CN103382182B - Phenylurea coupling quinazoline compounds and preparation method thereof, pharmaceutical composition and medicinal usage - Google Patents
Phenylurea coupling quinazoline compounds and preparation method thereof, pharmaceutical composition and medicinal usage Download PDFInfo
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- 0 CC1(CCCC1)N=*C Chemical compound CC1(CCCC1)N=*C 0.000 description 9
- CMLLYEWYLZTWNB-UHFFFAOYSA-N CC(C1)C1c(cc1C)ccc1N Chemical compound CC(C1)C1c(cc1C)ccc1N CMLLYEWYLZTWNB-UHFFFAOYSA-N 0.000 description 1
- FZERHIULMFGESH-UHFFFAOYSA-N CC(Nc1ccccc1)=O Chemical compound CC(Nc1ccccc1)=O FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 1
- DLZDSURBVRGIHK-NSHDSACASA-N C[O](C)c1cc2c(N[C@H]3C=CC=CC3)ncnc2cc1[N+]([O-])=O Chemical compound C[O](C)c1cc2c(N[C@H]3C=CC=CC3)ncnc2cc1[N+]([O-])=O DLZDSURBVRGIHK-NSHDSACASA-N 0.000 description 1
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Abstract
The present invention provides the phenylurea coupling quinazoline compounds shown in a kind of formula (I) or its pharmaceutically acceptable salt,Wherein, R1For H;Br, Cl or F;‑CH3、‑CH2‑CH3、‑CH2(CH3)2Or CF3;‑O‑CH3、‑O‑CH2‑CH3Or O CH2(CH3)2；C ≡ CH or C ≡ N;n1It is 1,2,3,4 or 5;R2Or R3One of for the group shown in formula (II);R4For H;Br, Cl or F;‑CH3、‑CH3‑CH3、‑CH2(CH3)2Or CF3;‑O‑CH3、‑O‑CH2‑CH3Or O CH2(CH3)2;‑NH2;Or NO2;n2It is 1,2,3,4 or 5;R2Or R3In another one be H, O CH3、‑O‑CH2‑CH3、‑O‑CH2(CH3)2、Or
Description
Technical field
The present invention relates to a kind of phenylurea coupling quinazoline compounds, be specifically related to one and there is protein tyrosine kinase
Phenylurea coupling quinazoline compounds of inhibitory action and preparation method thereof, the preparation method of this derivatives intermediates, medicine
Compositions and the purposes in the medicine preparing the disease relating to protein tyrosine kinase overexpression thereof.
Background technology
EGF-R ELISA (EGFR) is a kind of transmembrane glycoprotein being made up of Single polypeptide chain, it and outside
Somatomedin (EGF) combine after be activated, can optionally make the receptor protein phosphorylation containing tyrosine residue.This
Tyrosine phosphorylation effect is relevant with many cell regulation process, such as T cell and the activation of B cell, mitosis, breaks up and sends out
(F.Al-Obeidi et al., the Peptide such as the reaction, cell survival and the upgrowth situation regulation that educate, stimulate to external world
Science47 (1998), 197 and T.Hunter, Cell88 (1997), 333).Research shows, when tyrosine protein kinase is excessive
During expression, the adjusting and controlling growth of cell is out of control, is in proliferative state all the time, so develop into malignant tumor (R.Patarca,
Critical Reviews in Oncogenesis7 (1996), 343).
In the research of epidermal growth factor receptor inhibitor, tyrosine kinase PTK (ProteinTyrosine
Kinase) it is the important molecule target spot of antitumor drug effect of discovered in recent years.Little molecule cheese ammonia based on this shot design
Acid kinase class (4-anilinoquinazoline class) inhibitor, side effect is slight, has good toleration, becomes the various entities for the treatment of and swells
New effective medicine of tumor.
Therefore, to have the noval chemical compound of protein tyrosine kinase inhibitory action significant in exploitation.
Summary of the invention
For the problems referred to above, it is an object of the present invention to provide a kind of phenylurea coupling quinazoline compounds or its
Pharmaceutically acceptable salt, this quinazoline compounds or its pharmaceutically acceptable salt can be used in treatment and relate to albumen cheese ammonia
The disease of acid kinase overexpression.
Another object of the present invention is to provide one to prepare above-mentioned phenylurea coupling quinazoline compounds or its pharmacy
The method of upper acceptable salt.
It is still another object of the present invention to provide one and prepare above-mentioned phenylurea coupling quinazoline compounds and centre thereof
The method of body.
It is still another object of the present invention to provide a kind of pharmaceutical composition.
It is still another object of the present invention to provide above-mentioned phenylurea coupling quinazoline compounds or it is pharmaceutically acceptable
Salt preparation relate to protein tyrosine kinase overexpression disease medicine in purposes.
For reaching above-mentioned purpose, the present invention provide the phenylurea coupling quinazoline compounds shown in a kind of formula (I) or its
Pharmaceutically acceptable salt.
Wherein, R1For H；Br, Cl or F；-CH3、-CH2-CH3、-CH2(CH3)2Or-CF3；-O-CH3、-O-CH2-CH3Or-O-
CH2(CH3)2；-C ≡ CH or-C ≡ N；
n1It is 1,2,3,4 or 5；
R2Or R3One of for the group shown in formula (II)；
Wherein, R4For H；Br, Cl or F；-CH3、-CH2-CH3、-CH2(CH3)2Or-CF3；-O-CH3、-O-CH2-CH3Or-O-
CH2(CH3)2；-NH2；Or-NO2；
n2It is 1,2,3,4 or 5；
R2Or R3In another one be H ,-O-CH3、-O-CH2-CH3、-O-CH2(CH3)2、
Preferably, the phenylurea coupling quinazoline compounds shown in described formula I or the choosing of its pharmaceutically acceptable salt
From following compound:
1-phenyl-3-(4-anilinoquinazoline-7-base) urea,
1-phenyl-3-[4-(4-toluidine) quinazoline-7-base] urea,
1-phenyl-3-[4-(3-toluidine) quinazoline-7-base] urea,
1-phenyl-3-[4-(2-aminotoluene base) quinazoline-7-base] urea,
1-phenyl-3-[4-(4-methoxybenzene amido) quinazoline-7-base] urea,
1-phenyl-3-[4-(2-fluoro-4-bromobenzene amido) quinazoline-7-base] urea,
1-phenyl-3-[4-(3-cumene amido) quinazoline-7-base] urea,
1-phenyl-3-[4-(3-chloro-4-fluoroanilino) quinazoline-7-base] urea,
1-phenyl-3-[4-(2，4，6-trimethyl aniline base) quinazoline-7-base] urea,
1-phenyl-3-[4-(2,3-dimethyl benzene amido) quinazoline-7-base] urea,
1-(2-aminomethyl phenyl)-3-(4-anilinoquinazoline-7-base) urea,
1-phenyl-3-[4-(2-chloroanilino) quinazoline-7-base] urea,
1-phenyl-3-[4-(2,4 difluorobenzene amido) quinazoline-7-base] urea,
1-phenyl-3-[4-(3-trifluoromethylbenzene amido) quinazoline-7-base] urea,
1-(2,3-3,5-dimethylphenyl)-3-(4-anilinoquinazoline-7-base) urea,
1-(2,4 difluorobenzene base)-3-(4-anilinoquinazoline-7-base) urea,
1-(4-methoxyphenyl)-3-(4-anilinoquinazoline-7-base) urea,
1-(2,4,6-trimethylphenyl)-3-(4-anilinoquinazoline-7-base) urea,
1-(4-nitrobenzophenone)-3-(4-anilinoquinazoline-7-base) urea,
1-(4-methoxyphenyl)-3-[4-(2,3-dimethyl benzene amido) quinazoline-7-base] urea,
1-phenyl-3-[4-(4-fluoroanilino) quinazoline-7-base] urea,
1-(4-fluorophenyl)-3-[4-(4-toluidine) quinazoline-7-base] urea,
1-(4-methoxyphenyl)-3-[4-(4-toluidine) quinazoline-7-base] urea,
1-phenyl-3-[4-(4-fluoroanilino) quinazoline-6-base] urea,
1-phenyl-3-(7-methoxyl group-4-anilinoquinazoline-6-base) urea,
1-phenyl-3-(4-anilinoquinazoline-6-base) urea,
1-phenyl-3-[4-(3-bromobenzene amido) quinazoline-7-base] urea,
1-phenyl-3-[4-(4-toluidine) quinazoline-6-base] urea,
1-phenyl-3-[4-(3-bromobenzene amido) quinazoline-6-base] urea,
1-phenyl-3-[4-(2,3-dimethyl benzene amido) quinazoline-6-base] urea,
1-phenyl-3-[4-(3-chloro-4-fluoroanilino) quinazoline-6-base] urea,
1-phenyl-3-[7-methoxyl group-4-(4-toluidine) quinazoline-6-base] urea,
1-phenyl-3-[7-methoxyl group-4-(3-toluidine) quinazoline-6-base] urea,
1-phenyl-3-[7-methoxyl group-4-(2,3-dimethyl benzene amido) quinazoline-6-base] urea,
1-phenyl-3-[7-methoxyl group-4-(3-bromobenzene amido) quinazoline-6-base] urea,
1-phenyl-3-[7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline-6-base] urea,
1-phenyl-3-[7-methoxyl group-4-(2-fluoro-4-bromobenzene amido) quinazoline-6-base] urea,
1-phenyl-3-[7-methoxyl group-4-(3-acetylenylbenzene amido) quinazoline-6-base] urea,
1-phenyl-3-[7-methoxyl group-4-(4-bromobenzene amido) quinazoline-6-base] urea,
1-phenyl-3-[7-methoxyl group-4-(3-cyano-aniline base) quinazoline-6-base] urea,
1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline-6-base] urea,
1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(3-bromobenzene amido) quinazoline-6-base] urea,
1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(2-fluoro-4-bromobenzene amido) quinazoline-6-base] urea,
1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(2-methyl-4-methoxybenzene amido) quinazoline-6-base]
Urea,
1-phenyl-3-[7-(morpholine-4-base)-4-(3-chloro-4-fluoroanilino) quinazoline-6-base] urea,
1-phenyl-3-(6-methoxyl group-4-anilinoquinazoline-7-base) urea,
1-phenyl-3-[6-(4-methylpiperazine-1-yl)-4-anilinoquinazoline-7-base] urea,
1-phenyl-3-[6-(morpholine-4-base)-4-anilinoquinazoline-7-base] urea or
1-phenyl-3-[7-methoxyl group-4-(3-chloro-4-fluoroanilino) quinazoline-6-base] urea；Or these compounds
Salt.
Preferably, described pharmaceutically acceptable salt includes but not limited to hydrochlorate, hydrobromate, sulfate, hemisulfic acid
Salt, phosphate or carboxylate, preferred amino acid salt.
The present invention also provide for a kind of phenylurea coupling quinazoline compounds prepared shown in above-mentioned formula (I) or its pharmaceutically
The method of acceptable salt, comprises the following steps:
Step a: the compound shown in formula (III) in organic solvent with catalyst reaction, preferably back flow reaction 1h, generate
Compound shown in formula (IV)；
Wherein, R5Or R6One of for NO2；
R5Or R6In another one be H ,-O-CH3、-O-CH2-CH3、-O-CH2(CH3)2、
Step b: the compound shown in formula (IV) reacts in organic solvent with the compound shown in formula V, preferably refluxes
Reaction 1.5h, generates the compound shown in formula (VI)；
Wherein, R1、n1Definition with R in formula I1、n1Definition identical；
Step c: the compound shown in formula (VI) reacts with reducing agent in organic solvent, preferably back flow reaction 1h, generates
Compound shown in formula (VII)；
Wherein R7Or R8One of for NH2；
R7Or R8In another one be H ,-O-CH3、-O-CH2-CH3、-O-CH2(CH3)2、
Step d: the compound shown in formula (VII) and the compound shown in formula (VIII) in organic solvent, preferably in room
Temperature reaction 3h, generates the compound shown in formula (I);
Wherein, R4、n2Definition and formula (I) in R4、n2Definition identical.
Preferably, described method farther includes:
Step e: under room temperature, the compound shown in formula (I) reacts shown in production (Ⅹ) in organic solvent with acid or alkali
Compound；
Wherein, M is hydrochloric acid, hydrobromic acid, sulphuric acid, hemisulfic acid, phosphoric acid or carboxylic acid, preferred amino acid or hydrochloric acid；R1、n1、R2、
R3Definition with R in formula I1、n1、R2、R3Definition identical.
Preferably, the organic solvent in described step a is thionyl chloride, and catalyst is dimethylformamide (DMF)；
Preferably, the organic solvent in described step b is isopropanol, anhydrous acetonitrile or anhydrous tetrahydro furan；
Preferably, the organic solvent in described step c is ethyl acetate or dehydrated alcohol；The preferred stannous chloride of reducing agent,
One or more in hydrazine hydrate or Raney's nickel.
Preferably, the organic solvent in described step d is acetonitrile or anhydrous tetrahydro furan；
Preferably, the organic solvent in described step e is dehydrated alcohol or dichloromethane；
Preferably, the preparation method of the compound shown in formula (VIII) includes: the compound shown in formula (IX) and triphosgene
(BTC) reaction generates the compound shown in formula (VIII) in organic solvent.
The present invention also provides for a kind of method of intermediate preparing the compound shown in above-mentioned formula (I), and described intermediate is
Phenyl isocyanate, the method includes:
The 1,2-dichloroethane solution of the compound shown in formula (IX) and triethylamine is added drop-wise to the 1,2-dichloro of triphosgene
In ethane solution, after reaction, obtain the phenyl isocyanate intermediate that formula (IX) compound is corresponding,
Wherein, R4、n2Definition and formula (I) in R4、n2Definition identical.
