CN108033949B - 6- (2- dipropyl aminoacetylamino) quinazoline compounds and preparation and application - Google Patents
6- (2- dipropyl aminoacetylamino) quinazoline compounds and preparation and application Download PDFInfo
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- CN108033949B CN108033949B CN201810070315.1A CN201810070315A CN108033949B CN 108033949 B CN108033949 B CN 108033949B CN 201810070315 A CN201810070315 A CN 201810070315A CN 108033949 B CN108033949 B CN 108033949B
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- C07—ORGANIC CHEMISTRY
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- 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 kind of 6- (2- dipropyl aminoacetylamino) quinazoline compounds and preparations and application.6- (2- dipropyl aminoacetylamino) quinazoline compounds provided by the invention all have significant inhibitory activity to MCF-7 cell strainHJ2mm, human lung cancer cell lines A-549, people in loop strain HL-60, human cervical carcinoma cell lines Siha, be expected to be applied to preparation prevention or treatment human breast carcinoma, human lung cancer, human leukemia, human cervical carcinoma drug in.The present invention provides the preparation methods of 6- (the 2- dipropyl aminoacetylamino) quinazoline compounds, and the preparation method is simple, and easily operated, raw material is easy to get and lower production costs, are suitable for practical.
Description
(1) technical field
The present invention relates to a kind of quinazoline compounds and its application, in particular to a kind of 6- (2- dipropyl glycyl ammonia
Base) quinazoline compounds and preparation method thereof and the compound be in the drug of preparation prevention or treatment tumor disease
Application.
(2) background technique
Quinazoline compounds have many preferable bioactivity, have a wide range of applications in field of medicaments, and especially one
The quinazoline derivative of a little special constructions has apparent antiviral activity, antibacterial activity, anti-tumor activity etc., quinazoline ditosylate salt
Compound has had listed some kinds as anti-tumor drug.Such as the Gefitinib for being used to treat lung cancer of listing
(Gefitinib) and Tarceva (Erlotinib), and the Lapatinib (Lapatinib) for treating breast cancer, they
Belong to quinazoline compounds.Novel quinazoline compounds and its bioactivity also common document report (refering to 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).Certainly majority quinazoline
Class compound does not simultaneously have anti-tumor activity.
(3) summary of the invention
The purpose of the present invention is to provide a kind of novel quinazoline quinoline class compound with anticancer activity -6- (2- dipropyl ammonia
Base acetylamino) quinazoline compounds and its preparation method and application, such compound is thin to human lung cancer under doses
Born of the same parents' strain A-549, MCF-7 cell strainHJ2mm, people in loop strain HL-60 or human cervical carcinoma cell lines Siha tool
There is good inhibitory effect；And such compounds process for production thereof is easy, easily operated, raw material is easy to get, and lower production costs, fits
In industrial applications.
For achieving the above object, the present invention adopts the following technical scheme:
In a first aspect, the present invention provides 6- shown in a kind of formula (I) (2- dipropyl aminoacetylamino) quinazoline ditosylate salts
Object is closed,
Second aspect, the present invention provide 6- (2- dipropyl aminoacetylamino) quinazoline ditosylate salt chemical combination shown in a kind of formula (I)
The preparation method of object, the method are as follows: (1) mix compound shown in formula (II) with compound shown in formula (III), organic
In solvent A, under the action of basic catalyst B, 25~120 DEG C reacted (TLC tracking and monitoring, solvent be ethyl acetate/
Petroleum ether=1:3 (v/v), preferably 40~100 DEG C 0.5~12h of reaction), after fully reacting, reaction solution is isolated and purified, is made
Compound shown in formula (IV)；The organic solvent A is selected from one of following: chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, second
Nitrile or N,N-dimethylformamide；The basic catalyst B is selected from one of following: pyridine, diethylamine, triethylamine, quinoline, N,
N- dimethylaniline, 4-dimethylaminopyridine, 4- pyrollidinopyridine or sodium carbonate (preferably pyridine, diethylamine, triethylamine, N, N-
Dimethylaniline or 4-dimethylaminopyridine)；
(2) formula (IV) compound represented under reducing agent E effect, has been reacted in organic solvent D at 25~100 DEG C
(TLC tracking and monitoring, solvent are ethyl acetate/petroleum ether=1:1 (v/v), preferably 40~80 DEG C 0.5~12h of reaction) entirely, instead
Liquid is answered to filter, the concentrate after filtrate decompression concentration is dry (preferably 25 DEG C vacuum drying), and formula (V) compound represented is made；
The organic solvent D is one of following: chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N- dimethyl formyl
Amine；The reducing agent E is one of following: iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate；It is described
Iron powder/concentrated hydrochloric acid refers to that the mixing of iron powder and concentrated hydrochloric acid arbitrary proportion, iron powder/acetic acid refer to the mixed of iron powder and acetic acid arbitrary proportion
It closes, the palladium carbon/ammonium formate refers to the mixing of palladium carbon Yu ammonium formate arbitrary proportion, and the palladium carbon/hydrazine hydrate is palladium carbon and hydration
The mixture of hydrazine arbitrary proportion；
(3) compound shown in formula (V) is mixed with chloracetyl chloride or chloroacetic anhydride, under basic catalyst F effect, in
In organic solvent G, -10~50 DEG C of fully reactings (TLC tracking and monitoring, solvent are ethyl acetate/petroleum ether=1:1 (v/v),
It is preferred that -10~50 DEG C of 3~12h of reaction), formula (VI) compound represented is made in the post-treated A of reaction solution；The alkalinity is urged
Agent F is one of following: pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylaniline, 4-dimethylaminopyridine, 4- pyrrolidines
Yl pyridines or sodium carbonate；The organic solvent G is one of following: tetrahydrofuran, methylene chloride, chloroform, ethyl acetate, ether,
Acetonitrile, toluene or benzene；
(4) compound shown in formula (VI) is mixed with di-n-propylamine, in organic solvent J, in the effect of basic catalyst K
Under, 25~120 DEG C reacted (TLC tracking and monitoring, solvent be ethyl acetate/petroleum ether=1:1 (v/v), preferably 40~
100 DEG C of 0.5~36h of reaction), after fully reacting, by the post-treated B of reaction solution, compound shown in formula (I) is made；It is described organic
Solvent J is selected from one of following: chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N,N-dimethylformamide；It is described
Basic catalyst K be selected from it is one of following: pyridine, triethylamine, quinoline, N, N- dimethylaniline, 4-dimethylaminopyridine, 4- pyrroles
Alkyl pyridine or sodium carbonate (preferably pyridine, quinoline, triethylamine, N, N- dimethylaniline or 4-dimethylaminopyridine).
