CN108863950B - Diaryl substituted quinazoline compound and synthetic method thereof - Google Patents
Diaryl substituted quinazoline compound and synthetic method thereof Download PDFInfo
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- CN108863950B CN108863950B CN201810612951.2A CN201810612951A CN108863950B CN 108863950 B CN108863950 B CN 108863950B CN 201810612951 A CN201810612951 A CN 201810612951A CN 108863950 B CN108863950 B CN 108863950B
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- -1 quinazoline compound Chemical class 0.000 title claims abstract description 28
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 title claims abstract description 14
- 238000010189 synthetic method Methods 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 74
- 238000001308 synthesis method Methods 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 46
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical group O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 18
- 239000013110 organic ligand Substances 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 17
- 239000003054 catalyst Substances 0.000 claims description 13
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 12
- 238000003786 synthesis reaction Methods 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 239000000654 additive Substances 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 7
- 230000000996 additive effect Effects 0.000 claims description 7
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
- 238000011160 research Methods 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 5
- 206010061218 Inflammation Diseases 0.000 abstract description 4
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 230000004054 inflammatory process Effects 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000000376 reactant Substances 0.000 abstract description 2
- 238000007039 two-step reaction Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 230000000052 comparative effect Effects 0.000 description 20
- 239000003480 eluent Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 12
- 150000003246 quinazolines Chemical class 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
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- 239000002244 precipitate Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000007832 Na2SO4 Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- 108090001005 Interleukin-6 Proteins 0.000 description 3
- 102000004889 Interleukin-6 Human genes 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000000078 anti-malarial effect Effects 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RVWUHFFPEOKYLB-UHFFFAOYSA-N 2,2,6,6-tetramethyl-1-oxidopiperidin-1-ium Chemical compound CC1(C)CCCC(C)(C)[NH+]1[O-] RVWUHFFPEOKYLB-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000005749 Copper compound Substances 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 101001076414 Mus musculus Interleukin-6 Proteins 0.000 description 1
- QLNRMDOCAQPOHP-UHFFFAOYSA-N N1C(N=CC2=CC=CC=C12)=O.C(=O)O Chemical compound N1C(N=CC2=CC=CC=C12)=O.C(=O)O QLNRMDOCAQPOHP-UHFFFAOYSA-N 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
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- 238000010828 elution Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- VYFOAVADNIHPTR-UHFFFAOYSA-N o-aminobenzyl alcohol Natural products NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 229960001289 prazosin Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000009333 weeding Methods 0.000 description 1
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Classifications
-
- 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
- C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Pharmacology & Pharmacy (AREA)
- Rheumatology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a diaryl substituted quinazoline compound shown in a formula (5),
wherein R is selected from halogen and C1‑C6Alkyl or C1‑C6The alkoxy group, the compound has obvious inflammation inhibition effect, and has good research prospect and application potential in the field of medicines. The synthesis method takes simple and easily-obtained raw materials as reactants, and the aryl-substituted quinazoline compound is obtained through two-step reaction, so that the diaryl-substituted quinazoline compound has good application prospect and research value.
Description
Technical Field
The invention relates to a nitrogen-containing fused ring compound and a synthetic method thereof, in particular to an aryl substituted quinazoline compound and a synthetic method thereof, belonging to the field of organic chemical synthesis.
Background
The quinazoline compound generally has activities of weeding, sterilization, disinsection, antivirus, anti-inflammation, anti-hypertension, anti-spasm, anti-tumor, anti-malaria, anti-tuberculosis and the like, and optical activity, so that the quinazoline compound has good application prospect and potential in a plurality of fields of medicine, agriculture, organic electroluminescence and the like.
For example, quinazoline compounds have been found to have excellent inhibitory effects on various disease-causing agents at specific targets in their biological activities. For example:
the 2-trichloromethyl-4-arylthioquinazoline derivative has good antimalarial activity (see bioorg.Med.chem.Lett., 21, p 6003-one 6006, 2011);
some 4-heteroarylthioquinazoline derivatives have antiproliferative activity against some cancer cells (see bioorg.med.chem.lett., 17, p 2193-2196, 2007);
certain quinazoline compounds have strong inhibitory effect on Epidermal Growth Factor Receptor (EGFR) and tyrosine kinase (EGFR-TK), and can be used for resisting cancer.