Preferably, said method specifically includes: under ice-water bath cooling condition, by the compound shown in formula (IX) and triethylamine
1,2-dichloroethane solution, be added drop-wise to the 1 of triphosgene, in 2-dichloroethanes, control rate of addition, preferably 2 drops/sec, dropping
After, 1h is stirred at room temperature, is heated to reflux 3h, place to room temperature, after filtration, obtain filtrate, with 1, the washing filter of 2-dichloroethanes
Cake, merging filtrate, obtain grease after solvent is evaporated off, then after vacuum fractionation, obtain the phenyl that the compound shown in formula (IX) is corresponding
Isocyanate intermediate.
The present invention further provides a kind of pharmaceutical composition, it comprises phenylurea coupling quinazoline ditosylate salt chemical combination as above
Thing or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier, excipient or diluent.Load for the present invention
Body, excipient or diluent can be carrier, excipient or diluent commonly used in the art, such as magnesium stearate, Pulvis Talci, dioxy
SiClx, dried starch, carboxycellulose sodium, carboxymethylstach sodium, hydroxypropyl cellulose and polyvinylpolypyrrolidone etc..
Preferably, the pharmaceutical composition of the present invention can further include except above-mentioned phenylurea coupling quinazoline compounds or
Other active substances outside its pharmaceutically acceptable salt, such as magnesium stearate, silicon dioxide, dried starch and carboxymethylstach sodium
Deng, additionally may also comprise other additive and adjuvant etc., such as ethanol, water, sodium bicarbonate, sucrose and citric acid etc..
The present invention further provides above-mentioned phenylurea coupling quinazoline compounds or its pharmaceutically acceptable salt in system
Purposes in the medicine of the standby disease relating to protein tyrosine kinase overexpression.
Wherein, described in relate to the disease of protein tyrosine kinase overexpression be malignant tumor, include but not limited to: lung
Cancer, preferably nonsmall-cell lung cancer；Cancer of pancreas；Phosphorus columnar epithelium cancer；Medullary thyroid carcinoma；Incidence cancer；Esophageal carcinoma；Gastric cancer；Or woman
The preferred bladder cancer of section's carcinoma and breast carcinoma.
The present invention is by research (L.Hennequin, the Journal of to 4-anilinoquinazoline class medicine structure activity relationship
Medicinal Chemistry (1999), 42 (26), 5369-5389), according in prior art to 4-anilinoquinazoline class
4 bit substituents and 7 (or 6), with 4-anilinoquinazoline as mother nucleus structure, are replaced by the understanding of medicine structure activity relationship respectively
Base is modified, to obtain the lead compound with the Mutiple Targets inhibitory action of tyrosine kinase.4 bit substituents are repaiied
Decorations, mainly based on aromatic ring structure, and to the modification of 7 (or 6) substituent groups mainly based on substituted-phenyl urea structure, with
This obtains the phenylurea coupling quinazoline compounds of the present invention.
Additionally, in the structure of the 4-anilinoquinazoline compounds of present invention synthesis, it has been found that part-structure has
Significantly pharmacologically active.The phenylurea coupling quinazoline compounds of the present invention or its pharmaceutically acceptable salt can be effectively
Treatment relates to the disease of protein tyrosine kinase overexpression.
Accompanying drawing explanation
Fig. 1 shows the compound 2 of the present invention IC to A549 cell50Collection of illustrative plates；
Fig. 2 shows the compound 18 of the present invention IC to A549 cell50Collection of illustrative plates；
Fig. 3 shows the compound 33 of the present invention IC to A549 cell50Collection of illustrative plates.
Detailed description of the invention
Referring to specific embodiment, the present invention is described.Only it will be appreciated by those skilled in the art that these embodiments
For the present invention is described, it limits the scope of the present invention never in any form.
Experimental technique in following embodiment, if no special instructions, is conventional method.Medicine used in following embodiment
Product, reagent etc., if no special instructions, be commercially available purchase product.
End-product in the embodiment of the present invention by mass spectrography (ESI-MS) and1H-NMR(500MHz, at dimethyl sulfoxide
(DMSO) in) it is measured.
Embodiment 1The synthesis of 1-phenyl-3-(4-anilinoquinazoline-7-base) urea (compound 1)
Synthetic route and the method for compound 1 are as follows:
The preparation of step 1:7-nitro-3H-quinazoline-4-one
2-Amino-4-nitrobenzoic Acid (7.28g, 40.0mmol) and ammonium formate (3.78g, 60.0mmol) are joined
In 100mL Methanamide, it is heated to 150 DEG C, insulation reaction 16h, it is cooled to room temperature, separates out solid, filter, wash with isopropanol,
Being dried, obtain brown needles solid 7-nitro-3H-quinazoline-4-one 6.62g, productivity 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 SOCl2In solution, then add
Entering 0.2mL DMF, return stirring 1h, solution gradually becomes brown clarification, stopped reaction, is cooled to room temperature, and excess is evaporated off
SOCl2, obtain yellow solid 7-nitro-4-chloro-quinazoline.The yellow solid obtained is blended, adds 10mL petroleum ether, decompression
Steam petroleum ether, repeat to add petroleum ether and operate 2 times, to remove remaining SOCl2, obtain yellow solid.The most purified upwards
State and yellow solid adds aniline (1.31g, 14.1mmol), isopropanol 37mL, return stirring 1.5h, have solid to separate out, cooling
To room temperature, filtering, wash with isopropanol, be dried, obtain yellow solid 7-nitro-4-anilinoquinazoline 1.87g, productivity is
59.7%。
The preparation of step 3:7-amino-4-anilinoquinazoline
By 7-nitro-4-anilinoquinazoline (1.31g, 4.9mmol), two hydrated stannous chlorides (4.42g, 19.6mmol)
Mix with ethyl acetate 49mL, back flow reaction 1h.Reactant liquor first becomes clarification, occurs precipitation afterwards, after completion of the reaction, places to room
Temperature, filters, and gained precipitation ethyl acetate is washed, combined ethyl acetate solution, with saturated sodium bicarbonate solution regulation to neutral,
Separating ethyl acetate layer, washs with 10mL water, anhydrous Na2SO4It is dried, is evaporated to do, be dried, obtain yellow solid 7-ammonia
Base-4-anilinoquinazoline 0.95g, productivity is 81.1%.
Step 4: the preparation of phenyl isocyanate
Under ice-water bath cooling, by aniline (0.73g, 7.8mmol) and the 1 of triethylamine (1.64g, 16.2mmol), 2-dichloro
The mixed solution of ethane (4mL) is slowly dropped to triphosgene (0.94g, 3.2mmol) and be dried 1,2-dichloroethanes (8mL)
In solution, control rate of addition (2 drops/sec), after dropping, 1h is stirred at room temperature, be heated to reflux 3h, place to room temperature, filter
Obtain filtrate, with 1,2-dichloroethanes washing filter cake, merging filtrate, obtain grease after solvent is evaporated off, then obtain nothing through vacuum fractionation
Color liquid benzene based isocyanate 0.70g, productivity is 75.4%.
The preparation of step 5:1-phenyl-3-(4-anilinoquinazoline-7-base) urea
Phenyl isocyanate (0.26g, 2.2mmol) is joined in 20mL acetonitrile, is stirred at room temperature down, be dividedly in some parts 7-ammonia
Base-4-anilinoquinazoline (0.47g, 2.0mmol), is stirred at room temperature 3h, filters to obtain solid, washs with acetonitrile, is dried, then uses
80% ethyl alcohol recrystallization, obtains faint yellow solid 1-phenyl-3-(4-anilinoquinazoline-7-base) urea (compound 1) 0.62g, produces
Rate is 79.5%.
Embodiment 2The synthesis of 1-phenyl-3-[4-(4-toluidine) quinazoline-7-base] urea (compound 2)
Step 1: see step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(4-toluidine) quinazoline
Seeing step 2 experimental implementation in embodiment 1, unique difference is to be replaced to by the aniline added in this step
The 4-monomethylaniline. of mole.
The preparation of step 3:7-amino-4-(4-toluidine) quinazoline
Seeing step 3 experimental implementation in embodiment 1, unique difference is by the reactant 7-nitro-4-in this step
Anilinoquinazoline replaces to 7-nitro-4-(4-toluidine) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(4-toluidine) quinazoline-7-base] urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by the reactant 7-amino-4-in this step
Anilinoquinazoline replaces to 7-amino-4-(4-toluidine) quinazoline of equimolar amounts.
Embodiment 3The synthesis of 1-phenyl-3-[4-(3-toluidine) quinazoline-7-base] urea (compound 3)
Step 1: see step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(3-toluidine) quinazoline
Seeing step 2 experimental implementation in embodiment 1, unique difference is to be replaced to by the aniline added in this step
The 3-monomethylaniline. of mole.
The preparation of step 3:7-amino-4-(3-toluidine) quinazoline
Seeing step 3 experimental implementation in embodiment 1, unique difference is by the reactant 7-nitro-4-in this step
Anilinoquinazoline replaces to 7-nitro-4-(3-toluidine) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(3-toluidine) quinazoline-7-base] urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by the reactant 7-amino-4-in this step
Anilinoquinazoline replaces to 7-amino-4-(3-toluidine) quinazoline of equimolar amounts.
Embodiment 4The synthesis of 1-phenyl-3-[4-(4-methoxybenzene amido) quinazoline-7-base] urea (compound 4)
Step 1: see step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(4-methoxybenzene amido) quinazoline
Seeing step 2 experimental implementation in embodiment 1, unique difference is to be replaced to by the aniline added in this step
The 4-aminoanisole of mole.
The preparation of step 3:7-amino-4-(4-methoxybenzene amido) quinazoline
Seeing step 3 experimental implementation in embodiment 1, unique difference is by the reactant 7-nitro-4-in this step
Anilinoquinazoline replaces to 7-nitro-4-(the 4-methoxybenzene amido) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(4-methoxybenzene amido) quinazoline-7-base] urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by the reactant 7-amino-4-in this step
Anilinoquinazoline replaces to 7-amino-4-(the 4-methoxybenzene amido) quinazoline of equimolar amounts.
Embodiment 5The synthesis of 1-phenyl-3-[4-(2-fluoro-4-bromobenzene amido) quinazoline-7-base] urea (compound 5)
Step 1: see step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(2-fluoro-4-bromobenzene amido) quinazoline
Seeing step 2 experimental implementation in embodiment 1, unique difference is to be replaced to by the aniline added in this step
The 2-fluoro-4-bromaniline of mole.
The preparation of step 3:7-amino-4-(2-fluoro-4-bromobenzene amido) quinazoline
Seeing step 3 experimental implementation in embodiment 1, unique difference is by the reactant 7-nitro-4-in this step
Anilinoquinazoline replaces to 7-nitro-4-(the 2-fluoro-4-bromobenzene amido) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(2-fluoro-4-bromobenzene amido) quinazoline-7-base] urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by the reactant 7-amino-4-in this step
Anilinoquinazoline replaces to 7-amino-4-(the 2-fluoro-4-bromobenzene amido) quinazoline of equimolar amounts.
Embodiment 6The synthesis of 1-phenyl-3-[4-(3-cumene amido) quinazoline-7-base] urea (compound 6)
Step 1: see step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(3-cumene amido) quinazoline
Seeing step 2 experimental implementation in embodiment 1, unique difference is to be replaced to by the aniline added in this step
The 3-isopropyl aniline of mole.
The preparation of step 3:7-amino-4-(3-cumene amido) quinazoline
Seeing step 3 experimental implementation in embodiment 1, unique difference is by the reactant 7-nitro-4-in this step
Anilinoquinazoline replaces to 7-nitro-4-(the 3-cumene amido) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(3-cumene amido) quinazoline-7-base] urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by the reactant 7-amino-4-in this step
Anilinoquinazoline replaces to 7-amino-4-(the 3-cumene amido) quinazoline of equimolar amounts.
Embodiment 7The synthesis of 1-phenyl-3-[4-(3-chloro-4-fluoroanilino) quinazoline-7-base] urea (compound 7)
Step 1: see step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(3-chloro-4-fluoroanilino) quinazoline
Seeing step 2 experimental implementation in embodiment 1, unique difference is to be replaced to by the aniline added in this step
The 3-chloro-4-fluoroaniline of mole.
The preparation of step 3:7-amino-4-(3-chloro-4-fluoroanilino) quinazoline
Seeing step 3 experimental implementation in embodiment 1, unique difference is by the reactant 7-nitro-4-in this step
Anilinoquinazoline replaces to 7-nitro-4-(the 3-chloro-4-fluoroanilino) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(3-chloro-4-fluoroanilino) quinazoline-7-base] urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by the reactant 7-amino-4-in this step
Anilinoquinazoline replaces to 7-amino-4-(the 3-chloro-4-fluoroanilino) quinazoline of equimolar amounts.
Embodiment 8The conjunction of 1-phenyl-3-[4-(2,4,6-trimethylbenzene amido) quinazoline-7-base] urea (compound 8)
Become
Step 1: see step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(2,4,6-trimethylbenzene amido) quinazoline
Seeing step 2 experimental implementation in embodiment 1, unique difference is to be replaced to by the aniline added in this step
The 2,4,6-trimethylaniline of mole.
The preparation of step 3:7-amino-4-(2,4,6-trimethylbenzene amido) quinazoline
Seeing step 3 experimental implementation in embodiment 1, unique difference is by the reactant 7-nitro-4-in this step
Anilinoquinazoline replaces to 7-nitro-4-(the 2,4,6-trimethylbenzene amido) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(2,4,6-trimethylbenzene amido) quinazoline-7-base] urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by the reactant 7-amino-4-in this step
Anilinoquinazoline replaces to 7-amino-4-(the 2,4,6-trimethylbenzene amido) quinazoline of equimolar amounts.
Embodiment 9The synthesis of 1-phenyl-3-[4-(2 3 dimethyl aniline base) quinazoline-7-base] urea (compound 9)
Step 1: see step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(2 3 dimethyl aniline base) quinazoline
Seeing step 2 experimental implementation in embodiment 1, unique difference is to be replaced to by the aniline added in this step
The 23 dimethyl aniline of mole.
