CN108078992B - Application of pivaloyl-amino-dimethoxy-benzo [ d ] aza-quinazoline compound in preparation of drugs for treating leukemia - Google Patents

Application of pivaloyl-amino-dimethoxy-benzo [ d ] aza-quinazoline compound in preparation of drugs for treating leukemia Download PDF

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CN108078992B
CN108078992B CN201810069168.6A CN201810069168A CN108078992B CN 108078992 B CN108078992 B CN 108078992B CN 201810069168 A CN201810069168 A CN 201810069168A CN 108078992 B CN108078992 B CN 108078992B
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ethyl acetate
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petroleum ether
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CN108078992A (en
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刘宇宁
饶国武
胡成海
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Zhejiang University of Technology ZJUT
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The invention discloses pivaloyl amino dimethoxy benzo [ d]Aza derivatives

Description

Application of pivaloyl-amino-dimethoxy-benzo [ d ] aza-quinazoline compound in preparation of drugs for treating leukemia
(I) technical field
The invention relates to an application of quinazoline compounds, in particular to pivaloyl amino dimethoxy benzo [ d]Aza derivatives
Figure BDA0001557619230000012
Application of the fluoroquinazoline compound in preparing medicaments for preventing or treating human leukemia.
(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.vatte, l. gosense, p.depenux, j.chem.1204, d.m.1189, d.1189). Of course most quinazoline compounds do not have anti-tumor activity.
Disclosure of the invention
The invention aims to provide a novel quinazoline compound, namely pivaloylaminodimethoxybenzo [ d]Aza derivatives
Figure BDA0001557619230000013
The application of the quinazoline compound has good inhibition effect on human promyelocytic leukemia cell line HL-60 under a certain dosage; and the preparation method of the compound is simple and convenient, easy to operate, easy to obtain raw materials, low in production cost and suitable for industrial application.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides pivaloyl amino dimethoxy benzo [ d ] shown in formula (I)]Aza derivatives
Figure BDA0001557619230000023
The application of the fluoroquinazoline compound in preparing the medicaments for preventing or treating tumors, in particular the application in preparing the medicaments for preventing or treating human leukemia:
Figure BDA0001557619230000021
preferably, the medicament is a medicament for inhibiting the activity of the human promyelocytic leukemia cell line HL-60.
In addition, the invention provides pivaloylaminodimethoxybenzo [ d ] of formula (I)]Aza derivatives
Figure BDA0001557619230000024
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);
Figure BDA0001557619230000022
(2) completely reacting a compound shown in a formula (IV) in an organic solvent D under the action of a reducing agent E at 25-100 ℃ (TLC tracking monitoring, a developing agent is ethyl acetate/petroleum ether which is 1: 1(v/v), and preferably reacting for 0.5-12 h at 40-80 ℃), filtering a reaction solution, concentrating a filtrate under reduced pressure, and drying a concentrate (preferably drying at 25 ℃ in vacuum) to obtain a compound shown in a formula (V); the organic solvent D is one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the reducing agent E is one of the following: iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium on carbon/ammonium formate or palladium on carbon/hydrazine hydrate; the iron powder/concentrated hydrochloric acid refers to the mixing of iron powder and concentrated hydrochloric acid in any proportion, the iron powder/acetic acid refers to the mixing of iron powder and acetic acid in any proportion, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate in any proportion, and the palladium carbon/hydrazine hydrate refers to the mixing of palladium carbon and hydrazine hydrate in any proportion;
(3) mixing a compound shown as a formula (V) with pivaloyl chloride or pivalic anhydride, completely reacting in an organic solvent G at-10-50 ℃ under the action of a basic catalyst F (TLC tracking monitoring, a developing agent is ethyl acetate/petroleum ether ═ 1: 1(v/v), preferably reacting at-10-50 ℃ for 3-12 h), and carrying out aftertreatment on a reaction solution to obtain a compound shown as a formula (I); the alkaline catalyst F is one of the following: pyridine, diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate; the organic solvent G is one of the following: tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, diethyl ether, acetonitrile, toluene or benzene.
