OA10277A - Quinazoline derivatives - Google Patents

Info

Publication number

OA10277A

OA10277A OA60807A OA60807A OA10277A OA 10277 A OA10277 A OA 10277A OA 60807 A OA60807 A OA 60807A OA 60807 A OA60807 A OA 60807A OA 10277 A OA10277 A OA 10277A

Authority

OA

OAPI

Prior art keywords

amine

quinazolin

phenyl

ethynyl

alkyl

Prior art date

1995-03-30

Links

• Espacenet
• Global Dossier
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• 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 98
• -1 4-(substitutedphenylamino)quinazoline Chemical class 0.000 claims abstract description 92
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
• 150000003839 salts Chemical class 0.000 claims abstract description 11
• 201000010099 disease Diseases 0.000 claims abstract description 10
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 49
• 125000005843 halogen group Chemical group 0.000 claims description 49
• 229910052739 hydrogen Inorganic materials 0.000 claims description 44
• 239000001257 hydrogen Substances 0.000 claims description 44
• 125000000217 alkyl group Chemical group 0.000 claims description 33
• 238000000034 method Methods 0.000 claims description 31
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
• 229910052757 nitrogen Inorganic materials 0.000 claims description 25
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
• 150000001412 amines Chemical class 0.000 claims description 21
• 229910052760 oxygen Inorganic materials 0.000 claims description 19
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
• 229910052717 sulfur Inorganic materials 0.000 claims description 16
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
• 239000001301 oxygen Substances 0.000 claims description 15
• 125000001424 substituent group Chemical group 0.000 claims description 15
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
• 125000004122 cyclic group Chemical group 0.000 claims description 12
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 10
• 238000004519 manufacturing process Methods 0.000 claims description 10
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
• 125000005842 heteroatom Chemical group 0.000 claims description 9
• 239000011593 sulfur Substances 0.000 claims description 9
• 125000003282 alkyl amino group Chemical group 0.000 claims description 8
• 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 8
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
• 229920000642 polymer Polymers 0.000 claims description 7
• 125000003545 alkoxy group Chemical group 0.000 claims description 6
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 6
• 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
• 239000008194 pharmaceutical composition Substances 0.000 claims description 6
• 230000008569 process Effects 0.000 claims description 6
• 125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 claims description 6
• 241000124008 Mammalia Species 0.000 claims description 5
• 229910052799 carbon Inorganic materials 0.000 claims description 5
• 229910052736 halogen Inorganic materials 0.000 claims description 5
• 150000002367 halogens Chemical class 0.000 claims description 5
• XSMVZQAPXNUGBP-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-7-(2-methoxyethoxy)quinazolin-6-yl]oxyethyl acetate Chemical compound C=12C=C(OCCOC(C)=O)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 XSMVZQAPXNUGBP-UHFFFAOYSA-N 0.000 claims description 4
• 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 4
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
• PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 4
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
• 125000003118 aryl group Chemical group 0.000 claims description 4
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
• 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