Further, in step (1), compound shown in the formula (III) and compound, basic catalyst B shown in formula (II)
The ratio between the amount of substance of feeding intake is 1.0 ﹕, 0.8~1.2 ﹕ 1.0~8.0.
Further, in step (1), the dosage of the organic solvent A is calculated as 10 with the quality of compound shown in formula (III)~
50mL/g。
Further, the method that reaction solution described in step (1) of the present invention isolates and purifies are as follows: after fully reacting, by reaction solution
Solvent is evaporated off, concentrate is taken to be dissolved with organic solvent C, obtain lysate, then into lysate be added concentrate 1.0~
After mixing, solvent is evaporated off in the column chromatography silica gel of 2.0 times of weight, dry, the mixture of concentrate and silica gel is obtained, by mixture
Fill column, then using volume ratio for 1:0.1~10 petroleum ether and ethyl acetate mixture as eluant, eluent, collect contain target components
Efflux (preferably with ethyl acetate/petroleum ether=1:3 (v/v) be solvent tracing detection, collect target components, preferably receive
Collect the component that Rf value is 0.5), it is concentrated under reduced pressure, dry (preferably 50 DEG C of dryings) obtain formula (IV) compound represented；It is described to have
Solvent C is one of following: ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.The organic solvent C dosage is residual can dissolve
Stay object.
Further, in step (2), when the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, formula (IV) institute
The mass ratio that feeds intake of the iron powder in compound and reducing agent E, concentrated hydrochloric acid or the acetic acid that show is 1.0 ﹕, 1.0~3.0 ﹕ 0.2~1.0.
In the present invention, concentrated hydrochloric acid mass concentration is 36%~38%, and acetic acid uses glacial acetic acid.
Further, in step (2), when the reducing agent E is palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate, formula (IV) institute
The compound that shows and the mass ratio that feeds intake of palladium carbon in reducing agent E, ammonium formate or hydrazine hydrate be 1.0 ﹕, 0.1~0.5 ﹕ 1.0~
3.0.In the present invention be applicable in palladium carbon in palladium mass loading amount be 2~10%, preferably 5%, hydrazine hydrate mass concentration be 40~
80%, preferably 80%.
Further, in step (2), the dosage of the organic solvent D is calculated as 10 with the quality of formula (IV) compound represented
~50mL/g.
Further, in step (3), compound shown in the formula (V) and chloracetyl chloride or chloroacetic anhydride, base catalysis
The ratio between amount for the substance that feeds intake of agent F is 1 ﹕, 1.0~8.0 ﹕ 1.0~3.0.
Further, in step (3), the dosage of the organic solvent G is calculated as 11 with the quality of compound shown in formula (V)~
100mL/g。
Further, the specific recommendation step of the present invention (3) carries out as follows: under the conditions of -10~10 DEG C, toward formula
(V) in the organic solvent G solution of compound shown in and basic catalyst F or toward compound and base catalysis shown in formula (V)
The organic solvent G solution of chloracetyl chloride or chloroacetic anhydride is added dropwise in agent F, drop finishes, and -10~50 DEG C are reacted 3~12 hours, and gained is anti-
The post-treated A of liquid is answered to obtain compound shown in formula (VI)；Dissolve the organic solvent volume dosage pair of chloracetyl chloride or chloroacetic anhydride
The present invention does not influence, and total dosage of the organic solvent G is calculated as 11~100mL/g with the quality of compound shown in formula (V).Have
Total dosage of solvent G refers to the organic solvent G and dissolution chloracetyl chloride of compound shown in dissolution basic catalyst F and formula (V)
Or the total volume of chloroacetic anhydride organic solvent G.
Further, the method for step (3) the of the present invention reaction solution post-processing A are as follows: after fully reacting, by reaction solution mistake
Filter, filtrate steaming removal solvent take concentrate to be dissolved with organic solvent H, obtain lysate, and concentration is then added into lysate
After mixing, solvent is evaporated off in the column chromatography silica gel of 1.0~2.0 times of weight of object, dry, obtains the mixture of concentrate and silica gel, will
Mixture fill column, then using volume ratio for 1:0.1~10 petroleum ether and ethyl acetate mixture as eluant, eluent, collect contain mesh
Mark component efflux (preferably with ethyl acetate/petroleum ether=1:1 (v/v) be solvent tracing detection, collect target components,
It is preferred that collecting the component that Rf value is 0.5), it is concentrated under reduced pressure, dry (preferably 50 DEG C of dryings) obtain formula (VI) compound represented；
The organic solvent H is one of following: ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.The organic solvent H dosage is with can
Dissolution residual substance.
Further, in step (4), the substance that feeds intake of compound shown in the formula (VI) and di-n-propylamine, basic catalyst K
The ratio between amount be 1.0 ﹕, 0.8~8.0 1.0~8.0. of ﹕
Further, in step (4), the dosage of the organic solvent J is calculated as 10 with the quality of compound shown in formula (VI)~
60mL/g。
Further, the method for the post-processing of reaction solution described in step (4) of the present invention B are as follows: after fully reacting, reaction solution is steamed
Except solvent, concentrate is taken to be dissolved with organic solvent M, obtain lysate, then into lysate be added concentrate 1.0~
After mixing, solvent is evaporated off in the column chromatography silica gel of 2.0 times of weight, dry, the mixture of concentrate and silica gel is obtained, by mixture
Fill column, then using volume ratio for 1:0.1~10 petroleum ether and ethyl acetate mixture as eluant, eluent, collect contain target components
Efflux (preferably with ethyl acetate/petroleum ether=1:1 (v/v) be solvent tracing detection, collect target components, preferably receive
Collect the component that Rf value is 0.5), it is concentrated under reduced pressure, dry (preferably 50 DEG C of dryings) obtain formula (I) compound represented；It is described organic
Solvent M is one of following: ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.The organic solvent M dosage is can dissolve residual
Object.
The third aspect, the invention further relates to 6- shown in formula (I) (2- dipropyl aminoacetylamino) quinazoline compounds to exist
Application in preparation prevention or tumor, particularly useful for making the application in prevention or treatment human breast carcinoma drug.
Preferably, the drug is with the inhibition active drug of MCF-7 cell strainHJ2mm.Provided by the inventionization
Closing object (I) has preferable inhibitory effect to MCF-7 cell strainHJ2mm.
6- shown in formula (I) of the present invention (2- dipropyl aminoacetylamino) quinazoline compounds are also to human lung carcinoma cell
Strain A-549, people in loop strain HL-60 or human cervical carcinoma cell lines Siha have significant inhibiting effect, can answer
It is used to prepare prevention or treats in human lung cancer, human leukemia or the drug of human cervical carcinoma.
