CN104876882B - 6- amino-quinazoline compounds and application - Google Patents
6- amino-quinazoline compounds and application Download PDFInfo
- Publication number
- CN104876882B CN104876882B CN201510243810.4A CN201510243810A CN104876882B CN 104876882 B CN104876882 B CN 104876882B CN 201510243810 A CN201510243810 A CN 201510243810A CN 104876882 B CN104876882 B CN 104876882B
- Authority
- CN
- China
- Prior art keywords
- anilino
- formula
- solvent
- milliliters
- gram
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
Abstract
Application the invention discloses 6 amino-quinazoline compounds shown in a kind of formula (I a) and in prevention or treatment human lung cancer or human breast carcinoma medicine is prepared, the compounds of this invention preparation method is simply easily operated, raw material is easy to get, and production cost is relatively low, there is good active anticancer；In formula (I a), R1For ethyl or propyl group, R3With R1Structure is identical.
Description
(1) technical field
The present invention relates to a kind of quinazoline compounds and its application, more particularly to 6- amino-quinazoline compounds and
Prepare the application in the medicine of prevention or treatment 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 obvious antiviral activity, antibacterial activity, antitumor activity etc., quinazoline ditosylate salt
Compound has had listed some kinds as antitumor drug.Such as the Gefitinib for being used to treat lung cancer of listing
(Gefitinib) and Tarceva (Erlotinib), and for treating the Lapatinib (Lapatinib) of breast cancer, they
Belong to 4- anilinoquinazoline class compounds.New quinazoline compounds and its bioactivity also common document report
(refer 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 it is most
Quinazoline compounds simultaneously do not have antitumor activity.
(3) content of the invention
It is an object of the invention to provide a kind of novel quinazoline quinoline class compound with active anticancer -6- amino quinoline azoles
Quinoline class compound and application, such compound is under doses to human lung cancer cell lines A-549 or Breast cancer lines
MCF-7 has preferable 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, suitable for industrial applications.
For achieving the above object, the present invention adopts the following technical scheme that：
The present invention provides 6- amino-quinazoline compounds shown in a kind of formula (I-a),
In formula (I-a), R1For ethyl or propyl group, R3With R1Structure is identical.
The present invention also provides the intermediate that one kind is used to prepare compound shown in formula (I-a),
In formula (I-b), R1For ethyl or propyl group, R3With R1Structure is identical.
The present invention provides application of the compound in compound shown in formula (I) shown in a kind of formula (I-a),
In formula (I), R1For ethyl or propyl group, R3With R1Structure is identical；R2For RCONH, wherein R is C1-C3 alkyl or benzene
Base.
The invention further relates to compound shown in a kind of formula (I-a) to prepare prevention or treatment human lung cancer or human breast carcinoma medicine
In application, the human lung cancer is human lung cancer cell lines A-549, and the human breast carcinoma is MCF-7 cell strainHJ2mm.
Further, the 4- shown in formula (I) [3- (2- disubstituted amidos acetylamino) anilino-] -6- substituent quinazoline ditosylate salts
Compound is preferably one of following：
Further, the 4- [3- (2- disubstituted amidos acetylamino) anilino-] -6- substituent quinazoline ditosylate salts
Compound (I) is preferably one of following：
The present invention provides a kind of 4- [3- (2- disubstituted amidos acetylamino) anilino-] -6- substituent quinazoline ditosylate salts
The preparation method of compound, the method are：(1) compound shown in formula (II) is mixed with compound shown in formula (III),
Under the action of basic catalyst B1, in organic solvent A 1,25~120 DEG C are reacted that (TLC tracking and monitorings, solvent are second
Acetoacetic ester/petroleum ether=1：1 (v/v), preferably 40~100 DEG C 0.5~12h of reaction), after the reaction was complete, by reacting liquid filtering, filter
Liquid concentrates, and dry (preferably 40 DEG C vacuum drying), obtains compound shown in formula (I-b)；The basic catalyst B1 is selected from down
One of row：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrollidinopyridines or carbon
Sour sodium (preferably pyridine, diethylamine, triethylamine, N, N- dimethylanilines or 4-dimethylaminopyridine)；The organic solvent A 1 is selected from
It is one of following：Chloroform, toluene, methanol, ethanol, propyl alcohol, isopropanol, acetonitrile or N,N-dimethylformamide；Formula (III) institute
Show the ratio between compound, amount for the material that feeds intake of basic catalyst B1 shown in compound and formula (II) for 1.0 ﹕, 0.8~1.2 ﹕ 1.0~
8.0, the dosage of the organic solvent A 1 is calculated as 10~50mL/g with the quality of compound shown in formula (III)；
In formula (II), R1For ethyl or propyl group, R3With R1Structure is identical；
In formula (I-b), R1For ethyl or propyl group, R3With R1Structure is identical；R in formula (I-b)1With R in formula (II)1It is identical, formula
R in (I-b)3With R in formula (II)3It is identical；
(2) compound shown in formula (I-b) is under reducing agent B2 effects, in organic solvent A 2, in 25~100 DEG C of reactions
(TLC tracking and monitorings, solvent are ethyl acetate/petroleum ether=1 completely：1 (v/v), preferably 40~80 DEG C 0.5~12h of reaction),
Reacting liquid filtering, the concentrate drying (preferably 25 DEG C of dryings) after filtrate decompression concentration, is made the compound shown in formula (I-a)；
The reducing agent B2 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 to have
Solvent A2 is one of following：Chloroform, toluene, methanol, ethanol, propyl alcohol, isopropanol, acetonitrile or N,N-dimethylformamide；When
When the reducing agent B2 is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, in the compound and reducing agent B2 shown in formula (I-b)
The mass ratio that feeds intake of iron powder, concentrated hydrochloric acid or acetic acid is 1.0 ﹕, 1.0~3.0 ﹕ 0.2~1.0；When the reducing agent B2 for palladium carbon/
When ammonium formate or palladium carbon/hydrazine hydrate, compound and the palladium carbon in reducing agent B2, ammonium formate or hydrazine hydrate shown in formula (I-b)
The mass ratio that feeds intake is 1.0 ﹕, 0.1~0.5 ﹕ 1.0~3.0；The dosage of the organic solvent A 2 is with the compound shown in formula (I-b)
Quality is calculated as 10~50mL/g；Iron powder/the concentrated hydrochloric acid, iron powder/acetic acid refer to the mixing of iron powder and concentrated hydrochloric acid or acetic acid, wherein
Concentrated hydrochloric acid mass concentration is 36%~38%；Palladium carbon/the ammonium formate or palladium carbon/hydrazine hydrate refer to palladium carbon and ammonium formate or hydration
The mass loading amount of palladium is 5% in the mixture of hydrazine, wherein palladium carbon, and hydrazine hydrate mass concentration is 80%；
In formula (I-a), R1For ethyl or propyl group, R3With R1Structure is identical；
(3) compound shown in formula (I-a) is mixed with acid anhydrides or acyl chlorides, under basic catalyst B3 effects, in organic molten
In agent A3, -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 the compound shown in formula (I) is made；The basic catalyst B3 is
It is one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrollidinopyridines or
Sodium carbonate；The organic solvent A 3 is one of following：Tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ether, acetonitrile, first
Benzene or benzene；The acid anhydrides or acyl chlorides are one of following：Acetic anhydride, chloroacetic chloride, isobutyric anhydride, isobutyryl chloride, benzoyl oxide, benzene first
Acyl chlorides, propionic andydride, propionyl chloride, butyric anhydride or n-butyryl chloride；Compound shown in the formula (I-a) and acid anhydrides or acyl chlorides, alkalescence
The ratio between amount for the material that feeds intake of catalyst B3 is 1 ﹕, 1.0~8.0 ﹕ 1.0~3.0, and the dosage of the organic solvent A 3 is with formula (I-a)
The quality of shown compound is calculated as 10~95mL/g.