The antihypertensive drug prazosin, the diuretic quinazolinone formate, the anti-intestinal cancer drug raltitrexed, the antimalarial drug dichroine, the anticancer drug gefitinib, the bactericidal drug propoxymidine and the like, and the compounds all comprise quinazoline structural units.
Due to the wide application prospect and potential therapeutic effect of quinazoline compounds, the synthesis of corresponding compounds and the search and research of novel quinazoline compounds have become a research hotspot and focus of organic chemical synthesis, and a plurality of reactions and synthetic routes have been developed, such as:
dan ZHao et al ("powdered iodine-catalyzed present-component Synthesis of 2-arylauinazolines via amino of phenyl of C-H bonds of methyl", Advanced Synthesis & Catalysis,2015,357,339-344) disclose a method for preparing quinazoline compounds from o-aminoarylaldehydes, which has the following reaction formula:
the applicant's CN201610403652.9 discloses a method for synthesizing diphenyl-substituted quinazoline compound, which is to react a compound of the following formula (I) with a compound of the following formula (II), and then perform post-treatment after the reaction is finished, so as to obtain a compound of the formula (III),
CN103275016A, CN103467388A, and CN103467388A disclose a method for synthesizing a 2-substituted quinazoline compound represented by the following formula (I), wherein the method comprises reacting an o-aminobenzyl alcohol compound of the formula (II) with an aromatic aldehyde compound of the formula (III) in a reaction solvent in the presence of a two-component catalyst composed of a copper compound and a cerium compound, an ammonium source compound (or an organic ligand), a base, and oxygen (or 2,2,6, 6-tetramethylpiperidine-1-oxide) to obtain the compound of the formula (I):
CN103113311A discloses a preparation method of quinazoline compound, which comprises reacting aryl aldehyde or heteroaryl aldehyde with anthranilamide to obtain 2-aryl quinazolinone or 2-heteroaryl quinazolinone, and then reducing to obtain 2-aryl quinazoline or 2-heteroaryl quinazoline, wherein the reaction formula is as follows:
as described above, many novel quinazoline compounds and methods for synthesizing the same have been disclosed in the prior art, but there is still a need for further research and exploration in order to obtain more quinazoline compounds and study on methods for synthesizing the same, which is one of the research hotspots and focuses in the field of organic synthesis technology.
Disclosure of Invention
The present inventors have conducted intensive studies in order to find out novel quinazoline compounds and methods for synthesizing the same, and as a result, have completed the present invention after having made a great deal of creative efforts.
Specifically, in a first aspect, the present invention relates to a diaryl substituted quinazoline compound represented by the following formula (5):
wherein R is selected from halogen and C1-C6Alkyl or C1-C6An alkoxy group.
In the diaryl substituted quinazoline compound of the formula (5) according to the present invention, the meaning of the "halogen" means a halogen element, which may be, for example, without limitation, F, Cl, Br or I.
In the diaryl substituted quinazoline compound of the formula (5) of the present invention, the "C" is1-C6By alkyl is meant a straight or branched chain alkyl group having 1 to 6 carbon atoms, which includes C1Alkyl radical, C2Alkyl radical, C3Alkyl radical, C4Alkyl radical, C5Alkyl or C6Alkyl groups, such as but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, or n-hexyl, and the like.
In the diaryl substituted quinazoline compound of the formula (5) of the present invention, the "C" is1-C6Alkoxy "means" C "as defined above1-C6Alkyl "a group attached to an O atom.
The diaryl substituted quinazoline compound shown in the formula (5) is a brand new compound, and has a quinazoline ring and an active group amino group, so that more quinazoline compounds can be subsequently synthesized as described in the background technology, and the diaryl substituted quinazoline compound has good application development potential and research value in multiple technical fields. The research of the inventor discovers that the compound has an obvious inflammation inhibition effect and has good research prospect and application potential in the field of medicines.
