CN108276384A - Acetylamino benzo [d] azepine * bases quinazoline compounds and its preparation and application - Google Patents
Acetylamino benzo [d] azepine * bases quinazoline compounds and its preparation and application Download PDFInfo
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Abstract
The invention discloses a kind of acetylamino benzo [d] azepinesBase quinazoline compounds and its preparation and application, the present invention provides it is a kind of it is novel, have good anticancer (especially human breast carcinoma) active quinazoline compounds, be expected to be applied to prepare prevent or treatment human breast carcinoma drug in；Acetylamino benzo [d] azepine provided by the invention
Description
(1) technical field
The present invention relates to a kind of acetylamino benzo [d] azepinesBase quinazoline compounds and preparation and describedization
It closes object and is preparing the application in preventing or treating the drug of tumor disease.
(2) background technology
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, antitumor activity etc., quinazoline ditosylate salt
Compound has had listed some kinds as antitumor drug.Such as the Gefitinib for treating 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 antitumor activity.
(3) invention content
It is an object of the present invention to provide a kind of novel quinazoline quinoline class compound-acetylamino benzos with anti-tumor activity
[d] azepineBase quinazoline compounds, such compound is under doses to human lung cancer cell lines A-549, human breast carcinoma
Cell strain MCF-7 all has significant inhibiting rate；And such compounds process for production thereof is easy, easily operated, raw material is easy to get, and raw
It is relatively low to produce cost, is suitable for industrial applications.
The technical solution adopted by the present invention is：
In a first aspect, the present invention provides acetylamino benzo [d] azepines shown in a kind of formula (I)Base quinazoline ditosylate salt chemical combination
Object,
Second aspect, the present invention provide acetylamino benzo [d] azepine shown in a kind of formula (I)Base quinazoline ditosylate salt chemical combination
The preparation method of object, the method are：(1) compound shown in formula (II) is mixed 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 monitorings, solvent be ethyl acetate/
Petroleum ether=1：3 (v/v), preferably 40~100 DEG C 0.5~12h of reaction), after the reaction was complete, 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- dimethylanilines, 4-dimethylaminopyridine, 4- pyrollidinopyridines or sodium carbonate (preferably pyridine, diethylamine, triethylamine, N, N-
Dimethylaniline or 4-dimethylaminopyridine)；
(2) formula (IV) compound represented under reducing agent E effects, has been reacted in organic solvent D at 25~100 DEG C
(TLC tracking and monitorings, solvent are ethyl acetate/petroleum ether=1 entirely：1 (v/v), preferably 40~80 DEG C 0.5~12h of reaction), instead
Liquid is answered to filter, formula (V) compound represented is made in the concentrate drying (preferably 25 DEG C vacuum drying) after filtrate decompression concentration；
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 organic
Solvent D is one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N,N-dimethylformamide；
(3) compound shown in formula (V) is mixed with chloroacetic chloride or acetic anhydride, under basic catalyst F effects, in organic
In solvent G, -10~50 DEG C the reaction was complete, and (TLC tracking and monitorings, solvent are ethyl acetate/petroleum ether=1：1 (v/v), preferably-
10~50 DEG C of 3~12h of reaction), reaction solution isolates and purifies, and formula (I) compound represented is made；The basic catalyst F is
It is one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrollidinopyridines or
Sodium carbonate；The organic solvent G is one of following：Tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ether, acetonitrile, toluene
Or benzene.
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 isolates and purifies described in step (1) of the present invention is：After the reaction was complete, 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~
The column chromatography silica gel (preferably 300~400 mesh gross porosity (zcx.II) type column chromatography silica gels) of 2.0 times of weight after mixing, is evaporated off molten
Agent, it is dry, the mixture of concentrate and silica gel is obtained, mixture is filled into column, then with volume ratio for 1：0.1~10 petroleum ether
It is eluant, eluent with ethyl acetate mixture, collects the efflux containing target components (preferably with ethyl acetate/petroleum ether=1：3
(v/v) it is solvent tracing detection, collects target components, preferably collect the component that Rf values are 0.5), it is concentrated under reduced pressure, drying is (excellent
Select 50 DEG C of dryings), obtain formula (IV) compound represented；The organic solvent C is one of following：Ethyl alcohol, chloroform, tetrahydrofuran
Or ethyl acetate；The organic solvent C dosages are with being capable of dissolution residual substance.
