CN108084162B - Dimethoxy benzene aminoacetylamino benzo [d] azepine * base quinazoline compounds and preparation and application - Google Patents
Dimethoxy benzene aminoacetylamino benzo [d] azepine * base quinazoline compounds and preparation and application Download PDFInfo
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Abstract
The invention discloses a kind of dimethoxy benzene aminoacetylamino benzo [d] azepinesBase quinazoline compounds and preparation and application.Dimethoxy benzene aminoacetylamino benzo [d] azepine provided by the inventionBase quinazoline compounds are expected to be applied to the drug of preparation treatment human breast carcinoma, human lung cancer, human promyelocytic leukemia, human cervical carcinoma's drug for all having 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.The present invention provides dimethoxy benzene aminoacetylamino benzo [d] azepines
Description
(1) technical field
The present invention relates to a kind of quinazoline compounds and its application, in particular to a kind of dimethoxy benzene glycyl ammonia
Base benzo [d] azepineBase quinazoline compounds and preparation method thereof and the compound are swollen in preparation prevention or treatment
Application in the drug of tumor disease.
(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-dimethoxy benzene with anticancer activity
Aminoacetylamino benzo [d] azepineBase quinazoline compounds and its preparation method and application, such compound is certain
To human lung cancer cell lines A-549, MCF-7 cell strainHJ2mm, people in loop strain HL-60 or people palace under dosage
Neck cancer cell strain Siha has good inhibitory effect；And such compounds process for production thereof is easy, easily operated, raw material is easy to get,
And lower production costs, it is suitable for industrial applications.
For achieving the above object, the present invention adopts the following technical scheme:
In a first aspect, the present invention provides dimethoxy benzene aminoacetylamino benzo [d] azepines shown in a kind of formula (I)Base quinazoline compounds,
Second aspect, the present invention provide dimethoxy benzene aminoacetylamino benzo [d] azepine shown in a kind of formula (I)
The preparation method of base quinazoline compounds, the method are as follows: (1) by chemical combination shown in compound shown in formula (II) and formula (III)
Object mixing, in organic solvent A, under the action of basic catalyst B, 25~120 DEG C are reacted (TLC tracking and monitoring, expansion
Agent is ethyl acetate/petroleum ether=1:3 (v/v), preferably 40~100 DEG C 0.5~12h of reaction), after fully reacting, by reaction solution
It isolates and purifies, compound shown in formula (IV) is made；The organic solvent A is selected from one of following: chloroform, toluene, methanol, ethyl alcohol,
Propyl alcohol, isopropanol, acetonitrile 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, diethyl
Amine, 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) by compound and 3 shown in formula (VI), 4- dimethoxyaniline mixing, in organic solvent J, in base catalysis
Under the action of agent K, 25~120 DEG C reacted (TLC tracking and monitoring, solvent be ethyl acetate/petroleum ether=1:1 (v/v),
It is preferred that 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；
The organic solvent J is selected from one of following: chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N- dimethyl methyl
Amide；The basic catalyst K is selected from one of following: pyridine, triethylamine, quinoline, N, N- dimethylaniline, 4- dimethylamino pyrrole
Pyridine, 4- pyrollidinopyridine 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 that step (3) the of the present invention reaction solution isolates and purifies 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), compound and 3 shown in the formula (VI), 4- dimethoxyaniline, basic catalyst K
The ratio between the amount of substance of feeding intake is 1.0 ﹕, 0.8~8.0 ﹕ 1.0~8.0.
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 dimethoxy benzene aminoacetylamino benzo [d] azepines shown in formula (I)Base quinoline
Application of the oxazoline compound in preparation prevention or tumor, particularly useful for making prevention or treatment human breast carcinoma
Application in 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.
Dimethoxy benzene aminoacetylamino benzo [d] azepine shown in formula (I) of the present inventionBase quinazoline ditosylate salt chemical combination
Object also has human lung cancer cell lines A-549, people in loop strain HL-60 or human cervical carcinoma cell lines Siha significant
Inhibiting effect, can be applied to preparation prevention or treatment human lung cancer, human leukemia or human cervical carcinoma drug in.
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, is named for the ease of distinguishing post-processing difference used in different step, letter itself does not have meaning.
The beneficial effects are mainly reflected as follows: (1) of the present invention dimethoxy benzene aminoacetylamino benzo
[d] azepineThe anticancer activity that base quinazoline compounds (I) have had is expected to be applied to preparation prevention or treatment tumor disease
Drug in, the application especially in human breast carcinoma, human lung cancer, human leukemia or human cervical carcinoma's drug；(2) provided by the invention
Dimethoxy benzene aminoacetylamino benzo [d] azepineThe preparation method of base quinazoline compounds (I), is simply easy to grasp
Make, raw material is easy to get, and lower production costs, is suitable for 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.1HNMR 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 same
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.
