CN103382182A - Phenylurea coupling quinazoline compound, and preparation method, pharmaceutical composition and pharmaceutical use thereof - Google Patents

Phenylurea coupling quinazoline compound, and preparation method, pharmaceutical composition and pharmaceutical use thereof Download PDF

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CN103382182A
CN103382182A CN2013102483702A CN201310248370A CN103382182A CN 103382182 A CN103382182 A CN 103382182A CN 2013102483702 A CN2013102483702 A CN 2013102483702A CN 201310248370 A CN201310248370 A CN 201310248370A CN 103382182 A CN103382182 A CN 103382182A
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quinazoline
urea
phenyl
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anilinoquinazoline
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CN103382182B (en
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张恺
曹德英
薛娜
史清文
杜玉民
董玫
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Hebei Medical University
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Hebei Medical University
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Abstract

The invention provides a phenylurea coupling quinazoline compound or a pharmaceutically acceptable salt thereof represented by formula (I), wherein R1 represents H, represents Br, Cl or F, represents -CH3, -CH2-CH3, -CH2(CH3)2 or -CF3, represents -O-CH3, -O-CH2-CH3 or -O-CH2(CH3)2, or represents -C[triple bond]CH or -C[triple bond]N; n1 is 1, 2, 3, 4 or 5; one of R2 and R3 is a group represented by formula (II); R4 represents H, represents Br, Cl or F, represents -CH3, -CH2-CH3, -CH2(CH3)2 or -CF3, represents -O-CH3, -O-CH2-CH3 or -O-CH2(CH3)2, represents -NH2, or represents -NO2; n2 is 1, 2, 3, 4 or 5; and the other one of R2 and R3 represents H, -O-CH3, -O-CH2-CH3, -O-CH2(CH3)2, or the following groups.

Description

Phenylurea coupling quinazoline compounds and preparation method thereof, pharmaceutical composition and pharmaceutical use
Technical field
The present invention relates to a kind of phenylurea coupling quinazoline compounds, be specifically related to a kind of preparation method with the inhibiting phenylurea coupling of protein tyrosine kinase quinazoline compounds and preparation method thereof, this derivatives intermediates, pharmaceutical composition and relate to purposes in the medicine of disease of protein tyrosine kinase overexpression in preparation.
Background technology
EGF-R ELISA (EGFR) is a kind of transmembrane glycoprotein that is comprised of Single polypeptide chain, the somatomedin (EGF) of it and outside in conjunction with after be activated, can optionally make the receptor protein phosphorylation that contains tyrosine residues.This tyrosine phosphorylation effect is relevant with many Cell regulate processes, reaction, cell survival and the upgrowth situation adjusting etc. that stimulate as activation, mitotic division, differentiation and the growth of T cell and B cell, the to external world (people such as F.Al-Obeidi, Peptide Science47 (1998), 197 and T.Hunter, Cell88 (1997), 333).Studies show that, when the tyrosine protein kinase overexpression, the adjusting and controlling growth of cell is out of control, is in all the time proliferative state, and then develops into malignant tumour (R.Patarca, Critical Reviews in Oncogenesis7 (1996), 343).
In the research of epidermal growth factor receptor inhibitor, Tyrosylprotein kinase PTK (ProteinTyrosine Kinase) is the important molecule target spot of the antitumor drug effect of discovered in recent years.Based on small molecules tyrosine-kinase enzyme (the 4-anilinoquinazoline class) inhibitor of this shot design, side effect is slight, and good tolerance is arranged, and becomes new effective medicine of the various noumenal tumours for the treatment of.
Therefore, it is significant that exploitation has the inhibiting new compound of protein tyrosine kinase.
Summary of the invention
For the problems referred to above, one object of the present invention is to provide a kind of phenylurea coupling quinazoline compounds or its pharmacy acceptable salt, and this quinazoline compounds or its pharmacy acceptable salt can be used in the disease that treatment relates to the protein tyrosine kinase overexpression.
Another object of the present invention is to provide a kind of method for preparing above-mentioned phenylurea coupling quinazoline compounds or its pharmacy acceptable salt.
A further object of the present invention is to provide a kind of method for preparing above-mentioned phenylurea coupling quinazoline compounds and intermediate thereof.
A further object of the present invention is to provide a kind of pharmaceutical composition.
A further object of the present invention is to provide above-mentioned phenylurea coupling quinazoline compounds or its pharmacy acceptable salt to relate to purposes in the medicine of disease of protein tyrosine kinase overexpression in preparation.
For achieving the above object, the invention provides the phenylurea coupling quinazoline compounds shown in a kind of formula (I) or its pharmacy acceptable salt.
Figure BDA00003382604900021
Wherein, R 1Be H; Br, Cl or F;-CH 3,-CH 2-CH 3,-CH 2(CH 3) 2Or-CF 3-O-CH 3,-O-CH 2-CH 3Or-O-CH 2(CH 3) 2-C ≡ CH or-C ≡ N;
n 1Be 1,2,3,4 or 5;
R 2Or R 3One of be the group shown in formula (II);
Figure BDA00003382604900022
Wherein, R 4Be H; Br, Cl or F;-CH 3,-CH 2-CH 3,-CH 2(CH 3) 2Or-CF 3-O-CH 3,-O-CH 2-CH 3Or-O-CH 2(CH 3) 2-NH 2Or-NO 2
n 2Be 1,2,3,4 or 5;
R 2Or R 3In another one be H ,-O-CH 3,-O-CH 2-CH 3,-O-CH 2(CH 3) 2,
Figure BDA00003382604900023
Preferably, the phenylurea coupling quinazoline compounds shown in described formula I or its pharmacy acceptable salt are selected from following compound:
1-phenyl-3-(4-anilinoquinazoline-7-yl) urea,
1-phenyl-3-[4-(4-toluidine) quinazoline-7-yl] urea,
1-phenyl-3-[4-(3-toluidine) quinazoline-7-yl] urea,
1-phenyl-3-[4-(2-aminotoluene base) quinazoline-7-yl] urea,
1-phenyl-3-[4-(4-anisole amido) quinazoline-7-yl] urea,
1-phenyl-3-[4-(2-fluoro-4-bromobenzene amido) quinazoline-7-yl] urea,
1-phenyl-3-[4-(3-isopropyl benzene amido) quinazoline-7-yl] urea,
1-phenyl-3-[4-(3-chloro-4-fluoroanilino) quinazoline-7-yl] urea,
1-phenyl-3-[4-(2，4，6-trimethyl aniline base) quinazoline-7-yl] urea,
1-phenyl-3-[4-(2 3 dimethyl aniline base) quinazoline-7-yl] urea,
1-(2-aminomethyl phenyl)-3-(4-anilinoquinazoline-7-yl) urea,
1-phenyl-3-[4-(2-chloroanilino) quinazoline-7-yl] urea,
1-phenyl-3-[4-(2,4 difluorobenzene amido) quinazoline-7-yl] urea,
1-phenyl-3-[4-(3-trifluoromethylbenzene amido) quinazoline-7-yl] urea,
1-(2,3-3,5-dimethylphenyl)-3-(4-anilinoquinazoline-7-yl) urea,
1-(2,4 difluorobenzene base)-3-(4-anilinoquinazoline-7-yl) urea,
1-(4-p-methoxy-phenyl)-3-(4-anilinoquinazoline-7-yl) urea,
1-(2,4,6-trimethylphenyl)-3-(4-anilinoquinazoline-7-yl) urea,
1-(4-nitrophenyl)-3-(4-anilinoquinazoline-7-yl) urea,
1-(4-p-methoxy-phenyl)-3-[4-(2 3 dimethyl aniline base) quinazoline-7-yl] urea,
1-phenyl-3-[4-(4-fluoroanilino) quinazoline-7-yl] urea,
1-(4-fluorophenyl)-3-[4-(4-toluidine) quinazoline-7-yl] urea,
1-(4-p-methoxy-phenyl)-3-[4-(4-toluidine) quinazoline-7-yl] urea,
1-phenyl-3-[4-(4-fluoroanilino) quinazoline-6-yl] urea,
1-phenyl-3-(7-methoxyl group-4-anilinoquinazoline-6-yl) urea,
1-phenyl-3-(4-anilinoquinazoline-6-yl) urea,
1-phenyl-3-[4-(3-bromobenzene amido) quinazoline-7-yl] urea,
1-phenyl-3-[4-(4-toluidine) quinazoline-6-yl] urea,
1-phenyl-3-[4-(3-bromobenzene amido) quinazoline-6-yl] urea,
1-phenyl-3-[4-(2 3 dimethyl aniline base) quinazoline-6-yl] urea,
1-phenyl-3-[4-(3-chloro-4-fluoroanilino) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(4-toluidine) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(3-toluidine) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(2 3 dimethyl aniline base) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(3-bromobenzene amido) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(2-fluoro-4-bromobenzene amido) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(3-acetylenylbenzene amido) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(4-bromobenzene amido) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(3-cyano-aniline base) quinazoline-6-yl] urea,
1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline-6-yl] urea,
1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(3-bromobenzene amido) quinazoline-6-yl] urea,
1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(2-fluoro-4-bromobenzene amido) quinazoline-6-yl] urea,
1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(2-methyl-4-anisole amido) quinazoline-6-yl] urea,
1-phenyl-3-[7-(morpholine-4-yl)-4-(3-chloro-4-fluoroanilino) quinazoline-6-yl] urea,
1-phenyl-3-(6-methoxyl group-4-anilinoquinazoline-7-yl) urea,
1-phenyl-3-[6-(4-methylpiperazine-1-yl)-4-anilinoquinazoline-7-yl] urea,
1-phenyl-3-[6-(morpholine-4-yl)-4-anilinoquinazoline-7-yl] urea or
1-phenyl-3-[7-methoxyl group-4-(3-chloro-4-fluoroanilino) quinazoline-6-yl] urea; Or the salt of these compounds.
Preferably, described pharmacy acceptable salt includes but not limited to hydrochloride, hydrobromate, vitriol, Hemisulphate, phosphoric acid salt or carboxylate salt, preferred amino acid salt.
The present invention also provides a kind of phenylurea coupling quinazoline compounds shown in above-mentioned formula (I) or method of its pharmacy acceptable salt of preparing, and comprises the following steps:
Step a: the compound shown in formula (III) in organic solvent with catalyst reaction, preferred back flow reaction 1h, the compound shown in production (IV);
Figure BDA00003382604900041
Wherein, R 5Or R 6One of be NO 2
R 5Or R 6In another one be H ,-O-CH 3,-O-CH 2-CH 3,-O-CH 2(CH 3) 2,
Step b: the compound shown in formula (IV) and the compound shown in formula V react in organic solvent, preferred back flow reaction 1.5h, the compound shown in production (VI);
Figure BDA00003382604900052
Wherein, R 1, n 1Definition with R in formula I 1, n 1Definition identical;
Step c: the compound shown in formula (VI) reacts with reductive agent in organic solvent, preferred back flow reaction 1h, the compound shown in production (VII);
Figure BDA00003382604900054
R wherein 7Or R 8One of be NH 2
R 7Or R 8In another one be H ,-O-CH 3,-O-CH 2-CH 3,-O-CH 2(CH 3) 2,
Figure BDA00003382604900055
Steps d: the compound shown in the compound shown in formula (VII) and formula (VIII) in organic solvent, preferably at room temperature reaction 3h, the compound shown in production (I);
Figure BDA00003382604900056
Wherein, R 4, n 2Definition and formula (I) in R 4, n 2Definition identical.
Preferably, described method further comprises:
Step e: under room temperature, the compound shown in formula (I) and acid or alkali react the compound shown in production (X) in organic solvent;
Figure BDA00003382604900061
Wherein, M is hydrochloric acid, Hydrogen bromide, sulfuric acid, hemisulfic acid, phosphoric acid or carboxylic acid, preferred amino acid or hydrochloric acid; R 1, n 1, R 2, R 3Definition with R in formula I 1, n 1, R 2, R 3Definition identical.
Preferably, the organic solvent in described step a is sulfur oxychloride, and catalyzer is dimethyl formamide (DMF);
Preferably, the organic solvent in described step b is Virahol, anhydrous acetonitrile or anhydrous tetrahydro furan;
Preferably, the organic solvent in described step c is ethyl acetate or dehydrated alcohol; One or more in the preferred tin protochloride of reductive agent, hydrazine hydrate or Raney's nickel.
Preferably, the organic solvent in described steps d is acetonitrile or anhydrous tetrahydro furan;
Preferably, the organic solvent in described step e is dehydrated alcohol or methylene dichloride;
Preferably, the preparation method of the compound shown in formula (VIII) comprises: the compound shown in formula (IX) and triphosgene (BTC) are reacted the compound shown in production (VIII) in organic solvent.
The present invention also provides a kind of method for preparing the intermediate of the compound shown in above-mentioned formula (I), and described intermediate is phenyl isocyanate, and the method comprises:
With 1 of the compound shown in formula (IX) and triethylamine, the 2-dichloroethane solution is added drop-wise to 1 of triphosgene, in the 2-dichloroethane solution, obtains phenyl isocyanate intermediate corresponding to formula (IX) compound after reaction,
Wherein, R 4, n 2Definition and formula (I) in R 4, n 2Definition identical.
Preferably, aforesaid method specifically comprises: under the ice-water bath cooling conditions, with 1 of the compound shown in formula (IX) and triethylamine, the 2-dichloroethane solution is added drop-wise to 1 of triphosgene, in the 2-ethylene dichloride, control rate of addition, preferred 2 drops/secs, after dropwising, stirring at room 1h, reflux 3h, be placed to room temperature, obtain filtrate after filtration, with 1,2-ethylene dichloride washing leaching cake, merging filtrate gets oily matter after steaming desolventizes, then obtain phenyl isocyanate intermediate corresponding to the compound shown in formula (IX) after vacuum fractionation.