• MTLKTHNRZJKPRP-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-6-(2-methoxyethoxy)quinazolin-7-yl]oxyethanol Chemical compound N1=CN=C2C=C(OCCO)C(OCCOC)=CC2=C1NC1=CC=CC(C#C)=C1 MTLKTHNRZJKPRP-UHFFFAOYSA-N 0.000 claims description 3
• NRKMCAKKJSZIRN-UHFFFAOYSA-N 4-n-(3-ethynylphenyl)quinazoline-4,6-diamine Chemical compound C12=CC(N)=CC=C2N=CN=C1NC1=CC=CC(C#C)=C1 NRKMCAKKJSZIRN-UHFFFAOYSA-N 0.000 claims description 3
• MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 3
• 125000004432 carbon atom Chemical group C* 0.000 claims description 3
• 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 3
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
• 125000004434 sulfur atom Chemical group 0.000 claims description 3
• YWSAEKIQJPQSDJ-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-7-(2-hydroxyethoxy)quinazolin-6-yl]oxyethanol Chemical compound C=12C=C(OCCO)C(OCCO)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 YWSAEKIQJPQSDJ-UHFFFAOYSA-N 0.000 claims description 2
• RPBDPTCBOMUIEM-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)quinazolin-6-yl]guanidine Chemical compound C12=CC(NC(=N)N)=CC=C2N=CN=C1NC1=CC=CC(C#C)=C1 RPBDPTCBOMUIEM-UHFFFAOYSA-N 0.000 claims description 2
• MLFVZJQGCZIVJI-UHFFFAOYSA-N 4-n-(3-ethynylphenyl)quinazoline-4,7-diamine Chemical compound N=1C=NC2=CC(N)=CC=C2C=1NC1=CC=CC(C#C)=C1 MLFVZJQGCZIVJI-UHFFFAOYSA-N 0.000 claims description 2
• KNIMCHSAQRHRKH-UHFFFAOYSA-N 6,7-dibutoxy-n-(3-ethynylphenyl)-2h-quinazolin-1-amine Chemical compound C1=2C=C(OCCCC)C(OCCCC)=CC=2C=NCN1NC1=CC=CC(C#C)=C1 KNIMCHSAQRHRKH-UHFFFAOYSA-N 0.000 claims description 2
• AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims description 2
• VVCIISBATPBTBZ-UHFFFAOYSA-N n-(3-azidophenyl)-6,7-dimethoxyquinazolin-4-amine Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=CC(N=[N+]=[N-])=C1 VVCIISBATPBTBZ-UHFFFAOYSA-N 0.000 claims description 2
• 239000000651 prodrug Substances 0.000 claims description 2
• 229940002612 prodrug Drugs 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 16
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 7
• BLEIGNISAJGLGG-UHFFFAOYSA-N 2-[[1-(3-ethynylanilino)-7-(2-hydroxyethoxy)-2h-quinazolin-6-yl]oxy]ethanol Chemical compound C1=2C=C(OCCO)C(OCCO)=CC=2C=NCN1NC1=CC=CC(C#C)=C1 BLEIGNISAJGLGG-UHFFFAOYSA-N 0.000 claims 2
• AZMJCKIZWVLDEH-UHFFFAOYSA-N 6,7-diethoxy-n-(3-ethynylphenyl)-2h-quinazolin-1-amine Chemical compound C1=2C=C(OCC)C(OCC)=CC=2C=NCN1NC1=CC=CC(C#C)=C1 AZMJCKIZWVLDEH-UHFFFAOYSA-N 0.000 claims 2
• BDGHRVPXZUKXIP-UHFFFAOYSA-N 1-n-(3-ethynylphenyl)-2h-quinazoline-1,6-diamine Chemical compound C1N=CC2=CC(N)=CC=C2N1NC1=CC=CC(C#C)=C1 BDGHRVPXZUKXIP-UHFFFAOYSA-N 0.000 claims 1
• 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims 1
• KOQIAZNBAWFSQM-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-7-(2-methoxyethoxy)quinazolin-6-yl]oxyethanol Chemical compound C=12C=C(OCCO)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 KOQIAZNBAWFSQM-UHFFFAOYSA-N 0.000 claims 1
• DUGLQQONGNNEMW-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]acetamide Chemical compound C=12C=C(CC(N)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 DUGLQQONGNNEMW-UHFFFAOYSA-N 0.000 claims 1
• COYVNRXIBHVWOA-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-7-propan-2-yloxyquinazolin-6-yl]acetamide Chemical compound C=12C=C(CC(N)=O)C(OC(C)C)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 COYVNRXIBHVWOA-UHFFFAOYSA-N 0.000 claims 1
• TYRDQXAAPHCGHJ-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-7-propoxyquinazolin-6-yl]acetamide Chemical compound C=12C=C(CC(N)=O)C(OCCC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 TYRDQXAAPHCGHJ-UHFFFAOYSA-N 0.000 claims 1
