CN103254143B - 4-[4-(2-diethylin kharophen) anilino]-6-substituted quinazoline compounds and Synthesis and applications - Google Patents
4-[4-(2-diethylin kharophen) anilino]-6-substituted quinazoline compounds and Synthesis and applications Download PDFInfo
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Abstract
The invention discloses a kind of 4-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds and Synthesis and applications thereof, described compound has having structure and leads to formula I, in general structure (I), R is sec.-propyl or cyclohexyl.4-of the present invention [4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds 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-[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 formamido group quinazoline and preparation method thereof, and described two 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-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds 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-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds, it has having structure and leads to formula I:
In general structure (I), R is sec.-propyl or cyclohexyl.
Present invention also offers the intermediate that two kinds are prepared described 4-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds, namely the 4-of structure as shown in formula IV [4-(2-diethylin kharophen) anilino]-6-nitro-quinazoline and structure are such as formula 4-[4-(2-diethylin kharophen) the anilino]-6-amido quinazoline shown in (V):
The invention provides a kind of preparation method of described 4-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds, described preparation method comprises:
(1) the chloro-6-nitro-quinazoline of 2-diethylin-N-(4-aminophenyl) 4-shown in ethanamide and formula III shown in formula II reacts obtained 4-[4-(2-diethylin kharophen) 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-[4-(2-diethylin kharophen) the anilino]-6-nitro-quinazoline shown in formula IV reacts obtained 4-[4-(2-diethylin kharophen) 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-[4-(2-diethylin kharophen) the anilino]-6-amido quinazoline shown in formula (V) and isobutyl chlorocarbonate or chloroformic acid cyclohexylmethyl react obtained 4-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds 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 sec.-propyl or cyclohexyl.
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 the chloro-6-nitro-quinazoline of described 4-, 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 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-diethylin-N-(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-[4-(2-diethylin kharophen) 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-[4-(2-diethylin kharophen) 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-[4-(2-diethylin kharophen) 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-[4-(2-diethylin kharophen) 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-[4-(2-diethylin kharophen) 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-[4-(2-diethylin kharophen) 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.Described 4-[4-(2-diethylin kharophen) anilino]-6-amido quinazoline (V), isobutyl chlorocarbonate or chloroformic acid cyclohexylmethyl, the molar ratio of basic catalyst B3 are 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-[4-(2-diethylin kharophen) 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-[4-(2-diethylin kharophen) 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 chloroformic acid cyclohexylmethyl, drip and finish,-10 ~ 50 DEG C are reacted 3 ~ 12 hours, filter, filtrate steaming removal solvent, residue column chromatography obtains corresponding 4-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds (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-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) the formamido group quinazoline compounds of dry acquisition shown in formula I.Described organic solvent C is one of following: ethanol, chloroform, tetrahydrofuran (THF) or ethyl acetate.
4-of the present invention [4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds (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 disease.Compound provided by the invention has good inhibiting rate to human lung cancer cell lines A-549 or MCF-7 cell strainHJ2mm.4-[4-(2-diethylin kharophen) 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 16.9 μMs and 7.83 μMs.4-[4-(2-diethylin kharophen) anilino]-6-cyclohexyl methoxy formamido group quinazoline (I-2) is to the IC of human lung cancer cell lines A-549 and MCF-7 cell strainHJ2mm
50be respectively 5.38 μMs and 4.18 μMs.
Beneficial effect of the present invention is mainly reflected in: the antitumour activity that (1) 4-of the present invention [4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds (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 [4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds (I), simple easy handling, raw material is easy to get, and production cost is lower, be 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-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.2006,128,15972-15973) method prepare
The preparation of embodiment 1:2-diethylin-N-(4-aminophenyl) ethanamide (II)
(1) successively by chloro-for compound 2-N-(4-nitrophenyl) ethanamide 5.00 grams (23.30mmol), dehydrated alcohol 30.0 milliliters, diethylamine 4.50 grams (61.53mmol), join in 100 milliliters of there-necked flasks, be heated to 50 DEG C of reaction 20h, by reaction solution evaporate to dryness, acetic acid ethyl dissolution also washs with water, organic phase anhydrous magnesium sulfate drying, concentrate and obtain 2.95 grams of faint yellow product 2-(diethylin)-N-(4-nitrophenyl) ethanamides, yield 50.4%.IR(film):v=3205,2968,1694cm
-1。
(2) successively by compound 2-(diethylin)-N-(4-nitrophenyl) ethanamide 2.80 grams (11.14mmol), anhydrous methanol 30.0 milliliters, ammonium formiate 4.20 grams (66.60mmol), 5%Pd/C0.28 gram joins in 100 milliliters of there-necked flasks, be heated to 50 DEG C of reaction 4h, by reaction solution evaporate to dryness, acetic acid ethyl dissolution also washs with water, organic phase anhydrous magnesium sulfate drying, concentrate and obtain 2.15 grams of brown product 2-diethylin-N-(4-aminophenyl) ethanamides (II), yield 87.2%.IR(film):v=3334,2968,1663cm
-1。
The preparation of embodiment 2:4-[4-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (IV)
Successively by 1.20 grams of chloro-6-nitro-quinazolines (III) of (5.73mmol) 4-and 1.52 grams of (6.87mmol) 2-diethylin-N-(4-aminophenyl) 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 degree, 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-[4-(2-diethylin kharophen) the anilino]-6-nitro-quinazoline yellow solid 1.89 grams shown in formula IV, yield 83.7%, fusing point 235 ~ 238 DEG C.
