CN103254143A - 4-[4-(2-diethylamino acetamido)phenylamino]-6-(substituted methoxyl)formylamino quinazoline compound as well as preparation method and application thereof - Google Patents
4-[4-(2-diethylamino acetamido)phenylamino]-6-(substituted methoxyl)formylamino quinazoline compound as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a 4-[4-(2-diethylamino acetamido)phenylamino]-6-(substituted methoxyl)formylamino quinazoline compound as well as a preparation method and application thereof. The compound has a structural general formula shown in the specification, wherein R is isopropyl or cyclohexyl in the structural general formula (I). The 4-[4-(2-diethylamino acetamido)phenylamino]-6-(substituted methoxyl)formylamino quinazoline compound disclosed by the invention can be used for preparing drugs for preventing or treating human lung cancer or breast cancer and has favorable anticancer activity.
Description
(1) technical field
The present invention relates to 4-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds---4-[4-(2-diethylin kharophen) anilino]-6-isobutoxy formamido group quinazoline and 4-[4-(2-diethylin kharophen) anilino]-6-cyclohexyl methoxy methyl amido quinazoline and preparation method thereof, and the application of described two 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-[4-(2-diethylin kharophen) anilino with antitumour activity]-6-(methoxyl group displacement) formamido group quinazoline compounds 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-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds, it has following general structure (I):
In the general structure (I), R is sec.-propyl or cyclohexyl.
The present invention also provides two kinds and has prepared described 4-[4-(2-diethylin kharophen) anilino]-intermediate of 6-(methoxyl group displacement) formamido group quinazoline compounds, i.e. 4-[4-(the 2-diethylin kharophen) anilino of structure shown in formula IV]-6-nitro-quinazoline and structure be suc as formula the 4-[4-shown in (V) (2-diethylin kharophen) anilino]-the 6-amido quinazoline:
The invention provides a kind of described 4-[4-(2-diethylin kharophen) anilino]-preparation method of 6-(methoxyl group displacement) formamido group quinazoline compounds, described preparation method comprises:
(1) the 4-chloro-6-nitro-quinazoline shown in (4-aminophenyl) ethanamide of the 2-diethylin-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-[4-shown in the formula IV (2-diethylin kharophen) 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) 4-[4-shown in the formula IV (2-diethylin kharophen) anilino]-the 6-nitro-quinazoline in organic solvent A 2 under reductive agent B2 effect reaction make the 4-[4-shown in the formula (V) (2-diethylin kharophen) 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) 4-[4-shown in the formula (V) (2-diethylin kharophen) anilino]-6-amido quinazoline and isobutyl chlorocarbonate or chloroformic acid cyclohexyl methyl esters in organic solvent A 3 under basic catalyst B3 effect reaction make the 4-[4-shown in the formula I (2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds; 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 sec.-propyl or cyclohexyl.
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, 2-diethylin-N-(4-aminophenyl) ethanamide, 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 (4-aminophenyl) ethanamide of the 2-diethylin-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-[4-shown in the formula IV (2-diethylin kharophen) 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-[4-(2-diethylin kharophen) 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-[4-(2-diethylin kharophen) 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-[4-(2-diethylin kharophen) 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-[4-shown in the formula IV (2-diethylin kharophen) 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-[4-shown in the formula (V) (2-diethylin kharophen) 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-[4-(2-diethylin kharophen) anilino]-molar ratio of 6-amido quinazoline (V), isobutyl chlorocarbonate or chloroformic acid cyclohexyl methyl esters, basic catalyst B3 is 1 ﹕, 1.0～8.0 ﹕ 1.0～3.0, the consumption of described organic solvent A 3 is with 4-[4-(2-diethylin kharophen) 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-[4-shown in the formula (V) (2-diethylin kharophen) 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 chloroformic acid cyclohexyl methyl esters, drip and finish,-10～50 ℃ were reacted 3～12 hours, filter, filtrate steaming removal solvent, residue column chromatography obtain corresponding 4-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds (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-[4-(the 2-diethylin kharophen) anilino shown in the formula I]-6-(methoxyl group displacement) formamido group quinazoline compounds.Described organic solvent C is one of following: ethanol, chloroform, tetrahydrofuran (THF) or ethyl acetate.