In a second aspect, the present invention relates to a method for synthesizing diaryl substituted quinazoline compounds of the formula (5), wherein the route of the method is as follows:
the synthesis method comprises the following steps:
s1: reacting the compound of the formula (1) with the compound of the formula (2), and performing post-treatment after the reaction is finished to obtain a compound of the formula (3);
s2: reacting a compound of the formula (3) with a compound of the formula (4) in an organic solvent under the action of a palladium catalyst, an organic ligand and an acidic additive, and performing post-treatment after the reaction to obtain a compound of the formula (5);
wherein R is as defined above and is not repeated herein.
Hereinafter, each technical feature in each step will be further described in detail, specifically as follows.
[ step S1]
In step S1, the molar ratio of the compound of formula (1) to the compound of formula (2) is 1:0.5 to 1.5, for example may be 1:0.5, 1:1 or 1: 1.5.
In step S1, the reaction temperature is 70-90 deg.C, and may be, for example, 70 deg.C, 80 deg.C, or 90 deg.C.
In step S1, the reaction time is 8 to 16 hours, and may be, for example, 8 hours, 10 hours, 12 hours, 14 hours, or 16 hours.
In step S1, the post-processing after the reaction is specifically as follows: after the reaction is finished, naturally cooling the reaction mixture to room temperature, adding a proper amount of deionized water, standing until the precipitation is complete, filtering out the precipitate, and fully drying by using an infrared lamp to obtain the compound of the formula (3).
The amount of the deionized water added can be suitably selected and determined, for example, as long as the precipitate can be completely precipitated, which can be determined by those skilled in the art after reading the present invention without any inventive work.
[ step S2]
In step S2, the palladium catalyst is palladium acetate (Pd (OAc)2) Palladium acetylacetonate (Pd (acac)2) Palladium chloride, tris (dibenzylideneacetone) dipalladium (Pd)2(dba)3) Or palladium trifluoroacetate (Pd (TFA)2) Most preferably palladium acetate (Pd (OAc)2)。
In step S2, the organic ligand is any one of the following formulas L1-L6,
most preferably, the organic ligand is L1.
In step S2, the acidic additive is any one of p-toluenesulfonic acid monohydrate, acetic acid, trifluoroacetic acid, benzoic acid, methanesulfonic acid, trifluoromethanesulfonic acid, or camphorsulfonic acid, preferably p-toluenesulfonic acid monohydrate or camphorsulfonic acid, and most preferably p-toluenesulfonic acid monohydrate.
In step S2, the organic solvent is any one of Tetrahydrofuran (THF), N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethanol, 1, 4-dioxane, dichloromethane, cyclohexane or toluene, preferably toluene, dichloromethane or cyclohexane, and most preferably toluene.
The amount of the organic solvent is not strictly limited, and can be appropriately selected and determined by those skilled in the art according to actual conditions, for example, the amount is determined to facilitate the reaction and the post-treatment, and will not be described in detail herein.
In step S2, the molar ratio of the compound of formula (3) to the compound of formula (4) is 1:1.5-2.5, and may be, for example, 1:1.5, 1:2, or 1: 2.5.
In step S2, the molar ratio of the compound of formula (3) to the palladium catalyst is 1:0.02 to 0.1, and may be, for example, 1:0.02, 1:0.04, 1:0.06, 1:0.08, or 1: 0.1.
In step S2, the molar ratio of the compound of formula (3) to the organic ligand is 1:0.05-0.15, and may be, for example, 1:0.05, 1:0.1, or 1: 0.15.
In step S2, the molar ratio of the compound of formula (3) to the acidic additive is 1:8 to 12, and may be, for example, 1:8, 1:10, or 1: 12.
In step S2, the reaction temperature is 70 to 90 ℃ and may be, for example, 70 ℃, 80 ℃ or 90 ℃ without limitation.
In step S2, the reaction time is not particularly limited, and a suitable reaction time can be determined by, for example, detecting the residual amount of the starting material by liquid chromatography or TLC, and may be, for example, 16 to 28 hours, but is not limited to, for example, 16 hours, 20 hours, 24 hours, or 28 hours.
In step S2, the post-processing after the reaction is finished may be specifically as follows: after the reaction is finished, naturally cooling the reaction system to room temperature, washing the reaction system by using saturated potassium carbonate aqueous solution, adding ethyl acetate for extraction for three times, combining organic phases, and using anhydrous Na2SO4Drying, distilling under reduced pressure, eluting the residue by flash column chromatography on silica gel (16: 1 by volume mixture of petroleum ether and ethyl acetate as eluent), collecting the eluent and evaporating off the eluent to obtain the compound of formula (5).