Specific recommendation step (3) of the invention carries out as follows：By compound, basic catalyst shown in formula (I-a)
B3, which is added in organic solvent A 3, (can not also add organic solvent A 3), and under the conditions of -10~10 DEG C, the organic molten of acid anhydrides is added dropwise
3 solution of organic solvent A of agent A3 solution or acyl chlorides, drop finish, when -10~50 DEG C of reactions 3~12 are small, filtering, and filtrate steaming removal solvent,
Concentrate column chromatography obtains compound shown in formula (I)；The organic solvent volume dosage of dissolving acid anhydrides or acyl chlorides there is not shadow to the present invention
Ring, the dosage of the organic solvent A 3 is calculated as 10~95mL/g with the quality of compound shown in formula (I-a), and organic solvent A 3 refers to
The organic solvent of compound shown in catalyst-solvent and formula (I-a) and dissolving acid anhydrides or the cumulative volume of acyl chlorides 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, takes concentrate to be dissolved with organic solvent D, obtains lysate, and concentration is then added into lysate
The column chromatography silica gel of 1.0~2.0 times of weight of thing, after mixing, is evaporated off solvent, dry, obtains the mixture of concentrate and silica gel, will
Mixture fills column, then using volume ratio as 1：0.1~10 petroleum ether and ethyl acetate mixture are eluant, eluent, and collection contains mesh
The efflux of component is marked (preferably with ethyl acetate/petroleum ether=1：1 (v/v) is solvent tracing detection, collects target components),
It is concentrated under reduced pressure, dry (preferably 50 DEG C of dryings), obtain the compound shown in formula (I)；The organic solvent D is one of following：Second
Alcohol, chloroform, tetrahydrofuran or ethyl acetate.
The invention further relates to 4- shown in formula (I) [3- (2- disubstituted amidos acetylamino) anilino-] -6- substituent quinoline azoles
Application of the quinoline class compound in prevention or tumor is prepared, particularly useful for making prevention or treatment human lung cancer or people
Application in breast cancer medicines.Compound provided by the invention is to human lung cancer cell lines A-549 or MCF-7 cell strainHJ2mm
With preferable inhibiting rate.4- [3- (2- lignocaines acetylamino) anilino-] -6- acetylaminos quinazoline (I -1) is to human milk
The IC of adenocarcinoma cell strain MCF-750Respectively 62.71 μM.4- [3- (2- lignocaines acetylamino) anilino-] -6- benzene carbon amides
Base quinazoline (I -3) is to the IC of human lung cancer cell lines A-54950For 31.69 μM.4- [3- (2- dipropyls aminoacetylamino) aniline
Base] -6- acetylaminos quinazoline (I -6) is to the IC of human lung cancer cell lines A-549 and MCF-7 cell strainHJ2mm50Respectively
40.30 μM and 64.24 μM.
Organic solvent A 1 of the present invention, A2, A3 and D are organic solvent, are had for the ease of distinguishing used in different step
Solvent is different and names, and letter itself does not have implication；The catalyst B1, reducing agent B2 and catalyst B3 are catalyst,
Named for the ease of distinguishing different step used catalyst difference, letter itself does not have implication.
The beneficial effects are mainly as follows：(1) 6- amino-quinazoline chemical combination shown in formula (I-a) of the present invention
The active anticancer that thing has had, is expected to be applied to prepare in the medicine for preventing or treating tumor disease；4- [3- (2- dipropyl amino
Acetylamino) anilino-] -6- amido quinazolines (I-a2) are to human lung cancer cell lines A-549 and MCF-7 cell strainHJ2mm
IC50Respectively 30.10 μM and 17.11 μM；(2) 6- amino-quinazoline compounds shown in formula (I-a) provided by the invention are used for
The method for preparing 4- [3- (2- disubstituted amidos acetylamino) anilino-] -6- substituents quinazoline compounds (I) is simply easy
In operation, raw material is easy to get, and production cost is relatively low, suitable for practicality.
(4) embodiment
The present invention is further described in conjunction with specific embodiments, and following embodiment is to illustrate the present invention, rather than
It limit the invention in any way.
2- disubstituted amidos-N- (3- aminophenyls) acetamides (II) prepare reference literature (Lombardo, C.M.；
Welsh,S.J.；Strauss,S.J.；Dale,A.G.；Todd,A.K.；Nanjunda,R.；Wilson,W.D.；Neidle,
S.,Bioorg.Med.Chem.Lett.2012,22(18),5984-5988；Fosdick,L.S.；Rapp,
G.W.J.Am.Chem.Soc.1943,65,2307-2308 method) is prepared.The system of the chloro- 6- nitro-quinazolines (III) of 4-
Standby reference literature (Fernandes, C.；Oliveira,C.；Gano,L.；Bourkoula,A.；Pirmettis,I.；Santos,
I.Bioorg.Med.Chem.2007,15,3974-3980 method) is prepared.
Embodiment 1：The preparation of 4- [3- (2- lignocaines acetylamino) anilino-] -6- nitro-quinazolines (I-b1)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.52 grams of (6.87mmol) 2- diethylaminos
Base-N- (3- aminophenyls) acetamide (II -1), 3.62 grams of (45.76mmol) pyridines, 12 milliliters of chloroforms add 50 milliliters anti-
Answer in bottle, be heated to 40 DEG C, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), stirring reaction 10 is small
When, reaction is closed, filtering, filtrate concentration, 40 DEG C of vacuum drying, obtain yellow oil product 4- [3- (2- lignocaine acetyl ammonia
Base) anilino-] -6- nitro-quinazolines (I-b1), yield 87.3%.