Organic solvent A of the present invention, C, D, G, H, J and M are organic solvent, for the ease of distinguishing used in different step
Organic solvent is different and names, and letter itself does not have meaning；The catalyst B, reducing agent E, catalyst F and catalyst K are
Catalyst is named for the ease of distinguishing different step used catalyst difference, and letter itself does not have meaning；The post-processing A,
Post-processing B is post-processing, and the post-processing step for the ease of distinguishing different step is different and names, and letter does not contain itself
Justice.
The beneficial effects are mainly reflected as follows: (1) of the present invention 6- (2- dipropyl aminoacetylamino) quinoline azoles
The anticancer activity that quinoline class compound (I) has had is expected in the drug for being applied to preparation prevention or treatment tumor disease, especially
Application in human breast carcinoma, human lung cancer, human leukemia or human cervical carcinoma's drug；(2) 6- (2- dipropyl amino second provided by the invention
Acylamino-) quinazoline compounds (I) preparation method, simple easily operated, raw material is easy to get, and lower production costs, is suitable for
It is practical.
(4) specific embodiment
The present invention is further described in conjunction with specific embodiments, embodiment below illustrate it is of the invention, rather than
It limit the invention in any way.
Compound (II) prepare reference literature (Weinstock, J.et al.J.Med.Chem., 1986,29 (11),
Method 2315-2325) is prepared.The chloro- 6- nitro-quinazoline (III) of 4- prepares reference literature (Fernandes, C.et
Al.Bioorg.Med.Chem., 2007,15 (12), 3974-3980) method be prepared.
Palladium carbon (Pd/C) model D5H5A that the embodiment of the present invention uses, is purchased from Shaanxi Ruike New Materials Co., Ltd..
The preparation of embodiment 1:6- nitro-quinazoline (IV)
Successively by the chloro- 6- nitro-quinazoline (III) of 1.20 grams of (5.73mmol) 4- and 2.39 grams of (6.87mmol) compounds
(II), 3.62 grams of (45.76mmol) pyridines, 12 milliliters of chloroforms are added in 50 milliliters of reaction flask, are heated to 40 DEG C, TLC tracking
Detection (solvent is ethyl acetate/petroleum ether=1:3 (v/v)), is stirred to react 10 hours, closes reaction, reaction solution is evaporated off molten
10 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, obtains lysate, 3.0 grams of columns is added into lysate for agent
Chromatographic silica gel (300~400 mesh column chromatography silica gel), after mixing, is evaporated off solvent, obtains the mixture of dry concentrate and silica gel,
Mixture is filled into column, then using volume ratio for 1:10 petrol ether/ethyl acetate mixed solution as eluant, eluent, elution, TLC tracking
Detection (solvent is ethyl acetate/petroleum ether=1:3 (v/v)), is collected according to TLC detection containing formula (IV) compound represented
Eluent (Rf value is 0.5), collection liquid concentration, 50 DEG C are dried to obtain faint yellow solid product shown in formula (IV), yield
85.1%, 164~166 DEG C of fusing point.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。
The preparation of embodiment 2:6- nitro-quinazoline (IV)
Successively by the chloro- 6- nitro-quinazoline (III) of 1.20 grams of (5.73mmol) 4- and 1.59 grams of (4.57mmol) compounds
(II), 1.67 grams of (22.83mmol) diethylamine, 60 milliliters of toluene are added in 100 milliliters of three-necked flask, are heated to 100 DEG C,
TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:3 (v/v)), is stirred to react 2 hours, closes reaction, reaction solution
Solvent is evaporated off, 20 milliliters of ethyl alcohol are added in obtained concentrate and are dissolved, lysate is obtained, 2.5 grams are added into lysate
Column chromatography silica gel (300~400 mesh column chromatography silica gel), after mixing, is evaporated off solvent, obtains the mixing of dry concentrate and silica gel
Mixture is filled column by object, then using volume ratio for 1:5 petrol ether/ethyl acetate mixed solution as eluant, eluent, elution, TLC with
Track detection (solvent is ethyl acetate/petroleum ether=1:3 (v/v)), collects according to TLC detection and contains formula (IV) compound represented
Eluent (Rf value be 0.5), collection liquid concentration, 50 DEG C are dried to obtain faint yellow solid product shown in formula (IV), yield
72.6%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
The preparation of embodiment 3:6- nitro-quinazoline (IV)
Successively by the chloro- 6- nitro-quinazoline (III) of 1.20 grams of (5.73mmol) 4- and 1.99 grams of (5.72mmol) compounds
(II), 0.58 gram of (5.73mmol) triethylamine, 60 milliliters of ethyl alcohol are added in 100 milliliters of three-necked flask, are heated to 60 DEG C, TLC
Tracing detection (solvent is ethyl acetate/petroleum ether=1:3 (v/v)), is stirred to react 8 hours, closes reaction, reaction solution is evaporated off
20 milliliters of chloroforms are added in obtained concentrate and are dissolved, obtains lysate, 2.5 grams of column layers is added into lysate for solvent
It analyses silica gel (300~400 mesh column chromatography silica gel), after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, it will
Mixture fill column, then using volume ratio for 10:1 petrol ether/ethyl acetate mixed solution as eluant, eluent, elution, TLC tracking inspection
(solvent is ethyl acetate/petroleum ether=1:3 (v/v)) is surveyed, is detected according to TLC and collects washing for (IV) compound represented Han formula
De- liquid (Rf value is 0.5), collection liquid concentration, 50 DEG C are dried to obtain faint yellow solid product shown in formula (IV), yield 77.2%,
164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
The preparation of embodiment 4:6- nitro-quinazoline (IV)
Successively by the chloro- 6- nitro-quinazoline (III) of 1.20 grams of (5.73mmol) 4- and 2.20 grams of (6.32mmol) compounds
(II), 1.40 grams of (11.46mmol) 4-dimethylaminopyridine, 60 milliliters of isopropanols are added in 100 milliliters of three-necked flask, room temperature
25 DEG C of stirrings, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:3 (v/v)), react 12 hours, close reaction,
Solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, lysate are obtained, into lysate
4.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) is added, after mixing, solvent is evaporated off, obtains dry concentrate and silicon
Mixture is filled column by the mixture of glue, then using volume ratio for 5:1 petrol ether/ethyl acetate mixed solution as eluant, eluent, wash
De-, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:3 (v/v)) is collected according to TLC detection containing shown in formula (IV)
Compound eluent (Rf value be 0.5), collection liquid concentration, 50 DEG C are dried to obtain the production of faint yellow solid shown in formula (IV)
Object, yield 80.2%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
The preparation of embodiment 5:6- nitro-quinazoline (IV)
Successively by the chloro- 6- nitro-quinazoline (III) of 1.20 grams of (5.73mmol) 4- and 1.79 grams of (5.15mmol) compounds
(II), 1.04 grams of (8.58mmol) N, N- dimethylanilines, 12 milliliters of n,N-Dimethylformamide are added in 50 milliliters of reaction flask,
120 DEG C are heated to, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:3 (v/v)) is stirred to react 0.5 hour, closes
Reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, lysate is obtained, to
5.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in lysate, after mixing, solvent is evaporated off, obtain dry dense
Mixture is filled column by the mixture of contracting object and silica gel, is then for the petrol ether/ethyl acetate mixed solution of 1:1 with volume ratio
Eluant, eluent, elution, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:3 (v/v)) are collected according to TLC detection and are contained
The eluent (Rf value be 0.5) of formula (IV) compound represented, collection liquid concentration, 50 DEG C be dried to obtain it is yellowish shown in formula (IV)
Color solid product, yield 89.6%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
The preparation of embodiment 6:6- nitro-quinazoline (IV)
Successively by the chloro- 6- nitro-quinazoline (III) of 1.20 grams of (5.73mmol) 4- and 2.39 grams of (6.87mmol) compounds
(II), 3.62 grams of (45.76mmol) pyridines, 20 milliliters of propyl alcohol are added in 50 milliliters of reaction flask, are heated to 40 DEG C, TLC tracking
Detection (solvent is ethyl acetate/petroleum ether=1:3 (v/v)), is stirred to react 10 hours, closes reaction, reaction solution is evaporated off molten
20 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, obtains lysate, 3.5 grams of columns is added into lysate for agent
Chromatographic silica gel (300~400 mesh column chromatography silica gel), after mixing, is evaporated off solvent, obtains the mixture of dry concentrate and silica gel,
Mixture is filled into column, then using volume ratio for 1:1 petrol ether/ethyl acetate mixed solution as eluant, eluent, elution, TLC tracking
Detection (solvent is ethyl acetate/petroleum ether=1:3 (v/v)), is collected according to TLC detection containing formula (IV) compound represented
Eluent (Rf value is 0.5), collection liquid concentration, 50 DEG C are dried to obtain faint yellow solid product shown in formula (IV), yield
78.3%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
The preparation of embodiment 7:6- amido quinazoline (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 1 method of embodiment, 0.40 gram
(6.34mmol) ammonium formate, 0.04 gram of 5%Pd/C, 4.0 milliliters of chloroforms are added in reaction flask, 25 DEG C of room temperature stirrings, TLC tracking
Detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)), reacts 12 hours, filtering, filtrate concentration, 25 DEG C of vacuum drying
Obtain faint yellow solid product 6- amido quinazoline (V), yield 98.2%, 122~126 DEG C of fusing point.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。
The preparation of embodiment 8:6- amido quinazoline (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 2 method of embodiment, 1.20 grams
(19.18mmol) 80wt% hydrazine hydrate, 0.20 gram of 5%Pd/C, 20.0 milliliters of toluene are added in 50 milliliters of reaction flask, heating
To 100 DEG C, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)) is stirred to react 0.5 hour, cooled
Filter, filtrate concentration, 25 DEG C of vacuum drying obtain faint yellow solid product 6- amido quinazoline (V), yield 100.0%, fusing point
122~126 DEG C.1H NMR and IR is the same as embodiment 7.
The preparation of embodiment 9:6- amido quinazoline (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 3 method of embodiment, 0.08 gram of concentrated hydrochloric acid
(mass concentration 36~38%), 0.40 gram of iron powder, 20.0 ml methanols are added in 50 milliliters of reaction flask, are heated to 40 DEG C,
TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)), is stirred to react 8 hours, cold filtration, filtrate is dense
Contracting, 25 DEG C of vacuum drying obtain faint yellow solid product 6- amido quinazoline (V), yield 94.1%, and 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
The preparation of embodiment 10:6- amido quinazoline (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 4 method of embodiment, 0.40 gram of acetic acid,
1.20 grams of iron powders, 20.0 milliliters of isopropanols are added in 50 milliliters of reaction flask, are heated to 80 DEG C, TLC tracing detection (solvent
It for ethyl acetate/petroleum ether=1:1 (v/v)), is stirred to react 3 hours, cold filtration, filtrate concentration, 25 DEG C of vacuum drying obtain
Faint yellow solid product 6- amido quinazoline (V), yield 97.5%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 11: the preparation of chloro acetylamino quinazoline (VI)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 7 method of embodiment, 0.13 gram
(1.64mmol) pyridine, 3 milliliters of tetrahydrofurans are added in reaction flask, and 0.497 gram is added dropwise under -10 DEG C of stirring conditions
(4.40mmol) chloracetyl chloride, drop finish, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1), under the conditions of -10 DEG C
Reaction 12 hours, filtering, filtrate steaming removal solvent, concentrate are added 10 milliliters of ethyl acetate and are dissolved, and obtain lysate, Xiang Rong
It solves and 0.60 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in liquid, after mixing, solvent is evaporated off, obtains dry concentration
Mixture is filled column by the mixture of object and silica gel, and then the petrol ether/ethyl acetate mixed solution with volume ratio for 1:10 is to wash
De- agent, elution, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)) are collected according to TLC detection and contain formula
(VI) eluent (Rf value is 0.5) of compound represented, collection liquid concentration, 50 DEG C are dried to obtain chloracetyl shown in formula (VI)
Amido quinazoline yellow solid, yield 95.6%, 255~258 DEG C of fusing point.1H NMR(500MHz,CDCl3)δ:3.26-3.33
(m, 1H), 3.54 (dt, J=3.7,15.4Hz, 1H), 3.74 (s, 3H), 3.81-3.82 (m, 7H), 3.95-4.05 (m, 2H),
4.28 (s, 2H), 4.64 (dd, J=8.2,14.4Hz, 1H), 5.24 (t, J=8.8Hz, 1H) .6.64 (s, 1H), 6.88 (d, J
=8.8Hz, 2H), 7.07 (d, J=8.7Hz, 2H), 7.53 (dd, J=2.3,9.0Hz, 1H), 7.83 (d, J=9.0Hz, 1H),
8.54 (s, 1H), 8.60 (s, 1H), 8.69 (d, J=2.2Hz, 1H).IR(KBr,cm-1)ν:3396,2998,2937,2835,
1694,1557,1525,1510,1489,1463,1349,1249,1179,1036,840。
Embodiment 12: the preparation of chloro acetylamino quinazoline (VI)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 8 method of embodiment, 0.04 gram
(0.55mmol) diethylamine, 10.0 milliliters of chloroforms are added in 50 milliliters of reaction flask, and 0.07 gram is added dropwise under 10 DEG C of stirring conditions
(0.55mmol) chloracetyl chloride and 5.0 milliliters of chloroform mixed solutions, drop finish, and (solvent is ethyl acetate/stone to TLC tracing detection
Oily ether=1:1 (v/v)), it reacts 8 hours under the conditions of 10 DEG C, filters, filtrate steaming removal solvent, 20 milliliters of ethyl alcohol are added in concentrate will
It is dissolved, and obtains lysate, and 0.26 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added into lysate, is mixed
Afterwards, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, is then the petroleum of 1:5 with volume ratio
Ether/ethyl acetate mixture is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1:1 (v/ to TLC tracing detection
V)), the eluent (Rf value is 0.5) containing formula (VI) compound represented is collected according to TLC detection, collection liquid concentration, 50 DEG C dry
It is dry to obtain chloro acetylamino quinazoline yellow solid shown in formula (VI), yield 83.4%, 255~258 DEG C of fusing point.1H NMR and
IR is the same as embodiment 11.
