CN106008480A - Quinazoline compound containing cinnamamide structure and preparation method and application thereof - Google Patents

Quinazoline compound containing cinnamamide structure and preparation method and application thereof Download PDF

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CN106008480A
CN106008480A CN201610334018.4A CN201610334018A CN106008480A CN 106008480 A CN106008480 A CN 106008480A CN 201610334018 A CN201610334018 A CN 201610334018A CN 106008480 A CN106008480 A CN 106008480A
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base
amino
chloro
fluorophenyl
quinazoline
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郑鹏武
朱五福
涂远彪
徐珊
唐启东
欧阳宜强
王文惠
王林啸
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Jiangxi Science and Technology Normal University
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Jiangxi Science and Technology Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a quinazoline compound containing cinnamamide structure, geometric isomers of the quinazoline compound, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the quinazoline compound, as well as a preparation method of the quinazoline compound. The invention also discloses application in the preparation of drugs for treating and/or preventing proliferative diseases, application in the preparation of drugs for treating and/or preventing cancers, and application in the preparation of drugs for treating and/or preventing prostate cancer, lung cancer and cervical cancer. Cyano groups are removed, side chains such as S-tetrahydrofuran-3-oxy, and activity for A549 has a significant increase. In-vitro antitumor activity screening for various EGFR (epidermal growth factor receptor) inhibitor highly-expressed cell strains shows high antitumor activity and selectivity, some compounds good in in-vitro antitumor activity are also selected for in-vivo activity testing of EGFR and VEGFR2/KDR. Experiments show that some compounds have efficient antitumor activity.

Description

Quinazoline compounds containing cinnamamide structure and its preparation method and application
Technical field
The present invention relates to treat the medicine of tumor, in particular to a kind of quinazoline compounds containing cinnamamide structure and Its preparation method and application.
Background technology
Cancer, also referred to as malignant tumor, it is common that cause owing to cell proliferation machinery is not normal.The annual newly-increased cancer in the whole world Disease case load will be up to 19,300,000 examples.And cancer presents the trend prosperity of three change two wires, rejuvenation, aging, send out Sick rate and the high trend of mortality rate " two wires ".Therefore, cancer is to threaten one big " killer " of human health.
EGF-R ELISA (epidermal growth factor receptor, EGFR) is ErbB family member One of, there is tyrosine kinase activity, be a kind of important transmembrane receptor.EGFR is started intracellular signal and is passed after ligand activation Lead, the cascade reaction of adaptin, enzyme in Cytoplasm, regulation the transcribing of transcription factor activation gene, instruct cell migration, Stick, breed, break up, apoptosis, and with the formation of tumor and deteriorate closely related.The research and development of EGFR inhibitor are controlled molecular targeted Treat human cancer direction and become focus.As shown in Equation 1, it has been reported substantial amounts of EGFR micromolecular inhibitor at present, at these In micromolecular inhibitor, document (Suda.K, Murakami.I, Katayama.T, et al.Clin.Cancer.Res.16 (2010) 5489-5498.) report Afatinib there is in biological cell activity and antitumor enzymatic activity efficient effect, In addition, the most a lot of EGFR micromolecular inhibitors have excellent anti-tumor activity, as gefitinib (Fukuoka.M, Yano.S, Giaccone G, et al.J.Clin.Oncol.21 (2003) 2237-2246.), reach grammeter for you (Gonzales.A.J,Hook.K.E,Althaus.I.W,Mol,et al.Cancer.Ther.7(2008)1880-1889.)、 LP-7(Lai.Y.S,Pang.J.X,Luo.M.H,C.N.Patent 201510184302,2015)。
In above-mentioned patent, the cinnamide compound of report is the class chemical combination that the hydrogen on olefinic double bonds carbon is replaced by cyano group Thing, this compounds is inactive to A549 lung carcinoma cell.What the present invention investigated emphatically is different substituted containing cinnamamide structure The anti-tumor activity of quinazoline compounds, to filtering out activity and selectivity more preferably antitumor drug.
Summary of the invention
It is an object of the invention to provide a kind of quinazoline compounds containing cinnamamide structure and preparation method thereof and Application.
The present invention provides a kind of quinazoline compounds containing cinnamamide structure as shown in formula I, its geometrical isomerism Body and pharmaceutically acceptable salt, hydrate, solvate or prodrug, formula I is as follows:
Wherein:
R1, R3Be 1～3 identical or different selected from hydrogen, halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amino, mercapto Base, carboxyl, trifluoromethoxy, dimethylamino, diethylin, morpholinyl, pyrrolidin-1-yl, piperidin-1-yl, N-methyl-piperazine Piperazine-1-base, (C1-C4) alkyl, (C3～C6) cycloalkyl, (C2～C4) thiazolinyl, (C2～C4) alkynyl, (C1～C4) alkoxyl, Azido, (C1～C4) alkoxy methyl, (C2～C4) alkyl acyl or (C1～C4) alkylthio group；
R2Selected from hydrogen, trifluoromethoxy, S-oxolane-3-epoxide, 3-(piperidin-1-yl) propoxyl group, 3-(morpholine-1- Base) propoxyl group, piperidin-4-yl methoxyl group, (C1～C4) alkyl, (C1～C4) alkoxyl or (C1～C4) alkylthio group.
Present invention is preferably related to definition such as formula I compound, its geometric isomer and pharmaceutically acceptable salt thereof, Hydrate, solvate or prodrug；
R1, R3Be 1～3 identical or different selected from hydrogen, halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amino, trifluoro Methoxyl group, dimethylamino, diethylin, morpholinyl, pyrrolidin-1-yl, piperidin-1-yl, N-thyl-piperazin-1-base, methyl, Ethyl, n-pro-pyl, isopropyl, cyclopropyl, normal-butyl, methoxyl group, ethyoxyl, tert-butoxy, acetyl group, vinyl, pi-allyl, Acetenyl or methyl mercapto；
R2Selected from hydrogen, trifluoromethoxy, S-oxolane-3-epoxide, 3-(piperidin-1-yl) propoxyl group, 3-(morpholine-1- Base) propoxyl group, piperidin-4-yl methoxyl group, methoxyl group, ethyoxyl, tert-butoxy, methyl, ethyl or methyl mercapto.
The quinazoline compounds containing cinnamamide structure of above-mentioned formula I is the one in following compounds, but These compounds are not meant to any limitation of the invention:
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (4-cyano-phenyl) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (2-nitrobenzophenone) acrylamide,
(S)-3-(2-chloro-4-fluorophenyl)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base oxygen Base) quinazoline-6-base) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (2,5-Dimethoxyphenyl) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (4-methoxyphenyl) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (2,4-Dimethoxyphenyl) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (3,5-Dimethoxyphenyl) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (3,4,5-trimethoxyphenyl) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (4-nitrobenzophenone) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (2,3-Dichlorobenzene base) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (2,3,4-trimethoxyphenyl) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (3,5-bis-bromo-4-hydroxy phenyl) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (4-hydroxyl-3,5-Dimethoxyphenyl) acrylamide,
(S)-3-(3-bromophenyl)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinoline Oxazoline-6-base) acrylamide,
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(4-methoxyphenyl) propylene Amide,
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(2-nitrobenzophenone) acryloyl Amine,
3-(2-chloro-4-fluorophenyl)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base) propylene Amide,
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(2,5-Dimethoxyphenyl) Acrylamide,
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(4-methoxyphenyl) propylene Amide,
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(2,4-Dimethoxyphenyl) Acrylamide,
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(3,5-Dimethoxyphenyl) Acrylamide,
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(3,4,5-trimethoxy-benzene Base) acrylamide,
N-(4-((4-chloro-3-(trifluoromethyl) phenyl) amino)-7-methoxy quinoline-6-base)-3-(2,3,4-trimethoxy Base phenyl) acrylamide,
N-(7-(4-morpholino butyl)-4-(4-ethenylphenyl) amino) quinazoline-6-base)-3-(3-morpholino benzene Base) acrylamide,
N-(4-(4-ethynyl phenyl) amino)-7-(3-(piperidin-1-yl) propoxyl group) quinazoline-6-base)-3-(4- Quinoline is for phenyl) acrylamide,
N-(4-((3-methyl mercapto phenyl) amino)-7-(4-piperidines methoxyl group) quinazoline-6-base)-3-(4-morpholino benzene Base) acrylamide.