Embodiment 2：The preparation of 4- [3- (2- lignocaines acetylamino) anilino-] -6- nitro-quinazolines (I-b1)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.01 grams of (4.56mmol) 2- diethylaminos
Base-N- (3- aminophenyls) acetamide (II -1), 1.67 grams of (22.83mmol) diethylamine, 60 milliliters of toluene add 100 milliliters
In three-necked flask, 100 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), stirring is anti-
Answer 2 it is small when, close reaction, filtering, filtrate concentration, 40 DEG C of vacuum drying obtain yellow oil product 4- [3- (2- lignocaine second
Acylamino-) anilino-] -6- nitro-quinazolines (I-b1), yield 62.4%.
Embodiment 3：The preparation of 4- [3- (2- lignocaines acetylamino) anilino-] -6- nitro-quinazolines (I-b1)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.27 grams of (5.74mmol) 2- diethylaminos
Base-N- (3- aminophenyls) acetamide (II -1), 0.58 gram of (5.73mmol) triethylamine, 60 ml methanols add 100 milliliters
In three-necked flask, 60 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), stirring reaction
8 it is small when, close reaction, filtering, filtrate concentration, 40 DEG C of vacuum drying obtain yellow oil product 4- [3- (2- lignocaine acetyl
Amino) anilino-] -6- nitro-quinazolines (I-b1), yield 72.5%.
Embodiment 4：The preparation of 4- [3- (2- lignocaines acetylamino) anilino-] -6- nitro-quinazolines (I-b1)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.40 grams of (6.33mmol) 2- diethylaminos
Base-N- (3- aminophenyls) acetamide (II -1), 1.40 grams of (11.46mmol) 4-dimethylaminopyridine, 60 milliliters of isopropanols add
Enter in 100 milliliters of three-necked flask, 25 DEG C of stirrings of room temperature, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1
(v/v)) when, reaction 12 is small, reaction, filtering are closed, filtrate concentrates, and 40 DEG C of vacuum drying obtain yellow oil product 4- [3- (2-
Lignocaine acetylamino) anilino-] -6- nitro-quinazolines (I-b1), yield 76.8%.
Embodiment 5：The preparation of 4- [3- (2- lignocaines acetylamino) anilino-] -6- nitro-quinazolines (I-b1)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.14 grams of (5.15mmol) 2- diethylaminos
Base-N- (3- aminophenyls) acetamide (II -1), 1.04 grams of (8.58mmol) N, N- dimethylanilines, 12 milliliters of N, N- dimethyl methyls
Acid amides is added in 50 milliliters of reaction bulb, is heated to 120 DEG C, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1
(v/v)) when, stirring reaction 0.5 is small, reaction is closed, is filtered, filtrate concentration, 40 DEG C of vacuum drying obtain yellow oil product 4-
[3- (2- lignocaines acetylamino) anilino-] -6- nitro-quinazolines (I-b1), yield 50.6%.
Embodiment 6：The preparation of 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- nitro-quinazolines (I-b2)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.71 grams of (6.86mmol) 2- dipropyl ammonia
Base-N- (3- aminophenyls) acetamide (II -2), 3.62 grams of (45.76mmol) pyridines, 12 milliliters of chloroforms add 50 milliliters anti-
Answer in bottle, be heated to 40 DEG C, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), stirring reaction 10 is small
When, reaction, filtering are closed, filtrate concentrates, and 40 DEG C of vacuum drying obtain yellow oil product 4- [3- (2- dipropyl glycyl ammonia
Base) anilino-] -6- nitro-quinazolines (I-b2), yield 84.2%.
Embodiment 7：The preparation of 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- nitro-quinazolines (I-b2)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.14 grams of (4.57mmol) 2- dipropyl ammonia
Base-N- (3- aminophenyls) acetamide (II -2), 1.67 grams of (22.83mmol) diethylamine, 60 milliliters of toluene add 100 milliliters
In three-necked flask, 100 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), stirring is anti-
Answer 2 it is small when, close reaction, filtering, filtrate concentration, 40 DEG C of vacuum drying obtain yellow oil product 4- [3- (2- dipropyl amino second
Acylamino-) anilino-] -6- nitro-quinazolines (I-b2), yield 73.4%.
Embodiment 8：The preparation of 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- nitro-quinazolines (I-b2)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.43 grams of (5.73mmol) 2- dipropyl ammonia
Base-N- (3- aminophenyls) acetamide (II -2), 0.58 gram of (5.73mmol) triethylamine, 60 ml methanols add 100 milliliters
In three-necked flask, 60 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), stirring reaction
8 it is small when, close reaction, filtering, filtrate concentration, 40 DEG C of vacuum drying obtain yellow oil product 4- [3- (2- dipropyl glycyls
Amino) anilino-] -6- nitro-quinazolines (I-b2), yield 81.7%.
Embodiment 9：The preparation of 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- nitro-quinazolines (I-b2)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.57 grams of (6.30mmol) 2- dipropyl ammonia
Base-N- (3- aminophenyls) acetamide (II -2), 1.40 grams of (11.46mmol) 4-dimethylaminopyridine, 60 milliliters of isopropanols add
Enter in 100 milliliters of three-necked flask, 25 DEG C of stirrings of room temperature, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1
(v/v)) when, reaction 12 is small, reaction, filtering are closed, filtrate concentrates, and 40 DEG C of vacuum drying obtain yellow oil product 4- [3- (2-
Dipropyl aminoacetylamino) anilino-] -6- nitro-quinazolines (I-b2), yield 73.5%.
Embodiment 10：The preparation of 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- nitro-quinazolines (I-b2)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.29 grams of (5.17mmol) 2- dipropyl ammonia
Base-N- (3- aminophenyls) acetamide (II -2), 1.04 grams of (8.58mmol) N, N- dimethylanilines, 12 milliliters of N, N- dimethyl methyls
Acid amides is added in 50 milliliters of reaction bulb, is heated to 120 DEG C, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1
(v/v)) when, stirring reaction 0.5 is small, reaction is closed, is filtered, filtrate concentration, 40 DEG C of vacuum drying obtain yellow oil product 4-
[3- (2- dipropyls aminoacetylamino) anilino-] -6- nitro-quinazolines (I-b2), yield 66.3%.
Embodiment 11：The preparation of 4- [3- (2- lignocaines acetylamino) anilino-] -6- amido quinazolines (I-a1)
Successively by 0.40 gram of (1.01mmol) 4- [3- (2- lignocaines acetylamino) anilino-] -6- nitro-quinazolines
(I-b1), 0.40 gram of (6.34mmol) ammonium formate, 0.04 gram of 5%Pd/C (Pd mass loadings amount is 5%), 4.0 milliliters of chloroforms add
Enter into reaction bulb, 25 DEG C of stirrings of room temperature, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), reaction
12 it is small when, filtering, filtrate concentration, 25 DEG C vacuum drying, obtain sepia oil product 4- [3- (2- lignocaines acetylamino)
Anilino-] -6- amido quinazolines (I-a1), yield 79.2%.
