 4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazoline yellow solid shown in formula (IV). 73.1%, melting point 235-238°C. ¹ H NMR(500MHz,[D6]DMSO):δ=1.05(t,J=7.1Hz,6H),2.63(q,J=7.1Hz,4H),3.17(s,2H),7.70-7.71(m ,2H),7.77(d,J=9.0Hz,2H),7.93(d,J=9.2Hz,1H),8.56(dd,J=2.4,9.2Hz,1H),8.69(s,1H),9.67 (d,J=2.5Hz,1H),9.69(s,1H),10.45ppm(s,1H);IR(KBr):v=3308,3209,2971,2938,1661,1628,1604,675cm ^-1 .

Example 5: Preparation of 4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazoline (IV)

1.20 grams (5.73 mmol) of 4-chloro-6-nitroquinazoline (Ⅲ) and 1.40 grams (6.33 mmol) of 2-diethylamino-N-(4-aminophenyl) acetamide (Ⅱ) were successively added, Add 1.40 g (11.46 mmol) of 4-dimethylaminopyridine and 60 ml of isopropanol into a 100 ml three-neck flask, stir at room temperature at 25 degrees, and perform TLC tracking detection (developing solvent: ethyl acetate/petroleum ether = 1:1), Reacted for 12 hours, closed the reaction, stood overnight, filtered, and dried to obtain 4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazoline yellow solid 1.75 grams, the yield is 77.5%, and the melting point is 235-238°C. ¹ H NMR(500MHz,[D6]DMSO):δ=1.05(t,J=7.1Hz,6H),2.63(q,J=7.1Hz,4H),3.17(s,2H),7.70-7.71(m ,2H),7.77(d,J=9.0Hz,2H),7.93(d,J=9.2Hz,1H),8.56(dd,J=2.4,9.2Hz,1H),8.69(s,1H),9.67 (d,J=2.5Hz,1H),9.69(s,1H),10.45ppm(s,1H);IR(KBr):v=3308,3209,2971,2938,1661,1628,1604,675cm ^-1 .

Example 6: Preparation of 4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazoline (IV)

1.20 grams (5.73 mmol) of 4-chloro-6-nitroquinazoline (Ⅲ) and 1.14 grams (5.15 mmol) of 2-diethylamino-N-(4-aminophenyl) acetamide (Ⅱ) were successively added, Add 1.04 g (8.58 mmol) of N,N-xylaniline and 60 ml of N,N-dimethylformamide into a 100 ml three-neck flask, heat to 120 degrees, and perform TLC tracking detection (the developing solvent is ethyl acetate/petroleum Ether = 1:1), stirred for 0.5 hours, closed the reaction, stood overnight, filtered, and dried to obtain 4-[4-(2-diethylaminoacetamido)anilino]-6- Nitroquinazoline yellow solid 1.05g, yield 51.7%, melting point 235-238°C. ¹ H NMR(500MHz,[D6]DMSO):δ=1.05(t,J=7.1Hz,6H),2.63(q,J=7.1Hz,4H),3.17(s,2H),7.70-7.71(m ,2H),7.77(d,J=9.0Hz,2H),7.93(d,J=9.2Hz,1H),8.56(dd,J=2.4,9.2Hz,1H),8.69(s,1H),9.67 (d,J=2.5Hz,1H),9.69(s,1H),10.45ppm(s,1H);IR(KBr):v=3308,3209,2971,2938,1661,1628,1604,675cm ^-1 . HRMS (ESI): m/z: [M+H] ⁺ calcd for C ₂₀ H ₂₃ N ₆ O ₃ : 395.1826, found: 395.1826.

