CN103275018B - 4-[the chloro-4-substituted anilinic of 3-]-6-substituted formyl amino-quinazoline compound and Synthesis and applications - Google Patents
4-[the chloro-4-substituted anilinic of 3-]-6-substituted formyl amino-quinazoline compound and Synthesis and applications Download PDFInfo
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- CN103275018B CN103275018B CN201310153507.6A CN201310153507A CN103275018B CN 103275018 B CN103275018 B CN 103275018B CN 201310153507 A CN201310153507 A CN 201310153507A CN 103275018 B CN103275018 B CN 103275018B
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- dipropyl
- aminoacetylamino
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- -1 formyl amino-quinazoline compound Chemical class 0.000 title claims abstract description 55
- 230000015572 biosynthetic process Effects 0.000 title abstract description 4
- 238000003786 synthesis reaction Methods 0.000 title abstract description 4
- 230000000694 effects Effects 0.000 claims abstract description 13
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 10
- 201000005202 lung cancer Diseases 0.000 claims abstract description 10
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 8
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 6
- 201000008275 breast carcinoma Diseases 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 110
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 93
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 44
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- 238000002360 preparation method Methods 0.000 claims description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 239000003795 chemical substances by application Substances 0.000 claims description 29
- 239000003960 organic solvent Substances 0.000 claims description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 238000001035 drying Methods 0.000 claims description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
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- 239000003054 catalyst Substances 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
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- 230000002829 reductive effect Effects 0.000 claims description 14
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 10
- LZOSFEDULGODDH-UHFFFAOYSA-N 4-chloro-6-nitroquinazoline Chemical compound N1=CN=C(Cl)C2=CC([N+](=O)[O-])=CC=C21 LZOSFEDULGODDH-UHFFFAOYSA-N 0.000 claims description 9
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 8
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- 239000002904 solvent Substances 0.000 claims description 8
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 7
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 7
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Abstract
The invention discloses a kind of 4-[the chloro-4-substituted anilinic of 3-]-6-substituted formyl amino-quinazoline compound and Synthesis and applications and Synthesis and applications thereof, described compound has having structure and leads to formula I, in general structure (I), R is isobutoxy, ethyl or sec.-propyl.4-of the present invention [the chloro-4-substituted anilinic of 3-]-6-substituted formyl amino-quinazoline compound can be used for the medicine preparing prevention or treatment people's lung cancer or human breast carcinoma disease, has good antitumour activity.
Description
(1) technical field
The present invention relates to 4-[the chloro-4-substituted anilinic of 3-]-6-substituted formyl amino-quinazoline compound, be specifically related to 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound---4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-isobutoxy formamido group quinazoline, 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-propionamido quinazoline and 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-isobutyryl amido quinazoline and preparation method thereof, and described three compounds prevent in preparation or treat the application in the medicine of tumor disease.
(2) background technology
Quinazoline compounds has many good biological activitys, have a wide range of applications at field of medicaments, especially the quinazoline derivative of some special constructions has obvious antiviral activity, anti-microbial activity, anti-tumor activity etc., and quinazoline compounds to have gone on the market some kinds as antitumor drug.The Gefitinib (Gefitinib) being used for the treatment of lung cancer of such as going on the market and Tarceva (Erlotinib), and the lapatinibditosylate (Lapatinib) being used for the treatment of mammary cancer, they all belong to 4-anilinoquinazoline compounds.Novel quinazoline compounds and biological activity thereof also common bibliographical information (consult 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, ChemMedChem2013,8,136-148; A.Garofalo, A.Farce, S.Ravez, A.Lemoine, P.Six, P.Chavatte, L.Goossens, P.Depreux, J.Med.Chem.2012,55,1189-1204).Certain most quinazoline compounds does not have anti-tumor activity.
(3) summary of the invention
The object of the present invention is to provide a kind of novel 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound with antitumour activity and its preparation method and application, this compounds has good inhibiting rate to human lung cancer cell lines A-549 or MCF-7 cell strainHJ2mm under doses; And such compounds process for production thereof is easy, easy handling, raw material is easy to get, and production cost is lower, is suitable for industrial applications.
For achieving the above object, the present invention adopts following technical scheme:
The invention provides a kind of 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound, it has having structure and leads to formula I:
In general structure (I), R is isobutoxy, ethyl or sec.-propyl.
Present invention also offers the intermediate that two kinds are prepared described 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound, namely structure is such as formula 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-nitro-quinazoline shown in (IV) and the 4-of structure as shown in formula V [the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline:
The invention provides a kind of preparation method of described 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound, described preparation method comprises:
(1) 2-dipropyl amino-N-(2-chloro-4-aminophenyl) the 4-chloro-6-nitro-quinazoline shown in ethanamide and formula III shown in formula II reacts obtained 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline shown in formula IV in organic solvent A 1 under the effect of basic catalyst B1; Described basic catalyst B1 is selected from one of following: pyridine, diethylamine, triethylamine, quinoline, N, N-xylidene(s), DMAP, 4-pyrollidinopyridine or sodium carbonate; Described organic solvent A 1 is selected from one of following: chloroform, toluene, methyl alcohol, ethanol, propyl alcohol, Virahol, acetonitrile or DMF;
(2) 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-nitro-quinazoline shown in formula IV reacts obtained 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline shown in formula (V) in organic solvent A 2 under reductive agent B2 effect; Described reductive agent B2 is one of following: iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium carbon/ammonium formiate or palladium carbon/hydrazine hydrate; Described organic solvent A 2 is one of following: chloroform, toluene, methyl alcohol, ethanol, propyl alcohol, Virahol, acetonitrile or N, N-dimethyl formyl;
(3) 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-amido quinazoline shown in formula (V) and isobutyl chlorocarbonate, propionic anhydride or isobutyric anhydride react obtained 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound shown in formula I in organic solvent A 3 under basic catalyst B3 effect; Described basic catalyst B3 is one of following: pyridine, diethylamine, triethylamine, quinoline, N, N-xylidene(s), DMAP, 4-pyrollidinopyridine or sodium carbonate; Described organic solvent A 3 is one of following: tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate, ether, acetonitrile, toluene or benzene;
In described formula I, R is isobutoxy, ethyl or sec.-propyl.