The present invention further provides a kind of pharmaceutical composition, it comprises phenylurea coupling quinazoline compounds as above or its pharmacy acceptable salt, and pharmaceutically acceptable carrier, vehicle or thinner.Be used for carrier of the present invention, vehicle or thinner and can be this area carrier, vehicle or thinner commonly used, such as Magnesium Stearate, talcum powder, silicon-dioxide, dry starch, carboxy cellulose sodium, carboxymethylstach sodium, hydroxypropylcellulose and polyvinylpolypyrrolidone etc.
Preferably, pharmaceutical composition of the present invention can further comprise other active substances except above-mentioned phenylurea coupling quinazoline compounds or its pharmacy acceptable salt, such as Magnesium Stearate, silicon-dioxide, dry starch and carboxymethylstach sodium etc., additive and the auxiliary etc. that also can comprise in addition other, such as ethanol, water, sodium bicarbonate, sucrose and Citric Acid etc.
The present invention further provides above-mentioned phenylurea coupling quinazoline compounds or its pharmacy acceptable salt and relate to purposes in the medicine of disease of protein tyrosine kinase overexpression in preparation.
Wherein, the described disease that relates to the protein tyrosine kinase overexpression is malignant tumour, includes but not limited to: lung cancer, preferred nonsmall-cell lung cancer; Carcinoma of the pancreas; Phosphorus columnar epithelium cancer; Medullary thyroid carcinoma; The incidence cancer; Esophagus cancer; Cancer of the stomach; Or the preferred bladder cancer of gynecological cancer knurl and mammary cancer.
The present invention is by the research (L.Hennequin to 4-anilinoquinazoline class medicine structure activity relationship, Journal of Medicinal Chemistry (1999), 42 (26), 5369-5389), according in prior art to the understanding of 4-anilinoquinazoline class medicine structure activity relationship, take the 4-anilinoquinazoline as mother nucleus structure, respectively 4 bit substituents and 7 (or 6) substituting groups are modified, to obtain having the inhibiting lead compound of many target spots of Tyrosylprotein kinase.To the modification of 4 bit substituents, mainly take aromatic ring structure as main, and to 7 (or 6) substituent modifications mainly take the substituted-phenyl urea structure as main, obtain phenylurea coupling quinazoline compounds of the present invention with this.
In addition, in the structure of the 4-anilinoquinazoline compounds that the present invention synthesizes, have been found that part-structure has obvious pharmacologically active.Phenylurea coupling quinazoline compounds of the present invention or its pharmacy acceptable salt can be treated the disease that relates to the protein tyrosine kinase overexpression effectively.
Description of drawings
Fig. 1 shows the IC of 2 pairs of A549 cells of compound of the present invention 50Collection of illustrative plates;
Fig. 2 shows the IC of 18 pairs of A549 cells of compound of the present invention 50Collection of illustrative plates;
Fig. 3 shows the IC of 33 pairs of A549 cells of compound of the present invention 50Collection of illustrative plates.
Embodiment
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiment only are used for explanation the present invention, the scope that it does not limit the present invention in any way.
Experimental technique in following embodiment if no special instructions, is ordinary method.In following embodiment, medicine used, reagent etc., if no special instructions, be commercially available purchase product.
End product in the embodiment of the present invention by mass spectroscopy (ESI-MS) and 1H-NMR(500MHz is in dimethyl sulfoxide (DMSO) (DMSO)) measure.
Embodiment 1Synthesizing of 1-phenyl-3-(4-anilinoquinazoline-7-yl) urea (compound 1)
Synthetic route and the method for compound 1 are as follows:
Figure BDA00003382604900081
The preparation of step 1:7-nitro-3H-quinazoline-4-one
With 2-Amino-4-nitrobenzoic Acid (7.28g, 40.0mmol) and ammonium formiate (3.78g, 60.0mmol) join in the 100mL methane amide, be heated to 150 ℃, insulation reaction 16h, be cooled to room temperature, separate out solid, filter, use washed with isopropyl alcohol, drying gets brown needle-like solid 7-nitro-3H-quinazoline-4-one 6.62g, and productive rate is 86.6%.
The preparation of step 2:7-nitro-4-anilinoquinazoline
7-nitro-3H-quinazoline-4-one (2.25g, 11.8mmol) is joined 23mL SOCl 2In solution, then add 0.2mL DMF, return stirring 1h, solution gradually become brown clarification, and stopped reaction is cooled to room temperature, steam except excessive SOCl 2, obtain yellow solid 7-nitro-4-chloro-quinazoline.The yellow solid that obtains is blended, add the 10mL sherwood oil, decompression steams sherwood oil, repeats to add sherwood oil operation 2 times, to remove remaining SOCl 2, obtain yellow solid.Not purified upwards stating adds aniline (1.31g, 14.1mmol) in yellow solid, Virahol 37mL, return stirring 1.5h, there is solid to separate out, is cooled to room temperature, filter, use washed with isopropyl alcohol, drying gets yellow solid 7-nitro-4-anilinoquinazoline 1.87g, and productive rate is 59.7%.
The preparation of step 3:7-amino-4-anilinoquinazoline
7-nitro-4-anilinoquinazoline (1.31g, 4.9mmol), two hydrated stannous chlorides (4.42g, 19.6mmol) and ethyl acetate 49mL are mixed back flow reaction 1h.Reaction solution first becomes clarification, rear appearance precipitation, react complete after, be placed to room temperature, filter, the gained precipitation is washed with ethyl acetate, combined ethyl acetate solution is adjusted to neutrality with saturated sodium bicarbonate solution, the separating ethyl acetate layer is used the 10mL water washing, anhydrous Na 2SO 4Drying is evaporated to driedly, and drying obtains yellow solid 7-amino-4-anilinoquinazoline 0.95g, and productive rate is 81.1%.
Step 4: the preparation of phenyl isocyanate
under ice-water bath is cooling, with aniline (0.73g, 7.8mmol) and triethylamine (1.64g, 16.2mmol) 1, the mixing solutions of 2-ethylene dichloride (4mL) slowly is added drop-wise to triphosgene (0.94g, 3.2mmol) and dry 1, in the solution of 2-ethylene dichloride (8mL), control rate of addition (2 drops/secs), after dropwising, stirring at room 1h, reflux 3h, be placed to room temperature, filter to get filtrate, with 1, 2-ethylene dichloride washing leaching cake, merging filtrate, after desolventizing, steaming gets oily matter, obtain colourless liquid phenyl isocyanate 0.70g through vacuum fractionation again, productive rate is 75.4%.
The preparation of step 5:1-phenyl-3-(4-anilinoquinazoline-7-yl) urea
With phenyl isocyanate (0.26g, 2.2mmol) join in the 20mL acetonitrile, under stirring at room, add 7-amino-4-anilinoquinazoline (0.47g in batches, 2.0mmol), stirring at room 3h filters to get solid, washs with acetonitrile, dry, use 80% ethyl alcohol recrystallization again, obtain faint yellow solid 1-phenyl-3-(4-anilinoquinazoline-7-yl) urea (compound 1) 0.62g, productive rate is 79.5%.
Embodiment 21-phenyl-3-[4-(4-toluidine) quinazoline-7-yl] urea (compound 2) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(4-toluidine) quinazoline
Referring to step 2 experimental implementation in embodiment 1, unique difference is for replacing to the aniline that adds in this step the 4-monomethylaniline of equimolar amount.
The preparation of step 3:7-amino-4-(4-toluidine) quinazoline
Referring to step 3 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-nitro in this step-4-anilinoquinazoline 7-nitro-4-(4-toluidine) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(4-toluidine) quinazoline-7-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-amino in this step-4-anilinoquinazoline 7-amino-4-(4-toluidine) quinazoline of equimolar amount.
Embodiment 31-phenyl-3-[4-(3-toluidine) quinazoline-7-yl] urea (compound 3) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(3-toluidine) quinazoline
Referring to step 2 experimental implementation in embodiment 1, unique difference is for replacing to the aniline that adds in this step the 3-monomethylaniline of equimolar amount.
The preparation of step 3:7-amino-4-(3-toluidine) quinazoline
Referring to step 3 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-nitro in this step-4-anilinoquinazoline 7-nitro-4-(3-toluidine) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(3-toluidine) quinazoline-7-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-amino in this step-4-anilinoquinazoline 7-amino-4-(3-toluidine) quinazoline of equimolar amount.
Embodiment 41-phenyl-3-[4-(4-anisole amido) quinazoline-7-yl] urea (compound 4) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(4-anisole amido) quinazoline
Referring to step 2 experimental implementation in embodiment 1, unique difference is for replacing to the aniline that adds in this step the 4-anisidine of equimolar amount.
The preparation of step 3:7-amino-4-(4-anisole amido) quinazoline
Referring to step 3 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-nitro in this step-4-anilinoquinazoline 7-nitro-4-(4-anisole amido) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(4-anisole amido) quinazoline-7-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-amino in this step-4-anilinoquinazoline 7-amino-4-(4-anisole amido) quinazoline of equimolar amount.
Embodiment 51-phenyl-3-[4-(2-fluoro-4-bromobenzene amido) quinazoline-7-yl] urea (compound 5) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(2-fluoro-4-bromobenzene amido) quinazoline
Referring to step 2 experimental implementation in embodiment 1, unique difference is for replacing to the aniline that adds in this step the 2-fluoro-4-bromaniline of equimolar amount.
The preparation of step 3:7-amino-4-(2-fluoro-4-bromobenzene amido) quinazoline
Referring to step 3 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-nitro in this step-4-anilinoquinazoline 7-nitro-4-(2-fluoro-4-bromobenzene amido) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(2-fluoro-4-bromobenzene amido) quinazoline-7-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-amino in this step-4-anilinoquinazoline 7-amino-4-(2-fluoro-4-bromobenzene amido) quinazoline of equimolar amount.
Embodiment 61-phenyl-3-[4-(3-isopropyl benzene amido) quinazoline-7-yl] urea (compound 6) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(3-isopropyl benzene amido) quinazoline
Referring to step 2 experimental implementation in embodiment 1, unique difference is for replacing to the aniline that adds in this step the 3-isopropyl aniline of equimolar amount.
The preparation of step 3:7-amino-4-(3-isopropyl benzene amido) quinazoline
Referring to step 3 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-nitro in this step-4-anilinoquinazoline 7-nitro-4-(3-isopropyl benzene amido) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(3-isopropyl benzene amido) quinazoline-7-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-amino in this step-4-anilinoquinazoline 7-amino-4-(3-isopropyl benzene amido) quinazoline of equimolar amount.
Embodiment 71-phenyl-3-[4-(3-chloro-4-fluoroanilino) quinazoline-7-yl] urea (compound 7) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(3-chloro-4-fluoroanilino) quinazoline
Referring to step 2 experimental implementation in embodiment 1, unique difference is for replacing to the aniline that adds in this step the 3-chloro-4-fluoroaniline of equimolar amount.
The preparation of step 3:7-amino-4-(3-chloro-4-fluoroanilino) quinazoline
Referring to step 3 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-nitro in this step-4-anilinoquinazoline 7-nitro-4-(3-chloro-4-fluoroanilino) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(3-chloro-4-fluoroanilino) quinazoline-7-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-amino in this step-4-anilinoquinazoline 7-amino-4-(3-chloro-4-fluoroanilino) quinazoline of equimolar amount.
Embodiment 81-phenyl-3-[4-(2，4，6-trimethyl aniline base) quinazoline-7-yl] urea (compound 8) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(2，4，6-trimethyl aniline base) quinazoline
Referring to step 2 experimental implementation in embodiment 1, unique difference is for replacing to the aniline that adds in this step the 2，4，6-trimethyl aniline of equimolar amount.
The preparation of step 3:7-amino-4-(2，4，6-trimethyl aniline base) quinazoline
Referring to step 3 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-nitro in this step-4-anilinoquinazoline 7-nitro-4-(2，4，6-trimethyl aniline base) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(2，4，6-trimethyl aniline base) quinazoline-7-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-amino in this step-4-anilinoquinazoline 7-amino-4-(2，4，6-trimethyl aniline base) quinazoline of equimolar amount.
Embodiment 91-phenyl-3-[4-(2 3 dimethyl aniline base) quinazoline-7-yl] urea (compound 9) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(2 3 dimethyl aniline base) quinazoline
Referring to step 2 experimental implementation in embodiment 1, unique difference is for replacing to the aniline that adds in this step the 23 dimethyl aniline of equimolar amount.
The preparation of step 3:7-amino-4-(2 3 dimethyl aniline base) quinazoline
Referring to step 3 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-nitro in this step-4-anilinoquinazoline 7-nitro-4-(2 3 dimethyl aniline base) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(2 3 dimethyl aniline base) quinazoline-7-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-amino in this step-4-anilinoquinazoline 7-amino-4-(2 3 dimethyl aniline base) quinazoline of equimolar amount.
Embodiment 10Synthesizing of 1-(2-aminomethyl phenyl)-3-(4-anilinoquinazoline-7-yl) urea (compound 10)
Step 1: referring to step 1 experimental implementation in embodiment 1.
Step 2: referring to step 2 experimental implementation in embodiment 1.
Step 3: referring to step 3 experimental implementation in embodiment 1.