Following synthetic route describes the system of the quinazoline compounds containing cinnamamide structure of formula I of the present invention Standby, all of raw material be all by the way of described in synthetic route, well-known to the ordinarily skilled artisan by organic chemistry filed Prepared by method or commercially available.The whole final quinazoline compounds containing cinnamamide structure of the present invention is all by closing Becoming method described in route or prepared by similar method, these methods are organic chemistry filed ordinary skill people Known to Yuan.In synthetic route, whole variable factors of application are such as definition hereafter or such as the definition in claim.
Work as R1For 3-chloro-4-fluorine, R2For S-oxolane-3-epoxide or methoxyl group, R3For fluorine, chlorine, bromine, methoxyl group, nitre When base, hydroxyl or cyano group, synthetic method is as follows, and all raw materials are commercially available analytical pure.
The synthetic route of route 1 target compound
The present invention, with 4-fluoro-2-amino benzoic Acid as raw material, obtains intermediate V through series reaction, then by intermediate V with (S)-3-hydroxyl tetrahydrofuran or methanol reaction obtain intermediate VIa or VIb, then obtain VIIa or VIIb by nitro reduction； With different substituted benzaldehydes, it is respectively synthesized IXa-n through series reaction；Finally, intermediate VIIa or VIIb is anti-with IXa-n Should, obtain target compound.
According to usual methods more of the art, above-mentioned formula I's containing cinnamamide structure in the present invention Quinazoline compounds can generate pharmaceutically acceptable salt with acid.Pharmaceutically acceptable addition salts includes mineral acid and organic acid addition Salt, with following acid addition salt be particularly preferred: hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulfonic acid, ethyl sulfonic acid, to toluene sulphur Acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propanoic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, Benzoic acid etc..
Additionally, present invention additionally comprises the prodrug of derivant of the present invention.The prodrug of derivant of the present invention is spreading out of above-mentioned formula I Biology, their own is likely to be of more weak activity even without activity, but upon administration, (the most logical in physiological conditions Cross metabolism, solvolysis or other mode) it is converted to corresponding biologically active form.
The present invention containing the quinazoline compounds containing cinnamamide structure of above-mentioned formula I, and can pharmaceutically may be used The salt, hydrate or the solvate that accept, as active ingredient, are prepared by mixing into pharmaceutically acceptable carrier or excipient Compositions, and be prepared as the most acceptable dosage form, above-mentioned pharmaceutically acceptable excipient refers to any can be used for pharmacy The diluent in field, adjuvant and/or carrier.The derivant of the present invention can be applied in combination with other active ingredients, as long as it Do not produce other disadvantageous effects, such as anaphylaxis.
The quinazoline compounds containing cinnamamide structure of the present invention above-mentioned formula I is permissible for the clinical dosage of patient According to: active component therapeutic efficiency in vivo and bioavailability, their metabolism and discharge rate and the age of patient, property Not, the disease phase suitably adjust, but adult daily dosage typically should be 10～500mg, preferably 50～ 300mg.Therefore, when the pharmaceutical composition of the present invention is made into unit dosage forms, it is contemplated that above-mentioned effective dose, per unit preparation Should containing 10～500mg above-mentioned formula I containing cinnamamide structure quinazoline compounds, preferably 50～300mg.According to Doctor or the guidance of pharmacist, these preparations can divide administration (preferably to six time) several times at certain intervals.
The Pharmaceutical composition of the present invention can be configured to several dosage form, wherein contains the figuration that in drug world, some are conventional Agent.Several dosage form as above can use injection, tablet, capsule, aerosol, suppository, membrane, drop pill, outer With the drug form such as liniment, ointment.
Carrier for pharmaceutical composition of the present invention is available common type in drug world, including: binding agent, profit Lubrication prescription, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, non-pigment, correctives, preservative, solubilizer and substrate etc.. Pharmaceutical preparation can be administered with oral administration or parenteral (such as intravenous, subcutaneous, intraperitoneal or local), if some drugs Under the conditions of stomach, instability, can be configured to enteric coated tablets.
The reactive compound of the present invention or its officinal salt and solvate thereof can be as unique anti-proliferate medicine lists Solely use, or can be used for treating and/or preventing proliferative disease with the anti-proliferate Drug combination listed, Such as psoriasis, benign prostatauxe, atherosclerosis and restenosis.
The compounds of this invention is external has a suppression tumor cell growth activity, therefore, it can serve as preparation treatment and/or The medicine of prophylaxis of cancer, such as mammary gland, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus, pancreas, bone marrow, testis Ball, ovary, lymph, soft tissue, head and neck, thyroid, the cancer of esophagus and leukemia, neuroblastoma etc..
By vitro inhibition lung cell A549, Human Prostate Cancer Cells PC-3, human breast cancer cell line Bcap-37 and cervical cancer Cell Hela activity test, the compounds of this invention is to lung carcinoma cell, prostate gland cancer cell, breast cancer cell and cervical cancer cell There is the effect of significantly inhibiting, it is especially useful in preparation treatment and/or prevention carcinoma of prostate, pulmonary carcinoma and the medicine of cervical cancer.
By finding the test of EGFR and VEGFR2/KDR kinase activity, the compounds of this invention has and significantly suppresses EGFR With VEGFR2/KDR kinase activity, lung carcinoma cell, Human Prostate Cancer Cells, breast cancer cell and the cervix uteri to EGFR high expressed Cancerous cell etc. have stronger inhibitory action, it is especially useful in preparation treatment and/or the medicine of prevention pulmonary carcinoma.
The reactive compound of the present invention or its officinal salt and solvate thereof can be independent as unique antitumor drug Use, or can be with the antitumor drug listed (such as platinum medicine cisplatin, camptothecine irinotecan, Changchun Flower bases medicine nvelbine, deoxidation born of the same parents' former times class medicine gemcitabine, etoposide, paclitaxel etc.) it is used in combination.Therapeutic alliance is led to Cross each therapeutic component simultaneously, order or separate administration and realize.
The present invention designs and has synthesized a series of quinazoline compounds containing cinnamamide structure, and this series compound is compared Compound L P-7 (Lai.Y.S, Pang.J.X, Luo.M.H, C.N.Patent 201510184302,2015) in patent report Have significantly different.In patent, the cinnamide compound of report is the class chemical combination that the hydrogen on olefinic double bonds carbon is replaced by cyano group Thing, this compounds is inactive to A549 lung carcinoma cell.Cyano group is removed by the present invention, and introduces S-oxolane-3-epoxide After side chain, A549 activity is significantly improved.Multiple EGFR inhibitor overexpression cell line is resisted by the present invention through external Tumor promotion screens, and result shows have stronger anti-tumor activity and selectivity, also selects that extracorporeal anti-tumor is lived by some Property good compound carried out the test of EGFR and VEGFR2/KDR kinase whose activity in vivo.Experiment shows that some compound has height The anti-tumor activity of effect.