In step of the present invention (1), described organic solvent A 1 is preferably one of following: chloroform, toluene, methyl alcohol or Virahol.Shown basic catalyst B1 is preferably one of following: pyridine, diethylamine, triethylamine or DMAP.The molar ratio of described 4-chloro-6-nitro-quinazoline (III), 2-dipropyl amino-N-(the chloro-4-aminophenyl of 2-) ethanamide (II), basic catalyst B1 is 1.0 ﹕ 0.8 ~ 1.2 ﹕ 1.0 ~ 8.0, and the consumption of described organic solvent A 1 counts 10 ~ 50mL/g with the quality of the chloro-6-nitro-quinazoline (III) of 4-.Reaction described in step (1) is carried out under the temperature condition of 25 ~ 120 DEG C, and preferable reaction temperature is 40 ~ 100 DEG C, and reaction end is by method monitorings such as TLC, and the reaction times is generally at 0.5 ~ 12 hour.
The present invention specifically recommends described step (1) according to carrying out as follows: by the chloro-6-nitro-quinazoline of 4-shown in 2-dipropyl amino-N-(2-chloro-4-aminophenyl) ethanamide and the formula III shown in formula II, react in 25 ~ 120 DEG C under the effect of basic catalyst B1 in organic solvent A 1, hold over night after completion of the reaction, filtration, drying obtain 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-nitro-quinazoline shown in formula IV.
In step of the present invention (2), described organic solvent A 2 is preferably one of following: chloroform, toluene, methyl alcohol or Virahol.In step (2), when described reductive agent B2 be iron powder/concentrated hydrochloric acid or iron powder/acetic acid time, the mass ratio that feeds intake of iron powder, concentrated hydrochloric acid or acetic acid in 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (IV) and reductive agent B2 is 1.0 ﹕ 1.0 ~ 3.0 ﹕ 0.2 ~ 1.0; When described reductive agent B2 be palladium carbon/ammonium formiate or palladium carbon/hydrazine hydrate time, 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (IV) is 1.0 ﹕ 0.1 ~ 0.5 ﹕ 1.0 ~ 3.0 with the mass ratio that feeds intake of palladium carbon, ammonium formiate or hydrazine hydrate in reductive agent B2, and the consumption of described organic solvent A 2 counts 10 ~ 50mL/g with the quality of 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (IV).Reaction described in step (2) is carried out under the temperature condition of 25 ~ 100 DEG C, and preferable reaction temperature is 40 ~ 80 DEG C, and reaction end is by method monitorings such as TLC, and the reaction times is generally at 0.5 ~ 12 hour.
The present invention specifically recommends described step (2) according to carrying out as follows: add in organic solvent A 2 by 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-nitro-quinazoline shown in formula IV, reductive agent B2, fully react at 25 ~ 100 DEG C, filter, filtrate is concentrated separates out solid, filter, drying obtains 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-amido quinazoline shown in formula (V).
In step of the present invention (3), described organic solvent A 3 is preferably one of following: tetrahydrofuran (THF), chloroform, ethyl acetate or toluene.Described basic catalyst B3 is preferably one of following: pyridine, diethylamine, triethylamine or DMAP.The molar ratio of described 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (V), isobutyl chlorocarbonate or propionic anhydride or isobutyric anhydride, basic catalyst B3 is 1 ﹕ 1.0 ~ 8.0 ﹕ 1.0 ~ 3.0, and the consumption of described organic solvent A 3 counts 10 ~ 95mL/g with the quality of 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (V).Reaction described in step (3) is carried out under the temperature condition of-10 ~ 50 DEG C, and reaction end is by method monitorings such as TLC, and the reaction times is generally at 3 ~ 12 hours.
The present invention specifically recommends described step (3) according to carrying out as follows: by 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-amido quinazoline shown in formula (V), basic catalyst B3 adds in organic solvent A 3, under-10 ~ 10 DEG C of conditions, drip organic solvent A 3 solution of isobutyl chlorocarbonate or propionic anhydride or isobutyric anhydride, drip and finish,-10 ~ 50 DEG C are reacted 3 ~ 12 hours, filter, filtrate steaming removal solvent, residue column chromatography obtains corresponding 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound (I).
Residue column chromatography described in step of the present invention (3) can carry out as follows: get and steam the residue after desolventizing in single port bottle, add organic solvent C to be dissolved, obtain lysate, then in lysate, add the column chromatography silica gel of 1.0 ~ 2.0 times amount of residue quality, after mixing, steaming desolventizes, obtain the mixture of dry residue and silica gel, mixture is filled post, then be 1:12 ~ 0(1:12 with volume ratio, 1:8, 1:4, 1:2, 1:1, ethyl acetate 1:0), sherwood oil mixing solutions is eluent, gradient elution, collecting eluent is ethyl acetate/petroleum ether (1:4, 1:2, 1:1 or 1:0) flow point, collection liquid concentrates, 4-[3-chloro-4-(2-dipropyl aminoacetylamino) the anilino]-6-substituted formyl amino-quinazoline compound of dry acquisition shown in formula I.Described organic solvent C is one of following: methyl alcohol, ethanol, methylene dichloride, chloroform, tetrahydrofuran (THF) or ethyl acetate.