4-[4-of the present invention (2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds (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 disease.Compound provided by the invention has inhibiting rate preferably to human lung carcinoma cell line A-549 or human breast cancer cell strain MCF-7.4-[4-(2-diethylin kharophen) 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 16.9 μ M and 7.83 μ M.4-[4-(2-diethylin kharophen) anilino]-6-cyclohexyl methoxy methyl amido quinazoline (I-2) is to the IC of human lung carcinoma cell line A-549 and human breast cancer cell strain MCF-7
50Be respectively 5.38 μ M and 4.18 μ M.
Beneficial effect of the present invention is mainly reflected in: (1) 4-[4-of the present invention (2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds (I) has good antitumour activity, is expected to be applied to prepare in the medicine of prevention or treatment tumor disease; (2) 4-[4-of the present invention provided by the invention (2-diethylin kharophen) anilino]-preparation method of 6-(methoxyl group displacement) formamido group quinazoline compounds (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-diethylin-N-(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-diethylin-N-(4-aminophenyl) ethanamide (II)
(1) successively with compound 2-chloro-N-(4-nitrophenyl) ethanamide 5.00 gram (23.30mmol), 30.0 milliliters of dehydrated alcohols, diethylamine 4.50 grams (61.53mmol), join in 100 milliliters of there-necked flasks, be heated to 50 ℃ of reaction 20h, with the reaction solution evaporate to dryness, acetic acid ethyl dissolution and water wash, the organic phase anhydrous magnesium sulfate drying concentrates and obtains 2.95 gram faint yellow product 2-(diethylin)-N-(4-nitrophenyl) ethanamides, yield 50.4%.IR(film):v=3205,2968,1694cm
-1。
(2) successively with compound 2-(diethylin)-N-(4-nitrophenyl) ethanamide 2.80 grams (11.14mmol), 30.0 milliliters of anhydrous methanols, ammonium formiate 4.20 grams (66.60mmol), the 5%Pd/C0.28 gram joins in 100 milliliters of there-necked flasks, is heated to 50 ℃ of reaction 4h, with the reaction solution evaporate to dryness, acetic acid ethyl dissolution and water wash, the organic phase anhydrous magnesium sulfate drying concentrates and obtains 2.15 gram brown product 2-diethylin-N-(4-aminophenyl) ethanamides (II), yield 87.2%.IR(film):v=3334,2968,1663cm
-1。
Embodiment 2:4-[4-(2-diethylin kharophen) anilino]-preparation of 6-nitro-quinazoline (IV)
Successively with 1.20 gram (5.73mmol) 4-chloro-6-nitro-quinazolines (III) and 1.52 gram (6.87mmol) 2-diethylin-N-(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 degree, 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-[4-shown in the formula IV (2-diethylin kharophen) anilino]-6-nitro-quinazoline yellow solid 1.89 grams, yield 83.7%, 235～238 ℃ of fusing points.
1H?NMR(500MHz,[D6]DMSO):δ=1.05(t,J=7.1Hz,6H),2.63(q,J=7.1Hz,4H),3.17(s,2H),7.70-7.71(m,2H),7.77(d,J=9.0Hz,2H),7.93(d,J=9.2Hz,1H),8.56(dd,J=2.4,9.2Hz,1H),8.69(s,1H),9.67(d,J=2.5Hz,1H),9.69(s,1H),10.45ppm(s,1H);IR(KBr):v=3308,3209,2971,2938,1661,1628,1604,675cm
-1。
Embodiment 3:4-[4-(2-diethylin kharophen) anilino]-preparation of 6-nitro-quinazoline (IV)
Successively with 1.20 gram (5.73mmol) 4-chloro-6-nitro-quinazolines (III) and 1.01 gram (4.56mmol) 2-diethylin-N-(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 degree, 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-[4-shown in the formula IV (2-diethylin kharophen) anilino]-6-nitro-quinazoline yellow solid 1.22 grams, yield 67.8%, 235～238 ℃ of fusing points.