The preparation of step 3:7-amino-4-(2 3 dimethyl aniline base) quinazoline
Seeing step 3 experimental implementation in embodiment 1, unique difference is by the reactant 7-nitro-4-in this step
Anilinoquinazoline replaces to 7-nitro-4-(2 3 dimethyl aniline base) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(2 3 dimethyl aniline base) quinazoline-7-base] urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by the reactant 7-amino-4-in this step
Anilinoquinazoline replaces to 7-amino-4-(2 3 dimethyl aniline base) quinazoline of equimolar amounts.
Embodiment 10The synthesis of 1-(2-aminomethyl phenyl)-3-(4-anilinoquinazoline-7-base) urea (compound 10)
Step 1: see step 1 experimental implementation in embodiment 1.
Step 2: see step 2 experimental implementation in embodiment 1.
Step 3: see step 3 experimental implementation in embodiment 1.
The preparation of step 4:2-methylphenyl isocyanate
Seeing step 4 experimental implementation in embodiment 1, unique difference is for replace to reactant aniline in this step
The 2-aminotoluene of mole.
The preparation of step 5:1-(2-aminomethyl phenyl)-3-(4-anilinoquinazoline-7-base) urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by reactant phenyl isocyanate in this step
Replace to the 2-methylphenyl isocyanate of equimolar amounts.
Embodiment 11The synthesis of 1-phenyl-3-[4-(2-chloroanilino) quinazoline-7-base] urea (compound 11)
Step 1: see step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(2-chloroanilino) quinazoline
Seeing step 2 experimental implementation in embodiment 1, unique difference is to be replaced to by the aniline added in this step
The 2-chloroaniline of mole.
The preparation of step 3:7-amino-4-(2-chloroanilino) quinazoline
Seeing step 3 experimental implementation in embodiment 1, unique difference is by the reactant 7-nitro-4-in this step
Anilinoquinazoline replaces to 7-nitro-4-(2-chloroanilino) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(2-chloroanilino) quinazoline-7-base] urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by the reactant 7-amino-4-in this step
Anilinoquinazoline replaces to 7-amino-4-(2-chloroanilino) quinazoline of equimolar amounts.
Embodiment 12The synthesis of 1-phenyl-3-[4-(2,4 difluorobenzene amido) quinazoline-7-base] urea (compound 12)
Step 1: see step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(2,4 difluorobenzene amido) quinazoline
Seeing step 2 experimental implementation in embodiment 1, unique difference is to be replaced to by the aniline added in this step
The 2,4 difluorobenzene amine of mole.
The preparation of step 3:7-amino-4-(2,4 difluorobenzene amido) quinazoline
Seeing step 3 experimental implementation in embodiment 1, unique difference is by the reactant 7-nitro-4-in this step
Anilinoquinazoline replaces to 7-nitro-4-(2,4 difluorobenzene amido) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(2,4 difluorobenzene amido) quinazoline-7-base] urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by the reactant 7-amino-4-in this step
Anilinoquinazoline replaces to 7-amino-4-(2,4 difluorobenzene amido) quinazoline of equimolar amounts.
Embodiment 13The synthesis of 1-(2,4 difluorobenzene base)-3-(4-anilinoquinazoline-7-base) urea (compound 13)
Step 1: see step 1 experimental implementation in embodiment 1.
Step 2: see step 2 experimental implementation in embodiment 1.
Step 3: see step 3 experimental implementation in embodiment 1.
The synthesis of step 4:2,4-difluorophenyl isocyanate
Seeing step 4 experimental implementation in embodiment 1, unique difference is for replace to reactant aniline in this step
The 2,4 difluorobenzene amine of mole.
The preparation of step 5:1-(2,4 difluorobenzene base)-3-(4-anilinoquinazoline-7-base) urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by reactant phenyl isocyanate in this step
Replace to the 2,4 difluorobenzene based isocyanate of equimolar amounts.
Embodiment 14The synthesis of 1-(4-methoxyphenyl)-3-(4-anilinoquinazoline-7-base) urea (compound 14)
Step 1: see step 1 experimental implementation in embodiment 1.
Step 2: see step 2 experimental implementation in embodiment 1.
Step 3: see step 3 experimental implementation in embodiment 1.
The synthesis of step 4:4-methoxyphenyl isocyanate
Seeing step 4 experimental implementation in embodiment 1, unique difference is for replace to reactant aniline in this step
The 4-aminoanisole of mole.
The preparation of step 5:1-(4-methoxyphenyl)-3-(4-anilinoquinazoline-7-base) urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by reactant phenyl isocyanate in this step
Replace to the 4-methoxyphenyl isocyanate of equimolar amounts.
Embodiment 151-(4-methoxyphenyl)-3-[4-(2 3 dimethyl aniline base) quinazoline-7-base] urea (chemical combination
Thing 15) synthesis
Step 1: see step 1 experimental implementation in embodiment 1.
Step 2: see step 2 experimental implementation in embodiment 9.
Step 3: see step 3 experimental implementation in embodiment 9.
Step 4: see step 4 experimental implementation in embodiment 14.
The preparation of step 5:1-(4-methoxyphenyl)-3-[4-(2 3 dimethyl aniline base) quinazoline-7-base] urea
Seeing step 5 experimental implementation in embodiment 9, unique difference is by reactant phenyl isocyanate in this step
Replace to the 4-methoxyphenyl isocyanate of equimolar amounts.
Embodiment 16The synthesis of 1-phenyl-3-[4-(4-fluoroanilino) quinazoline-7-base] urea (compound 16)
Step 1: see step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(4-fluoroanilino) quinazoline
Seeing step 2 experimental implementation in embodiment 1, unique difference is to be replaced to by the aniline added in this step
The 4-fluoroaniline of mole.
The preparation of step 3:7-amino-4-(4-fluoroanilino) quinazoline
Seeing step 3 experimental implementation in embodiment 1, unique difference is by the reactant 7-nitro-4-in this step
Anilinoquinazoline replaces to 7-nitro-4-(4-fluoroanilino) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(4-fluoroanilino) quinazoline-7-base] urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by the reactant 7-amino-4-in this step
Anilinoquinazoline replaces to 7-amino-4-(4-fluoroanilino) quinazoline of equimolar amounts.
Embodiment 171-(4-fluorophenyl)-3-[4-(4-toluidine) quinazoline-7-base] urea (compound 17)
Synthesis
Step 1: see step 1 experimental implementation in embodiment 1.
Step 2: see step 2 experimental implementation in embodiment 2.
Step 3: see step 3 experimental implementation in embodiment 2.
The synthesis of step 4:4-fluorophenylisocyanate
Seeing step 4 experimental implementation in embodiment 1, unique difference is for replace to reactant aniline in this step
The 4-fluoroaniline of mole.
The preparation of step 5:1-(4-fluorophenyl)-3-[4-(4-toluidine) quinazoline-7-base] urea
Seeing step 5 experimental implementation in embodiment 2, unique difference is by reactant phenyl isocyanate in this step
Replace to the 4-fluorophenylisocyanate of equimolar amounts.
Embodiment 181-(4-methoxyphenyl)-3-[4-(4-toluidine) quinazoline-7-base] urea (compound
18) synthesis
Step 1: see step 1 experimental implementation in embodiment 1.
Step 2: see step 2 experimental implementation in embodiment 2.
Step 3: see step 3 experimental implementation in embodiment 2.
Step 4: see step 4 experimental implementation in embodiment 14.
The preparation of step 5:1-(4-methoxyphenyl)-3-[4-(4-toluidine) quinazoline-7-base] urea
Seeing step 5 experimental implementation in embodiment 2, unique difference is by reactant phenyl isocyanate in this step
Replace to the 4-methoxyphenyl isocyanate of equimolar amounts.
Embodiment 19The synthesis of 1-phenyl-3-(7-methoxyl group-4-anilinoquinazoline-6-base) urea (compound 19)
Synthetic route and the method for compound 19 are as follows:
The preparation of step 1:7-chloro-3H-quinazoline-4-one
Chloro-for 4-2-amino benzoic Acid (10.26g, 60.0mmol) and formamidine acetate (12.50g, 120.0mmol) are added
In 250mL glycol monoethyl ether, it is heated to 120 DEG C, insulation reaction 16h, it is cooled to room temperature, is evaporated to do, use
0.01mol/L ammonia is washed till neutrality, sucking filtration, is dried, obtains pale solid 7-chloro-3H-quinazoline-4-one 9.52g, and productivity is
88.1%。
The preparation of step 2:7-chloro-6-nitro-3H-quinazoline-4-one
Under ice-water bath cooling, chloro-for 7-3H-quinazoline-4-one (9.00g, 50.0mmol) is added to nitration mixture (concentrated sulphuric acid in batches
30mL and fuming nitric aicd 30mL) in, finish, 1h is stirred at room temperature, be heated to 45 DEG C, be stirred overnight.Then reactant liquor is poured into
In 60mL frozen water, filter, filter gained solids washed with water, use Recrystallisation from acetic acid, be dried, obtain yellow solid 7-chloro-6-nitre
Base-3H-quinazoline-4-one 7.78g, productivity is 68.3%.
The preparation of step 3:6-nitro-7-methoxyl group-3H-quinazoline-4-one
Chloro-for 7-6-nitro-3H-quinazoline-4-one (7.01g, 31.1mmol) is dissolved in dry 120mLDMF, after
Add absolute methanol solution (120mL) and the potassium iodide (5.16g, 31.1mmol) of Feldalat NM (5.45g, 101.0mmol), heating
To 90 DEG C, react 20h.By reactant liquor sucking filtration, with acetic acid regulation filtrate to neutral, dilute with water, separate out solid, sucking filtration, obtain yellow
Color solid 6-nitro-7-methoxyl group-3H-quinazoline-4-one 6.02g, productivity 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 45mLSOCl2Solution
In, it being subsequently adding 0.4mL DMF, return stirring 2h, solution gradually becomes brown clarification, stopped reaction, is cooled to room temperature, is evaporated off
The SOCl of excess2, obtain light yellow solid 4-chloro-6-nitro-7-methoxyquinazoline hydrochloride.The light yellow solid obtained is blended, adds
Entering 30mL petroleum ether, decompression steams petroleum ether, repeats to add petroleum ether and operates 2 times, removes remaining SOCl2, obtain yellow solid
Body.The most purified yellow solid is transferred in there-necked flask, add aniline (2.05g, 22.0mmol), isopropanol 170mL, backflow
Stirring 2h, is cooled to room temperature, collects solid, washs with isopropanol, is dried, obtains yellow solid 6-nitro-7-methoxyl group-4-aniline
Base quinazoline 3.67g, productivity is 61.9%.
The preparation of step 5:6-amino-7-methoxyl group-4-anilinoquinazoline
By 6-nitro-7-methoxyl group-4-anilinoquinazoline (2.37g, 8.0mmol) and two hydrated stannous chlorides
(10.84g, 48.0mmol) joins in 250mL ethyl acetate, back flow reaction 1h.React complete, place to room temperature, filter, mistake
Filter gained solid with ethyl acetate washing, combined ethyl acetate solution, with saturated sodium bicarbonate solution regulation to neutral, separate second
Ethyl acetate layer, washs with 30mL water, anhydrous Na2SO4Be dried, be evaporated to do, obtain sepia solid 6-amino-7-methoxyl group-
4-anilinoquinazoline 1.50g, productivity is 70.4%.
Step 6: see step 4 experimental implementation in embodiment 1.
The preparation of step 7:1-phenyl-3-(7-methoxyl group-4-anilinoquinazoline-6-base) urea
Phenyl isocyanate (0.26g, 2.2mmol) is joined in 20mL acetonitrile, is stirred at room temperature down and is dividedly in some parts 6-ammonia
Base-7-methoxyl group-4-anilinoquinazoline (0.53g, 2.0mmol), is stirred at room temperature 3h, filters to obtain solid, washs with acetonitrile, dry
Dry, then use 80% ethyl alcohol recrystallization, obtain faint yellow solid 1-phenyl-3-(7-methoxyl group-4-anilinoquinazoline-6-base) urea and (change
Compound 19) 0.51g, productivity is 66.2%.
Embodiment 20The conjunction of 1-phenyl-3-[4-(3-trifluoromethylbenzene amido) quinazoline-7-base] urea (compound 20)
Become
Step 1 sees step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(3-trifluoromethylbenzene amido) quinazoline
Seeing step 2 experimental implementation in embodiment 1, unique difference is to be replaced to by the aniline added in this step
The 3-5-trifluoromethylaniline of mole.
The preparation of step 3:7-amino-4-(3-trifluoromethylbenzene amido) quinazoline
Seeing step 3 experimental implementation in embodiment 1, unique difference is by the reactant 7-nitro-4-in this step
Anilinoquinazoline replaces to 7-nitro-4-(the 3-trifluoromethylbenzene amido) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(3-trifluoromethylbenzene amido) quinazoline-7-base] urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by the reactant 7-amino-4-in this step
Anilinoquinazoline replaces to 7-amino-4-(the 3-trifluoromethylbenzene amido) quinazoline of equimolar amounts.
Embodiment 21The conjunction of 1-(2,3-3,5-dimethylphenyl)-3-(4-anilinoquinazoline-7-base) urea (compound 21)
Become
Step 1: see step 1 experimental implementation in embodiment 1.
Step 2: see step 2 experimental implementation in embodiment 1.
Step 3: see step 3 experimental implementation in embodiment 1.
The preparation of step 4:2,3-dimethylphenyl isocyanate
Seeing step 4 experimental implementation in embodiment 1, unique difference is for replace to reactant aniline in this step
The 23 dimethyl aniline of mole.
The preparation of step 5:1-(2,3-3,5-dimethylphenyl)-3-(4-anilinoquinazoline-7-base) urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by reactant phenyl isocyanate in this step
Replace to the 2,3-dimethylphenyl isocyanate of equimolar amounts.