Embodiment 12：The preparation of 4- [3- (2- lignocaines acetylamino) anilino-] -6- amido quinazolines (I-a1)
Successively by 0.40 gram of (1.01mmol) 4- [3- (2- lignocaines acetylamino) anilino-] -6- nitro-quinazolines
(I-b1), 1.20 grams of (19.18mmol) 80% hydrazine hydrates, 0.20 gram of 5%Pd/C, 20.0 milliliters of toluene are added to 50 milliliters anti-
Answer in bottle, be heated to 100 DEG C, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), stirring reaction 0.5
Hour, cold filtration, filtrate concentrates, and 25 DEG C of vacuum drying obtain sepia oil product 4- [3- (2- lignocaine acetyl ammonia
Base) anilino-] -6- amido quinazolines (I-a1), yield 65.7%.
Embodiment 13：The preparation of 4- [3- (2- lignocaines acetylamino) anilino-] -6- amido quinazolines (I -13)
Successively by 0.40 gram of (1.01mmol) 4- [3- (2- lignocaines acetylamino) anilino-] -6- nitro-quinazolines
(I -11), 0.08 gram of concentrated hydrochloric acid (mass concentration 36%~38%), 0.40 gram of iron powder, 20.0 ml methanols are added to 50 milliliters
In reaction bulb, 40 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), stirring reaction 8
Hour, cold filtration, filtrate concentrates, and 25 DEG C of vacuum drying obtain sepia oil product 4- [3- (2- lignocaine acetyl ammonia
Base) anilino-] -6- amido quinazolines (I-a1), yield 44.6%.
Embodiment 14：The preparation of 4- [3- (2- lignocaines acetylamino) anilino-] -6- amido quinazolines (I-a1)
Successively by 0.40 gram of (1.01mmol) 4- [3- (2- lignocaines acetylamino) anilino-] -6- nitro-quinazolines
(I -11), 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,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), when stirring reaction 3 is small, cold filtration, filtrate is dense
Contracting, 25 DEG C of vacuum drying obtain sepia oil product 4- [3- (2- lignocaines acetylamino) anilino-] -6- amino quinoline azoles
Quinoline (I-a1), yield 76.0%.
Embodiment 15：The preparation of 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- amido quinazolines (I-a2)
Successively by 0.40 gram of (0.95mmol) 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- nitro-quinazolines
(I-b2), 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, room temperature 25
DEG C stirring, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), when reaction 12 is small, filter, filtrate is dense
Contracting, 25 DEG C of vacuum drying obtain sepia solid product 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- amino quinoline azoles
Quinoline (I-a2), yield 73.2%, 84~85 DEG C of fusing point.1H NMR(500MHz,CDCl3)δ:0.95 (t, J=7.3Hz, 6H)；
1.48-1.55(m,4H)；2.51 (t, J=7.8Hz, 4H)；7.03 (d, J=2.4Hz, 1H)；7.06-7.08(m,1H)；7.16
(dd, J=2.4,8.9Hz, 1H)；7.27(s,1H)；7.32 (t, J=8.1Hz, 1H)；7.66-7.69(m,2H)；8.24(t,J
=2.0Hz, 1H)；8.57(s,1H)；9.51(s,1H).
Embodiment 16：The preparation of 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- amido quinazolines (I-a2)
Successively by 0.40 gram of (0.95mmol) 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- nitro-quinazolines
(I-b2), 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
In reaction bulb, 100 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), stirring reaction
0.5 it is small when, cold filtration, filtrate concentration, 25 DEG C of vacuum drying obtain sepia solid product 4- [3- (2- dipropyl glycyls
Amino) anilino-] -6- amido quinazolines (I-a2), yield 70.5%, 84~85 DEG C of fusing point.1H NMR are the same as embodiment 15.
Embodiment 17：The preparation of 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- amido quinazolines (I-a2)
Successively by 0.40 gram of (0.95mmol) 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- nitro-quinazolines
(I-b2), 0.08 gram of concentrated hydrochloric acid (mass concentration 36~38%), 0.40 gram of iron powder, 20.0 ml methanols are added to 50 milliliters anti-
Answer in bottle, be heated to 40 DEG C, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), stirring reaction 8 is small
When, cold filtration, filtrate concentrates, and 25 DEG C of vacuum drying obtain sepia solid product 4- [3- (2- dipropyls aminoacetylamino)
Anilino-] -6- amido quinazolines (I-a2), yield 64.4%, 84~85 DEG C of fusing point.1H NMR are the same as embodiment 15.
Embodiment 18：The preparation of 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- amido quinazolines (I-a2)
Successively by 0.40 gram of (0.95mmol) 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- nitro-quinazolines
(I-b2), 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,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), when stirring reaction 3 is small, cold filtration, filtrate is dense
Contracting, 25 DEG C of vacuum drying obtain sepia solid product 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- amino quinoline azoles
Quinoline (I-a2), yield 67.3%, 84~85 DEG C of fusing point.1H NMR are the same as embodiment 15.
Embodiment 19：The preparation of 4- [3- (2- lignocaines acetylamino) anilino-] -6- acetylaminos quinazoline (I -1)
Successively by 0.20 gram of (0.55mmol) 4- [3- (2- lignocaines acetylamino) anilino-] -6- amido quinazolines
(I-a1), 0.13 gram of (1.64mmol) pyridine, 2.0 milliliters of tetrahydrofurans are added in reaction bulb, are added dropwise under -10 DEG C of stirring conditions
0.449 gram of (4.40mmol) acetic anhydride, drop finish, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1), -10 DEG C
Under the conditions of reaction 12 it is small when, filtering, filtrate steaming removal solvent, concentrate add 10 milliliters of ethyl acetate dissolved, dissolved
Liquid, 0.40 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added into lysate, after mixing, solvent is evaporated off, obtains dry
Dry concentrate and the mixture of silica gel, fill column, then using volume ratio as 1 by mixture：10 petrol ether/ethyl acetate mixing
Solution is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), detected according to TLC
The eluent (Rf values are 0.5) containing the compound shown in formula (I -1) is collected, collection liquid concentration, 50 DEG C are dried to obtain formula (I -1) institute
4- [3- (2- lignocaines acetylamino) the anilino-] -6- acetylamino quinazoline faint yellow solids shown, yield 67.3%, melts
136~138 DEG C of point.1H NMR(500MHz,DMSO)δ:0.89 (t, J=7.3Hz, 6H)；1.44-1.52(m,4H)；2.14(s,
3H)；2.51 (t, J=7.4Hz, 4H)；3.19(s,2H)；7.30-7.36(m,2H)；7.57 (d, J=7.8Hz, 1H)；7.75
(d, J=8.9Hz, 1H)；7.85 (dd, J=1.8,7.9Hz, 1H)；8.09(s,1H)；8.50(s,1H)；8.66 (d, J=
1.3Hz,1H)；9.60(s,1H)；9.80(s,1H)；10.27(s,1H).