1H?NMR(500MHz,[D6]DMSO):δ=1.05(t,J=7.1Hz,6H),2.63(q,J=7.1Hz,4H),3.17(s,2H),7.70-7.71(m,2H),7.77(d,J=9.0Hz,2H),7.93(d,J=9.2Hz,1H),8.56(dd,J=2.4,9.2Hz,1H),8.69(s,1H),9.67(d,J=2.5Hz,1H),9.69(s,1H),10.45ppm(s,1H);IR(KBr):v=3308,3209,2971,2938,1661,1628,1604,675cm
-1。
Embodiment 4:4-[4-(2-diethylin kharophen) anilino]-preparation of 6-nitro-quinazoline (IV)
Successively with 1.20 gram (5.73mmol) 4-chloro-6-nitro-quinazolines (III) and 1.27 gram (5.74mmol) 2-diethylin-N-(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 degree, 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-[4-shown in the formula IV (2-diethylin kharophen) anilino]-6-nitro-quinazoline yellow solid 1.65 grams, yield 73.1%, 235～238 ℃ of fusing points.
1H?NMR(500MHz,[D6]DMSO):δ=1.05(t,J=7.1Hz,6H),2.63(q,J=7.1Hz,4H),3.17(s,2H),7.70-7.71(m,2H),7.77(d,J=9.0Hz,2H),7.93(d,J=9.2Hz,1H),8.56(dd,J=2.4,9.2Hz,1H),8.69(s,1H),9.67(d,J=2.5Hz,1H),9.69(s,1H),10.45ppm(s,1H);IR(KBr):v=3308,3209,2971,2938,1661,1628,1604,675cm
-1。
Embodiment 5:4-[4-(2-diethylin kharophen) anilino]-preparation of 6-nitro-quinazoline (IV)
Successively with 1.20 gram (5.73mmol) 4-chloro-6-nitro-quinazolines (III) and 1.40 gram (6.33mmol) 2-diethylin-N-(4-aminophenyl) ethanamides (II), 1.40 gram (11.46mmol) 4-Dimethylamino pyridine, 60 milliliters of Virahols add in 100 milliliters the there-necked flask, room temperature 25 degree stir, 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-[4-shown in the formula IV (2-diethylin kharophen) anilino]-6-nitro-quinazoline yellow solid 1.75 grams, yield 77.5%, 235～238 ℃ of fusing points.
1H?NMR(500MHz,[D6]DMSO):δ=1.05(t,J=7.1Hz,6H),2.63(q,J=7.1Hz,4H),3.17(s,2H),7.70-7.71(m,2H),7.77(d,J=9.0Hz,2H),7.93(d,J=9.2Hz,1H),8.56(dd,J=2.4,9.2Hz,1H),8.69(s,1H),9.67(d,J=2.5Hz,1H),9.69(s,1H),10.45ppm(s,1H);IR(KBr):v=3308,3209,2971,2938,1661,1628,1604,675cm
-1。
Embodiment 6:4-[4-(2-diethylin kharophen) anilino]-preparation of 6-nitro-quinazoline (IV)
Successively with 1.20 gram (5.73mmol) 4-chloro-6-nitro-quinazolines (III) and 1.14 gram (5.15mmol) 2-diethylin-N-(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 degree, 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-[4-shown in the formula IV (2-diethylin kharophen) anilino]-6-nitro-quinazoline yellow solid 1.05 grams, yield 51.7%, 235～238 ℃ of fusing points.
1H?NMR(500MHz,[D6]DMSO):δ=1.05(t,J=7.1Hz,6H),2.63(q,J=7.1Hz,4H),3.17(s,2H),7.70-7.71(m,2H),7.77(d,J=9.0Hz,2H),7.93(d,J=9.2Hz,1H),8.56(dd,J=2.4,9.2Hz,1H),8.69(s,1H),9.67(d,J=2.5Hz,1H),9.69(s,1H),10.45ppm(s,1H);IR(KBr):v=3308,3209,2971,2938,1661,1628,1604,675cm
-1。HRMS(ESI):m/z:[M+H]
+calcd?for?C
20H
23N
6O
3:395.1826,found:395.1826。
Embodiment 7:4-[4-(2-diethylin kharophen) anilino]-preparation of 6-amido quinazoline (V)
Successively with 0.40 gram (1.01mmol) 4-[4-(2-diethylin kharophen) 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, room temperature 25 degree stir, 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-[4-shown in the 0.20 gram formula (V) (2-diethylin kharophen) anilino]-the 6-amido quinazoline, yield 54.1%.IR(KBr):v=3328,3215,2969,2926,2879,2861,1670,1632,1605,1576,1514,937,836,788,653cm
-1。
Embodiment 8:4-[4-(2-diethylin kharophen) anilino]-preparation of 6-amido quinazoline (V)
Successively with 0.40 gram (1.01mmol) 4-[4-(2-diethylin kharophen) 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 degree, 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-[4-shown in the 0.25 gram formula (V) (2-diethylin kharophen) anilino]-the 6-amido quinazoline, yield 67.6%.IR(KBr):v=3328,3215,2969,2926,2879,2861,1670,1632,1605,1576,1514,937,836,788,653cm
-1。
Embodiment 9:4-[4-(2-diethylin kharophen) anilino]-preparation of 6-amido quinazoline (V)
Successively with 0.40 gram (1.01mmol) 4-[4-(2-diethylin kharophen) 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 degree, 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-[4-shown in the 0.16 gram formula (V) (2-diethylin kharophen) anilino]-the 6-amido quinazoline, yield 43.3%.IR(KBr):v=3328,3215,2969,2926,2879,2861,1670,1632,1605,1576,1514,937,836,788,653cm
-1。
Embodiment 10:4-[4-(2-diethylin kharophen) anilino]-preparation of 6-amido quinazoline (V)
Successively with 0.40 gram (1.01mmol) 4-[4-(2-diethylin kharophen) 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 degree, 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-[4-shown in the 0.17 gram formula (V) (2-diethylin kharophen) anilino]-the 6-amido quinazoline, yield 46.0%.IR(KBr):v=3328,3215,2969,2926,2879,2861,1670,1632,1605,1576,1514,937,836,788,653cm
-1。
Embodiment 11:4-[4-(2-diethylin kharophen) anilino]-preparation of 6-isobutoxy formamido group quinazoline (I-1)
Successively with 0.20 gram (0.55mmol) 4-[4-(2-diethylin kharophen) 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 5.0 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 0.40 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 the 4-[4-shown in the formula (I-1) (2-diethylin kharophen) anilino]-6-isobutoxy formamido group quinazoline faint yellow solid 0.11 gram, yield 43.1%, 179～181 ℃ of fusing points.
1H?NMR(500MHz,[D6]DMSO):δ=0.97(d,J=6.7Hz,6H),1.05(t,J=7.1Hz,6H),1.93-2.01(m,1H),2.62(q,J=7.1Hz,4H),3.16(s,2H),3.95(d,J=6.6Hz,2H),7.64(d,J=9.0Hz,2H),7.71-7.77(m,4H),8.46(s,1H),8.53(s,1H),9.62(s,1H),9.72(s,1H),9.92ppm(s,1H);IR(KBr):v=3303,2966,2932,1705,1678,1632,1609,648cm
-1；HRMS(ESI):m/z:[M+H]
+calcd?for?C
25H
33N
6O
3:465.2609,found:465.2610。
Embodiment 12:4-[4-(2-diethylin kharophen) anilino]-preparation of 6-isobutoxy formamido group quinazoline (I-1)
Successively with 0.20 gram (0.55mmol) 4-[4-(2-diethylin kharophen) 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 5.0 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 0.20 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 the 4-[4-shown in the formula (I-1) (2-diethylin kharophen) anilino]-6-isobutoxy formamido group quinazoline faint yellow solid 0.08 gram, yield 31.4%, 179～181 ℃ of fusing points.
1H?NMR(500MHz,[D6]DMSO):δ=0.97(d,J=6.7Hz,6H),1.05(t,J=7.1Hz,6H),1.93-2.01(m,1H),2.62(q,J=7.1Hz,4H),3.16(s,2H),3.95(d,J=6.6Hz,2H),7.64(d,J=9.0Hz,2H),7.71-7.77(m,4H),8.46(s,1H),8.53(s,1H),9.62(s,1H),9.72(s,1H),9.92ppm(s,1H);IR(KBr):v=3303,2966,2932,1705,1678,1632,1609,648cm
-1；HRMS(ESI):m/z:[M+H]
+calcd?for?C
25H
33N
6O
3:465.2609,found:465.2610。
Embodiment 13:4-[4-(2-diethylin kharophen) anilino]-preparation of 6-cyclohexyl methoxy methyl amido quinazoline (I-2)
Successively with 0.20 gram (0.55mmol) 4-[4-(2-diethylin kharophen) 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 0.19 gram (1.08mmol) chloroformic acid cyclohexyl methyl esters and 5.0 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 0.20 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 the 4-[4-shown in the formula (I-2) (2-diethylin kharophen) anilino]-6-cyclohexyl methoxy methyl amido quinazoline faint yellow solid 0.09 gram, yield 32.5%, 216～218 ℃ of fusing points.