4-of the present invention [the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound (I) can be applicable to the medicine preparing prevention or treatment tumor disease, is particularly useful for making the medicine of prevention or treatment people's lung cancer or human breast carcinoma (especially human breast carcinoma) disease.Compound provided by the invention has good inhibiting rate to human lung cancer cell lines A-549 or MCF-7 cell strainHJ2mm (especially MCF-7 cell strainHJ2mm).Such as: 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-isobutoxy formamido group quinazoline (I-1) is to the IC of human lung cancer cell lines A-549 and MCF-7 cell strainHJ2mm
50be respectively 30.3 μMs and 9.38 μMs.In addition, intermediate provided by the invention (IV) also has good inhibiting rate to human lung cancer cell lines A-549 or MCF-7 cell strainHJ2mm (especially MCF-7 cell strainHJ2mm).
Beneficial effect of the present invention is mainly reflected in: the antitumour activity that (1) 4-of the present invention [the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound (I) has had, and is expected to be applied in the medicine of preparation prevention or treatment tumor disease; (2) preparation method of 4-of the present invention provided by the invention [the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound (I), simple easy handling, raw material is easy to get, and production cost is lower, is suitable for practicality.
(4) embodiment
The present invention is further described in conjunction with specific embodiments, and following embodiment illustrates of the present invention, instead of limits the present invention by any way.
The method preparing reference literature (C.Fernandes, C.Oliveira, L.Gano, A.Bourkoula, I.Pirmettis, I.Santos, Bioorg.Med.Chem.2007,15,3974-3980) of the chloro-6-nitro-quinazoline (III) of 4-prepares.The preparation of 2-dipropyl amino-N-(2-chloro-4-aminophenyl) ethanamide (II) is by following reaction scheme (a) reference literature (A.D.Moorhouse, A.M.Santos, M.Gunaratnam, M.Moore, S.Neidle, J.E.Moses, J.Am.Chem.Soc.2006,128,15972-15973) method prepare
The preparation of embodiment 1:2-dipropyl amino-N-(the chloro-4-aminophenyl of 2-) ethanamide (II)
Successively by chloro-for compound 2-4-N-methyl-p-nitroaniline 6.20 grams (35.93mmol), triethylamine 5.5 milliliters (39.46mmol), methylene dichloride 100.0 milliliters, join in 250 milliliters of there-necked flasks, 0 ~ 5 DEG C is stirred lower dropping chloroacetyl chloride 6.0 milliliters (79.69mmol), drip and finish, under room temperature condition, react 20h, reaction solution is extremely neutral with saturated sodium carbonate solution washing.By organic phase, dipropyl amine 10.00 grams (98.82mmol) joins in 250 milliliters of there-necked flasks successively, back flow reaction 20h, by reaction solution evaporate to dryness, acetic acid ethyl dissolution also washs with water, organic phase anhydrous magnesium sulfate drying, concentrate brown color product 2-dipropyl amino-N-(2-chloro-4 nitrophenyl) ethanamide and dehydrated alcohol 50.0 milliliters that obtain, concentrated hydrochloric acid 3.0 milliliters, 6.0 milliliters, water, iron powder 7.80 grams (139.68mmol), join in 100 milliliters of there-necked flasks successively, back flow reaction 4h, cooling, reaction solution saturated sodium carbonate solution is neutralized, filter, filtrate evaporate to dryness, acetic acid ethyl dissolution also washs with water, organic phase anhydrous magnesium sulfate drying, concentrate drying obtains 7.51 grams of brown product 2-dipropyl amino-N-(the chloro-4-aminophenyl of 2-) ethanamides (II), yield 73.7%.
The preparation of embodiment 2:4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (IV)
Successively by 1.20 grams of (5.73mmol) 4-chloro-6-nitro-quinazoline (III) and 1.95 grams of (6.87mmol) 2-dipropyl amino-N-(the chloro-4-aminophenyl of 2-) ethanamides (II), 3.62 grams of (45.76mmol) pyridines, 60 milliliters of chloroforms add in the there-necked flask of 100 milliliters, be heated to 40 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1), stirring reaction 10 hours, off-response, hold over night, filter, drying obtains 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-nitro-quinazoline yellow solid 1.61 grams shown in formula IV, yield 61.5%, fusing point 224 ~ 226 DEG C.
1HNMR(500MHz,[D6]DMSO):δ=0.91(t,J=7.4Hz,6H),1.49-1.54(m,4H),2.50-2.53(m,4H),3.23(s,2H),7.80(dd,J=2.4,9.0Hz,1H),7.96(d,J=9.2Hz,1H),8.19(d,J=2.4Hz,1H),8.39(d,J=8.9Hz,1H),8.57(dd,J=2.4,9.2Hz,1H),8.77(s,1H),9.66(d,J=2.4Hz,1H),9.95(s,1H),10.50ppm(s,1H);HRMS(ESI):m/z:[M+H]
+calcdforC
22H
26ClN
6O
3:457.1749,found:457.1757。
The preparation of embodiment 3:4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (IV)
Successively by 1.20 grams of (5.73mmol) 4-chloro-6-nitro-quinazoline (III) and 1.30 grams of (4.58mmol) 2-dipropyl amino-N-(the chloro-4-aminophenyl of 2-) ethanamides (II), 1.67 grams of (22.83mmol) diethylamine, 60 milliliters of toluene add in the there-necked flask of 100 milliliters, be heated to 100 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1), stirring reaction 2 hours, off-response, hold over night, filter, drying obtains 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-nitro-quinazoline yellow solid 1.59 grams shown in formula IV, yield 76.0%, fusing point 224 ~ 226 DEG C.