Embodiment 20：The system of 4- [3- (2- lignocaines acetylamino) anilino-] -6- isobutyryls amido quinazoline (I -2)
It is standby
Successively by 0.20 gram of (0.55mmol) 4- [3- (2- lignocaines acetylamino) anilino-] -6- amido quinazolines
(I-a1), 0.04 gram of (0.55mmol) diethylamine, 10.0 milliliters of chloroforms are added in 50 milliliters of reaction bulb, 10 DEG C of stirring conditions
0.087 gram of (0.55mmol) isobutyric anhydride of lower dropwise addition and 5.0 milliliters of chloroform mixed solutions, drop finish, TLC tracing detection (solvents
For ethyl acetate/petroleum ether=1：1 (v/v)), when reaction 8 is small under the conditions of 10 DEG C, filtering, filtrate steaming removal solvent, concentrate adds
20 milliliters of ethanol are dissolved, and obtain lysate, and 0.20 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
For 1：5 petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/oil to TLC tracing detections
Ether=1：1 (v/v)), the eluent (Rf values are 0.4) containing the compound shown in formula (I -2), collection liquid are collected according to TLC detections
Concentration, 50 DEG C of 4- [3- (2- lignocaines acetylamino) anilino-] -6- isobutyryl amino quinolines being dried to obtain shown in formula (I -2)
Oxazoline pale solid, yield 73.4%, 144~145 DEG C of fusing point.1H NMR(500MHz,DMSO)δ:1.04 (t, J=
7.1Hz,6H)；1.17 (d, J=6.8Hz, 6H)；2.62 (q, J=7.1Hz, 4H)；2.68 (dd, J=6.8,13.7Hz, 1H)；
3.17(s,2H)；7.30 (t, J=8.0Hz, 1H)；7.36 (d, J=8.9Hz, 1H)；7.59 (d, J=8.0Hz, 1H)；7.75
(d, J=8.9Hz, 1H)；7.85 (dd, J=2.2,9.0Hz, 1H)；8.09 (t, J=2.0Hz, 1H)；8.50(s,1H)；8.75
(d, J=2.2Hz, 1H)；9.66(s,1H)；9.81(s,1H)；10.17(s,1H).
Embodiment 21：The system of 4- [3- (2- lignocaines acetylamino) anilino-] -6- benzamidos quinazoline (I -3)
It is standby
Successively by 0.20 gram of (0.55mmol) 4- [3- (2- lignocaines acetylamino) anilino-] -6- amido quinazolines
(I-a1), 0.11 gram of (1.09mmol) triethylamine, 10.0 milliliters of ethyl acetate are added in 50 milliliters of reaction bulb, 0 DEG C of stirring
Under the conditions of 0.249 gram of (1.10mmol) benzoyl oxide and 5.0 milliliters of ethyl acetate solutions are added dropwise, drop finishes, (the exhibition of TLC tracing detections
It is ethyl acetate/petroleum ether=1 to open agent：1) when, reaction 6 is small under the conditions of 25 DEG C, filtering, filtrate steaming removal solvent, concentrate adds
20 milliliters of chloroforms are dissolved, and obtain lysate, and 0.20 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
For 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 0.6) containing the compound shown in formula (I -3) is collected according to TLC detections, is collected
Liquid concentrates, 50 DEG C of 4- [3- (2- lignocaines acetylamino) anilino-] -6- benzamidos being dried to obtain shown in formula (I -3)
Quinazoline pale solid, yield 43.5%, 140~142 DEG C of fusing point.1H NMR(500MHz,DMSO)δ:1.04 (t, J=
7.1Hz,6H)；2.62 (q, J=7.1Hz, 4H)；3.18(s,2H)；7.28-7.40(m,2H)；7.55-7.68(m,4H)；7.82
(d, J=8.9Hz, 1H)；7.99-8.09(m,3H)；8.12 (t, J=2.0Hz, 1H)；8.55(s,1H)；8.92 (d, J=
2.1Hz,1H)；9.67(s,1H)；9.86(s,1H)；10.61(s,1H).
Embodiment 22：The preparation of 4- [3- (2- lignocaines acetylamino) anilino-] -6- propionamidos quinazoline (I -4)
Successively by 0.20 gram of (0.55mmol) 4- [3- (2- lignocaines acetylamino) anilino-] -6- amido quinazolines
(I-a1), 0.067 gram of (0.55mmol) 4-dimethylaminopyridine, 15.0 milliliters of toluene are added in 50 milliliters of reaction bulb, 5 DEG C
The solution of 0.286 gram of (2.20mmol) propionic andydride and 4.0 milliliters of toluene is added dropwise under stirring condition, drop finishes, and is heated to 50 DEG C, TLC
(solvent is ethyl acetate/petroleum ether=1 to tracing detection：1) when, reaction 3 is small, filtering, filtrate steaming removal solvent, concentrate addition
20 milliliters of tetrahydrofurans are dissolved, and obtain lysate, and 0.40 gram of column chromatography silica gel (300~400 mesh column is added into lysate
Chromatographic silica gel), after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then with body
Product is than being 5：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, elution, TLC tracing detections (solvent for ethyl acetate/
Petroleum ether=1：1 (v/v)), the eluent (Rf values are 0.5) containing the compound shown in formula (I -4) is collected according to TLC detections, is received
Liquid collecting concentrates, 50 DEG C of 4- [3- (2- lignocaines acetylamino) anilino-] -6- propionamidos being dried to obtain shown in formula (I -4)
Quinazoline pale solid, yield 75.3%, 132~133 DEG C of fusing point.1H NMR(500MHz,DMSO)δ:1.04 (t, J=
7.1Hz,6H)；1.15 (t, J=7.6Hz, 3H)；2.42 (q, J=7.5Hz, 2H)；2.61 (q, J=7.1Hz, 4H)；3.17(s,
2H)；7.31 (t, J=8.0Hz, 1H)；7.37 (d, J=8.7Hz, 1H)；7.59 (d, J=8.8Hz, 1H)；7.76 (d, J=
8.9Hz,1H)；7.85 (dd, J=2.1,9.0Hz, 1H)；8.10 (t, J=1.9Hz, 1H)；8.51(s,1H)；8.73 (d, J=
1.9Hz,1H)；9.66(s,1H)；9.81(s,1H)；10.20(s,1H).