The preparation of step 4:2-aminomethyl phenyl isocyanic ester
Referring to step 4 experimental implementation in embodiment 1, unique difference is for replacing to reactant aniline in this step the 2-aminotoluene of equimolar amount.
The preparation of step 5:1-(2-aminomethyl phenyl)-3-(4-anilinoquinazoline-7-yl) urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to reactant phenyl isocyanate in this step the 2-aminomethyl phenyl isocyanic ester of equimolar amount.
Embodiment 111-phenyl-3-[4-(2-chloroanilino) quinazoline-7-yl] urea (compound 11) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(2-chloroanilino) quinazoline
Referring to step 2 experimental implementation in embodiment 1, unique difference is for replacing to the aniline that adds in this step the 2-chloroaniline of equimolar amount.
The preparation of step 3:7-amino-4-(2-chloroanilino) quinazoline
Referring to step 3 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-nitro in this step-4-anilinoquinazoline 7-nitro-4-(2-chloroanilino) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(2-chloroanilino) quinazoline-7-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-amino in this step-4-anilinoquinazoline 7-amino-4-(2-chloroanilino) quinazoline of equimolar amount.
Embodiment 121-phenyl-3-[4-(2,4 difluorobenzene amido) quinazoline-7-yl] urea (compound 12) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(2,4 difluorobenzene amido) quinazoline
Referring to step 2 experimental implementation in embodiment 1, unique difference is for replacing to the aniline that adds in this step the 2,4 difluorobenzene amine of equimolar amount.
The preparation of step 3:7-amino-4-(2,4 difluorobenzene amido) quinazoline
Referring to step 3 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-nitro in this step-4-anilinoquinazoline 7-nitro-4-(2,4 difluorobenzene amido) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(2,4 difluorobenzene amido) quinazoline-7-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-amino in this step-4-anilinoquinazoline 7-amino-4-(2,4 difluorobenzene amido) quinazoline of equimolar amount.
Embodiment 13Synthesizing of 1-(2,4 difluorobenzene base)-3-(4-anilinoquinazoline-7-yl) urea (compound 13)
Step 1: referring to step 1 experimental implementation in embodiment 1.
Step 2: referring to step 2 experimental implementation in embodiment 1.
Step 3: referring to step 3 experimental implementation in embodiment 1.
Step 4:2,4-difluorophenyl isocyanate synthetic
Referring to step 4 experimental implementation in embodiment 1, unique difference is for replacing to reactant aniline in this step the 2,4 difluorobenzene amine of equimolar amount.
The preparation of step 5:1-(2,4 difluorobenzene base)-3-(4-anilinoquinazoline-7-yl) urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to reactant phenyl isocyanate in this step the 2,4 difluorobenzene based isocyanate of equimolar amount.
Embodiment 14Synthesizing of 1-(4-p-methoxy-phenyl)-3-(4-anilinoquinazoline-7-yl) urea (compound 14)
Step 1: referring to step 1 experimental implementation in embodiment 1.
Step 2: referring to step 2 experimental implementation in embodiment 1.
Step 3: referring to step 3 experimental implementation in embodiment 1.
Synthesizing of step 4:4-anisole based isocyanate
Referring to step 4 experimental implementation in embodiment 1, unique difference is for replacing to reactant aniline in this step the 4-anisidine of equimolar amount.
The preparation of step 5:1-(4-p-methoxy-phenyl)-3-(4-anilinoquinazoline-7-yl) urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to reactant phenyl isocyanate in this step the 4-anisole based isocyanate of equimolar amount.
Embodiment 151-(4-p-methoxy-phenyl)-3-[4-(2 3 dimethyl aniline base) quinazoline-7-yl] urea (compound 15) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 1.
Step 2: referring to step 2 experimental implementation in embodiment 9.
Step 3: referring to step 3 experimental implementation in embodiment 9.
Step 4: referring to step 4 experimental implementation in embodiment 14.
Step 5:1-(4-p-methoxy-phenyl)-3-[4-(2 3 dimethyl aniline base) quinazoline-7-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 9, unique difference is for replacing to reactant phenyl isocyanate in this step the 4-anisole based isocyanate of equimolar amount.
Embodiment 161-phenyl-3-[4-(4-fluoroanilino) quinazoline-7-yl] urea (compound 16) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(4-fluoroanilino) quinazoline
Referring to step 2 experimental implementation in embodiment 1, unique difference is for replacing to the aniline that adds in this step the 4-fluoroaniline of equimolar amount.
The preparation of step 3:7-amino-4-(4-fluoroanilino) quinazoline
Referring to step 3 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-nitro in this step-4-anilinoquinazoline 7-nitro-4-(4-fluoroanilino) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(4-fluoroanilino) quinazoline-7-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-amino in this step-4-anilinoquinazoline 7-amino-4-(4-fluoroanilino) quinazoline of equimolar amount.
Embodiment 171-(4-fluorophenyl)-3-[4-(4-toluidine) quinazoline-7-yl] urea (compound 17) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 1.
Step 2: referring to step 2 experimental implementation in embodiment 2.
Step 3: referring to step 3 experimental implementation in embodiment 2.
Step 4:4-fluorophenyl isocyanic acid ester synthesis
Referring to step 4 experimental implementation in embodiment 1, unique difference is for replacing to reactant aniline in this step the 4-fluoroaniline of equimolar amount.
Step 5:1-(4-fluorophenyl)-3-[4-(4-toluidine) quinazoline-7-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 2, unique difference is for replacing to reactant phenyl isocyanate in this step the 4-fluorophenyl isocyanic ester of equimolar amount.
Embodiment 181-(4-p-methoxy-phenyl)-3-[4-(4-toluidine) quinazoline-7-yl] urea (compound 18) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 1.
Step 2: referring to step 2 experimental implementation in embodiment 2.
Step 3: referring to step 3 experimental implementation in embodiment 2.
Step 4: referring to step 4 experimental implementation in embodiment 14.
Step 5:1-(4-p-methoxy-phenyl)-3-[4-(4-toluidine) quinazoline-7-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 2, unique difference is for replacing to reactant phenyl isocyanate in this step the 4-anisole based isocyanate of equimolar amount.
Embodiment 19Synthesizing of 1-phenyl-3-(7-methoxyl group-4-anilinoquinazoline-6-yl) urea (compound 19)
Synthetic route and the method for compound 19 are as follows:
Figure BDA00003382604900171
The preparation of step 1:7-chloro-3H-quinazoline-4-one
With 4-chloro-2-benzaminic acid (10.26g, 60.0mmol) and FORMAMIDINE ACETATE (12.50g, 120.0mmol) join in the 250mL ethylene glycol monomethyl ether, be heated to 120 ℃, insulation reaction 16h, be cooled to room temperature, be evaporated to driedly, be washed till neutrality with 0.01mol/L ammoniacal liquor, suction filtration, drying gets pale solid 7-chloro-3H-quinazoline-4-one 9.52g, and productive rate is 88.1%.
The preparation of step 2:7-chloro-6-nitro-3H-quinazoline-4-one
Under ice-water bath is cooling, 7-chloro-3H-quinazoline-4-one (9.00g, 50.0mmol) is added in nitration mixture (vitriol oil 30mL and nitrosonitric acid 30mL) in batches, finishes, stirring at room 1h is heated to 45 ℃, and stirring is spent the night.Then reaction solution is poured in the 60mL frozen water, filtered, filter the gained solid and wash with water, adopt the acetic acid recrystallization, drying gets yellow solid 7-chloro-6-nitro-3H-quinazoline-4-one 7.78g, and productive rate is 68.3%.
The preparation of step 3:6-nitro-7-methoxyl group-3H-quinazoline-4-one
7-chloro-6-nitro-3H-quinazoline-4-one (7.01g, 31.1mmol) is dissolved in dry 120mLDMF, after add sodium methylate (5.45g, 101.0mmol) absolute methanol solution (120mL) and potassiumiodide (5.16g, 31.1mmol), be heated to 90 ℃, reaction 20h.With the reaction solution suction filtration, regulate filtrate to neutral with acetic acid, dilute with water is separated out solid, and suction filtration gets yellow solid 6-nitro-7-methoxyl group-3H-quinazoline-4-one 6.02g, and productive rate is 87.6%.
The preparation of step 4:6-nitro-7-methoxyl group-4-anilinoquinazoline
6-nitro-7-methoxyl group-3H-quinazoline-4-one (4.42g, 20.0mmol) is joined 45mLSOCl 2In solution, then add 0.4mL DMF, return stirring 2h, solution gradually become the brown clarification, and stopped reaction is cooled to room temperature, steams except excessive SOCl 2, get light yellow solid 4-chloro-6-nitro-7-methoxyl group quinazoline.The light yellow solid that obtains is blended, add the 30mL sherwood oil, decompression steams sherwood oil, repeats to add sherwood oil operation 2 times, removes remaining SOCl 2, obtain yellow solid.Not purified yellow solid is transferred in there-necked flask, add aniline (2.05g, 22.0mmol), Virahol 170mL, return stirring 2h, be cooled to room temperature, collect solid, use washed with isopropyl alcohol, drying, get yellow solid 6-nitro-7-methoxyl group-4-anilinoquinazoline 3.67g, productive rate is 61.9%.
The preparation of step 5:6-amino-7-methoxyl group-4-anilinoquinazoline
6-nitro-7-methoxyl group-4-anilinoquinazoline (2.37g, 8.0mmol) and two hydrated stannous chlorides (10.84g, 48.0mmol) are joined in the 250mL ethyl acetate back flow reaction 1h.React complete, be placed to room temperature, filter, filter the gained solid and wash with ethyl acetate, combined ethyl acetate solution is adjusted to neutrality with saturated sodium bicarbonate solution, and the separating ethyl acetate layer is used the 30mL water washing, anhydrous Na 2SO 4Drying is evaporated to driedly, gets brown solid 6-amino-7-methoxyl group-4-anilinoquinazoline 1.50g, and productive rate is 70.4%.
Step 6: referring to step 4 experimental implementation in embodiment 1.
The preparation of step 7:1-phenyl-3-(7-methoxyl group-4-anilinoquinazoline-6-yl) urea
With phenyl isocyanate (0.26g, 2.2mmol) join in the 20mL acetonitrile, add 6-amino-7-methoxyl group-4-anilinoquinazoline (0.53g, 2.0mmol) under stirring at room, stirring at room 3h in batches, filter to get solid, with acetonitrile washing, drying, then use 80% ethyl alcohol recrystallization, get faint yellow solid 1-phenyl-3-(7-methoxyl group-4-anilinoquinazoline-6-yl) urea (compound 19) 0.51g, productive rate is 66.2%.
Embodiment 201-phenyl-3-[4-(3-trifluoromethylbenzene amido) quinazoline-7-yl] urea (compound 20) synthetic
Step 1 is referring to step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(3-trifluoromethylbenzene amido) quinazoline
Referring to step 2 experimental implementation in embodiment 1, unique difference is for replacing to the aniline that adds in this step the 3-5-trifluoromethylaniline of equimolar amount.
The preparation of step 3:7-amino-4-(3-trifluoromethylbenzene amido) quinazoline
Referring to step 3 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-nitro in this step-4-anilinoquinazoline 7-nitro-4-(3-trifluoromethylbenzene amido) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(3-trifluoromethylbenzene amido) quinazoline-7-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-amino in this step-4-anilinoquinazoline 7-amino-4-(3-trifluoromethylbenzene amido) quinazoline of equimolar amount.
Embodiment 21Synthesizing of 1-(2,3-3,5-dimethylphenyl)-3-(4-anilinoquinazoline-7-yl) urea (compound 21)
Step 1: referring to step 1 experimental implementation in embodiment 1.
Step 2: referring to step 2 experimental implementation in embodiment 1.
Step 3: referring to step 3 experimental implementation in embodiment 1.
Step 4:2, the preparation of 3-dimethylphenyl isocyanate
Referring to step 4 experimental implementation in embodiment 1, unique difference is for replacing to reactant aniline in this step the 23 dimethyl aniline of equimolar amount.
The preparation of step 5:1-(2,3-3,5-dimethylphenyl)-3-(4-anilinoquinazoline-7-yl) urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for to replace to 2 of equimolar amount with reactant phenyl isocyanate in this step, the 3-dimethylphenyl isocyanate.
Embodiment 221-phenyl-3-[4-(2-aminotoluene base) quinazoline-7-yl] urea (compound 22) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(2-aminotoluene base) quinazoline
Referring to step 2 experimental implementation in embodiment 1, unique difference is for replacing to the aniline that adds in this step the 2-aminotoluene of equimolar amount.
The preparation of step 3:7-amino-4-(2-aminotoluene base) quinazoline
Referring to step 3 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-nitro in this step-4-anilinoquinazoline 7-nitro-4-(2-aminotoluene base) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(2-aminotoluene base) quinazoline-7-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-amino in this step-4-anilinoquinazoline 7-amino-4-(2-aminotoluene base) quinazoline of equimolar amount.
Embodiment 23Synthesizing of 1-(2,4,6-trimethylphenyl)-3-(4-anilinoquinazoline-7-yl) urea (compound 23)
Step 1: referring to step 1 experimental implementation in embodiment 1.
Step 2: referring to step 2 experimental implementation in embodiment 1.
Step 3: referring to step 3 experimental implementation in embodiment 1.
Step 4:2,4,6-Three methyl Benzene based isocyanate synthetic
Referring to step 4 experimental implementation in embodiment 1, unique difference is for replacing to reactant aniline in this step the 2，4，6-trimethyl aniline of equimolar amount.