1HNMR(500MHz,[D6]DMSO):δ=0.91(t,J=7.4Hz,6H),1.49-1.54(m,4H),2.50-2.53(m,4H),3.23(s,2H),7.80(dd,J=2.4,9.0Hz,1H),7.96(d,J=9.2Hz,1H),8.19(d,J=2.4Hz,1H),8.39(d,J=8.9Hz,1H),8.57(dd,J=2.4,9.2Hz,1H),8.77(s,1H),9.66(d,J=2.4Hz,1H),9.95(s,1H),10.50ppm(s,1H);HRMS(ESI):m/z:[M+H]
+calcdforC
22H
26ClN
6O
3:457.1749,found:457.1757。
The preparation of embodiment 4:4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (IV)
Successively by 1.20 grams of (5.73mmol) 4-chloro-6-nitro-quinazoline (III) and 1.63 grams of (5.74mmol) 2-dipropyl amino-N-(the chloro-4-aminophenyl of 2-) ethanamides (II), 0.58 gram of (5.73mmol) triethylamine, 60 ml methanol add in the there-necked flask of 100 milliliters, be heated to 60 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1), stirring reaction 8 hours, off-response, hold over night, filter, drying obtains 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-nitro-quinazoline yellow solid 2.18 grams shown in formula IV, yield 83.3%, fusing point 224 ~ 226 DEG C.
1HNMR(500MHz,[D6]DMSO):δ=0.91(t,J=7.4Hz,6H),1.49-1.54(m,4H),2.50-2.53(m,4H),3.23(s,2H),7.80(dd,J=2.4,9.0Hz,1H),7.96(d,J=9.2Hz,1H),8.19(d,J=2.4Hz,1H),8.39(d,J=8.9Hz,1H),8.57(dd,J=2.4,9.2Hz,1H),8.77(s,1H),9.66(d,J=2.4Hz,1H),9.95(s,1H),10.50ppm(s,1H);HRMS(ESI):m/z:[M+H]
+calcdforC
22H
26ClN
6O
3:457.1749,found:457.1757。
The preparation of embodiment 5:4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (IV)
Successively by 1.20 grams of (5.73mmol) 4-chloro-6-nitro-quinazoline (III) and 1.79 grams of (6.31mmol) 2-dipropyl amino-N-(the chloro-4-aminophenyl of 2-) ethanamides (II), 1.40 grams of (11.46mmol) DMAPs, 60 milliliters of Virahols add in the there-necked flask of 100 milliliters, room temperature 25 DEG C stirring, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1), react 12 hours, off-response, hold over night, filter, drying obtains 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-nitro-quinazoline yellow solid 1.70 grams shown in formula IV, yield 65.0%, fusing point 224 ~ 226 DEG C.
1HNMR(500MHz,[D6]DMSO):δ=0.91(t,J=7.4Hz,6H),1.49-1.54(m,4H),2.50-2.53(m,4H),3.23(s,2H),7.80(dd,J=2.4,9.0Hz,1H),7.96(d,J=9.2Hz,1H),8.19(d,J=2.4Hz,1H),8.39(d,J=8.9Hz,1H),8.57(dd,J=2.4,9.2Hz,1H),8.77(s,1H),9.66(d,J=2.4Hz,1H),9.95(s,1H),10.50ppm(s,1H);HRMS(ESI):m/z:[M+H]
+calcdforC
22H
26ClN
6O
3:457.1749,found:457.1757。
The preparation of embodiment 6:4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (IV)
Successively by 1.20 grams of (5.73mmol) 4-chloro-6-nitro-quinazoline (III) and 1.47 grams of (5.18mmol) 2-dipropyl amino-N-(the chloro-4-aminophenyl of 2-) ethanamides (II), 1.04 grams of (8.58mmol) N, N-xylidene(s), 60 milliliters of N, dinethylformamide adds in the there-necked flask of 100 milliliters, be heated to 120 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1), stirring reaction 0.5 hour, off-response, hold over night, filter, drying obtains 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-nitro-quinazoline yellow solid 2.13 grams shown in formula IV, yield 81.4%, fusing point 224 ~ 226 DEG C.
1HNMR(500MHz,[D6]DMSO):δ=0.91(t,J=7.4Hz,6H),1.49-1.54(m,4H),2.50-2.53(m,4H),3.23(s,2H),7.80(dd,J=2.4,9.0Hz,1H),7.96(d,J=9.2Hz,1H),8.19(d,J=2.4Hz,1H),8.39(d,J=8.9Hz,1H),8.57(dd,J=2.4,9.2Hz,1H),8.77(s,1H),9.66(d,J=2.4Hz,1H),9.95(s,1H),10.50ppm(s,1H);HRMS(ESI):m/z:[M+H]
+calcdforC
22H
26ClN
6O
3:457.1749,found:457.1757。
The preparation of embodiment 7:4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (V)
Successively by 0.40 gram of (0.88mmol) 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (IV), 0.40 gram of (6.34mmol) ammonium formiate, 0.04 gram of 5%Pd/C, 30.0 milliliters of chloroforms join in the there-necked flask of 50 milliliters, room temperature 25 DEG C stirring, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1), react 12 hours, filter, filtrate is concentrated separates out yellow solid, filter, drying obtains 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-amido quinazoline shown in 0.30 gram of formula (V), yield 80.3%.IR(KBr):v=3434,3345,3198,2959,2912,2872,2808,1676,1625,1604,1570,1529,945,908,878,830,769,779,694,647cm
-1。
The preparation of embodiment 8:4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (V)
Successively by 0.40 gram of (0.88mmol) 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (IV), 1.20 grams (19.18mmol) 80% hydrazine hydrate, 0.20 gram of 5%Pd/C, 30.0 milliliters of toluene join in the there-necked flask of 50 milliliters, be heated to 100 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1), stirring reaction 0.5 hour, cold filtration, filtrate is concentrated separates out yellow solid, filter, drying obtains 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-amido quinazoline shown in 0.27 gram of formula (V), yield 72.2%.IR(KBr):v=3434,3345,3198,2959,2912,2872,2808,1676,1625,1604,1570,1529,945,908,878,830,769,779,694,647cm
-1。
The preparation of embodiment 9:4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (V)
Successively by 0.40 gram of (0.88mmol) 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (IV), 0.08 gram of concentrated hydrochloric acid, 0.40 gram of iron powder, 30.0 ml methanol join in the there-necked flask of 50 milliliters, be heated to 40 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1), stirring reaction 8 hours, cold filtration, filtrate is concentrated separates out yellow solid, filter, drying obtains 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-amido quinazoline shown in 0.24 gram of formula (V), yield 64.2%.IR(KBr):v=3434,3345,3198,2959,2912,2872,2808,1676,1625,1604,1570,1529,945,908,878,830,769,779,694,647cm