Wherein, during the purification process of the silica gel flash column chromatography, the proper elution end point can be determined by TLC tracking monitoring.
As described above, the diaryl substituted quinazoline compound of the formula (5) and the synthesis method thereof are provided, the quinazoline compound is a brand new compound, has a quinazoline ring and an active group amino group, can be used for subsequently synthesizing more quinazoline compounds, and has an obvious inflammation inhibition effect, so that the quinazoline compound has good application and development potential and research value in a plurality of technical fields.
Drawings
FIG. 1 is a graph showing the inhibitory effect of the compound K1-K2 of the present invention on IL-6.
Detailed Description
The present invention is described in detail below with reference to specific examples, but the use and purpose of these exemplary embodiments are merely to exemplify the present invention, and do not set forth any limitation on the actual scope of the present invention in any form, and the scope of the present invention is not limited thereto.
Example 1
The reaction route is as follows:
the method specifically comprises the following steps:
s1: adding 100mmol of the compound of the above formula (1) and 50mmol of the compound of the above formula (2) to a reaction vessel, and reacting at 70 ℃ for 16 hours;
after the reaction is finished, naturally cooling the reaction mixture to room temperature, adding a proper amount of deionized water, standing until the precipitation is complete, filtering out the precipitate, and fully drying by using an infrared lamp to obtain the compound of the formula (3) as a white solid, wherein the yield is 93.6%;
1H NMR(500MHz,DMSO-d6)δ8.34(s,1H),8.03(s,1H),7.93(s,1H),7.69-7.77(m,4H),2.49(s,3H),2.45(s,3H)；
s2: adding 100mmol of the compound of the above formula (3), 150mmol of the compound of the above formula (4), 10mmol of palladium acetate, 5mmol of organic ligand L1 and 1200mmol of p-toluenesulfonic acid monohydrate to an appropriate amount of organic solvent toluene at room temperature, then stirring and heating to 70 ℃ and stirring at the temperature for reaction for 28 hours;
after the reaction is finished, naturally cooling the reaction system to room temperature, washing the reaction system by using saturated potassium carbonate aqueous solution, adding ethyl acetate for extraction for three times, combining organic phases, and using anhydrous Na2SO4Drying, distilling under reduced pressure, passing the residue through siliconElution was performed by gel flash column chromatography (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 16:1 as eluent), and the eluent was collected and evaporated to give the compound of formula (5) above as a yellow solid, which was named K1, with a yield of 82.5%.
Melting point: 141 ℃ and 142 ℃.
1H NMR(500MHz,DMSO-d6)δ8.31(s,1H),8.00(d,J＝8.5Hz,1H),7.81-7.83(m,3H),7.76(s,1H),7.65-7.66(m,3H),7.21(s,2H),7.01(d,J＝8.5Hz,1H),6.76(d,J＝8Hz,1H),2.46(s,3H),2.23(s,3H)；
Example 2
The reaction route is as follows:
the method specifically comprises the following steps:
s1: adding 100mmol of the compound of the above formula (1) and 150mmol of the compound of the above formula (2) to a reaction vessel, and reacting at 90 ℃ for 8 hours;
after the reaction is finished, naturally cooling the reaction mixture to room temperature, adding a proper amount of deionized water, standing until the precipitation is complete, filtering out the precipitate, and fully drying by using an infrared lamp to obtain the compound of the formula (3) as a white solid, wherein the yield is 90.5%;
1H NMR(500MHz,DMSO-d6)δ8.39(s,1H),8.11(d,J＝8Hz,1H),7.98(d,J＝8Hz,1H),7.67(s,1H),7.61(s,1H),7.57(d,J＝8Hz,1H),7.47(d,J＝8Hz,1H),2.51(s,3H),2.47(s,3H)。
s2: adding 100mmol of the compound of the formula (3) above, 250mmol of the compound of the formula (4) above, 2mmol of palladium acetate, 15mmol of organic ligand L1 and 800mmol of p-toluenesulfonic acid monohydrate to an appropriate amount of organic solvent toluene at room temperature, then stirring and heating to 90 ℃ and stirring at the temperature for reaction for 16 hours;
after the reaction is finished, naturally cooling the reaction system to room temperature, washing the reaction system by using saturated potassium carbonate aqueous solution, adding ethyl acetate for extraction for three times, combining organic phases, and using anhydrous Na2SO4DryingAnd, distillation under reduced pressure, the residue was eluted by flash column chromatography on silica gel (16: 1 by volume of a mixture of petroleum ether and ethyl acetate as eluent), the eluent was collected and evaporated to give the compound of the above formula (5) as a yellow solid, which was named K2, in 79.8% yield.