Detailed description of the invention
In order to preferably explain the present invention, below in conjunction with specific embodiment, the present invention is described in further detail, but They do not constitute restriction to the present invention.
Embodiment is intended to illustrate rather than limit the scope of the present invention.The proton nmr spectra BrukerARX-of derivant 400 measure, and mass spectrum Agilent 1100LC/MSD measures；Agents useful for same is analytical pure or chemical pure.
The quinazoline compounds containing cinnamamide structure of formula I:
The structural formula of the embodiment of the present invention 1～26 is as shown in table 1 below.
The structural formula of table 1 embodiment 1～26
The synthesis of step A 7-Fluquinconazole quinoline-4-ketone (II)
4-fluoro-2-amino benzoic Acid and the 67.0g of 50.0g is added successively in the three-necked bottle equipped with 300mL dehydrated alcohol Formamidine acetate, mixture heating reflux reaction 24h.React complete, evaporated under reduced pressure major part solvent, pour reactant liquor into 1000mL Stirring 30min, sucking filtration in sodium-chloride water solution, filter cake washs with the ethanol water of 60%, is dried, obtains 51.0g white solid, That is, 7-Fluquinconazole quinoline-4-ketone (II), yield: 96.4%.
Mp 260.1～261.0,1H NMR (400MHz, CDCl3) δ 12.35 (s, 1H), 8.17 (d, J=6.8Hz, 1H), 8.14 (d, J=7.2Hz, 1H), 7.43 (d, J=9.8Hz, 1H), 7.37 (t, J=8.8Hz, 1H).
The synthesis of step B 7-fluoro-6-nitro-quinazoline-4-ketone (III)
7-Fluquinconazole quinoline-4-ketone (II) of 50.0g is slowly added into 103mL concentrated sulphuric acid under ice bath and 105mL is fuming In the nitration mixture that nitric acid is made into, 1h post-heating is stirred at room temperature and reacts 3h to 110 DEG C.React complete, be cooled to room temperature, reactant liquor is fallen Enter strong agitation in 1000mL mixture of ice and water, sucking filtration, the water washing of filter cake 500mL, the second of dried filter cake 300mL Alcohol is heated to reflux 30min, while hot sucking filtration, is dried, obtains faint yellow solid 48.5g, i.e. 7-fluoro-6-nitro-quinazoline-4-ketone (III), yield: 76.1%.
Mp 277.3～278.5, ESI-MS [M-H] m/z:208,1H NMR (400MHz, DMSO) δ 12.77 (s, 1H), 8.68 (dd, J=8.2,2.7Hz, 1H), 8.28 (s, 1H), 7.73 (dd, J=12.2,2.8Hz, 1H).
The synthesis of step C 7-fluoro-6-nitro-4-chloro-quinazoline (IV)
Fluoro-for the 7-of 48.0g 6-nitro-quinazoline-4-ketone (III) is joined 407.0mL thionyl chloride and 75.0mL trichlorine In oxygen phosphorus mixed liquor, to the DMF (DMF) of mixed liquor dropping 2.4mL, 80 DEG C are heated to reflux 3h, and reactant liquor becomes Yellow clarification after again 110 DEG C be heated to reflux 6h.React complete, evaporated under reduced pressure excess of solvent, take away a small amount of solvent with toluene, Gu Body powder is poured slowly in the sodium bicarbonate aqueous solution of ice stirring 1h, sucking filtration, washing, is dried, obtains 50.7g yellow solid, i.e. 7- Fluoro-6-nitro-4-chloro-quinazoline (IV), yield: 97.0%.
Mp 118.2～119.3 DEG C, 1H NMR (400MHz, DMSO) δ 8.66 (dd, J=8.2,1.2Hz, 1H), 8.41 (s, 1H), 7.75 (d, J=12.2Hz, 1H).
The synthesis of step D 4-[(3-chloro-4-fluorophenyl) amino]-6-nitro-7-Fluquinconazole quinoline (V)
The 7-fluoro-6-nitro-4-chloro-quinazoline (IV) of 50.0g, the 4-of 32.3g is added successively in the isopropanol of 400mL Fluoro-3-chloroaniline, drips 34.0mL triethylamine, stirring at normal temperature 1.5h in reactant liquor.React complete, sucking filtration, filter cake isopropyl Alcohol and water washs, and is dried, and filtrate adds the stirring of a large amount of water and separates out solid, sucking filtration, washing, is dried, merges, obtains 65.0g buff solid Body, i.e. 4-[(3-chloro-4-fluorophenyl) amino]-6-nitro-7-Fluquinconazole quinoline (V), yield: 87.8%.
Mp 261.4-262.5, ESI-MS [M+H] m/z:337.1,1H NMR (400MHz, DMSO) δ 10.43 (s, 1H), 9.51 (d, J=7.8Hz, 1H), 8.68 (s, 1H), 8.08 (d, J=6.4Hz, 1H), 7.79 (d, J=5.2Hz, 1H), 7.76 (s, 1H), 7.45 (t, J=9.0Hz, 1H).
Step E1
4-[(3-chloro-4-fluorophenyl) amino]-6-nitro-7-[(S)-(oxolane-3-base)-epoxide]-quinazoline (VIa) synthesis
60% sodium hydride 4.7g is joined stirring in 400mL oxolane (THF), is slowly added dropwise (S)-3-of 12.0mL Hydroxyl tetrahydrofuran, ice bath stirring 45min.The 4-[(3-chloro-4-fluorophenyl) amino] that 20.0g is dissolved in the THF of 200mL- 6-nitro-7-Fluquinconazole quinoline (V) is slowly dropped into, normal-temperature reaction 5h.React complete, evaporated under reduced pressure solvent, add 500mL sodium bicarbonate Aqueous solution stirring 30min, sucking filtration, filter cake washs with the ethanol water of 40%, is dried, obtains 23.9g dark yellow solid, i.e. 4- [(3-chloro-4-fluorophenyl) amino]-6-nitro-7-[(S)-(oxolane-3-base)-epoxide]-quinazoline (VIa), yield: 99.5%.
Mp 210.1-211.0, [M+H] m/z:405.1,1H NMR (400MHz, DMSO) δ 10.10 (d, J=11.8Hz, 1H), 9.16 (d, J=13.2Hz, 1H), 8.62 (d, J=13.4Hz, 1H), 8.13 (d, J=6.8Hz, 1H), 7.75 (s, 1H), 7.45 7.35 (m, 2H), 5.40 (s, 1H), 3.99 3.79 (m, 4H), 2.34 (dd, J=13.8,6.2Hz, 1H), 2.04 (d, J =5.6Hz, 1H).
Step E2
4-[(3-chloro-4-fluorophenyl) amino]-6-nitro-7-methoxyl group] synthesis of-quinazoline (VIb)
4-[(3-chloro-4-fluorophenyl) amino]-6-nitro-7-Fluquinconazole quinoline (V) of 11.37g is joined 227mL methanol With in 50% sodium hydrate aqueous solution of 15mL, it is heated to reflux 1.5h, is cooled to room temperature after completion of the reaction, pour 200mL frozen water into Middle strong agitation 30min, sucking filtration, washing, it is dried, obtains 11.2g yellow solid, i.e. 4-[(3-chloro-4-fluorophenyl) amino]-6- Nitro-7-methoxyl group]-quinazoline (VIb), yield: 94.9%.
m.p.292.3-293.0℃.ESI-MS m/z:[M+H]+349.1.1H NMR(400MHz,DMSO)δ10.13(s, 1H),9.20(s,1H),8.66(s,1H),8.20–8.10(m,1H),7.84–7.73(m,1H),7.51–7.41(m,2H), 4.05(s,3H).