Example 7: Preparation of 4-[4-(2-diethylaminoacetamido)anilino]-6-aminoquinazoline (Ⅴ)

Sequentially add 0.40 g (1.01 mmol) of 4-[4-(2-diethylaminoacetamido) anilino]-6-nitroquinazoline (Ⅳ), 0.40 g (6.34 mmol) of ammonium formate, 0.04 g of 5% Pd/C, 30.0 ml of chloroform was added to a 50 ml three-neck flask, stirred at room temperature 25 degrees, followed by TLC detection (developing solvent: ethyl acetate/petroleum ether = 1:1), reacted for 12 hours, filtered, and the filtrate was concentrated to precipitate yellow The solid was filtered and dried to obtain 0.20 g of 4-[4-(2-diethylaminoacetamido)anilino]-6-aminoquinazoline represented by formula (V), with a yield of 54.1%. IR(KBr):v=3328,3215,2969,2926,2879,2861,1670,1632,1605,1576,1514,937,836,788,653cm ^-1 .

Example 8: Preparation of 4-[4-(2-diethylaminoacetamido)anilino]-6-aminoquinazoline (Ⅴ)

Sequentially add 0.40 g (1.01 mmol) 4-[4-(2-diethylaminoacetamido) anilino]-6-nitroquinazoline (Ⅳ), 1.20 g (19.18 mmol) 80% hydrazine hydrate, 0.20 g 5% Pd/C, 30.0 ml of toluene was added to a 50 ml three-necked flask, heated to 100 degrees, followed by TLC detection (developing solvent: ethyl acetate/petroleum ether = 1:1), stirred for 0.5 hours, cooled and filtered, The filtrate was concentrated to precipitate a yellow solid, which was filtered and dried to obtain 0.25 g of 4-[4-(2-diethylaminoacetamido)anilino]-6-aminoquinazoline represented by formula (V), with a yield of 67.6%. IR(KBr):v=3328,3215,2969,2926,2879,2861,1670,1632,1605,1576,1514,937,836,788,653cm ^-1 .

Example 9: Preparation of 4-[4-(2-diethylaminoacetamido)anilino]-6-aminoquinazoline (Ⅴ)

Sequentially add 0.40 g (1.01 mmol) of 4-[4-(2-diethylaminoacetamido) anilino]-6-nitroquinazoline (IV), 0.08 g of concentrated hydrochloric acid, 0.40 g of iron powder, and 30.0 ml of methanol Add it into a 50 ml three-neck flask, heat to 40 degrees, TLC tracking detection (developing agent: ethyl acetate/petroleum ether = 1:1), stir for 8 hours, cool and filter, the filtrate is concentrated to precipitate a yellow solid, filter, and dry 0.16 g of 4-[4-(2-diethylaminoacetamido)anilino]-6-aminoquinazoline represented by the formula (V) was obtained with a yield of 43.3%. IR(KBr):v=3328,3215,2969,2926,2879,2861,1670,1632,1605,1576,1514,937,836,788,653cm ^-1 .

Example 10: Preparation of 4-[4-(2-diethylaminoacetamido)anilino]-6-aminoquinazoline (V)

Add 0.40 g (1.01 mmol) 4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazoline (IV), 0.40 g acetic acid, 1.20 g iron powder, 30.0 ml isopropyl Alcohol was added to a 50 ml three-necked flask, heated to 80 degrees, followed by TLC detection (developing agent: ethyl acetate/petroleum ether = 1:1), stirred for 3 hours, cooled and filtered, the filtrate was concentrated to precipitate a yellow solid, filtered, Drying gave 0.17 g of 4-[4-(2-diethylaminoacetamido)anilino]-6-aminoquinazoline represented by formula (V), with a yield of 46.0%. IR(KBr):v=3328,3215,2969,2926,2879,2861,1670,1632,1605,1576,1514,937,836,788,653cm ^-1 .

