CN104876882A - 6-aminoquinazoline compound and application thereof - Google Patents
6-aminoquinazoline compound and application thereof Download PDFInfo
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- CN104876882A CN104876882A CN201510243810.4A CN201510243810A CN104876882A CN 104876882 A CN104876882 A CN 104876882A CN 201510243810 A CN201510243810 A CN 201510243810A CN 104876882 A CN104876882 A CN 104876882A
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- 0 *N(*)CC(Nc1cc(Nc(c2c3)ncnc2ccc3[N+]([O-])=O)ccc1)=O Chemical compound *N(*)CC(Nc1cc(Nc(c2c3)ncnc2ccc3[N+]([O-])=O)ccc1)=O 0.000 description 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
Abstract
The invention discloses a 6-aminoquinazoline compound shown in a formula (I-a) and an application thereof in preparation method of medicines for preventing or treating a human lung cancer or human breast cancer. The preparation method of the compound disclosed by the invention is simple and easy to operate, available in raw material, and relatively low in production cost, and has good anti-tumor activity. The formula (I-a) is as shown in the description, wherein R1 is ethyl and propyl; and R3 and R1 are the same in structure.
Description
(1) technical field
The present invention relates to a kind of quinazoline compounds and application thereof, particularly 6-amino-quinazoline compound and the application in the medicine preparing prevention or treatment 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 being used for the treatment of the lapatinibditosylate (Lapatinib) 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, ChemMedChem 2013,8,136-148; A.Garofalo, A.Farce, S.Ravez, A.Lemoine, P.Six, P.Chavatte, L.Goossens, P.Depreux, J.Med.Chem.2012,55,1189-1204).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 quinazoline quinoline compounds-6-amino-quinazoline compound and the application with antitumour activity, 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 6-amino-quinazoline compound shown in a kind of formula (I-a),
In formula (I-a), R
1for ethyl or propyl group, R
3with R
1structure is identical.
The present invention also provides a kind of intermediate for the preparation of compound formula (I-a) Suo Shi,
In formula (I-b), R
1for ethyl or propyl group, R
3with R
1structure is identical.
The invention provides compound shown in a kind of formula (I-a) and prepare the application in compound shown in formula I,
In formula I, R
1for ethyl or propyl group, R
3with R
1structure is identical; R
2for RCONH, wherein R is C1-C3 alkyl or phenyl.
The invention still further relates to the application of compound shown in a kind of formula (I-a) in preparation prevention or treatment people's lung cancer or human breast carcinoma medicine, described people's lung cancer is human lung cancer cell lines A-549, and described human breast carcinoma is MCF-7 cell strainHJ2mm.
Further, 4-[3-(2-disubstituted amido kharophen) the anilino]-6-substituting group quinazoline compounds shown in formula I is preferably one of following:
Further, described 4-[3-(2-disubstituted amido kharophen) anilino]-6-substituting group quinazoline compounds (I) is preferably one of following:
The invention provides the preparation method of a kind of described 4-[3-(2-disubstituted amido kharophen) anilino]-6-substituting group quinazoline compounds, described method for: (1) is by compound shown in compound and formula III shown in formula II, under the effect of basic catalyst B1, in organic solvent A 1, 25 ~ 120 DEG C are carried out reacting (TLC tracking monitor, developping agent is ethyl acetate/petroleum ether=1:1 (v/v), preferably 40 ~ 100 DEG C of reaction 0.5 ~ 12h), after reacting completely, by reacting liquid filtering, filtrate concentrates, dry (preferably 40 DEG C of vacuum-dryings), obtain compound shown in formula (I-b), described basic catalyst B1 is selected from one of following: pyridine, diethylamine, triethylamine, quinoline, N, N-xylidene(s), DMAP, 4-pyrollidinopyridine or sodium carbonate (preferred pyridine, diethylamine, triethylamine, N, N-xylidene(s) or DMAP), described organic solvent A 1 is selected from one of following: chloroform, toluene, methyl alcohol, ethanol, propyl alcohol, Virahol, acetonitrile or DMF, the ratio of the amount of substance that feeds intake of compound shown in compound with formula II, basic catalyst B1 shown in described formula III 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 compound shown in formula III,
In formula II, R
1for ethyl or propyl group, R
3with R
1structure is identical;
In formula (I-b), R
1for ethyl or propyl group, R
3with R
1structure is identical; R in formula (I-b)
1with R in formula II
1identical, R in formula (I-b)
3with R in formula II
3identical;
(2) compound shown in formula (I-b) is under reductive agent B2 effect, in organic solvent A 2, at 25 ~ 100 DEG C of (TLC tracking monitor that react completely, developping agent is ethyl acetate/petroleum ether=1:1 (v/v), preferably 40 ~ 80 DEG C of reaction 0.5 ~ 12h), reacting liquid filtering, the enriched material drying (preferably 25 DEG C of dryings) after filtrate reduced in volume, obtained compound shown in formula (I-a); 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 DMF; When described reductive agent B2 be iron powder/concentrated hydrochloric acid or iron powder/acetic acid time, the mass ratio that feeds intake of the compound shown in formula (I-b) and iron powder, concentrated hydrochloric acid or acetic acid in 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, the mass ratio that feeds intake of the compound shown in formula (I-b) and palladium carbon, ammonium formiate or hydrazine hydrate in reductive agent B2 is 1.0 ﹕ 0.1 ~ 0.5 ﹕ 1.0 ~ 3.0; The consumption of described organic solvent A 2 counts 10 ~ 50mL/g with the quality of the compound shown in formula (I-b); Described iron powder/concentrated hydrochloric acid, iron powder/acetic acid refers to mixing of iron powder and concentrated hydrochloric acid or acetic acid, and wherein concentrated hydrochloric acid mass concentration is 36% ~ 38%; Described palladium carbon/ammonium formiate or palladium carbon/hydrazine hydrate refer to the mixture of palladium carbon and ammonium formiate or hydrazine hydrate, and wherein in palladium carbon, the mass loading amount of palladium is 5%, and hydrazine hydrate mass concentration is 80%;