Embodiment 17: dimethoxy benzene aminoacetylamino benzo [d] azepineThe preparation of base quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 11 method of embodiment preparation and 1.053 grams
50 milliliters anti-is added in (6.87mmol) 3,4- dimethoxyaniline, 3.626 grams of (45.84mmol) pyridines, 32.5 ml methanols
It answers in bottle, is heated to 40 DEG C, it is small to be stirred to react 10 for TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v))
When, reaction is closed, solvent is evaporated off in reaction solution, and 10 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, are dissolved
1.5 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added into lysate, after mixing, solvent is evaporated off, obtains drying for liquid
Concentrate and silica gel mixture, mixture is filled into column, then with volume ratio for 1:10 petrol ether/ethyl acetate mixing it is molten
Liquid is eluant, eluent, elution, and TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)) is detected according to TLC and received
Eluent (Rf value be 0.5) of the collection containing formula (I) compound represented, collection liquid concentration, 50 DEG C are dried to obtain Huang shown in formula (I)
Color solid product, yield 52.7%, 124~127 DEG C of fusing point.1HNMR(500MHz,[D6]DMSO)δ:3.14-3.20(m,1H),
3.33-3.39(m,1H),3,61(s,6H),3,68(s,3H),3,70(s,3H),3,72(s,3H),3.75-3.82(m,1H),
3.84-3.93 (m, 4H), 4.52 (dd, J=8.5,14.4Hz, 1H), 5.28 (t, J=8.4Hz, 1H), 5.74 (s, 1H), 6.08
(dd, J=2.6,8.8Hz, 1H), 6.40 (d, J=7.6Hz, 1H), 6.72 (d, J=8.6Hz, 1H), 6.86-6.88 (m, 3H),
7.02 (d, J=8.7Hz, 2H), 7.70-7.72 (m, 1H), 7.75-7.77 (m, 1H), 8.45 (s, 1H), 8.72 (s, 1H),
10.38(s,1H)。HRMS-ESI m/z:684.2589[M+H]+。IR(KBr,cm-1)ν:3324,2933,2832,1688,
1595,1513,1462,1349,1232,1032,837。
Embodiment 18: dimethoxy benzene aminoacetylamino benzo [d] azepineThe preparation of base quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 12 method of embodiment preparation and 0.702 gram
Three mouthfuls of 100 milliliters are added in (4.58mmol) 3,4- dimethoxyaniline, 2.95 grams of (22.84mmol) quinoline, 80 milliliters of toluene
In flask, 100 DEG C are heated to, it is small to be stirred to react 2 for TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v))
When, reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of ethyl alcohol are added in obtained concentrate and are dissolved, lysate is obtained, to
2.5 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 1:5 with volume ratio
Eluant, eluent, elution, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)) are collected according to TLC detection and are contained
The eluent (Rf value is 0.5) of formula (I) compound represented, collection liquid concentration, 50 DEG C are dried to obtain yellow shown in formula (I) and consolidate
Body product, yield 41.1%, 124~127 DEG C of fusing point.1HNMR and IR is the same as embodiment 17.
Embodiment 19: dimethoxy benzene aminoacetylamino benzo [d] azepineThe preparation of base quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 13 method of embodiment preparation and 0.878 gram
Three mouthfuls of 100 milliliters are added in (5.73mmol) 3,4- dimethoxyaniline, 0.58 gram of (5.73mmol) triethylamine, 80 milliliters of ethyl alcohol
In flask, 60 DEG C are heated to, it is small to be stirred to react 8 for TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v))
When, reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of chloroforms are added in obtained concentrate and are dissolved, lysate is obtained, to
2.5 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 10:1 with volume ratio
Eluant, eluent, elution, TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)) are collected according to TLC detection and are contained
The eluent (Rf value is 0.5) of formula (I) compound represented, collection liquid concentration, 50 DEG C are dried to obtain yellow shown in formula (I) and consolidate
Body product, yield 46.4%, 124~127 DEG C of fusing point.1HNMR and IR is the same as embodiment 17.
Embodiment 20: dimethoxy benzene aminoacetylamino benzo [d] azepineThe preparation of base quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 14 method of embodiment preparation and 3.511 grams
(22.92mmol) 3,4- dimethoxyaniline, 1.40 grams of (11.46mmol) 4-dimethylaminopyridine, 60 milliliters of isopropanols are added
In 100 milliliters of three-necked flask, 25 DEG C of room temperature stirrings, (solvent is ethyl acetate/petroleum ether=1:1 (v/ to TLC tracing detection
V)), react 36 hours, close reaction, solvent is evaporated off in reaction solution, 20 milliliters of tetrahydrofurans is added in obtained concentrate its is molten
Solution obtains lysate, and 3.0 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 5:1 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) yellow solid product shown in, yield 58.1%, 124~127 DEG C of fusing point.1H NMR and IR is the same as embodiment 17.