Further, in step (2), the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, shown in formula (IV)
The mass ratio that feeds intake of iron powder, concentrated hydrochloric acid or acetic acid in compound and reducing agent E is 1.0 ﹕, 1.0~3.0 ﹕ 0.2~1.0；This hair
In bright, 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, shown in formula (IV)
Compound and reducing agent E in palladium carbon, ammonium formate or hydrazine hydrate the mass ratio that feeds intake be 1.0 ﹕, 0.1~0.5 ﹕ 1.0~3.0；
The mass loading amount of palladium is 2~10%, preferably 5% in the palladium carbon being applicable in the present invention, and hydrazine hydrate mass concentration is 40~80%,
It is preferred that 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 chloroacetic chloride or acetic anhydride, basic catalyst F
The ratio between the amount of substance of feeding intake 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, step (3) carries out as follows：Under the conditions of -10~10 DEG C, toward compound shown in formula (V) and
Chloroacetic chloride or acetic acid are added dropwise into compound shown in formula (V) and basic catalyst F for the organic solvent G solution of basic catalyst F
The organic solvent G solution of acid anhydride, drop finish, and -10~50 DEG C are reacted 3~12 hours, and gained reaction solution isolates and purifies, and obtains formula (I) institute
Show compound；Dissolving the organic solvent volume dosage of chloroacetic chloride or acetic anhydride does not influence the present invention, and the organic solvent G's is total
Dosage is calculated as 11~100mL/g with the quality of compound shown in formula (V), and the total dosages of organic solvent G refer to catalyst-solvent and formula
(V) organic solvent of compound shown in and dissolving chloroacetic chloride or the total volume of acetic anhydride organic solvent.
Further, the method that step (3) the of the present invention reaction solution isolates and purifies is：After the reaction was complete, 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
The column chromatography silica gel (preferably 300~400 mesh gross porosity (zcx.II) type column chromatography silica gels) of 1.0~2.0 times of weight of object, after mixing,
Solvent is evaporated off, it is dry, the mixture of concentrate and silica gel is obtained, mixture is filled into column, then with volume ratio for 1：0.1~10
Petroleum ether is eluant, eluent with ethyl acetate mixture, collects the efflux containing target components (preferably with ethyl acetate/petroleum ether
=1：1 (v/v) is solvent tracing detection, collects target components, preferably collects the component that Rf values are 0.5), it is concentrated under reduced pressure, does
Dry (preferably 50 DEG C of dryings) obtain formula (I) compound represented；The organic solvent H is one of following：Ethyl alcohol, chloroform, tetrahydrochysene
Furans or ethyl acetate；The organic solvent H dosages are with being capable of dissolution residual substance.
Organic solvent A of the present invention, C, D, G and H are organic solvent, organic used in different step for the ease of distinguishing
Solvent is different and names, and letter itself does not have meaning；The catalyst B, reducing agent E and catalyst F are catalyst, in order to just
It is named in differentiation different step used catalyst difference, letter itself does not have meaning.
The third aspect, the present invention also provides acetylamino benzo [d] azepines shown in a kind of formula (I)Base quinazoline ditosylate salt
Application of the object in preparing prevention or tumor is closed, prevention or treatment human breast carcinoma or human lung cancer drug are especially prepared
In application.
Preferably, the drug is to inhibit the active drug of MCF-7 cell strainHJ2mm.Acetyl ammonia of the present invention
Base benzo [d] azepineBase quinazoline (I) has significant inhibiting effect to MCF-7 cell strainHJ2mm.
Acetylamino benzo [d] azepine of the present inventionBase quinazoline compounds (I) are also to human lung carcinoma cell line A-
549 have significant inhibiting effect, can be applied to prepare the drug for preventing or treating human lung cancer.