In formula (I-a), R
1for ethyl or propyl group, R
3with R
1structure is identical;
(3) compound formula (I-a) Suo Shi is mixed with acid anhydrides or acyl chlorides, under basic catalyst B3 effect, in organic solvent A 3,-10 ~ 50 DEG C of (TLC tracking monitor that react completely, developping agent is ethyl acetate/petroleum ether=1:1 (v/v), preferably-10 ~ 50 DEG C of reaction 3 ~ 12h), reaction solution separation and purification, obtained compound shown in formula I; 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; Described acid anhydrides or acyl chlorides are one of following: diacetyl oxide, Acetyl Chloride 98Min., isobutyric anhydride, isobutyryl chloride, benzoyl oxide, Benzoyl chloride, propionic anhydride, propionyl chloride, butyryl oxide or n-butyryl chloride; The ratio of the amount of substance that feeds intake of compound shown in described formula (I-a) and acid anhydrides or acyl chlorides, basic catalyst B3 is 1 ﹕ 1.0 ~ 8.0 ﹕ 1.0 ~ 3.0, and the consumption of described organic solvent A 3 counts 10 ~ 95mL/g with the quality of compound formula (I-a) Suo Shi.
The concrete recommendation step of the present invention (3) is carried out as follows: compound formula (I-a) Suo Shi, basic catalyst B3 added in organic solvent A 3 and (also can not add organic solvent A 3), under-10 ~ 10 DEG C of conditions, drip organic solvent A 3 solution of acid anhydrides or organic solvent A 3 solution of acyl chlorides, drip and finish,-10 ~ 50 DEG C are reacted 3 ~ 12 hours, filter, filtrate steaming removal solvent, enriched material column chromatography obtains compound shown in formula I; Dissolve the organic solvent volume consumption of acid anhydrides or acyl chlorides to the present invention's no impact, the consumption of described organic solvent A 3 counts 10 ~ 95mL/g with the quality of compound formula (I-a) Suo Shi, and organic solvent A 3 refers to the organic solvent of compound shown in catalyst-solvent and formula (I-a) and the cumulative volume dissolving acid anhydrides or acyl chlorides organic solvent.
Further, the method of the described reaction solution separation and purification of step of the present invention (3) is: after reacting completely, by reacting liquid filtering, filtrate steaming removal solvent, get enriched material organic solvent D to be dissolved, obtain lysate, then in lysate, add the column chromatography silica gel of enriched material 1.0 ~ 2.0 times of weight, after mixing, steaming desolventizes, dry, obtain the mixture of enriched material and silica gel, mixture is filled post, then be sherwood oil and the ethyl acetate mixture of 1:0.1 ~ 10 with volume ratio be eluent, collect containing target components effluent liquid (preferably with ethyl acetate/petroleum ether=1:1 (v/v) for developping agent tracing detection, collect target components), concentrating under reduced pressure, dry (preferably 50 DEG C of dryings), obtain the compound shown in formula I, described organic solvent D is one of following: ethanol, chloroform, tetrahydrofuran (THF) or ethyl acetate.
The invention still further relates to the application of 4-shown in formula I [3-(2-disubstituted amido kharophen) anilino]-6-substituting group quinazoline compounds in preparation prevention or tumor, the application being particularly useful for making prevention or treating in people's lung cancer or human breast carcinoma medicine.Compound provided by the invention has good inhibiting rate to human lung cancer cell lines A-549 or MCF-7 cell strainHJ2mm.4-[3-(2-diethylin kharophen) anilino]-6-kharophen quinazoline (I-1) IC to MCF-7 cell strainHJ2mm
50be respectively 62.71 μMs.4-[3-(2-diethylin kharophen) anilino]-6-benzamido quinazoline (I-3) IC to human lung cancer cell lines A-549
50it is 31.69 μMs.4-[3-(2-dipropyl aminoacetylamino) anilino]-6-kharophen quinazoline (I-6) is to the IC of human lung cancer cell lines A-549 and MCF-7 cell strainHJ2mm
50be respectively 40.30 μMs and 64.24 μMs.
Organic solvent A 1 of the present invention, A2, A3 and D are organic solvent, and name for the ease of distinguishing different step organic solvent difference used, letter itself does not have implication; Described catalyst B 1, reductive agent B2 and catalyst B 3 are catalyzer, and name for the ease of distinguishing different step used catalyst difference, letter itself does not have implication.
Beneficial effect of the present invention is mainly reflected in: the antitumour activity that shown in (1) formula of the present invention (I-a), 6-amino-quinazoline compound has had, and is expected to be applied in the medicine of preparation prevention or treatment tumor disease; 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (I-a2) is to the IC of human lung cancer cell lines A-549 and MCF-7 cell strainHJ2mm
50be respectively 30.10 μMs and 17.11 μMs; (2) 6-amino-quinazoline compound shown in formula provided by the invention (I-a) is for the preparation of the simple easy handling of method of 4-[3-(2-disubstituted amido kharophen) anilino]-6-substituting group quinazoline compounds (I), 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.