Embodiment 21: dimethoxy benzene aminoacetylamino benzo [d] azepineThe preparation of base quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 15 method of embodiment preparation and 0.790 gram
(5.16mmol) 3,4- dimethoxyaniline, 1.04 grams of (8.58mmol) N, N- dimethylanilines, 33 milliliters of N, N- dimethyl formyl
Amine is added in 50 milliliters of reaction flask, is heated to 120 DEG C, (solvent is ethyl acetate/petroleum ether=1:1 to TLC tracing detection
(v/v)) it, is stirred to react 0.5 hour, closes reaction, solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydro furans are added in obtained concentrate
It mutters and is dissolved, obtain lysate, 4.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are 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 1:1 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 (I) compound represented, is collected according to TLC detection, collection liquid is concentrated, and 50 DEG C
It is dried to obtain yellow solid product shown in formula (I), yield 32.8%, 124~127 DEG C of fusing point.1The same embodiment of H NMR and IR
17。
Embodiment 22: dimethoxy benzene aminoacetylamino benzo [d] azepineThe preparation of base quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 16 method of embodiment preparation and 7.022 grams
500 milliliters anti-is added in (45.84mmol) 3,4- dimethoxyaniline, 3.626 grams of (45.84mmol) pyridines, 195 milliliters of propyl alcohol
It answers in bottle, is heated to 40 DEG C, it is small to be stirred to react 10 for TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v))
When, reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, are dissolved
6.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added into lysate, after mixing, solvent is evaporated off, obtains drying for liquid
Concentrate and silica gel mixture, mixture is filled into column, then with volume ratio for 1:1 petrol ether/ethyl acetate mixing it is molten
Liquid is eluant, eluent, elution, and TLC tracing detection (solvent is ethyl acetate/petroleum ether=1:1 (v/v)) is detected according to TLC and received
Eluent (Rf value be 0.5) of the collection containing formula (I) compound represented, collection liquid concentration, 50 DEG C are dried to obtain Huang shown in formula (I)
Color solid product, yield 54.5%, 124~127 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 17,3,4- dimethylaniline or di-n-propylamine is used to replace respectively 3,4- dimethoxyaniline,
He operates with embodiment 17, has been respectively synthesized quinazoline compounds (d) and (f), structure is as follows:
According to the above method by quinazoline compounds (d) obtained and (f) carried out MCF-7 cell strainHJ2mm,
People in loop strain HL-60 biological activity test, the results showed that quinazoline compounds (d) and (f) are to human milk gland
Cancer cell line MCF-7, people in loop strain HL-60 anticancer activity be not so good as compound (I).Concrete outcome such as table 7,
Shown in table 8:
The inhibiting effect that 7. compound (d) of table and (f) grow cancer cell line MCF-7
The inhibiting effect that 8. compound (d) of table and (f) grow cancer cell line HL-60
(4) method of reference literature (Rao, G.-W.et al.ChemMedChem, 2013,8 (6), 928-933) is prepared into
To 4- chloro-quinazoline, further according to embodiment 1, the chloro- 6- nitro-quinazoline of 4- is replaced with 4- chloro-quinazoline, other operations are the same as implementation
Example 1 has synthesized quinazoline compounds (g), and structure is as follows:
Quinazoline compounds (g) obtained MCF-7 cell strainHJ2mm biology has been carried out according to the above method to live
Property test, test result shows that quinazoline compounds (g) can not show a candle to chemical combination to the anticancer activity of MCF-7 cell strainHJ2mm
Object (I).Concrete outcome is as shown in table 9:
The inhibiting effect that 9. compound (g) of table grows cancer cell line MCF-7
Claims (10)
1. dimethoxy benzene aminoacetylamino benzo [d] azepine shown in a kind of formula (I)Base quinazoline compounds:
2. dimethoxy benzene aminoacetylamino benzo [d] azepine shown in a kind of formula as described in claim 1 (I)Base quinoline
The preparation method of oxazoline compound, 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) by compound and 3 shown in formula (VI), 4- dimethoxyaniline mixing, in organic solvent J, in basic catalyst K's
Under effect, 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；Institute
Organic solvent J 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 K is selected from one of following: pyridine, triethylamine, quinoline, N, N- dimethylaniline, 4- dimethylamino pyrrole
Pyridine, 4- pyrollidinopyridine 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 (VI) 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 and 3 shown in the formula (VI), 4- bis-
The ratio between amount for the substance that feeds intake of aminoanisole, basic catalyst K is 1.0 ﹕, 0.8~8.0 ﹕ 1.0~8.0；The organic solvent J
Dosage 10~60mL/g is calculated as with the quality of compound shown in formula (VI)；
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.
9. dimethoxy benzene aminoacetylamino benzo [d] azepine shown in formula (I) as described in claim 1Base quinazoline
Application of the class compound in preparation 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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| 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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| 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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