Embodiment 13: the preparation of chloro acetylamino quinazoline (VI)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 9 method of embodiment, 0.111 gram
(1.10mmol) triethylamine, 10.0 milliliters of ethyl acetate are added in 50 milliliters of reaction flask, are added dropwise 0.14 under 0 DEG C of stirring condition
Gram (1.09mmol) chloracetyl chloride and 5.0 milliliters of ethyl acetate solutions, drop finish, TLC tracing detection (solvent be ethyl acetate/
Petroleum ether=1:1), it reacts 6 hours under the conditions of 25 DEG C, filters, filtrate steaming removal solvent, 20 milliliters of chloroforms are added in concentrate, and its is molten
Solution obtains lysate, and 0.30 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added into lysate, after mixing, steams
Except solvent, obtain the mixture of dry concentrate and silica gel, mixture filled into column, then with volume ratio for 10:1 petroleum ether/
Ethyl acetate mixture is eluant, eluent, elution, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)),
The eluent (Rf value be 0.5) containing formula (VI) compound represented is collected according to TLC detection, and collection liquid concentration, 50 DEG C dry
To chloro acetylamino quinazoline yellow solid shown in formula (VI), yield 70.5%, 255~258 DEG C of fusing point.1H NMR and IR is same
Embodiment 11.
Embodiment 14: the preparation of chloro acetylamino quinazoline (VI)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 10 method of embodiment, 0.067 gram
(0.55mmol) 4-dimethylaminopyridine, 20.0 milliliters of toluene are added in 50 milliliters of reaction flask, are added dropwise under 5 DEG C of stirring conditions
The solution of 0.376 gram of (2.20mmol) chloroacetic anhydride and 7.0 milliliters of toluene, drop finish, and are heated to 50 DEG C, (the expansion of TLC tracing detection
Agent is ethyl acetate/petroleum ether=1:1), it reacts 3 hours, filtering, filtrate steaming removal solvent, 20 milliliters of tetrahydro furans are added in concentrate
It mutters and is dissolved, obtain lysate, 0.40 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added into lysate, mix
After even, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, is then the stone of 5:1 with volume ratio
Oily ether/ethyl acetate mixture is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1:1 to TLC tracing detection
(v/v)) eluent (Rf value is 0.5) containing formula (VI) compound represented, is collected according to TLC detection, collection liquid is concentrated, and 50 DEG C
It is dried to obtain chloro acetylamino quinazoline yellow solid shown in formula (VI), yield 85.3%, 255~258 DEG C of fusing point.1H NMR
With IR with embodiment 11.
Embodiment 15: the preparation of chloro acetylamino quinazoline (VI)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 7 method of embodiment, 0.213 gram
(1.65mmol) quinoline, 15.0 milliliters of benzene are added in 50 milliliters of reaction flask, and 0.28 gram is added dropwise under -10 DEG C of stirring conditions
The solution of (2.19mmol) chloracetyl chloride and 5.0 milliliters of benzene, drop finish, and (solvent is ethyl acetate/petroleum ether to TLC tracing detection
=1:1), it reacts 12 hours under the conditions of -10 DEG C, filters, filtrate steaming removal solvent, 20 milliliters of tetrahydrofurans are added in concentrate, and its is molten
Solution obtains lysate, and 0.40 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added into lysate, after mixing, steams
Except solvent, the mixture of dry concentrate and silica gel is obtained, mixture is filled into column, is then petroleum ether/second of 1:1 with volume ratio
Acetoacetic ester mixed solution is eluant, eluent, elution, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)), root
The eluent (Rf value is 0.5) containing formula (VI) compound represented is collected according to TLC detection, collection liquid concentration, 50 DEG C are dried to obtain
Chloro acetylamino quinazoline yellow solid shown in formula (VI), yield 82.1%, 255~258 DEG C of fusing point.1H NMR and IR are the same as real
Apply example 11.
Embodiment 16: the preparation of chloro acetylamino quinazoline (VI)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 7 method of embodiment, 0.164 gram
(1.10mmol) 4- pyrollidinopyridine, 15.0 milliliters of methylene chloride are added in 50 milliliters of reaction flask, 10 DEG C of stirring conditions
00.14 gram of (1.09mmol) chloracetyl chloride of lower dropwise addition and 5.0 milliliters of dichloromethane solutions, drop finish, TLC tracing detection (solvent
It for ethyl acetate/petroleum ether=1:1), reacts 8 hours, filters, filtrate steaming removal solvent under the conditions of 10 DEG C, 20 millis are added in concentrate
It rises ethyl alcohol to be dissolved, obtains lysate, 0.50 gram of column chromatography silica gel is added into lysate, and (300~400 mesh columns chromatograph silicon
Glue), after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, is then with volume ratio
The petrol ether/ethyl acetate mixed solution of 10:1 is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum to TLC tracing detection
Ether=1:1 (v/v)), the eluent (Rf value is 0.5) containing formula (VI) compound represented is collected according to TLC detection, collection liquid is dense
Contracting, 50 DEG C are dried to obtain chloro acetylamino quinazoline yellow solid, yield 90.2%, fusing point 255~258 shown in formula (VI)
℃。1H NMR and IR is the same as embodiment 11.