Example 11: Preparation of 4-[4-(2-diethylaminoacetamido)anilino]-6-isobutoxycarboxamidoquinazoline (I-1)

0.20 g (0.55 mmol) 4-[4-(2-diethylaminoacetamido) anilino base]-6-aminoquinazoline (Ⅴ), 0.13 g (1.64 mmol) pyridine, and 10.0 ml tetrahydrofuran were added to 50 Add 0.60 g (4.39 mmol) of isobutyl chloroformate and 5.0 ml of tetrahydrofuran solution dropwise to a three-necked flask at -10°C under stirring conditions. After the drop is complete, TLC tracking detection (developing solvent is ethyl acetate/petroleum ether=1: 1), react at -10°C for 12 hours, filter, evaporate the filtrate to remove the solvent, add 20 ml of ethyl acetate to the residue to dissolve it, and obtain a solution, add 0.40 g of column chromatography silica gel (300-400 column chromatography silica gel), after mixing, the solvent was evaporated to obtain a mixture of dry residue and silica gel. : 4, 1: 2, 1: 1, 1: 0) mixed solution of ethyl acetate and petroleum ether as eluent, gradient elution, collect the fraction of ethyl acetate/petroleum ether (1:4), collect The solution was concentrated and dried to obtain 0.11 grams of 4-[4-(2-diethylaminoacetamido)anilino]-6-isobutoxycarboxamidoquinazoline pale yellow solid shown in formula (I-1). The yield is 43.1%, and the melting point is 179-181°C. ¹ H NMR(500MHz,[D6]DMSO):δ=0.97(d,J=6.7Hz,6H),1.05(t,J=7.1Hz,6H),1.93-2.01(m,1H),2.62(q ,J=7.1Hz,4H),3.16(s,2H),3.95(d,J=6.6Hz,2H),7.64(d,J=9.0Hz,2H),7.71-7.77(m,4H),8.46 (s,1H),8.53(s,1H),9.62(s,1H),9.72(s,1H),9.92ppm(s,1H);IR(KBr):v=3303,2966,2932,1705, 1678, 1632, 1609, 648 cm ^-1 ; HRMS (ESI): m/z: [M+H] ⁺ calcd for C ₂₅ H ₃₃ N ₆ O ₃ : 465.2609, found: 465.2610.

Example 12: Preparation of 4-[4-(2-diethylaminoacetamido)anilino]-6-isobutoxycarboxamidoquinazoline (I-1)

Add 0.20 g (0.55 mmol) of 4-[4-(2-diethylaminoacetamido) anilino]-6-aminoquinazoline (Ⅴ), 0.04 g (0.55 mmol) of diethylamine, and 10.0 ml of chloroform in sequence Into a 50 ml three-necked flask, add 0.075 g (0.55 mmol) of isobutyl chloroformate and 5.0 ml of chloroform solution dropwise under stirring at 10°C, after the drop is complete, TLC tracking detection (developing solvent is ethyl acetate/petroleum ether=1 : 1), react at 10°C for 8 hours, filter, evaporate the filtrate to remove the solvent, add 20 ml of ethanol to the residue to dissolve it, and obtain a solution, add 0.20 g of column chromatography silica gel (300-400 mesh column) to the solution Chromatographic silica gel), after mixing, evaporate the solvent to obtain a mixture of dry residue and silica gel, put the mixture on the column, and then use the volume ratio of 1:12～0 (1:12,1:8,1:4 , 1:2, 1:1, 1:0) mixed solution of ethyl acetate and petroleum ether as the eluent, gradient elution, collect the fraction of ethyl acetate/petroleum ether (1:1), and concentrate the collected solution , dry to obtain 4-[4-(2-diethylaminoacetamido) anilino base]-6-isobutoxycarboxamidoquinazoline light yellow solid 0.08 grams shown in formula (I-1), yield 31.4%, melting point 179～181℃. ¹ H NMR(500MHz,[D6]DMSO):δ=0.97(d,J=6.7Hz,6H),1.05(t,J=7.1Hz,6H),1.93-2.01(m,1H),2.62(q ,J=7.1Hz,4H),3.16(s,2H),3.95(d,J=6.6Hz,2H),7.64(d,J=9.0Hz,2H),7.71-7.77(m,4H),8.46 (s,1H),8.53(s,1H),9.62(s,1H),9.72(s,1H),9.92ppm(s,1H);IR(KBr):v=3303,2966,2932,1705, 1678, 1632, 1609, 648 cm ^-1 ; HRMS (ESI): m/z: [M+H] ⁺ calcd for C ₂₅ H ₃₃ N ₆ O ₃ : 465.2609, found: 465.2610.

