CN108186649B - Application of propionyl amino chloro benzo [ d ] aza-quinazoline in preparing medicament for treating leukemia - Google Patents
Application of propionyl amino chloro benzo [ d ] aza-quinazoline in preparing medicament for treating leukemia Download PDFInfo
- Publication number
- CN108186649B CN108186649B CN201810069197.2A CN201810069197A CN108186649B CN 108186649 B CN108186649 B CN 108186649B CN 201810069197 A CN201810069197 A CN 201810069197A CN 108186649 B CN108186649 B CN 108186649B
- Authority
- CN
- China
- Prior art keywords
- ethyl acetate
- formula
- petroleum ether
- silica gel
- quinazoline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- 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 a propionyl amino chloro benzo [ d]Aza derivatives
Description
(I) technical field
(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 chloro benzo [ d]Aza derivativesMethod for preparing fluoroquinazoline compound for preventing or treating humanThe compound has obvious inhibition rate on human promyelocytic leukemia cell strain 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 propionylamino chlorobenzo [ d ] as shown in formula (I)]Aza derivativesThe application of the fluoroquinazoline compound in preparing the medicines for preventing or treating the tumor diseases, in particular the application in preparing the medicines for preventing or treating the human leukemia:
preferably, the medicament is a medicament for inhibiting the activity of the human promyelocytic leukemia cell line HL-60.
The invention provides propionylamino chlorobenzo [ d ] as shown in formula (I)]Aza derivativesThe 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 leukemia, and the compound has obvious inhibitory activity on a human promyelocytic leukemia cell line 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.
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。
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.
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 were added in this order to a 100ml three-necked flaskHeating to 60 ℃, performing TLC (follow-up detection by TLC (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring and reacting for 8 hours, closing the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of chloroform into the obtained concentrate to dissolve the obtained 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 a dried concentrate and the silica gel, filling the mixture into a column, and then performing TLC (follow-up detection) on the mixture according to 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.
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.
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.
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: 1 Petroleum ether/Ethyl acetate blendsEluting the combined solution by using an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to the 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.
0.40 g (0.77mmol) of nitrobenzo [ d ] prepared by the method of example 1 are successively introduced]Aza derivativesThe 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 derivativesThe 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。
0.40 g (0.77mmol) of nitrobenzo [ d ] prepared by the method of example 2 are successively introduced]Aza derivativesThe 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 derivativesThe 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.
0.40 g (0.77mmol) of nitrobenzo [ d ] prepared by the method of example 3 are successively reacted]Aza derivativesAdding 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 derivativesThe 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.
0.40 g (0.77mmol) of nitrobenzo [ d ] prepared by the method of example 4 are successively reacted]Aza derivativesAdding 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 derivativesThe 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.
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 7 are successively reacted]Aza derivativesAdding 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, tracking and 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 propionylaminochlorobenzo [ d ] shown in formula (I)]Aza derivativesThe 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。
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 8 are successively reacted]Aza derivativesAdding 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, tracking and 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 propionylaminochlorobenzo [ d ] shown in formula (I)]Aza derivativesThe yield of the quinazoline is 62.0 percent, and the melting point is 125-129 DEG C。1H NMR and IR were the same as in example 11.
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 9 are successively reacted]Aza derivativesAdding 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, tracking and 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 propionylaminochlorobenzo [ d ] shown in formula (I)]Aza derivativesThe 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.
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 10 are successively reacted]Aza derivativesAdding 0.067 g (0.55mmol) of 4-dimethylaminopyridine and 20.0 ml of toluene into a 50ml reaction bottle, dropwise adding a solution of 0.286 g (2.20mmol) of propionic anhydride and 7.0 ml of toluene under the condition of stirring at 5 ℃, heating to 50 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1), reacting for 3 hours, filtering, evaporating the solvent from the filtrate, dissolving the concentrate by adding 20 ml of tetrahydrofuran 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 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 5: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, tracking and 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 propionylaminochlorobenzo [ d ] shown in formula (I)]Aza derivativesThe quinazoline is an off-white solid, and the yield is 54.5%, and the melting point is 125-129 ℃.1H NMR and IR were the same as in example 11.
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 7 are successively reacted]Aza derivativesAdding 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, carrying out 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 0.4 to the dissolved solution to obtain a solution, and adding the solution to a solvent0g of column chromatography silica gel (300-400 mesh column chromatography silica gel), 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 mixing the mixture with the volume ratio of 1: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, tracking and 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 propionylaminochlorobenzo [ d ] shown in formula (I)]Aza derivativesThe 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.