The preparation of step 5:1-(2,4,6-trimethylphenyl)-3-(4-anilinoquinazoline-7-yl) urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for to replace to 2,4 of equimolar amount with reactant phenyl isocyanate in this step, 6-Three methyl Benzene based isocyanate.
Embodiment 24Synthesizing of 1-(4-nitrophenyl)-3-(4-anilinoquinazoline-7-yl) urea (compound 24)
Step 1: referring to step 1 experimental implementation in embodiment 1.
Step 2: referring to step 2 experimental implementation in embodiment 1.
Step 3: referring to step 3 experimental implementation in embodiment 1.
Step 4:4-nitrophenyl isocyanic acid ester synthesis
Referring to step 4 experimental implementation in embodiment 1, unique difference is for replacing to reactant aniline in this step the 4-N-methyl-p-nitroaniline of equimolar amount.
The preparation of step 5:1-(4-nitrophenyl)-3-(4-anilinoquinazoline-7-yl) urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to reactant phenyl isocyanate in this step the 4-nitrophenyl isocyanic ester of equimolar amount.
Embodiment 251-phenyl-3-[4-(4-fluoroanilino) quinazoline-6-yl] urea (compound 25) synthetic
Synthetic route and the method for compound 25 are as follows:
Figure BDA00003382604900201
The preparation of step 1:6-nitro-3H-quinazoline-4-one
2-amino-5-nitrobenzoic acid (7.28g, 40.0mmol) is joined in the 60mL methane amide, be heated to 120 ℃, insulation reaction 16h, be cooled to room temperature, separate out solid, filter, use washed with isopropyl alcohol, drying gets brown solid 6-nitro-3H-quinazoline-4-one 3.94g, and productive rate is 51.6%.
The preparation of step 2:6-nitro-4-(4-fluoroanilino) quinazoline
6-nitro-3H-quinazoline-4-one (2.25g, 11.8mmol) is joined 23mLSOCl 2In solution, then add 0.2mL DMF, return stirring 1h, solution gradually become brown clarification, and stopped reaction is cooled to room temperature, steam except excessive SOCl 2, get yellow solid 4-chloro-6-nitro-quinazoline.The yellow solid that obtains is blended, add the 10mL sherwood oil, decompression steams sherwood oil, repeats to add sherwood oil operation 2 times, removes remaining SOCl 2, get yellow solid.Not purifiedly add 4-fluoroaniline (1.27g in yellow solid, 14.1mmol), Virahol 37mL, return stirring 2h separates out solid, be cooled to room temperature, solid collected by filtration is used washed with isopropyl alcohol, drying, get yellow solid 6-nitro-4-(4-fluoroanilino) quinazoline 2.52g, productive rate is 75.2%.
The preparation of step 3:6-amino-4-(4-fluoroanilino) quinazoline
With 6-nitro-4-(4-fluoroanilino) quinazoline (1.39g, 4.9mmol) and two hydrated stannous chlorides (4.42g, 19.6mmol) and ethyl acetate 49mL mixing, back flow reaction 1h.Reaction solution first becomes clarification, rear appearance precipitation, react complete after, be placed to room temperature, filter, the gained precipitation is washed with ethyl acetate, combined ethyl acetate solution is adjusted to neutrality with saturated sodium bicarbonate solution, the separating ethyl acetate layer is used the 10mL water washing, anhydrous Na 2SO 4Drying is evaporated to driedly, gets yellow-green colour solid 6-amino-4-(4-fluoroanilino) quinazoline 1.12g, and productive rate is 89.9%.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(4-fluoroanilino) quinazoline-6-yl] preparation of urea
With phenyl isocyanate (0.26g, 2.2mmol) join in the 20mL acetonitrile, under stirring at room, add 6-amino-4-(4-fluoroanilino) quinazoline (0.56g in batches, 2.0mmol), stirring at room 3h obtains solid after filtration, wash with acetonitrile, dry, use again 80% ethyl alcohol recrystallization, get faint yellow solid 1-phenyl-3-[4-(4-fluoroanilino) quinazoline-6-yl] urea (compound 25) 0.51g, productive rate is 68.3%.
Embodiment 26Synthesizing of 1-phenyl-3-(4-anilinoquinazoline-6-yl) urea (compound 26)
Step 1: referring to step 1 experimental implementation in embodiment 25.
The preparation of step 2:6-nitro-4-anilinoquinazoline
Referring to step 2 experimental implementation in embodiment 25, unique difference is for replacing to the 4-fluoroaniline that adds in this step the aniline of equimolar amount.
The preparation of step 3:6-amino-4-anilinoquinazoline
Referring to step 3 experimental implementation in embodiment 25, unique difference is for replacing to reactant 6-nitro-4-(4-fluoroanilino) quinazoline in this step the 6-nitro of equimolar amount-4-anilinoquinazoline.
Step 4: referring to step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-(4-phenylamino quinazoline-6-yl) urea
Referring to step 5 experimental implementation in embodiment 25, unique difference is for replacing to reactant 6-amino-4-(4-fluoroanilino) quinazoline in this step the 6-amino of equimolar amount-4-anilinoquinazoline.
Embodiment 271-phenyl-3-[4-(4-toluidine) quinazoline-6-yl] urea (compound 27) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 25.
The preparation of step 2:6-nitro-4-(4-toluidine) quinazoline
Referring to step 2 experimental implementation in embodiment 25, unique difference is for replacing to the 4-fluoroaniline that adds in this step the 4-monomethylaniline of equimolar amount.
The preparation of step 3:6-amino-4-(4-toluidine) quinazoline
Referring to step 3 experimental implementation in embodiment 25, unique difference is for replacing to reactant 6-nitro-4-(4-fluoroanilino) quinazoline in this step 6-nitro-4-(4-toluidine) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(4-toluidine) quinazoline-6-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 25, unique difference is for replacing to reactant 6-amino-4-(4-fluoroanilino) quinazoline in this step 6-amino-4-(4-toluidine) quinazoline of equimolar amount.
Embodiment 281-phenyl-3-[4-(3-bromobenzene amido) quinazoline-6-yl] urea (compound 28) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 25.
The preparation of step 2:6-nitro-4-(3-bromobenzene amido) quinazoline
Referring to step 2 experimental implementation in embodiment 25, unique difference is for replacing to the 4-fluoroaniline that adds in this step the 3-bromaniline of equimolar amount.
The preparation of step 3:6-amino-4-(3-bromobenzene amido) quinazoline
Referring to step 3 experimental implementation in embodiment 25, unique difference is for replacing to reactant 6-nitro-4-(4-fluoroanilino) quinazoline in this step 6-nitro-4-(3-bromobenzene amido) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(3-bromobenzene amido) quinazoline-6-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 25, unique difference is for replacing to reactant 6-amino-4-(4-fluoroanilino) quinazoline in this step 6-amino-4-(3-bromobenzene amido) quinazoline of equimolar amount.
Embodiment 291-phenyl-3-[4-(3-chloro-4-fluoroanilino) quinazoline-6-yl] urea (compound 29) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 25.
The preparation of step 2:6-nitro-4-(3-chloro-4-fluoroanilino) quinazoline
Referring to step 2 experimental implementation in embodiment 25, unique difference is for replacing to the 4-fluoroaniline that adds in this step the 3-chloro-4-fluoroaniline of equimolar amount.
The preparation of step 3:6-amino-4-(3-chloro-4-fluoroanilino) quinazoline
Referring to step 3 experimental implementation in embodiment 25, unique difference is for replacing to reactant 6-nitro-4-(4-fluoroanilino) quinazoline in this step 6-nitro-4-(3-chloro-4-fluoroanilino) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(3-chloro-4-fluoroanilino) quinazoline-6-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 25, unique difference is for replacing to reactant 6-amino-4-(4-fluoroanilino) quinazoline in this step 6-amino-4-(3-chloro-4-fluoroanilino) quinazoline of equimolar amount.
Embodiment 301-phenyl-3-[4-(2 3 dimethyl aniline base) quinazoline-6-yl] urea (compound 30) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 25.
The preparation of step 2:6-nitro-4-(2 3 dimethyl aniline base) quinazoline
Referring to step 2 experimental implementation in embodiment 25, unique difference is for replacing to the 4-fluoroaniline that adds in this step the 23 dimethyl aniline of equimolar amount.
The preparation of step 3:6-amino-4-(2 3 dimethyl aniline base) quinazoline
Referring to step 3 experimental implementation in embodiment 25, unique difference is for replacing to reactant 6-nitro-4-(4-fluoroanilino) quinazoline in this step 6-nitro-4-(2 3 dimethyl aniline base) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(2 3 dimethyl aniline base) quinazoline-6-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 25, unique difference is for replacing to reactant 6-amino-4-(4-fluoroanilino) quinazoline in this step 6-amino-4-(2 3 dimethyl aniline base) quinazoline of equimolar amount.
Embodiment 311-phenyl-3-[7-methoxyl group-4-(3-toluidine) quinazoline-6-yl] urea (compound 31) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 19.
Step 2: referring to step 2 experimental implementation in embodiment 19.
Step 3: referring to step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(3-toluidine) quinazoline
Referring to step 4 experimental implementation in embodiment 19, unique difference is for replacing to the aniline that adds in this step the 3-monomethylaniline of equimolar amount.
The preparation of step 5:6-amino-7-methoxyl group-4-(3-toluidine) quinazoline
Referring to step 5 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-nitro in this step-7-methoxyl group-4-anilinoquinazoline the 6-nitro of equimolar amount-7-methoxyl group-4-(3-toluidine) quinazoline.
Step 6: referring to step 4 experimental implementation in embodiment 1.
Step 7:1-phenyl-3-[7-methoxyl group-4-(3-toluidine) quinazoline-6-yl] preparation of urea
Referring to step 7 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-amino in this step-7-methoxyl group-4-anilinoquinazoline the 6-amino of equimolar amount-7-methoxyl group-4-(3-toluidine) quinazoline.
Embodiment 321-phenyl-3-[7-methoxyl group-4-(4-toluidine) quinazoline-6-yl] urea (compound 32) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 19.
Step 2: referring to step 2 experimental implementation in embodiment 19.
Step 3: referring to step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(4-toluidine) quinazoline
Referring to step 4 experimental implementation in embodiment 19, unique difference is for replacing to the aniline that adds in this step the 4-monomethylaniline of equimolar amount.
The preparation of step 5:6-amino-7-methoxyl group-4-(4-toluidine) quinazoline
Referring to step 5 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-nitro in this step-7-methoxyl group-4-anilinoquinazoline the 6-nitro of equimolar amount-7-methoxyl group-4-(4-toluidine) quinazoline.
Step 6: referring to step 4 experimental implementation in embodiment 1.
Step 7:1-phenyl-3-[7-methoxyl group-4-(4-toluidine) quinazoline-6-yl] preparation of urea
Referring to step 7 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-amino in this step-7-methoxyl group-4-anilinoquinazoline the 6-amino of equimolar amount-7-methoxyl group-4-(4-toluidine) quinazoline.
Embodiment 331-phenyl-3-[7-methoxyl group-4-(3-bromobenzene amido) quinazoline-6-yl] urea (compound 33) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 19.
Step 2: referring to step 2 experimental implementation in embodiment 19.
Step 3: referring to step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(3-bromobenzene amido) quinazoline
Referring to step 4 experimental implementation in embodiment 19, unique difference is for replacing to the aniline that adds in this step the 3-bromaniline of equimolar amount.
The preparation of step 5:6-amino-7-methoxyl group-4-(3-bromobenzene amido) quinazoline
Referring to step 5 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-nitro in this step-7-methoxyl group-4-anilinoquinazoline the 6-nitro of equimolar amount-7-methoxyl group-4-(3-bromobenzene amido) quinazoline.
Step 6: referring to step 4 experimental implementation in embodiment 1.
Step 7:1-phenyl-3-[7-methoxyl group-4-(3-bromobenzene amido) quinazoline-6-yl] preparation of urea
Referring to step 7 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-amino in this step-7-methoxyl group-4-anilinoquinazoline the 6-amino of equimolar amount-7-methoxyl group-4-(3-bromobenzene amido) quinazoline.
Embodiment 341-phenyl-3-[7-methoxyl group-4-(3-chloro-4-fluoroanilino) quinazoline-6-yl] urea (compound 34) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 19.
Step 2: referring to step 2 experimental implementation in embodiment 19.
Step 3: referring to step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(3-chloro-4-fluoroanilino) quinazoline
Referring to step 4 experimental implementation in embodiment 19, unique difference is for replacing to the aniline that adds in this step the 3-chloro-4-fluoroaniline of equimolar amount.
The preparation of step 5:6-amino-7-methoxyl group-4-(3-chloro-4-fluoroanilino) quinazoline
Referring to step 5 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-nitro in this step-7-methoxyl group-4-anilinoquinazoline the 6-nitro of equimolar amount-7-methoxyl group-4-(3-chloro-4-fluoroanilino) quinazoline.
Step 6: referring to step 4 experimental implementation in embodiment 1.
Step 7:1-phenyl-3-[7-methoxyl group-4-(3-chloro-4-fluoroanilino) quinazoline-6-yl] preparation of urea
Referring to step 7 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-amino in this step-7-methoxyl group-4-anilinoquinazoline the 6-amino of equimolar amount-7-methoxyl group-4-(3-chloro-4-fluoroanilino) quinazoline.
Embodiment 351-phenyl-3-[7-methoxyl group-4-(2 3 dimethyl aniline base) quinazoline-6-yl] urea (compound 35) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 19.
Step 2: referring to step 2 experimental implementation in embodiment 19.
Step 3: referring to step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(2 3 dimethyl aniline base) quinazoline
Referring to step 4 experimental implementation in embodiment 19, unique difference is for replacing to the aniline that adds in this step the 23 dimethyl aniline of equimolar amount.