Example 13: Preparation of 4-[4-(2-diethylaminoacetamido)anilino]-6-cyclohexylmethoxycarboxamidoquinazoline (I-2)

Sequentially add 0.20 g (0.55 mmol) of 4-[4-(2-diethylaminoacetamido) anilino]-6-aminoquinazoline (Ⅴ), 0.11 g (1.09 mmol) of triethylamine, and 10.0 ml of ethyl acetate The ester was added to a 50 ml three-necked flask, and 0.19 g (1.08 mmol) of cyclohexylmethyl chloroformate and 5.0 ml of ethyl acetate solution were added dropwise under stirring at 0°C. /petroleum ether=1:1), reacted at 25°C for 6 hours, filtered, evaporated the filtrate to remove the solvent, and dissolved the residue by adding 20 ml of chloroform to obtain a solution, and added 0.20 g of column chromatography silica gel ( 300 ~ 400 mesh column chromatography silica gel), after mixing, evaporate the solvent to obtain a mixture of dry residue and silica gel, put the mixture on the column, and then use the volume ratio of 1:12 ~ 0 (1:12,1: 8, 1:4, 1:2, 1:1, 1:0) mixed solution of ethyl acetate and petroleum ether as eluent, gradient elution, collect the stream of ethyl acetate/petroleum ether (1:2) points, the collected solution is concentrated, and dried to obtain 4-[4-(2-diethylaminoacetamido)anilino]-6-cyclohexylmethoxycarboxamidoquinazoline shown in formula (I-2) light yellow The solid is 0.09 g, the yield is 32.5%, and the melting point is 216-218°C. ¹ H NMR(500MHz,[D6]DMSO):δ=1.05(t,J=7.1Hz,8H),1.17-1.26(m,3H),1.67-1.78(m,6H),2.62(q,J= 7.1Hz, 4H), 3.16(s, 2H), 3.97(d, J=6.6Hz, 2H), 7.64(d, J=9.0Hz, 2H), 7.71-7.74(m, 4H), 8.46(s, 1H),8.52(s,1H),9.62(s,1H),9.72(s,1H),9.91ppm(s,1H);IR(KBr):v=3428,3284,2970,2924,1725,1677 , 1635, 1615, 648cm ^-1 ; HRMS (ESI): m/z: [M+H] ⁺ calcd for C ₂₈ H ₃₇ N ₆ O ₃ : 505.2922, found: 505.2927.

Example 14: Preparation of 4-[4-(2-diethylaminoacetamido)anilino]-6-cyclohexylmethoxycarboxamidoquinazoline (I-2)

Sequentially add 0.20 g (0.55 mmol) 4-[4-(2-diethylaminoacetamido) anilino]-6-aminoquinazoline (Ⅴ), 0.067 g (0.55 mmol) 4-dimethylaminopyridine, 10.0 Add 0.39 g (2.21 mmol) of cyclohexylmethyl chloroformate and 5.0 ml of toluene solution dropwise under stirring condition at 5°C, and heat to 50°C after dropping, TLC tracking detection (developer Ethyl acetate/petroleum ether = 1:1), react for 3 hours, filter, evaporate the filtrate to remove the solvent, add 20 ml of tetrahydrofuran to the residue and dissolve it to obtain a solution, add 0.40 g of column chromatography silica gel ( 300 ~ 400 mesh column chromatography silica gel), after mixing, evaporate the solvent to obtain a mixture of dry residue and silica gel, put the mixture on the column, and then use the volume ratio of 1:12 ~ 0 (1:12,1: 8, 1:4, 1:2, 1:1, 1:0) mixed solution of ethyl acetate and petroleum ether as the eluent, gradient elution, collect the fraction of ethyl acetate, concentrate the collected solution, and dry to obtain 0.13 g of 4-[4-(2-diethylaminoacetamido)anilino]-6-cyclohexylmethoxycarboxamidoquinazoline light yellow solid represented by formula (I-2), yield 46.9% , Melting point 216～218℃. ¹ H NMR(500MHz,[D6]DMSO):δ=1.05(t,J=7.1Hz,8H),1.17-1.26(m,3H),1.67-1.78(m,6H),2.62(q,J= 7.1Hz, 4H), 3.16(s, 2H), 3.97(d, J=6.6Hz, 2H), 7.64(d, J=9.0Hz, 2H), 7.71-7.74(m, 4H), 8.46(s, 1H),8.52(s,1H),9.62(s,1H),9.72(s,1H),9.91ppm(s,1H);IR(KBr):v=3428,3284,2970,2924,1725,1677 , 1635, 1615, 648cm ^-1 ; HRMS (ESI): m/z: [M+H] ⁺ calcd for C ₂₈ H ₃₇ N ₆ O ₃ : 505.2922, found: 505.2927.