The beneficial effects are mainly as follows：(1) provide it is a kind of it is novel, have good anticancer (especially
Human breast carcinoma or lung cancer) active quinazoline compounds, it is expected to be applied to prepare and prevent or treatment human breast carcinoma or lung cancer
In drug；(2) acetylamino benzo [d] azepine provided by the inventionThe preparation method of base quinazoline compounds (I), simply
Easily operated, raw material is easy to get, and production cost is relatively low, is suitable for practicality.
(4) specific implementation mode
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in
This：
Compound (II) prepare reference literature (Weinstock, J.et al.J.Med.Chem., 1986,29 (11),
Method 2315-2325) is prepared.The chloro- 6- nitro-quinazolines (III) of 4- prepare 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..
Embodiment 1：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (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 bulb, are heated to 40 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it 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 with volume ratio for 1：10 petrol ether/ethyl acetate mixed solution is eluant, eluent, elution, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it is collected containing formula (IV) compound represented according to TLC detections
Eluent (Rf values are 0.5), the eluent concentration of collection, 50 DEG C are dried to obtain faint yellow solid product shown in formula (IV), receive
Rate 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。
Embodiment 2：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (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,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it 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 with volume ratio for 1：5 petrol ether/ethyl acetate mixed solution be eluant, eluent, elution, TLC with
(solvent is ethyl acetate/petroleum ether=1 for track detection：3 (v/v)), it is collected according to TLC detections and contains formula (IV) compound represented
Eluent (Rf values be 0.5), the eluent concentration of collection, 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.
Embodiment 3：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (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
(solvent is ethyl acetate/petroleum ether=1 to tracing detection：3 (v/v)), it 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
Silica gel (300~400 mesh column chromatography silica gel) is analysed, after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, it will
Mixture fills column, then with volume ratio for 10：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, elution, TLC tracking inspections
(solvent is ethyl acetate/petroleum ether=1 for survey：3 (v/v)), it is detected according to TLC and collects washing for (IV) compound represented Han formula
De- liquid (Rf values are 0.5), the eluent concentration of collection, 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.
Embodiment 4：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (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, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it reacts 12 hours, closes 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) are added, after mixing, solvent is evaporated off, obtains dry concentrate and silicon
Mixture is filled column by the mixture of glue, then with volume ratio for 5：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, is washed
De-, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it is collected containing shown in formula (IV) according to TLC detections
Compound eluent (Rf values be 0.5), the eluent concentration of collection, 50 DEG C are dried to obtain pale yellow colored solid shown in formula (IV)
Body product, yield 80.2%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 5：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (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 bulb,
120 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it 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, then with volume ratio for 1：1 petrol ether/ethyl acetate mixed solution is
Eluant, eluent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it is collected and is contained according to TLC detections
The eluent (Rf values are 0.5) of formula (IV) compound represented, the eluent concentration of collection, 50 DEG C are dried to obtain shown in formula (IV)
Faint yellow solid product, yield 89.6%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 6：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (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 bulb, are heated to 40 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it 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 with volume ratio for 1：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, elution, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it is collected containing formula (IV) compound represented according to TLC detections
Eluent (Rf values are 0.5), the eluent concentration of collection, 50 DEG C are dried to obtain faint yellow solid product shown in formula (IV), receive
Rate 78.3%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 7：Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 1 method of embodimentBase quinazoline (IV),