The preparation of embodiment 17:6- (2- dipropyl aminoacetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 11 method of embodiment preparation and 0.694 gram
(6.86mmol) di-n-propylamine, 3.626 grams of (45.84mmol) pyridines, 32.5 ml methanols are added in 50 milliliters of reaction flask, add
To 40 DEG C, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)) is stirred to react 10 hours, closes anti-heat
It answers, solvent is evaporated off in reaction solution, and 10 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, lysate are obtained, to dissolution
1.5 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in liquid, after mixing, solvent is evaporated off, obtains dry concentrate
With the mixture of silica gel, mixture is filled into column, then using volume ratio for 1:10 petrol ether/ethyl acetate mixed solution as elution
Agent, elution, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)) detect according to TLC and collect (I) containing formula
The eluent (Rf value is 0.5) of compound represented, collection liquid concentration, 50 DEG C are dried to obtain the production of gray solid shown in formula (I)
Object, yield 48.2%, 147~150 DEG C of fusing point.1H NMR(500MHz,[D6] DMSO) δ: 0.88 (t, J=7.4Hz, 6H), 1.48
(dd, J=14.8,7.4Hz, 4H), 2.54 (t, J=7.3Hz, 4H), 3.19-3.25 (m, 1H), 3.29 (d, J=4.6Hz,
2H),3.39-3.42(m,1H),3.69(s,3H),3.70(s,3H),3.72(s,3H),3.76-3.93(m,3H),4.49(dd,
J=8.3,14.4Hz, 1H), 5.28 (t, J=8.5Hz, 1H), 6.84-6.89 (m, 3H), 7.07 (d, J=8.7Hz, 2H),
7.71 (d, J=9.0Hz, 1H), 7.78 (dd, J=2.2,9.0Hz, 1H), 8.45 (s, 1H), 8.70 (s, 1H), 9.97 (s,
1H)。HRMS-ESI m/z:632.2991[M+H]+。IR(KBr,cm-1)ν:2959,2933,2871,2834,1687,1567,
1524,1461,1347,1249,1037,834。
The preparation of embodiment 18:6- (2- dipropyl aminoacetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 12 method of embodiment preparation and 0.462 gram
(4.57mmol) di-n-propylamine, 2.95 grams of (22.84mmol) quinoline, 80 milliliters of toluene are added in 100 milliliters of three-necked flask, add
To 100 DEG C, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)) is stirred to react 2 hours, closes anti-heat
It answers, solvent is evaporated off in reaction solution, and 20 milliliters of ethyl alcohol are added in obtained concentrate and are dissolved, lysate are obtained, into lysate
2.5 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) is added, after mixing, solvent is evaporated off, obtains dry concentrate and silicon
Mixture is filled column by the mixture of glue, then using volume ratio for 1:5 petrol ether/ethyl acetate mixed solution as eluant, eluent, wash
De-, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)) is collected according to TLC detection containing shown in formula (I)
Compound eluent (Rf value be 0.5), collection liquid concentration, 50 DEG C are dried to obtain product as off-white solid shown in formula (I),
Yield 53.7%, 147~150 DEG C of fusing point.1H NMR and IR is the same as embodiment 17.
The preparation of embodiment 19:6- (2- dipropyl aminoacetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 13 method of embodiment preparation and 0.580 gram
(5.73mmol) di-n-propylamine, 0.58 gram of (5.73mmol) triethylamine, 80 milliliters of ethyl alcohol are added in 100 milliliters of three-necked flask,
60 DEG C are heated to, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)) is stirred to react 8 hours, closes
Solvent is evaporated off in reaction, reaction solution, and 20 milliliters of chloroforms are added in obtained concentrate and are dissolved, lysate are obtained, to lysate
2.5 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) of middle addition, after mixing, are evaporated off solvent, obtain dry concentrate with
Mixture is filled column by the mixture of silica gel, then using volume ratio for 10:1 petrol ether/ethyl acetate mixed solution as elution
Agent, elution, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)) detect according to TLC and collect (I) containing formula
The eluent (Rf value is 0.5) of compound represented, collection liquid concentration, 50 DEG C are dried to obtain pale solid shown in formula (I)
Product, yield 48.1%, 147~150 DEG C of fusing point.1H NMR and IR is the same as embodiment 17.
The preparation of embodiment 20:6- (2- dipropyl aminoacetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 14 method of embodiment preparation and 2.319 grams
(22.92mmol) di-n-propylamine, 1.40 grams of (11.46mmol) 4-dimethylaminopyridine, 60 milliliters of isopropanols are added 100 milliliters
In three-necked flask, 25 DEG C of room temperature stirrings, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)), reaction 36
Hour, reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, obtain molten
Liquid is solved, 3.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added into lysate, after mixing, solvent is evaporated off, obtains dry
Mixture is filled column by the mixture of dry concentrate and silica gel, is then mixed with volume ratio for the petrol ether/ethyl acetate of 5:1
Solution is eluant, eluent, elution, and TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)) is detected according to TLC
The eluent (Rf value is 0.5) containing formula (I) compound represented is collected, collection liquid concentration, 50 DEG C are dried to obtain shown in formula (I)
Product as off-white solid, yield 51.9%, 147~150 DEG C of fusing point.1H NMR and IR is the same as embodiment 17.
The preparation of embodiment 21:6- (2- dipropyl aminoacetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 15 method of embodiment preparation and 0.521 gram
(5.15mmol) di-n-propylamine, 1.04 grams of (8.58mmol) N, N- dimethylanilines, 33 milliliters of n,N-Dimethylformamide are added 50
In the reaction flask of milliliter, 120 DEG C are heated to, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)) stirs
Reaction 0.5 hour is mixed, reaction is closed, solvent is evaporated off in reaction solution, 20 milliliters of tetrahydrofurans is added in obtained concentrate its is molten
Solution obtains lysate, and 4.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added into lysate, after mixing, are evaporated off
Solvent, obtains the mixture of dry concentrate and silica gel, and mixture is filled column, is then petroleum ether/acetic acid of 1:1 with volume ratio
Ethyl ester mixed solution is eluant, eluent, is eluted, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)), according to
The eluent (Rf value is 0.5) containing formula (I) compound represented is collected in TLC detection, and collection liquid concentration, 50 DEG C are dried to obtain formula
(I) product as off-white solid shown in, yield 45.3%, 147~150 DEG C of fusing point.1H NMR and IR is the same as embodiment 17.
The preparation of embodiment 22:6- (2- dipropyl aminoacetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 16 method of embodiment preparation and 4.639 grams
(45.84mmol) di-n-propylamine, 3.626 grams of (45.84mmol) pyridines, 195 milliliters of propyl alcohol are added in 500 milliliters of reaction flask,
40 DEG C are heated to, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)) is stirred to react 10 hours, closes
Solvent is evaporated off in reaction, reaction solution, and 20 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, lysate, Xiang Rong are obtained
It solves and 6.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) is added in liquid, after mixing, solvent is evaporated off, obtains dry concentration
Mixture is filled column by the mixture of object and silica gel, and then the petrol ether/ethyl acetate mixed solution with volume ratio for 1:1 is to wash
De- agent, elution, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)) are collected according to TLC detection and contain formula
(I) eluent (Rf value is 0.5) of compound represented, collection liquid concentration, 50 DEG C are dried to obtain canescence shown in formula (I) and consolidate
Body product, yield 55.5%, 147~150 DEG C of fusing point.1H NMR and IR is the same as embodiment 17.