• UBUGNWMTGOQPCM-UHFFFAOYSA-N 2-[7-(2-acetyloxyethoxy)-4-(3-ethynylanilino)quinazolin-6-yl]oxyethyl acetate Chemical compound C=12C=C(OCCOC(C)=O)C(OCCOC(=O)C)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 UBUGNWMTGOQPCM-UHFFFAOYSA-N 0.000 claims 1
• OLQYOMSHERWQMA-UHFFFAOYSA-N 2-[7-ethoxy-4-(3-ethynylanilino)quinazolin-6-yl]acetamide Chemical compound C=12C=C(CC(N)=O)C(OCC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 OLQYOMSHERWQMA-UHFFFAOYSA-N 0.000 claims 1
• 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 1
• XCMVOGXJGDEPQM-UHFFFAOYSA-N 3-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]propanamide Chemical compound C=12C=C(CCC(N)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 XCMVOGXJGDEPQM-UHFFFAOYSA-N 0.000 claims 1
• JIKUZGKMYUACPU-UHFFFAOYSA-N 3-[7-ethoxy-4-(3-ethynylanilino)quinazolin-6-yl]propanamide Chemical compound C=12C=C(CCC(N)=O)C(OCC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 JIKUZGKMYUACPU-UHFFFAOYSA-N 0.000 claims 1
• OPZQXOBOVGSGMM-UHFFFAOYSA-N 6,7-bis(2-chloroethoxy)-n-(3-ethynylphenyl)quinazolin-4-amine Chemical compound C=12C=C(OCCCl)C(OCCCl)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 OPZQXOBOVGSGMM-UHFFFAOYSA-N 0.000 claims 1
• FIXQTOIVGLSWPU-UHFFFAOYSA-N 6,7-diethoxy-n-(3-ethynyl-2-methylphenyl)-2h-quinazolin-1-amine Chemical compound C1=2C=C(OCC)C(OCC)=CC=2C=NCN1NC1=CC=CC(C#C)=C1C FIXQTOIVGLSWPU-UHFFFAOYSA-N 0.000 claims 1
• DBLVDARHJKFUSK-UHFFFAOYSA-N 6-(2-chloroethoxy)-n-(3-ethynylphenyl)-7-(2-methoxyethoxy)quinazolin-4-amine Chemical compound C=12C=C(OCCCl)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 DBLVDARHJKFUSK-UHFFFAOYSA-N 0.000 claims 1
• VAGMISGAVFFXMY-UHFFFAOYSA-N 6-(aminomethyl)-n-(3-ethynylphenyl)-7-methoxyquinazolin-4-amine Chemical compound C=12C=C(CN)C(OC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 VAGMISGAVFFXMY-UHFFFAOYSA-N 0.000 claims 1
• BIHHIONDWPZXJC-UHFFFAOYSA-N 7-(2-chloroethoxy)-n-(3-ethynylphenyl)-6-(2-methoxyethoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCCl)C(OCCOC)=CC2=C1NC1=CC=CC(C#C)=C1 BIHHIONDWPZXJC-UHFFFAOYSA-N 0.000 claims 1
• 229920006037 cross link polymer Polymers 0.000 claims 1
• YVEQUSIQTPNUHB-UHFFFAOYSA-N n-(3-ethynyl-2-methylphenyl)-6,7-bis(2-methoxyethoxy)-2h-quinazolin-1-amine Chemical compound C1=2C=C(OCCOC)C(OCCOC)=CC=2C=NCN1NC1=CC=CC(C#C)=C1C YVEQUSIQTPNUHB-UHFFFAOYSA-N 0.000 claims 1
• UEKLAZGZLXRYAO-UHFFFAOYSA-N n-(3-ethynyl-4-fluorophenyl)-6,7-dimethoxyquinazolin-4-amine Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(C#C)=C1 UEKLAZGZLXRYAO-UHFFFAOYSA-N 0.000 claims 1
• YHGQPRLZLURJKG-UHFFFAOYSA-N n-(3-ethynylphenyl)-6,7-dimethoxy-2h-quinazolin-1-amine Chemical compound C1=2C=C(OC)C(OC)=CC=2C=NCN1NC1=CC=CC(C#C)=C1 YHGQPRLZLURJKG-UHFFFAOYSA-N 0.000 claims 1
• OHTXAZFSJVRZLD-UHFFFAOYSA-N n-(3-ethynylphenyl)-6-(2-methoxyethoxy)-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCN3CCN(C)CC3)C(OCCOC)=CC2=C1NC1=CC=CC(C#C)=C1 OHTXAZFSJVRZLD-UHFFFAOYSA-N 0.000 claims 1
• LBAXXGJEHLZEQP-UHFFFAOYSA-N n-(3-ethynylphenyl)-[1,3]dioxolo[4,5-g]quinazolin-8-amine Chemical compound C#CC1=CC=CC(NC=2C3=CC=4OCOC=4C=C3N=CN=2)=C1 LBAXXGJEHLZEQP-UHFFFAOYSA-N 0.000 claims 1
• OVBFNQKSLJYVCB-UHFFFAOYSA-N n-(4-ethynylphenyl)-6,7-dimethoxyquinazolin-4-amine Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=C(C#C)C=C1 OVBFNQKSLJYVCB-UHFFFAOYSA-N 0.000 claims 1
• UWWQPGAHDVXTLK-UHFFFAOYSA-N n-[1-(3-ethynylanilino)-2h-quinazolin-6-yl]methanesulfonamide Chemical compound C1N=CC2=CC(NS(=O)(=O)C)=CC=C2N1NC1=CC=CC(C#C)=C1 UWWQPGAHDVXTLK-UHFFFAOYSA-N 0.000 claims 1
• 230000003463 hyperproliferative effect Effects 0.000 abstract description 8
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
• 239000000047 product Substances 0.000 description 117
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 98
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 77
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 58