2-disubstituted amido-N-(3-aminophenyl) ethanamide (II) prepares reference literature (Lombardo, C.M.; Welsh, S.J.; Strauss, S.J.; Dale, A.G.; Todd, A.K.; Nanjunda, R.; Wilson, W.D.; Neidle, S., Bioorg.Med.Chem.Lett.2012,22 (18), 5984-5988; Fosdick, L.S.; Rapp, G.W.J.Am.Chem.Soc.1943,65,2307-2308) method prepare.The chloro-6-nitro-quinazoline (III) of 4-prepare reference literature (Fernandes, C.; Oliveira, C.; Gano, L.; Bourkoula, A.; Pirmettis, I.; Santos, I.Bioorg.Med.Chem.2007,15,3974-3980) method prepare.
The preparation of embodiment 1:4-[3-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (I-b1)
Successively by 1.20 grams of chloro-6-nitro-quinazolines (III) of (5.73mmol) 4-and 1.52 grams of (6.87mmol) 2-diethylins-N-(3-aminophenyl) ethanamide (II-1), 3.62 grams of (45.76mmol) pyridines, 12 milliliters of chloroforms add in the reaction flask of 50 milliliters, be heated to 40 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), stirring reaction 10 hours, off-response, filter, filtrate concentrates, 40 DEG C of vacuum-dryings, obtain yellow oil product 4-[3-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (I-b1), yield 87.3%.
The preparation of embodiment 2:4-[3-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (I-b1)
Successively by 1.20 grams of chloro-6-nitro-quinazolines (III) of (5.73mmol) 4-and 1.01 grams of (4.56mmol) 2-diethylins-N-(3-aminophenyl) ethanamide (II-1), 1.67 grams of (22.83mmol) diethylamine, 60 milliliters of toluene add in the there-necked flask of 100 milliliters, be heated to 100 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), stirring reaction 2 hours, off-response, filter, filtrate concentrates, 40 DEG C of vacuum-dryings obtain yellow oil product 4-[3-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (I-b1), yield 62.4%.
The preparation of embodiment 3:4-[3-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (I-b1)
Successively by 1.20 grams of chloro-6-nitro-quinazolines (III) of (5.73mmol) 4-and 1.27 grams of (5.74mmol) 2-diethylins-N-(3-aminophenyl) ethanamide (II-1), 0.58 gram of (5.73mmol) triethylamine, 60 ml methanol add in the there-necked flask of 100 milliliters, be heated to 60 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), stirring reaction 8 hours, off-response, filter, filtrate concentrates, 40 DEG C of vacuum-dryings obtain yellow oil product 4-[3-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (I-b1), yield 72.5%.
The preparation of embodiment 4:4-[3-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (I-b1)
Successively by 1.20 grams of chloro-6-nitro-quinazolines (III) of (5.73mmol) 4-and 1.40 grams of (6.33mmol) 2-diethylins-N-(3-aminophenyl) ethanamide (II-1), 1.40 grams of (11.46mmol) DMAPs, 60 milliliters of Virahols add in the there-necked flask of 100 milliliters, room temperature 25 DEG C stirring, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), react 12 hours, off-response, filter, filtrate concentrates, 40 DEG C of vacuum-dryings obtain yellow oil product 4-[3-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (I-b1), yield 76.8%.
The preparation of embodiment 5:4-[3-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (I-b1)
Successively by 1.20 grams of chloro-6-nitro-quinazolines (III) of (5.73mmol) 4-and 1.14 grams of (5.15mmol) 2-diethylins-N-(3-aminophenyl) ethanamide (II-1), 1.04 grams of (8.58mmol) N, N-xylidene(s), 12 milliliters of N, dinethylformamide adds in the reaction flask of 50 milliliters, be heated to 120 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), stirring reaction 0.5 hour, off-response, filter, filtrate concentrates, 40 DEG C of vacuum-dryings obtain yellow oil product 4-[3-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (I-b1), yield 50.6%.
The preparation of embodiment 6:4-[3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (I-b2)
Successively by 1.20 grams of chloro-6-nitro-quinazolines (III) of (5.73mmol) 4-and 1.71 grams of (6.86mmol) 2-dipropyls amino-N-(3-aminophenyl) ethanamide (II-2), 3.62 grams of (45.76mmol) pyridines, 12 milliliters of chloroforms add in the reaction flask of 50 milliliters, be heated to 40 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), stirring reaction 10 hours, off-response, filter, filtrate concentrates, 40 DEG C of vacuum-dryings obtain yellow oil product 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (I-b2), yield 84.2%.
The preparation of embodiment 7:4-[3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (I-b2)
Successively by 1.20 grams of chloro-6-nitro-quinazolines (III) of (5.73mmol) 4-and 1.14 grams of (4.57mmol) 2-dipropyls amino-N-(3-aminophenyl) ethanamide (II-2), 1.67 grams of (22.83mmol) diethylamine, 60 milliliters of toluene add in the there-necked flask of 100 milliliters, be heated to 100 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), stirring reaction 2 hours, off-response, filter, filtrate concentrates, 40 DEG C of vacuum-dryings obtain yellow oil product 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (I-b2), yield 73.4%.
The preparation of embodiment 8:4-[3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (I-b2)
Successively by 1.20 grams of chloro-6-nitro-quinazolines (III) of (5.73mmol) 4-and 1.43 grams of (5.73mmol) 2-dipropyls amino-N-(3-aminophenyl) ethanamide (II-2), 0.58 gram of (5.73mmol) triethylamine, 60 ml methanol add in the there-necked flask of 100 milliliters, be heated to 60 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), stirring reaction 8 hours, off-response, filter, filtrate concentrates, 40 DEG C of vacuum-dryings obtain yellow oil product 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (I-b2), yield 81.7%.
The preparation of embodiment 9:4-[3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (I-b2)
Successively by 1.20 grams of chloro-6-nitro-quinazolines (III) of (5.73mmol) 4-and 1.57 grams of (6.30mmol) 2-dipropyls amino-N-(3-aminophenyl) ethanamide (II-2), 1.40 grams of (11.46mmol) DMAPs, 60 milliliters of Virahols add in the there-necked flask of 100 milliliters, room temperature 25 DEG C stirring, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), react 12 hours, off-response, filter, filtrate concentrates, 40 DEG C of vacuum-dryings obtain yellow oil product 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (I-b2), yield 73.5%.
The preparation of embodiment 10:4-[3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (I-b2)
Successively by 1.20 grams of chloro-6-nitro-quinazolines (III) of (5.73mmol) 4-and 1.29 grams of (5.17mmol) 2-dipropyls amino-N-(3-aminophenyl) ethanamide (II-2), 1.04 grams of (8.58mmol) N, N-xylidene(s), 12 milliliters of N, dinethylformamide adds in the reaction flask of 50 milliliters, be heated to 120 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), stirring reaction 0.5 hour, off-response, filter, filtrate concentrates, 40 DEG C of vacuum-dryings obtain yellow oil product 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (I-b2), yield 66.3%.
The preparation of embodiment 11:4-[3-(2-diethylin kharophen) anilino]-6-amido quinazoline (I-a1)
Successively by 0.40 gram of (1.01mmol) 4-[3-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (I-b1), 0.40 gram of (6.34mmol) ammonium formiate, 0.04 gram of 5%Pd/C (Pd mass loading amount is 5%), 4.0 milliliters of chloroforms join in reaction flask, room temperature 25 DEG C stirring, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), react 12 hours, filter, filtrate concentrates, 25 DEG C of vacuum-dryings, obtain brown oil product 4-[3-(2-diethylin kharophen) anilino]-6-amido quinazoline (I-a1), yield 79.2%.
The preparation of embodiment 12:4-[3-(2-diethylin kharophen) anilino]-6-amido quinazoline (I-a1)
Successively by 0.40 gram of (1.01mmol) 4-[3-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (I-b1), 1.20 grams (19.18mmol) 80% hydrazine hydrate, 0.20 gram of 5%Pd/C, 20.0 milliliters of toluene join in the reaction flask of 50 milliliters, be heated to 100 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), stirring reaction 0.5 hour, cold filtration, filtrate concentrates, 25 DEG C of vacuum-dryings obtain brown oil product 4-[3-(2-diethylin kharophen) anilino]-6-amido quinazoline (I-a1), yield 65.7%.
The preparation of embodiment 13:4-[3-(2-diethylin kharophen) anilino]-6-amido quinazoline (I-13)
Successively by 0.40 gram of (1.01mmol) 4-[3-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (I-11), 0.08 gram of concentrated hydrochloric acid (mass concentration 36% ~ 38%), 0.40 gram of iron powder, 20.0 ml methanol join in the reaction flask of 50 milliliters, be heated to 40 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), stirring reaction 8 hours, cold filtration, filtrate concentrates, 25 DEG C of vacuum-dryings obtain brown oil product 4-[3-(2-diethylin kharophen) anilino]-6-amido quinazoline (I-a1), yield 44.6%.
The preparation of embodiment 14:4-[3-(2-diethylin kharophen) anilino]-6-amido quinazoline (I-a1)
Successively by 0.40 gram of (1.01mmol) 4-[3-(2-diethylin kharophen) anilino]-6-nitro-quinazoline (I-11), 0.40 gram of acetic acid, 1.20 gram iron powder, 20.0 milliliters of Virahols join in the reaction flask of 50 milliliters, be heated to 80 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), stirring reaction 3 hours, cold filtration, filtrate concentrates, 25 DEG C of vacuum-dryings obtain brown oil product 4-[3-(2-diethylin kharophen) anilino]-6-amido quinazoline (I-a1), yield 76.0%.
The preparation of embodiment 15:4-[3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (I-a2)
Successively by 0.40 gram of (0.95mmol) 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (I-b2), 0.40 gram of (6.34mmol) ammonium formiate, 0.04 gram of 5%Pd/C, 4.0 milliliters of chloroforms join in reaction flask, room temperature 25 DEG C stirring, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), react 12 hours, filter, filtrate concentrates, 25 DEG C of vacuum-dryings obtain brown solid product 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (I-a2), yield 73.2%, fusing point 84 ~ 85 DEG C.
1H NMR(500MHz,CDCl
3)δ:0.95(t,J＝7.3Hz,6H)；1.48-1.55(m,4H)；2.51(t,J＝7.8Hz,4H)；7.03(d,J＝2.4Hz,1H)；7.06-7.08(m,1H)；7.16(dd,J＝2.4,8.9Hz,1H)；7.27(s,1H)；7.32(t,J＝8.1Hz,1H)；7.66-7.69(m,2H)；8.24(t,J＝2.0Hz,1H)；8.57(s,1H)；9.51(s,1H)。
The preparation of embodiment 16:4-[3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (I-a2)
Successively by 0.40 gram of (0.95mmol) 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (I-b2), 1.20 grams of (19.18mmol) 80wt% hydrazine hydrates, 0.20 gram of 5%Pd/C, 20.0 milliliters of toluene join in the reaction flask of 50 milliliters, be heated to 100 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), stirring reaction 0.5 hour, cold filtration, filtrate concentrates, 25 DEG C of vacuum-dryings obtain brown solid product 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (I-a2), yield 70.5%, fusing point 84 ~ 85 DEG C.
1h NMR is with embodiment 15.
The preparation of embodiment 17:4-[3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (I-a2)
Successively by 0.40 gram of (0.95mmol) 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (I-b2), 0.08 gram of concentrated hydrochloric acid (mass concentration 36 ~ 38%), 0.40 gram of iron powder, 20.0 ml methanol join in the reaction flask of 50 milliliters, be heated to 40 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), stirring reaction 8 hours, cold filtration, filtrate concentrates, 25 DEG C of vacuum-dryings obtain brown solid product 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (I-a2), yield 64.4%, fusing point 84 ~ 85 DEG C.
1h NMR is with embodiment 15.
The preparation of embodiment 18:4-[3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (I-a2)
Successively by 0.40 gram of (0.95mmol) 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-nitro-quinazoline (I-b2), 0.40 gram of acetic acid, 1.20 gram iron powder, 20.0 milliliters of Virahols join in the reaction flask of 50 milliliters, be heated to 80 DEG C, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), stirring reaction 3 hours, cold filtration, filtrate concentrates, 25 DEG C of vacuum-dryings obtain brown solid product 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (I-a2), yield 67.3%, fusing point 84 ~ 85 DEG C.
1h NMR is with embodiment 15.
The preparation of embodiment 19:4-[3-(2-diethylin kharophen) anilino]-6-kharophen quinazoline (I-1)
Successively by 0.20 gram of (0.55mmol) 4-[3-(2-diethylin kharophen) anilino]-6-amido quinazoline (I-a1), 0.13 gram of (1.64mmol) pyridine, 2.0 milliliters of tetrahydrofuran (THF)s join in reaction flask, 0.449 gram of (4.40mmol) diacetyl oxide is 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, enriched material adds 10 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 enriched material and silica gel, mixture is filled post, then be the petrol ether/ethyl acetate mixing solutions of 1:10 with volume ratio be eluent, wash-out, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), the elutriant (Rf value is 0.5) collected containing the compound shown in formula (I-1) is detected according to TLC, collection liquid concentrates, 50 DEG C of dryings obtain 4-[3-(2-diethylin kharophen) the anilino]-6-kharophen quinazoline faint yellow solid shown in formula (I-1), yield 67.3%, fusing point 136 ~ 138 DEG C.
1H NMR(500MHz,DMSO)δ:0.89(t,J＝7.3Hz,6H)；1.44-1.52(m,4H)；2.14(s,3H)；2.51(t,J＝7.4Hz,4H)；3.19(s,2H)；7.30-7.36(m,2H)；7.57(d,J＝7.8Hz,1H)；7.75(d,J＝8.9Hz,1H)；7.85(dd,J＝1.8,7.9Hz,1H)；8.09(s,1H)；8.50(s,1H)；8.66(d,J＝1.3Hz,1H)；9.60(s,1H)；9.80(s,1H)；10.27(s,1H)。
The preparation of embodiment 20:4-[3-(2-diethylin kharophen) anilino]-6-isobutyryl amido quinazoline (I-2)
Successively by 0.20 gram of (0.55mmol) 4-[3-(2-diethylin kharophen) anilino]-6-amido quinazoline (I-a1), 0.04 gram of (0.55mmol) diethylamine, 10.0 milliliters of chloroforms join in the reaction flask of 50 milliliters, 0.087 gram of (0.55mmol) isobutyric anhydride and 5.0 milliliters of chloroform mixing solutionss are dripped under 10 DEG C of agitation conditions, drip and finish, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), react 8 hours under 10 DEG C of conditions, filter, filtrate steaming removal solvent, enriched material 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 enriched material and silica gel, mixture is filled post, then be the petrol ether/ethyl acetate mixing solutions of 1:5 with volume ratio be eluent, wash-out, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), the elutriant (Rf value is 0.4) collected containing the compound shown in formula (I-2) is detected according to TLC, collection liquid concentrates, 50 DEG C of dryings obtain 4-[3-(2-diethylin kharophen) the anilino]-6-isobutyryl amido quinazoline pale solid shown in formula (I-2), yield 73.4%, fusing point 144 ~ 145 DEG C.