0.27 g (0.55mmol) of aminobenzo [ d ] prepared by the method of example 7 are successively reacted]Aza derivativesAdding 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, tracking and 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 propionamidochlorobenzo shown in formula (I)[d]Aza derivativesThe 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 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
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. Under the same conditions without the sample,cells cultured in the same concentration of DMSO-containing medium were used as controls, and the IC of the samples 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
(2) Quinazoline compounds (b) and (c) were synthesized according to example 11 by substituting propionyl chloride with 3-methoxybenzoyl chloride or cinnamoyl chloride, respectively, and following the same procedure as in example 11:
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
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) According to example 11, propionyl chloride was replaced with cyclohexylmethylchloroformate, and the procedure of example 11 was otherwise the same to synthesize a quinazoline compound (k) having the following structure:
the prepared quinazoline compound (k) is subjected to biological activity test on a human promyelocytic leukemia cell line HL-60 according to the method, and the test result shows that the anticancer activity of the compound (k) on the human promyelocytic leukemia cell line HL-60 is far lower than that of the compound (I). Specific results are shown in table 3:
TABLE 3 inhibitory Effect of Compound (k) on the growth of cancer cell line HL-60
Claims (2)
2. the use of claim 1, wherein: the medicine is a medicine for inhibiting the activity of a human promyelocytic leukemia cell strain HL-60.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810069197.2A CN108186649B (en) | 2018-01-24 | 2018-01-24 | Application of propionyl amino chloro benzo [ d ] aza-quinazoline in preparing medicament for treating leukemia |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810069197.2A CN108186649B (en) | 2018-01-24 | 2018-01-24 | Application of propionyl amino chloro benzo [ d ] aza-quinazoline in preparing medicament for treating leukemia |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108186649A CN108186649A (en) | 2018-06-22 |
CN108186649B true CN108186649B (en) | 2020-05-26 |
Family
ID=62590985
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810069197.2A Active CN108186649B (en) | 2018-01-24 | 2018-01-24 | Application of propionyl amino chloro benzo [ d ] aza-quinazoline in preparing medicament for treating leukemia |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108186649B (en) |
Citations (1)
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 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HUT64533A (en) * | 1990-11-06 | 1994-01-28 | Pfizer | Method for producing quinazoline derivatives for improving anti-tumoric activity and preparations containing said compounds |
-
2018
- 2018-01-24 CN CN201810069197.2A patent/CN108186649B/en active Active
Patent Citations (1)
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 |
Also Published As
Publication number | Publication date |
---|---|
CN108186649A (en) | 2018-06-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108014113B (en) | Application of butyrylamidodimethoxybenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating cervical cancer | |
CN108125961B (en) | Application of morpholinyl acetamido methoxyphenyl benzazepinyl quinazoline compound in preparation of drugs for treating leukemia | |
CN108078994B (en) | Application of 6- (2-morpholinyl acetamido) quinazoline compound in preparation of medicine for treating lung cancer | |
CN109251196B (en) | Aminobenzo [ d ] aza-quinazoline compound and preparation method and application thereof | |
CN108042546B (en) | Application of morpholinyl acetamidobenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating cervical cancer | |
CN108017621B (en) | Morpholinyl acetamido dimethoxy benzo [ d ] aza-based quinazoline compound and preparation and application thereof | |
CN108295076B (en) | Application of propionyl-amino-dimethoxy-benzo [ d ] aza-quinazoline in preparation of drugs for treating lung cancer | |
CN108309984B (en) | Application of propionyl aminoquinazoline compound in preparation of medicine for treating cervical cancer | |
CN108117542B (en) | Propionyl amino methoxyphenyl benzo [ d ] nitrogen hetero-pinyl quinazoline compound, preparation and application | |
CN108329299B (en) | Butyrylamino chloro benzo [ d ] aza-based quinazoline compound, preparation and application thereof | |
CN108129461B (en) | Benzoylaminobenzo [ d ] aza-quinazoline compound, preparation and application thereof | |
CN108324718B (en) | Application of cyclohexyl methoxy formyl amino chloro benzo aza group quinazoline compound in leukemia treatment drug | |
CN108324717B (en) | Application of pivaloylchlorobenzo [ d ] aza-quinazoline compound in preparation of drugs for treating cervical cancer | |
CN108324719B (en) | Application of o-toluidino-acetamido-methoxy-phenyl benzazepinyl-quinazoline compound in preparation of cervical cancer treatment drug | |
CN108014112B (en) | Application of o-toluidine amino acetamido benzo [ d ] aza-based quinazoline compound in preparation of drugs for treating lung cancer | |
CN108276384B (en) | acetaminobenzo [ d ] azepinyl quinazoline compound and preparation and application thereof | |
CN108186649B (en) | Application of propionyl amino chloro benzo [ d ] aza-quinazoline in preparing medicament for treating leukemia | |
CN108125962B (en) | Application of benzo [ d ] aza-quinazoline compound in preparation of drugs for treating lung cancer | |
CN108329300B (en) | Nitrobenzo [ d ] aza-quinazoline compound and preparation method and application thereof | |
CN108143736B (en) | Application of butyrylaminobenzo [ d ] aza-based quinazoline in preparation of drugs for treating lung cancer | |
CN108014114B (en) | Application of chloroacetylamidoquinazoline compounds in preparation of drugs for treating lung cancer | |
CN108078992B (en) | Application of pivaloyl-amino-dimethoxy-benzo [ d ] aza-quinazoline compound in preparation of drugs for treating leukemia | |
CN108245519B (en) | Application of butyrylaminoquinazoline compound in preparation of drugs for treating leukemia | |
CN108125960B (en) | Application of isobutyrylaminobenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating lung cancer | |
CN108164510B (en) | Chloroacetamidobenzo [ d ] aza-based quinazoline compound and preparation method and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |