CN108309984A - Propionamido quinazoline compounds are preparing the application in treating uterine neck cancer drug - Google Patents
Propionamido quinazoline compounds are preparing the application in treating uterine neck cancer drug Download PDFInfo
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Abstract
The invention discloses a kind of propionamido quinazoline compounds to prepare the application in preventing or treating human cervical carcinoma's medicine, to inhibiting human cervical carcinoma cell lines Siha activity to have remarkable result.
Description
(1) technical field
The present invention relates to a kind of propionamido quinazoline compounds in the drug for preparing prevention or treatment human cervical carcinoma
Application.
(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 quinazoline compounds to exist
The application in the drug for preventing or treating human cervical carcinoma is prepared, such compound is under doses to human cervical carcinoma cell lines
Siha has significant inhibiting rate；And such compounds process for production thereof is easy, easily operated, raw material is easy to get, and production cost compared with
It is low, it is suitable for industrial applications.
For achieving the above object, the present invention adopts the following technical scheme that：
The present invention provides propionamido quinazoline compounds shown in a kind of formula (I) to prepare prevention or treatment tumour
Application in drug is especially preparing the application in preventing or treating the drug of human cervical carcinoma：
Preferably, the drug is with the inhibition active drugs of human cervical carcinoma cell lines Siha.
The preparation method of propionamido quinazoline compounds, the method shown in a kind of formula (I) of present invention offer
For：
(1) compound shown in formula (II) is mixed with compound shown in formula (III), in organic solvent A, in base catalysis
Under the action of agent B, 25~120 DEG C reacted (TLC tracking and monitorings, solvent be ethyl acetate/petroleum ether=1：3 (v/v),
It is preferred that 40~100 DEG C of 0.5~12h of reaction), after the reaction was complete, reaction solution is isolated and purified, compound shown in formula (IV) is made；
The organic solvent A is selected from one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N- dimethyl methyls
Amide；The basic catalyst B is selected from one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4- bis-
Methylamino pyridine, 4- pyrollidinopyridines or sodium carbonate (preferably pyridine, diethylamine, triethylamine, N, N- dimethylanilines or 4- diformazans
Aminopyridine)；
(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 cervical carcinoma is treated, which has significant inhibitory activity to human cervical carcinoma cell lines Siha.
(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：The preparation of 6- nitro-quinazolines (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：The preparation of 6- nitro-quinazolines (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：The preparation of 6- nitro-quinazolines (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：The preparation of 6- nitro-quinazolines (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：The preparation of 6- nitro-quinazolines (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：The preparation of 6- nitro-quinazolines (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：The preparation of 6- amido quinazolines (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 1 method of embodiment, 0.40 gram
(6.34mmol) ammonium formate, 0.04 gram of 5%Pd/C, 4.0 milliliters of chloroforms are added in reaction bulb, 25 DEG C of stirrings of room temperature, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：1 (v/v)), it reacts 12 hours, filtering, filtrate concentration, 25 DEG C of vacuum drying
Obtain faint yellow solid product 6- amido quinazolines (V), yield 98.2%, 122~126 DEG C of fusing point.1H NMR(500MHz,
CDCl3)δ:3.40-3.48(m,2H),3.71(s,3H),3.82(s,3H),3.83(s,3H),3.87-3.98(m,5H),4.45
(dd, J=6.3,13.8Hz, 1H), 4.95 (dd, J=6.5,9.2Hz, 1H), 6.47 (s, 1H), 6.90 (d, J=8.7Hz,
2H), 6.95 (d, J=2.5Hz, 1H), 7.11 (d, J=8.6Hz, 2H), 7.15 (dd, J=8.9,2.5Hz, 1H), 7.69 (d, J
=8.9Hz, 1H), 8.50 (s, 1H).IR(KBr,cm-1)ν:3368,3215,2932,2825,1628,1566,1512,1487,
1353,1248,1036,834。
Embodiment 8：The preparation of 6- amido quinazolines (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 2 method of embodiment, 1.20 grams
(19.18mmol) 80wt% hydrazine hydrates, 0.20 gram of 5%Pd/C, 20.0 milliliters of toluene are added in 50 milliliters of reaction bulb, heating
To 100 DEG C, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 0.5 hour, it is cooled
Filter, filtrate concentration, 25 DEG C of vacuum drying obtain faint yellow solid product 6- amido quinazolines (V), yield 100.0%, fusing point
122~126 DEG C.1H NMR and IR is the same as embodiment 7.