1H NMR(500MHz,DMSO)δ:1.04(t,J＝7.1Hz,6H)；1.17(d,J＝6.8Hz,6H)；2.62(q,J＝7.1Hz,4H)；2.68(dd,J＝6.8,13.7Hz,1H)；3.17(s,2H)；7.30(t,J＝8.0Hz,1H)；7.36(d,J＝8.9Hz,1H)；7.59(d,J＝8.0Hz,1H)；7.75(d,J＝8.9Hz,1H)；7.85(dd,J＝2.2,9.0Hz,1H)；8.09(t,J＝2.0Hz,1H)；8.50(s,1H)；8.75(d,J＝2.2Hz,1H)；9.66(s,1H)；9.81(s,1H)；10.17(s,1H)。
The preparation of embodiment 21:4-[3-(2-diethylin kharophen) anilino]-6-benzamido quinazoline (I-3)
Successively by 0.20 gram of (0.55mmol) 4-[3-(2-diethylin kharophen) anilino]-6-amido quinazoline (I-a1), 0.11 gram of (1.09mmol) triethylamine, 10.0 milliliters of ethyl acetate join in the reaction flask of 50 milliliters, 0.249 gram of (1.10mmol) benzoyl oxide 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, enriched material 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 enriched material and silica gel, mixture is filled post, then be the petrol ether/ethyl acetate mixing solutions of 10:1 with volume ratio be eluent, wash-out, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), the elutriant (Rf value is 0.6) collected containing the compound shown in formula (I-3) is detected according to TLC, collection liquid concentrates, 50 DEG C of dryings obtain 4-[3-(2-diethylin kharophen) the anilino]-6-benzamido quinazoline pale solid shown in formula (I-3), yield 43.5%, fusing point 140 ~ 142 DEG C.
1H NMR(500MHz,DMSO)δ:1.04(t,J＝7.1Hz,6H)；2.62(q,J＝7.1Hz,4H)；3.18(s,2H)；7.28-7.40(m,2H)；7.55-7.68(m,4H)；7.82(d,J＝8.9Hz,1H)；7.99-8.09(m,3H)；8.12(t,J＝2.0Hz,1H)；8.55(s,1H)；8.92(d,J＝2.1Hz,1H)；9.67(s,1H)；9.86(s,1H)；10.61(s,1H)。
The preparation of embodiment 22:4-[3-(2-diethylin kharophen) anilino]-6-propionamido quinazoline (I-4)
Successively by 0.20 gram of (0.55mmol) 4-[3-(2-diethylin kharophen) anilino]-6-amido quinazoline (I-a1), 0.067 gram of (0.55mmol) DMAP, 15.0 milliliters of toluene join in the reaction flask of 50 milliliters, the solution of 0.286 gram of (2.20mmol) propionic anhydride and 4.0 milliliters of toluene is 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, enriched material 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 enriched material and silica gel, mixture is filled post, then be the petrol ether/ethyl acetate mixing solutions of 5:1 with volume ratio be eluent, wash-out, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), the elutriant (Rf value is 0.5) collected containing the compound shown in formula (I-4) is detected according to TLC, collection liquid concentrates, 50 DEG C of dryings obtain 4-[3-(2-diethylin kharophen) the anilino]-6-propionamido quinazoline pale solid shown in formula (I-4), yield 75.3%, fusing point 132 ~ 133 DEG C.
1H NMR(500MHz,DMSO)δ:1.04(t,J＝7.1Hz,6H)；1.15(t,J＝7.6Hz,3H)；2.42(q,J＝7.5Hz,2H)；2.61(q,J＝7.1Hz,4H)；3.17(s,2H)；7.31(t,J＝8.0Hz,1H)；7.37(d,J＝8.7Hz,1H)；7.59(d,J＝8.8Hz,1H)；7.76(d,J＝8.9Hz,1H)；7.85(dd,J＝2.1,9.0Hz,1H)；8.10(t,J＝1.9Hz,1H)；8.51(s,1H)；8.73(d,J＝1.9Hz,1H)；9.66(s,1H)；9.81(s,1H)；10.20(s,1H)。
The preparation of embodiment 23:4-[3-(2-diethylin kharophen) anilino]-6-butyrylamino quinazoline (I-5)
Successively by 0.20 gram of (0.55mmol) 4-[3-(2-diethylin kharophen) anilino]-6-amido quinazoline (I-a1), 0.067 gram of (0.55mmol) DMAP, 10.0 milliliters of benzene join in the reaction flask of 50 milliliters, the solution of 0.348 gram of (2.20mmol) butyryl oxide and 5.0 milliliters of benzene is 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, enriched material 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 enriched material and silica gel, mixture is filled post, then be the petrol ether/ethyl acetate mixing solutions of 1:1 with volume ratio be eluent, wash-out, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), the elutriant (Rf value is 0.4) collected containing the compound shown in formula (I-5) is detected according to TLC, collection liquid concentrates, 50 DEG C of dryings obtain 4-[3-(2-diethylin kharophen) the anilino]-6-butyrylamino quinazoline pale solid shown in formula (I-5), yield 72.1%, fusing point 128 ~ 130 DEG C.