Embodiment 22The synthesis of 1-phenyl-3-[4-(2-aminotoluene base) quinazoline-7-base] urea (compound 22)
Step 1: see step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(2-aminotoluene base) quinazoline
Seeing step 2 experimental implementation in embodiment 1, unique difference is to be replaced to by the aniline added in this step
The 2-aminotoluene of mole.
The preparation of step 3:7-amino-4-(2-aminotoluene base) quinazoline
Seeing step 3 experimental implementation in embodiment 1, unique difference is by the reactant 7-nitro-4-in this step
Anilinoquinazoline replaces to 7-nitro-4-(2-aminotoluene base) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(2-aminotoluene base) quinazoline-7-base] urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by the reactant 7-amino-4-in this step
Anilinoquinazoline replaces to 7-amino-4-(2-aminotoluene base) quinazoline of equimolar amounts.
Embodiment 231-(2,4,6-trimethylphenyl)-3-(4-anilinoquinazoline-7-base) urea (compound 23)
Synthesis
Step 1: see step 1 experimental implementation in embodiment 1.
Step 2: see step 2 experimental implementation in embodiment 1.
Step 3: see step 3 experimental implementation in embodiment 1.
The synthesis of step 4:2,4,6-trimethylbenzene based isocyanate
Seeing step 4 experimental implementation in embodiment 1, unique difference is for replace to reactant aniline in this step
The 2,4,6-trimethylaniline of mole.
The preparation of step 5:1-(2,4,6-trimethylphenyl)-3-(4-anilinoquinazoline-7-base) urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by reactant phenyl isocyanate in this step
Replace to the 2,4,6-trimethylbenzene based isocyanate of equimolar amounts.
Embodiment 24The synthesis of 1-(4-nitrobenzophenone)-3-(4-anilinoquinazoline-7-base) urea (compound 24)
Step 1: see step 1 experimental implementation in embodiment 1.
Step 2: see step 2 experimental implementation in embodiment 1.
Step 3: see step 3 experimental implementation in embodiment 1.
The synthesis of step 4:4-nitrophenyl isocyanate
Seeing step 4 experimental implementation in embodiment 1, unique difference is for replace to reactant aniline in this step
The 4-nitroaniline of mole.
The preparation of step 5:1-(4-nitrobenzophenone)-3-(4-anilinoquinazoline-7-base) urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by reactant phenyl isocyanate in this step
Replace to the 4-nitrophenyl isocyanate of equimolar amounts.
Embodiment 25The synthesis of 1-phenyl-3-[4-(4-fluoroanilino) quinazoline-6-base] urea (compound 25)
Synthetic route and the method for compound 25 are as follows:
The preparation of step 1:6-nitro-3H-quinazoline-4-one
2-amino-5-nitrobenzoic acid (7.28g, 40.0mmol) is joined in 60mL Methanamide, is heated to 120 DEG C,
Insulation reaction 16h, is cooled to room temperature, separates out solid, filters, and washs with isopropanol, is dried, obtains brown solid 6-nitro-3H-quinoline
Oxazoline-4-ketone 3.94g, productivity 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 23mLSOCl2In solution, it is subsequently adding
0.2mL DMF, return stirring 1h, solution gradually becomes brown clarification, stopped reaction, is cooled to room temperature, excess is evaporated off
SOCl2, obtain yellow solid 4-chloro-6-nitro-quinazoline.Being blended by the yellow solid obtained, add 10mL petroleum ether, decompression is steamed
Go out petroleum ether, repeat to add petroleum ether and operate 2 times, remove remaining SOCl2, obtain yellow solid.The most purified to yellow solid
Middle addition 4-fluoroaniline (1.27g, 14.1mmol), isopropanol 37mL, return stirring 2h, separate out solid, be cooled to room temperature, filter
Collecting solid, wash with isopropanol, be dried, obtain yellow solid 6-nitro-4-(4-fluoroanilino) quinazoline 2.52g, productivity is
75.2%。
The preparation of step 3:6-amino-4-(4-fluoroanilino) quinazoline
By 6-nitro-4-(4-fluoroanilino) quinazoline (1.39g, 4.9mmol) and two hydrated stannous chlorides (4.42g,
19.6mmol) mix with ethyl acetate 49mL, back flow reaction 1h.Reactant liquor first becomes clarification, occurs afterwards precipitating, after completion of the reaction,
Placing to room temperature, filter, gained precipitation ethyl acetate is washed, and combined ethyl acetate solution is adjusted with saturated sodium bicarbonate solution
Joint is to neutral, and separating ethyl acetate layer, by the washing of 10mL water, anhydrous Na2SO4It is dried, is evaporated to do, obtains greenish yellow solid
6-amino-4-(4-fluoroanilino) quinazoline 1.12g, productivity is 89.9%.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(4-fluoroanilino) quinazoline-6-base] urea
Phenyl isocyanate (0.26g, 2.2mmol) is joined in 20mL acetonitrile, is stirred at room temperature down, be dividedly in some parts 6-ammonia
Base-4-(4-fluoroanilino) quinazoline (0.56g, 2.0mmol), is stirred at room temperature 3h, obtains solid after filtration, washs with acetonitrile,
It is dried, then uses 80% ethyl alcohol recrystallization, obtain faint yellow solid 1-phenyl-3-[4-(4-fluoroanilino) quinazoline-6-base] urea and (change
Compound 25) 0.51g, productivity is 68.3%.
Embodiment 26The synthesis of 1-phenyl-3-(4-anilinoquinazoline-6-base) urea (compound 26)
Step 1: see step 1 experimental implementation in embodiment 25.
The preparation of step 2:6-nitro-4-anilinoquinazoline
Seeing step 2 experimental implementation in embodiment 25, unique difference is to be replaced by the 4-fluoroaniline added in this step
Change the aniline of equimolar amounts into.
The preparation of step 3:6-amino-4-anilinoquinazoline
Seeing step 3 experimental implementation in embodiment 25, unique difference is by the reactant 6-nitro-4-in this step
(4-fluoroanilino) quinazoline replaces to the 6-nitro-4-anilinoquinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-(4-phenylamino quinazoline-6-base) urea
Seeing step 5 experimental implementation in embodiment 25, unique difference is by the reactant 6-amino-4-in this step
(4-fluoroanilino) quinazoline replaces to the 6-amino-4-anilinoquinazoline of equimolar amounts.
Embodiment 27The synthesis of 1-phenyl-3-[4-(4-toluidine) quinazoline-6-base] urea (compound 27)
Step 1: see step 1 experimental implementation in embodiment 25.
The preparation of step 2:6-nitro-4-(4-toluidine) quinazoline
Seeing step 2 experimental implementation in embodiment 25, unique difference is to be replaced by the 4-fluoroaniline added in this step
Change the 4-monomethylaniline. of equimolar amounts into.
The preparation of step 3:6-amino-4-(4-toluidine) quinazoline
Seeing step 3 experimental implementation in embodiment 25, unique difference is by the reactant 6-nitro-4-in this step
(4-fluoroanilino) quinazoline replaces to 6-nitro-4-(4-toluidine) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(4-toluidine) quinazoline-6-base] urea
Seeing step 5 experimental implementation in embodiment 25, unique difference is by the reactant 6-amino-4-in this step
(4-fluoroanilino) quinazoline replaces to 6-amino-4-(4-toluidine) quinazoline of equimolar amounts.
Embodiment 28The synthesis of 1-phenyl-3-[4-(3-bromobenzene amido) quinazoline-6-base] urea (compound 28)
Step 1: see step 1 experimental implementation in embodiment 25.
The preparation of step 2:6-nitro-4-(3-bromobenzene amido) quinazoline
Seeing step 2 experimental implementation in embodiment 25, unique difference is to be replaced by the 4-fluoroaniline added in this step
Change the 3-bromaniline of equimolar amounts into.
The preparation of step 3:6-amino-4-(3-bromobenzene amido) quinazoline
Seeing step 3 experimental implementation in embodiment 25, unique difference is by the reactant 6-nitro-4-in this step
(4-fluoroanilino) quinazoline replaces to 6-nitro-4-(the 3-bromobenzene amido) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(3-bromobenzene amido) quinazoline-6-base] urea
Seeing step 5 experimental implementation in embodiment 25, unique difference is by the reactant 6-amino-4-in this step
(4-fluoroanilino) quinazoline replaces to 6-amino-4-(the 3-bromobenzene amido) quinazoline of equimolar amounts.
Embodiment 29The synthesis of 1-phenyl-3-[4-(3-chloro-4-fluoroanilino) quinazoline-6-base] urea (compound 29)
Step 1: see step 1 experimental implementation in embodiment 25.
The preparation of step 2:6-nitro-4-(3-chloro-4-fluoroanilino) quinazoline
Seeing step 2 experimental implementation in embodiment 25, unique difference is to be replaced by the 4-fluoroaniline added in this step
Change the 3-chloro-4-fluoroaniline of equimolar amounts into.
The preparation of step 3:6-amino-4-(3-chloro-4-fluoroanilino) quinazoline
Seeing step 3 experimental implementation in embodiment 25, unique difference is by the reactant 6-nitro-4-in this step
(4-fluoroanilino) quinazoline replaces to 6-nitro-4-(the 3-chloro-4-fluoroanilino) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(3-chloro-4-fluoroanilino) quinazoline-6-base] urea
Seeing step 5 experimental implementation in embodiment 25, unique difference is by the reactant 6-amino-4-in this step
(4-fluoroanilino) quinazoline replaces to 6-amino-4-(the 3-chloro-4-fluoroanilino) quinazoline of equimolar amounts.
Embodiment 30The conjunction of 1-phenyl-3-[4-(2 3 dimethyl aniline base) quinazoline-6-base] urea (compound 30)
Become
Step 1: see step 1 experimental implementation in embodiment 25.
The preparation of step 2:6-nitro-4-(2 3 dimethyl aniline base) quinazoline
Seeing step 2 experimental implementation in embodiment 25, unique difference is to be replaced by the 4-fluoroaniline added in this step
Change the 23 dimethyl aniline of equimolar amounts into.
The preparation of step 3:6-amino-4-(2 3 dimethyl aniline base) quinazoline
Seeing step 3 experimental implementation in embodiment 25, unique difference is by the reactant 6-nitro-4-in this step
(4-fluoroanilino) quinazoline replaces to 6-nitro-4-(2 3 dimethyl aniline base) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(2 3 dimethyl aniline base) quinazoline-6-base] urea
Seeing step 5 experimental implementation in embodiment 25, unique difference is by the reactant 6-amino-4-in this step
(4-fluoroanilino) quinazoline replaces to 6-amino-4-(2 3 dimethyl aniline base) quinazoline of equimolar amounts.
Embodiment 311-phenyl-3-[7-methoxyl group-4-(3-toluidine) quinazoline-6-base] urea (compound 31)
Synthesis
Step 1: see step 1 experimental implementation in embodiment 19.
Step 2: see step 2 experimental implementation in embodiment 19.
Step 3: see step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(3-toluidine) quinazoline
Seeing step 4 experimental implementation in embodiment 19, unique difference is to be replaced to by the aniline added in this step
The 3-monomethylaniline. of equimolar amounts.
The preparation of step 5:6-amino-7-methoxyl group-4-(3-toluidine) quinazoline
Seeing step 5 experimental implementation in embodiment 19, unique difference is by the reactant 6-nitro-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-nitro-7-methoxyl group-4-(3-toluidine) quinazoline of equimolar amounts.
Step 6: see step 4 experimental implementation in embodiment 1.
The preparation of step 7:1-phenyl-3-[7-methoxyl group-4-(3-toluidine) quinazoline-6-base] urea
Seeing step 7 experimental implementation in embodiment 19, unique difference is by the reactant 6-amino-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-amino-7-methoxyl group-4-(3-toluidine) quinazoline of equimolar amounts.
Embodiment 321-phenyl-3-[7-methoxyl group-4-(4-toluidine) quinazoline-6-base] urea (compound 32)
Synthesis
Step 1: see step 1 experimental implementation in embodiment 19.
Step 2: see step 2 experimental implementation in embodiment 19.
Step 3: see step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(4-toluidine) quinazoline
Seeing step 4 experimental implementation in embodiment 19, unique difference is to be replaced to by the aniline added in this step
The 4-monomethylaniline. of equimolar amounts.
The preparation of step 5:6-amino-7-methoxyl group-4-(4-toluidine) quinazoline
Seeing step 5 experimental implementation in embodiment 19, unique difference is by the reactant 6-nitro-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-nitro-7-methoxyl group-4-(4-toluidine) quinazoline of equimolar amounts.
Step 6: see step 4 experimental implementation in embodiment 1.
The preparation of step 7:1-phenyl-3-[7-methoxyl group-4-(4-toluidine) quinazoline-6-base] urea
Seeing step 7 experimental implementation in embodiment 19, unique difference is by the reactant 6-amino-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-amino-7-methoxyl group-4-(4-toluidine) quinazoline of equimolar amounts.
Embodiment 331-phenyl-3-[7-methoxyl group-4-(3-bromobenzene amido) quinazoline-6-base] urea (compound 33)
Synthesis
Step 1: see step 1 experimental implementation in embodiment 19.
Step 2: see step 2 experimental implementation in embodiment 19.
Step 3: see step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(3-bromobenzene amido) quinazoline
Seeing step 4 experimental implementation in embodiment 19, unique difference is to be replaced to by the aniline added in this step
The 3-bromaniline of equimolar amounts.
The preparation of step 5:6-amino-7-methoxyl group-4-(3-bromobenzene amido) quinazoline
Seeing step 5 experimental implementation in embodiment 19, unique difference is by the reactant 6-nitro-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-nitro-7-methoxyl group-4-(the 3-bromobenzene amido) quinazoline of equimolar amounts.
Step 6: see step 4 experimental implementation in embodiment 1.
