CN108295076A - Propionamido dimethoxy benzo [d] azepine * bases quinazoline ditosylate salt is preparing the application in treating lung-cancer medicament - Google Patents
Propionamido dimethoxy benzo [d] azepine * bases quinazoline ditosylate salt is preparing the application in treating lung-cancer medicament Download PDFInfo
- Publication number
- CN108295076A CN108295076A CN201810069813.4A CN201810069813A CN108295076A CN 108295076 A CN108295076 A CN 108295076A CN 201810069813 A CN201810069813 A CN 201810069813A CN 108295076 A CN108295076 A CN 108295076A
- Authority
- CN
- China
- Prior art keywords
- solvent
- azepine
- ethyl acetate
- milliliters
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of propionamido dimethoxy benzo [d] azepines
Description
(1) technical field
The present invention relates to a kind of propionamido dimethoxy benzo [d] azepinesBase quinazoline compounds are preparing prevention
Or the application in the drug for the treatment of human lung cancer 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
The purpose of the present invention is to provide a kind of novel quinazoline quinoline class compound-propionamido dimethoxy benzo [d] nitrogen
It is miscellaneousBase quinazoline compounds are preparing the application in preventing or treating lung-cancer medicament, such compound is right under doses
Human lung cancer cell lines A-549 has significant inhibiting rate；And such compounds process for production thereof is easy, easily operated, raw material is easy to get,
And production cost is relatively low, is suitable for industrial applications.
For achieving the above object, the present invention adopts the following technical scheme that：
The present invention provides propionamido dimethoxy benzo [d] azepines shown in a kind of formula (I)Base quinazoline ditosylate salt
Application of the object in preparation prevents or treats tumor disease drug is closed, especially in preparation prevents or treat human lung cancer drug
Using；
Preferably, the drug is with the inhibition active drug of human lung cancer cell lines A-549.
Propionamido dimethoxy benzo [d] azepine shown in a kind of formula (I) of present invention offerBase 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 obtained by step (1) is dissolved in organic solvent D, under reducing agent E effects,
At 25~100 DEG C, the reaction was complete, and (TLC tracking and monitorings, solvent are ethyl acetate/petroleum ether=1：1 (v/v), preferably 40~80
DEG C 0.5~12h of reaction), reaction solution filtering, the concentrate drying (preferably 25 DEG C vacuum drying) after filtrate decompression concentration is made
Formula (V) compound represented；The organic solvent D is one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, second
Nitrile or N,N-dimethylformamide；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 refers to iron powder that the iron powder/concentrated hydrochloric acid, which refers to the mixing of iron powder and concentrated hydrochloric acid arbitrary proportion, iron powder/acetic acid,
With the mixing of acetic acid arbitrary proportion, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate arbitrary proportion, the palladium carbon/
Hydrazine hydrate is the mixture of palladium carbon and hydrazine hydrate arbitrary proportion；
(3) compound shown in formula (V) obtained by step (2) is mixed with propionyl chloride or propionic andydride, is made in basic catalyst F
Under, in organic 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 3~12h of reaction), reaction solution is post-treated, and formula (I) compound represented is made；It is described organic
Solvent G is one of following：Tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ether, acetonitrile, toluene or benzene；The alkalinity
Catalyst F is one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrroles
Alkyl pyridine or sodium carbonate；
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
Concentrated hydrochloric acid mass concentration described in bright is 36%~38%, and the acetic acid is glacial acetic acid.
Further, in step (2), 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.This
The mass loading amount of palladium is 2~10%, preferably 5% in the palladium carbon being applicable in invention, and hydrazine hydrate mass concentration is 40~80%, excellent
Select 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 propionyl chloride or propionic andydride, 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
Be added dropwise in the organic solvent G solution of basic catalyst F or into compound shown in formula (V) and basic catalyst F propionyl chloride or
The organic solvent G solution of propionic andydride, drop finish, and -10~50 DEG C are reacted 3~12 hours, and gained reaction solution is post-treated to obtain formula (I)
Shown compound；Dissolving the organic solvent volume dosage of propionyl chloride or propionic andydride does not influence the present invention, the organic solvent G's
Total dosage is calculated as 11~100mL/g with the quality of compound shown in formula (V).Total dosage of organic solvent G refers to that dissolving alkalinity is urged
The organic solvent G of compound shown in agent F and formula (V) and dissolving propionyl chloride or the total volume of propionic andydride organic solvent G.