1H NMR(500MHz,DMSO)δ:0.97(t,J＝7.4Hz,3H)；1.04(t,J＝7.1Hz,6H)；1.67(dt,J＝14.7,7.4Hz,2H)；2.38(t,J＝7.3Hz,2H)；2.63(q,J＝7.1Hz,4H)；3.18(s,2H)；7.27–7.40(m,2H)；7.58(d,J＝8.0Hz,1H)；7.75(d,J＝8.9Hz,1H)；7.85(dd,J＝9.0,2.1Hz,1H)；8.09(s,1H)；8.50(s,1H)；8.71(d,J＝1.9Hz,1H)；9.66(s,1H)；9.80(s,1H)；10.20(s,1H)。
The preparation of embodiment 24:4-[3-(2-dipropyl aminoacetylamino) anilino]-6-kharophen quinazoline (I-6)
Successively by 0.216 gram of (0.55mmol) 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (I-a2), 0.13 gram of (1.64mmol) pyridine, 2.2 milliliters of ether join in reaction flask, 0.345 gram of (4.39mmol) Acetyl Chloride 98Min. is dripped under-10 DEG C of agitation conditions, drip and finish, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), react 12 hours under-10 DEG C of conditions, filter, filtrate steaming removal solvent, enriched material adds 20 milliliters of ethyl acetate and is dissolved, obtain lysate, 0.54 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 enriched material and silica gel, mixture is filled post, then be the petrol ether/ethyl acetate mixing solutions of 1:1 with volume ratio be eluent, wash-out, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), the elutriant (Rf value is 0.6) collected containing the compound shown in formula (I-6) is detected according to TLC, collection liquid concentrates, 50 DEG C of dryings obtain 4-[3-(2-dipropyl aminoacetylamino) the anilino]-6-kharophen quinazoline faint yellow solid shown in formula (I-6), yield 67.3%, fusing point 136 ~ 138 DEG C.
1H NMR(500MHz,DMSO)δ:0.89(t,J＝7.3Hz,6H)；1.44-1.52(m,4H)；2.14(s,3H)；2.51(t,J＝7.4Hz,4H)；3.19(s,2H)；7.30-7.36(m,2H)；7.57(d,J＝7.8Hz,1H)；7.75(d,J＝8.9Hz,1H)；7.85(dd,J＝1.8,7.9Hz,1H)；8.09(s,1H)；8.50(s,1H)；8.66(d,J＝1.3Hz,1H)；9.60(s,1H)；9.80(s,1H)；10.27(s,1H)。
The preparation of embodiment 25:4-[3-(2-dipropyl aminoacetylamino) anilino]-6-benzamido quinazoline (I-7)
Successively by 0.216 gram of (0.55mmol) 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (I-a2), 0.04 gram of (0.55mmol) diethylamine, 15.0 milliliters of methylene dichloride join in the reaction flask of 50 milliliters, 0.077 gram of (0.55mmol) Benzoyl chloride and 5.0 milliliters of dichloromethane solutions are dripped under 10 DEG C of agitation conditions, drip and finish, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1), react 8 hours under 10 DEG C of conditions, filter, filtrate steaming removal solvent, enriched material adds 20 milliliters of ethanol and is dissolved, obtain lysate, 0.27 gram of column chromatography silica gel (300 ~ 400 order column chromatography silica gel) is added in lysate, after mixing, steaming desolventizes, obtain the mixture of dry enriched material and silica gel, mixture is filled post, then be the petrol ether/ethyl acetate mixing solutions of 10:1 with volume ratio be eluent, wash-out, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), the elutriant (Rf value is 0.5) collected containing the compound shown in formula (I-7) is detected according to TLC, collection liquid concentrates, 50 DEG C of dryings obtain 4-[3-(2-dipropyl aminoacetylamino) the anilino]-6-benzamido quinazoline pale solid shown in formula (I-7), yield 67.7%, fusing point 184 ~ 185 DEG C.
1H NMR(500MHz,DMSO)δ:0.90(t,J＝7.4Hz,6H)；1.46-1.50(m,4H)；2.50-2.52(m,4H)；3.19(s,2H)；7.31-7.37(m,2H)；7.57-7.66(m,4H)；7.82(d,J＝9.0Hz,1H)；8.03(dd,J＝2.2,9.0Hz,1H)；8.05-8.08(m,2H)；8.13(t,J＝2.0Hz,1H)；8.55(s,1H)；8.92(d,J＝7.2Hz,1H)；9.61(s,1H)；9.87(s,1H)；10.61(s,1H)。
The preparation of embodiment 26:4-[3-(2-dipropyl aminoacetylamino) anilino]-6-butyrylamino quinazoline (I-8)
Successively by 0.216 gram of (0.55mmol) 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (I-a2), 0.11 gram of (1.09mmol) triethylamine, 15.0 milliliters of acetonitriles join in the reaction flask of 50 milliliters, 0.117 gram of (1.10mmol) n-butyryl chloride and 5.0 milliliters of acetonitrile 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, enriched material adds 20 milliliters of chloroforms and is dissolved, obtain lysate, 0.25 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 enriched material and silica gel, mixture is filled post, then be the petrol ether/ethyl acetate mixing solutions of 1:10 with volume ratio be eluent, wash-out, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), the elutriant (Rf value is 0.4) collected containing the compound shown in formula (I-8) is detected according to TLC, collection liquid concentrates, 50 DEG C of dryings obtain 4-[3-(2-dipropyl aminoacetylamino) the anilino]-6-butyrylamino quinazoline pale solid shown in formula (I-8), yield 73.2%, fusing point 128 ~ 129 DEG C.