Melting point: 197 ℃ and 199 ℃.
1H NMR(500MHz,DMSO-d6)δ8.44(d,J＝8Hz,1H),7.89-7.92(m,2H),7.83-7.84(m,2H),7.65(s,3H),7.44-7.47(m,3H),6.65(s,1H),6.47(d,J＝8Hz,1H),2.56(s,3H),2.24(s,3H)。
Example 3
The reaction scheme is the same as example 1.
The method specifically comprises the following steps:
s1: adding 100mmol of the compound of formula (1) and 100mmol of the compound of formula (2) to a reaction vessel, and reacting at 80 ℃ for 12 hours;
after the reaction is finished, naturally cooling the reaction mixture to room temperature, adding a proper amount of deionized water, standing until the precipitation is complete, filtering out the precipitate, and fully drying by using an infrared lamp to obtain the compound of the formula (3) as a white solid, wherein the yield is 93.2%;
the NMR data were the same as for the compound of formula (3) obtained in step S1 of example 1.
S2: adding 100mmol of the compound shown in the formula (3), 200mmol of the compound shown in the formula (4), 6mmol of palladium acetate, 10mmol of organic ligand L1 and 1000mmol of p-toluenesulfonic acid monohydrate into an appropriate amount of organic solvent toluene at room temperature, and then stirring and heating to 80 ℃ and stirring at the temperature for reaction for 22 hours;
after the reaction is finished, naturally cooling the reaction system to room temperature, washing the reaction system by using saturated potassium carbonate aqueous solution, adding ethyl acetate for extraction for three times, combining organic phases, and using anhydrous Na2SO4Drying, distillation under reduced pressure, and flash column chromatography on silica gel (16: 1 by volume mixture of petroleum ether and ethyl acetate as eluent), collecting the eluent and evaporating off the eluent, to obtain said compound of formula (5) as a yellow solid in 82.8% yield.
Melting point and nuclear magnetic characterization data were the same as for the compound of formula (5), which was the product of step S2 of example 1.
Example 4
The reaction scheme is the same as example 2.
The method specifically comprises the following steps:
s1: adding 100mmol of the compound of formula (1) and 75mmol of the compound of formula (2) to a reaction vessel, and reacting at 85 ℃ for 10 hours;
after the reaction is finished, naturally cooling the reaction mixture to room temperature, adding a proper amount of deionized water, standing until the precipitation is complete, filtering out the precipitate, and fully drying by using an infrared lamp to obtain the compound of the formula (3) which is a white solid, wherein the yield is 90.2%;
the NMR data were the same as for the compound of formula (3) produced in step S1 of example 2.
S2: adding 100mmol of the compound of the formula (3), 175mmol of the compound of the formula (4), 8mmol of palladium acetate, 7.5mmol of organic ligand L1 and 1100mmol of p-toluenesulfonic acid monohydrate to an appropriate amount of organic solvent toluene at room temperature, then stirring and heating to 75 ℃ and stirring at the temperature for reaction for 25 hours;
after the reaction is finished, naturally cooling the reaction system to room temperature, washing the reaction system by using saturated potassium carbonate aqueous solution, adding ethyl acetate for extraction for three times, combining organic phases, and using anhydrous Na2SO4Drying, distillation under reduced pressure, and flash column chromatography on silica gel (16: 1 by volume mixture of petroleum ether and ethyl acetate as eluent), collecting the eluent and evaporating off the eluent, to obtain said compound of formula (5) as a yellow solid in a yield of 80.4%.