-1。
The preparation of embodiment 10:4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (V)
Successively by 0.40 gram of (0.88mmol) 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (IV), 0.40 gram of acetic acid, 1.20 gram iron powder, 30.0 milliliters of Virahols join in the there-necked flask of 50 milliliters, be heated to 80 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1), stirring reaction 3 hours, cold filtration, filtrate is concentrated separates out yellow solid, filter, drying obtains 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-amido quinazoline shown in 0.29 gram of formula (V), yield 77.6%.IR(KBr):v=3434,3345,3198,2959,2912,2872,2808,1676,1625,1604,1570,1529,945,908,878,830,769,779,694,647cm
-1。
The preparation of embodiment 11:4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-isobutoxy formamido group quinazoline (I-1)
Successively by 0.235 gram of (0.55mmol) 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (V), 0.13 gram of (1.64mmol) pyridine, 10.0 milliliters of tetrahydrofuran (THF)s join in the there-necked flask of 50 milliliters, 0.60 gram of (4.39mmol) isobutyl chlorocarbonate and 10.0 milliliters of tetrahydrofuran solutions are dripped under-10 DEG C of agitation conditions, drip and finish, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1), react 12 hours under-10 DEG C of conditions, filter, filtrate steaming removal solvent, residue adds 20 milliliters of ethyl acetate and is dissolved, obtain lysate, 0.58 gram of column chromatography silica gel (300 ~ 400 order column chromatography silica gel) is added in lysate, after mixing, steaming desolventizes, obtain the mixture of dry residue and silica gel, mixture is filled post, then be 1:12 ~ 0 (1:12 with volume ratio, 1:8, 1:4, 1:2, 1:1, ethyl acetate 1:0), sherwood oil mixing solutions is eluent, gradient elution, collect the flow point of ethyl acetate/petroleum ether (1:4), collection liquid concentrates, drying obtains 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-isobutoxy formamido group quinazoline (I-1) white solid 0.26 gram, yield 89.6%, fusing point 241 ~ 243 DEG C.
1HNMR(500MHz,[D6]DMSO):δ=0.91(t,J=7.3Hz,6H),0.97(d,J=6.8Hz,6H),1.49-1.53(m,4H),1.95-2.00(m,1H),2.50-2.51(m,4H),3.22(s,2H),3.95(d,J=6.7Hz,2H),7.74-7.77(m,3H),8.14(d,J=2.4Hz,1H),8.33(d,J=9.0Hz,1H),8.54(d,J=8.1Hz,2H),9.86(s,1H),9.89(s,1H),9.97ppm(s,1H);IR(KBr):v=3286,2959,2920,1728,1682,1633,1612,694cm
-1;HRMS(ESI):m/z:[M+H]
+calcdforC
27H
36ClN
6O
3:527.2532,found:527.2530。
The preparation of embodiment 12:4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-isobutoxy formamido group quinazoline (I-1)
Successively by 0.235 gram of (0.55mmol) 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (V), 0.04 gram of (0.55mmol) diethylamine, 10.0 milliliters of chloroforms join in the there-necked flask of 50 milliliters, 0.075 gram of (0.55mmol) isobutyl chlorocarbonate and 10.0 milliliters of chloroformic solutions are dripped under 10 DEG C of agitation conditions, drip and finish, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1), react 8 hours under 10 DEG C of conditions, filter, filtrate steaming removal solvent, residue adds 20 milliliters of ethanol and is dissolved, obtain lysate, 0.29 gram of column chromatography silica gel (300 ~ 400 order column chromatography silica gel) is added in lysate, after mixing, steaming desolventizes, obtain the mixture of dry residue and silica gel, mixture is filled post, then be 1:12 ~ 0 (1:12 with volume ratio, 1:8, 1:4, 1:2, 1:1, ethyl acetate 1:0), sherwood oil mixing solutions is eluent, gradient elution, collect the flow point of ethyl acetate/petroleum ether (1:1), collection liquid concentrates, drying obtains 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-isobutoxy formamido group quinazoline (I-1) white solid 0.19 gram, yield 65.5%, fusing point 241 ~ 243 DEG C.
1HNMR(500MHz,[D6]DMSO):δ=0.91(t,J=7.3Hz,6H),0.97(d,J=6.8Hz,6H),1.49-1.53(m,4H),1.95-2.00(m,1H),2.50-2.51(m,4H),3.22(s,2H),3.95(d,J=6.7Hz,2H),7.74-7.77(m,3H),8.14(d,J=2.4Hz,1H),8.33(d,J=9.0Hz,1H),8.54(d,J=8.1Hz,2H),9.86(s,1H),9.89(s,1H),9.97ppm(s,1H);IR(KBr):v=3286,2959,2920,1728,1682,1633,1612,694cm
-1;HRMS(ESI):m/z:[M+H]
+calcdforC
27H
36ClN
6O
3:527.2532,found:527.2530。
The preparation of embodiment 13:4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-propionamido quinazoline (I-2)
Successively by 0.235 gram of (0.55mmol) 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (V), 0.11 gram of (1.09mmol) triethylamine, 10.0 milliliters of ethyl acetate join in the there-necked flask of 50 milliliters, 0.143 gram of (1.10mmol) propionic anhydride and 10.0 milliliters of ethyl acetate solutions are dripped under 0 DEG C of agitation condition, drip and finish, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1), react 6 hours under 25 DEG C of conditions, filter, filtrate steaming removal solvent, residue adds 20 milliliters of chloroforms and is dissolved, obtain lysate, 0.53 gram of column chromatography silica gel (300 ~ 400 order column chromatography silica gel) is added in lysate, after mixing, steaming desolventizes, obtain the mixture of dry residue and silica gel, mixture is filled post, then be 1:12 ~ 0 (1:12 with volume ratio, 1:8, 1:4, 1:2, 1:1, ethyl acetate 1:0), sherwood oil mixing solutions is eluent, gradient elution, collect the flow point of ethyl acetate/petroleum ether (1:2), collection liquid concentrates, drying obtains 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-propionamido quinazoline (I-2) faint yellow solid 0.20 gram, yield 75.2%, fusing point 112 ~ 114 DEG C.