1H NMR(500MHz,DMSO)δ:0.90(t,J＝7.4Hz,6H)；0.97(t,J＝7.2Hz,3H)；1.44-1.52(m,4H)；1.64-1.72(m,2H)；2.38(t,J＝7.3Hz,2H)；2.51(t,J＝6.7Hz,4H)；3.19(s,2H)；7.29-7.36(m,2H)；7.57(d,J＝7.4Hz,1H)；7.75(d,J＝7.0Hz,1H)；7.85-7.88(m,1H)；8.09(s,1H)；8.50(s,1H)；8.72(d,J＝1.7Hz,1H)；9.59(s,1H)；9.81(s,1H)；10.20(s,1H)。
The preparation of embodiment 27:4-[3-(2-dipropyl aminoacetylamino) anilino]-6-propionamido quinazoline (I-9)
Successively by 0.216 gram of (0.55mmol) 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (I-a2), 0.067 gram of (0.55mmol) DMAP, 15 milliliters of toluene join in the reaction flask of 50 milliliters, 0.204 gram of (2.20mmol) propionyl chloride and 5.5 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, enriched material adds 20 milliliters of tetrahydrofuran (THF)s and is dissolved, obtain lysate, 0.50 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 enriched material and silica gel, mixture is filled post, then be the petrol ether/ethyl acetate mixing solutions of 1:4 with volume ratio be eluent, wash-out, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), the elutriant (Rf value is 0.7) collected containing the compound shown in formula (I-9) is detected according to TLC, collection liquid concentrates, 50 DEG C of dryings obtain 4-[3-(2-dipropyl aminoacetylamino) the anilino]-6-propionamido quinazoline pale solid shown in formula (I-9), yield 53.2%, fusing point 118 ~ 119 DEG C.
1H NMR(500MHz,DMSO)δ:0.90(t,J＝7.4Hz,6H)；1.15(t,J＝7.6Hz,3H)；1.43-1.53(m,4H)；2.41(q,J＝7.5Hz,2H)；2.50-2.52(m,4H),3.19(s,2H)；7.29-7.36(m,2H)；7.56-7.58(m,1H)；7.75(d,J＝9.0Hz,1H)；7.85(dd,J＝2.2,9.0Hz,1H)；8.09(t,J＝2.0Hz,1H)；8.50(s,1H)；8.71(d,J＝2.1Hz,1H)；9.60(s,1H)；9.81(s,1H)；10.20(s,1H)。
The preparation of embodiment 28:4-[3-(2-dipropyl aminoacetylamino) anilino]-6-isobutyryl amido quinazoline (I-10)
Successively by 0.216 gram of (0.55mmol) 4-[3-(2-dipropyl aminoacetylamino) anilino]-6-amido quinazoline (I-a2), 0.067 gram of (0.55mmol) DMAP, 15.0 milliliters of toluene join in the reaction flask of 50 milliliters, the solution of 0.234 gram of (2.20mmol) isobutyryl chloride and 5.0 milliliters of toluene is 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, enriched material adds 20 milliliters of tetrahydrofuran (THF)s and is dissolved, obtain lysate, 0.50 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 enriched material and silica gel, mixture is filled post, then be the petrol ether/ethyl acetate mixing solutions of 4:1 with volume ratio be eluent, wash-out, TLC tracing detection (developping agent is ethyl acetate/petroleum ether=1:1 (v/v)), the elutriant (Rf value is 0.3) collected containing the compound shown in formula (I-10) is detected according to TLC, collection liquid concentrates, 50 DEG C of dryings obtain 4-[3-(2-dipropyl aminoacetylamino) the anilino]-6-isobutyryl amido quinazoline pale solid shown in formula (I-10), yield 71.1%, fusing point 148 ~ 150 DEG C.
1H NMR(500MHz,DMSO)δ:0.90(t,J＝7.3Hz,6H)；1.17(d,J＝6.8Hz,6H)；1.41–1.55(m,4H)；2.51(dd,J＝1.8,3.6Hz,4H)；2.64–2.75(m,1H)；3.19(s,2H)；7.27–7.38(m,2H)；7.55–7.61(m,1H)；7.75(d,J＝8.9Hz,1H)；7.86(dd,J＝2.2,9.0Hz,1H)；8.09(d,J＝1.9Hz,1H)；8.50(s,1H)；8.74(d,J＝2.1Hz,1H)；9.60(s,1H)；9.82(s,1H)；10.17(s,1H)。
Embodiment 29: antitumour activity vitro test
The compound (I) obtained in embodiment is carried out people's lung cancer and human breast carcinoma biological activity test.
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 2 μ L, 1000 μ L substratum and dilute, make concentration be 100 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, is added in 96 porocyte culture plates, and every hole 100 μ L, puts 37 DEG C, 5%CO
2cultivate in incubator.After inoculation 24h, add 100 μ g/mL, the 10 μ g/mL with substratum dilution or 1 μ g/mL sample, 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 (5)
1. a 6-amino-quinazoline compound shown in formula (I-a),
In formula (I-a), R
1for ethyl or propyl group, R
3with R
1structure is identical.
2. for the preparation of an intermediate for compound formula described in claim 1 (I-a) Suo Shi,
In formula (I-b), R
1for ethyl or propyl group, R
3with R
1structure is identical.
3. compound shown in formula described in claim 1 (I-a) is preparing the application in compound shown in formula I,
In formula I, R
1for ethyl or propyl group, R
3with R
1structure is identical; R
2for RCONH, wherein R is C1-C3 alkyl or phenyl.
4. the application of compound shown in formula (I-a) described in a claim 1 in preparation prevention or treatment people's lung cancer or human breast carcinoma medicine.
5. apply as claimed in claim 4, it is characterized in that described people's lung cancer is human lung cancer cell lines A-549, described human breast carcinoma is MCF-7 cell strainHJ2mm.
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