Embodiment 23：The preparation of 4- [3- (2- lignocaines acetylamino) anilino-] -6- butyrylaminos quinazoline (I -5)
Successively by 0.20 gram of (0.55mmol) 4- [3- (2- lignocaines acetylamino) anilino-] -6- amido quinazolines
(I-a1), 0.067 gram of (0.55mmol) 4-dimethylaminopyridine, 10.0 milliliters of benzene are added in 50 milliliters of reaction bulb, and 5 DEG C are stirred
The solution of 0.348 gram of (2.20mmol) butyric anhydride and 5.0 milliliters of benzene is added dropwise under the conditions of mixing, drop finishes, and is heated to 50 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：1) when, reaction 3 is small, filtering, filtrate steaming removal solvent, 20 milli of concentrate addition
Rise tetrahydrofuran to be dissolved, obtain lysate, 0.40 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
For 1：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/oil to TLC tracing detections
Ether=1：1 (v/v)), the eluent (Rf values are 0.4) containing the compound shown in formula (I -5), collection liquid are collected according to TLC detections
Concentration, 50 DEG C of 4- [3- (2- lignocaines acetylamino) anilino-] -6- butyrylamino quinoline azoles being dried to obtain shown in formula (I -5)
Quinoline pale solid, yield 72.1%, 128~130 DEG C of fusing point.1H NMR(500MHz,DMSO)δ:0.97 (t, J=7.4Hz,
3H)；1.04 (t, J=7.1Hz, 6H)；1.67 (dt, J=14.7,7.4Hz, 2H)；2.38 (t, J=7.3Hz, 2H)；2.63(q,
J=7.1Hz, 4H)；3.18(s,2H)；7.27–7.40(m,2H)；7.58 (d, J=8.0Hz, 1H)；7.75 (d, J=8.9Hz,
1H)；7.85 (dd, J=9.0,2.1Hz, 1H)；8.09(s,1H)；8.50(s,1H)；8.71 (d, J=1.9Hz, 1H)；9.66
(s,1H)；9.80(s,1H)；10.20(s,1H).
Embodiment 24：The preparation of 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- acetylaminos quinazoline (I -6)
Successively by 0.216 gram of (0.55mmol) 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- amido quinazolines
(I-a2), 0.13 gram of (1.64mmol) pyridine, 2.2 milliliters of ether are added in reaction bulb, are added dropwise under -10 DEG C of stirring conditions
0.345 gram of (4.39mmol) chloroacetic chloride, drop finish, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)) ,-
When reaction 12 is small under the conditions of 10 DEG C, filter, filtrate steaming removal solvent, concentrate adds 20 milliliters of ethyl acetate and dissolved, and obtains
Lysate, 0.54 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added into lysate, after mixing, solvent is evaporated off,
The concentrate and the mixture of silica gel that must be dried, fill column, then using volume ratio as 1 by mixture：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)), according to TLC
The eluent (Rf values are 0.6) containing the compound shown in formula (I -6) is collected in detection, and collection liquid concentrates, 50 DEG C be dried to obtain formula (I -
6) 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- acetylamino quinazoline faint yellow solids shown in, yield
67.3%, 136~138 DEG C of fusing point.1H NMR(500MHz,DMSO)δ:0.89 (t, J=7.3Hz, 6H)；1.44-1.52(m,
4H)；2.14(s,3H)；2.51 (t, J=7.4Hz, 4H)；3.19(s,2H)；7.30-7.36(m,2H)；7.57 (d, J=
7.8Hz,1H)；7.75 (d, J=8.9Hz, 1H)；7.85 (dd, J=1.8,7.9Hz, 1H)；8.09(s,1H)；8.50(s,1H)；
8.66 (d, J=1.3Hz, 1H)；9.60(s,1H)；9.80(s,1H)；10.27(s,1H).
Embodiment 25：The system of 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- benzamidos quinazoline (I -7)
It is standby
Successively by 0.216 gram of (0.55mmol) 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- amido quinazolines
(I-a2), 0.04 gram of (0.55mmol) diethylamine, 15.0 milliliters of dichloromethane are added in 50 milliliters of reaction bulb, 10 DEG C of stirrings
Under the conditions of 0.077 gram of (0.55mmol) chlorobenzoyl chloride and 5.0 milliliters of dichloromethane solutions are added dropwise, drop finishes, (the exhibition of TLC tracing detections
It is ethyl acetate/petroleum ether=1 to open agent：1) when, reaction 8 is small under the conditions of 10 DEG C, filtering, filtrate steaming removal solvent, concentrate adds
20 milliliters of ethanol are dissolved, and obtain lysate, and 0.27 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
For 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 the compound shown in formula (I -7) is collected according to TLC detections, is collected
Liquid concentrates, 50 DEG C of 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- benzamidos being dried to obtain shown in formula (I -7)
Quinazoline pale solid, yield 67.7%, 184~185 DEG C of fusing point.1H NMR(500MHz,DMSO)δ:0.90 (t, J=
7.4Hz,6H)；1.46-1.50(m,4H)；2.50-2.52(m,4H)；3.19(s,2H)；7.31-7.37(m,2H)；7.57-
7.66(m,4H)；7.82 (d, J=9.0Hz, 1H)；8.03 (dd, J=2.2,9.0Hz, 1H)；8.05-8.08(m,2H)；8.13
(t, J=2.0Hz, 1H)；8.55(s,1H)；8.92 (d, J=7.2Hz, 1H)；9.61(s,1H)；9.87(s,1H)；10.61(s,
1H)。
Embodiment 26：The preparation of 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- butyrylaminos quinazoline (I -8)
Successively by 0.216 gram of (0.55mmol) 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- amido quinazolines
(I-a2), 0.11 gram of (1.09mmol) triethylamine, 15.0 milliliters of acetonitriles are added in 50 milliliters of reaction bulb, 0 DEG C of stirring condition
0.117 gram of (1.10mmol) n-butyryl chloride of lower dropwise addition and 5.0 milliliters of acetonitrile solutions, drop finish, and (solvent is second to TLC tracing detections
Acetoacetic ester/petroleum ether=1：1) when, reaction 6 is small under the conditions of 25 DEG C, filtering, filtrate steaming removal solvent, concentrate adds 20 milliliters of chlorine
It is imitative to be dissolved, lysate is obtained, 0.25 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 using volume ratio as 1：10
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 0.4) containing the compound shown in formula (I -8), is collected according to TLC detections, collection liquid concentrates, and 50
DEG C 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- butyrylamino quinazolines being dried to obtain shown in formula (I -8) are greyish white
Color solid, yield 73.2%, 128~129 DEG C of fusing point.1H NMR(500MHz,DMSO)δ:0.90 (t, J=7.4Hz, 6H)；
0.97 (t, J=7.2Hz, 3H)；1.44-1.52(m,4H)；1.64-1.72(m,2H)；2.38 (t, J=7.3Hz, 2H)；2.51
(t, J=6.7Hz, 4H)；3.19(s,2H)；7.29-7.36(m,2H)；7.57 (d, J=7.4Hz, 1H)；7.75 (d, J=
7.0Hz,1H)；7.85-7.88(m,1H)；8.09(s,1H)；8.50(s,1H)；8.72 (d, J=1.7Hz, 1H)；9.59(s,
1H)；9.81(s,1H)；10.20(s,1H).