Example 15: In vitro test of anticancer activity

The compounds (I-1), (I-2) and (IV) prepared in the examples were tested for their biological activity in human lung cancer and human breast cancer. DDP (cisplatin) was used as the control drug. Cisplatin is a commonly used chemical drug in cancer treatment and has a high curative effect.

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

Cell lines: human lung cancer cell line A-549 and human breast cancer cell line MCF-7. 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:

(1) Sample preparation: For soluble samples, dissolve each 1 mg with 40 μL DMSO, take 2 uL and dilute with 1000 μL culture medium to make the concentration 50 μg/mL, and then serially dilute with culture medium to the use concentration.

(2) Cell culture

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

2) Cell culture: the tumor cells were inoculated in the culture medium, cultured in a 37°C, 5% CO ₂ incubator, and passaged for 3-5 days.

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

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

The test results are shown in the table below:

Claims (10)

1. a 4-[4-(2-diethylaminoacetamido) anilino]-6-(substituted methoxy) formamidoquinazoline compound, which has the following general structural formula (I): In the general structural formula (I), R is isopropyl or cyclohexyl. 2.4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazoline, its structure is as shown in formula (Ⅳ): 3.4-[4-(2-diethylaminoacetamido) anilino]-6-aminoquinazoline, its structure is as shown in formula (Ⅴ): 4. a preparation method of 4-[4-(2-diethylaminoacetamido) anilino]-6-(substituted methoxy) formamidoquinazoline compounds as claimed in claim 1, wherein It is characterized in that the preparation method comprises: (1) 2-diethylamino-N-(4-aminophenyl) acetamide shown in formula (II) and 4-chloro-6-nitroquinazoline shown in formula (Ⅲ) in organic solvent A1 4-[4-(2-diethylaminoacetamido) anilino base]-6-nitroquinazoline is reacted under the effect of basic catalyst B1 to make formula (IV); Catalyst B1 is selected from one of the following: pyridine, diethylamine, triethylamine, quinoline, N,N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate; the organic solvent A1 is selected from one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N,N-dimethylformamide; (2) 4-[4-(2-diethylaminoacetamido) anilino base]-6-nitroquinazoline shown in formula (IV) reacts under the effect of reducing agent B2 in organic solvent A2 to obtain formula (Ⅴ) shown 4-[4-(2-diethylaminoacetamido) anilino base]-6-aminoquinazoline; Described reducing agent B2 is one of following: iron powder/concentrated hydrochloric acid, iron powder/ Acetic acid, palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate; the organic solvent A2 is one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, or acetonitrile; (3) 4-[4-(2-diethylaminoacetamido) anilino base shown in (Ⅴ)]-6-aminoquinazoline and isobutyl chloroformate or cyclohexyl methyl chloroformate in organic solvent In A3, 4-[4-(2-diethylaminoacetamido)anilino]-6-(substituted methoxy)formylaminoquinazoles shown in formula (I) are reacted under the action of basic catalyst B3 Phenyl compounds; the basic catalyst B3 is one of the following: pyridine, diethylamine, triethylamine, quinoline, N,N-xylidine, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate; the organic solvent A3 is one of the following: THF, methylene chloride, chloroform, ethyl acetate, ether, acetonitrile, toluene or benzene; In the formula (I), R is isopropyl or cyclohexyl. 