1H?NMR(500MHz,[D6]DMSO):δ=1.05(t,J=7.1Hz,8H),1.17-1.26(m,3H),1.67-1.78(m,6H),2.62(q,J=7.1Hz,4H),3.16(s,2H),3.97(d,J=6.6Hz,2H),7.64(d,J=9.0Hz,2H),7.71-7.74(m,4H),8.46(s,1H),8.52(s,1H),9.62(s,1H),9.72(s,1H),9.91ppm(s,1H);IR(KBr):v=3428,3284,2970,2924,1725,1677,1635,1615,648cm
-1；HRMS(ESI):m/z:[M+H]
+calcd?for?C
28H
37N
6O
3:505.2922,found:505.2927。
Embodiment 14:4-[4-(2-diethylin kharophen) anilino]-preparation of 6-cyclohexyl methoxy methyl amido quinazoline (I-2)
Successively with 0.20 gram (0.55mmol) 4-[4-(2-diethylin kharophen) 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 0.39 gram (2.21mmol) chloroformic acid cyclohexyl methyl esters and 5.0 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, filter, filtrate steaming removal solvent, residue adds 20 milliliters of tetrahydrofuran (THF)s it is dissolved, obtain lysate, in lysate, add 0.40 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, collect liquid and concentrate, drying obtains the 4-[4-shown in the formula (I-2) (2-diethylin kharophen) anilino]-6-cyclohexyl methoxy methyl amido quinazoline faint yellow solid 0.13 gram, yield 46.9%, 216～218 ℃ of fusing points.
1H?NMR(500MHz,[D6]DMSO):δ=1.05(t,J=7.1Hz,8H),1.17-1.26(m,3H),1.67-1.78(m,6H),2.62(q,J=7.1Hz,4H),3.16(s,2H),3.97(d,J=6.6Hz,2H),7.64(d,J=9.0Hz,2H),7.71-7.74(m,4H),8.46(s,1H),8.52(s,1H),9.62(s,1H),9.72(s,1H),9.91ppm(s,1H);IR(KBr):v=3428,3284,2970,2924,1725,1677,1635,1615,648cm
-1；HRMS(ESI):m/z:[M+H]
+calcd?for?C
28H
37N
6O
3:505.2922,found:505.2927。
Embodiment 15: the antitumour activity vitro test
The compound (I-1), (I-2) 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, 1.0g Streptomycin sulphate, 10% inactivated fetal bovine serum in every 1000mL substratum.
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/ mL 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. a 4-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds, it has following general structure (I):
In the general structure (I), R is sec.-propyl or cyclohexyl.
(2.4-[4-2-diethylin kharophen) anilino]-the 6-nitro-quinazoline, its structure is shown in formula IV:
(3.4-[4-2-diethylin kharophen) anilino]-the 6-amido quinazoline, its structure is suc as formula shown in (V):
4. a 4-[4-as claimed in claim 1 (2-diethylin kharophen) anilino]-preparation method of 6-(methoxyl group displacement) formamido group quinazoline compounds, it is characterized in that described preparation method comprises:
(1) the 4-chloro-6-nitro-quinazoline shown in (4-aminophenyl) ethanamide of the 2-diethylin-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-[4-shown in the formula IV (2-diethylin kharophen) 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) 4-[4-shown in the formula IV (2-diethylin kharophen) anilino]-the 6-nitro-quinazoline in organic solvent A 2 under reductive agent B2 effect reaction make the 4-[4-shown in the formula (V) (2-diethylin kharophen) 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) 4-[4-shown in the formula (V) (2-diethylin kharophen) anilino]-6-amido quinazoline and isobutyl chlorocarbonate or chloroformic acid cyclohexyl methyl esters in organic solvent A 3 under basic catalyst B3 effect reaction make the 4-[4-shown in the formula I (2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds; 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 sec.-propyl or cyclohexyl.