Embodiment 27：The preparation of 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- propionamidos quinazoline (I -9)
Successively by 0.216 gram of (0.55mmol) 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- amido quinazolines
(I-a2), 0.067 gram of (0.55mmol) 4-dimethylaminopyridine, 15 milliliters of toluene are added in 50 milliliters of reaction bulb, and 5 DEG C are stirred
0.204 gram of (2.20mmol) propionyl chloride and 5.5 milliliters of toluene solutions are added dropwise under the conditions of mixing, drop finishes, and is heated to 50 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：1) when, reaction 3 is small, filtering, filtrate steaming removal solvent, 20 milli of concentrate addition
Rise tetrahydrofuran to be dissolved, obtain lysate, 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
For 1：4 petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/oil to TLC tracing detections
Ether=1：1 (v/v)), the eluent (Rf values are 0.7) containing the compound shown in formula (I -9), collection liquid are collected according to TLC detections
Concentration, 50 DEG C of 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- propionamido quinoline azoles being dried to obtain shown in formula (I -9)
Quinoline pale solid, yield 53.2%, 118~119 DEG C of fusing point.1H NMR(500MHz,DMSO)δ:0.90 (t, J=7.4Hz,
6H)；1.15 (t, J=7.6Hz, 3H)；1.43-1.53(m,4H)；2.41 (q, J=7.5Hz, 2H)；2.50-2.52(m,4H),
3.19(s,2H)；7.29-7.36(m,2H)；7.56-7.58(m,1H)；7.75 (d, J=9.0Hz, 1H)；7.85 (dd, J=
2.2,9.0Hz,1H)；8.09 (t, J=2.0Hz, 1H)；8.50(s,1H)；8.71 (d, J=2.1Hz, 1H)；9.60(s,1H)；
9.81(s,1H)；10.20(s,1H).
Embodiment 28：4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- isobutyryls amido quinazoline (I -10)
Prepare
Successively by 0.216 gram of (0.55mmol) 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- amido quinazolines
(I-a2), 0.067 gram of (0.55mmol) 4-dimethylaminopyridine, 15.0 milliliters of toluene are added in 50 milliliters of reaction bulb, 5 DEG C
The solution of 0.234 gram of (2.20mmol) isobutyryl chloride and 5.0 milliliters of toluene is added dropwise under stirring condition, drop finishes, and is heated to 50 DEG C,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1) when, reaction 3 is small, filtering, filtrate steaming removal solvent, concentrate
Add 20 milliliters of tetrahydrofurans to be dissolved, obtain lysate, 0.50 gram of column chromatography silica gel (300~400 is added into lysate
Mesh column chromatography silica gel), after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then
Using volume ratio as 4：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, (solvent is acetic acid to TLC tracing detections
Ethyl ester/petroleum ether=1：1 (v/v)), collecting the eluent containing the compound shown in formula (I -10) according to TLC detections, (Rf values are
0.3), collection liquid concentrates, 50 DEG C of 4- [3- (2- dipropyls aminoacetylamino) anilino-] -6- being dried to obtain shown in formula (I -10)
Isobutyryl amido quinazoline pale solid, yield 71.1%, 148~150 DEG C of fusing point.1H NMR(500MHz,DMSO)δ:
0.90 (t, J=7.3Hz, 6H)；1.17 (d, J=6.8Hz, 6H)；1.41–1.55(m,4H)；2.51 (dd, J=1.8,3.6Hz,
4H)；2.64–2.75(m,1H)；3.19(s,2H)；7.27–7.38(m,2H)；7.55–7.61(m,1H)；7.75 (d, J=
8.9Hz,1H)；7.86 (dd, J=2.2,9.0Hz, 1H)；8.09 (d, J=1.9Hz, 1H)；8.50(s,1H)；8.74 (d, J=
2.1Hz,1H)；9.60(s,1H)；9.82(s,1H)；10.17(s,1H).
Embodiment 29：Active anticancer testing in vitro
Obtained compound (I) in embodiment is subjected to human lung cancer and human breast carcinoma biological activity test.
Test method：Tetrazolium reduction method (mtt assay).
Cell line：Human lung cancer cell lines A-549 and MCF-7 cell strainHJ2mm.Above-mentioned tumor cell line is purchased from China
Academy of sciences's Shanghai school of life and health sciences cell bank.
Experimental procedure is as follows：
(1) preparation of sample：For solvable sample, dissolved per 1mg with 40 μ L DMSO, take 2 μ L dilute with 1000 μ L culture mediums
Release, it is 100 μ g/mL to make concentration, then with nutrient solution serial dilution to concentration.
(2) culture of cell
1) preparation of culture medium:Contain 800,000 units of Penicillin, 1.0g streptomysins, 10% inactivation tire in per 1000mL culture mediums
Cow's serum.
2) culture of cell：By tumor cell inoculation in culture medium, 37 DEG C are put, 5%CO2Cultivated in incubator, 3~5d
Passage.
3) inhibitory action of the determination sample to growth of tumour cell
Cell EDTA- pancreatin digestive juice is digested, and 1 × 10 is diluted to culture medium6/ mL, is added to 96 hole cell trainings
Support in plate, per 100 μ L of hole, put 37 DEG C, 5%CO2Cultivated in incubator.After being inoculated with 24h, the diluted 100 μ g/ of addition culture medium
ML, 10 μ g/mL or 1 μ g/mL samples, per 100 μ L of hole, each concentration adds 3 holes, puts 37 DEG C, 5%CO2Cultivated in incubator, 72h
The MTT of 5mg/mL is added in cell culture well afterwards, per 10 μ L of hole, 37 DEG C of incubation 3h is put, adds DMSO, per 150 μ L of hole, with shaking
Swing device vibration, Shi Jia Za is completely dissolved, with microplate reader under 570nm wavelength colorimetric.With similarity condition with sample is free of, containing same
The cell of the medium culture of concentration DMSO calculates IC of the sample to growth of tumour cell as control50。
The result of test is as shown in the table：
Claims (3)
1. 6- amino-quinazoline compounds shown in a kind of formula (I-a),
In formula (I-a), R1For propyl group, R3With R1Structure is identical.