The preparation of step 7:1-phenyl-3-[7-methoxyl group-4-(3-bromobenzene amido) quinazoline-6-base] urea
Seeing step 7 experimental implementation in embodiment 19, unique difference is by the reactant 6-amino-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-amino-7-methoxyl group-4-(the 3-bromobenzene amido) quinazoline of equimolar amounts.
Embodiment 341-phenyl-3-[7-methoxyl group-4-(3-chloro-4-fluoroanilino) quinazoline-6-base] urea (compound
34) synthesis
Step 1: see step 1 experimental implementation in embodiment 19.
Step 2: see step 2 experimental implementation in embodiment 19.
Step 3: see step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(3-chloro-4-fluoroanilino) quinazoline
Seeing step 4 experimental implementation in embodiment 19, unique difference is to be replaced to by the aniline added in this step
The 3-chloro-4-fluoroaniline of equimolar amounts.
The preparation of step 5:6-amino-7-methoxyl group-4-(3-chloro-4-fluoroanilino) quinazoline
Seeing step 5 experimental implementation in embodiment 19, unique difference is by the reactant 6-nitro-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-nitro-7-methoxyl group-4-(3-chloro-4-fluoroanilino) the quinoline azoles of equimolar amounts
Quinoline.
Step 6: see step 4 experimental implementation in embodiment 1.
The preparation of step 7:1-phenyl-3-[7-methoxyl group-4-(3-chloro-4-fluoroanilino) quinazoline-6-base] urea
Seeing step 7 experimental implementation in embodiment 19, unique difference is by the reactant 6-amino-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-amino-7-methoxyl group-4-(3-chloro-4-fluoroanilino) the quinoline azoles of equimolar amounts
Quinoline.
Embodiment 351-phenyl-3-[7-methoxyl group-4-(2 3 dimethyl aniline base) quinazoline-6-base] urea (chemical combination
Thing 35) synthesis
Step 1: see step 1 experimental implementation in embodiment 19.
Step 2: see step 2 experimental implementation in embodiment 19.
Step 3: see step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(2 3 dimethyl aniline base) quinazoline
Seeing step 4 experimental implementation in embodiment 19, unique difference is to be replaced to by the aniline added in this step
The 23 dimethyl aniline of equimolar amounts.
The preparation of step 5:6-amino-7-methoxyl group-4-(2 3 dimethyl aniline base) quinazoline
Seeing step 5 experimental implementation in embodiment 19, unique difference is by the reactant 6-nitro-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-nitro-7-methoxyl group-4-(2 3 dimethyl aniline base) the quinoline azoles of equimolar amounts
Quinoline.
Step 6: see step 4 experimental implementation in embodiment 1.
The preparation of step 7:1-phenyl-3-[7-methoxyl group-4-(2 3 dimethyl aniline base) quinazoline-6-base] urea
Seeing step 7 experimental implementation in embodiment 19, unique difference is by the reactant 6-amino-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-amino-7-methoxyl group-4-(2 3 dimethyl aniline base) the quinoline azoles of equimolar amounts
Quinoline.
Embodiment 36The synthesis of 1-phenyl-3-[4-(3-bromobenzene amido) quinazoline-7-base] urea (compound 36)
Step 1: see step 1 experimental implementation in embodiment 1.
The preparation of step 2:7-nitro-4-(3-bromobenzene amido) quinazoline
Seeing step 2 experimental implementation in embodiment 1, unique difference is to be replaced to by the aniline added in this step
The 3-bromaniline of mole.
The preparation of step 3:7-amino-4-(3-bromobenzene amido) quinazoline
Seeing step 3 experimental implementation in embodiment 1, unique difference is by the reactant 7-nitro-4-in this step
Anilinoquinazoline replaces to 7-nitro-4-(the 3-bromobenzene amido) quinazoline of equimolar amounts.
Step 4: see step 4 experimental implementation in embodiment 1.
The preparation of step 5:1-phenyl-3-[4-(3-bromobenzene amido) quinazoline-7-base] urea
Seeing step 5 experimental implementation in embodiment 1, unique difference is by the reactant 7-amino-4-in this step
Anilinoquinazoline replaces to 7-amino-4-(the 3-bromobenzene amido) quinazoline of equimolar amounts.
Embodiment 371-phenyl-3-[7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline-6-base] urea
The synthesis of (compound 37)
Step 1: see step 1 experimental implementation in embodiment 19.
Step 2: see step 2 experimental implementation in embodiment 19.
Step 3: see step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline
Seeing step 4 experimental implementation in embodiment 19, unique difference is to be replaced to by the aniline added in this step
The 4-chloro-3-5-trifluoromethylaniline of equimolar amounts.
The preparation of step 5:6-amino-7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline
Seeing step 5 experimental implementation in embodiment 19, unique difference is by the reactant 6-nitro-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-nitro-7-methoxyl group-4-(the 4-chloro-3-5-trifluoromethylaniline of equimolar amounts
Base) quinazoline.
Step 6: see step 4 experimental implementation in embodiment 1.
The system of step 7:1-phenyl-3-[7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline-6-base] urea
Standby
Seeing step 7 experimental implementation in embodiment 19, unique difference is by the reactant 6-amino-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-amino-7-methoxyl group-4-(the 4-chloro-3-5-trifluoromethylaniline of equimolar amounts
Base) quinazoline.
Embodiment 381-phenyl-3-[7-methoxyl group-4-(2-fluoro-4-bromobenzene amido) quinazoline-6-base] urea (compound
38) synthesis
Step 1: see step 1 experimental implementation in embodiment 19.
Step 2: see step 2 experimental implementation in embodiment 19.
Step 3: see step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(2-fluoro-4-bromobenzene amido) quinazoline
Seeing step 4 experimental implementation in embodiment 19, unique difference is to be replaced to by the aniline added in this step
The 2-fluoro-4-bromaniline of equimolar amounts.
The preparation of step 5:6-amino-7-methoxyl group-4-(2-fluoro-4-bromobenzene amido) quinazoline
Seeing step 5 experimental implementation in embodiment 19, unique difference is by the reactant 6-nitro-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-nitro-7-methoxyl group-4-(2-fluoro-4-bromobenzene amido) the quinoline azoles of equimolar amounts
Quinoline.
Step 6: see step 4 experimental implementation in embodiment 1.
The preparation of step 7:1-phenyl-3-[7-methoxyl group-4-(2-fluoro-4-bromobenzene amido) quinazoline-6-base] urea
Seeing step 7 experimental implementation in embodiment 19, unique difference is by the reactant 6-amino-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-amino-7-methoxyl group-4-(2-fluoro-4-bromobenzene amido) the quinoline azoles of equimolar amounts
Quinoline.
Embodiment 391-phenyl-3-[7-methoxyl group-4-(3-acetylenylbenzene amido) quinazoline-6-base] urea (compound
39) synthesis
Step 1: see step 1 experimental implementation in embodiment 19.
Step 2: see step 2 experimental implementation in embodiment 19.
Step 3: see step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(3-acetylenylbenzene amido) quinazoline
Seeing step 4 experimental implementation in embodiment 19, unique difference is to be replaced to by the aniline added in this step
The 3-acetylenylaniline of equimolar amounts.
The preparation of step 5:6-amino-7-methoxyl group-4-(3-acetylenylbenzene amido) quinazoline
Seeing step 5 experimental implementation in embodiment 19, unique difference is by the reactant 6-nitro-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-nitro-7-methoxyl group-4-(3-acetylenylbenzene amido) the quinoline azoles of equimolar amounts
Quinoline.
Step 6: see step 4 experimental implementation in embodiment 1.
The preparation of step 7:1-phenyl-3-[7-methoxyl group-4-(3-acetylenylbenzene amido) quinazoline-6-base] urea
Seeing step 7 experimental implementation in embodiment 19, unique difference is by the reactant 6-amino-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-amino-7-methoxyl group-4-(3-acetylenylbenzene amido) the quinoline azoles of equimolar amounts
Quinoline.
Embodiment 401-phenyl-3-[7-methoxyl group-4-(4-bromobenzene amido) quinazoline-6-base] urea (compound 40)
Synthesis
Step 1: see step 1 experimental implementation in embodiment 19.
Step 2: see step 2 experimental implementation in embodiment 19.
Step 3: see step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(4-bromobenzene amido) quinazoline
Seeing step 4 experimental implementation in embodiment 19, unique difference is to be replaced to by the aniline added in this step
The 4-bromaniline of equimolar amounts.
The preparation of step 5:6-amino-7-methoxyl group-4-(4-bromobenzene amido) quinazoline
Seeing step 5 experimental implementation in embodiment 19, unique difference is by the reactant 6-nitro-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-nitro-7-methoxyl group-4-(the 4-bromobenzene amido) quinazoline of equimolar amounts.
Step 6: see step 4 experimental implementation in embodiment 1.
The preparation of step 7:1-phenyl-3-[7-methoxyl group-4-(4-bromobenzene amido) quinazoline-6-base] urea
Seeing step 7 experimental implementation in embodiment 19, unique difference is by the reactant 6-amino-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-amino-7-methoxyl group-4-(the 4-bromobenzene amido) quinazoline of equimolar amounts.
Embodiment 411-phenyl-3-[7-methoxyl group-4-(3-cyano-aniline base) quinazoline-6-base] urea (compound 41)
Synthesis
Step 1: see step 1 experimental implementation in embodiment 19.
Step 2: see step 2 experimental implementation in embodiment 19.
Step 3: see step 3 experimental implementation in embodiment 19.
The preparation of step 4:6-nitro-7-methoxyl group-4-(3-cyano-aniline base) quinazoline
Seeing step 4 experimental implementation in embodiment 19, unique difference is to be replaced to by the aniline added in this step
The 3-cyano-aniline of equimolar amounts.
The preparation of step 5:6-amino-7-methoxyl group-4-(3-cyano-aniline base) quinazoline
Seeing step 5 experimental implementation in embodiment 19, unique difference is by the reactant 6-nitro-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-nitro-7-methoxyl group-4-(the 3-cyano-aniline base) quinazoline of equimolar amounts.
Step 6: see step 4 experimental implementation in embodiment 1.
The preparation of step 7:1-phenyl-3-[7-methoxyl group-4-(3-cyano-aniline base) quinazoline-6-base] urea
Seeing step 7 experimental implementation in embodiment 19, unique difference is by the reactant 6-amino-7-in this step
Methoxyl group-4-anilinoquinazoline replaces to 6-amino-7-methoxyl group-4-(the 3-cyano-aniline base) quinazoline of equimolar amounts.
Embodiment 421-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline-6-base]
The synthesis of urea (compound 42)
Synthetic route and the method for compound 42 are as follows:
Step 1: see step 1 experimental implementation in embodiment 19.
Step 2: see step 2 experimental implementation in embodiment 19.
The preparation of the chloro-4-of step 3:6-nitro-7-(3-toluidine) quinazoline
6-nitro-7-obtained above chloro-3H-quinazoline-4-one (9.00g, 40.0mmol) is joined 90mL
SOCl2In solution, being subsequently adding 0.9mL DMF, return stirring 2h, solution gradually becomes buff clarification, stopped reaction, cooling
To room temperature, the SOCl of excess is evaporated off2, obtain yellow solid 4,7-bis-chloro-6-nitro-quinazoline.Yellow solid is blended, adds
50mL petroleum ether, decompression steams petroleum ether, repeats to add petroleum ether and operates 2 times, removes remaining SOCl2, obtain yellow solid.
The most purified yellow solid is transferred in there-necked flask, add 3-monomethylaniline. (4.71g, 44.0mmol), isopropanol 170mL,
Return stirring 2h, separates out solid, is cooled to room temperature, collects solid, washs with isopropanol, is dried, obtains yellow solid 6-nitro-7-
Chloro-4-(3-toluidine) quinazoline 6.87g, productivity is 54.7%.
The preparation of step 4:6-nitro-7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline
The 6-chloro-4-of nitro-7-(3-toluidine) quinazoline (6.28g, 20.0mmol) is added N methyl piperazine
In (20.0g, 200.0mmol), in a nitrogen atmosphere, it is heated to 70 DEG C, insulation reaction 4h, it is cooled to room temperature, evaporated under reduced pressure, adds
Entering ethyl acetate to extract, sucking filtration, filtrate is spin-dried for, and residue adds 60mL ethanol, the lower dropping 120mL distilled water of stirring, stirring
30min, separates out yellow solid, sucking filtration, obtains yellow solid 6-nitro-7-(4-methylpiperazine-1-yl)-4-(3-toluidine)
Quinazoline 4.32g, productivity 57.1%.
The preparation of step 5:6-amino-7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline
By 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), in a nitrogen atmosphere, are heated to back
Stream, insulation reaction 2h, by reactant liquor sucking filtration, and filtrate decompression is evaporated, uses petroleum ether to wash with ethyl acetate (3:1) mixed liquor
Wash residue, sucking filtration, obtain yellow solid 6-amino-7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline
2.15g, productivity 61.7%.
Step 6: see step 4 experimental implementation in embodiment 1.
Step 7:1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline-6-base] urea
Preparation
By 6-amino-7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline (0.70g, 2.0mmol) in
60 DEG C of thermosols, in 20mL acetonitrile, add phenyl isocyanate (0.26g, 2.2mmol), back flow reaction 2h, filter, and acetonitrile washs
Filter cake, is dried, obtains faint yellow solid 1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline-6-
Base] urea 0.68g, productivity is 72.8%.
Embodiment 431-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(3-bromobenzene amido) quinazoline-6-base] urea
The synthesis of (compound 43)
Step 1: see step 1 experimental implementation in embodiment 19.
Step 2: see step 2 experimental implementation in embodiment 19.
The preparation of the chloro-4-of step 3:6-nitro-7-(3-bromobenzene amido) quinazoline
Seeing step 3 experimental implementation in embodiment 42, unique difference is to be replaced to by the aniline added in this step
The 3-bromaniline of equimolar amounts.