1HNMR(500MHz,[D6]DMSO):δ=0.90(t,J=7.4Hz,6H),1.15(t,J=7.6Hz,3H),1.49-1.53(m,4H),2.42(q,J=7.6Hz,2H),2.50-2.53(m,4H),3.21(s,2H),7.75-7.77(m,2H),7.83(dd,J=2.1,9.0Hz,1H,),8.15(d,J=2.4Hz,1H),8.33(d,J=9.0Hz,1H),8.55(s,1H),8.73(d,J=1.8Hz,1H),9.89(s,2H),10.21ppm(s,1H);IR(KBr):v=3286,2960,2934,1673,1628,1608,698cm
-1;HRMS(ESI):m/z:[M+H]
+calcdforC
25H
32ClN
6O
2:483.2270,found:483.2273。
The preparation of embodiment 14:4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-propionamido quinazoline (I-2)
Successively by 0.235 gram of (0.55mmol) 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (V), 0.067 gram of (0.55mmol) DMAP, 10.0 milliliters of toluene join in the there-necked flask of 50 milliliters, 0.286 gram of (2.20mmol) propionic anhydride and 10.0 milliliters of toluene solutions are dripped under 5 DEG C of agitation conditions, drip and finish, be heated to 50 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1), react 3 hours, cooling, filter, filtrate steaming removal solvent, residue adds 20 milliliters of tetrahydrofuran (THF)s and is dissolved, obtain lysate, 0.27 gram of column chromatography silica gel (300 ~ 400 order column chromatography silica gel) is added in lysate, after mixing, steaming desolventizes, obtain the mixture of dry residue and silica gel, mixture is filled post, then be 1:12 ~ 0 (1:12 with volume ratio, 1:8, 1:4, 1:2, 1:1, ethyl acetate 1:0), sherwood oil mixing solutions is eluent, gradient elution, collect the flow point of ethyl acetate, collection liquid concentrates, drying obtains 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-propionamido quinazoline (I-2) faint yellow solid 0.17 gram, yield 63.9%, fusing point 112 ~ 114 DEG C.
1HNMR(500MHz,[D6]DMSO):δ=0.90(t,J=7.4Hz,6H),1.15(t,J=7.6Hz,3H),1.49-1.53(m,4H),2.42(q,J=7.6Hz,2H),2.50-2.53(m,4H),3.21(s,2H),7.75-7.77(m,2H),7.83(dd,J=2.1,9.0Hz,1H,),8.15(d,J=2.4Hz,1H),8.33(d,J=9.0Hz,1H),8.55(s,1H),8.73(d,J=1.8Hz,1H),9.89(s,2H),10.21ppm(s,1H);IR(KBr):v=3286,2960,2934,1673,1628,1608,698cm
-1;HRMS(ESI):m/z:[M+H]
+calcdforC
25H
32ClN
6O
2:483.2270,found:483.2273。
The preparation of embodiment 15:4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-isobutyryl amido quinazoline (I-3)
Successively by 0.235 gram of (0.55mmol) 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (V), 0.20 gram of (1.65mmol) N, N-xylidene(s), 10.0 milliliters of methylene dichloride join in the there-necked flask of 50 milliliters, 0.087 gram of (0.55mmol) isobutyric anhydride and 10.0 milliliters of dichloromethane solutions are dripped under-10 DEG C of agitation conditions, drip and finish, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1), react 11 hours under 0 DEG C of condition, filter, filtrate steaming removal solvent, residue adds 20 ml methanol and is dissolved, obtain lysate, 0.30 gram of column chromatography silica gel (300 ~ 400 order column chromatography silica gel) is added in lysate, after mixing, steaming desolventizes, obtain the mixture of dry residue and silica gel, mixture is filled post, then be 1:12 ~ 0 (1:12 with volume ratio, 1:8, 1:4, 1:2, 1:1, ethyl acetate 1:0), sherwood oil mixing solutions is eluent, gradient elution, collect the flow point of ethyl acetate/petroleum ether (1:4), collection liquid concentrates, drying obtains 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-isobutyryl amido quinazoline (I-3) yellow solid 0.17 gram, yield 62.1%, fusing point 116 ~ 118 DEG C.
1HNMR(500MHz,[D6]DMSO):δ=0.91(t,J=7.4Hz,6H),1.17(d,J=6.8Hz,6H),1.50-1.52(m,4H),2.50-2.51(m,4H),2.68-2.71(m,1H),3.21(s,2H),7.77(d,J=8.9Hz,2H),7.84(dd,J=2.1,8.9Hz,1H),8.15(d,J=2.4Hz,1H),8.33(d,J=9.0Hz,1H),8.55(s,1H),8.76(d,J=2.1Hz,1H),9.89(s,1H),9.90(s,1H),10.18ppm(s,1H);IR(KBr):v=3294,2963,2933,1672,1628,1603,700cm
-1;HRMS(ESI):m/z:[M+H]
+calcdforC
26H
34ClN
6O
2:497.2426,found:497.2433。
The preparation of embodiment 16:4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-isobutyryl amido quinazoline (I-3)
Successively by 0.235 gram of (0.55mmol) 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (V), 0.058 gram of (0.55mmol) sodium carbonate, 10.0 milliliters of acetonitriles join in the there-necked flask of 50 milliliters, 0.696 gram of (4.40mmol) isobutyric anhydride and 10.0 milliliters of acetonitrile solutions are dripped under-5 DEG C of agitation conditions, drip and finish, be heated to 50 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1), react 4 hours, cooling, filter, filtrate steaming removal solvent, residue adds 20 milliliters of methylene dichloride and is dissolved, obtain lysate, 0.60 gram of column chromatography silica gel (300 ~ 400 order column chromatography silica gel) is added in lysate, after mixing, steaming desolventizes, obtain the mixture of dry residue and silica gel, mixture is filled post, then be 1:12 ~ 0 (1:12 with volume ratio, 1:8, 1:4, 1:2, 1:1, ethyl acetate 1:0), sherwood oil mixing solutions is eluent, gradient elution, collect the flow point of ethyl acetate, collection liquid concentrates, drying obtains 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-isobutyryl amido quinazoline (I-3) yellow solid 0.21 gram, yield 76.8%, fusing point 116 ~ 118 DEG C.
1HNMR(500MHz,[D6]DMSO):δ=0.91(t,J=7.4Hz,6H),1.17(d,J=6.8Hz,6H),1.50-1.52(m,4H),2.50-2.51(m,4H),2.68-2.71(m,1H),3.21(s,2H),7.77(d,J=8.9Hz,2H),7.84(dd,J=2.1,8.9Hz,1H),8.15(d,J=2.4Hz,1H),8.33(d,J=9.0Hz,1H),8.55(s,1H),8.76(d,J=2.1Hz,1H),9.89(s,1H),9.90(s,1H),10.18ppm(s,1H);IR(KBr):v=3294,2963,2933,1672,1628,1603,700cm
-1;HRMS(ESI):m/z:[M+H]
+calcdforC
26H
34ClN
6O
2:497.2426,found:497.2433。
Embodiment 17: antitumour activity vitro test
People's lung cancer and human breast carcinoma biological activity test are carried out in the compound obtained in embodiment (I-1), (I-2), (I-3) and (IV).DDP(cis-platinum) medicine in contrast, cis-platinum is the conventional chemicals of cancer therapy, has higher curative effect.
Testing method: tetrazolium reduction method (mtt assay).
Cell strain: human lung cancer cell lines A-549 and MCF-7 cell strainHJ2mm.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:
(1) preparation of sample: for solvable sample, every 1mg 40 μ LDMSO dissolve, and get 2uL 1000 μ L nutrient solutions and dilute, make concentration be 50 μ g/mL, then use nutrient solution serial dilution to working concentration.
(2) cultivation of cell
1) preparation of substratum: containing 800,000 units of Penicillin in every 1000 milliliters of substratum, 1.0 grams of Streptomycin sulphates, 10% inactivated fetal bovine serum.
2) cultivation of cell: by tumor cell inoculation in substratum, puts 37 DEG C, 5%CO
2cultivate in incubator, 3 ~ 5d goes down to posterity.
3) working sample is to the restraining effect of growth of tumour cell
By cell EDTA-trysinization liquid digestion, and be diluted to 1 × 10 with substratum
6/ milliliter, be added in 96 porocyte culture plates, every hole 100uL, puts 37 DEG C, 5%CO
2cultivate in incubator.After inoculation 24h, add the sample with substratum dilution, every hole 100 μ L, each concentration adds 3 holes, puts 37 DEG C, 5%CO
2cultivate in incubator, add the MTT of 5mg/mL after 72h in cell culture well, every hole 10 μ L, puts 37 DEG C and hatches 3h, add DMSO, every hole 150 μ L, and with oscillator vibrates, Shi Jia Za dissolves completely, by microplate reader colorimetric under 570nm wavelength.With similarity condition with containing sample, containing the culture medium culturing of same concentration DMSO cell in contrast, calculation sample is to the IC of growth of tumour cell
50.
The result of test is as shown in the table:
Claims (10)
1.4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound, it has having structure and leads to formula I:
In general structure (I), R is isobutoxy, ethyl or sec.-propyl.
2.4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline, its structure is such as formula shown in (IV):
3.4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline, its structure is as shown in formula V:
4. a preparation method for 4-as claimed in claim 1 [the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound, is characterized in that described preparation method comprises:
(1) 2-dipropyl amino-N-(2-chloro-4-aminophenyl) the 4-chloro-6-nitro-quinazoline shown in ethanamide and formula III shown in formula II reacts obtained 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline shown in formula IV in organic solvent A 1 under the effect of basic catalyst B1; Described basic catalyst B1 is selected from one of following: pyridine, diethylamine, triethylamine, quinoline, N, N-xylidene(s), DMAP, 4-pyrollidinopyridine or sodium carbonate; Described organic solvent A 1 is selected from one of following: chloroform, toluene, methyl alcohol, ethanol, propyl alcohol, Virahol, acetonitrile or DMF;
(2) 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-nitro-quinazoline shown in formula IV reacts obtained 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline shown in formula (V) in organic solvent A 2 under reductive agent B2 effect; Described reductive agent B2 is one of following: iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium carbon/ammonium formiate or palladium carbon/hydrazine hydrate; Described organic solvent A 2 is one of following: chloroform, toluene, methyl alcohol, ethanol, propyl alcohol, Virahol or acetonitrile;
(3) 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-amido quinazoline shown in formula (V) and isobutyl chlorocarbonate, propionic anhydride or isobutyric anhydride react obtained 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound shown in formula I in organic solvent A 3 under basic catalyst B3 effect; Described basic catalyst B3 is one of following: pyridine, diethylamine, triethylamine, quinoline, N, N-xylidene(s), DMAP, 4-pyrollidinopyridine or sodium carbonate; Described organic solvent A 3 is one of following: tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate, ether, acetonitrile, toluene or benzene;
In described formula I, R is isobutoxy, ethyl or sec.-propyl.