2. compound shown in formula described in a kind of claim 1 (I-a) is preparing prevention or treatment human lung cancer or human breast carcinoma medicine
In application.
3. application as claimed in claim 2, it is characterised in that the human lung cancer is human lung cancer cell lines A-549, the human milk
Gland cancer is MCF-7 cell strainHJ2mm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510243810.4A CN104876882B (en) | 2015-05-13 | 2015-05-13 | 6- amino-quinazoline compounds and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510243810.4A CN104876882B (en) | 2015-05-13 | 2015-05-13 | 6- amino-quinazoline compounds and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104876882A CN104876882A (en) | 2015-09-02 |
| CN104876882B true CN104876882B (en) | 2018-05-08 |
Family
ID=53944599
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510243810.4A Active CN104876882B (en) | 2015-05-13 | 2015-05-13 | 6- amino-quinazoline compounds and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104876882B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012030160A2 (en) * | 2010-08-31 | 2012-03-08 | Hanmi Holdings Co., Ltd. | Quinoline or quinazoline derivatives with apoptosis inducing activity on cells |
| CN103254141A (en) * | 2013-04-26 | 2013-08-21 | 浙江工业大学 | 4-[4-(2-dipropylamino acetamido) phenylamino]-6-substituted quinazoline compound as well as preparation method and application thereof |
| CN103254143A (en) * | 2013-04-26 | 2013-08-21 | 浙江工业大学 | 4-[4-(2-diethylamino acetamido)phenylamino]-6-(substituted methoxyl)formylamino quinazoline compound as well as preparation method and application thereof |
| CN103275019A (en) * | 2013-04-26 | 2013-09-04 | 浙江工业大学 | 4-(3-chloro-4-substituted anilino)-6-substituted methoxyl carbamonyl quinazoline compounds, and a preparation method and applications thereof |
| 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 |
-
2015
- 2015-05-13 CN CN201510243810.4A patent/CN104876882B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012030160A2 (en) * | 2010-08-31 | 2012-03-08 | Hanmi Holdings Co., Ltd. | Quinoline or quinazoline derivatives with apoptosis inducing activity on cells |
| CN103254141A (en) * | 2013-04-26 | 2013-08-21 | 浙江工业大学 | 4-[4-(2-dipropylamino acetamido) phenylamino]-6-substituted quinazoline compound as well as preparation method and application thereof |
| CN103254143A (en) * | 2013-04-26 | 2013-08-21 | 浙江工业大学 | 4-[4-(2-diethylamino acetamido)phenylamino]-6-(substituted methoxyl)formylamino quinazoline compound as well as preparation method and application thereof |
| CN103275019A (en) * | 2013-04-26 | 2013-09-04 | 浙江工业大学 | 4-(3-chloro-4-substituted anilino)-6-substituted methoxyl carbamonyl quinazoline compounds, and a preparation method and applications thereof |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104876882A (en) | 2015-09-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103275018B (en) | 4-[the chloro-4-substituted anilinic of 3-]-6-substituted formyl amino-quinazoline compound and Synthesis and applications | |
| CN104926737B (en) | 4 (3 substituted anilinic) 6 substituent quinazoline compounds and preparation and application | |
| CN103275019B (en) | The chloro-4-substituted anilinic of 4-[3-]-6-methoxyl group displacement formamido group quinazoline compounds and preparation and application | |
| CN103254141B (en) | 4-[4-(2-dipropyl aminoacetylamino) anilino]-6-substituted quinazoline compounds and Synthesis and applications | |
| CN103254142B (en) | 4-[4-(2-substituted-amino kharophen) anilino] quinazoline derivative and Synthesis and applications | |
| CN109251196A (en) | Amino benzo [d] azepine * base quinazoline compounds and its preparation method and application | |
| CN104876882B (en) | 6- amino-quinazoline compounds and application | |
| CN108014113A (en) | Butyrylamino dimethoxy benzo [d] azepine * bases quinazoline compounds are preparing the application in treating uterine neck cancer drug | |
| CN103254143B (en) | 4-[4-(2-diethylin kharophen) anilino]-6-substituted quinazoline compounds and Synthesis and applications | |
| CN108078994A (en) | 6- (2- morpholinyls acetylamino) quinazoline compounds are preparing the application in treating lung-cancer medicament | |
| CN108042546A (en) | Morpholinyl acetylamino benzo [d] azepine * bases quinazoline compounds are preparing the application in treating uterine neck cancer drug | |
| CN108125961A (en) | Morpholinyl acetylamino anisyl benzo-aza * bases quinazoline compounds are preparing the application in treating leukemia medicament | |
| CN108309984A (en) | Propionamido quinazoline compounds are preparing the application in treating uterine neck cancer drug | |
| CN108276384A (en) | Acetylamino benzo [d] azepine * bases quinazoline compounds and its preparation and application | |
| CN108129461A (en) | Benzamido 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 | |
| CN108324718A (en) | Application of the cyclohexyl methoxy formamido group chloro benzo azepine * bases quinazoline compounds in treating leukemia medicament | |
| CN108117542A (en) | Propionamido anisyl benzo [d] azepine * bases quinazoline compounds and preparation and application | |
| CN108329299A (en) | Butyrylamino chloro benzo [d] azepine * bases quinazoline compounds and preparation and application | |
| CN108047206B (en) | Pivaloyl amino benzo [d] azepine * base quinazoline compounds and preparation and application | |
| CN108125962A (en) | Benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament | |
| CN108295076A (en) | Propionamido dimethoxy benzo [d] azepine * bases quinazoline ditosylate salt is preparing the application in treating lung-cancer medicament | |
| CN108084162A (en) | Dimethoxy benzene aminoacetylamino benzo [d] azepine * bases quinazoline compounds and preparation and application | |
| CN108014112A (en) | Adjacent toluidino acetylamino benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament | |
| CN108484623A (en) | Camptothecin derivative and the preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20201217 Address after: Room 1 / F, No.618 fenghang Road, fenghang District, Beijing Patentee after: Beijing Shangda hengshuo pharmaceutical technology partnership (L.P.) Address before: 310014 No. 18 Chao Wang Road, Xiacheng District, Zhejiang, Hangzhou Patentee before: ZHEJIANG University OF TECHNOLOGY |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210701 Address after: 100070 room 329a, 3 / F, building 1, yard 8, Hangfeng Road, Fengtai District, Beijing Patentee after: Beijing fangdaxun Pharmaceutical Technology Co.,Ltd. Address before: Room 1 / F, No.618 fenghang Road, fenghang District, Beijing Patentee before: Beijing Shangda hengshuo pharmaceutical technology partnership (L.P.) |
|
| TR01 | Transfer of patent right |