Further, in the step (1), the ratio of the amount of the compound represented by the formula (III) to the amount of the compound represented by the formula (II) and the amount of the substance charged as the basic catalyst B is 1.0: 0.8 to 1.2: 1.0 to 8.0.
Further, in the step (1), the amount of the organic solvent A is 10-50 mL/g based on the mass of the compound represented by the formula (III).
Further, the method for separating and purifying the reaction solution in the step (1) of the present invention comprises: after the reaction is completed, evaporating the solvent from the reaction solution, dissolving the concentrate with an organic solvent C to obtain a dissolved solution, adding column chromatography silica gel of which the weight is 1.0-2.0 times that of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture with the organic solvent C in a volume ratio of 1: taking a mixed solution of petroleum ether and ethyl acetate of 0.1-10 as an eluent, collecting an effluent containing a target component (preferably, ethyl acetate/petroleum ether is 1: 3(v/v) is taken as a developing agent for tracking detection, collecting the target component, preferably, collecting a component with an Rf value of 0.5), concentrating under reduced pressure, and drying (preferably, drying at 50 ℃) to obtain a compound shown in a formula (IV); the organic solvent C is one of the following solvents: ethanol, chloroform, tetrahydrofuran or ethyl acetate. The organic solvent C is used in an amount capable of dissolving the residue.
Further, in the step (2), when the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, the charging mass ratio of the compound represented by the formula (iv) to the iron powder, concentrated hydrochloric acid or acetic acid in the reducing agent E is 1.0: 1.0 to 3.0: 0.2 to 1.0. In the invention, the mass concentration of the concentrated hydrochloric acid is 36-38%, and the acetic acid is glacial acetic acid.
Further, in the step (2), when the reducing agent E is palladium on carbon/ammonium formate or palladium on carbon/hydrazine hydrate, the feeding mass ratio of the compound represented by the formula (iv) to palladium on carbon, ammonium formate or hydrazine hydrate in the reducing agent E is 1.0: 0.1 to 0.5: 1.0 to 3.0. The mass loading amount of palladium in the palladium-carbon applicable to the invention is 2-10%, preferably 5%, and the mass concentration of hydrazine hydrate is 40-80%, preferably 80%.
Further, in the step (2), the amount of the organic solvent D is 10-50 mL/g based on the mass of the compound represented by the formula (IV).
Further, in the step (3), the ratio of the compound represented by the formula (v) to the amounts of pivaloyl chloride or pivalic 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 specific recommended step (3) of the present invention is performed as follows: dropwise adding an organic solvent G solution of pivaloyl chloride or pivalic anhydride into a compound shown in the formula (V) and an organic solvent G solution of a basic catalyst F or into the compound shown in the formula (V) and the basic catalyst F at-10 ℃, reacting for 3-12 hours at-10-50 ℃, and carrying out aftertreatment on the obtained reaction liquid to obtain a compound shown in the formula (I); the volume dosage of the organic solvent for dissolving pivaloyl chloride or pivalic 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 pivaloyl chloride or pivalic anhydride is dissolved.
Further, the method for post-treating the reaction solution in the step (3) of the present invention comprises: after the reaction is completed, filtering the reaction solution, evaporating the solvent from the filtrate, dissolving the concentrate with an organic solvent H to obtain a dissolved solution, adding column chromatography silica gel of which the weight is 1.0-2.0 times that of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture with the organic solvent H according to a volume ratio of 1: taking a mixed solution of petroleum ether and ethyl acetate of 0.1-10 as an eluent, collecting an effluent containing a target component (preferably, ethyl acetate/petroleum ether is 1: 1(v/v) is used as a developing agent for tracking detection, collecting the target component), concentrating under reduced pressure, and drying (preferably, drying at 50 ℃) to obtain a compound shown in a 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 a novel pivaloylamidodimethoxybenzo [ d]Aza derivatives
Figure BDA0001557619230000051
The application of the quinazoline compound (I) in preparing the medicament for preventing or treating human leukemia has obvious inhibitory activity on human promyelocytic leukemia cell strain HL-60.
(IV) detailed description of the preferred embodiments
The invention is further illustrated by reference to specific examples, which are intended to illustrate the invention, but not to limit it in any way.