Embodiment 23: anticancer activity testing in vitro
(1) compound (I) obtained in embodiment human lung cancer cell lines A-549, Breast cancer lines have been subjected to
MCF-7, people in loop strain HL-60 and human cervical carcinoma cell lines Siha biological activity test.
Test method: tetrazolium reduction method (mtt assay).
Cell strain: human lung cancer cell lines A-549, MCF-7 cell strainHJ2mm, people in loop strain HL-
60 and human cervical carcinoma cell lines Siha.Above-mentioned tumor cell line is purchased from Chinese Academy of Sciences Shanghai school of life and health sciences cell bank.
Experimental procedure is as follows:
(a) preparation of sample: for solvable sample, every 1mg is dissolved with 40 μ L DMSO, takes 2 μ L dilute with 1000 μ L culture mediums
It releases, makes 100 μ g/mL of concentration, then with culture solution serial dilution to using concentration.
(b) culture of cell
1. the preparation of culture medium: containing 800,000 units of Penicillin, 1.0g strepto- in every 1000mL DMEM culture medium (Gibco)
Element, 10% inactivated fetal bovine serum.
2. the culture of cell: by tumor cell inoculation in culture medium, setting 37 DEG C, 5%CO2It is cultivated in incubator, 3~5d
Passage.
3. measuring sample to the inhibiting effect of growth of tumour cell
10th generation cell EDTA- pancreatin digestive juice is digested, and is diluted to 1 × 10 with culture medium6/ mL is added to 96 holes
In tissue culture plate, every 100 μ L of hole sets 37 DEG C, 5%CO2It is cultivated in incubator.After inoculation for 24 hours, it is added diluted with culture medium
100 μ g/mL, 10 μ g/mL and 1 μ g/mL sample, every 100 μ L of hole, each concentration add 3 holes, set 37 DEG C, 5%CO2It is trained in incubator
It supports, MTT, the every 10 μ L of hole of 5mg/mL is added after 72h in cell culture well, set 37 DEG C of incubation 3h, DMSO, every 150 μ of hole is added
L is vibrated with oscillator, and Shi formazan is completely dissolved, with microplate reader under 570nm wavelength colorimetric.To be free of sample under similarity condition,
The cell of culture medium culture containing same concentration DMSO calculates sample to the IC of growth of tumour cell as control50。
The result of test is as shown in table 1, table 2, table 3, table 4:
The inhibiting effect that 1. compound of table (I) grows cancer cell line MCF-7
The inhibiting effect that 2. compound of table (I) grows cancer cell line A-549
The inhibiting effect that 3. compound of table (I) grows cancer cell line HL-60
The inhibiting effect that 4. compound of table (I) grows cancer cell line Siha
(2) according to embodiment 11, chloracetyl chloride is used to 4- iodobenzoyl chloride, 3- methoxy benzoyl chloride or cinnamoyl respectively
Chloro replaces, other operations have been respectively synthesized quinazoline compounds (a) with embodiment 11, and (b) and (c), structure are as follows:
According to the above method by quinazoline compounds (a) obtained, (b) and (c) has carried out Breast cancer lines
MCF-7 biological activity test, test result show quinazoline compounds (a), and (b) and (c) is to MCF-7 cell strainHJ2mm
Inhibitory effect is unobvious, compound (a), and (b) and (c) can not show a candle to chemical combination to the anticancer activity of MCF-7 cell strainHJ2mm
Object (I).Quinazoline compounds (b) obtained and (c) people in loop strain HL- has been subjected to according to the above method
60 biological activity tests, test result show quinazoline compounds (b) and (c) to people in loop strain HL-60
Inhibitory effect is unobvious, can not show a candle to of anticancer activity of compound (b) and (c) to people in loop strain HL-60
It closes object (I).
Concrete outcome is as shown in table 5, table 6:
The inhibiting effect that 5. compound (a) of table, (b) and (c) grow cancer cell line MCF-7
The inhibiting effect that 6. compound (b) of table and (c) grow cancer cell line HL-60
(3) according to embodiment 17, di-n-propylamine 3,4- dimethylaniline is replaced, other operations are the same as embodiment 17, synthesis
Quinazoline compounds (d), structure are as follows:
Quinazoline compounds (d) obtained MCF-7 cell strainHJ2mm, the early children of people have been subjected to according to the above method
Grain leukemia cell line HL-60 biological activity test, test result show quinazoline compounds (d) to Breast cancer lines
MCF-7, people in loop strain HL-60 inhibitory effect are unobvious, and compound (d) is to Breast cancer lines MCF-
7, the anticancer activity of people in loop strain HL-60 can not show a candle to compound (I).Concrete outcome is as shown in table 7, table 8:
The inhibiting effect that 7. compound (d) of table grows cancer cell line MCF-7
The inhibiting effect that 8. compound (d) of table grows cancer cell line HL-60
Claims (10)
- 6- shown in a kind of formula (I) 1. (2- dipropyl aminoacetylamino) quinazoline compounds:
- 6- shown in a kind of formula as described in claim 1 (I) 2. (2- dipropyl aminoacetylamino) quinazoline compounds Preparation method, it is characterised in that the method are as follows:(1) compound shown in formula (II) is mixed with compound shown in formula (III), in organic solvent A, in basic catalyst B's Under effect, 25~120 DEG C are reacted, and after fully reacting, reaction solution is isolated and purified, and compound shown in formula (IV) is made；Institute Organic solvent A is stated selected from one of following: chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N- dimethyl formyl Amine；The basic catalyst B is selected from one of following: pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylaniline, 4- diformazan Aminopyridine, 4- pyrollidinopyridine or sodium carbonate；(2) formula (IV) compound represented is in organic solvent D, under reducing agent E effect, in 25~100 DEG C of fully reactings, instead Liquid is answered to filter, the concentrate after filtrate decompression concentration is dry, and formula (V) compound represented is made；Under the organic solvent D is One of column: chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N,N-dimethylformamide；Under the reducing agent E is One of column: iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate；Iron powder/the concentrated hydrochloric acid refers to iron powder Mixing, iron powder/acetic acid with concentrated hydrochloric acid arbitrary proportion refer to the mixing of iron powder Yu acetic acid arbitrary proportion, the palladium carbon/ammonium formate Refer to the mixing of palladium carbon Yu ammonium formate arbitrary proportion, the palladium carbon/hydrazine hydrate is the mixture of palladium carbon Yu hydrazine hydrate arbitrary proportion；(3) compound shown in formula (V) is mixed with chloracetyl chloride or chloroacetic anhydride, under basic catalyst F effect, Yu Youji In solvent G, formula (VI) compound represented is made in -10~50 DEG C of fully reactings, the post-treated A of reaction solution；The alkalinity is urged Agent F is one of following: pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylaniline, 4-dimethylaminopyridine, 4- pyrrolidines Yl pyridines or sodium carbonate；The organic solvent G is one of following: tetrahydrofuran, methylene chloride, chloroform, ethyl acetate, ether, Acetonitrile, toluene or benzene；(4) compound shown in formula (VI) is mixed with di-n-propylamine, in organic solvent J, under the action of basic catalyst K, 25~120 DEG C are reacted, and after fully reacting, by the post-treated B of reaction solution, compound shown in formula (I) is made；It is described organic molten Agent J is selected from one of following: chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N,N-dimethylformamide；Described Basic catalyst K is selected from one of following: pyridine, triethylamine, quinoline, N, N- dimethylaniline, 4-dimethylaminopyridine, 4- pyrrolidines Yl pyridines or sodium carbonate.