Step F 4-[(3-chloro-4-fluorophenyl) amino]-6-amino-7-[(S)-(oxolane-3-base)-epoxide]-quinoline The synthesis of oxazoline (VIIa)
21.4g intermediate VIa is joined in 700mL ethanol, is heated to when 60 DEG C adding 15.0g activated carbon, 4.2g tri- Iron chloride, rises to be slowly added dropwise when 80 DEG C 80% hydrazine hydrate of 24.5mL, continues to be heated to reflux 1.5h.React complete, take out while hot Filter, filtering residue ethyl acetate rinse, vacuum rotary steam filtrate, it is threaded to during 10% solvent add 500mL water, strong agitation, sucking filtration, does Dry, obtain 17.3g pale solid, i.e. 4-[(3-chloro-4-fluorophenyl) amino]-6-amino-7-[(S)-(oxolane-3- Base)-epoxide]-quinazoline (VIIa), yield: 87.3%.
Mp 139.3-140.1, [M+H] m/z:375.2,1H NMR (400MHz, DMSO) δ 9.41 (s, 1H), 8.38 (s, 1H), 8.17 (t, J=12.6Hz, 1H), 7.88 7.73 (m, 1H), 7.38 (dd, J=17.2,8.2Hz, 2H), 7.05 (s, 1H), 5.41 (s, 2H), 5.20 (s, 1H), 4.00 3.87 (m, 3H), 3.77 (dd, J=12.6,7.8Hz, 1H), 2.29 (td, J =14.2,7.2Hz, 1H), 2.19 2.06 (m, 1H).
According to step F, by 4-[(3-chloro-4-fluorophenyl) amino]-6-nitro-7-methoxyl group]-quinazoline (VIb) can close Become VIIb.
The synthesis to cyano cinnamic acid (VIIIa) of step G
Cyanobenzaldehyde and 0.74g malonic acid are joined in 20mL pyridine and 0.2mL piperidines mixed liquor by 0.32g, adds Hot reflux 12h, is cooled to room temperature after having reacted, dilute hydrochloric acid regulation solution is acid, sucking filtration, and washing is dried, obtains 0.34g yellow Color solid, i.e. to cyano cinnamic acid (VIIIa), yield 80%.
With different substituted benzaldehydes, it is respectively synthesized VIIIb-n according to step G standby.
The synthesis to cyano group cinnamoyl chloride (IXa) of step H
Cyano cinnamic acid (VIIIa) is joined in 16.0mL dichloromethane by 0.173g, adds the DMF of catalytic amount, past Instilling 0.24g oxalyl chloride in solution, 10min is stirred at room temperature, reduce pressure after having reacted solvent distillation, is rapidly added 16.0mL dichloro In dichloromethane, obtain cyano group cinnamoyl chloride (IXa), stand-by.
According to step H, VIIIb-n it is respectively synthesized IXb-n.
The synthesis of step I target compound I
Intermediate VIIa or VIIb that step F synthesizes is joined N, the N-diisopropyl of 16.0mL dichloromethane and 0.05g In base ethamine mixed liquor, under ice bath, drip, in mixed liquor, intermediate compound I Xa-n that step H synthesizes, drip rear room temperature reaction 30min, after having reacted, solution with 10% K2CO3Washing with saline, organic facies separates, and is dried, decompression distillation, obtains target Compound I, yield: 50%.
Embodiment 1
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (4-cyano-phenyl) acrylamide
First synthesize 4-[(3-chloro-4-fluorophenyl) amino]-6-nitro-7-Fluquinconazole quinoline (V) according to step A～D, then by Mesosome V synthesizes 4-[(3-chloro-4-fluorophenyl) amino]-6-nitro-7-[(S)-(oxolane-3-base)-oxygen by step E1 Base]-quinazoline (VIa), then synthesize 4-[(3-chloro-4-fluorophenyl) amino]-6-amino-7-[(S)-(tetrahydrochysene furan by step F Mutter-3-base)-epoxide]-quinazoline (VIIa)；
Synthesized cyano cinnamic acid (VIIIa) by step G, then synthesized cyano group cinnamoyl chloride (IXa) by step H；
Finally, VIIa with IXa dock and obtain 0.121g yellow solid, yield: 50%.That is, (((3-is chloro-for 4-for (S)-N- 4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3-(4-cyano-phenyl) acrylamide.
m.p.267.5-268.9℃.ESI-MS m/z:[M+H]+530.1.
1H NMR (400MHz, DMSO) δ 9.78 (s, 1H), 9.18 (s, 1H), 8.75 (s, 1H), 8.04 (d, J=6.4Hz, 1H), 7.93 (d, J=8.2Hz, 2H), 7.87 (d, J=8.2Hz, 2H), 7.70 (d, J=15.8Hz, 2H), 7.60 7.40 (m, 4H), 5.30 (s, 1H), 4.10 3.93 (m, 3H), 3.80 (d, J=5.4Hz, 1H), 2.45 2.34 (m, 1H), 2.23 (s, 1H).
According to the method for embodiment 1, first according to step A～D synthetic intermediate V, then by intermediate V by step E1 or E2 Synthetic intermediate VIa or VIb, then synthesize VIIa or VIIb by step F；With different substituted benzaldehydes, according to step G respectively Synthesis VIIIa-n, then it is respectively synthesized IXa-n by step H；Finally, intermediate VIIa or VIIb is reacted with IXa-n, respectively Prepare embodiment 2～26 compound.
Embodiment 2
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (2-nitrobenzophenone) acrylamide
m.p.176.5-177.1℃.ESI-MS m/z:[M+H]+550.1.
1H NMR (400MHz, DMSO) δ 9.84 (s, 1H), 9.27 (s, 1H), 8.83 (s, 1H), 8.12 (dd, J=8.2, 1.0Hz, 1H), 8.03 7.94 (m, 2H), 7.93 7.80 (m, 3H), 7.73 7.67 (m, 2H), 7.53 (t, J=9.2Hz, 1H), 7.42 (s, 1H), 7.28 (d, J=15.6Hz, 1H), 5.32 (d, J=6.2Hz, 1H), 4.12 (d, J=9.8Hz, 1H), 4.05 3.97 (m, 2H), 3.81 (td, J=8.2,5.4Hz, 1H), 2.40 (dt, J=14.2,7.1Hz, 1H), 2.26 2.18 (m,1H).
Embodiment 3
(S)-3-(2-chloro-4-fluorophenyl)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base oxygen Base) quinazoline-6-base) acrylamide
m.p.179.6-181.5℃.ESI-MS m/z:[M+H]+558.1.
1H NMR (400MHz, DMSO) δ 9.62 (s, 1H), 9.12 (s, 1H), 8.61 (s, 1H), 8.09 (d, J=4.4Hz, 1H), 7.98 7.85 (m, 2H), 7.77 (s, 1H), 7.58 (d, J=8.8Hz, 1H), 7.41 (dt, J=15.4,7.8Hz, 2H), 7.33 7.20 (m, 2H), 5.33 (s, 1H), 4.11 3.90 (m, 4H), 3.80 (d, J=5.4Hz, 1H), 2.39 (dd, J= 14.2,7.0Hz,1H),2.21(s,1H).
Embodiment 4
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (2,5-Dimethoxyphenyl) acrylamide
m.p.278.9-280.3℃.ESI-MS m/z:[M+H]+565.1.