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。
The preparation of embodiment 3:4-[4-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (IV)
Successively by 1.20 grams of chloro-6-nitro-quinazolines (III) of (5.73mmol) 4-and 1.01 grams of (4.56mmol) 2-diethylin-N-(4-aminophenyl) 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 degree, 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-[4-(2-diethylin kharophen) the anilino]-6-nitro-quinazoline yellow solid 1.22 grams shown in formula IV, yield 67.8%, fusing point 235 ~ 238 DEG C.
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。
The preparation of embodiment 4:4-[4-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (IV)
Successively by 1.20 grams of chloro-6-nitro-quinazolines (III) of (5.73mmol) 4-and 1.27 grams of (5.74mmol) 2-diethylin-N-(4-aminophenyl) 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 degree, 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-[4-(2-diethylin kharophen) the anilino]-6-nitro-quinazoline yellow solid 1.65 grams shown in formula IV, yield 73.1%, fusing point 235 ~ 238 DEG C.
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。
The preparation of embodiment 5:4-[4-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (IV)
Successively by 1.20 grams of chloro-6-nitro-quinazolines (III) of (5.73mmol) 4-and 1.40 grams of (6.33mmol) 2-diethylin-N-(4-aminophenyl) 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 degree 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-[4-(2-diethylin kharophen) the anilino]-6-nitro-quinazoline yellow solid 1.75 grams shown in formula IV, yield 77.5%, fusing point 235 ~ 238 DEG C.
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。
The preparation of embodiment 6:4-[4-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (IV)
Successively by 1.20 grams of chloro-6-nitro-quinazolines (III) of (5.73mmol) 4-and 1.14 grams of (5.15mmol) 2-diethylin-N-(4-aminophenyl) 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 degree, 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-[4-(2-diethylin kharophen) the anilino]-6-nitro-quinazoline yellow solid 1.05 grams shown in formula IV, yield 51.7%, fusing point 235 ~ 238 DEG C.
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。
The preparation of embodiment 7:4-[4-(2-diethylin kharophen) anilino]-6-amido quinazoline (V)
Successively by 0.40 gram of (1.01mmol) 4-[4-(2-diethylin kharophen) 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 degree 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-[4-(2-diethylin kharophen) the anilino]-6-amido quinazoline shown in 0.20 gram of formula (V), yield 54.1%.IR(KBr):v=3328,3215,2969,2926,2879,2861,1670,1632,1605,1576,1514,937,836,788,653cm
-1。
The preparation of embodiment 8:4-[4-(2-diethylin kharophen) anilino]-6-amido quinazoline (V)
Successively by 0.40 gram of (1.01mmol) 4-[4-(2-diethylin kharophen) 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 degree, 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-[4-(2-diethylin kharophen) the anilino]-6-amido quinazoline shown in 0.25 gram of formula (V), yield 67.6%.IR(KBr):v=3328,3215,2969,2926,2879,2861,1670,1632,1605,1576,1514,937,836,788,653cm
-1。
The preparation of embodiment 9:4-[4-(2-diethylin kharophen) anilino]-6-amido quinazoline (V)
Successively by 0.40 gram of (1.01mmol) 4-[4-(2-diethylin kharophen) 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 degree, 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-[4-(2-diethylin kharophen) the anilino]-6-amido quinazoline shown in 0.16 gram of formula (V), yield 43.3%.IR(KBr):v=3328,3215,2969,2926,2879,2861,1670,1632,1605,1576,1514,937,836,788,653cm
-1。
The preparation of embodiment 10:4-[4-(2-diethylin kharophen) anilino]-6-amido quinazoline (V)
Successively by 0.40 gram of (1.01mmol) 4-[4-(2-diethylin kharophen) 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 degree, 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-[4-(2-diethylin kharophen) the anilino]-6-amido quinazoline shown in 0.17 gram of formula (V), yield 46.0%.IR(KBr):v=3328,3215,2969,2926,2879,2861,1670,1632,1605,1576,1514,937,836,788,653cm
-1。
The preparation of embodiment 11:4-[4-(2-diethylin kharophen) anilino]-6-isobutoxy formamido group quinazoline (I-1)
Successively by 0.20 gram of (0.55mmol) 4-[4-(2-diethylin kharophen) 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 5.0 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, 0.40 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-[4-(2-diethylin kharophen) the anilino]-6-isobutoxy formamido group quinazoline faint yellow solid 0.11 gram shown in formula (I-1), yield 43.1%, fusing point 179 ~ 181 DEG C.