Melting point and nuclear magnetic characterization data were the same as for the compound of formula (5), which was the product of step S2 of example 2.
Some technical features in step S2 are considered below to make an inventive selection of the most preferable conditions, specifically as follows.
Examination of technical characteristics in step S2
Investigation of the catalyst
Comparative examples S201 to S204: except that step S is respectivelyCatalyst Palladium acetate in 2 was replaced with Palladium acetylacetonate (Pd (acac)2) Otherwise, the other operations were not changed, so that examples 1 to 4 were repeated to obtain comparative examples S201 to S204 in this order.
Comparative examples S205 to S208: examples 1 to 4 were repeated except that the palladium acetate catalyst in step S2 was replaced with palladium chloride, respectively, to thereby obtain comparative examples S205 to S208.
Comparative examples S209 to S212: except that the catalyst palladium acetate in step S2 was replaced with tris (dibenzylideneacetone) dipalladium (Pd) respectively2(dba)3) Otherwise, the other operations were not changed, so that examples 1 to 4 were repeated to obtain comparative examples S209 to S212 in this order.
Comparative examples S213 to S216: except that the catalyst palladium acetate in step S2 was replaced with palladium trifluoroacetate (Pd (TFA))2) Otherwise, the other operations were not changed, so that examples 1 to 4 were repeated to obtain comparative examples S213 to S216 in this order.
The results are shown in Table 1 below (wherein the product yield refers to the yield of compound (5) in step S2).
TABLE 1
It follows that slight variations in the effect for the catalyst in step S2 can result, for example in a significant reduction in yield when palladium trifluoroacetate is used, albeit highly similar to palladium acetate. This demonstrates the unpredictability and non-obvious effect of catalyst selection on species.
Investigation of organic ligands
Examples 1-6 were repeated except that organic ligand L1 was replaced with the other organic ligands in Table 2 below, respectively, and the organic ligands used, the example correspondences, and the product yields are shown in Table 2 below (where the product yields refer to the yield of compound (5) in step S2).
TABLE 2
It follows that L1 is most preferred for organic ligands, while other organic ligands all have a significant reduction in effect; it can also be seen that even with very similar L2-L3, there is a significant reduction in the effect, whereas L5 does not even give a product, which demonstrates that the choice of organic ligands is not obvious.
Examination of acidic additives
Comparative examples S222 to S225: examples 1 to 4 were repeated except that the p-toluenesulfonic acid monohydrate in step S2 was replaced with acetic acid, respectively, to obtain comparative examples S222 to S225.
Comparative examples S226 to S229: examples 1 to 4 were repeated except that p-toluenesulfonic acid monohydrate in step S2 was replaced with trifluoroacetic acid, respectively, to obtain comparative examples S226 to S229 in this order.
Comparative examples S230 to S233: examples 1 to 4 were repeated except that p-toluenesulfonic acid monohydrate in step S2 was replaced with benzoic acid, respectively, to obtain comparative examples S230 to S233 in this order.
Comparative examples S234 to S237: examples 1 to 4 were repeated except that p-toluenesulfonic acid monohydrate in step S2 was replaced with methanesulfonic acid, respectively, to obtain comparative examples S234 to S237.
Comparative examples S238 to S241: examples 1 to 4 were repeated except that p-toluenesulfonic acid monohydrate in step S2 was replaced with trifluoromethanesulfonic acid, respectively, to obtain comparative examples S238 to S241.
Comparative examples S242 to S245: examples 1 to 4 were repeated except that p-toluenesulfonic acid monohydrate in step S2 was replaced with camphorsulfonic acid, respectively, to obtain comparative examples S242 to S245 in this order.
The results are shown in Table 3 below (wherein the product yield refers to the yield of compound (5) in step S2).
TABLE 3
NR indicates no product detected.
It follows that slight variations in the acidic additive in step S2 can result in significant changes in effect, for example in the case of benzoic acid, which, although highly similar to p-toluenesulfonic acid monohydrate, still does not give a product. This demonstrates the unpredictability of the choice of the acid additive in kind and non-obvious in effect.