1H NMR (400MHz, DMSO) δ 9.72 (s, 1H), 9.28 (s, 1H), 8.89 (s, 1H), 7.98 (dd, J=6.8, 2.6Hz, 1H), 7.92 (d, J=15.8Hz, 1H), 7.68 (ddd, J=8.8,4.3,2.6Hz, 1H), 7.55 (t, J=9.0Hz, 1H), 7.49 (s, 1H), 7.24 (t, J=9.6Hz, 2H), 7.06 (d, J=9.0Hz, 1H), 7.02 (dd, J=9.0,2.8Hz, 1H), 5.30 (t, J=5.6Hz, 1H), 4.13 (d, J=9.8Hz, 1H), 4.01 (dt, J=15.6,6.1Hz, 2H), 3.83 (d, J=4.4Hz, 3H), 3.80 (dd, J=7.0,4.2Hz, 1H), 3.78 (s, 3H), 2.41 (dt, J=14.4,7.1Hz, 1H), 2.27–2.19(m,1H).
Embodiment 5
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (4-methoxyphenyl) acrylamide
m.p.240.9-242.3℃.ESI-MS m/z:[M+H]+535.1.
1H NMR (400MHz, DMSO) δ 9.43 (s, 1H), 9.08 (s, 1H), 8.59 (s, 1H), 8.10 (dt, J=13.0, 6.5Hz, 1H), 7.78 (ddd, J=9.0,4.4,2.8Hz, 1H), 7.63 (d, J=8.6Hz, 2H), 7.59 (s, 1H), 7.44 (t, J=9.2Hz, 1H), 7.28 (s, 1H), 7.09 (d, J=15.8Hz, 1H), 7.04 (s, 1H), 7.01 (s, 1H), 5.32 (dd, J=6.2,4.8Hz, 1H), 4.02 (ddd, J=10.8,10.4,5.8Hz, 2H), 3.95 (dd, J=15.4,7.8Hz, 1H), 3.81 (d, J=4.2Hz, 3H), 3.78 (dd, J=8.2,5.2Hz, 1H), 2.37 (dt, J=14.2,7.1Hz, 1H), 2.24–2.15(m,1H).
Embodiment 6
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (2,4-Dimethoxyphenyl) acrylamide
m.p.295.5-296.3℃.ESI-MS m/z:[M+H]+565.2.
1H NMR (400MHz, DMSO) δ 9.61 (s, 1H), 9.26 (s, 1H), 8.86 (s, 1H), 7.99 (dd, J=6.8, 2.6Hz, 1H), 7.88 (d, J=15.8Hz, 1H), 7.69 (ddd, J=8.8,4.4,2.6Hz, 1H), 7.60 (d, J=9.2Hz, 1H), 7.54 (t, J=9.2Hz, 1H), 7.47 (s, 1H), 7.10 (d, J=15.8Hz, 1H), 6.67 6.61 (m, 2H), 5.29 (t, J=5.6Hz, 1H), 4.12 (d, J=10.0Hz, 1H), 4.05 3.94 (m, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 3.82 3.77 (m, 1H), 2.40 (dt, J=14.2,7.0Hz, 1H), 2.26 2.17 (m, 1H).
Embodiment 7
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (3,5-Dimethoxyphenyl) acrylamide
m.p.181.0-182.3℃.ESI-MS m/z:[M+H]+565.1.
1H NMR (400MHz, DMSO) δ 9.55 (s, 1H), 9.20 (s, 1H), 8.78 (s, 1H), 8.02 (d, J=5.6Hz, 1H), 7.87 (d, J=15.8Hz, 1H), 7.71 (s, 1H), 7.60 (d, J=8.2Hz, 1H), 7.50 (t, J=9.0Hz, 1H), (7.43 s, 1H), 7.09 (d, J=15.8Hz, 1H), 6.64 (d, J=7.4Hz, 2H), 5.29 (s, 1H), 4.10 (d, J= 10.2Hz, 1H), 4.06 3.92 (m, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 3.80 3.75 (m, 1H), 2.40 (dd, J= 13.6,6.6Hz,1H),2.28–2.15(m,1H).
Embodiment 8
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (3,4,5-trimethoxyphenyl) acrylamide
m.p.143.8-144.5℃.ESI-MS m/z:[M+H]+596.1.
1H NMR(400MHz,DMSO)δ9.86(s,1H),9.46(s,1H),9.03(s,1H),8.54(s,1H),8.14 (dd, J=6.8,2.6Hz, 1H), 7.81 (ddd, J=9.0,4.2,2.8Hz, 1H), 7.61 (d, J=15.6Hz, 1H), 7.43 (t, J=9.2Hz, 1H), 7.27 (s, 1H), 7.13 (d, J=15.6Hz, 1H), 7.02 (s, 2H), 5.33 (s, 1H), 4.08 4.01 (m, 2H), 4.00 3.95 (m, 1H), 3.86 (s, 6H), 3.82 3.77 (m, 1H), 3.71 (d, J=4.8Hz, 3H), 2.38 (dt, J=14.4,7.2Hz, 1H), 2.23 2.15 (m, 1H).
Embodiment 9
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (4-nitrobenzophenone) acrylamide
m.p.245.7-246.8℃.ESI-MS m/z:[M+H]+550.1.
1H NMR (400MHz, DMSO) δ 9.69 (s, 1H), 9.07 (s, 1H), 8.58 (s, 1H), 8.31 (d, J=8.4Hz, 2H), 8.11 (d, J=6.4Hz, 1H), 7.95 (d, J=5.6Hz, 1H), 7.93 (s, 1H), 7.77 (s, 1H), 7.73 (s, 1H), (7.44 m, 2H), 7.30 (s, 1H), 5.32 (s, 1H), 4.09 3.87 (m, 4H), 3.79 (d, J=6.0Hz, 1H), 2.38 (dd, J=13.4,6.9Hz, 1H), 2.20 (d, J=6.4Hz, 1H).
Embodiment 10
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (2,3-Dichlorobenzene base) acrylamide
m.p.273.5-274.8℃.ESI-MS m/z:[M+H]+574.1.
1H NMR(400MHz,DMSO)δ9.90(s,1H),9.30(s,1H),8.89(s,1H),8.02–7.98(m,1H), 7.97 (d, J=3.0Hz, 1H), 7.83 (dd, J=7.8,1.2Hz, 1H), 7.74 (dd, J=8.0,1.2Hz, 1H), 7.69 (ddd, J=8.8,4.3,2.6Hz, 1H), 7.59 7.46 (m, 3H), 7.37 (d, J=15.6Hz, 1H), 5.31 (s, 1H), 4.13 (d, J=10.4Hz, 1H), 4.05 3.95 (m, 2H), 3.81 (td, J=8.2,5.4Hz, 1H), 2.42 (dt, J= 14.2,7.4Hz,1H),2.27–2.18(m,1H).
Embodiment 11
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (2,3,4-trimethoxyphenyl) acrylamide
m.p.244.0-245.8℃.ESI-MS m/z:[M+H]+596.1.
1H NMR (400MHz, DMSO) δ 9.62 (s, 1H), 9.25 (s, 1H), 8.80 (s, 1H), 8.02 (dd, J=6.8, 2.6Hz, 1H), 7.82 (d, J=15.8Hz, 1H), 7.71 (ddd, J=8.9,4.4,2.6Hz, 1H), 7.52 (t, J=9.2Hz, 1H), 7.45 (d, J=8.8Hz, 1H), 7.37 (s, 1H), 7.15 (d, J=15.8Hz, 1H), 6.95 (d, J=8.8Hz, 1H), 5.32 (d, J=6.4Hz, 1H), 4.11 (d, J=10.6Hz, 1H), 4.05 3.94 (m, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.81 (dd, J=8.2,2.8Hz, 1H), 3.78 (s, 3H), 2.40 (dt, J=14.2,7.2Hz, 1H), 2.26 2.16 (m,1H).
Embodiment 12
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (3,5-bis-bromo-4-hydroxy phenyl) acrylamide
m.p.279.6-281.3℃.ESI-MS m/z:[M+H]+679.2.