The preparation of step 5:6-amino-7-methoxyl group-4-(2 3 dimethyl aniline base) quinazoline
Referring to step 5 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-nitro in this step-7-methoxyl group-4-anilinoquinazoline the 6-nitro of equimolar amount-7-methoxyl group-4-(2 3 dimethyl aniline base) quinazoline.
Step 6: referring to step 4 experimental implementation in embodiment 1.
Step 7:1-phenyl-3-[7-methoxyl group-4-(2 3 dimethyl aniline base) quinazoline-6-yl] preparation of urea
Referring to step 7 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-amino in this step-7-methoxyl group-4-anilinoquinazoline the 6-amino of equimolar amount-7-methoxyl group-4-(2 3 dimethyl aniline base) quinazoline.
Embodiment 361-phenyl-3-[4-(3-bromobenzene amido) quinazoline-7-yl] urea (compound 36) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(3-bromobenzene amido) quinazoline
Referring to step 2 experimental implementation in embodiment 1, unique difference is for replacing to the aniline that adds in this step the 3-bromaniline of equimolar amount.
The preparation of step 3:7-amino-4-(3-bromobenzene amido) quinazoline
Referring to step 3 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-nitro in this step-4-anilinoquinazoline 7-nitro-4-(3-bromobenzene amido) quinazoline of equimolar amount.
Step 4: referring to step 4 experimental implementation in embodiment 1.
Step 5:1-phenyl-3-[4-(3-bromobenzene amido) quinazoline-7-yl] preparation of urea
Referring to step 5 experimental implementation in embodiment 1, unique difference is for replacing to the reactant 7-amino in this step-4-anilinoquinazoline 7-amino-4-(3-bromobenzene amido) quinazoline of equimolar amount.
Embodiment 371-phenyl-3-[7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline-6-yl] urea (compound 37) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 19.
Step 2: referring to step 2 experimental implementation in embodiment 19.
Step 3: referring to step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline
Referring to step 4 experimental implementation in embodiment 19, unique difference is for replacing to the aniline that adds in this step the 4-chloro-3-5-trifluoromethylaniline of equimolar amount.
The preparation of step 5:6-amino-7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline
Referring to step 5 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-nitro in this step-7-methoxyl group-4-anilinoquinazoline the 6-nitro of equimolar amount-7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline.
Step 6: referring to step 4 experimental implementation in embodiment 1.
Step 7:1-phenyl-3-[7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline-6-yl] preparation of urea
Referring to step 7 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-amino in this step-7-methoxyl group-4-anilinoquinazoline the 6-amino of equimolar amount-7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline.
Embodiment 381-phenyl-3-[7-methoxyl group-4-(2-fluoro-4-bromobenzene amido) quinazoline-6-yl] urea (compound 38) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 19.
Step 2: referring to step 2 experimental implementation in embodiment 19.
Step 3: referring to step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(2-fluoro-4-bromobenzene amido) quinazoline
Referring to step 4 experimental implementation in embodiment 19, unique difference is for replacing to the aniline that adds in this step the 2-fluoro-4-bromaniline of equimolar amount.
The preparation of step 5:6-amino-7-methoxyl group-4-(2-fluoro-4-bromobenzene amido) quinazoline
Referring to step 5 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-nitro in this step-7-methoxyl group-4-anilinoquinazoline the 6-nitro of equimolar amount-7-methoxyl group-4-(2-fluoro-4-bromobenzene amido) quinazoline.
Step 6: referring to step 4 experimental implementation in embodiment 1.
Step 7:1-phenyl-3-[7-methoxyl group-4-(2-fluoro-4-bromobenzene amido) quinazoline-6-yl] preparation of urea
Referring to step 7 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-amino in this step-7-methoxyl group-4-anilinoquinazoline the 6-amino of equimolar amount-7-methoxyl group-4-(2-fluoro-4-bromobenzene amido) quinazoline.
Embodiment 391-phenyl-3-[7-methoxyl group-4-(3-acetylenylbenzene amido) quinazoline-6-yl] urea (compound 39) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 19.
Step 2: referring to step 2 experimental implementation in embodiment 19.
Step 3: referring to step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(3-acetylenylbenzene amido) quinazoline
Referring to step 4 experimental implementation in embodiment 19, unique difference is for replacing to the aniline that adds in this step the 3-acetylenylaniline of equimolar amount.
The preparation of step 5:6-amino-7-methoxyl group-4-(3-acetylenylbenzene amido) quinazoline
Referring to step 5 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-nitro in this step-7-methoxyl group-4-anilinoquinazoline the 6-nitro of equimolar amount-7-methoxyl group-4-(3-acetylenylbenzene amido) quinazoline.
Step 6: referring to step 4 experimental implementation in embodiment 1.
Step 7:1-phenyl-3-[7-methoxyl group-4-(3-acetylenylbenzene amido) quinazoline-6-yl] preparation of urea
Referring to step 7 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-amino in this step-7-methoxyl group-4-anilinoquinazoline the 6-amino of equimolar amount-7-methoxyl group-4-(3-acetylenylbenzene amido) quinazoline.
Embodiment 401-phenyl-3-[7-methoxyl group-4-(4-bromobenzene amido) quinazoline-6-yl] urea (compound 40) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 19.
Step 2: referring to step 2 experimental implementation in embodiment 19.
Step 3: referring to step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(4-bromobenzene amido) quinazoline
Referring to step 4 experimental implementation in embodiment 19, unique difference is for replacing to the aniline that adds in this step the 4-bromaniline of equimolar amount.
The preparation of step 5:6-amino-7-methoxyl group-4-(4-bromobenzene amido) quinazoline
Referring to step 5 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-nitro in this step-7-methoxyl group-4-anilinoquinazoline the 6-nitro of equimolar amount-7-methoxyl group-4-(4-bromobenzene amido) quinazoline.
Step 6: referring to step 4 experimental implementation in embodiment 1.
Step 7:1-phenyl-3-[7-methoxyl group-4-(4-bromobenzene amido) quinazoline-6-yl] preparation of urea
Referring to step 7 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-amino in this step-7-methoxyl group-4-anilinoquinazoline the 6-amino of equimolar amount-7-methoxyl group-4-(4-bromobenzene amido) quinazoline.
Embodiment 411-phenyl-3-[7-methoxyl group-4-(3-cyano-aniline base) quinazoline-6-yl] urea (compound 41) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 19.
Step 2: referring to step 2 experimental implementation in embodiment 19.
Step 3: referring to step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(3-cyano-aniline base) quinazoline
Referring to step 4 experimental implementation in embodiment 19, unique difference is for replacing to the aniline that adds in this step the 3-cyano-aniline of equimolar amount.
The preparation of step 5:6-amino-7-methoxyl group-4-(3-cyano-aniline base) quinazoline
Referring to step 5 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-nitro in this step-7-methoxyl group-4-anilinoquinazoline the 6-nitro of equimolar amount-7-methoxyl group-4-(3-cyano-aniline base) quinazoline.
Step 6: referring to step 4 experimental implementation in embodiment 1.
Step 7:1-phenyl-3-[7-methoxyl group-4-(3-cyano-aniline base) quinazoline-6-yl] preparation of urea
Referring to step 7 experimental implementation in embodiment 19, unique difference is for replacing to the reactant 6-amino in this step-7-methoxyl group-4-anilinoquinazoline the 6-amino of equimolar amount-7-methoxyl group-4-(3-cyano-aniline base) quinazoline.
Embodiment 421-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline-6-yl] urea (compound 42) synthetic
Synthetic route and the method for compound 42 are as follows:
Figure BDA00003382604900291
Step 1: referring to step 1 experimental implementation in embodiment 19.
Step 2: referring to step 2 experimental implementation in embodiment 19.
The preparation of step 3:6-nitro-7-chloro-4-(3-toluidine) quinazoline
6-nitro obtained above-7-chloro-3H-quinazoline-4-one (9.00g, 40.0mmol) is joined 90mL SOCl 2In solution, then add 0.9mL DMF, return stirring 2h, solution gradually become the deep yellow clarification, and stopped reaction is cooled to room temperature, steams except excessive SOCl 2, obtain yellow solid 4,7-two chloro-6-nitro-quinazolines.Yellow solid is blended, add the 50mL sherwood oil, decompression steams sherwood oil, repeats to add sherwood oil operation 2 times, removes remaining SOCl 2, obtain yellow solid.Not purified yellow solid is transferred in there-necked flask, add 3-monomethylaniline (4.71g, 44.0mmol), Virahol 170mL, return stirring 2h, separate out solid, be cooled to room temperature, collect solid, use washed with isopropyl alcohol, drying gets yellow solid 6-nitro-7-chloro-4-(3-toluidine) quinazoline 6.87g, and productive rate is 54.7%.
The preparation of step 4:6-nitro-7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline
With 6-nitro-7-chloro-4-(3-toluidine) quinazoline (6.28g, 20.0mmol) add N methyl piperazine (20.0g, 200.0mmol) in, under nitrogen atmosphere, be heated to 70 ℃, insulation reaction 4h, be cooled to room temperature, evaporated under reduced pressure adds ethyl acetate extraction, suction filtration, filtrate is spin-dried for, residue adds 60mL ethanol, stirs the lower 120mL of dropping distilled water, stirs 30min, separate out yellow solid, suction filtration gets yellow solid 6-nitro-7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline 4.32g, productive rate 57.1%.
The preparation of step 5:6-amino-7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline
with 6-nitro-7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline (3.79g, 10.0mmol), hydrazine hydrate (0.20g, 4.0mmol) and Raney's nickel (7.6mL) join in ethanol (500mL), under nitrogen atmosphere, be heated to reflux, insulation reaction 2h, with the reaction solution suction filtration, and with the filtrate decompression evaporate to dryness, adopt sherwood oil and ethyl acetate (3:1) mixed solution washing residue, suction filtration, obtain yellow solid 6-amino-7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline 2.15g, productive rate 61.7%.
Step 6: referring to step 4 experimental implementation in embodiment 1.
Step 7:1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline-6-yl] preparation of urea
With 6-amino-7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline (0.70g, 2.0mmol) in 60 ℃ of thermosols in the 20mL acetonitrile, add phenyl isocyanate (0.26g, 2.2mmol), back flow reaction 2h filters, the acetonitrile washing leaching cake, drying gets faint yellow solid 1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline-6-yl] urea 0.68g, productive rate is 72.8%.
Embodiment 431-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(3-bromobenzene amido) quinazoline-6-yl] urea (compound 43) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 19.
Step 2: referring to step 2 experimental implementation in embodiment 19.
The preparation of step 3:6-nitro-7-chloro-4-(3-bromobenzene amido) quinazoline
Referring to step 3 experimental implementation in embodiment 42, unique difference is for replacing to the aniline that adds in this step the 3-bromaniline of equimolar amount.
The preparation of step 4:6-nitro-7-(4-methylpiperazine-1-yl)-4-(3-bromobenzene amido) quinazoline
Referring to step 4 experimental implementation in embodiment 42, unique difference is for replacing to the reactant 6-nitro in this step-7-chloro-4-(3-toluidine) quinazoline the 6-nitro of equimolar amount-7-chloro-4-(3-bromobenzene amido) quinazoline.
The preparation of step 5:6-amino-7-(4-methylpiperazine-1-yl)-4-(3-bromobenzene amido) quinazoline
Referring to step 5 experimental implementation in embodiment 42, unique difference is for replacing to the reactant 6-nitro-7-(4-methylpiperazine-1-yl) in this step-4-(3-toluidine) quinazoline the 6-nitro-7-(4-methylpiperazine-1-yl) of equimolar amount-4-(3-bromobenzene amido) quinazoline.
Step 6: referring to step 4 experimental implementation in embodiment 1.
Step 7:1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(3-bromobenzene amido) quinazoline-6-yl] preparation of urea
Referring to step 7 experimental implementation in embodiment 42, unique difference is for replacing to the reactant 6-amino-7-(4-methylpiperazine-1-yl) in this step-4-(3-toluidine) quinazoline the 6-amino-7-(4-methylpiperazine-1-yl) of equimolar amount-4-(3-bromobenzene amido) quinazoline.
Embodiment 441-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(2-fluoro-4-bromobenzene amido) quinazoline-6-yl] urea (compound 44) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 19.
Step 2: referring to step 2 experimental implementation in embodiment 19.
The preparation of step 3:6-nitro-7-chloro-4-(2-fluoro-4-bromobenzene amido) quinazoline
Referring to step 3 experimental implementation in embodiment 42, unique difference is for replacing to the aniline that adds in this step the 2-fluoro-4-bromaniline of equimolar amount.
The preparation of step 4:6-nitro-7-(4-methylpiperazine-1-yl)-4-(2-fluoro-4-bromobenzene amido) quinazoline
Referring to step 4 experimental implementation in embodiment 42, unique difference is for replacing to the reactant 6-nitro in this step-7-chloro-4-(3-toluidine) quinazoline the 6-nitro of equimolar amount-7-chloro-4-(2-fluoro-4-bromobenzene amido) quinazoline.
The preparation of step 5:6-amino-7-(4-methylpiperazine-1-yl)-4-(2-fluoro-4-bromobenzene amido) quinazoline
Referring to step 5 experimental implementation in embodiment 42, unique difference is for replacing to the reactant 6-nitro-7-(4-methylpiperazine-1-yl) in this step-4-(3-toluidine) quinazoline the 6-nitro-7-(4-methylpiperazine-1-yl) of equimolar amount-4-(2-fluoro-4-bromobenzene amido) quinazoline.