5. 4-[4-as claimed in claim 4 (2-diethylin kharophen) anilino]-preparation method of 6-(methoxyl group displacement) formamido group quinazoline compounds, it is characterized in that described being reflected under 25～120 ℃ the temperature condition of step (1) carry out.
6. 4-[4-as claimed in claim 4 (2-diethylin kharophen) anilino]-preparation method of 6-(methoxyl group displacement) formamido group quinazoline compounds, it is characterized in that described being reflected under 25～100 ℃ the temperature condition of step (2) carry out.
7. 4-[4-as claimed in claim 4 (2-diethylin kharophen) anilino]-preparation method of 6-(methoxyl group displacement) formamido group quinazoline compounds, it is characterized in that carrying out under the temperature condition of step (3) described being reflected at-10～50 ℃.
8. 4-[4-as claimed in claim 4 (2-diethylin kharophen) anilino]-preparation method of 6-(methoxyl group displacement) formamido group quinazoline compounds, it is characterized in that: in the described step (1), the molar ratio of described 4-chloro-6-nitro-quinazoline, 2-diethylin-N-(4-aminophenyl) ethanamide, 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-[4-(2-diethylin kharophen) anilino]-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, perhaps described reductive agent B2 is palladium carbon/ammonium formiate or palladium carbon/hydrazine hydrate, 4-[4-(2-diethylin kharophen) anilino]-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-[4-(2-diethylin kharophen) anilino]-molar ratio of 6-amido quinazoline (V), isobutyl chlorocarbonate or chloroformic acid cyclohexyl methyl esters, basic catalyst B3 is 1 ﹕, 1.0～8.0 ﹕ 1.0～3.0.
9. 4-[4-as claimed in claim 8 (2-diethylin kharophen) anilino]-preparation method of 6-(methoxyl group displacement) formamido group quinazoline compounds, it is characterized in that described preparation method carries out according to following:
(1) with the 4-chloro-6-nitro-quinazoline shown in (4-aminophenyl) ethanamide of the 2-diethylin-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-[4-shown in the formula IV (2-diethylin kharophen) anilino]-the 6-nitro-quinazoline;
(2) with the 4-[4-shown in the formula IV (2-diethylin kharophen) 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-[4-shown in the formula (V) (2-diethylin kharophen) anilino]-the 6-amido quinazoline;
(3) with the 4-[4-shown in the formula (V) (2-diethylin kharophen) 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 chloroformic acid cyclohexyl methyl esters, drip and finish,-10～50 ℃ were reacted 3～12 hours, filter, filtrate steaming removal solvent, residue column chromatography obtain corresponding 4-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds (I).
10. 4-[4-as claimed in claim 1 (2-diethylin kharophen) anilino]-application of 6-(methoxyl group displacement) formamido group quinazoline compounds in the medicine of preparation prevention or treatment people's lung cancer or human breast carcinoma disease.
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| CN106349160A (en) * | 2016-08-05 | 2017-01-25 | 浙江工业大学 | 8-aminoquinoline derivative and preparation and application thereof |
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| CN1492860A (en) * | 2001-02-21 | 2004-04-28 | ������ҩ��ʽ���� | Quinazoline derivatives |
| US20080004297A1 (en) * | 2003-07-03 | 2008-01-03 | Myriad Genetics, Inc. | Compounds and therapeutical use thereof |
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| CN1492860A (en) * | 2001-02-21 | 2004-04-28 | ������ҩ��ʽ���� | Quinazoline derivatives |
| US20080004297A1 (en) * | 2003-07-03 | 2008-01-03 | Myriad Genetics, Inc. | Compounds and therapeutical use thereof |
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| CN104876882A (en) * | 2015-05-13 | 2015-09-02 | 浙江工业大学 | 6-aminoquinazoline compound and application thereof |
| CN104876882B (en) * | 2015-05-13 | 2018-05-08 | 浙江工业大学 | 6- amino-quinazoline compounds and application |
| CN106349160A (en) * | 2016-08-05 | 2017-01-25 | 浙江工业大学 | 8-aminoquinoline derivative and preparation and application thereof |
| CN106349160B (en) * | 2016-08-05 | 2019-07-26 | 浙江工业大学 | A kind of 8-aminoquinoline derivatives and its preparation and application |
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