1H NMR(400MHz,DMSO)δ9.91(s,1H),9.35(s,1H),9.08(s,1H),8.55(s,1H),8.21– 8.09 (m, 2H), 7.90 (d, J=13.8Hz, 2H), 7.53 (d, J=15.6Hz, 1H), 7.43 (dd, J=16.0,7.0Hz, 1H), 7.27 (s, 1H), 7.17 (d, J=15.6Hz, 1H), 5.34 (s, 1H), 4.05 (s, 1H), 3.96 (dd, J=15.2, 9.5Hz, 2H), 3.80 (dd, J=12.8,7.5Hz, 2H), 2.45 2.31 (m, 1H), 2.26 2.14 (m, 1H).
Embodiment 13
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3- (4-hydroxyl-3,5-Dimethoxyphenyl) acrylamide
m.p.184.3-186.2℃.ESI-MS m/z:[M+H]+581.2.
1H NMR(400MHz,DMSO)δ9.85(s,1H),9.35(s,1H),9.03(s,1H),8.52(s,1H),8.13 (dd, J=6.8,2.6Hz, 1H), 7.80 (dd, J=8.4,3.4Hz, 1H), 7.56 (d, J=15.6Hz, 1H), 7.42 (t, J= 9.2Hz, 1H), 7.25 (s, 1H), 7.01 (d, J=15.6Hz, 1H), 6.96 (s, 2H), 5.32 (s, 1H), 4.08 3.93 (m, 3H), 3.86 3.79 (m, 6H), 3.80 3.75 (m, 1H), 2.38 (td, J=14.2,7.6Hz, 1H), 2.22 2.13 (m, 1H).
Embodiment 14
(S)-3-(3-bromophenyl)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinoline Oxazoline-6-base) acrylamide
m.p.277.1-282.6℃.ESI-MS m/z:[M+H]+584.1.
1H NMR (400MHz, DMSO) δ 9.74 (s, 1H), 9.29 (s, 1H), 8.89 (s, 1H), 7.98 (dd, J=6.8, 2.4Hz, 1H), 7.91 (s, 1H), 7.73 7.59 (m, 4H), 7.54 (t, J=9.0Hz, 2H), 7.48 7.33 (m, 2H), 5.75 (s, 1H), 5.29 (s, 1H), 4.14 (d, J=10.4Hz, 1H), 4.01 (m, 2H), 3.81 (dd, J=13.6,8.0Hz, 1H), 2.41 (dt, J=14.2,7.0Hz, 1H), 2.23 (dd, J=12.8,6.4Hz, 1H).
Embodiment 15
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(4-methoxyphenyl) propylene Amide
m.p.240.1-242.0℃.ESI-MS m/z:[M+H]+474.1.
1H NMR(400MHz,DMSO)δ9.94(s,1H),9.14(s,1H),8.70(s,1H),8.09–8.02(m,1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.85 (s, 1H), 7.83 (s, 1H), 7.79 7.72 (m, 1H), 7.69 (d, J=15.8Hz, 1H), 7.46 (dd, J=15.6,6.0Hz, 2H), 7.39 (d, J=4.8Hz, 1H), 4.08 (s, 3H).
Embodiment 16
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(2-nitrobenzophenone) acryloyl M.p.278.9-281.3 DEG C of .ESI-MS m/z:[M+H of amine]+494.1.
1H NMR(400MHz,DMSO)δ9.94(s,1H),9.86(s,1H),9.06(s,1H),8.54(s,1H),8.14 (dd, J=6.8,2.2Hz, 1H), 8.10 (d, J=8.2Hz, 1H), 7.92 (t, J=11.2Hz, 1H), 7.90 7.83 (m, 2H), 7.83 7.78 (m, 1H), 7.69 (t, J=7.6Hz, 1H), 7.42 (t, J=9.2Hz, 1H), 7.31 (d, J=11.0Hz, 1H), 7.26 (d, J=15.4Hz, 1H), 4.06 (s, 3H).
Embodiment 17
3-(2-chloro-4-fluorophenyl)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base) propylene Amide
m.p.256.5-257.9℃.ESI-MS m/z:[M+H]+502.1.
1H NMR(400MHz,DMSO)δ9.86(s,1H),9.85(s,1H),9.07(s,1H),8.55(s,1H),8.13 (d, J=5.6Hz, 1H), 7.90 (d, J=12.8Hz, 1H), 7.88 7.84 (m, 1H), 7.81 (d, J=8.2Hz, 1H), 7.59 (d, J=8.6Hz, 1H), 7.43 (t, J=7.0Hz, 1H), 7.41 7.35 (m, 1H), 7.31 (d, J=6.8Hz, 1H), 7.28 (d, J=15.6Hz, 1H), 4.06 (s, 3H).
Embodiment 18
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(2,5-Dimethoxyphenyl) Acrylamide
m.p.272.1-273.0℃.ESI-MS m/z:[M+H]+509.1.
1H NMR (400MHz, DMSO) δ 9.93 (s, 1H), 9.27 (s, 1H), 8.86 (s, 1H), 7.99 (dd, J=6.2, 2.3Hz, 1H), 7.90 (d, J=15.8Hz, 1H), 7.70 (dd, J=8.2,3.5Hz, 1H), 7.54 (t, J=9.2Hz, 1H), 7.44 (s, 1H), 7.27 (d, J=15.8Hz, 1H), 7.19 (d, J=2.6Hz, 1H), 7.06 (d, J=9.2Hz, 1H), 7.01 (dd, J=9.0,2.8Hz, 1H), 4.11 (s, 3H), 3.83 (s, 3H), 3.78 (s, 3H).
Embodiment 19
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(4-methoxyphenyl) propylene Amide
m.p.253.4-254.7℃.ESI-MS m/z:[M+H]+479.1.
1H NMR (400MHz, DMSO) δ 9.66 (s, 1H), 9.05 (s, 1H), 8.56 (s, 1H), 8.12 (dd, J=6.8, 2.2Hz, 1H), 7.84 7.76 (m, 1H), 7.62 (s, 1H), 7.60 (s, 1H), 7.57 (s, 1H), 7.43 (t, J=9.2Hz, 1H), 7.31 (s, 1H), 7.10 (d, J=15.8Hz, 1H), 7.04 (s, 1H), 7.01 (s, 1H), 4.05 (s, 3H), 3.81 (s, 3H).
Embodiment 20
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(2,4-Dimethoxyphenyl) Acrylamide
m.p.247.1-248.3℃.ESI-MS m/z:[M+H]+509.1.
1H NMR(400MHz,DMSO)δ9.87(s,1H),9.28(s,1H),8.88(s,1H),8.01–7.93(m,1H), 7.84 (d, J=15.8Hz, 1H), 7.72 7.65 (m, 1H), 7.57 (s, 1H), 7.54 (d, J=7.2Hz, 1H), 7.50 (s, 1H), 7.14 (d, J=15.8Hz, 1H), 6.65 (s, 1H), 6.62 (d, J=8.8Hz, 1H), 4.10 (s, 3H), 3.89 (s, 3H), 3.82 (d, J=6.8Hz, 3H).
Embodiment 21
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(3,5-Dimethoxyphenyl) Acrylamide
m.p.253.2-254.3℃.ESI-MS m/z:[M+H]+509.1.
1H NMR(400MHz,DMSO)δ9.88(s,1H),9.28(s,1H),8.89(s,1H),8.03–7.96(m,1H), 7.85 (d, J=15.8Hz, 1H), 7.73 7.65 (m, 1H), 7.57 (d, J=5.8Hz, 1H), 7.55 (s, 1H), 7.52 (d, J =4.8Hz, 1H), 7.15 (d, J=15.8Hz, 1H), 6.65 (d, J=6.4Hz, 2H), 4.10 (s, 3H), 3.88 (d, J= 10.2Hz, 3H), 3.83 (d, J=8.8Hz, 3H).