Further, the post-processing approach of step (3) the of the present invention reaction solution is：Reaction solution is filtered, filtrate is evaporated off molten
Agent takes concentrate to be dissolved with organic solvent H, obtains lysate, and 1.0~2.0 times of concentrate is then added into lysate
After mixing, solvent is evaporated off in the column chromatography silica gel (preferably 300~400 mesh gross porosity (zcx.II) type column chromatography silica gels) of weight, does
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 and second
Acetoacetic ester mixed solution is eluant, eluent, collects the efflux containing target components (preferably with ethyl acetate/petroleum ether=1：1(v/v)
For solvent tracing detections, target components are collected, the component that Rf values are 0.5 is preferably collected), it is concentrated under reduced pressure, it is (preferably 50 DEG C dry
It is dry), obtain formula (I) compound represented；The organic solvent H is one of following：Ethyl alcohol, chloroform, tetrahydrofuran or acetic acid
Ethyl ester.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 beneficial effects are mainly as follows：Provide a kind of novel quinazoline compounds prevent preparing or
The application in the drug of human lung cancer is treated, which has significant inhibitory activity to human lung cancer cell lines A-549.
(4) specific implementation mode
The present invention is further described in conjunction with specific embodiments, and embodiment below illustrates the present 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), 2315-2325) method be prepared.The chloro- 6- nitro-quinazolines (III) of 4- prepare reference literature
The method of (Fernandes, C.et al.Bioorg.Med.Chem., 2007,15 (12), 3974-3980) is 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), 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。
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), 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.
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), 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.
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), collection liquid concentration, 50 DEG C are dried to obtain faint yellow solid shown in formula (IV) and produce
Object, 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 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.
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), 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.
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.1HNMR 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：Propionamido dimethoxy 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 0.407 gram is added dropwise under -10 DEG C of stirring conditions
(4.40mmol) propionyl 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, collection liquid concentration, 50 DEG C are dried to obtain propionamido two shown in formula (I)
Methoxyl group benzo [d] azepineBase quinazoline pale solid, yield 63.2%, 125~129 DEG C of fusing point.1H NMR
(500MHz,CDCl3)δ:1.30 (t, J=7.6Hz, 3H), 2.44-2.53 (m, 2H), 3.26-3.32 (m, 1H), 3.57-3.49
(m, 1H), 3.75 (s, 3H), 3.76-3.82 (m, 7H), 3.95-4.06 (m, 2H), 4.64 (dd, J=8.2,14.3Hz, 1H),
5.27 (t, J=8.6Hz, 1H), 6.69 (s, 1H), 6.88 (d, J=8.7Hz, 2H), 7.08 (d, J=8.6Hz, 2H), 7.44-
7.48 (m, 2H), 7.78 (d, J=8.9Hz, 1H), 8.57 (s, 1H), 8.72 (s, 1H).HRMS-ESI m/z:547.2107[M+
H]+。IR(KBr,cm-1)ν:2936,2831,1690,1557,1523,1511,1460,1351,1247,1037,840。
Embodiment 12：Propionamido dimethoxy 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
0.051 gram of (0.55mmol) propionyl 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, collection liquid concentrates, 50 DEG C
It is dried to obtain propionamido dimethoxy benzo [d] azepine shown in formula (I)Base quinazoline pale solid, yield
62.0%, 125~129 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 13：Propionamido dimethoxy 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
0.102 gram of (1.10mmol) propionyl 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, collection liquid concentrates, 50 DEG C
It is dried to obtain propionamido dimethoxy benzo [d] azepine shown in formula (I)Base quinazoline pale solid, yield
58.8%, 125~129 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 14：Propionamido dimethoxy 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 0.286 gram of (2.20mmol) propionic andydride 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, collection liquid are collected according to TLC detections
Concentration, 50 DEG C are dried to obtain propionamido dimethoxy benzo [d] azepine shown in formula (I)Base quinazoline pale solid,
125~129 DEG C of 54.5% fusing point of yield.1HNMR and IR is the same as embodiment 11.
Embodiment 15：Propionamido dimethoxy 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),
0.213 gram of (1.65mmol) quinoline, 15.0 milliliters of benzene are added in 50 milliliters of reaction bulb, are added dropwise under -10 DEG C of stirring conditions
The solution of 0.204 gram of (2.20mmol) propionyl chloride and 5.0 milliliters of benzene, drop finish, and (solvent is ethyl acetate/stone to TLC tracing detections
Oily 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 will
It is dissolved, and obtains lysate, and 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, collection liquid concentration, 50 DEG C of dryings are collected according to TLC detections
Obtain propionamido dimethoxy benzo [d] azepine shown in formula (I)Base quinazoline pale solid, yield 72.1% melt
125~129 DEG C of point.1H NMR and IR is the same as embodiment 11.