0.40 gram of (6.34mmol) ammonium formate, 0.04 gram of 5%Pd/C, 4.0 milliliters of chloroforms are added in reaction bulb, 25 DEG C of stirrings of room temperature,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it reacts 12 hours, filtering, filtrate concentration, 25 DEG C
Vacuum drying obtains faint yellow solid product amino benzo [d] azepineBase quinazoline (V), yield 98.2%, fusing point 122~
126℃。1H NMR(500MHz,CDCl3)δ:3.40-3.48(m,2H),3.71(s,3H),3.82(s,3H),3.83(s,3H),
3.87-3.98 (m, 5H), 4.45 (dd, J=6.3,13.8Hz, 1H), 4.95 (dd, J=6.5,9.2Hz, 1H), 6.47 (s,
1H), 6.90 (d, J=8.7Hz, 2H), 6.95 (d, J=2.5Hz, 1H), 7.11 (d, J=8.6Hz, 2H), 7.15 (dd, J=
8.9,2.5Hz, 1H), 7.69 (d, J=8.9Hz, 1H), 8.50 (s, 1H).IR(KBr,cm-1)ν:3368,3215,2932,
2825,1628,1566,1512,1487,1353,1248,1036,834。
Embodiment 8：Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 2 method of embodimentBase quinazoline (IV),
1.20 grams of (19.18mmol) 80wt% hydrazine hydrates, 0.20 gram of 5%Pd/C, 20.0 milliliters of toluene are added to 50 milliliters of reaction bulb
In, 100 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is small to be stirred to react 0.5
When, cold filtration, filtrate concentrates, and 25 DEG C of vacuum drying obtain faint yellow solid product amino benzo [d] azepineBase quinazoline
(V), yield 100.0%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 9：Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 3 method of embodimentBase quinazoline (IV),
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 bulb,
40 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 8 hours, it is cooling
Filtering, filtrate concentration, 25 DEG C of vacuum drying obtain faint yellow solid product amino benzo [d] azepineBase quinazoline (V) is received
Rate 94.1%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 10：Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 4 method of embodimentBase quinazoline (IV),
0.40 gram of acetic acid, 1.20 grams of iron powders, 20.0 milliliters of isopropanols are added in 50 milliliters of reaction bulb, are heated to 80 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：1 (v/v)), it is stirred to react 3 hours, cold filtration, filtrate concentration, 25 DEG C
Vacuum drying obtains faint yellow solid product amino benzo [d] azepineBase quinazoline (V), yield 97.5%, fusing point 122~
126℃。1H NMR and IR is the same as embodiment 7.
Embodiment 11：Acetylamino benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 7 method of embodimentBase quinazoline (V),
0.13 gram of (1.64mmol) pyridine, 3 milliliters of tetrahydrofurans are added in reaction bulb, and 0.345 gram is added dropwise under -10 DEG C of stirring conditions
(4.39mmol) chloroacetic chloride, drop finish, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1), anti-under the conditions of -10 DEG C
It answers 12 hours, filters, filtrate steaming removal solvent, concentrate is added 10 milliliters of ethyl acetate and is dissolved, and lysate is obtained, to dissolving
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 concentrate
With the mixture of silica gel, mixture is filled into column, then with volume ratio for 1：10 petrol ether/ethyl acetate mixed solution is elution
Agent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is detected according to TLC and collects (I) containing formula
The eluent (Rf values are 0.5) of compound represented, the eluent concentration of collection, 50 DEG C are dried to obtain acetyl shown in formula (I)
Amino benzo [d] azepineBase quinazoline white solid, yield 67.6%, 190~194 DEG C of fusing point.1H NMR(500MHz,
CDCl3)δ:2.27 (s, 3H), 3.26-3.33 (m, 1H), 3.52 (dt, J=15.3,3.6Hz, 1H), 3.75 (s, 3H), 3.79-
3.84 (m, 7H), 3.95-4.07 (m, 2H), 4.65 (dd, J=7.9,14.1Hz, 1H), 5.24 (t, J=8.7Hz, 1H), 6.65
(s, 1H), 6.88 (d, J=8.7Hz, 2H), 7.08 (d, J=8.7Hz, 2H), 7.48 (d, J=8.9Hz, 1H), 7.65 (s,
1H), 7.81 (d, J=8.9Hz, 1H), 8.57 (s, 1H), 8.70 (s, 1H).IR(KBr,cm-1)ν:3274,2936,1682,
1562,1525,1509,1450,1350,1245,1034,837。
Embodiment 12：Acetylamino benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 8 method of embodimentBase quinazoline (V),
0.04 gram of (0.55mmol) diethylamine, 10.0 milliliters of chloroforms are added in 50 milliliters of reaction bulb, are added dropwise under 10 DEG C of stirring conditions
0.043 gram of (0.55mmol) chloroacetic chloride and 5.0 milliliters of chloroform mixed solutions, drop finish, and (solvent is acetic acid second to TLC tracing detections
Ester/petroleum ether=1：1 (v/v)), it reacts 8 hours under the conditions of 10 DEG C, filters, filtrate steaming removal solvent, 20 milliliters of second are added in concentrate
Alcohol is dissolved, and lysate is obtained, and 0.26 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added into lysate, is mixed
After even, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then with volume ratio for 1：5 stone
Oily ether/ethyl acetate mixture is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1
(v/v)) eluent (Rf values are 0.5) containing formula (I) compound represented, is collected according to TLC detections, the eluent of collection is dense
Contracting, 50 DEG C are dried to obtain acetylamino benzo [d] azepine shown in formula (I)Base quinazoline white solid, yield 82.3% melt
190~194 DEG C of point.1H NMR and IR is the same as embodiment 11.