The preparation of step 4:6-nitro-7-(4-methylpiperazine-1-yl)-4-(3-bromobenzene amido) quinazoline
Seeing step 4 experimental implementation in embodiment 42, unique difference is by the reactant 6-nitro-7-in this step
Chloro-4-(3-toluidine) quinazoline replaces to the 6-chloro-4-of nitro-7-(the 3-bromobenzene amido) quinazoline of equimolar amounts.
The preparation of step 5:6-amino-7-(4-methylpiperazine-1-yl)-4-(3-bromobenzene amido) quinazoline
Seeing step 5 experimental implementation in embodiment 42, unique difference is by the reactant 6-nitro-7-in this step
(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline replace to equimolar amounts 6-nitro-7-(4-methyl piperazine-
1-yl)-4-(3-bromobenzene amido) quinazoline.
Step 6: see step 4 experimental implementation in embodiment 1.
The system of step 7:1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(3-bromobenzene amido) quinazoline-6-base] urea
Standby
Seeing step 7 experimental implementation in embodiment 42, unique difference is by the reactant 6-amino-7-in this step
(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline replace to equimolar amounts 6-amino-7-(4-methyl piperazine-
1-yl)-4-(3-bromobenzene amido) quinazoline.
Embodiment 441-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(2-fluoro-4-bromobenzene amido) quinazoline-6-
Base] synthesis of urea (compound 44)
Step 1: see step 1 experimental implementation in embodiment 19.
Step 2: see step 2 experimental implementation in embodiment 19.
The preparation of the chloro-4-of step 3:6-nitro-7-(2-fluoro-4-bromobenzene amido) quinazoline
Seeing step 3 experimental implementation in embodiment 42, unique difference is to be replaced to by the aniline added in this step
The 2-fluoro-4-bromaniline of equimolar amounts.
The preparation of step 4:6-nitro-7-(4-methylpiperazine-1-yl)-4-(2-fluoro-4-bromobenzene amido) quinazoline
Seeing step 4 experimental implementation in embodiment 42, unique difference is by the reactant 6-nitro-7-in this step
Chloro-4-(3-toluidine) quinazoline replaces to the 6-chloro-4-of nitro-7-(2-fluoro-4-bromobenzene amido) the quinoline azoles of equimolar amounts
Quinoline.
The preparation of step 5:6-amino-7-(4-methylpiperazine-1-yl)-4-(2-fluoro-4-bromobenzene amido) quinazoline
Seeing step 5 experimental implementation in embodiment 42, unique difference is by the reactant 6-nitro-7-in this step
(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline replace to equimolar amounts 6-nitro-7-(4-methyl piperazine-
1-yl)-4-(2-fluoro-4-bromobenzene amido) quinazoline.
Step 6: see 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-base] urea
Preparation
Seeing step 7 experimental implementation in embodiment 42, unique difference is by the reactant 6-amino-7-in this step
(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline replace to equimolar amounts 6-amino-7-(4-methyl piperazine-
1-yl)-4-(2-fluoro-4-bromobenzene amido) quinazoline.
Embodiment 451-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(2-methyl-4-methoxybenzene amido) quinoline azoles
Quinoline-6-base] synthesis of urea (compound 45)
Step 1 sees step 1 experimental implementation in embodiment 19.
Step 2 sees step 2 experimental implementation in embodiment 19.
The preparation of the chloro-4-of step 3:6-nitro-7-(2-methyl-4-methoxybenzene amido) quinazoline
Seeing step 3 experimental implementation in embodiment 42, unique difference is to be replaced to by the aniline added in this step
2-methyl-4-the aminoanisole of equimolar amounts.
The system of step 4:6-nitro-7-(4-methylpiperazine-1-yl)-4-(2-methyl-4-methoxybenzene amido) quinazoline
Standby
Seeing step 4 experimental implementation in embodiment 42, unique difference is by the reactant 6-nitro-7-in this step
Chloro-4-anilinoquinazoline replaces to the 6-chloro-4-of nitro-7-(2-methyl-4-methoxybenzene amido) quinazoline of equimolar amounts.
The system of step 5:6-amino-7-(4-methylpiperazine-1-yl)-4-(2-methyl-4-methoxybenzene amido) quinazoline
Standby
Seeing step 5 experimental implementation in embodiment 42, unique difference is by the reactant 6-nitro-7-in this step
(4-methylpiperazine-1-yl)-4-anilinoquinazoline replaces to 6-nitro-7-(4-the methylpiperazine-1-yl)-4-of equimolar amounts
(2-methyl-4-methoxybenzene amido) quinazoline.
Step 6 sees step 4 experimental implementation in embodiment 1.
Step 7:1-phenyl-3-[7-(4-methylpiperazine-1-yl)-4-(2-methyl-4-methoxybenzene amido) quinazoline-
6-yl] preparation of urea
Seeing step 7 experimental implementation in embodiment 42, unique difference is by the reactant 6-amino-7-in this step
(4-methylpiperazine-1-yl)-4-anilinoquinazoline replaces to 6-amino-7-(4-the methylpiperazine-1-yl)-4-of equimolar amounts
(2-methyl-4-methoxybenzene amido) quinazoline.
Embodiment 461-phenyl-3-[7-(morpholine-4-base)-4-(3-chloro-4-fluoroanilino) quinazoline-6-base] urea
The synthesis of (compound 46)
Synthetic route and the method for compound 46 are as follows:
Step 1: see step 1 experimental implementation in embodiment 19.
Step 2: see step 2 experimental implementation in embodiment 19.
The preparation of the chloro-4-of step 3:6-nitro-7-(3-chloro-4-fluoroanilino) quinazoline
Seeing step 3 experimental implementation in embodiment 42, unique difference is to be replaced to by the aniline added in this step
The 3-chloro-4-fluoroaniline of equimolar amounts.
The preparation of step 4:6-nitro-7-(morpholine-4-base)-4-(3-chloro-4-fluoroanilino) quinazoline
The 6-chloro-4-of nitro-7-(3-chloro-4-fluoroanilino) quinazoline (70.62g, 20.0mmol) is added morpholine
In (17.42g, 200.0mmol), in a nitrogen atmosphere, it is heated to 70 DEG C, insulation reaction 4h, it is cooled to room temperature, evaporated under reduced pressure,
Adding ethyl acetate to extract, sucking filtration, filtrate is spin-dried for, and residue adds 60mL ethanol, the lower dropping 120mL distilled water of stirring, stirring
30min, separates out yellow solid, sucking filtration, obtains yellow solid 6-nitro-7-(morpholine-4-base)-4-(3-chloro-4-fluoroanilino) quinoline
Oxazoline 4.73g, productivity 58.6%.
The preparation of step 5:6-amino-7-(morpholine-4-base)-4-(3-chloro-4-fluoroanilino) quinazoline
Seeing step 5 experimental implementation in embodiment 42, unique difference is by the reactant 6-nitro-7-in this step
(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline replace to the 6-nitro-7-(morpholine-4-base) of equimolar amounts-
4-(3-chloro-4-fluoroanilino) quinazoline.
Step 6: see step 4 experimental implementation in embodiment 1.
The preparation of step 7:1-phenyl-3-[7-(morpholine-4-base)-4-(3-chloro-4-fluoroanilino) quinazoline-6-base] urea
Seeing step 7 experimental implementation in embodiment 42, unique difference is by the reactant 6-amino-7-in this step
(4-methylpiperazine-1-yl)-4-(3-toluidine) quinazoline replace to the 6-amino-7-(morpholine-4-base) of equimolar amounts-
4-(3-chloro-4-fluoroanilino) quinazoline.
Embodiment 47The synthesis of 1-phenyl-3-(6-methoxyl group-4-anilinoquinazoline-7-base) urea (compound 47)
Synthetic route and the method for compound 47 are as follows:
The synthesis of step 1:N-(2-methyl-4-methoxyl group-phenyl) acetamide
4-methoxyl group-2-aminotoluene (18.40g, 134.1mmol) is added dropwise to acetic anhydride (13.69g,
134.1mmol) with in the mixed solution of 140mL acetic acid, it is heated to 60 DEG C, insulation reaction 30min, it is evaporated to do, residue
Using 80mL acetic acid ethyl dissolution, regulate pH to 8.0 with saturated sodium bicarbonate solution, separating ethyl acetate layer, with distilled water with full
And brine It, anhydrous Na2SO4It is dried, is evaporated to do, obtains yellow solid N-(2-methyl-4-methoxyl group-phenyl) second
Amide 18.22g, productivity is 75.8%.
Step 2:N-(2-methyl-4-methoxyl group-5-nitrobenzophenone) acetamide
N-(2-methyl-4-methoxyl group-phenyl) acetamide (16.18g, 90.3mmol) is dissolved in 166ml trifluoroacetic acid,
Ice-water bath is cooled to 0 DEG C.It is slowly added to potassium nitrate (10.11g, 100.0mmol), 1h is stirred at room temperature.Pour reactant liquor into frozen water
Middle quenching, extracts by ethyl acetate (2 × 50mL), combined ethyl acetate solution, with saturated sodium bicarbonate solution regulation to neutral,
Wash with distilled water and saturated aqueous common salt, anhydrous Na2SO4Being dried, be evaporated to do, residue adds in 100mL ethyl acetate,
Stirring 1h, sucking filtration, obtain yellow solid N-(2-methyl-4-methoxyl group-5-nitrobenzophenone) acetamide 16.84g, productivity is 83.2%.
Step 3:2-acetamido-5-methoxyl group-4-nitrobenzoic acid
N-(2-methyl-4-methoxyl group-5-nitrobenzophenone) acetamide (15.04g, 67.1mmol) is joined magnesium sulfate
In the 671mL aqueous solution of (10.11g, 84.0mmol) and potassium permanganate (29.22g, 184.9mmol), it is warming up to 80 DEG C, reaction
After 45min, add magnesium sulfate (5.08g, 42.2mmol) and potassium permanganate (14.63g, 92.6mmol), react 1h.Sucking filtration, filter
Cake hot water (2 × 300mL) washs.It is 3.0 that filtrate 3.0N HCl solution is acidified to pH, adds 300mL dichloromethane separatory,
Extracting with dichloromethane (2 × 200mL), combined dichloromethane solution, anhydrous magnesium sulfate is dried, and is evaporated to do, obtains yellow
Solid 2-acetamido-5-methoxyl group-4-nitrobenzoic acid 11.37g, productivity is 66.7%.
Step 4:2-amino-5-methoxyl group-4-nitrobenzoic acid
2-acetamido-5-methoxyl group-4-nitrobenzoic acid (10.67g, 42.0mmol) is joined 38mL distilled water and
In the mixed liquor of 15mL concentrated hydrochloric acid, reflux 3h, is cooled to 0 DEG C, separates out solid, sucking filtration, with distillation washing, is dried, obtains yellow solid
Body 2-amino-5-methoxyl group-4-nitrobenzoic acid 7.50g, productivity is 84.2%.
Step 5:6-methoxyl group-7-nitro-3H-quinazoline-4-one
2-amino-5-methoxyl group-4-nitrobenzoic acid (6.70g, 31.5mmol) is joined in 100mL Methanamide, adds
Hot to 150 DEG C, insulation reaction 4.5h, it is cooled to 0 DEG C, separates out solid, sucking filtration, drying under reduced pressure, obtain yellow solid 6-methoxyl group-7-
Nitro-3H-quinazoline-4-one 5.38g, productivity is 77.2%.
Step 6:6-methoxyl group-7-nitro-4-anilinoquinazoline
6-methoxyl group-7-nitro-3H-quinazoline-4-one (4.42g, 20.0mmol) obtained above is joined 44mL
SOCl2In solution, being subsequently adding 0.4mL DMF, return stirring 2h, solution gradually becomes buff clarification, stopped reaction, cooling
To room temperature, the SOCl of excess is evaporated off2, obtain yellow solid 4-chloro-6-methoxyl group-7-nitro-quinazoline.Yellow solid is blended,
Adding 10mL petroleum ether, decompression steams petroleum ether, repeats to add petroleum ether and operates 2 times, removes remaining SOCl2, obtain yellow
Solid.The most purified yellow solid is transferred in there-necked flask, add aniline (2.04g, 22.0mmol), isopropanol 70mL, return
Stream stirring 2h, separates out solid, is cooled to room temperature, collect solid, wash with isopropanol, be dried, obtain yellow solid 6-methoxyl group-7-
Nitro-4-anilinoquinazoline 3.89g, productivity is 65.6%.
Step 7:6-methoxyl group-7-amino-4-anilinoquinazoline
By 6-methoxyl group-7-nitro-4-anilinoquinazoline (5.92g, 20.0mmol) and two hydrated stannous chlorides
(18.05g, 80.0mmol) joins in 250mL ethyl acetate, back flow reaction 1h.React complete, place to room temperature, filter, mistake
Filter gained solid with ethyl acetate washing, combined ethyl acetate solution, with saturated sodium bicarbonate solution regulation to neutral, separate second
Ethyl acetate layer, washs with 30mL water, anhydrous Na2SO4Be dried, be evaporated to do, obtain faint yellow solid 6-methoxyl group-7-amino-
4-anilinoquinazoline 4.48g, productivity is 84.1%.
Step 8: see step 4 experimental implementation in embodiment 1.
Step 9:1-phenyl-3-(6-methoxyl group-4-anilinoquinazoline-7-base) urea
Phenyl isocyanate (0.26g, 2.2mmol) is joined in 10mL acetonitrile solution, is stirred at room temperature down and is dividedly in some parts
6-methoxyl group-7-amino-4-anilinoquinazoline (0.53g, 2.0mmol), is stirred at room temperature 3h, filters to obtain solid, washes with acetonitrile
Washing (5mL × 3), be dried, added in 30ml methanol by gained solid, reflux 1h, while hot sucking filtration, obtain faint yellow solid 1-phenyl-
3-(6-methoxyl group-4-anilinoquinazoline-7-base) urea 0.60g, productivity is 77.8%.