Embodiment 16：Propionamido dimethoxy 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),
0.164 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
0.102 gram of (1.10mmol) propionyl 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, collection liquid are collected according to TLC detections
Concentration, 50 DEG C are dried to obtain propionamido dimethoxy benzo [d] azepine shown in formula (I)Base quinazoline pale solid,
Yield 57.8%, 125~129 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) human lung cancer cell lines A-549 biological activity test has been subjected to.
Test method：Tetrazolium reduction method (mtt assay).
Cell strain：Human lung cancer cell lines A-549.Above-mentioned tumor cell line is thin purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences
Born of the same parents library.
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 per 1000mL DMEM culture mediums (Gibco)
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, it is separately added into dilute with culture medium
100 μ g/mL, the 10 μ g/mL and 1 μ g/mL samples released, per 100 μ L of hole, each concentration adds 3 holes, sets 37 DEG C, 5%CO2Incubator
The MTT of 5mg/mL is added after 72h in cell culture well for middle culture, per 10 μ L of hole, sets 37 DEG C of incubation 3h, DMSO is added, per hole
150 μ L, are vibrated with oscillator, and Shi Jia Za is completely dissolved, with microplate reader under 570nm wavelength colorimetric.To be free of under similarity condition
Sample, the cell of the medium culture containing same concentration DMSO as a contrast, calculate IC of the sample to growth of tumour cell50。
The results are shown in Table 1 for test：
The inhibiting effect that 1. compound of table (I) and (IV) grow cancer cell line A-549
(2) according to embodiment 11, propionyl chloride is used into 4- iodobenzoyl chlorides, 3- methoxy benzoyl chlorides or 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 cancer cell lines A-549
Biological activity test, test result show quinazoline compounds (a), and (b) and (c) inhibits to imitate to human lung cancer cell lines A-549
The equal unobvious of fruit, compound (a), (b) and (c) can not show a candle to compound (I) to the active anticancer of human lung cancer cell lines A-549.Tool
The results are shown in Table 2 for body：
The inhibiting effect that 2. compound (a) of table, (b) and (c) grow cancer cell line A-549
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 growths.The inhibition that compound (I) grows human lung cancer cell lines A-549
Effect is notable, hence it is evident that is 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 bioactivity has been subjected to according to the above method
Test, test result show that quinazoline compounds (d) can not show a candle to compound to the active anticancer of human lung cancer cell lines A-549
(Ⅰ).Concrete outcome is as shown in table 3：
The inhibiting effect that 3. compound (d) of table grows cancer cell line A-549
(4) according to embodiment 11, propionyl chloride is replaced with chlorobenzoyl chloride, chloracetyl chloride or isobutyryl chloride respectively, other behaviour
Make, with embodiment 11, to be respectively synthesized quinazoline compounds (e), (g) and (h), structure is as follows：
Quinazoline compounds (e) obtained, (g) and (h) human lung cancer cell lines A-549 has been subjected to according to the above method
Biological activity test, test result show the anticancer of quinazoline compounds (e), (g) with (h) to human lung cancer cell lines A-549
Activity is not so good as compound (I).Concrete outcome is as shown in table 4：
The inhibiting effect that 4. compound (e) of table, (g) and (h) grow cancer cell line A-549
Claims (2)
1. propionamido dimethoxy benzo [d] azepine shown in a kind of formula (I)Base quinazoline compounds are preparing prevention
Or the application in treatment human lung cancer drug；
2. application as described in claim 1, it is characterised in that：The drug is to live with inhibition human lung cancer cell lines A-549
The drug of property.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810069813.4A CN108295076B (en) | 2018-01-24 | 2018-01-24 | Application of propionyl-amino-dimethoxy-benzo [ d ] aza-quinazoline in preparation of drugs for treating lung cancer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810069813.4A CN108295076B (en) | 2018-01-24 | 2018-01-24 | Application of propionyl-amino-dimethoxy-benzo [ d ] aza-quinazoline in preparation of drugs for treating lung cancer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108295076A true CN108295076A (en) | 2018-07-20 |
| CN108295076B CN108295076B (en) | 2020-05-22 |
Family
ID=62866344