Embodiment 9：The preparation of 6- amido quinazolines (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 3 method of embodiment, 0.08 gram of concentrated hydrochloric acid
(mass concentration 36~38%), 0.40 gram of iron powder, 20.0 ml methanols are added in 50 milliliters of reaction bulb, are heated to 40 DEG C,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 8 hours, cold filtration, filtrate is dense
Contracting, 25 DEG C of vacuum drying obtain faint yellow solid product 6- amido quinazolines (V), yield 94.1%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 10：The preparation of 6- amido quinazolines (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 4 method of embodiment, 0.40 gram of acetic acid,
1.20 grams of iron powders, 20.0 milliliters of isopropanols are added in 50 milliliters of reaction bulb, are heated to 80 DEG C, TLC tracing detection (solvents
For ethyl acetate/petroleum ether=1：1 (v/v)), it is stirred to react 3 hours, cold filtration, filtrate concentration, 25 DEG C of vacuum drying obtain
Faint yellow solid product 6- amido quinazolines (V), yield 97.5%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 11：The preparation of propionamido quinazoline (I)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 7 method of embodiment, 0.13 gram
(1.64mmol) pyridine, 3 milliliters of tetrahydrofurans are added in reaction 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 quinoline shown in formula (I)
Oxazoline 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：The preparation of propionamido quinazoline (I)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 8 method of embodiment, 0.04 gram
(0.55mmol) diethylamine, 10.0 milliliters of chloroforms are added in 50 milliliters of reaction bulb, and 0.051 gram is added dropwise under 10 DEG C of stirring conditions
(0.55mmol) propionyl chloride and 5.0 milliliters of chloroform mixed solutions, drop finish, and (solvent is ethyl acetate/oil to TLC tracing detections
Ether=1：1 (v/v)), react 8 hours under the conditions of 10 DEG C, filter, filtrate steaming removal solvent, concentrate be added 20 milliliters of ethyl alcohol by its
Dissolving obtains lysate, 0.26 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) of addition into lysate, after mixing,
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 petroleum ether/
Ethyl acetate mixture is eluant, eluent, elution, and (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, collection liquid concentration, 50 DEG C are dried to obtain
Propionamido quinazoline pale solid shown in formula (I), yield 62.0%, 125~129 DEG C of fusing point.1H NMR and IR are the same as real
Apply example 11.
Embodiment 13：The preparation of propionamido quinazoline (I)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 9 method of embodiment, 0.111 gram
(1.10mmol) triethylamine, 10.0 milliliters of ethyl acetate are added in 50 milliliters of reaction bulb, are added dropwise under 0 DEG C of stirring condition
0.102 gram of (1.10mmol) propionyl chloride and 5.0 milliliters of ethyl acetate solutions, drop finish, and (solvent is acetic acid second to TLC tracing detections
Ester/petroleum ether=1：1) it, reacts 6 hours under the conditions of 25 DEG C, filters, filtrate steaming removal solvent, 20 milliliters of chloroforms are added in concentrate will
It is dissolved, and obtains lysate, and 0.30 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 10：1 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 quinazoline pale solid shown in formula (I), yield 58.8%, 125~129 DEG C of fusing point.1H NMR
With IR with embodiment 11.
Embodiment 14：The preparation of propionamido quinazoline (I)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 10 method of embodiment, 0.067 gram
(0.55mmol) 4-dimethylaminopyridine, 20.0 milliliters of toluene are added in 50 milliliters of reaction bulb, are added dropwise under 5 DEG C of stirring conditions
The solution of 0.286 gram of (2.20mmol) propionic andydride and 7.0 milliliters of toluene, drop finish, and are heated to 50 DEG C, TLC tracing detection (solvents
For ethyl acetate/petroleum ether=1：1) it, reacts 3 hours, filtering, 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 5：1 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 quinazoline pale solid shown in formula (I), 125~129 DEG C of 54.5% fusing point of yield.1H NMR and IR is same
Embodiment 11.