Embodiment 13：Acetylamino benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 9 method of embodimentBase quinazoline (V),
0.111 gram of (1.10mmol) triethylamine, 10.0 milliliters of ethyl acetate are added in 50 milliliters of reaction bulb, under 0 DEG C of stirring condition
0.086 gram of (1.10mmol) chloroacetic chloride and 5.0 milliliters of ethyl acetate solutions are added dropwise, drop finishes, and (solvent is second to TLC tracing detections
Acetoacetic ester/petroleum ether=1：1) it, reacts 6 hours under the conditions of 25 DEG C, filters, filtrate steaming removal solvent, 20 milliliters of chlorine are added in concentrate
It is imitative to be dissolved, lysate is obtained, 0.30 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added into lysate, is mixed
After even, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then with volume ratio for 10：1
Petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1
(v/v)) eluent (Rf values are 0.5) containing formula (I) compound represented, is collected according to TLC detections, the eluent of collection is dense
Contracting, 50 DEG C are dried to obtain acetylamino benzo [d] azepine shown in formula (I)Base quinazoline white solid, yield 88.7% melt
190~194 DEG C of point.1H NMR and IR is the same as embodiment 11.
Embodiment 14：Acetylamino benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 10 method of embodimentBase quinazoline
(V), 0.067 gram of (0.55mmol) 4-dimethylaminopyridine, 20.0 milliliters of toluene are added in 50 milliliters of reaction bulb, and 5 DEG C are stirred
The solution of 0.224 gram of (2.19mmol) acetic anhydride and 7.0 milliliters of toluene is added dropwise under the conditions of mixing, drop finishes, and is heated to 50 DEG C, TLC with
(solvent is ethyl acetate/petroleum ether=1 for track detection：1) it, reacts 3 hours, filtering, filtrate steaming removal solvent, concentrate is added 20
Milliliter tetrahydrofuran is dissolved, and lysate is obtained, and 0.40 gram of column chromatography silica gel (300~400 mesh column layer is added into lysate
Analyse silica gel), after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then with volume
Than being 5：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/stone to TLC tracing detections
Oily ether=1：1 (v/v)), the eluent (Rf values are 0.5) containing formula (I) compound represented is collected according to TLC detections, collection
Eluent concentrates, and 50 DEG C are dried to obtain acetylamino benzo [d] azepine shown in formula (I)Base quinazoline white solid, yield
74.2%, 190~194 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 15：Acetylamino benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 10 method of embodimentBase quinazoline
(V), 0.213 gram of (1.65mmol) quinoline, 15.0 milliliters of benzene are added in 50 milliliters of reaction bulb, are dripped under -10 DEG C of stirring conditions
Add the solution of 0.173 gram of (2.20mmol) chloroacetic chloride and 5.0 milliliters of benzene, drop finishes, TLC tracing detections (solvent be ethyl acetate/
Petroleum ether=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
It is dissolved, obtains lysate, 0.40 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel), mixing are added into lysate
Afterwards, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then with volume ratio for 1：1 oil
Ether/ethyl acetate mixture is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1(v/
V)), the eluent (Rf values are 0.5) containing formula (I) compound represented is collected according to TLC detections, the eluent of collection concentrates, and 50
DEG C it is dried to obtain acetylamino benzo [d] azepine shown in formula (I)Base quinazoline white solid, yield 62.5%, fusing point 190
~194 DEG C.1H NMR and IR is the same as embodiment 11.