Embodiment 481-phenyl-3-[6-(4-methylpiperazine-1-yl)-4-anilinoquinazoline-7-base] urea (compound
48) synthesis
Synthetic route and the method for compound 48 are as follows:
The synthesis of step 1:N-(the chloro-phenyl of 2-methyl-4-) acetamide
4-chloro-2-methyl aniline (18.98g, 134.1mmol) is added dropwise to acetic anhydride (13.69g, 134.1mmol)
With in the mixed solution of 140mL acetic acid, it is heated to 60 DEG C, insulation reaction 60min, it is evaporated to do, residue 80mL acetic acid
Ethyl ester dissolves, and regulates pH to 8.0, separating ethyl acetate layer with saturated sodium bicarbonate solution, washes with distilled water and saturated common salt
Wash, anhydrous Na2SO4It is dried, is evaporated to do, obtains yellow solid N-(the chloro-phenyl of 2-methyl-4-) acetamide 16.70g, productivity
It is 67.8%.
Step 2:N-(2-methyl-4-chloro-5-nitrobenzophenone) acetamide
N-(the chloro-phenyl of 2-methyl-4-) acetamide (16.58g, 90.3mmol) is dissolved in 166ml trifluoroacetic acid, frozen water
Bath is cooled to 0 DEG C.It is slowly added to potassium nitrate (10.11g, 100.0mmol), 1h is stirred at room temperature.Reactant liquor is poured in frozen water and quenches
Fire, extracts by ethyl acetate (2 × 50mL), combined ethyl acetate solution, with saturated sodium bicarbonate solution regulation to neutral, with steaming
Distilled water and saturated aqueous common salt washing, anhydrous Na2SO4Being dried, be evaporated to do, residue adds in 100mL ethyl acetate, stirring
1h, sucking filtration, obtain yellow solid N-(2-methyl-4-chloro-5-nitrobenzophenone) acetamide 15.93g, productivity is 77.1%.
Step 3:2-acetamido-5-chloro-4-nitrobenzoic acid
N-(2-methyl-4-chloro-5-nitrobenzophenone) acetamide (15.34g, 67.1mmol) is joined magnesium sulfate
In the 671mL aqueous solution of (10.11g, 84.0mmol) and potassium permanganate (29.22g, 184.9mmol), it is warming up to 80 DEG C, reaction
After 45min, add magnesium sulfate (5.08g, 42.2mmol) and potassium permanganate (14.63g, 92.6mmol), react 1h.Sucking filtration, filter
Cake hot water (2 × 300mL) washs.It is 3.0 that filtrate 3.0N HCl solution is acidified to pH, adds 300mL dichloromethane separatory,
Extracting with dichloromethane (2 × 200mL), combined dichloromethane solution, anhydrous magnesium sulfate is dried, and is evaporated to do, obtains yellow
Solid 2-acetamido-5-chloro-4-nitrobenzoic acid 11.84g, productivity is 68.2%.
Step 4:2-amino-5-chloro-4-nitrobenzoic acid
2-acetamido-5-chloro-4-nitrobenzoic acid (10.86g, 42.0mmol) is joined 38mL distilled water and 15mL
In the mixed liquor of concentrated hydrochloric acid, reflux 3h, is cooled to 0 DEG C, separates out solid, sucking filtration, with distilled water wash, is dried, obtains yellow solid
2-amino-5-chloro-4-nitrobenzoic acid 8.39g, productivity 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 100mL Methanamide, is heated to
150 DEG C, insulation reaction 4.5h, it is cooled to 0 DEG C, separates out solid, sucking filtration, drying under reduced pressure, obtain yellow solid 6-chloro-7-nitro-3H-
Quinazoline-4-one 6.03g, productivity is 84.9%.
Step 6:6-chloro-7-nitro-4-anilinoquinazoline
Chloro-for 6-obtained above 7-nitro-3H-quinazoline-4-one (4.51g, 20.0mmol) is joined 45mL
SOCl2In solution, being subsequently adding 0.4mL DMF, return stirring 2h, solution gradually becomes buff clarification, stopped reaction, cooling
To room temperature, the SOCl of excess is evaporated off2, obtain yellow solid 4,6-bis-chloro-7-nitro-quinazoline.Yellow solid is blended, adds
10mL petroleum ether, decompression steams petroleum ether, repeats to add petroleum ether and operates 2 times, removes remaining SOCl2, obtain yellow solid.
The most purified yellow solid is transferred in there-necked flask, add aniline (2.04g, 22.0mmol), isopropanol 70mL, return stirring
2h, separates out solid, is cooled to room temperature, collects solid, washs with isopropanol, is dried, obtains yellow solid 6-chloro-7-nitro-4-benzene
Amido quinazoline 4.25g, productivity is 70.8%.
The preparation of step 7:6-(4-methylpiperazine-1-yl)-7-nitro-4-anilinoquinazoline
By chloro-for 6-7-nitro-4-anilinoquinazoline (6.01g, 20.0mmol) add N methyl piperazine (20.0g,
In 200.0mmol), in a nitrogen atmosphere, it is heated to 70 DEG C, insulation reaction 4h, it is cooled to room temperature, evaporated under reduced pressure, adds acetic acid
Ethyl ester extracts, sucking filtration, and filtrate is spin-dried for, and residue adds 60mL ethanol, the lower dropping 120mL distilled water of stirring, stirs 30min, separates out
Yellow solid, sucking filtration, obtain yellow solid 6-(4-methylpiperazine-1-yl)-7-nitro-4-anilinoquinazoline 5.46g, productivity
90.8%。
The preparation of step 8:6-(4-methylpiperazine-1-yl)-7-amino-4-anilinoquinazoline
By 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), in a nitrogen atmosphere, are heated to backflow, protect
Temperature reaction 2h, by reactant liquor sucking filtration, and is evaporated filtrate decompression, uses petroleum ether residual with the washing of ethyl acetate (3:1) mixed liquor
Slag, sucking filtration, obtain yellow solid 6-(4-methylpiperazine-1-yl)-7-amino-4-anilinoquinazoline 2.79g, productivity 83.4%.
Step 9: see step 4 experimental implementation in embodiment 1.
Step 10:1-phenyl-3-[6-(4-methylpiperazine-1-yl)-4-anilinoquinazoline-7-base] urea
By 6-(4-methylpiperazine-1-yl)-7-amino-4-anilinoquinazoline (0.67g, 2.0mmol) in 60 DEG C of thermosols
In 20mL acetonitrile, add phenyl isocyanate (0.26g, 2.2mmol), back flow reaction 2h, filter, acetonitrile washing filter cake, dry
Dry, obtain off-white color solid 1-phenyl-3-[6-(4-methylpiperazine-1-yl)-4-anilinoquinazoline-7-base] urea 0.61g, productivity
It is 67.2%.
Embodiment 491-phenyl-3-[6-(morpholine-4-base)-4-anilinoquinazoline-7-base] urea (compound 49)
Synthesis
Step 1: see step 1 experimental implementation in embodiment 48.
Step 2: see step 2 experimental implementation in embodiment 48.
Step 3: see step 3 experimental implementation in embodiment 48.
Step 4: see step 4 experimental implementation in embodiment 48.
Step 5: see step 5 experimental implementation in embodiment 48.
Step 6: see step 6 experimental implementation in embodiment 48.
The preparation of step 7:6-(morpholine-4-base)-7-nitro-4-anilinoquinazoline
By chloro-for 6-7-nitro-4-anilinoquinazoline (6.01g, 20.0mmol) add morpholine (17.42g,
In 200.0mmol), in a nitrogen atmosphere, it is heated to 70 DEG C, insulation reaction 4h, it is cooled to room temperature, evaporated under reduced pressure, adds acetic acid
Ethyl ester extracts, sucking filtration, and filtrate is spin-dried for, and residue adds 60mL ethanol, the lower dropping 120mL distilled water of stirring, stirs 30min, separates out
Yellow solid, sucking filtration, obtain yellow solid 6-(morpholine-4-base)-7-nitro-4-anilinoquinazoline 5.10g, productivity 72.6%.
The preparation of step 8:6-(morpholine-4-base)-7-amino-4-anilinoquinazoline
Seeing step 8 experimental implementation in embodiment 48, unique difference is by reactant 6-(the 4-methyl in this step
Piperazine-1-base)-7-nitro-4-anilinoquinazoline replaces to 6-(morpholine-4-the base)-7-nitro-4-anilino-of equimolar amounts
Quinazoline.
Step 9: see step 4 experimental implementation in embodiment 1.
The preparation of step 10:1-phenyl-3-[6-(morpholine-4-base)-4-anilinoquinazoline-7-base] urea
Seeing step 10 experimental implementation in embodiment 48, unique difference is by reactant 6-(the 4-first in this step
Base piperazine-1-base)-7-amino-4-anilinoquinazoline replaces to 6-(morpholine-4-the base)-7-amino-4-aniline of equimolar amounts
Base quinazoline.
Embodiment 501-phenyl-3-[7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline-6-base] urea
The synthesis of hydrochlorate (compound 50)
Synthetic route and the method for compound 45 are as follows:
The method identical with embodiment 37 is used to prepare 1-phenyl-3-[7-methoxyl group-4-(4-chloro-3-5-trifluoromethylaniline
Base) quinazoline-6-base] urea, by preparation 1-phenyl-3-[7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline-
6-yl] and urea (0.2g, 0.41 × 10-3Mol) it is dissolved in the mixed solution of ethanol and dichloroethanes (3:7), adds 2N acidic alcohol
Solution (2mL) filters, and filtration cakes torrefaction obtains white solid 1-phenyl-3-[7-methoxyl group-4-(4-chloro-3-5-trifluoromethylaniline
Base) quinazoline-6-base] urea hydrochlorate.
Table 1 lists the yield result in above-described embodiment 1-49 in compound 1-49 preparation process.
The yield of each step in table 1 compound 1-49 preparation process
Table 2 lists molecular structure and the sign of the compound 1-that 1-according to embodiments of the present invention obtains.
Test case 1The mensuration of 1-phenyl-3-[4-(4-toluidine) quinazoline-7-base] urea (compound 2)
Chromatographic condition: C18Chromatographic column (Luna250 × 4.6mm5 μ), flow phase, acetonitrile: water (pH=3.0, phosphoric acid)=23:
77, flow velocity: 1.0mL/min, detect wavelength: 254nm, sample size: 10 μ L.
System suitability test: take compound 2 contrast solution (3mg/mL) and measure by sample introduction under chromatographic condition, theoretical tray
Number is calculated as 4120 with compound 2 peak, and retention time is: 14.454min.
Detection limit and quantitative limit: being 3 and 10 as inspection target with S/N respectively, the detection recording compound 2 is limited to 90ng,
Quantitatively it is limited to 210ng.
Repeatability is tested: under chromatographic condition, reference substance solution continuous sample introduction 5 times, the relative mark of compound 2 appearance time
Quasi-deviation (RSD) is 0.20%, and the RSD of peak area is 0.16%.
Sample determination: lab scale product solution (3mg/mL) sample introduction under chromatographic condition measures.Use above-mentioned separation method, root
According to area normalization method, respectively 3 batches of compound 2 lab scale samples being carried out content inspection, experimental result (as shown in table 3) shows, 3
Batch sample content is all not less than 99%.
Table 3: batch sample (compound 2) content checks result
| Lot number | % |
| 20110101 | 99.4 |
| 20110201 | 99.4 |
| 20110202 | 99.5 |
Embodiment 1 prepared by preparationThe preparation of pharmaceutical composition (tablet)
Take 10g compound 2, add amylum pregelatinisatum 200g, sucrose 50g, magnesium stearate 5g, mix homogeneously, powder is direct
Tabletting, makes 500, film coating.
Test case 2The antitumor activity screening of part of compounds
1) test material
Test medicine: 36 kinds of new quinazoline compounds (compound 1-36) of synthesis, positive control medicine in the present invention
Gefitinib (Gefitinib), ZD6474 (Vandetanib), cisplatin (Cisplatin), all pharmaceutical purity ＞
99.5%.
Reagent and instrument: DMEM culture medium (Gibco BRL)；Calf serum (HyClone) trypsin Amresco)；
Tetrazolium bromide (MTT, Sigma)；TK activity analysis enzyme-linked immunosorbent assay (enzyme-linked immunosorbent
Assay, ELISA) testing cassete (Chenicon)；Remaining reagent is domestic analytical reagent.Cell culture system is that Costar is public
Department's product；Constant temperature CO2Ovum case is purchased from Heraeus company；Microplate reader is Austria's 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(lymph node
Transfer).
2) tumor cell line is cultivated
A549 and NCI-H2921 cell strain growth is in containing 10% calf serum and dual anti-(penicillin 100U mL-1, streptomycin
100μg·mL-1) DMEM culture medium in, 37 DEG C, cultivate in 5% constant temperature incubator, trophophase cell of taking the logarithm is tested.
3) cell viability measures
Exponential phase cell use 0.25% trypsinization be uniformly inoculated in 96 hole trainings after becoming single-cell suspension liquid
Support in plate and carry out cellar culture, after cell grows to monolayer, discard former culture medium, random packet, be separately added into containing each tested and
The serum-free DMEM of positive drug, acts on 48h, then changes culture medium at 37 DEG C, each hole adds 20 μ l MTT(5mg mL-1),
After 37 DEG C of reaction 4h, liquid in sucking-off hole, add 150 μ l DMSO analytical pure solution shaking 10min, use microplate reader at 490nm
Absorbance OD value is measured at wavelength.Cell survival rate (%)=administration group OD value/matched group OD × 100%.
4) TK activity analysis
After exponential phase A549 cell is washed with ice-cold D-Hank ' s liquid, add lysate and crack 10min on ice, receive
Collection cell, 4 DEG C, relative centrifugal force(RCF) be 12000g under the conditions of centrifugal 10min, extract TK cell crude extract.Choose for A549
Cell strain MTT primary dcreening operation compounds effective acts on 20min with TK cell crude extract at 37 DEG C respectively, adds and analyzes liquid and peptide substrate
Hatch for 30 DEG C and terminate reaction with EDTA after 45min.Take each group of reaction system 50 μ l and act on 30min to 37 DEG C of enzyme mark hole, after washing
Closing 30min, PY20-HRP antibody at room temperature and hatch 1h, shaking table shakes.15min is acted on tetramethyl benzidine (TMB) after washing,
Microplate reader is used to measure absorbance at 450nm wavelength.