Investigation of organic solvents
Examples 1 to 4 were repeated except that the organic solvent toluene was replaced with the other organic solvents shown in Table 4 below, respectively, and the organic solvents used, the correspondence among examples, and the product yields are shown in Table 4 below (wherein the product yield refers to the yield of the compound (5) in step S2).
TABLE 4
It follows that toluene is most preferred for the organic solvent, while other organic solvents all have a significant reduction in effectiveness, even failing to yield the product, which demonstrates that the choice of organic solvent is not obvious.
Drug activity assay
The experimental procedure was as follows:
1. preparing broth, namely fixing the volume of 0.5g of peptone, 0.25g of NaCl, 3g of soluble starch and 0.15g of beef extract to 50ml by using sterilized water;
2. filtering the broth with a 0.22 μm filter membrane to obtain a filtered broth;
3. injecting 5ml of broth into abdominal cavity of ICR male mouse (purchased from Experimental animal center of Wenzhou university of medicine) with weight of 18-22g, killing ICR male mouse 72h later, and separating to obtain primary macrophage;
4. the isolated primary cells were resuspended by centrifugation and plated into six-well plates (5X 10 per well)5Individual cells), then 2ml of 1640 complete medium (Gibco) was added to each well and the cells were cultured at a volume concentration of 5% CO237 ℃ in a cell culture box;
5. replacing fresh 1640 culture medium 4-6 hours after the cells adhere to the wall;
6. 24 hours after the cells were attached, the medium was replaced again with fresh 1640 medium, 10nM of the compound of the invention was added to each well, followed by 0.5mg/ml of LPS (Sigma-Aldrich) and incubation continued for 24 hours;
7. cell culture media was collected and IL-6 levels in the media were measured and normalized by determining total protein concentration, expressed as a percentage of LPS (i.e., in% ordinate), following the instructions for the mouse IL-6 enzyme-linked immunosorbent assay (ELISA) kit purchased from eBioscience Inc.
The result is shown in figure 1, and it can be seen that the compound of the invention has obvious inhibition effect on IL-6, thereby having anti-inflammatory activity and good research prospect and application potential in the field of medicines.
In conclusion, the invention provides a diaryl substituted quinazoline compound and a synthesis method thereof, the compound has obvious anti-inflammatory activity and good research prospect and application potential in the field of medicines, the synthesis method takes simple and easily-obtained raw materials as reactants, the aryl substituted quinazoline compound is obtained through two-step reaction, and the diaryl substituted quinazoline compound has good application prospect and research value.
It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should also be understood that various alterations, modifications and/or variations can be made to the present invention by those skilled in the art after reading the technical content of the present invention, and all such equivalents fall within the protective scope defined by the claims of the present application.
Claims (6)
1. A method for synthesizing diaryl substituted quinazoline compound shown in the following formula (5),
wherein R is selected from halogen and C1-C6Alkyl or C1-C6An alkoxy group;
the synthetic method has the following route:
the synthesis method comprises the following steps:
s1: reacting the compound of the formula (1) with the compound of the formula (2), and performing post-treatment after the reaction is finished to obtain a compound of the formula (3);
s2: reacting a compound of the formula (3) with a compound of the formula (4) in an organic solvent under the action of a palladium catalyst, an organic ligand and an acidic additive, and performing post-treatment after the reaction to obtain a compound of the formula (5);
in step S2, the palladium catalyst is palladium acetate;
in step S2, the organic ligand is of the formula L1,
in step S2, the acidic additive is p-toluenesulfonic acid monohydrate;
in step S2, the organic solvent is toluene, dichloromethane, or cyclohexane.
2. The method of synthesis of claim 1, wherein: in step S1, the molar ratio of the compound of formula (1) to the compound of formula (2) is 1: 0.5-1.5.
3. The method of synthesis of claim 1, wherein: in step S1, the reaction temperature is 70-90 ℃ and the reaction time is 8-16 hours.
4. The method of synthesis of claim 1, wherein: in step S2, the organic solvent is toluene.
5. The method of synthesis of claim 1, wherein: in step S2, the molar ratio of the compound of formula (3) to the compound of formula (4) is 1: 1.5-2.5.
6. The method of synthesis according to any one of claims 1 to 5, wherein: the molar ratio of the compound of formula (3) to the palladium catalyst is 1: 0.02-0.1.
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