Embodiment 22
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(3,4,5-trimethoxy-benzene Base) acrylamide
m.p.179.6-181.2℃.ESI-MS m/z:[M+H]+539.2.
1H NMR(400MHz,DMSO)δ9.88(s,1H),9.65(s,1H),9.06(s,1H),8.54(s,1H),8.13 (d, J=5.2Hz, 1H), 7.80 (d, J=8.2Hz, 1H), 7.58 (d, J=15.6Hz, 1H), 7.43 (t, J=9.2Hz, 1H), (7.32 s, 1H), 7.21 (d, J=15.6Hz, 1H), 7.00 (s, 2H), 4.06 (s, 3H), 3.86 (s, 6H), 3.70 (d, J= 10.0Hz,3H).
Embodiment 23
N-(4-((4-chloro-3-(trifluoromethyl) phenyl) amino)-7-methoxy quinoline-6-base)-3-(2,3,4-trimethoxy Base phenyl) acrylamide
ESI-MS m/z:[M+H]+589.1
Embodiment 24
N-(7-(4-morpholinoethyl)-4-(4-ethenylphenyl) amino) quinazoline-6-base)-3-(3-morpholino benzene Base) acrylamide
ESI-MS m/z:[M+H]+620.3
Embodiment 25
N-(4-(4-ethynyl phenyl) amino)-7-(3-(piperidin-1-yl) propoxyl group) quinazoline-6-base)-3-(4- Quinoline is for phenyl) acrylamide
ESI-MS m/z:[M+H]+618.3
Embodiment 26
N-(4-((3-methyl mercapto phenyl) amino)-7-(4-piperidines methoxyl group) quinazoline-6-base)-3-(4-morpholino benzene Base) acrylamide
The pharmacological research of product of the present invention
In vitro cytotoxic effect
The quinazoline compounds derivant containing cinnamamide structure of the formula I according to the present invention has been carried out external pressing down Lung cell A549 processed, carcinoma of prostate PC-3, breast cancer cell MCF-7, cervical cancer cell Hela screening active ingredients, reference substance Ah Method prepares according to patent documentation (WO2007085638A1) described method for Buddhist nun.
1) cell recovery and pass on 2～3 times stable after, make it disappear bottom culture bottle with trypsin solution (0.25%) Change is got off.After being poured in centrifuge tube by cell dissociation buffer, add culture fluid afterwards to terminate digestion.By centrifuge tube at 800r/min Under be centrifuged 10min, after abandoning supernatant add 5mL culture fluid, piping and druming mixing cell, draw 10 μ L cell suspensions add cells Counting in counting chamber, adjusting cell concentration is 104Individual/hole.Removing A1 hole in 96 orifice plates is that blank well is not added with extracellular, and remaining all adds Enter 100 μ L cell suspensions.96 orifice plates are put into cultivation 24h in incubator.
2) with 50 μ L dmso solution given the test agent, it is subsequently adding appropriate culture fluid, makes sample be dissolved into 2mg/mL Medicinal liquid, is then 20,4,0.8,0.16,0.032 μ g/mL by diluted sample in 24 orifice plates.
Each concentration adds 3 holes, and wherein around two row two row cell growing ways are affected by environment relatively big, only and be blanc cell Hole uses.96 orifice plates are put into cultivation 72h in incubator.
3) band medicine culture fluid in 96 orifice plates is discarded, with phosphate buffer solution (PBS), cell is rinsed twice, in every hole Add MTT (tetrazole) (0.5mg/mL) 100 μ L and put in incubator after 4h, discard MTT solution, add dimethyl sulfoxide 100 μ L.On magnetic force agitator, vibration makes survivaling cell fully dissolve with MTT product first, puts into measurement result in microplate reader. Medicine IC can be obtained by Bliss method50Value.
The breast cancer cell MCF-7 of target compound I, lung cell A549, carcinoma of prostate PC-3 Activity Results such as table 2 institute Show.
EGFR enzymatic activity is tested
With Afatinib as positive control, utilize HTRF technology, test the suppression kinase whose to EGFR of newly synthesized compound and make With, and the IC that part of detecting compound is to EGFR kinase inhibitory activity50Value.
Concrete grammar: ATP, TK Substrate-biotin (TK-substrate biotin), the Kinase of preparation desired concn The working solution of buffer (kinase buffer liquid), ATP, TK Substrate-biotin, Kinase buffer by volume ratio 2: 2 : 2 take liquid mixing；It is formulated as desired concn with Kinase buffer dilution medicine；Preparation EGFR enzyme working solution.In white 384 holes In plate, every hole adds 6 μ L mixing liquids, 2 μ L medicines, 2 μ L kinases, mixing, is placed at 37 DEG C reaction 30min.It is subsequently adding 5 μ L chains The XL-665 and 5 μ L of kinases element labelling combine the cryptate antibody of Eu3+, mixing.In enzyme mark after room temperature placement 30min Instrument 314nm excites, the fluorescence at detection 665,620nm wavelength, calculates kinase inhibition rate.
Suppression ratio (%)=(Ratio665/620 control wells-Ratio665/620 dosing holes)/Ratio665/620 comparison Hole × 100%
Experimental result is as shown in table 2.Suppression ratio in table 2 >=80%, represent with " +++ ", 80% suppression ratio >=60%, Represent with " ++ ", 60% suppression ratio >=40%, with "+" represent that suppression ratio≤40% represents with "-", " NA " indicates without living Property, " ND " expression is not tested.
The enzymatic activity of table 2 target compound I and anti tumor activity in vitro
From above-mentioned result of the test it can be clearly seen that the compound of the claimed formula I of the present invention, have good Anti tumor activity in vitro.
The compound of formula of I of the present invention can be administered alone, but typically gives with pharmaceutical carrier mixture, described medicinal The selection of carrier will be according to required route of administration and standard pharmaceutical practice.Separately below with the various medicine agent of this compounds Type, the such as preparation method of tablet, capsule, injection, aerosol, suppository, membrane, drop pill, externally-applied liniment and ointment, Its new opplication in pharmaceutical field is described.
Application examples 1: tablet
With embodiment 2 compound 10g, after adding adjuvant 20g mixing according to the general pressed disc method of pharmaceutics, it is pressed into 100, often Tablet weight 300mg.
Application examples 2: capsule
With embodiment 4 compound 10g, after being mixed by adjuvant 20g according to the requirement of pharmaceutics capsule, load hollow glue Capsule, each capsule weight 300mg.
Application examples 3: injection
With embodiment 7 compound 10g, according to pharmaceutics conventional method, carry out activated carbon adsorption, through 0.65 μm microporous filter membrane After filtration, insert nitrogen pot and make hydro-acupuncture preparation, every dress 2mL, fill 100 bottles altogether.
Application examples 4: aerosol
With embodiment 10 compound 10g, after dissolving with appropriate propylene glycol, after adding distilled water and other spoke material, make The settled solution of 500mL and get final product.
Application examples 5: suppository
With embodiment 13 compound 10g, by finely ground addition glycerol appropriate, add the glycerin gelatine melted after grinding well, Grind uniformly, be poured into and be coated with in the model of lubricant, prepare suppository 50.
Application examples 6: membrane
With embodiment 15 compound 10g, the stirrings such as polyvinyl alcohol, medicinal glycerin, water are expanded post-heating and dissolves, 80 mesh sieves Net filtration, then embodiment 15 compound is joined stirring and dissolving in filtrate, film applicator masking 100.