Embodiment 15：The preparation of propionamido quinazoline (I)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 7 method of embodiment, 0.213 gram
(1.65mmol) quinoline, 15.0 milliliters of benzene are added in 50 milliliters of reaction bulb, and 0.204 gram is added dropwise under -10 DEG C of stirring conditions
The solution of (2.20mmol) propionyl chloride and 5.0 milliliters of benzene, drop finish, 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, and its is molten
Solution obtains lysate, 0.40 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) of addition into lysate, after mixing, steams
Except solvent, the mixture of dry concentrate and silica gel is obtained, mixture is filled into column, then with volume ratio for 1：1 petroleum ether/second
Acetoacetic ester mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), root
The eluent (Rf values are 0.5) containing formula (I) compound represented is collected according to TLC detections, collection liquid concentration, 50 DEG C are dried to obtain formula
(I) propionamido quinazoline pale solid shown in, yield 72.1%, 125~129 DEG C of fusing point.1H NMR and IR are the same as implementation
Example 11.
Embodiment 16：The preparation of propionamido quinazoline (I)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 7 method of embodiment, 0.164 gram
(1.10mmol) 4- pyrollidinopyridines, 15.0 milliliters of dichloromethane are added in 50 milliliters of reaction bulb, 10 DEG C of stirring conditions
0.102 gram of (1.10mmol) propionyl chloride of lower dropwise addition and 5.0 milliliters of dichloromethane solutions, drop finish, and (solvent is TLC tracing detections
Ethyl acetate/petroleum ether=1：1) it, reacts 8 hours under the conditions of 10 DEG C, filters, filtrate steaming removal solvent, concentrate is added 20 milliliters
Ethyl alcohol is dissolved, and lysate is obtained, and 0.50 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added into lysate,
After mixing, 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 be eluant, eluent, elution, TLC tracing detections (solvent be ethyl acetate/petroleum ether=
1：1 (v/v)), the eluent (Rf values are 0.5) containing formula (I) compound represented is collected according to TLC detections, collection liquid concentrates, and 50
DEG C it is dried to obtain propionamido quinazoline pale solid shown in formula (I), 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) human cervical carcinoma cell lines Siha biological activity tests have been subjected to.
Test method：Tetrazolium reduction method (mtt assay).
Cell strain：Human cervical carcinoma cell lines Siha.Above-mentioned tumor cell line is purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences
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 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) grows cancer cell line Siha
(2) according to embodiment 11, propionyl chloride is replaced with 3- methoxy benzoyl chlorides or cinnamoyl chloride respectively, other operations
With embodiment 11, quinazoline compounds (b) and (c) are respectively synthesized, structure is as follows：
Quinazoline compounds (b) obtained and (c) human cervical carcinoma cell lines Siha lifes have been subjected to according to the above method
Object active testing, test result show quinazoline compounds (b) and (c) to human cervical carcinoma cell lines Siha inhibitions not
Obviously, compound (b) and (c) can not show a candle to compound (I) to the active anticancer of human cervical carcinoma cell lines Siha.Concrete outcome such as table
Shown in 2：
The inhibiting effect that 2. compound (b) of table and (c) grow cancer cell line Siha
Above-mentioned active anticancer testing in vitro experiment shows：The similar compound (b) of other 2 structures and (c) are to people's uterine neck
The equal unobvious of inhibiting effect of cancer cell line Siha growths.Compound (I) makees the inhibition that human cervical carcinoma cell lines Siha is grown
With notable, hence it is evident that better than compound (b) and (c).
(3) according to embodiment 11, propionyl chloride is replaced with butyl chloride, other operations have synthesized quinazoline with embodiment 11
Class compound (f), structure are as follows：
Quinazoline compounds (f) obtained human cervical carcinoma cell lines Siha bioactivity has been subjected to according to the above method
Test, test result show that quinazoline compounds (f) can not show a candle to compound to the active anticancer of human cervical carcinoma cell lines Siha
(Ⅰ).Concrete outcome is as shown in table 3：
The inhibiting effect that 3. compound (f) of table grows cancer cell line Siha
Claims (2)
1. propionamido quinazoline compounds shown in a kind of formula (I) are in the drug for preparing prevention or treatment human cervical carcinoma
Using：
2. application as described in claim 1, it is characterised in that：The drug is to live with inhibition human cervical carcinoma cell lines Siha
The drug of property.
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| 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 |
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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 |
| 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 |
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| 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 |
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