Step 6: referring to step 4 experimental implementation in embodiment 1.
Step 7:1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(2-fluoro-4-bromobenzene amido) quinazoline-6-yl] preparation of urea
Referring to step 7 experimental implementation in embodiment 42, unique difference is for replacing to the reactant 6-amino-7-(4-methylpiperazine-1-yl) in this step-4-(3-toluidine) quinazoline the 6-amino-7-(4-methylpiperazine-1-yl) of equimolar amount-4-(2-fluoro-4-bromobenzene amido) quinazoline.
Embodiment 451-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(2-methyl-4-anisole amido) quinazoline-6-yl] urea (compound 45) synthetic
Step 1 is referring to step 1 experimental implementation in embodiment 19.
Step 2 is referring to step 2 experimental implementation in embodiment 19.
The preparation of step 3:6-nitro-7-chloro-4-(2-methyl-4-anisole amido) quinazoline
Referring to step 3 experimental implementation in embodiment 42, unique difference is for replacing to the aniline that adds in this step the 2-methyl of equimolar amount-4-anisidine.
The preparation of step 4:6-nitro-7-(4-methylpiperazine-1-yl)-4-(2-methyl-4-anisole amido) quinazoline
Referring to step 4 experimental implementation in embodiment 42, unique difference is for replacing to the reactant 6-nitro in this step-7-chloro-4-anilinoquinazoline the 6-nitro of equimolar amount-7-chloro-4-(2-methyl-4-anisole amido) quinazoline.
The preparation of step 5:6-amino-7-(4-methylpiperazine-1-yl)-4-(2-methyl-4-anisole amido) quinazoline
Referring to step 5 experimental implementation in embodiment 42, unique difference is for replacing to the reactant 6-nitro-7-(4-methylpiperazine-1-yl) in this step-4-anilinoquinazoline the 6-nitro-7-(4-methylpiperazine-1-yl) of equimolar amount-4-(2-methyl-4-anisole amido) quinazoline.
Step 6 is referring to step 4 experimental implementation in embodiment 1.
Step 7:1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(2-methyl-4-anisole amido) quinazoline-6-yl] preparation of urea
Referring to step 7 experimental implementation in embodiment 42, unique difference is for replacing to the reactant 6-amino-7-(4-methylpiperazine-1-yl) in this step-4-anilinoquinazoline the 6-amino-7-(4-methylpiperazine-1-yl) of equimolar amount-4-(2-methyl-4-anisole amido) quinazoline.
Embodiment 461-phenyl-3-[7-(morpholine-4-yl)-4-(3-chloro-4-fluoroanilino) quinazoline-6-yl] urea (compound 46) synthetic
Synthetic route and the method for compound 46 are as follows:
Step 1: referring to step 1 experimental implementation in embodiment 19.
Step 2: referring to step 2 experimental implementation in embodiment 19.
The preparation of step 3:6-nitro-7-chloro-4-(3-chloro-4-fluoroanilino) quinazoline
Referring to step 3 experimental implementation in embodiment 42, unique difference is for replacing to the aniline that adds in this step the 3-chloro-4-fluoroaniline of equimolar amount.
The preparation of step 4:6-nitro-7-(morpholine-4-yl)-4-(3-chloro-4-fluoroanilino) quinazoline
With 6-nitro-7-chloro-4-(3-chloro-4-fluoroanilino) quinazoline (70.62g, 20.0mmol) add morpholine (17.42g, 200.0mmol) in, under nitrogen atmosphere, be heated to 70 ℃, insulation reaction 4h, be cooled to room temperature, evaporated under reduced pressure adds ethyl acetate extraction, suction filtration, filtrate is spin-dried for, residue adds 60mL ethanol, stirs the lower 120mL of dropping distilled water, stirs 30min, separate out yellow solid, suction filtration gets yellow solid 6-nitro-7-(morpholine-4-yl)-4-(3-chloro-4-fluoroanilino) quinazoline 4.73g, productive rate 58.6%.
The preparation of step 5:6-amino-7-(morpholine-4-yl)-4-(3-chloro-4-fluoroanilino) quinazoline
Referring to step 5 experimental implementation in embodiment 42, unique difference is for replacing to the reactant 6-nitro-7-(4-methylpiperazine-1-yl) in this step-4-(3-toluidine) quinazoline the 6-nitro-7-(morpholine-4-yl) of equimolar amount-4-(3-chloro-4-fluoroanilino) quinazoline.
Step 6: referring to step 4 experimental implementation in embodiment 1.
Step 7:1-phenyl-3-[7-(morpholine-4-yl)-4-(3-chloro-4-fluoroanilino) quinazoline-6-yl] preparation of urea
Referring to step 7 experimental implementation in embodiment 42, unique difference is for replacing to the reactant 6-amino-7-(4-methylpiperazine-1-yl) in this step-4-(3-toluidine) quinazoline the 6-amino-7-(morpholine-4-yl) of equimolar amount-4-(3-chloro-4-fluoroanilino) quinazoline.
Embodiment 47Synthesizing of 1-phenyl-3-(6-methoxyl group-4-anilinoquinazoline-7-yl) urea (compound 47)
Synthetic route and the method for compound 47 are as follows:
Figure BDA00003382604900341
Synthesizing of step 1:N-(2-methyl-4-methoxyl group-phenyl) ethanamide
With 4-methoxyl group-2-aminotoluene (18.40g, 134.1mmol) dropwise join diacetyl oxide (13.69g, 134.1mmol) and the mixing solutions of 140mL acetic acid in, be heated to 60 ℃, insulation reaction 30min, be evaporated to dried, residue 80mL acetic acid ethyl dissolution is regulated pH to 8.0, separating ethyl acetate layer with saturated sodium bicarbonate solution, with distilled water and saturated common salt water washing, anhydrous Na 2SO 4Drying is evaporated to driedly, gets yellow solid N-(2-methyl-4-methoxyl group-phenyl) ethanamide 18.22g, and productive rate is 75.8%.
Step 2:N-(2-methyl-4-methoxyl group-5-nitrophenyl) ethanamide
N-(2-methyl-4-methoxyl group-phenyl) ethanamide (16.18g, 90.3mmol) is dissolved in the 166ml trifluoroacetic acid, and ice-water bath is cooled to 0 ℃.Slowly add saltpetre (10.11g, 100.0mmol), stirring at room 1h.Reaction solution is poured in frozen water quenched, (2 * 50mL) extractions, combined ethyl acetate solution is adjusted to neutrality with saturated sodium bicarbonate solution, with distilled water and saturated common salt water washing, anhydrous Na with ethyl acetate 2SO 4Drying is evaporated to driedly, and residue adds in the 100mL ethyl acetate, stirs 1h, and suction filtration gets yellow solid N-(2-methyl-4-methoxyl group-5-nitrophenyl) ethanamide 16.84g, and productive rate is 83.2%.
Step 3:2-acetamido-5-methoxyl group-4-nitrobenzoic acid
With N-(2-methyl-4-methoxyl group-5-nitrophenyl) ethanamide (15.04g, 67.1mmol) join sal epsom (10.11g, 84.0mmol) and potassium permanganate (29.22g, 184.9mmol) the 671mL aqueous solution in, be warming up to 80 ℃, the reaction 45min after, add sal epsom (5.08g, 42.2mmol) and potassium permanganate (14.63g, 92.6mmol), reaction 1h.Suction filtration, (2 * 300mL) wash filter cake with hot water.It is 3.0 that filtrate is acidified to pH with 3.0N HCl solution, add 300mL methylene dichloride separatory, with methylene dichloride (2 * 200mL) extractions, combined dichloromethane solution, anhydrous magnesium sulfate drying, be evaporated to driedly, get yellow solid 2-acetamido-5-methoxyl group-4-nitrobenzoic acid 11.37g, productive rate is 66.7%.
Step 4:2-amino-5-methoxyl group-4-nitrobenzoic acid
With 2-acetamido-5-methoxyl group-4-nitrobenzoic acid (10.67g, 42.0mmol) join in the mixed solution of 38mL distilled water and 15mL concentrated hydrochloric acid, backflow 3h, be cooled to 0 ℃, separate out solid, suction filtration, with the distillation washing, drying gets yellow solid 2-amino-5-methoxyl group-4-nitrobenzoic acid 7.50g, and productive rate is 84.2%.
Step 5:6-methoxyl group-7-nitro-3H-quinazoline-4-one
With 2-amino-5-methoxyl group-4-nitrobenzoic acid (6.70g, 31.5mmol) join in the 100mL methane amide, be heated to 150 ℃, insulation reaction 4.5h is cooled to 0 ℃, separates out solid, suction filtration, drying under reduced pressure gets yellow solid 6-methoxyl group-7-nitro-3H-quinazoline-4-one 5.38g, and productive rate is 77.2%.
Step 6:6-methoxyl group-7-nitro-4-anilinoquinazoline
6-methoxyl group obtained above-7-nitro-3H-quinazoline-4-one (4.42g, 20.0mmol) is joined 44mL SOCl 2In solution, then add 0.4mL DMF, return stirring 2h, solution gradually become the deep yellow clarification, and stopped reaction is cooled to room temperature, steams except excessive SOCl 2, obtain yellow solid 4-chloro-6-methoxyl group-7-nitro-quinazoline.Yellow solid is blended, add the 10mL sherwood oil, decompression steams sherwood oil, repeats to add sherwood oil operation 2 times, removes remaining SOCl 2, obtain yellow solid.Not purified yellow solid is transferred in there-necked flask, add aniline (2.04g, 22.0mmol), Virahol 70mL, return stirring 2h, separate out solid, be cooled to room temperature, collect solid, use washed with isopropyl alcohol, drying gets yellow solid 6-methoxyl group-7-nitro-4-anilinoquinazoline 3.89g, and productive rate is 65.6%.
Step 7:6-methoxyl group-7-amino-4-anilinoquinazoline
6-methoxyl group-7-nitro-4-anilinoquinazoline (5.92g, 20.0mmol) and two hydrated stannous chlorides (18.05g, 80.0mmol) are joined in the 250mL ethyl acetate back flow reaction 1h.React complete, be placed to room temperature, filter, filter the gained solid and wash with ethyl acetate, combined ethyl acetate solution is adjusted to neutrality with saturated sodium bicarbonate solution, and the separating ethyl acetate layer is used the 30mL water washing, anhydrous Na 2SO 4Drying is evaporated to driedly, gets faint yellow solid 6-methoxyl group-7-amino-4-anilinoquinazoline 4.48g, and productive rate is 84.1%.
Step 8: referring to step 4 experimental implementation in embodiment 1.
Step 9:1-phenyl-3-(6-methoxyl group-4-anilinoquinazoline-7-yl) urea
Phenyl isocyanate (0.26g, 2.2mmol) is joined in the 10mL acetonitrile solution, add 6-methoxyl group-7-amino-4-anilinoquinazoline (0.53g under stirring at room in batches, 2.0mmol), stirring at room 3h filters to get solid, with acetonitrile washing (5mL * 3), dry, the gained solid is added in 30ml methyl alcohol backflow 1h, suction filtration while hot, get faint yellow solid 1-phenyl-3-(6-methoxyl group-4-anilinoquinazoline-7-yl) urea 0.60g, productive rate is 77.8%.
Embodiment 481-phenyl-3-[6-(4-methylpiperazine-1-yl)-4-anilinoquinazoline-7-yl] urea (compound 48) synthetic
Synthetic route and the method for compound 48 are as follows:
Figure BDA00003382604900361
Synthesizing of step 1:N-(2-methyl-4-chloro-phenyl) ethanamide
With 4-chloro-2-methyl aniline (18.98g, 134.1mmol) dropwise join diacetyl oxide (13.69g, 134.1mmol) and the mixing solutions of 140mL acetic acid in, be heated to 60 ℃, insulation reaction 60min, be evaporated to dried, residue 80mL acetic acid ethyl dissolution is regulated pH to 8.0, separating ethyl acetate layer with saturated sodium bicarbonate solution, with distilled water and saturated common salt water washing, anhydrous Na 2SO 4Drying is evaporated to driedly, gets yellow solid N-(2-methyl-4-chloro-phenyl) ethanamide 16.70g, and productive rate is 67.8%.
Step 2:N-(2-methyl-4-chloro-5-nitrophenyl) ethanamide
N-(2-methyl-4-chloro-phenyl) ethanamide (16.58g, 90.3mmol) is dissolved in the 166ml trifluoroacetic acid, and ice-water bath is cooled to 0 ℃.Slowly add saltpetre (10.11g, 100.0mmol), stirring at room 1h.Reaction solution is poured in frozen water quenched, (2 * 50mL) extractions, combined ethyl acetate solution is adjusted to neutrality with saturated sodium bicarbonate solution, with distilled water and saturated common salt water washing, anhydrous Na with ethyl acetate 2SO 4Drying is evaporated to driedly, and residue adds in the 100mL ethyl acetate, stirs 1h, and suction filtration gets yellow solid N-(2-methyl-4-chloro-5-nitrophenyl) ethanamide 15.93g, and productive rate is 77.1%.
Step 3:2-acetamido-5-chloro-4-nitrobenzoic acid
With N-(2-methyl-4-chloro-5-nitrophenyl) ethanamide (15.34g, 67.1mmol) join sal epsom (10.11g, 84.0mmol) and potassium permanganate (29.22g, 184.9mmol) the 671mL aqueous solution in, be warming up to 80 ℃, the reaction 45min after, add sal epsom (5.08g, 42.2mmol) and potassium permanganate (14.63g, 92.6mmol), reaction 1h.Suction filtration, (2 * 300mL) wash filter cake with hot water.It is 3.0 that filtrate is acidified to pH with 3.0N HCl solution, add 300mL methylene dichloride separatory, with methylene dichloride (2 * 200mL) extractions, combined dichloromethane solution, anhydrous magnesium sulfate drying, be evaporated to driedly, get yellow solid 2-acetamido-5-chloro-4-nitrobenzoic acid 11.84g, productive rate is 68.2%.