The compound (II) can be prepared by the method described in Weinstock, J.et al.J.Med.chem.,1986, 29(11), 2315-2325. Preparation of 4-chloro-6-nitroquinazoline (III) according to the method of Fernandes, C.et al bioorg.Med.chem.,2007,15(12), 3974-3980.
The palladium-carbon (Pd/C) model D5H5A used in the embodiment of the invention is purchased from Shaanxi Rui New Material Co., Ltd.
Example 1: nitrobenzo [ d]Aza derivatives
Figure BDA0001557619230000061
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 10 mixed solution of petroleum ether and ethyl acetate as eluent, detecting by TLC (developing solvent of ethyl acetate/petroleum ether: 1: 3(v/v)),collecting eluent containing the compound shown in the formula (IV) according to TLC detection (the Rf value is 0.5), 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) :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
Figure BDA0001557619230000062
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
Figure BDA0001557619230000071
Preparation of the quinazolines (IV)
Sequentially adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 1.99 g (5.72mmol) of compound (II), 0.58 g (5.73mmol) of triethylamine and 60 ml of ethanol into a 100ml three-neck flask, heating to 60 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for 8 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of chloroform into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 2.5 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography by using a volume ratio of 10: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected 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
Figure BDA0001557619230000072
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 petroleum ether/ethyl acetate mixed solution of 1 as eluent, detecting by TLC (developing solvent ethyl acetate/petroleum ether is 1: 3(v/v)), and collecting compound containing formula (IV) according to TLC detectionAnd (3) eluting the product (the Rf value is 0.5), concentrating the collected solution, 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
Figure BDA0001557619230000081
Preparation of the quinazolines (IV)
Adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 1.79 g (5.15mmol) of compound (II), 1.04 g (8.58mmol) of N, N-dimethylaniline and 12 ml of N, N-dimethylformamide into a 50ml reaction bottle, heating to 120 ℃, performing TLC tracking detection (ethyl acetate/petroleum ether is 1: 3(v/v)) and stirring for 0.5 hour, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of tetrahydrofuran into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 5.0 g of silica gel (300-400 mesh silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of a dried concentrate and the silica gel, filling the mixture into a column, and then filling the mixture into the column according to the volume ratio of 1: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 89.6%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 6: nitrobenzo [ d]Aza derivatives
Figure BDA0001557619230000082
Preparation of the quinazolines (IV)
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, 20 ml of propanol were sequentially added to a 50ml reaction flask, heated to 40 ℃ and subjected to TLC follow-up detection (developing solvent ethyl acetate/petroleum ether: 1: 3(v/v)), the reaction was stirred for 10 hours, the reaction was stopped, the solvent was distilled off from the reaction solution, and 20 ml of ethyl acetate was added to the obtained concentrate to dissolve it,and (2) obtaining 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 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 on the mixture in a volume ratio of 1: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 78.3%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 7: aminobenzo [ d ] s]Aza derivatives
Figure BDA0001557619230000091
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
Figure BDA0001557619230000092
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
Figure BDA0001557619230000093
The yield of the quinazoline (V) is 98.2 percent, and the melting point is 122-126 ℃.1H NMR(500MHz,CDCl3) :3.40-3.48(m,2H),3.71(s,3H),3.82(s,3H),3.83(s,3H),3.87-3.98(m,5H), 4.45(dd,J＝6.3,13.8Hz,1H),4.95(dd,J＝6.5,9.2Hz,1H),6.47(s,1H),6.90(d,J＝ 8.7Hz,2H),6.95(d,J＝2.5Hz,1H),7.11(d,J＝8.6Hz,2H),7.15(dd,J＝8.9,2.5Hz, 1H),7.69(d,J＝8.9Hz,1H),8.50(s,1H)。IR(KBr,cm-1)ν:3368,3215,2932,2825, 1628,1566,1512,1487,1353,1248,1036,834。
Example 8: aminobenzo [ d ] s]Aza derivatives
Figure BDA0001557619230000094
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
Figure BDA0001557619230000095
The phenyl quinazoline (IV), 1.20 g (19.18mmol)80 wt% hydrazine hydrate, 0.20 g 5% Pd/C, 20.0 ml toluene were added into a 50ml reaction bottle, heated to 100 deg.C, monitored by TLC (developing solvent ethyl acetate/petroleum ether is 1: 1(v/v)), stirred for 0.5 hours, cooled and filtered, the filtrate was concentrated, and vacuum dried at 25 deg.C to obtain amino benzo [ d ] as a light yellow solid product]Aza derivatives
Figure BDA0001557619230000096
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
Figure BDA0001557619230000101
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
Figure BDA0001557619230000102
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
Figure BDA0001557619230000103
The yield of the quinazoline (V) is 94.1 percent, and the melting point is 122-126 ℃.1H NMR and IR were the same as in example 7.