- 3. method according to claim 2, it is characterised in that: compound shown in formula (III) described in step (1) and formula (II) The ratio between amount for the substance that feeds intake of shown compound, basic catalyst B is 1.0 ﹕, 0.8~1.2 ﹕ 1.0~8.0；The organic solvent A Dosage 10~50mL/g is calculated as with the quality of compound shown in formula (III).
- 4. method according to claim 2, it is characterised in that: the method that reaction solution described in step (1) isolates and purifies are as follows: anti- After answering completely, solvent is evaporated off in reaction solution, concentrate is taken to be dissolved with organic solvent C, lysate is obtained, then to lysate The middle column chromatography silica gel that 1.0~2.0 times of weight of concentrate is added, after mixing, is evaporated off solvent, dry, obtains concentrate and silica gel Mixture, mixture is filled into column, then using volume ratio for 1:0.1~10 petroleum ether and ethyl acetate mixture as elution The efflux containing target components is collected in agent, is concentrated under reduced pressure, dry, obtains formula (IV) compound represented；The organic solvent C It is one of following: ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.
- 5. method according to claim 2, it is characterised in that: in step (2), when the reducing agent E is iron powder/concentrated hydrochloric acid Or iron powder/acetic acid, formula (IV) compound represented and the mass ratio that feeds intake of iron powder, concentrated hydrochloric acid or acetic acid in reducing agent E are 1.0 ﹕, 1.0~3.0 ﹕ 0.2~1.0；When the reducing agent E is palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate, shown in formula (IV) The mass ratio that feeds intake of palladium carbon, ammonium formate or hydrazine hydrate in compound and reducing agent E is 1.0 ﹕, 0.1~0.5 ﹕ 1.0~3.0.
- 6. method according to claim 2, it is characterised in that: compound and chloroethene shown in formula (V) described in step (3) The ratio between amount for the substance that feeds intake of acyl chlorides or chloroacetic anhydride, basic catalyst F is 1 ﹕, 1.0~8.0 ﹕ 1.0~3.0；It is described organic molten The dosage of agent G is calculated as 11~100mL/g with the quality of compound shown in formula (V).
- 7. method according to claim 2, it is characterised in that: the method for step (3) the reaction solution post-processing A are as follows: will be anti- Liquid is answered to filter, filtrate steaming removal solvent takes concentrate to be dissolved with organic solvent H, obtains lysate, then adds into lysate After mixing, solvent is evaporated off in the column chromatography silica gel for entering 1.0~2.0 times of weight of concentrate, dry, obtains the mixed of concentrate and silica gel Close object, mixture is filled into column, then using volume ratio for 1:0.1~10 petroleum ether and ethyl acetate mixture as eluant, eluent, The efflux containing target components is collected, is concentrated under reduced pressure, it is dry, obtain formula (I) compound represented；Under the organic solvent H is One of column: ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.
- 8. method according to claim 2, it is characterised in that: in step (4), compound shown in the formula (VI) and two positive third The ratio between amount for the substance that feeds intake of amine, basic catalyst K is 1.0 ﹕, 0.8~8.0 ﹕ 1.0~8.0；The dosage of the organic solvent J with The quality of compound shown in formula (VI) is calculated as 10~60mL/g；The method of the reaction solution post-processing B are as follows: after fully reacting, solvent is evaporated off in reaction solution, takes concentrate organic solvent M It is dissolved, obtains lysate, the column chromatography silica gel of 1.0~2.0 times of weight of concentrate is then added into lysate, mixed Afterwards, solvent is evaporated off, it is dry, obtain the mixture of concentrate and silica gel, mixture filled into column, then with volume ratio for 1:0.1~ 10 petroleum ether and ethyl acetate mixture is eluant, eluent, collects the efflux containing target components, is concentrated under reduced pressure, dry, is obtained Obtain formula (I) compound represented；The organic solvent M is one of following: ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.
- Prepared by 6- shown in formula (I) as described in claim 1 9. (2- dipropyl aminoacetylamino) quinazoline compounds Application in prevention or treatment human breast carcinoma drug.
- 10. application as claimed in claim 9, it is characterised in that the drug is with inhibition MCF-7 cell strainHJ2mm Active drug.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1061411A (en) * | 1990-11-06 | 1992-05-27 | 美国辉瑞有限公司 | Be used to strengthen the active quinazoline derivant of antineoplastic agent |
| CN1141633A (en) * | 1994-02-23 | 1997-01-29 | 辉瑞大药厂 | 4-heterocyclyl-substituted Quinazoline derivatives, method for prepn. of same and the use as anti-cancer agent |
| CN103275018A (en) * | 2013-04-26 | 2013-09-04 | 浙江工业大学 | 4-(3-chloro-4-substituted anilino)-6-substituted carbamonyl quinazoline compounds, and preparation method and applications thereof |
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| WO2006074147A2 (en) * | 2005-01-03 | 2006-07-13 | Myriad Genetics, Inc. | Nitrogen containing bicyclic compounds and therapeutical use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1061411A (en) * | 1990-11-06 | 1992-05-27 | 美国辉瑞有限公司 | Be used to strengthen the active quinazoline derivant of antineoplastic agent |
| CN1141633A (en) * | 1994-02-23 | 1997-01-29 | 辉瑞大药厂 | 4-heterocyclyl-substituted Quinazoline derivatives, method for prepn. of same and the use as anti-cancer agent |
| CN103275018A (en) * | 2013-04-26 | 2013-09-04 | 浙江工业大学 | 4-(3-chloro-4-substituted anilino)-6-substituted carbamonyl quinazoline compounds, and preparation method and applications thereof |
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