Step 4:2-amino-5-chloro-4-nitrobenzoic acid
With 2-acetamido-5-chloro-4-nitrobenzoic acid (10.86g, 42.0mmol) join in the mixed solution of 38mL distilled water and 15mL concentrated hydrochloric acid, backflow 3h, be cooled to 0 ℃, separate out solid, suction filtration, use distilled water wash, drying gets yellow solid 2-amino-5-chloro-4-nitrobenzoic acid 8.39g, and productive rate is 92.2%.
Step 5:6-chloro-7-nitro-3H-quinazoline-4-one
2-amino-5-chloro-4-nitrobenzoic acid (6.82g, 31.5mmol) is joined in the 100mL methane amide, be heated to 150 ℃, insulation reaction 4.5h, be cooled to 0 ℃, separate out solid, suction filtration, drying under reduced pressure gets yellow solid 6-chloro-7-nitro-3H-quinazoline-4-one 6.03g, and productive rate is 84.9%.
Step 6:6-chloro-7-nitro-4-anilinoquinazoline
6-chloro-7-nitro obtained above-3H-quinazoline-4-one (4.51g, 20.0mmol) is joined 45mL SOCl 2In solution, then add 0.4mL DMF, return stirring 2h, solution gradually become the deep yellow clarification, and stopped reaction is cooled to room temperature, steams except excessive SOCl 2, obtain yellow solid 4,6-two chloro-7-nitro-quinazolines.Yellow solid is blended, add the 10mL sherwood oil, decompression steams sherwood oil, repeats to add sherwood oil operation 2 times, removes remaining SOCl 2, obtain yellow solid.Not purified yellow solid is transferred in there-necked flask, add aniline (2.04g, 22.0mmol), Virahol 70mL, return stirring 2h, separate out solid, be cooled to room temperature, collect solid, use washed with isopropyl alcohol, drying gets yellow solid 6-chloro-7-nitro-4-anilinoquinazoline 4.25g, and productive rate is 70.8%.
The preparation of step 7:6-(4-methylpiperazine-1-yl)-7-nitro-4-anilinoquinazoline
With 6-chloro-7-nitro-4-anilinoquinazoline (6.01g, 20.0mmol) add N methyl piperazine (20.0g, 200.0mmol) in, under nitrogen atmosphere, be heated to 70 ℃, insulation reaction 4h, be cooled to room temperature, evaporated under reduced pressure adds ethyl acetate extraction, suction filtration, filtrate is spin-dried for, residue adds 60mL ethanol, stirs the lower 120mL of dropping distilled water, stirs 30min, separate out yellow solid, suction filtration gets yellow solid 6-(4-methylpiperazine-1-yl)-7-nitro-4-anilinoquinazoline 5.46g, productive rate 90.8%.
The preparation of step 8:6-(4-methylpiperazine-1-yl)-7-amino-4-anilinoquinazoline
With 6-(4-methylpiperazine-1-yl)-7-nitro-4-anilinoquinazoline (3.64g, 10.0mmol), hydrazine hydrate (0.20g, 4.0mmol) and Raney's nickel (7.6mL) join in ethanol (500mL), under nitrogen atmosphere, be heated to reflux, insulation reaction 2h, with the reaction solution suction filtration, and with the filtrate decompression evaporate to dryness, adopt sherwood oil and ethyl acetate (3:1) mixed solution washing residue, suction filtration obtains yellow solid 6-(4-methylpiperazine-1-yl)-7-amino-4-anilinoquinazoline 2.79g, productive rate 83.4%.
Step 9: referring to step 4 experimental implementation in embodiment 1.
Step 10:1-phenyl-3-[6-(4-methylpiperazine-1-yl)-4-anilinoquinazoline-7-yl] urea
With 6-(4-methylpiperazine-1-yl)-7-amino-4-anilinoquinazoline (0.67g, 2.0mmol) in 60 ℃ of thermosols in the 20mL acetonitrile, add phenyl isocyanate (0.26g, 2.2mmol), back flow reaction 2h filters, the acetonitrile washing leaching cake, drying gets off-white color solid 1-phenyl-3-[6-(4-methylpiperazine-1-yl)-4-anilinoquinazoline-7-yl] urea 0.61g, productive rate is 67.2%.
Embodiment 491-phenyl-3-[6-(morpholine-4-yl)-4-anilinoquinazoline-7-yl] urea (compound 49) synthetic
Step 1: referring to step 1 experimental implementation in embodiment 48.
Step 2: referring to step 2 experimental implementation in embodiment 48.
Step 3: referring to step 3 experimental implementation in embodiment 48.
Step 4: referring to step 4 experimental implementation in embodiment 48.
Step 5: referring to step 5 experimental implementation in embodiment 48.
Step 6: referring to step 6 experimental implementation in embodiment 48.
The preparation of step 7:6-(morpholine-4-yl)-7-nitro-4-anilinoquinazoline
6-chloro-7-nitro-4-anilinoquinazoline (6.01g, 20.0mmol) is added in morpholine (17.42g, 200.0mmol), under nitrogen atmosphere, be heated to 70 ℃, insulation reaction 4h, be cooled to room temperature, evaporated under reduced pressure adds ethyl acetate extraction, suction filtration, filtrate is spin-dried for, and residue adds 60mL ethanol, stir the lower 120mL of dropping distilled water, stir 30min, separate out yellow solid, suction filtration gets yellow solid 6-(morpholine-4-yl)-7-nitro-4-anilinoquinazoline 5.10g, productive rate 72.6%.
The preparation of step 8:6-(morpholine-4-yl)-7-amino-4-anilinoquinazoline
Referring to step 8 experimental implementation in embodiment 48, unique difference is for replacing to the reactant 6-in this step (4-methylpiperazine-1-yl)-7-nitro-4-anilinoquinazoline the 6-(morpholine-4-yl) of equimolar amount-7-nitro-4-anilinoquinazoline.
Step 9: referring to step 4 experimental implementation in embodiment 1.
Step 10:1-phenyl-3-[6-(morpholine-4-yl)-4-anilinoquinazoline-7-yl] preparation of urea
Referring to step 10 experimental implementation in embodiment 48, unique difference is for replacing to the reactant 6-in this step (4-methylpiperazine-1-yl)-7-amino-4-anilinoquinazoline the 6-(morpholine-4-yl) of equimolar amount-7-amino-4-anilinoquinazoline.
Embodiment 501-phenyl-3-[7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline-6-yl] urea hydrochloride (compound 50) synthetic
Synthetic route and the method for compound 45 are as follows:
Figure BDA00003382604900391
Adopt the method identical with embodiment 37 to prepare 1-phenyl-3-[7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline-6-yl] urea, 1-phenyl-3-[7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline-6-yl with preparation] urea (0.2g, 0.41 * 10 -3Mol) be dissolved in the mixing solutions of ethanol and ethylene dichloride (3:7), add 2N ethanol solution hydrochloride (2mL) to filter, filtration cakes torrefaction obtains white solid 1-phenyl-3-[7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline-6-yl] the urea hydrochloride.
Table 1 has been listed the yield result in compound 1-49 preparation process in above-described embodiment 1-49.
The yield of each step in table 1 compound 1-49 preparation process
Figure BDA00003382604900392
Figure BDA00003382604900401
Figure BDA00003382604900411
Table 2 has been listed molecular structure and the sign of the compound 1-that obtains according to embodiment of the present invention 1-.
Figure BDA00003382604900412
Figure BDA00003382604900421
Figure BDA00003382604900431
Figure BDA00003382604900441
Figure BDA00003382604900451
Figure BDA00003382604900471
Figure BDA00003382604900481
Test case 11-phenyl-3-[4-(4-toluidine) quinazoline-7-yl] mensuration of urea (compound 2)
Chromatographic condition: C 18Chromatographic column (Luna250 * 4.6mm5 μ), moving phase, acetonitrile: water (pH=3.0, phosphoric acid)=23: 77, flow velocity: 1.0mL/min detects wavelength: 254nm, sample size: 10 μ L.
System suitability test: get compound 2 contrast solutions (3mg/mL) and press under chromatographic condition sample introduction and measure, theoretical plate number counts 4120 with compound 2 peaks, and retention time is: 14.454min.
Detectability and quantitative limit: respectively take S/N as 3 and 10 as investigating index, the detection that records compound 2 is limited to 90ng, quantitatively is limited to 210ng.
The circulation ratio experiment: under chromatographic condition, reference substance solution continuous sample introduction 5 times, the relative standard deviation (RSD) of compound 2 appearance times is 0.20%, the RSD of peak area is 0.16%.
Sample determination: lab scale product solution (3mg/mL) sample introduction under chromatographic condition is measured.Adopt above-mentioned separation method, according to area normalization method, respectively 3 batches of compounds, 2 lab scale samples are carried out the content inspection, experimental result (as shown in table 3) shows, 3 batch sample content all are not less than 99%.
Table 3: batch sample (compound 2) content check result
Lot number ％
20110101 99.4
20110201 99.4
20110202 99.5
Preparation Preparation Example 1The preparation of pharmaceutical composition (tablet)
Get 10g compound 2, add amylum pregelatinisatum 200g, sucrose 50g, Magnesium Stearate 5g mixes, and with direct powder compression, makes 500, film coating.
Test case 2The antitumor activity screening of part of compounds
1) test materials
Tested medicine: the 36 kinds of new quinazoline compounds (compound 1-36) that synthesize in the present invention, positive control medicine Gefitinib (Gefitinib), ZD6474 (Vandetanib), cis-platinum (Cisplatin), all pharmaceutical purity＞99.5%.
Reagent and instrument: DMEM substratum (Gibco BRL); Calf serum (HyClone) trypsin Amresco); Tetrazolium bromide (MTT, Sigma); TK activation analysis enzyme-linked immunosorbent assay (enzyme-linked immunosorbent assay, ELISA) testing cassete (Chenicon); All the other reagent are domestic analytical reagent.Cell cultures is Costar company product; Constant temperature CO 2The ovum case is available from Heraeus company; Microplate reader is Austrian TECAN-SUNRISE product, model F039246A.
Cell strain: humanized's non-cellule type Adenocarcinoma of lung cell line A549; Human lung carcinoma cell line NCI-H2921(nodus lymphoideus transferring rate).
2) tumor cell line is cultivated
A549 and NCI-H2921 cell strain growth are in containing 10% calf serum and two anti-(penicillin 100UmL -1, Streptomycin sulphate 100 μ gmL -1) the DMEM substratum in, cultivate in 37 ℃, 5% constant temperature incubator, the vegetative period cell of taking the logarithm is tested.
3) cell viability is measured
The logarithmic phase cell is adopted 0.25% tryptic digestion to become and evenly is inoculated in after single-cell suspension liquid carry out cellar culture in 96 well culture plates, discard former substratum until Growth of Cells to individual layer, random packet, add respectively and contain each serum-free DMEM tested and positive drug, act on 48h under 37 ℃, then replaced medium, each hole adds 20 μ l MTT(5mgmL -1), after 37 ℃ of reaction 4h, liquid in the sucking-off hole adds 150 μ l DMSO analytical pure solution jolting 10min, adopts microplate reader in the 490nm wavelength mensuration absorbancy OD of place value.Cell survival rate (%)=administration group OD value/control group OD * 100%.
4) TK activation analysis
With logarithmic phase A549 cell with the washing of ice-cold D-Hank ' s liquid after, add lysate cracking 10min on ice, collecting cell is centrifugal 10min under the 12000g condition at 4 ℃, relative centrifugal force, extracting TK cell crude extract.Choose for A549 cell strain MTT primary dcreening operation compounds effective respectively with the TK cell crude extract at 37 ℃ of effect 20min, use the EDTA termination reaction after adding 30 ℃ of analytic liquid and peptide substrates to hatch 45min.Get each group reaction system 50 μ l to enzyme mark 37 ℃, hole effect 30min, washing rear enclosed 30min, PY20-HRP antibody incubated at room 1h, shaking table jolting.With tetramethyl benzidine (TMB) effect 15min, adopt microplate reader in 450nm wavelength place mensuration absorbancy after washing.
5) cell proliferation experiment method (mtt assay)
In containing the D-MEM/hams substratum of 20% foetal calf serum, be 2 * 10 with tested cell furnishing density 5The suspension of cell/mL.In 96 well culture plates, every hole 50 μ l add respectively each 50 μ l of blank phosphate buffered saline buffer (PBS), solvent control 0.1% dimethyl sulfoxide (DMSO) and different concns monomeric compound with above-mentioned tumor cell line suspension inoculation, all establish 3 multiple holes for every group.Above-mentioned 96 well culture plates are placed in saturated humidity, 37 ℃ and 5%CO 2Cultivated 48 hours in incubator, cultivating front 4 hours of end, each culture hole adds 5mg/mL tetrazolium (MTT) 10 μ l, after cultivating end, discard culture supernatant, suspension cell needs centrifugal rear abandoning supernatant, and every hole adds reaction stop solution 150 μ l, standing 1 hour, detect each hole absorbancy (OD) value with enzyme-linked immunosorbent assay instrument, measure wavelength X=570nm, reference wavelength λ=630nm, and calculate the tumour cell survival rate.