Example 10: aminobenzo [ d ] s]Aza derivatives
Figure BDA0001557619230000104
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
Figure BDA0001557619230000105
Adding the quinazoline (IV), 0.40 g acetic acid, 1.20 g iron powder and 20.0 ml isopropanol into a 50ml reaction bottle, heating to 80 ℃, carrying out TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirring for reacting for 3 hours, cooling, filtering, concentrating the filtrate, and drying in vacuum at 25 ℃ to obtain a light yellow solid product, namely aminobenzo [ d]Aza derivatives
Figure BDA0001557619230000106
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: pivaloylamidodimethoxybenzo [ d]Aza derivatives
Figure BDA0001557619230000107
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
Figure BDA0001557619230000108
Adding 0.13 g (1.64mmol) of pyridine and 3 ml of tetrahydrofuran into a reaction bottle, dropwise adding 0.531 g (4.40mmol) of pivaloyl 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 under the condition of 10 ℃, filtering, evaporating the solvent from the filtrate, adding 10 ml of ethyl acetate into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.60 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating 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 of ethyl acetate/petroleum ether is 1: 1(v/v)), and collecting the eluate containing the compound of formula (I) according to TLC detectionThe eluate of the compound (5) (Rf value: 0.5) was concentrated and dried at 50 ℃ to give pivaloylaminodimethoxybenzo [ d ] represented by the formula (I)]Aza derivatives
Figure BDA0001557619230000111
The quinazoline is off-white solid, the yield is 64.2%, and the melting point is 131-133 ℃.1H NMR(500MHz,[D6]DMSO):1.29(s,9H), 3.22-3.28(m,1H),3.38-3.42(m,1H),3.68(s,3H),3.69(s,3H),3.73(s,3H), 3.78-3.84(m,1H),3.87-3.96(m,2H),4.49(dd,J＝8.2,14.7,1H),5.26(t,J＝8.6Hz,1H), 6.85(s,1H),6.89(d,J＝8.8Hz,2H),7.08(d,J＝8.7Hz,2H),7.69(d,J＝9.0,1H),7.88 (dd,J＝2.2,9.2Hz,1H),8.44(s,1H),8.66(s,1H),9.55(s,1H)。HRMS-ESI m/z: 575.2417[M+H]+。IR(KBr,cm-1)ν:2966,2921,2868,1665,1557,1522,1510,1490, 1163,1349,1248,1036,847。
Example 12: pivaloylamidodimethoxybenzo [ d]Aza derivatives
Figure BDA0001557619230000112
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
Figure BDA0001557619230000113
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 0.066 g (0.55mmol) of pivaloyl chloride and 5.0 ml of chloroform under the stirring condition at 10 ℃, after dropwise adding, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), reacting for 8 hours under the condition of 10 ℃, filtering, evaporating the filtrate to remove the solvent, adding 20 ml of ethanol into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.26 g of column chromatography silica gel (300-400 mesh silica gel column chromatography) into the dissolved solution, uniformly mixing, evaporating to remove the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography on the mixture according to the volume ratio of 1: eluting with petroleum ether/ethyl acetate mixed solution of 5 as eluent, detecting by TLC (developing solvent ethyl acetate/petroleum ether is 1: 1(v/v)), and collecting the compound containing formula (I) according to TLC detectionEluting with an eluent (Rf value of 0.5), concentrating the collected solution, and drying at 50 deg.C to obtain pivaloylamidodimethoxybenzo [ d ] of formula (I)]Aza derivatives
Figure BDA0001557619230000114
The quinazoline is off-white solid, the yield is 74.7%, and the melting point is 131-133 ℃.1H NMR and IR were the same as in example 11.