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。
The preparation of embodiment 12:4-[4-(2-diethylin kharophen) anilino]-6-isobutoxy formamido group quinazoline (I-1)
Successively by 0.20 gram of (0.55mmol) 4-[4-(2-diethylin kharophen) 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 5.0 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, 0.20 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-[4-(2-diethylin kharophen) the anilino]-6-isobutoxy formamido group quinazoline faint yellow solid 0.08 gram shown in formula (I-1), yield 31.4%, fusing point 179 ~ 181 DEG C.
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。
The preparation of embodiment 13:4-[4-(2-diethylin kharophen) anilino]-6-cyclohexyl methoxy formamido group quinazoline (I-2)
Successively by 0.20 gram of (0.55mmol) 4-[4-(2-diethylin kharophen) 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, 0.19 gram of (1.08mmol) chloroformic acid cyclohexylmethyl and 5.0 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, 0.20 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-[4-(2-diethylin kharophen) the anilino]-6-cyclohexyl methoxy formamido group quinazoline faint yellow solid 0.09 gram shown in formula (I-2), yield 32.5%, fusing point 216 ~ 218 DEG C.
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。
The preparation of embodiment 14:4-[4-(2-diethylin kharophen) anilino]-6-cyclohexyl methoxy formamido group quinazoline (I-2)
Successively by 0.20 gram of (0.55mmol) 4-[4-(2-diethylin kharophen) 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, 0.39 gram of (2.21mmol) chloroformic acid cyclohexylmethyl and 5.0 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, filter, filtrate steaming removal solvent, residue adds 20 milliliters of tetrahydrofuran (THF)s and is dissolved, obtain lysate, 0.40 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-[4-(2-diethylin kharophen) the anilino]-6-cyclohexyl methoxy formamido group quinazoline faint yellow solid 0.13 gram shown in formula (I-2), yield 46.9%, fusing point 216 ~ 218 DEG C.
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: 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) 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 L DMSO 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 1000mL substratum, 1.0g Streptomycin sulphate, 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/ mL, 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-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds, it has having structure and leads to formula I:
In general structure (I), R is sec.-propyl or cyclohexyl.
2.4-[4-(2-diethylin kharophen) anilino]-6-nitro-quinazoline, its structure is as shown in formula IV:
3.4-[4-(2-diethylin kharophen) anilino]-6-amido quinazoline, its structure is such as formula shown in (V):
4. a preparation method for 4-as claimed in claim 1 [4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds, is characterized in that described preparation method comprises:
(1) the chloro-6-nitro-quinazoline of 2-diethylin-N-(4-aminophenyl) 4-shown in ethanamide and formula III shown in formula II reacts obtained 4-[4-(2-diethylin kharophen) 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-[4-(2-diethylin kharophen) the anilino]-6-nitro-quinazoline shown in formula IV reacts obtained 4-[4-(2-diethylin kharophen) 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-[4-(2-diethylin kharophen) the anilino]-6-amido quinazoline shown in formula (V) and isobutyl chlorocarbonate or chloroformic acid cyclohexylmethyl react obtained 4-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds 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 sec.-propyl or cyclohexyl.
5. the preparation method of 4-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds 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-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds 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-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds 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-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds as claimed in claim 4, it is characterized in that: in described step (1), the molar ratio of the chloro-6-nitro-quinazoline of described 4-, 2-diethylin-N-(4-aminophenyl) ethanamide, 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, 4-[4-(2-diethylin kharophen) 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 is palladium carbon/ammonium formiate or palladium carbon/hydrazine hydrate, 4-[4-(2-diethylin kharophen) 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-[4-(2-diethylin kharophen) anilino]-6-amido quinazoline (V), isobutyl chlorocarbonate or chloroformic acid cyclohexylmethyl, basic catalyst B3 is 1 ﹕ 1.0 ~ 8.0 ﹕ 1.0 ~ 3.0.
9. the preparation method of 4-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds 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-diethylin-N-(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-[4-(2-diethylin kharophen) the anilino]-6-nitro-quinazoline shown in formula IV;
(2) 4-[4-(2-diethylin kharophen) 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-[4-(2-diethylin kharophen) the anilino]-6-amido quinazoline shown in formula (V);
(3) 4-[4-(2-diethylin kharophen) 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 chloroformic acid cyclohexylmethyl, drip and finish,-10 ~ 50 DEG C are reacted 3 ~ 12 hours, filter, filtrate steaming removal solvent, residue column chromatography obtains corresponding 4-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds (I).
10. 4-[4-(2-diethylin kharophen) anilino]-6-(methoxyl group displacement) formamido group quinazoline compounds 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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