Application examples 7: drop pill
With embodiment 16 compound 15g, after adding heat fusing mixing with substrate 50g such as gelatin, instill in cryogenic liquid paraffin, Prepare drop pill 1000 ball altogether.
Application examples 8: externally-applied liniment
With embodiment 19 compound 10g, according to adjuvant 2.5g mixed grindings such as conventional dose method and emulsifying agents, then add Distilled water prepares to 200mL.
Application examples 9: ointment
With embodiment 20 compound 10g, finely ground after grind well prepared with the oleaginous base 500g such as vaseline.
Although describing the present invention by particular, but amendment and equivalent variations being for being proficient in this field Will be apparent from for technical staff, and within they are included in the scope of the invention.

Claims (7)

1. the quinazoline compounds containing cinnamamide structure, it is characterised in that structure is as shown in following formula I:
Wherein:
R1, R3Be 1～3 identical or different selected from hydrogen, halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amino, sulfydryl, carboxylic Base, trifluoromethoxy, dimethylamino, diethylin, morpholinyl, pyrrolidin-1-yl, piperidin-1-yl, N-thyl-piperazin-1- Base, (C1-C4) alkyl, (C3～C6) cycloalkyl, (C2～C4) thiazolinyl, (C2～C4) alkynyl, (C1～C4) alkoxyl, nitrine Base, (C1～C4) alkoxy methyl, (C2～C4) alkyl acyl or (C1～C4) alkylthio group；
R2Selected from hydrogen, trifluoromethoxy, S-oxolane-3-epoxide, 3-(piperidin-1-yl) propoxyl group, 3-(morpholine-1-base) third Epoxide, piperidin-4-yl methoxyl group, (C1～C4) alkyl, (C1～C4) alkoxyl or (C1～C4) alkylthio group.
Quinazoline compounds containing cinnamamide structure the most according to claim 1, it is characterised in that:
R1, R3Be 1～3 identical or different selected from hydrogen, halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amino, trifluoro methoxy Base, dimethylamino, diethylin, morpholinyl, pyrrolidin-1-yl, piperidin-1-yl, N-thyl-piperazin-1-base, methyl, ethyl, N-pro-pyl, isopropyl, cyclopropyl, normal-butyl, methoxyl group, ethyoxyl, tert-butoxy, acetyl group, vinyl, pi-allyl, acetylene Base or methyl mercapto；
R2Selected from hydrogen, trifluoromethoxy, S-oxolane-3-epoxide, 3-(piperidin-1-yl) propoxyl group, 3-(morpholine-1-base) third Epoxide, piperidin-4-yl methoxyl group, methoxyl group, ethyoxyl, tert-butoxy, methyl, ethyl or methyl mercapto.
Quinazoline compounds containing cinnamamide structure the most according to claim 1, it is characterised in that: described formula I Compound be the one in following compounds:
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3-(4-cyanogen Base phenyl) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3-(2-nitre Base phenyl) acrylamide,
(S)-3-(2-chloro-4-fluorophenyl)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinoline Oxazoline-6-base) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3-(2,5- Dimethoxyphenyl) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3-(4-first Phenyl) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3-(2,4- Dimethoxyphenyl) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3-(3,5- Dimethoxyphenyl) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3-(3,4, 5-trimethoxyphenyl) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3-(4-nitre Base phenyl) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3-(2,3- Dichlorobenzene base) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3-(2,3, 4-trimethoxyphenyl) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3-(3, 5-bis-bromo-4-hydroxy phenyl) acrylamide,
(S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline-6-base)-3-(4-hydroxyl Base-3,5-Dimethoxyphenyl) acrylamide,
(S)-3-(3-bromophenyl)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((oxolane-3-base epoxide) quinazoline- 6-yl) acrylamide,
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(4-methoxyphenyl) acrylamide,
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(2-nitrobenzophenone) acrylamide,
3-(2-chloro-4-fluorophenyl)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base) acryloyl Amine,
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(2,5-Dimethoxyphenyl) propylene Amide,
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(4-methoxyphenyl) acrylamide,
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(2,4-Dimethoxyphenyl) propylene Amide,
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(3,5-Dimethoxyphenyl) propylene Amide,
N-(4-((3-chloro-4-fluorophenyl) amino)-7-methoxyquinazoline hydrochloride-6-base)-3-(3,4,5-trimethoxyphenyl) third Acrylamide,
N-(4-((4-chloro-3-(trifluoromethyl) phenyl) amino)-7-methoxy quinoline-6-base)-3-(2,3,4-trimethoxy-benzene Base) acrylamide,
N-(7-(4-morpholino butyl)-4-(4-ethenylphenyl) amino) quinazoline-6-base)-3-(3-morphlinophenyl) third Acrylamide,
N-(4-(4-ethynyl phenyl) amino)-7-(3-(piperidin-1-yl) propoxyl group) quinazoline-6-base)-3-(4-morpholino Phenyl) acrylamide,
N-(4-((3-methyl mercapto phenyl) amino)-7-(4-piperidines methoxyl group) quinazoline-6-base)-3-(4-morphlinophenyl) Acrylamide.
4. the preparation method of the quinazoline compounds containing cinnamamide structure as claimed in claim 1, it is characterised in that: Work as R1For 3-chloro-4-fluorine, R2For S-oxolane-3-epoxide or methoxyl group, R3For fluorine, chlorine, bromine, methoxyl group, nitro, hydroxyl or Cyano group；Described method passes through following reaction scheme, with 4-fluoro-2-amino benzoic Acid as raw material, obtains centre through series reaction Body V, then reacted with (S)-3-hydroxyl tetrahydrofuran or methanol by intermediate V and obtain intermediate VIa or VIb, then by nitro also Former obtain VIIa or VIIb；With different substituted benzaldehydes, it is respectively synthesized IXa-n through series reaction；Finally, by intermediate VIIa or VIIb reacts with IXa-n, obtains target compound；Reaction scheme is as follows:
。
5. the quinazoline compounds containing cinnamamide structure as claimed in claim 1, in preparation treatment and/or prevention Application in proliferative disease medicine.
6. the quinazoline compounds containing cinnamamide structure as claimed in claim 1, in preparation treatment and/or prevention Application in the medicine of cancer.
7. the quinazoline compounds containing cinnamamide structure as claimed in claim 1, in preparation treatment and/or prevention Application in the medicine of carcinoma of prostate, pulmonary carcinoma and cervical cancer.
CN201610334018.4A 2016-05-19 2016-05-19 Quinazoline compound containing cinnamamide structure and preparation method and application thereof Pending CN106008480A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109776514A (en) * 2019-03-22 2019-05-21 徐州工业职业技术学院 A kind of Afatinib highly finished product synthetic method
CN113861120A (en) * 2021-11-01 2021-12-31 湖南南新制药股份有限公司 Preparation method of dacomitinib

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6384223B1 (en) * 1998-07-30 2002-05-07 American Home Products Corporation Substituted quinazoline derivatives
CN1495172A (en) * 1996-04-12 2004-05-12 ��ʲ Irreversible inhibitor of tyrosine kinase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1495172A (en) * 1996-04-12 2004-05-12 ��ʲ Irreversible inhibitor of tyrosine kinase
US6384223B1 (en) * 1998-07-30 2002-05-07 American Home Products Corporation Substituted quinazoline derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YUANBIAO TU，等: "Design, synthesis, and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109776514A (en) * 2019-03-22 2019-05-21 徐州工业职业技术学院 A kind of Afatinib highly finished product synthetic method
CN113861120A (en) * 2021-11-01 2021-12-31 湖南南新制药股份有限公司 Preparation method of dacomitinib

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