Example 13: pivaloylamidodimethoxybenzo [ d]Aza derivatives
Figure BDA0001557619230000115
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
Figure BDA0001557619230000116
Adding 0.111 g (1.10mmol) of triethylamine and 10.0 ml of ethyl acetate into a 50ml reaction bottle, dropwise adding 0.133 g (1.10mmol) of pivaloyl 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 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 the volume ratio of 10: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, detecting by TLC (developing solvent 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 pivaloyl amino dimethoxy benzo [ d ] shown in formula (I)]Aza derivatives
Figure BDA0001557619230000121
The quinazoline is off-white solid, the yield is 50.5%, and the melting point is 131-133 ℃.1H NMR and IR were the same as in example 11.
Example 14: pivaloylamidomethoxybenzeneAnd [ d ]]Aza derivatives
Figure BDA0001557619230000122
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
Figure BDA0001557619230000123
Adding 0.067 g (0.55mmol) of 4-dimethylaminopyridine and 20.0 ml of toluene into a 50ml reaction bottle, dropwise adding a solution of 0.410 g (2.20mmol) of pivalic anhydride and 7.0 ml of toluene under the stirring condition at 5 ℃, heating to 50 ℃, performing TLC tracking detection (ethyl acetate/petroleum ether is used as a developing agent, namely 1: 1), reacting for 3 hours, filtering, evaporating the filtrate to remove the solvent, adding 20 ml of tetrahydrofuran into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.40 g of column chromatography silica gel (300-400 mesh silica gel column chromatography) 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 volume ratio of the mixture to 5: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, detecting by TLC (developing solvent 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 pivaloyl amino dimethoxy benzo [ d ] shown in formula (I)]Aza derivatives
Figure BDA0001557619230000124
The quinazoline is off-white solid, and the yield is 57.4 percent, and the melting point is 131-133 ℃.1H NMR and IR were the same as in example 11.
Example 15: pivaloylamidodimethoxybenzo [ d]Aza derivatives
Figure BDA0001557619230000131
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
Figure BDA0001557619230000132
Quinazoline (V), 0.213 g: (1.65mmol) of quinoline and 15.0 ml of benzene are added to a 50ml reaction flask and a solution of 0.265 g (2.20mmol) of pivaloyl chloride and 5.0 ml of benzene are added dropwise with stirring at-10 ℃, and the mixture is checked by TLC tracing (developing solvent ethyl acetate/petroleum ether ═ 1: 1) reacting at the temperature of-10 ℃ for 12 hours, filtering, evaporating the filtrate to remove the solvent, adding 20 ml of tetrahydrofuran into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.40 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of the dried concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture in a volume ratio of 1: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, detecting by TLC (developing solvent 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 pivaloyl amino dimethoxy benzo [ d ] shown in formula (I)]Aza derivatives
Figure BDA0001557619230000133
The quinazoline is off-white solid, the yield is 70.9%, and the melting point is 131-133 ℃.1H NMR and IR were the same as in example 11.
Example 16: pivaloylamidodimethoxybenzo [ d]Aza derivatives
Figure BDA0001557619230000134
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
Figure BDA0001557619230000135
Adding 0.164 g (1.10mmol) of 4-pyrrolidinyl pyridine and 15.0 ml of dichloromethane into a 50ml reaction bottle, dropwise adding 0.133 g (1.10mmol) of pivaloyl 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 is 1: 1), 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, and carrying out column chromatographyAfter homogenization, the solvent is evaporated off to give a mixture of dry concentrate and silica gel, the mixture is packed into a column and then mixed in a volume ratio of 10: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, detecting by TLC (developing solvent 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 pivaloyl amino dimethoxy benzo [ d ] shown in formula (I)]Aza derivatives
Figure BDA0001557619230000141
The quinazoline is off-white solid, the yield is 68.6 percent, and the melting point is 131-133 ℃.1H NMR and IR were the same as in example 11.