Embodiment 16：Acetylamino benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 9 method of embodimentBase quinazoline (V),
0.164 gram of (1.10mmol) 4- pyrollidinopyridine, 15.0 milliliters of dichloromethane are added in 50 milliliters of reaction bulb, and 10 DEG C are stirred
0.086 gram of (1.10mmol) chloroacetic chloride and 5.0 milliliters of dichloromethane solutions are added dropwise under the conditions of mixing, drop finishes, (the exhibition of TLC tracing detections
It is ethyl acetate/petroleum ether=1 to open agent：1) it, reacts 8 hours under the conditions of 10 DEG C, filters, filtrate steaming removal solvent, concentrate is added
20 milliliters of ethyl alcohol are dissolved, and lysate is obtained, and 0.50 gram of column chromatography silica gel (300~400 mesh column chromatography is added into lysate
Silica gel), after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then with volume ratio
It is 10：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/stone to TLC tracing detections
Oily ether=1：1 (v/v)), the eluent (Rf values are 0.5) containing formula (I) compound represented is collected according to TLC detections, collection
Eluent concentrates, and 50 DEG C are dried to obtain acetylamino benzo [d] azepine shown in formula (I)Base quinazoline white solid, yield
79.8%, 190~194 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 17：Active anticancer testing in vitro
(1) compound obtained (I) and (IV) are subjected to human lung cancer, human breast carcinoma biological activity test.
Test method：Tetrazolium reduction method (mtt assay).
Cell strain：Human lung cancer cell lines A-549, MCF-7 cell strainHJ2mm are purchased from Shanghai life section of the Chinese Academy of Sciences
Institute's cell bank.
Experimental procedure is as follows：
(a) preparation of sample：For solvable sample, per 1mg with 40 μ L DMSO dissolvings, take 2 μ L dilute with 1000 μ L culture mediums
It releases, makes a concentration of 100 μ g/mL, then concentration is extremely used with culture solution serial dilution.
(b) culture of cell
1. the preparation of culture medium:Contain 800,000 units of Penicillin, 1.0g strepto-s in DMEM culture mediums (Gibco) per 1000mL
Element, 10% inactivated fetal bovine serum.
2. the culture of cell：By tumor cell inoculation in culture medium, 37 DEG C are set, 5%CO2It is cultivated in incubator, 3~5d
Passage.
3. determination sample is to the inhibiting effect of growth of tumour cell
10th generation cell EDTA- pancreatin digestive juices are digested, culture medium is used in combination to be diluted to 1 × 106/ mL is added to 96 holes
In tissue culture plate, per 100 μ L of hole, 37 DEG C are set, 5%CO2It is cultivated in incubator.After inoculation for 24 hours, addition culture medium is diluted
100 μ g/mL, 10 μ g/mL and 1 μ g/mL samples, per 100 μ L of hole, each concentration adds 3 holes, sets 37 DEG C, 5%CO2It is trained in incubator
It supports, the MTT of 5mg/mL is added after 72h in cell culture well, per 10 μ L of hole, set 37 DEG C of incubation 3h, DMSO is added, per 150 μ of hole
L is vibrated with oscillator, and Shi Jia Za is completely dissolved, with microplate reader under 570nm wavelength colorimetric.To be free of sample under similarity condition,
The cell of medium culture containing same concentration DMSO as a contrast, calculates IC of the sample to growth of tumour cell50。
The result of test is as shown in table 1,2：
The inhibiting effect that 1. compound of table (I) and (IV) grow lung cancer cell line A-549
The inhibiting effect that 2. compound of table (I) and (IV) grow breast cancer cell line mcf-7
(2) according to embodiment 11, chloroacetic chloride is used into 4- iodobenzoyl chlorides, 3- methoxy benzoyl chlorides and cinnamoyl chloride respectively
Instead of 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 human lung carcinoma cell line A-
549, MCF-7 cell strainHJ2mm biological activity test, test result show quinazoline compounds (a), and (b) and (c) is right
Human lung cancer cell lines A-549, the equal unobvious of MCF-7 cell strainHJ2mm inhibition, compound (a), (b) and (c) is to people
Lung cancer cell line A-549, MCF-7 cell strainHJ2mm active anticancer can not show a candle to compound (I).Concrete outcome such as table 3,4
It is shown：
The inhibiting effect that 3. compound (a) of table, (b) and (c) grow lung cancer cell line A-549