• 239000007787 solid Substances 0.000 description 56
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 54
• 239000000203 mixture Substances 0.000 description 53
• 239000011541 reaction mixture Substances 0.000 description 37
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
• 229960004592 isopropanol Drugs 0.000 description 35
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 34
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 31
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
• 206010028980 Neoplasm Diseases 0.000 description 26
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 26
• 239000012267 brine Substances 0.000 description 26
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 26
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
• 238000004128 high performance liquid chromatography Methods 0.000 description 24
• 239000002904 solvent Substances 0.000 description 24
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 24
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
• 238000006243 chemical reaction Methods 0.000 description 22
• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 22
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
• NNKQLUVBPJEUOR-UHFFFAOYSA-N 3-ethynylaniline Chemical compound NC1=CC=CC(C#C)=C1 NNKQLUVBPJEUOR-UHFFFAOYSA-N 0.000 description 20
• 239000000243 solution Substances 0.000 description 20
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
• 229940073584 methylene chloride Drugs 0.000 description 18
• 238000010992 reflux Methods 0.000 description 18
• 239000007832 Na2SO4 Substances 0.000 description 16
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
• 229910052938 sodium sulfate Inorganic materials 0.000 description 16
• 235000011152 sodium sulphate Nutrition 0.000 description 16
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 239000012458 free base Substances 0.000 description 15
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
• 239000002585 base Substances 0.000 description 14
• 235000017557 sodium bicarbonate Nutrition 0.000 description 14
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 13
• 239000003795 chemical substances by application Substances 0.000 description 13
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 12
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 12
• 229920006395 saturated elastomer Polymers 0.000 description 12
• 229940093499 ethyl acetate Drugs 0.000 description 11
• 235000019439 ethyl acetate Nutrition 0.000 description 11
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 11
• 108060006698 EGF receptor Proteins 0.000 description 10
• 102000001301 EGF receptor Human genes 0.000 description 10
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
• 201000011510 cancer Diseases 0.000 description 10
• 229960000583 acetic acid Drugs 0.000 description 9
• 230000000694 effects Effects 0.000 description 9
• 239000000706 filtrate Substances 0.000 description 9
• 238000001914 filtration Methods 0.000 description 9
• 239000012044 organic layer Substances 0.000 description 9
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
• 238000004007 reversed phase HPLC Methods 0.000 description 9
• 239000000741 silica gel Substances 0.000 description 9
• 229910002027 silica gel Inorganic materials 0.000 description 9
• 239000000377 silicon dioxide Substances 0.000 description 9
• 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 8
• 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 8
• 239000002253 acid Substances 0.000 description 8
• 210000004027 cell Anatomy 0.000 description 8
• 239000012043 crude product Substances 0.000 description 8
• 239000000284 extract Substances 0.000 description 8
• 238000003818 flash chromatography Methods 0.000 description 8
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