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810069813.4A Active CN108295076B (en) | 2018-01-24 | 2018-01-24 | Application of propionyl-amino-dimethoxy-benzo [ d ] aza-quinazoline in preparation of drugs for treating lung cancer |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108295076B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111973601A (en) * | 2019-05-21 | 2020-11-24 | 浙江工业大学 | Application of cinnamyl amino quinazoline compound as EGFR (epidermal growth factor receptor) inhibitor in preparation of medicines |
Citations (2)
| 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 |
| WO1995023141A1 (en) * | 1994-02-23 | 1995-08-31 | Pfizer Inc. | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents |
-
2018
- 2018-01-24 CN CN201810069813.4A patent/CN108295076B/en active Active
Patent Citations (2)
| 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 |
| WO1995023141A1 (en) * | 1994-02-23 | 1995-08-31 | Pfizer Inc. | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111973601A (en) * | 2019-05-21 | 2020-11-24 | 浙江工业大学 | Application of cinnamyl amino quinazoline compound as EGFR (epidermal growth factor receptor) inhibitor in preparation of medicines |
| CN111973601B (en) * | 2019-05-21 | 2022-02-11 | 浙江工业大学 | Application of cinnamyl amino quinazoline compound as EGFR (epidermal growth factor receptor) inhibitor in preparation of medicines |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108295076B (en) | 2020-05-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108014113A (en) | Butyrylamino dimethoxy benzo [d] azepine * bases quinazoline compounds are preparing the application in treating uterine neck cancer drug | |
| CN108042546A (en) | Morpholinyl acetylamino benzo [d] azepine * bases quinazoline compounds are preparing the application in treating uterine neck cancer drug | |
| CN108078994A (en) | 6- (2- morpholinyls acetylamino) quinazoline compounds are preparing the application in treating lung-cancer medicament | |
| CN108125961A (en) | Morpholinyl acetylamino anisyl benzo-aza * bases quinazoline compounds are preparing the application in treating leukemia medicament | |
| CN109251196A (en) | Amino benzo [d] azepine * base quinazoline compounds and its preparation method and application | |
| CN108017621A (en) | Morpholinyl acetylamino dimethoxy benzo [d] azepine * bases quinazoline compounds and preparation and application | |
| CN108295076A (en) | Propionamido dimethoxy benzo [d] azepine * bases quinazoline ditosylate salt is preparing the application in treating lung-cancer medicament | |
| CN108117542A (en) | Propionamido anisyl benzo [d] azepine * bases quinazoline compounds and preparation and application | |
| CN108276384A (en) | Acetylamino benzo [d] azepine * bases quinazoline compounds and its preparation and application | |
| CN108084162B (en) | Dimethoxy benzene aminoacetylamino benzo [d] azepine * base quinazoline compounds and preparation and application | |
| CN108309984A (en) | Propionamido quinazoline compounds are preparing the application in treating uterine neck cancer drug | |
| CN108129461A (en) | Benzamido benzo [d] azepine * bases quinazoline compounds and preparation and application | |
| CN108329299A (en) | Butyrylamino chloro benzo [d] azepine * bases quinazoline compounds and preparation and application | |
| CN108324717A (en) | Pivaloyl amino chloro benzo [d] azepine * bases quinazoline compounds are preparing the application in treating uterine neck cancer drug | |
| CN108014112A (en) | Adjacent toluidino acetylamino benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament | |
| CN108324719A (en) | Adjacent toluidino acetylamino anisyl benzo-aza * bases quinazoline compounds are preparing the application in treating uterine neck cancer drug | |
| CN108324718A (en) | Application of the cyclohexyl methoxy formamido group chloro benzo azepine * bases quinazoline compounds in treating leukemia medicament | |
| CN108125962A (en) | Benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament | |
| CN108329300A (en) | Nitro benzo [d] azepine * base quinazoline compounds and its preparation method and application | |
| CN108047206B (en) | Pivaloyl amino benzo [d] azepine * base quinazoline compounds and preparation and application | |
| CN108143736A (en) | Butyrylamino benzo [d] azepine * bases quinazoline ditosylate salt is preparing the application in treating lung-cancer medicament | |
| CN108033949B (en) | 6- (2- dipropyl aminoacetylamino) quinazoline compounds and preparation and application | |
| CN108186649A (en) | Propionamido chloro benzo [d] azepine * bases quinazoline ditosylate salt is preparing the application in treating leukemia medicament | |
| CN108164510A (en) | Chloro acetylamino benzo [d] azepine * base quinazoline compounds and its preparation method and application | |
| CN108125960A (en) | Isobutyryl amino benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |