CN103275018A - 4-(3-chloro-4-substituted anilino)-6-substituted carbamonyl quinazoline compounds, and preparation method and applications thereof - Google Patents
4-(3-chloro-4-substituted anilino)-6-substituted carbamonyl quinazoline compounds, and preparation method and applications thereof Download PDFInfo
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Abstract
The invention discloses 4-(3-chloro-4-substituted anilino)-6-substituted carbamonyl quinazoline compounds, and a preparation method and applications thereof. Each of the compounds has the following structure of general formula (I), wherein R is isobutoxyl, ethyl or isopropyl. The 4-(3-chloro-4-substituted anilino)-6-substituted carbamonyl quinazoline compounds of the invention can be used to prepare drugs for prevention and treatment of diseases about human lung cancer or human breast cancer, and have good antitumor activity.
Description
(1) technical field
The present invention relates to 4-[3-chloro-4-substituted anilinic]-6-substituted formyl amino-quinazoline compound, be specifically related to 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-substituted formyl amino-quinazoline compound---4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-isobutoxy formamido group quinazoline, 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-propionamido quinazoline and 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-isobutyryl amido quinazoline and preparation method thereof, and the application of described three compounds in the medicine of preparation prevention or treatment tumor disease.
(2) background technology
Quinazoline compounds has many biological activitys preferably, have a wide range of applications at field of medicaments, especially the quinazoline derivative of some special constructions has tangible antiviral activity, anti-microbial activity, anti-tumor activity etc., and quinazoline compounds is as antitumor drug some kinds of having gone on the market.For example Shang Shi the Gefitinib that is used for the treatment of lung cancer (Gefitinib) and Tarceva (Erlotinib), and the lapatinibditosylate (Lapatinib) that is 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 (are consulted 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-[3-chloro-4-(2-dipropyl glycyl amino) anilino with antitumour activity]-6-substituted formyl amino-quinazoline compound and its preparation method and application, this compounds has inhibiting rate preferably to human lung carcinoma cell line A-549 or human breast cancer cell strain MCF-7 under doses; And such compounds process for production thereof is easy, easy handling, and 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-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-substituted formyl amino-quinazoline compound, it has following general structure (I):
In the general structure (I), R is isobutoxy, ethyl or sec.-propyl.
The present invention also provides two kinds and has prepared described 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-intermediate of 6-substituted formyl amino-quinazoline compound, namely structure is suc as formula the 4-[3-chloro-4-shown in (IV) (2-dipropyl glycyl amino) anilino]-6-nitro-quinazoline and 4-[3-chloro-4-(the 2-dipropyl glycyl amino) anilino of structure shown in formula V]-the 6-amido quinazoline:
The invention provides a kind of described 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-preparation method of 6-substituted formyl amino-quinazoline compound, described preparation method comprises:
(1) the 4-chloro-6-nitro-quinazoline shown in (the 2-chloro-4-aminophenyl) ethanamide of the 2-dipropyl amino-N-shown in the formula II and the formula III reacts under the effect of basic catalyst B1 in organic solvent A 1 and makes the 4-[3-chloro-4-shown in the formula IV (2-dipropyl glycyl amino) anilino]-the 6-nitro-quinazoline; It is one of following that described basic catalyst B1 is selected from: pyridine, diethylamine, triethylamine, quinoline, N, N-xylidene(s), 4-Dimethylamino pyridine, 4-pyrrolidyl pyridine or yellow soda ash; It is one of following that described organic solvent A 1 is selected from: chloroform, toluene, methyl alcohol, ethanol, propyl alcohol, Virahol, acetonitrile or N, dinethylformamide;
(2) the 4-[3-chloro-4-shown in the formula IV (2-dipropyl glycyl amino) anilino]-the 6-nitro-quinazoline in organic solvent A 2 under reductive agent B2 effect reaction make the 4-[3-chloro-4-shown in the formula (V) (2-dipropyl glycyl amino) anilino]-the 6-amido quinazoline; 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) the 4-[3-chloro-4-shown in the formula (V) (2-dipropyl glycyl amino) anilino]-6-amido quinazoline and isobutyl chlorocarbonate, propionic anhydride or isobutyric anhydride in organic solvent A 3 under basic catalyst B3 effect reaction make the 4-[3-chloro-4-shown in the formula I (2-dipropyl glycyl amino) anilino]-6-substituted formyl amino-quinazoline compound; Described basic catalyst B3 is one of following: pyridine, diethylamine, triethylamine, quinoline, N, N-xylidene(s), 4-Dimethylamino pyridine, 4-pyrrolidyl pyridine or yellow soda ash; Described organic solvent A 3 is one of following: tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate, ether, acetonitrile, toluene or benzene;
In the described formula I, R is isobutoxy, ethyl or sec.-propyl.
In the step of the present invention (1), one of described organic solvent A 1 is preferred following: chloroform, toluene, methyl alcohol or Virahol.One of shown basic catalyst B1 is preferred following: pyridine, diethylamine, triethylamine or 4-Dimethylamino pyridine.The molar ratio of described 4-chloro-6-nitro-quinazoline (III), 2-dipropyl amino-N-(2-chloro-4-aminophenyl) 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 is counted 10～50mL/g with the quality of 4-chloro-6-nitro-quinazoline (III).Step (1) is described to be reflected under 25～120 ℃ the temperature condition and to carry out, and preferable reaction temperature is 40～100 ℃, and reaction end can be by the monitoring of methods such as TLC, and the reaction times is generally at 0.5～12 hour.
The concrete described step (1) of recommending of the present invention is carried out according to following: with the 4-chloro-6-nitro-quinazoline shown in (the 2-chloro-4-aminophenyl) ethanamide of the 2-dipropyl amino-N-shown in the formula II and the formula III, in organic solvent A 1, under the effect of basic catalyst B1, react in 25～120 ℃, standing over night after reaction finishes, filtration, drying obtain the 4-[3-chloro-4-shown in the formula IV (2-dipropyl glycyl amino) anilino]-the 6-nitro-quinazoline.
In the step of the present invention (2), one of described organic solvent A 2 is preferred following: chloroform, toluene, methyl alcohol or Virahol.In the step (2), when described reductive agent B2 is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-mass ratio that feeds intake of iron powder, concentrated hydrochloric acid or acetic acid among 6-nitro-quinazoline (IV) and the reductive agent B2 is 1.0 ﹕, 1.0～3.0 ﹕ 0.2～1.0; When described reductive agent B2 is palladium carbon/ammonium formiate or palladium carbon/hydrazine hydrate, 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-mass ratio that feeds intake of palladium carbon, ammonium formiate or hydrazine hydrate among 6-nitro-quinazoline (IV) and the reductive agent B2 is 1.0 ﹕, 0.1～0.5 ﹕ 1.0～3.0, the consumption of described organic solvent A 2 is with 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-quality of 6-nitro-quinazoline (IV) counts 10～50mL/g.Step (2) is described to be reflected under 25～100 ℃ the temperature condition and to carry out, and preferable reaction temperature is 40～80 ℃, and reaction end can be by the monitoring of methods such as TLC, and the reaction times is generally at 0.5～12 hour.
The concrete described step (2) of recommending of the present invention is carried out according to following: with the 4-[3-chloro-4-shown in the formula IV (2-dipropyl glycyl amino) anilino]-6-nitro-quinazoline, reductive agent B2 add in the organic solvent A 2, in 25～100 ℃ of fully reactions down, filter, filtrate concentrating separated out solid, filter, drying obtains the 4-[3-chloro-4-shown in the formula (V) (2-dipropyl glycyl amino) anilino]-the 6-amido quinazoline.
In the step of the present invention (3), one of described organic solvent A 3 is preferred following: tetrahydrofuran (THF), chloroform, ethyl acetate or toluene.One of described basic catalyst B3 is preferred following: pyridine, diethylamine, triethylamine or 4-Dimethylamino pyridine.Described 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-molar ratio of 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, the consumption of described organic solvent A 3 is with 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-quality of 6-amido quinazoline (V) counts 10～95mL/g.Carry out under the temperature condition of step (3) described being reflected at-10～50 ℃, reaction end can be by the monitoring of methods such as TLC, and the reaction times is generally at 3～12 hours.
The concrete described step (3) of recommending of the present invention is carried out according to following: with the 4-[3-chloro-4-shown in the formula (V) (2-dipropyl glycyl amino) anilino]-the 6-amido quinazoline, basic catalyst B3 adds in the organic solvent A 3, under-10～10 ℃ of conditions, drip organic solvent A 3 solution of isobutyl chlorocarbonate or propionic anhydride or isobutyric anhydride, drip and finish,-10～50 ℃ were reacted 3～12 hours, filter, filtrate steaming removal solvent, residue column chromatography obtain corresponding 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-substituted formyl amino-quinazoline compound (I).
The described residue column chromatography of step of the present invention (3) can carry out as follows: get the residue that steams after desolventizing in the single port bottle, adding organic solvent C dissolves it, obtain lysate, the column chromatography silica gel that adds 1.0～2.0 times of amounts of residue quality then in the lysate, behind the mixing, steaming desolventizes, and gets dry residue and the mixture of silica gel, and mixture is adorned post, be 1:12～0(1:12 then with the volume ratio, 1:8,1:4,1:2,1:1, ethyl acetate 1:0), the sherwood oil mixing solutions is eluent, gradient elution, and collecting eluent is ethyl acetate/petroleum ether (1:4,1:2,1:1 or 1:0) flow point, collect liquid and concentrate, dryly obtain 4-[3-chloro-4-(the 2-dipropyl glycyl amino) anilino shown in the formula I]-6-substituted formyl amino-quinazoline compound.Described organic solvent C is one of following: methyl alcohol, ethanol, methylene dichloride, chloroform, tetrahydrofuran (THF) or ethyl acetate.
4-[3-chloro-4-of the present invention (2-dipropyl glycyl amino) anilino]-6-substituted formyl amino-quinazoline compound (I) can be applicable to prepare the medicine of 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 is to human lung carcinoma cell line A-549 or human breast cancer cell strain MCF-7(especially human breast cancer cell strain MCF-7) have an inhibiting rate preferably.For example: 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-isobutoxy formamido group quinazoline (I-1) is to the IC of human lung carcinoma cell line A-549 and human breast cancer cell strain MCF-7
50Be respectively 30.3 μ M and 9.38 μ M.In addition, intermediate provided by the invention (IV) is to human lung carcinoma cell line A-549 or human breast cancer cell strain MCF-7(especially human breast cancer cell strain MCF-7) also have an inhibiting rate preferably.
Beneficial effect of the present invention is mainly reflected in: (1) 4-[3-chloro-of the present invention 4-(2-dipropyl glycyl amino) anilino]-6-substituted formyl amino-quinazoline compound (I) has good antitumour activity, is expected to be applied to prepare in the medicine of prevention or treatment tumor disease; (2) 4-[3-chloro-4-of the present invention provided by the invention (2-dipropyl glycyl amino) anilino]-preparation method of 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 is that explanation is of the present invention, rather than limits the present invention by any way.
The preparation reference literature of 4-chloro-6-nitro-quinazoline (III) (C.Fernandes, C.Oliveira, L.Gano, A.Bourkoula, I.Pirmettis, I.Santos, Bioorg.Med.Chem.2007,15, method 3974-3980) 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, method 15972-15973) prepares
The preparation of embodiment 1:2-dipropyl amino-N-(2-chloro-4-aminophenyl) ethanamide (II)
Successively with compound 2-chloro-4-N-methyl-p-nitroaniline 6.20 grams (35.93mmol), 5.5 milliliters of triethylamines (39.46mmol), 100.0 milliliters of methylene dichloride, join in 250 milliliters of there-necked flasks, drip 6.0 milliliters of chloroacetyl chlorides (79.69mmol) under 0～5 ℃ of stirring, drip and finish, react 20h under the room temperature condition, reaction solution is extremely neutral with the saturated sodium carbonate solution washing.With organic phase, dipropyl amine 10.00 grams (98.82mmol) join in 250 milliliters of there-necked flasks successively, back flow reaction 20h, with the reaction solution evaporate to dryness, acetic acid ethyl dissolution and water wash, the organic phase anhydrous magnesium sulfate drying, 50.0 milliliters of concentrated pale brown look product 2-dipropyl amino-N-(the 2-chloro-4-nitrophenyl) ethanamide that obtains and dehydrated alcohols, 3.0 milliliters of concentrated hydrochloric acids, 6.0 milliliters in water, iron powder 7.80 grams (139.68mmol), join successively in 100 milliliters of there-necked flasks, back flow reaction 4h, cooling neutralizes reaction solution with saturated sodium carbonate solution, filter, the filtrate evaporate to dryness, acetic acid ethyl dissolution and water wash, the organic phase anhydrous magnesium sulfate drying, concentrate drying obtains 7.51 gram brown product 2-dipropyl amino-N-(2-chloro-4-aminophenyl) ethanamides (II), yield 73.7%.
Embodiment 2:4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-preparation of 6-nitro-quinazoline (IV)
Successively with 1.20 gram (5.73mmol) 4-chloro-6-nitro-quinazolines (III) and 1.95 gram (6.87mmol) 2-dipropyl amino-N-(2-chloro-4-aminophenyl) ethanamides (II), 3.62 gram (45.76mmol) pyridine, 60 milliliters of chloroforms add in 100 milliliters the there-necked flask, be heated to 40 ℃, TLC follow the tracks of to detect that (developping agent is ethyl acetate/petroleum ether=1:1), stirring reaction 10 hours, off-response, standing over night, filter, drying obtains the 4-[3-chloro-4-shown in the formula IV (2-dipropyl glycyl amino) anilino]-6-nitro-quinazoline yellow solid 1.61 grams, yield 61.5%, 224～226 ℃ of fusing points.
1H?NMR(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]
+calcd?for?C
22H
26ClN
6O
3:457.1749,found:457.1757。
Embodiment 3:4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-preparation of 6-nitro-quinazoline (IV)
Successively with 1.20 gram (5.73mmol) 4-chloro-6-nitro-quinazolines (III) and 1.30 gram (4.58mmol) 2-dipropyl amino-N-(2-chloro-4-aminophenyl) ethanamides (II), 1.67 gram (22.83mmol) diethylamine, 60 milliliters of toluene adds in 100 milliliters the there-necked flask, be heated to 100 ℃, TLC follow the tracks of to detect that (developping agent is ethyl acetate/petroleum ether=1:1), stirring reaction 2 hours, off-response, standing over night, filter, drying obtains the 4-[3-chloro-4-shown in the formula IV (2-dipropyl glycyl amino) anilino]-6-nitro-quinazoline yellow solid 1.59 grams, yield 76.0%, 224～226 ℃ of fusing points.
1H?NMR(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]
+calcd?for?C
22H
26ClN
6O
3:457.1749,found:457.1757。
Embodiment 4:4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-preparation of 6-nitro-quinazoline (IV)
Successively with 1.20 gram (5.73mmol) 4-chloro-6-nitro-quinazolines (III) and 1.63 gram (5.74mmol) 2-dipropyl amino-N-(2-chloro-4-aminophenyl) ethanamides (II), 0.58 gram (5.73mmol) triethylamine, in the there-necked flask that the adding of 60 ml methanol is 100 milliliters, be heated to 60 ℃, TLC follow the tracks of to detect that (developping agent is ethyl acetate/petroleum ether=1:1), stirring reaction 8 hours, off-response, standing over night, filter, drying obtains the 4-[3-chloro-4-shown in the formula IV (2-dipropyl glycyl amino) anilino]-6-nitro-quinazoline yellow solid 2.18 grams, yield 83.3%, 224～226 ℃ of fusing points.
1H?NMR(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]
+calcd?for?C
22H
26ClN
6O
3:457.1749,found:457.1757。
Embodiment 5:4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-preparation of 6-nitro-quinazoline (IV)
Successively with 1.20 gram (5.73mmol) 4-chloro-6-nitro-quinazolines (III) and 1.79 gram (6.31mmol) 2-dipropyl amino-N-(2-chloro-4-aminophenyl) ethanamides (II), 1.40 gram (11.46mmol) 4-Dimethylamino pyridine, 60 milliliters of Virahols add in 100 milliliters the there-necked flask, 25 ℃ of stirrings of room temperature, TLC follow the tracks of to detect that (developping agent is ethyl acetate/petroleum ether=1:1), reacted 12 hours, off-response, standing over night, filter, drying obtains the 4-[3-chloro-4-shown in the formula IV (2-dipropyl glycyl amino) anilino]-6-nitro-quinazoline yellow solid 1.70 grams, yield 65.0%, 224～226 ℃ of fusing points.
1H?NMR(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]
+calcd?forC
22H
26ClN
6O
3:457.1749,found:457.1757。
Embodiment 6:4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-preparation of 6-nitro-quinazoline (IV)
Successively with 1.20 gram (5.73mmol) 4-chloro-6-nitro-quinazolines (III) and 1.47 gram (5.18mmol) 2-dipropyl amino-N-(2-chloro-4-aminophenyl) ethanamides (II), 1.04 gram (8.58mmol) N, the N-xylidene(s), 60 milliliters of N, in the there-necked flask that the dinethylformamide adding is 100 milliliters, be heated to 120 ℃, TLC follow the tracks of to detect that (developping agent is ethyl acetate/petroleum ether=1:1), stirring reaction 0.5 hour, off-response, standing over night, filter, drying obtains the 4-[3-chloro-4-shown in the formula IV (2-dipropyl glycyl amino) anilino]-6-nitro-quinazoline yellow solid 2.13 grams, yield 81.4%, 224～226 ℃ of fusing points.
1H?NMR(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]
+calcd?forC
22H
26ClN
6O
3:457.1749,found:457.1757。
Embodiment 7:4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-preparation of 6-amido quinazoline (V)
Successively with 0.40 gram (0.88mmol) 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-nitro-quinazoline (IV), 0.40 gram (6.34mmol) ammonium formiate, 0.04 gram 5%Pd/C, 30.0 the milliliter chloroform joins in 50 milliliters the there-necked flask, 25 ℃ of stirrings of room temperature, TLC follow the tracks of to detect that (developping agent is ethyl acetate/petroleum ether=1:1), reacted 12 hours, filter, filtrate concentrating separated out yellow solid, filter, drying obtains the 4-[3-chloro-4-shown in the 0.30 gram formula (V) (2-dipropyl glycyl amino) anilino]-the 6-amido quinazoline, 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。
Embodiment 8:4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-preparation of 6-amido quinazoline (V)
Successively with 0.40 gram (0.88mmol) 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-nitro-quinazoline (IV), 1.20 gram (19.18mmol) 80% hydrazine hydrate, 0.20 gram 5%Pd/C, 30.0 milliliter toluene joins in 50 milliliters the there-necked flask, be heated to 100 ℃, TLC follow the tracks of to detect that (developping agent is ethyl acetate/petroleum ether=1:1), stirring reaction 0.5 hour, cold filtration, filtrate concentrating separated out yellow solid, filter, drying obtains the 4-[3-chloro-4-shown in the 0.27 gram formula (V) (2-dipropyl glycyl amino) anilino]-the 6-amido quinazoline, 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。
Embodiment 9:4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-preparation of 6-amido quinazoline (V)
Successively with 0.40 gram (0.88mmol) 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-nitro-quinazoline (IV), 0.08 gram concentrated hydrochloric acid, 0.40 gram iron powder, 30.0 ml methanol joins in 50 milliliters the there-necked flask, be heated to 40 ℃, TLC follow the tracks of to detect that (developping agent is ethyl acetate/petroleum ether=1:1), stirring reaction 8 hours, cold filtration, filtrate concentrating separated out yellow solid, filter, drying obtains the 4-[3-chloro-4-shown in the 0.24 gram formula (V) (2-dipropyl glycyl amino) anilino]-the 6-amido quinazoline, 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。
Embodiment 10:4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-preparation of 6-amido quinazoline (V)
Successively with 0.40 gram (0.88mmol) 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-nitro-quinazoline (IV), 0.40 gram acetic acid, 1.20 gram iron powder, 30.0 the milliliter Virahol joins in 50 milliliters the there-necked flask, be heated to 80 ℃, TLC follow the tracks of to detect that (developping agent is ethyl acetate/petroleum ether=1:1), stirring reaction 3 hours, cold filtration, filtrate concentrating separated out yellow solid, filter, drying obtains the 4-[3-chloro-4-shown in the 0.29 gram formula (V) (2-dipropyl glycyl amino) anilino]-the 6-amido quinazoline, 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。
Embodiment 11:4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-preparation of 6-isobutoxy formamido group quinazoline (I-1)
Successively with 0.235 gram (0.55mmol) 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-amido quinazoline (V), 0.13 gram (1.64mmol) pyridine, 10.0 the milliliter tetrahydrofuran (THF) joins in 50 milliliters the there-necked flask, drip 0.60 gram (4.39mmol) isobutyl chlorocarbonate and 10.0 milliliters of tetrahydrofuran solutions under-10 ℃ of agitation conditions, drip and finish, TLC follow the tracks of to detect that (developping agent is ethyl acetate/petroleum ether=1:1), reaction is 12 hours under-10 ℃ of conditions, filter, filtrate steaming removal solvent, residue adds 20 milliliters of ethyl acetate it is dissolved, obtain lysate, in lysate, add 0.58 gram column chromatography silica gel (300～400 order column chromatography silica gel), behind the mixing, steaming desolventizes, get dry residue and the mixture of silica gel, mixture is adorned post, be 1:12～0 (1:12 then with the volume ratio, 1:8,1:4,1:2,1:1, ethyl acetate 1:0), the sherwood oil mixing solutions is eluent, and gradient elution is collected the flow point of ethyl acetate/petroleum ether (1:4), collection liquid concentrates, drying obtains 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-isobutoxy formamido group quinazoline (I-1) white solid 0.26 gram, yield 89.6%, 241～243 ℃ of fusing points.
1H?NMR(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]
+calcd?forC
27H
36ClN
6O
3:527.2532,found:527.2530。
Embodiment 12:4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-preparation of 6-isobutoxy formamido group quinazoline (I-1)
Successively with 0.235 gram (0.55mmol) 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-amido quinazoline (V), 0.04 gram (0.55mmol) diethylamine, 10.0 the milliliter chloroform joins in 50 milliliters the there-necked flask, drip 0.075 gram (0.55mmol) isobutyl chlorocarbonate and 10.0 milliliters of chloroformic solutions under 10 ℃ of agitation conditions, drip and finish, TLC follow the tracks of to detect that (developping agent is ethyl acetate/petroleum ether=1:1), reaction is 8 hours under 10 ℃ of conditions, filter, filtrate steaming removal solvent, residue adds 20 milliliters of ethanol it is dissolved, obtain lysate, in lysate, add 0.29 gram column chromatography silica gel (300～400 order column chromatography silica gel), behind the mixing, steaming desolventizes, get dry residue and the mixture of silica gel, mixture is adorned post, be 1:12～0 (1:12 then with the volume ratio, 1:8,1:4,1:2,1:1, ethyl acetate 1:0), the sherwood oil mixing solutions is eluent, and gradient elution is collected the flow point of ethyl acetate/petroleum ether (1:1), collection liquid concentrates, drying obtains 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-isobutoxy formamido group quinazoline (I-1) white solid 0.19 gram, yield 65.5%, 241～243 ℃ of fusing points.
1H?NMR(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]
+calcd?forC
27H
36ClN
6O
3:527.2532,found:527.2530。
Embodiment 13:4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-preparation of 6-propionamido quinazoline (I-2)
Successively with 0.235 gram (0.55mmol) 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-amido quinazoline (V), 0.11 gram (1.09mmol) triethylamine, 10.0 the milliliter ethyl acetate joins in 50 milliliters the there-necked flask, drip 0.143 gram (1.10mmol) propionic anhydride and 10.0 milliliters of ethyl acetate solutions under 0 ℃ of agitation condition, drip and finish, TLC follow the tracks of to detect that (developping agent is ethyl acetate/petroleum ether=1:1), reaction is 6 hours under 25 ℃ of conditions, filter, filtrate steaming removal solvent, residue adds 20 milliliters of chloroforms it is dissolved, obtain lysate, in lysate, add 0.53 gram column chromatography silica gel (300～400 order column chromatography silica gel), behind the mixing, steaming desolventizes, get dry residue and the mixture of silica gel, mixture is adorned post, be 1:12～0 (1:12 then with the volume ratio, 1:8,1:4,1:2,1:1, ethyl acetate 1:0), the sherwood oil mixing solutions is eluent, and gradient elution is collected the flow point of ethyl acetate/petroleum ether (1:2), collection liquid concentrates, drying obtains 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-propionamido quinazoline (I-2) faint yellow solid 0.20 gram, yield 75.2%, 112～114 ℃ of fusing points.
1H?NMR(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]
+calcd?forC
25H
32ClN
6O
2:483.2270,found:483.2273。
Embodiment 14:4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-preparation of 6-propionamido quinazoline (I-2)
Successively with 0.235 gram (0.55mmol) 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-amido quinazoline (V), 0.067 gram (0.55mmol) 4-Dimethylamino pyridine, 10.0 milliliter toluene joins in 50 milliliters the there-necked flask, drip 0.286 gram (2.20mmol) propionic anhydride and 10.0 milliliters of toluene solutions under 5 ℃ of agitation conditions, drip and finish, be heated to 50 ℃, TLC follow the tracks of to detect that (developping agent is ethyl acetate/petroleum ether=1:1), reacted 3 hours, cooling, filter, filtrate steaming removal solvent, residue adds 20 milliliters of tetrahydrofuran (THF)s it is dissolved, obtain lysate, in lysate, add 0.27 gram column chromatography silica gel (300～400 order column chromatography silica gel), behind the mixing, steaming desolventizes, get dry residue and the mixture of silica gel, mixture is adorned post, be 1:12～0 (1:12 then with the volume ratio, 1:8,1:4,1:2,1:1, ethyl acetate 1:0), the sherwood oil mixing solutions is eluent, and gradient elution is collected the flow point of ethyl acetate, collection liquid concentrates, drying obtains 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-propionamido quinazoline (I-2) faint yellow solid 0.17 gram, yield 63.9%, 112～114 ℃ of fusing points.
1H?NMR(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]
+calcd?for?C
25H
32ClN
6O
2:483.2270,found:483.2273。
Embodiment 15:4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-preparation of 6-isobutyryl amido quinazoline (I-3)
Successively with 0.235 gram (0.55mmol) 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-amido quinazoline (V), 0.20 gram (1.65mmol) N, the N-xylidene(s), 10.0 the milliliter methylene dichloride joins in 50 milliliters the there-necked flask, drip 0.087 gram (0.55mmol) isobutyric anhydride and 10.0 milliliters of dichloromethane solutions under-10 ℃ of agitation conditions, drip and finish, TLC follow the tracks of to detect that (developping agent is ethyl acetate/petroleum ether=1:1), reaction is 11 hours under 0 ℃ of condition, filter, filtrate steaming removal solvent, residue adds 20 ml methanol it is dissolved, obtain lysate, in lysate, add 0.30 gram column chromatography silica gel (300～400 order column chromatography silica gel), behind the mixing, steaming desolventizes, get dry residue and the mixture of silica gel, mixture is adorned post, be 1:12～0 (1:12 then with the volume ratio, 1:8,1:4,1:2,1:1, ethyl acetate 1:0), the sherwood oil mixing solutions is eluent, gradient elution, collect the flow point of ethyl acetate/petroleum ether (1:4), collect liquid and concentrate, drying obtains 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-isobutyryl amido quinazoline (I-3) yellow solid 0.17 gram, yield 62.1%, 116～118 ℃ of fusing points.
1H?NMR(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]
+calcd?for?C
26H
34ClN
6O
2:497.2426,found:497.2433。
Embodiment 16:4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-preparation of 6-isobutyryl amido quinazoline (I-3)
Successively with 0.235 gram (0.55mmol) 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-amido quinazoline (V), 0.058 gram (0.55mmol) yellow soda ash, 10.0 the milliliter acetonitrile joins in 50 milliliters the there-necked flask, drip 0.696 gram (4.40mmol) isobutyric anhydride and 10.0 milliliters of acetonitrile solutions under-5 ℃ of agitation conditions, drip and finish, be heated to 50 ℃, TLC follow the tracks of to detect that (developping agent is ethyl acetate/petroleum ether=1:1), reacted 4 hours, cooling, filter, filtrate steaming removal solvent, residue adds 20 milliliters of methylene dichloride it is dissolved, obtain lysate, in lysate, add 0.60 gram column chromatography silica gel (300～400 order column chromatography silica gel), behind the mixing, steaming desolventizes, get dry residue and the mixture of silica gel, mixture is adorned post, be 1:12～0 (1:12 then with the volume ratio, 1:8,1:4,1:2,1:1, ethyl acetate 1:0), the sherwood oil mixing solutions is eluent, and gradient elution is collected the flow point of ethyl acetate, collection liquid concentrates, drying obtains 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-isobutyryl amido quinazoline (I-3) yellow solid 0.21 gram, yield 76.8%, 116～118 ℃ of fusing points.
1H?NMR(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]
+calcd?for?C
26H
34ClN
6O
2:497.2426,found:497.2433。
Embodiment 17: the antitumour activity vitro test
The compound (I-1), (I-2), (I-3) and (IV) that make among the embodiment are carried out people's lung cancer and human breast carcinoma biological activity test.The DDP(cis-platinum) medicine in contrast, cis-platinum is the chemicals commonly used of cancer therapy, has higher curative effect.
Testing method: tetrazolium reduction method (mtt assay).
Cell strain: human lung carcinoma cell line A-549 and human breast cancer cell strain MCF-7.Above-mentioned tumor cell line is available 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 dissolves with 40 μ L DMSO, gets 2uL and dilutes with 1000 μ L nutrient solutions, and making concentration is 50 μ g/mL, uses the nutrient solution serial dilution to working concentration again.
(2) cultivation of cell
1) culture medium preparation: contain 800,000 unit penicillin in per 1000 milliliters of substratum, 1.0 gram Streptomycin sulphates, 10% inactivated fetal bovine serum.
2) cultivation of cell: tumor cell inoculation in substratum, is put 37 ℃, 5%CO
2Cultivate in the incubator, 3～5d goes down to posterity.
3) working sample is to the restraining effect of growth of tumour cell
Cell is digested with EDTA-trysinization liquid, and be diluted to 1 * 10 with substratum
6/ milliliter is added in the 96 porocyte culture plates, and every hole 100uL puts 37 ℃, 5%CO
2Cultivate in the incubator.Behind the inoculation 24h, add the sample with the substratum dilution, every hole 100 μ L, each concentration adds 3 holes, puts 37 ℃, 5%CO
2Cultivate in the incubator, add the MTT of 5mg/mL behind the 72h in the cell cultures hole, every hole 10 μ L put 37 ℃ and hatch 3h, add DMSO, every hole 150 μ L, and with the vibrator vibration, Shi Jia Za dissolves fully, with microplate reader colorimetric under the 570nm wavelength.With similarity condition with not containing sample, contain same concentration DMSO culture medium culturing 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-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-substituted formyl amino-quinazoline compound, it has following general structure (I):
In the general structure (I), R is isobutoxy, ethyl or sec.-propyl.
2.4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-the 6-nitro-quinazoline, its structure is suc as formula shown in (IV):
3.4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-the 6-amido quinazoline, its structure is shown in formula V:
4. a 4-[3-chloro-4-as claimed in claim 1 (2-dipropyl glycyl amino) anilino]-preparation method of 6-substituted formyl amino-quinazoline compound, it is characterized in that described preparation method comprises:
(1) the 4-chloro-6-nitro-quinazoline shown in (the 2-chloro-4-aminophenyl) ethanamide of the 2-dipropyl amino-N-shown in the formula II and the formula III reacts under the effect of basic catalyst B1 in organic solvent A 1 and makes the 4-[3-chloro-4-shown in the formula IV (2-dipropyl glycyl amino) anilino]-the 6-nitro-quinazoline; It is one of following that described basic catalyst B1 is selected from: pyridine, diethylamine, triethylamine, quinoline, N, N-xylidene(s), 4-Dimethylamino pyridine, 4-pyrrolidyl pyridine or yellow soda ash; It is one of following that described organic solvent A 1 is selected from: chloroform, toluene, methyl alcohol, ethanol, propyl alcohol, Virahol, acetonitrile or N, dinethylformamide;
(2) the 4-[3-chloro-4-shown in the formula IV (2-dipropyl glycyl amino) anilino]-the 6-nitro-quinazoline in organic solvent A 2 under reductive agent B2 effect reaction make the 4-[3-chloro-4-shown in the formula (V) (2-dipropyl glycyl amino) anilino]-the 6-amido quinazoline; 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) the 4-[3-chloro-4-shown in the formula (V) (2-dipropyl glycyl amino) anilino]-6-amido quinazoline and isobutyl chlorocarbonate, propionic anhydride or isobutyric anhydride in organic solvent A 3 under basic catalyst B3 effect reaction make the 4-[3-chloro-4-shown in the formula I (2-dipropyl glycyl amino) anilino]-6-substituted formyl amino-quinazoline compound; Described basic catalyst B3 is one of following: pyridine, diethylamine, triethylamine, quinoline, N, N-xylidene(s), 4-Dimethylamino pyridine, 4-pyrrolidyl pyridine or yellow soda ash; Described organic solvent A 3 is one of following: tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate, ether, acetonitrile, toluene or benzene;
In the described formula I, R is isobutoxy, ethyl or sec.-propyl.
5. 4-[3-chloro-4-as claimed in claim 4 (2-dipropyl glycyl amino) anilino]-preparation method of 6-substituted formyl amino-quinazoline compound, it is characterized in that: step (1) is described to be reflected under 25～120 ℃ the temperature condition and to carry out.
6. 4-[3-chloro-4-as claimed in claim 4 (2-dipropyl glycyl amino) anilino]-preparation method of 6-substituted formyl amino-quinazoline compound, it is characterized in that: step (2) is described to be reflected under 25～100 ℃ the temperature condition and to carry out.
7. 4-[3-chloro-4-as claimed in claim 4 (2-dipropyl glycyl amino) anilino]-preparation method of 6-substituted formyl amino-quinazoline compound, it is characterized in that: carry out under the temperature condition of step (3) described being reflected at-10～50 ℃.
8. 4-[3-chloro-4-as claimed in claim 4 (2-dipropyl glycyl amino) anilino]-preparation method of 6-substituted formyl amino-quinazoline compound, it is characterized in that: in the described step (1), the molar ratio of 4-chloro-6-nitro-quinazoline (III), 2-dipropyl amino-N-(2-chloro-4-aminophenyl) ethanamide (II), basic catalyst B1 is 1.0 ﹕, 0.8～1.2 ﹕ 1.0～8.0; In the described step (2), described reductive agent B2 is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino wherein]-iron powder among 6-nitro-quinazoline (IV) and the 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, when perhaps described reductive agent B2 is palladium carbon/ammonium formiate or palladium carbon/hydrazine hydrate, 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino wherein]-palladium carbon among 6-nitro-quinazoline (IV) and the 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 the described step (3), 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-molar ratio of 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. 4-[3-chloro-4-as claimed in claim 8 (2-dipropyl glycyl amino) anilino]-preparation method of 6-substituted formyl amino-quinazoline compound, it is characterized in that described preparation method carries out according to following:
(1) with the 4-chloro-6-nitro-quinazoline shown in (the 2-chloro-4-aminophenyl) ethanamide of the 2-dipropyl amino-N-shown in the formula II and the formula III, in organic solvent A 1, under the effect of basic catalyst B1, react in 25～120 ℃, standing over night after reaction finishes, filtration, drying obtain the 4-[3-chloro-4-shown in the formula IV (2-dipropyl glycyl amino) anilino]-the 6-nitro-quinazoline;
(2) with the 4-[3-chloro-4-shown in the formula IV (2-dipropyl glycyl amino) anilino]-6-nitro-quinazoline, reductive agent B2 add in the organic solvent A 2, in 25～100 ℃ of fully reactions down, filter, filtrate concentrating separated out solid, filter, drying obtains the 4-[3-chloro-4-shown in the formula (V) (2-dipropyl glycyl amino) anilino]-the 6-amido quinazoline;
(3) with the 4-[3-chloro-4-shown in the formula (V) (2-dipropyl glycyl amino) anilino]-6-amido quinazoline, basic catalyst B3 add in the organic solvent A 3, under-10～10 ℃ of conditions, drip organic solvent A 3 solution of isobutyl chlorocarbonate or propionic anhydride or isobutyric anhydride, drip and finish,-10～50 ℃ were reacted 3～12 hours, filter, filtrate steaming removal solvent, residue column chromatography obtain corresponding 4-[3-chloro-4-(2-dipropyl glycyl amino) anilino]-6-substituted formyl amino-quinazoline compound (I).
10. 4-[3-chloro-4-as claimed in claim 1 (2-dipropyl glycyl amino) anilino]-application of 6-substituted formyl amino-quinazoline compound in the medicine of preparation prevention or treatment people's lung cancer or human breast carcinoma disease.
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|---|---|---|---|---|
| CN104876882A (en) * | 2015-05-13 | 2015-09-02 | 浙江工业大学 | 6-aminoquinazoline compound and application thereof |
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| CN109251196A (en) * | 2018-01-24 | 2019-01-22 | 浙江工业大学 | Amino benzo [d] azepine * base quinazoline compounds and its preparation method 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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| CN108329299B (en) * | 2018-01-24 | 2020-08-21 | 浙江工业大学 | Butyrylamino chloro benzo [ d ] aza-based quinazoline compound, preparation 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 |
| CN114276302A (en) * | 2022-01-11 | 2022-04-05 | 山东百启生物医药有限公司 | Method for preparing 2, 4-diamino quinazoline derivative |
| 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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