5. the preparation method of 4-[4-(2-diethylaminoacetamido) anilino base]-6-(substituted methoxy) formamidoquinazoline compound as claimed in claim 4, is characterized in that The reaction described in step (1) is carried out at a temperature of 25-120°C. 6. the preparation method of 4-[4-(2-diethylaminoacetamido) anilino as claimed in claim 4]-6-(substituted methoxy) formamidoquinazoline compounds, is characterized in that The reaction described in step (2) is carried out at a temperature of 25-100°C. 7. the preparation method of 4-[4-(2-diethylaminoacetamido) anilino base]-6-(substituted methoxy) formamidoquinazoline compounds as claimed in claim 4, is characterized in that The reaction described in step (3) is carried out at a temperature of -10 to 50°C. 8. the preparation method of 4-[4-(2-diethylaminoacetamido) anilino base]-6-(substituted methoxy) formamidoquinazoline compound as claimed in claim 4, is characterized in that : in the step (1), the molar ratio of the 4-chloro-6-nitroquinazoline, 2-diethylamino-N-(4-aminophenyl) acetamide, basic catalyst B1 is 1.0: 0.8～1.2: 1.0～8.0; in the step (2), the reducing agent B2 is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, 4-[4-(2-diethylaminoacetamido) The mass ratio of anilino]-6-nitroquinazoline (IV) to iron powder, concentrated hydrochloric acid or acetic acid in the reducing agent B2 is 1.0:1.0～3.0:0.2～1.0, or the reducing agent B2 is Palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate, palladium carbon and formic acid in 4-[4-(2-diethylaminoacetamido)anilino]-6-nitroquinazoline (IV) and reducing agent B2 The mass ratio of ammonium or hydrazine hydrate is 1.0:0.1～0.5:1.0～3.0; in the step (3), 4-[4-(2-diethylaminoacetamido)anilino]-6-aminoquinazole The molar ratio of morphine (Ⅴ), isobutyl chloroformate or cyclohexylmethyl chloroformate and basic catalyst B3 is 1:1.0～8.0:1.0～3.0. 9. the preparation method of 4-[4-(2-diethylaminoacetamido) anilino base]-6-(substituted methoxy) formamidoquinazoline compound as claimed in claim 8, is characterized in that The preparation method is carried out as follows: (1) 2-diethylamino-N-(4-aminophenyl) acetamide shown in formula (II) and 4-chloro-6-nitroquinazoline shown in formula (Ⅲ), in organic In the solvent A1, under the action of the basic catalyst B1, the reaction is carried out at 25 ~ 120 ° C. After the reaction is completed, it is left to stand overnight, filtered and dried to obtain 4-[4-(2-diethylaminoacetamido) represented by formula (IV). ) anilino]-6-nitroquinazoline; (2) 4-[4-(2-diethylaminoacetamido) anilino base]-6-nitroquinazoline and reducing agent B2 shown in formula (IV) are added in organic solvent A2, at 25～100 Fully react at ℃, filter, and concentrate the filtrate to separate solids, filter, and dry to obtain 4-[4-(2-diethylaminoacetamido)anilino]-6-aminoquinazoline shown in formula (Ⅴ); (3) 4-[4-(2-diethylaminoacetamido)anilino]-6-aminoquinazoline and basic catalyst B3 shown in formula (Ⅴ) are added in organic solvent A3, at -10～ Under the condition of 10°C, add dropwise the organic solvent A3 solution of isobutyl chloroformate or cyclohexylmethyl chloroformate, after dropping, react at -10-50°C for 3-12 hours, filter, evaporate the filtrate to remove the solvent, and the residue column layer The corresponding 4-[4-(2-diethylaminoacetamido)anilino]-6-(substituted methoxy)formamidoquinazoline compounds (I) were obtained by analysis. 10. 4-[4-(2-diethylaminoacetamido)anilino]-6-(substituted methoxy)formamidoquinazoline compounds as claimed in claim 1 in the preparation of prevention or treatment of human lung cancer Or the application in the medicine of human breast cancer disease.