The inhibiting effect that 4. compound (a) of table, (b) and (c) grow breast cancer cell line mcf-7
Above-mentioned active anticancer testing in vitro experiment shows：The similar compound (a) of other 3 structures, (b) and (c) is to people
The equal unobvious of inhibiting effect of lung cancer cell line A-549 and MCF-7 cell strainHJ2mm growth.Compound (I) is to human lung cancer
Cell strain A-549 and MCF-7 cell strainHJ2mm growth inhibiting effect it is notable, hence it is evident that be better than compound (a), (b) and
(c)。
(3) method of reference literature (Rao, G.-W.et al.ChemMedChem, 2013,8 (6), 928-933) is prepared into
The chloro- 6- nitro-quinazolines of 4- are replaced with 4- chloro-quinazolines further according to embodiment 1 to 4- chloro-quinazolines, other operations are the same as implementation
Example 1, has synthesized quinazoline compounds (d), and structure is as follows：
Quinazoline compounds (d) obtained human lung cancer cell lines A-549, human breast carcinoma have been subjected to according to the above method
Cell strain MCF-7 biological activity tests, test result show quinazoline compounds (d) to human lung cancer cell lines A-549, human milk
The active anticancer of adenocarcinoma cell strain MCF-7 can not show a candle to compound (I).Concrete outcome is as shown in table 5, table 6：
The inhibiting effect that 5. compound (d) of table grows cancer cell line A-549
The inhibiting effect that 6. compound (d) of table grows cancer cell line MCF-7
(4) according to embodiment 11, chloroacetic chloride is replaced with chlorobenzoyl chloride, butyl chloride, propionyl chloride or chloracetyl chloride respectively,
He operates with embodiment 11, has been respectively synthesized quinazoline compounds (e), (f), (g) and (h), and structure is as follows：
Quinazoline compounds (e) obtained, (f), (g) and (h) human lung carcinoma cell line has been subjected to according to the above method
A-549 biological activity tests, test result show quinazoline compounds (e), (f), (g) with (h) to human lung carcinoma cell line A-
549 active anticancer is not so good as compound (I).Quinazoline compounds (e) obtained, (f) and (g) are carried out according to the above method
MCF-7 cell strainHJ2mm biological activity test, test result show quinazoline compounds (e), (f) and (g) to people
The active anticancer of breast cancer cell line mcf-7 is not so good as compound (I).Concrete outcome is as shown in table 7, table 8：
The inhibiting effect that 7. compound (e) of table, (f), (g) and (h) grow cancer cell line A-549
The inhibiting effect that 8. compound (e) of table, (f) and (g) grow cancer cell line MCF-7
Claims (10)
1. acetylamino benzo [d] azepine shown in a kind of formula (I)Base quinazoline compounds,
2. acetylamino benzo [d] azepine described in a kind of claim 1The preparation method of base quinazoline compounds, feature
It is that the method is：(1) compound shown in formula (II) is mixed with compound shown in formula (III), in organic solvent A, in alkali
Property catalyst B under the action of, 25~120 DEG C are reacted, and after the reaction was complete, reaction solution is isolated and purified, and formula (IV) institute is made
Show compound；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- dimethylbenzene
Amine, 4-dimethylaminopyridine, 4- pyrollidinopyridines or sodium carbonate；
(2) formula (IV) compound represented is in organic solvent D, and under reducing agent E effects, at 25~100 DEG C, the reaction was complete, instead
Liquid is answered to filter, formula (V) compound represented is made in the concentrate drying after filtrate decompression concentration；The reducing agent E is following
One of：Iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate；The organic solvent D is one of following：
Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N,N-dimethylformamide；
(3) compound shown in formula (V) is mixed with chloroacetic chloride or acetic anhydride, under basic catalyst F effects, in organic solvent G
In, -10~50 DEG C the reaction was complete, and reaction solution isolates and purifies, and formula (I) compound represented is made；The basic catalyst F is
It is one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrollidinopyridines or
Sodium carbonate；The organic solvent G is one of following：Tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ether, acetonitrile, toluene
Or benzene.