Example 17: in vitro test for anti-cancer Activity
(1) The prepared compound (I) is subjected to biological activity test of a human promyelocytic leukemia cell strain HL-60.
The test method comprises the following steps: tetrazolium salt reduction (MTT process).
Cell lines: human promyelocytic leukemia cell line HL-60. The tumor cell strain is purchased from cell banks of Shanghai Life sciences of Chinese academy of sciences.
The experimental procedure was as follows:
(a) preparation of samples: for soluble samples, each 1mg was dissolved in 40. mu.L DMSO, 2. mu.L was diluted with 1000. mu.L of medium to a concentration of 100. mu.g/mL, and then serially diluted with the culture medium to the use concentration.
(b) Culture of cells
Preparation of culture medium, each 1000mL of DMEM culture medium (Gibco) contains 80 ten thousand units of penicillin, 1.0g of streptomycin and 10% inactivated fetal bovine serum.
② cultivation of cells, inoculating tumor cells into culture medium, standing at 37 deg.C and 5% CO2Culturing in an incubator, and carrying out passage for 3-5 days.
Measuring the inhibition of the sample on the growth of tumor cells
The 2 nd generation cells were digested with EDTA-pancreatin digest and diluted to 1 × 10 with medium6Perml, 100. mu.L/well in 96-well cell culture plates, 37 ℃ 5% CO2Culture boxCulturing in medium. 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 Compound (I) on the growth of cancer cell line HL-60
Figure BDA0001557619230000151
(2) Quinazoline compounds (b) and (c) were synthesized according to example 11 by substituting pivaloyl chloride with 3-methoxybenzoyl chloride or cinnamoyl chloride, respectively, and following structures as shown in the following, in the same manner as in example 11:
Figure BDA0001557619230000152
the prepared quinazoline compounds (b) and (c) are subjected to a biological activity test of a human promyelocytic leukemia cell line HL-60 according to the method, and test results show that the quinazoline compounds (b) and (c) have no obvious inhibition effect on the human promyelocytic leukemia cell line HL-60, and the anticancer activities of the compounds (b) and (c) on the human promyelocytic leukemia cell line HL-60 are far lower than that of the compound (I). The specific results are shown in table 2:
TABLE 2 inhibitory Effect of Compounds (b) and (c) on the growth of cancer cell line HL-60
Figure BDA0001557619230000153
Figure BDA0001557619230000161
The anti-cancer activity in vitro test experiment shows that: the other 2 compounds (b) and (c) with similar structures have no obvious inhibition effect on the growth of the human promyelocytic leukemia cell line HL-60. The compound (I) has obvious inhibition effect on the growth of human promyelocytic leukemia cell strain HL-60, and is obviously superior to the compounds (b) and (c).
(3) Quinazoline compounds (k) and (g) were synthesized according to example 11 by substituting pivaloyl chloride with cyclohexylmethylchloroformate or propionyl chloride, respectively, and following structures as shown in the following, in the same manner as in example 11:
Figure BDA0001557619230000162
the prepared quinazoline compounds (k) and (g) are subjected to bioactivity test on human promyelocytic leukemia cell line HL-60 according to the method, and the test result shows that the quinazoline compounds (k) and (g) have poorer anti-cancer activity than the compound (I) on the human promyelocytic leukemia cell line HL-60. Specific results are shown in table 3:
TABLE 3 inhibitory Effect of Compounds (k) and (g) on the growth of cancer cell line HL-60
Figure BDA0001557619230000163
Figure BDA0001557619230000171

Claims (2)

1. Pivaloylaminodimethoxybenzo [ d ] as shown in formula (I)]Aza derivatives
Figure FDA0001557619220000012
The application of the fluoroquinazoline compound in preparing the medicaments for preventing or treating the human leukemia;
Figure FDA0001557619220000011
2. the use according to claim 1, wherein the medicament is a medicament having activity against the human promyelocytic leukemia cell line HL-60.
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Publication number Priority date Publication date Assignee Title
WO1995023141A1 (en) * 1994-02-23 1995-08-31 Pfizer Inc. 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents

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