5. the preparation method of 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound as claimed in claim 4, is characterized in that: the reaction described in step (1) is carried out under the temperature condition of 25 ~ 120 DEG C.
6. the preparation method of 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound as claimed in claim 4, is characterized in that: the reaction described in step (2) is carried out under the temperature condition of 25 ~ 100 DEG C.
7. the preparation method of 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound as claimed in claim 4, is characterized in that: the reaction described in step (3) is carried out under the temperature condition of-10 ~ 50 DEG C.
8. the preparation method of 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound as claimed in claim 4, it is characterized in that: in described step (1), the molar ratio of 4-chloro-6-nitro-quinazoline (III), 2-dipropyl amino-N-(the chloro-4-aminophenyl of 2-) ethanamide (II), basic catalyst B1 is 1.0 ﹕ 0.8 ~ 1.2 ﹕ 1.0 ~ 8.0, in described step (2), described reductive agent B2 is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, wherein 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (IV) and the iron powder in reductive agent B2, the mass ratio that feeds intake of concentrated hydrochloric acid or acetic acid is 1.0 ﹕ 1.0 ~ 3.0 ﹕ 0.2 ~ 1.0, or described reductive agent B2 be palladium carbon/ammonium formiate or palladium carbon/hydrazine hydrate time, wherein 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (IV) and the palladium carbon in reductive agent B2, the mass ratio that feeds intake of ammonium formiate or hydrazine hydrate is 1.0 ﹕ 0.1 ~ 0.5 ﹕ 1.0 ~ 3.0, in described step (3), the molar ratio of 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (V), isobutyl chlorocarbonate or propionic anhydride or isobutyric anhydride, basic catalyst B3 is 1 ﹕ 1.0 ~ 8.0 ﹕ 1.0 ~ 3.0.
9. the preparation method of 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound as claimed in claim 8, is characterized in that described preparation method is according to carrying out as follows:
(1) by the chloro-6-nitro-quinazoline of 4-shown in 2-dipropyl amino-N-(2-chloro-4-aminophenyl) ethanamide and the formula III shown in formula II, react in 25 ~ 120 DEG C under the effect of basic catalyst B1 in organic solvent A 1, hold over night after completion of the reaction, filtration, drying obtain 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-nitro-quinazoline shown in formula IV;
(2) 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-nitro-quinazoline shown in formula IV, reductive agent B2 are added in organic solvent A 2, fully react at 25 ~ 100 DEG C, filter, filtrate is concentrated separates out solid, filter, drying obtains 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-amido quinazoline shown in formula (V);
(3) 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) the anilino]-6-amido quinazoline shown in formula (V), basic catalyst B3 are added in organic solvent A 3, under-10 ~ 10 DEG C of conditions, drip organic solvent A 3 solution of isobutyl chlorocarbonate or propionic anhydride or isobutyric anhydride, drip and finish,-10 ~ 50 DEG C are reacted 3 ~ 12 hours, filter, filtrate steaming removal solvent, residue column chromatography obtains corresponding 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound (I).
10. 4-[the chloro-4-of 3-(2-dipropyl aminoacetylamino) anilino]-6-substituted formyl amino-quinazoline compound as claimed in claim 1 prevents in preparation or treats the application in the medicine of people's lung cancer or human breast carcinoma disease.
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| CN104926737B (en) * | 2015-05-13 | 2017-11-07 | 浙江工业大学 | 4 (3 substituted anilinic) 6 substituent quinazoline compounds and preparation and application |
| CN108033949B (en) * | 2018-01-24 | 2019-11-29 | 浙江工业大学 | 6- (2- dipropyl aminoacetylamino) quinazoline compounds and preparation and application |
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| CN108084162B (en) * | 2018-01-24 | 2019-11-29 | 浙江工业大学 | Dimethoxy benzene aminoacetylamino benzo [d] azepine * base quinazoline compounds and preparation and application |
| CN108276384B (en) * | 2018-01-24 | 2019-12-06 | 浙江工业大学 | acetaminobenzo [ d ] azepinyl quinazoline compound and preparation and application thereof |
| CN108117542B (en) * | 2018-01-24 | 2019-12-24 | 浙江工业大学 | Propionyl amino methoxyphenyl benzo [ d ] nitrogen hetero-pinyl quinazoline compound, preparation and application |
| CN109251196B (en) * | 2018-01-24 | 2020-11-13 | 浙江工业大学 | Aminobenzo [ d ] aza-quinazoline compound and preparation method and application thereof |
| CN108129461B (en) * | 2018-01-24 | 2020-08-21 | 浙江工业大学 | Benzoylaminobenzo [ d ] aza-quinazoline compound, preparation and application thereof |
| CN108129460B (en) * | 2018-01-24 | 2020-10-09 | 浙江工业大学 | Methoxyphenylbenzo [ d ] aza-quinazoline compound and preparation and application thereof |
| CN108276385B (en) * | 2018-01-24 | 2019-12-06 | 浙江工业大学 | Isobutyrylaminoquinazoline compounds, and preparation and application thereof |
| CN108047206B (en) * | 2018-01-24 | 2019-11-29 | 浙江工业大学 | Pivaloyl amino benzo [d] azepine * base quinazoline compounds and preparation and application |
| CN114276302B (en) * | 2022-01-11 | 2023-07-25 | 山东百启生物医药有限公司 | Method for preparing 2, 4-diaminoquinazoline derivative |
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