The compounds of this invention is dissolved in DMSO, and the ultimate density after interpolation is below 0.1%.With the substratum that only adds DMSO in contrast.
The inhibition tumor cell proliferation activity result of the compounds of this invention (with respect to contrast (adding DMSO)) is as shown in table 4.
6) data statistics and analysis
Testing data mean ± SEM(mean+SD) difference of respectively organizing between numerical value is checked in expression in conjunction with Tukey with one-way analysis of variance (One-way ANOVA).P＜0.05 expression has statistical significance.
7) result
The impact of new compound on each tumor cell line cell proliferation: concentration be 10 μ M new compound (3 multiple hole/group) respectively with each cell strain effect 48h, the impact of mtt assay observation new compound on tumor cell proliferation.Its result is as shown in table 4:
Table 4: compound 1-36MTT method cytoactive garbled data
Figure BDA00003382604900511
Figure BDA00003382604900521
8) conclusion: as seen from Table 4, with control drug Gefitinib (Gefitinib), ZD6474 (Vandetanib), cis-platinum (Cisplatin) is compared, compound of the present invention is after antitumor activity screening, for the A549 cell, compound 2, 9, 11, 13, 17, 18, 19, 24, 27, 32, 33, 34 have shown obvious anti-tumor activity, its tumour cell survival rate is lower than tumour cell survival rate (Fig. 1 of control drug, Fig. 2 and Fig. 3 show respectively at compound 2, 18 and 33 under different concns to the restraining effect of A549 cell, in accompanying drawing, the * expression is compared with control group, difference has statistical significance, p＜0.01, * expression is compared with control group, and difference has statistical significance, p＜0.05), except compound 4,7,8,10,21,30, other compound also shows stronger anti-tumor activity in addition.For the NCI-H2921 cell, compound 2,4,9,10,18,22,33 has shown obvious anti-tumor activity, and its tumour cell survival rate is lower than the tumour cell survival rate of control drug, and other compound also shows stronger anti-tumor activity.Show thus, compound of the present invention can be to relating to the disease of protein tyrosine kinase overexpression, and especially malignant tumour is effectively treated.
Above specific description of embodiments of the present invention does not limit the present invention, and those skilled in the art can make according to the present invention various changes or distortion, only otherwise break away from spirit of the present invention, all should belong to the scope of claims of the present invention.

Claims (11)

1. the phenylurea coupling quinazoline compounds shown in a formula (I) or its pharmacy acceptable salt,
Figure FDA00003382604800011
Wherein, R 1Be H; Br, Cl or F;-CH 3,-CH 2-CH 3,-CH 2(CH 3) 2Or-CF 3-O-CH 3,-O-CH 2-CH 3Or-O-CH 2(CH 3) 2-C ≡ CH or-C ≡ N;
n 1Be 1,2,3,4 or 5;
R 2Or R 3One of be the group shown in formula (II);
Figure FDA00003382604800012
Wherein, R 4Be H; Br, Cl or F;-CH 3,-CH 2-CH 3,-CH 2(CH 3) 2Or-CF 3-O-CH 3,-O-CH 2-CH 3Or-O-CH 2(CH 3) 2-NH 2Or-NO 2
n 2Be 1,2,3,4 or 5;
R 2Or R 3In another one be H ,-O-CH 3,-O-CH 2-CH 3,-O-CH 2(CH 3) 2,
Figure FDA00003382604800013
2. phenylurea coupling quinazoline compounds according to claim 1 or its pharmacy acceptable salt, is characterized in that, the phenylurea coupling quinazoline compounds shown in described formula I or its pharmacy acceptable salt are selected from following compound:
1-phenyl-3-(4-anilinoquinazoline-7-yl) urea,
1-phenyl-3-[4-(4-toluidine) quinazoline-7-yl] urea,
1-phenyl-3-[4-(3-toluidine) quinazoline-7-yl] urea,
1-phenyl-3-[4-(2-aminotoluene base) quinazoline-7-yl] urea,
1-phenyl-3-[4-(4-anisole amido) quinazoline-7-yl] urea,
1-phenyl-3-[4-(2-fluoro-4-bromobenzene amido) quinazoline-7-yl] urea,
1-phenyl-3-[4-(3-isopropyl benzene amido) quinazoline-7-yl] urea,
1-phenyl-3-[4-(3-chloro-4-fluoroanilino) quinazoline-7-yl] urea,
1-phenyl-3-[4-(2，4，6-trimethyl aniline base) quinazoline-7-yl] urea,
1-phenyl-3-[4-(2 3 dimethyl aniline base) quinazoline-7-yl] urea,
1-(2-aminomethyl phenyl)-3-(4-anilinoquinazoline-7-yl) urea,
1-phenyl-3-[4-(2-chloroanilino) quinazoline-7-yl] urea,
1-phenyl-3-[4-(2,4 difluorobenzene amido) quinazoline-7-yl] urea,
1-phenyl-3-[4-(3-trifluoromethylbenzene amido) quinazoline-7-yl] urea,
1-(2,3-3,5-dimethylphenyl)-3-(4-anilinoquinazoline-7-yl) urea,
1-(2,4 difluorobenzene base)-3-(4-anilinoquinazoline-7-yl) urea,
1-(4-p-methoxy-phenyl)-3-(4-anilinoquinazoline-7-yl) urea,
1-(2,4,6-trimethylphenyl)-3-(4-anilinoquinazoline-7-yl) urea,
1-(4-nitrophenyl)-3-(4-anilinoquinazoline-7-yl) urea,
1-(4-p-methoxy-phenyl)-3-[4-(2 3 dimethyl aniline base) quinazoline-7-yl] urea,
1-phenyl-3-[4-(4-fluoroanilino) quinazoline-7-yl] urea,
1-(4-fluorophenyl)-3-[4-(4-toluidine) quinazoline-7-yl] urea,
1-(4-p-methoxy-phenyl)-3-[4-(4-toluidine) quinazoline-7-yl] urea,
1-phenyl-3-[4-(4-fluoroanilino) quinazoline-6-yl] urea,
1-phenyl-3-(7-methoxyl group-4-anilinoquinazoline-6-yl) urea,
1-phenyl-3-(4-anilinoquinazoline-6-yl) urea,
1-phenyl-3-[4-(3-bromobenzene amido) quinazoline-7-yl] urea,
1-phenyl-3-[4-(4-toluidine) quinazoline-6-yl] urea,
1-phenyl-3-[4-(3-bromobenzene amido) quinazoline-6-yl] urea,
1-phenyl-3-[4-(2 3 dimethyl aniline base) quinazoline-6-yl] urea,
1-phenyl-3-[4-(3-chloro-4-fluoroanilino) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(4-toluidine) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(3-toluidine) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(2 3 dimethyl aniline base) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(3-bromobenzene amido) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(2-fluoro-4-bromobenzene amido) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(3-acetylenylbenzene amido) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(4-bromobenzene amido) quinazoline-6-yl] urea,
1-phenyl-3-[7-methoxyl group-4-(3-cyano-aniline base) quinazoline-6-yl] urea,
1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline-6-yl] urea,
1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(3-bromobenzene amido) quinazoline-6-yl] urea,
1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(2-fluoro-4-bromobenzene amido) quinazoline-6-yl] urea,
1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(2-methyl-4-anisole amido) quinazoline-6-yl] urea,
1-phenyl-3-[7-(morpholine-4-yl)-4-(3-chloro-4-fluoroanilino) quinazoline-6-yl] urea,
1-phenyl-3-(6-methoxyl group-4-anilinoquinazoline-7-yl) urea,
1-phenyl-3-[6-(4-methylpiperazine-1-yl)-4-anilinoquinazoline-7-yl] urea,
1-phenyl-3-[6-(morpholine-4-yl)-4-anilinoquinazoline-7-yl] urea or
1-phenyl-3-[7-methoxyl group-4-(3-chloro-4-fluoroanilino) quinazoline-6-yl] urea; Or the salt of these compounds.
3. phenylurea coupling quinazoline compounds according to claim 1 and 2 or its pharmacy acceptable salt, it is characterized in that, described pharmacy acceptable salt is hydrochloride, hydrobromate, vitriol, Hemisulphate, phosphoric acid salt or carboxylate salt, preferred amino acid salt.
4. one kind prepares the phenylurea coupling quinazoline compounds shown in claim 1 Chinese style (I) or the method for its pharmacy acceptable salt, comprises the following steps:
Step a: the compound shown in formula (III) in organic solvent with catalyst reaction, preferred back flow reaction 1h, the compound shown in production (IV);
Figure FDA00003382604800031
Wherein, R 5Or R 6One of be NO 2
R 5Or R 6In another one be H ,-O-CH 3,-O-CH 2-CH 3,-O-CH 2(CH 3) 2,
Figure FDA00003382604800041
Step b: the compound shown in formula (IV) and the compound shown in formula V react in organic solvent, preferred back flow reaction 1.5h, and the compound shown in production (VI),
Figure FDA00003382604800042
Wherein, R 1, n 1Definition with R in formula I 1, n 1Definition identical;
Step c: the compound shown in formula (VI) reacts with reductive agent in organic solvent, preferred back flow reaction 1h, the compound shown in production (VII);
Figure FDA00003382604800043
R wherein 7Or R 8One of be NH 2
R 7Or R 8In another one be H ,-O-CH 3,-O-CH 2-CH 3,-O-CH 2(CH 3) 2,
Figure FDA00003382604800044
Steps d: the compound shown in the compound shown in formula (VII) and formula (VIII) in organic solvent, preferably at room temperature reaction 3h, the compound shown in production (I);
Figure FDA00003382604800051
Wherein, R 4, n 2Definition and formula (I) in R 4, n 2Definition identical;
Preferably, described method further comprises:
Step e: under room temperature, the compound shown in formula (I) and acid or alkali react the compound shown in production (X) in organic solvent;
Figure FDA00003382604800052
Wherein, M is hydrochloric acid, Hydrogen bromide, sulfuric acid, hemisulfic acid, phosphoric acid or carboxylic acid, preferred amino acid or hydrochloric acid, R 1, n 1, R 2, R 3Definition with R in formula I 1, n 1, R 2, R 3Definition identical.
5. method according to claim 4, is characterized in that, the organic solvent in described step a is sulfur oxychloride, and catalyzer is dimethyl formamide;
Preferably, the organic solvent in described step b is Virahol, anhydrous acetonitrile or anhydrous tetrahydro furan;
Preferably, the organic solvent in described step c is ethyl acetate or dehydrated alcohol; One or more in the preferred tin protochloride of reductive agent, hydrazine hydrate or Raney's nickel;
Preferably, the organic solvent in described steps d is the fine or anhydrous tetrahydro furan of second;
Preferably, the organic solvent in described step e is dehydrated alcohol or methylene dichloride;
Preferably, the preparation method of the compound shown in formula (VIII) comprises: the compound shown in formula (IX) and triphosgene are reacted the compound shown in production (VIII) in organic solvent.
Figure FDA00003382604800053
6. method for preparing the intermediate of the compound shown in claim 1 Chinese style (I), described intermediate is phenyl isocyanate, described method comprises:
With 1 of the compound shown in formula (IX) and triethylamine, the 2-dichloroethane solution is added drop-wise to 1 of triphosgene, in the 2-dichloroethane solution, obtains phenyl isocyanate intermediate corresponding to formula (IX) compound after reaction,
Figure FDA00003382604800061
Wherein, R 4, n 2Definition and formula (I) in R 4, n 2Definition identical.
7. method according to claim 6, it is characterized in that, described method specifically comprises: under the ice-water bath cooling conditions, with 1 of the compound shown in formula (IX) and triethylamine, the 2-dichloroethane solution, be added drop-wise to 1 of triphosgene, in the 2-ethylene dichloride, control rate of addition, preferred 2 drops/secs, after dropwising, stirring at room 1h, reflux 3h, be placed to room temperature, obtain filtrate after filtration, with 1, 2-ethylene dichloride washing leaching cake, merging filtrate, after desolventizing, steaming obtains oily matter, obtain again phenyl isocyanate intermediate corresponding to the compound shown in formula (IX) after vacuum fractionation.
8. a pharmaceutical composition, comprise any one described phenylurea coupling quinazoline compounds or its pharmacy acceptable salt in claim 1-3, and pharmaceutically acceptable carrier, vehicle or thinner.
9. pharmaceutical composition according to claim 8, is characterized in that, described pharmaceutical composition further comprises other active substance.
10. in claim 1-3, any one described phenylurea coupling quinazoline compounds or its pharmacy acceptable salt relate to purposes in the medicine of disease of protein tyrosine kinase overexpression in preparation.
11. purposes according to claim 10 is characterized in that, described disease is malignant tumour, and preferably, described malignant tumour is lung cancer, preferred nonsmall-cell lung cancer; Carcinoma of the pancreas; Phosphorus columnar epithelium cancer; Medullary thyroid carcinoma; The incidence cancer; Esophagus cancer; Cancer of the stomach; Or the preferred bladder cancer of gynecological cancer knurl and mammary cancer.
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CN105622507B (en) * 2016-02-23 2019-02-05 河南大学 A kind of naphthalimide derivative and its preparation method and application
CN107400094A (en) * 2017-09-08 2017-11-28 贾玉庆 Quinazolyl carboxylic acid ester compound and application thereof
CN107400094B (en) * 2017-09-08 2020-04-03 贾玉庆 Quinazolinyl carboxylic ester compound and application thereof
CN111499622A (en) * 2019-07-08 2020-08-07 山东省科学院菏泽分院 Preparation method of medicine for treating bile duct cancer
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