3. method as claimed in claim 2, it is characterised in that shown in compound shown in step (1) formula (III) and formula (II)
The ratio between compound, amount for the substance that feeds intake of basic catalyst B are 1.0 ﹕, 0.8~1.2 ﹕ 1.0~8.0, the use of the organic solvent A
Amount is calculated as 10~50mL/g with the quality of compound shown in formula (III).
4. method as claimed in claim 2, it is characterised in that the method that step (1) described reaction solution isolates and purifies is：Reaction
After completely, solvent is evaporated off in reaction solution, concentrate is taken to be dissolved with organic solvent C, lysate is obtained, then into lysate
The column chromatography silica gel of 1.0~2.0 times of weight of concentrate is added, after mixing, solvent is evaporated off, it is dry, obtain concentrate and silica gel
Mixture is filled column by mixture, then with volume ratio for 1：0.1~10 petroleum ether is elution with ethyl acetate mixture
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 as claimed in claim 2, it is characterised in that step (2) when the reducing agent E be iron powder/concentrated hydrochloric acid or
When 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)
Compound and reducing agent E in palladium carbon, ammonium formate or hydrazine hydrate the mass ratio that feeds intake be 1.0 ﹕, 0.1~0.5 ﹕ 1.0~3.0；
The dosage of the organic solvent D is calculated as 10~50mL/g with the quality of formula (IV) compound represented.
6. method as claimed in claim 2, it is characterised in that compound shown in the formula (V) described in step (3) and chloroacetic chloride or
The ratio between amount for the substance that feeds intake of acetic anhydride, basic catalyst F is 1 ﹕, 1.0~8.0 ﹕ 1.0~3.0, the dosage of the organic solvent G
It is calculated as 11~100mL/g with the quality of compound shown in formula (V).
7. method as claimed in claim 2, it is characterised in that step (3) carries out as follows：In -10~10 DEG C of conditions
Under, it is urged toward the organic solvent G solution of compound shown in formula (V) and basic catalyst F or toward compound and alkalinity shown in formula (V)
The organic solvent G solution of chloroacetic chloride or acetic anhydride is added dropwise in agent F, drop finishes, and -10~50 DEG C are reacted 3~12 hours, gained reaction
Liquid is post-treated to obtain compound shown in formula (I).
8. the method as described in claim 2 or 7, it is characterised in that the method that step (3) reaction solution isolates and purifies is：It has reacted
Quan Hou filters reaction solution, filtrate steaming removal solvent, and concentrate is taken to be dissolved with organic solvent H, obtain lysate, then to
The column chromatography silica gel of 1.0~2.0 times of weight of concentrate is added in lysate, after mixing, solvent is evaporated off, it is dry, obtain concentrate
With the mixture of silica gel, mixture is filled into column, then with volume ratio for 1：0.1~10 petroleum ether and ethyl acetate mixture
For eluant, eluent, the efflux containing target components is collected, is concentrated under reduced pressure, it is dry, obtain formula (I) compound represented；It is described organic
Solvent H is one of following：Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.
9. acetylamino benzo [d] azepine described in a kind of claim 1Base quinazoline compounds prevent or treat preparing
Application in 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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| CN112661759A (en) * | 2019-10-16 | 2021-04-16 | 浙江京新药业股份有限公司 | Benzodiazepine compound and preparation method thereof |
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