5) cell proliferation experiment method (mtt assay)
In the D-MEM/hams culture medium containing 20% hyclone, it is 2 × 10 by tested cell furnishing density5Cell/
The suspension of mL.By above-mentioned tumor cell line suspension inoculation in 96 well culture plates, every hole 50 μ l, it is separately added into blank phosphate
The each 50 μ l of buffer (PBS), solvent control 0.1% dimethyl sulfoxide and variable concentrations monomeric compound, often group is all provided with 3 again
Hole.Above-mentioned 96 well culture plates are placed in saturated humidity, 37 DEG C and 5%CO2Cultivating 48 hours in incubator, before cultivation terminates, 4 is little
Time, each culture hole adds 5mg/mL tetrazolium (MTT) 10 μ l, cultivates after terminating, discards culture supernatant, and suspension cell need to be from
Abandoning supernatant after the heart, every hole adds reaction stop solution 150 μ l, stands 1 hour, detects each hole extinction with enzyme-linked immunosorbent assay instrument
Degree (OD) value, measures wavelength X=570nm, reference wavelength λ=630nm, and calculates tumor cell survival rate.
The compounds of this invention is dissolved in DMSO, and the ultimate density after interpolation is below 0.1%.Only to add the cultivation of DMSO
Base is as comparison.
The suppression proliferative activity o f tumor result (relative to comparison (adding DMSO)) of the compounds of this invention is such as table 4 institute
Show.
6) data statistics and analysis
Test data mean ± SEM(mean+SD) represent, with one factor analysis of variance (One-way
ANOVA) difference between Tukey each group of numerical value of inspection is combined.P ＜ 0.05 represents statistically significant.
7) result
The noval chemical compound impact on each tumor cell line cell proliferation: concentration is the noval chemical compound (3 multiple hole/group) point of 10 μMs
Not with each cell strain effect 48h, mtt assay observes the noval chemical compound impact on tumor cell proliferation.Its result is as shown in table 4:
Table 4: compound 1-36MTT method cytoactive garbled data
8) conclusion: as seen from Table 4, with control drug gefitinib (Gefitinib), ZD6474 (Vandetanib),
Cisplatin (Cisplatin) is compared, and the compound of the present invention is after antitumor activity screening, for A549 cell, compound 2,
9,11,13,17,18,19,24,27,32,33,34 showing obvious anti-tumor activity, its tumor cell survival rate is less than
(it is right that Fig. 1, Fig. 2 and Fig. 3 respectively illustrate under compound 2,18 and 33 is at variable concentrations for the tumor cell survival rate of control drug
The inhibitory action of A549 cell, in accompanying drawing, * * represents compared with matched group, and difference has a statistical significance, p <
0.01；* representing with matched group compared with, difference has statistical significance, p < 0.05), additionally remove compound 4,7,8,10,21,
Outside 30, other compound also shows stronger anti-tumor activity.For NCI-H2921 cell, compound 2,4,9,10,
18,22,33 showing obvious anti-tumor activity, its tumor cell survival rate is less than the tumor cell existence of control drug
Rate, other compound also shows stronger anti-tumor activity.It is indicated above that the compound of the present invention can be to relating to albumen
The disease of tyrosine kinase overexpression, especially malignant tumor are effectively treated.
Specific description of embodiments of the present invention above is not limiting as the present invention, and those skilled in the art can be according to this
Invention is variously modified or deforms, and without departing from the spirit of the present invention, all should belong to the model of claims of the present invention
Enclose.
Claims (19)
1. the phenylurea coupling quinazoline compounds shown in formula (I) or its pharmaceutically acceptable salt,
Wherein, R1For H；Br, Cl or F；-CH3、-CH2-CH3、-CH2(CH3)2Or-CF3；-O-CH3、-O-CH2-CH3Or-O-CH2
(CH3)2；
n1It is 1,2,3,4 or 5；
R2Or R3One of for the group shown in formula (II)；
Wherein, R4For H or F；-CH3、-CH2-CH3Or-CH2(CH3)2；-O-CH3、-O-CH2-CH3Or-O-CH2(CH3)2；Or-
NO2；
n2It is 1,2,3,4 or 5；
R2Or R3In another one be-O-CH3、-O-CH2-CH3Or-O-CH2(CH3)2；Or
R3For the group shown in formula (II)；
Wherein, R4For H or F；-CH3、-CH2-CH3Or-CH2(CH3)2；-O-CH3、-O-CH2-CH3Or-O-CH2(CH3)2；Or-
NO2；
n2It is 1,2,3,4 or 5；
R2For H.
Phenylurea coupling quinazoline compounds the most according to claim 1 or its pharmaceutically acceptable salt, its feature
Being, the phenylurea coupling quinazoline compounds shown in described formula I or its pharmaceutically acceptable salt are selected from following chemical combination
Thing:
1-phenyl-3-(4-anilinoquinazoline-7-base) urea,
1-phenyl-3-[4-(4-toluidine) quinazoline-7-base] urea,
1-phenyl-3-[4-(3-toluidine) quinazoline-7-base] urea,
1-phenyl-3-[4-(2-aminotoluene base) quinazoline-7-base] urea,
1-phenyl-3-[4-(4-methoxybenzene amido) quinazoline-7-base] urea,
1-phenyl-3-[4-(2-fluoro-4-bromobenzene amido) quinazoline-7-base] urea,
1-phenyl-3-[4-(3-cumene amido) quinazoline-7-base] urea,
1-phenyl-3-[4-(3-chloro-4-fluoroanilino) quinazoline-7-base] urea,
1-phenyl-3-[4-(2，4，6-trimethyl aniline base) quinazoline-7-base] urea,
1-phenyl-3-[4-(2,3-dimethyl benzene amido) quinazoline-7-base] urea,
1-(2-aminomethyl phenyl)-3-(4-anilinoquinazoline-7-base) urea,
1-phenyl-3-[4-(2-chloroanilino) quinazoline-7-base] urea,
1-phenyl-3-[4-(2,4 difluorobenzene amido) quinazoline-7-base] urea,
1-phenyl-3-[4-(3-trifluoromethylbenzene amido) quinazoline-7-base] urea,
1-(2,3-3,5-dimethylphenyl)-3-(4-anilinoquinazoline-7-base) urea,
1-(2,4 difluorobenzene base)-3-(4-anilinoquinazoline-7-base) urea,
1-(4-methoxyphenyl)-3-(4-anilinoquinazoline-7-base) urea,
1-(2,4,6-trimethylphenyl)-3-(4-anilinoquinazoline-7-base) urea,
1-(4-nitrobenzophenone)-3-(4-anilinoquinazoline-7-base) urea,
1-(4-methoxyphenyl)-3-[4-(2,3-dimethyl benzene amido) quinazoline-7-base] urea,
1-phenyl-3-[4-(4-fluoroanilino) quinazoline-7-base] urea,
1-(4-fluorophenyl)-3-[4-(4-toluidine) quinazoline-7-base] urea,
1-(4-methoxyphenyl)-3-[4-(4-toluidine) quinazoline-7-base] urea,
1-phenyl-3-(7-methoxyl group-4-anilinoquinazoline-6-base) urea,
1-phenyl-3-[4-(3-bromobenzene amido) quinazoline-7-base] urea,
1-phenyl-3-[7-methoxyl group-4-(4-toluidine) quinazoline-6-base] urea,
1-phenyl-3-[7-methoxyl group-4-(3-toluidine) quinazoline-6-base] urea,
1-phenyl-3-[7-methoxyl group-4-(2,3-dimethyl benzene amido) quinazoline-6-base] urea,
1-phenyl-3-[7-methoxyl group-4-(3-bromobenzene amido) quinazoline-6-base] urea,
1-phenyl-3-[7-methoxyl group-4-(4-chloro-3-trifluoromethylbenzene amido) quinazoline-6-base] urea,
1-phenyl-3-[7-methoxyl group-4-(2-fluoro-4-bromobenzene amido) quinazoline-6-base] urea,
1-phenyl-3-[7-methoxyl group-4-(4-bromobenzene amido) quinazoline-6-base] urea,
1-phenyl-3-(6-methoxyl group-4-anilinoquinazoline-7-base) urea,
Or
1-phenyl-3-[7-methoxyl group-4-(3-chloro-4-fluoroanilino) quinazoline-6-base] urea；Or the salt of these compounds.
Phenylurea coupling quinazoline compounds the most according to claim 1 and 2 or its pharmaceutically acceptable salt, it is special
Levying and be, described pharmaceutically acceptable salt is hydrochlorate, hydrobromate, sulfate, Hemisulphate, phosphate or carboxylate.
Phenylurea coupling quinazoline compounds the most according to claim 3 or its pharmaceutically acceptable salt, its feature
Being, described pharmaceutically acceptable salt is amino acid salts.
5. prepare in claim 1 the phenylurea coupling quinazoline compounds shown in formula (I) or it is pharmaceutically acceptable for one kind
The method of salt, comprise the following steps:
Step a: the compound shown in formula (III) in organic solvent with catalyst back flow reaction 1h, raw
Become the compound shown in formula (IV)；
Wherein, R5Or R6One of for NO2；
R5Or R6In another one be H ,-O-CH3、-O-CH2-CH3Or-O-CH2(CH3)2, and wherein R6It is not hydrogen；
Step b: the compound shown in formula (IV) and compound back flow reaction 1.5h in organic solvent shown in formula (V), generates
Compound shown in formula (VI),
Wherein, R1、n1Definition with R in formula I1、n1Definition identical；
Step c: the compound shown in formula (VI) in organic solvent with reducing agent back flow reaction 1h, generate shown in formula (VII)
Compound；
Wherein R7Or R8One of for NH2；
R7Or R8In another one be H ,-O-CH3、-O-CH2-CH3Or-O-CH2(CH3)2, and wherein R8It is not hydrogen；
Step d: the compound shown in formula (VII) and the compound shown in formula (VIII) react 3h, production in organic solvent
(I) compound shown in；
Wherein, R4、n2Definition and formula (I) in R4、n2Definition identical.
Method the most according to claim 5, it is characterised in that in step d, reaction temperature is room temperature.
7. according to the method described in claim 5 or 6, it is characterised in that described method farther includes:
Step e: under room temperature, the compound shown in formula (I) reacts the change shown in production (Ⅹ) in organic solvent with acid or alkali
Compound；
Wherein, M is hydrochloric acid, hydrobromic acid, sulphuric acid, hemisulfic acid, phosphoric acid or carboxylic acid, R1、n1、R2、R3Definition with R in formula I1、n1、
R2、R3Definition identical.
Method the most according to claim 7, it is characterised in that M is aminoacid or hydrochloric acid.
Method the most according to claim 5, it is characterised in that the organic solvent in described step a is thionyl chloride, catalysis
Agent is dimethylformamide.
Method the most according to claim 5, it is characterised in that the organic solvent in described step b is isopropanol, anhydrous
Acetonitrile or anhydrous tetrahydro furan.
11. methods according to claim 5, it is characterised in that the organic solvent in described step c is ethyl acetate or nothing
Water-ethanol；One or more in stannous chloride, hydrazine hydrate or Raney's nickel of reducing agent.
12. methods according to claim 5, it is characterised in that the organic solvent in described step d is acetonitrile or anhydrous four
Hydrogen furan.
13. methods according to claim 5, it is characterised in that the organic solvent in described step e is dehydrated alcohol or two
Chloromethanes.
14. methods according to claim 5, it is characterised in that the preparation method of the compound shown in formula (VIII) includes:
Compound shown in formula (IX) reacts generation compound shown in formula (VIII) in organic solvent with triphosgene
15. 1 kinds of pharmaceutical compositions, comprise the phenylurea coupling quinazoline compounds according to any one of claim 1-4 or
Its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier or excipient.
Phenylurea coupling quinazoline compounds according to any one of 16. claim 1-4 or its pharmaceutically acceptable salt
Purposes in the medicine preparing the disease relating to protein tyrosine kinase overexpression.
17. purposes according to claim 16, it is characterised in that described disease is malignant tumor.
18. purposes according to claim 17, it is characterised in that described malignant tumor is pulmonary carcinoma；Cancer of pancreas；Phosphorus columnar epithelium
Cancer；Medullary thyroid carcinoma；Incidence cancer；Esophageal carcinoma；Gastric cancer；Or gynecological's carcinoma.
19. purposes according to claim 18, it is characterised in that described pulmonary carcinoma is nonsmall-cell lung cancer.
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| CN105753793B (en) * | 2016-01-19 | 2018-09-04 | 河北医科大学 | Fragrant formyl urea coupling quinazoline compounds and preparation method thereof, pharmaceutical composition and medicinal usage |
| CN105622507B (en) * | 2016-02-23 | 2019-02-05 | 河南大学 | A kind of naphthalimide derivative and its preparation method and application |
| CN107400094B (en) * | 2017-09-08 | 2020-04-03 | 贾玉庆 | Quinazolinyl carboxylic ester compound and application thereof |
| CN111499622B (en) * | 2019-07-08 | 2023-06-06 | 山东省科学院菏泽分院 | Preparation method of medicine for treating bile duct cancer |
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| CA2086968C (en) * | 1992-01-20 | 1998-06-23 | Andrew John Barker | Quinazoline derivatives |
| CN102219733A (en) * | 2010-04-14 | 2011-10-19 | 上海医药工业研究院 | Method for preparing sorafenib |
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|---|---|---|---|---|
| CA2086968C (en) * | 1992-01-20 | 1998-06-23 | Andrew John Barker | Quinazoline derivatives |
| CN102219733A (en) * | 2010-04-14 | 2011-10-19 | 上海医药工业研究院 | Method for preparing sorafenib |
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