JP4471404B2 - Ｖｅｇｆインヒビターとしてのキナゾリン誘導体 - Google Patents

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Publication number

JP4471404B2

JP4471404B2 JP52907897A JP52907897A JP4471404B2 JP 4471404 B2 JP4471404 B2 JP 4471404B2 JP 52907897 A JP52907897 A JP 52907897A JP 52907897 A JP52907897 A JP 52907897A JP 4471404 B2 JP4471404 B2 JP 4471404B2

Authority

JP

Japan

Prior art keywords

alkyl

hydroxy

quinazoline

fluoro

methoxy

Prior art date

1996-02-13

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired - Lifetime

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• 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title claims abstract description 9
• 239000002525 vasculotropin inhibitor Substances 0.000 title 1
• -1 trifluorometlyl Chemical group 0.000 claims abstract description 199
• 150000001875 compounds Chemical class 0.000 claims abstract description 177
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 100
• 150000003839 salts Chemical class 0.000 claims abstract description 85
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 80
• 239000001257 hydrogen Substances 0.000 claims abstract description 80
• 125000005843 halogen group Chemical group 0.000 claims abstract description 50
• 238000000034 method Methods 0.000 claims abstract description 49
• 150000002431 hydrogen Chemical group 0.000 claims abstract description 40
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 33
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 25
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 23
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 18
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 13
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 11
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 9
• 125000003342 alkenyl group Chemical group 0.000 claims abstract description 9
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 9
• 125000000304 alkynyl group Chemical group 0.000 claims abstract description 8
• 238000002360 preparation method Methods 0.000 claims abstract description 6
• 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims abstract description 3
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 269
• 125000001424 substituent group Chemical group 0.000 claims description 47
• 125000003545 alkoxy group Chemical group 0.000 claims description 44
• 238000006243 chemical reaction Methods 0.000 claims description 32
• 125000004043 oxo group Chemical group O=* 0.000 claims description 25
• 150000003246 quinazolines Chemical class 0.000 claims description 25
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
• 229910052757 nitrogen Inorganic materials 0.000 claims description 14
• 229910052799 carbon Inorganic materials 0.000 claims description 12
• 125000003386 piperidinyl group Chemical group 0.000 claims description 12
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 12
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 11
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
• 239000002253 acid Substances 0.000 claims description 10
• 125000004432 carbon atom Chemical group C* 0.000 claims description 10
• 239000003814 drug Substances 0.000 claims description 10
• 125000001153 fluoro group Chemical group F* 0.000 claims description 10
• 229910052717 sulfur Inorganic materials 0.000 claims description 10
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 9
• 125000004848 alkoxyethyl group Chemical group 0.000 claims description 9
• 229910052760 oxygen Inorganic materials 0.000 claims description 9
• 125000003277 amino group Chemical group 0.000 claims description 7
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
• LKTZZFOJGFXTKH-UHFFFAOYSA-N 4-fluoro-5-[[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino]-2-methylphenol Chemical compound C=12C=C(OC)C(OCCOC)=CC2=NC=NC=1NC1=CC(O)=C(C)C=C1F LKTZZFOJGFXTKH-UHFFFAOYSA-N 0.000 claims description 6
• FRYNFLZWVRHSQU-UHFFFAOYSA-N 4-fluoro-5-[[6-methoxy-7-(2-methylsulfanylethoxy)quinazolin-4-yl]amino]-2-methylphenol Chemical compound N1=CN=C2C=C(OCCSC)C(OC)=CC2=C1NC1=CC(O)=C(C)C=C1F FRYNFLZWVRHSQU-UHFFFAOYSA-N 0.000 claims description 6
• POLXJKGYTJUZNO-UHFFFAOYSA-N 4-fluoro-5-[[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino]-2-methylphenol Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1NC1=CC(O)=C(C)C=C1F POLXJKGYTJUZNO-UHFFFAOYSA-N 0.000 claims description 6
• XHXOJKOXEKXDSQ-UHFFFAOYSA-N 5-[(6,7-dimethoxyquinazolin-4-yl)amino]-4-fluoro-2-methylphenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC(O)=C(C)C=C1F XHXOJKOXEKXDSQ-UHFFFAOYSA-N 0.000 claims description 6
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
• WDTZDAYILMUQLA-UHFFFAOYSA-N n-(4-bromo-2,6-difluorophenyl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1NC1=C(F)C=C(Br)C=C1F WDTZDAYILMUQLA-UHFFFAOYSA-N 0.000 claims description 6
• NWEVEWXSLYZWJA-UHFFFAOYSA-N n-[4-(2-fluoro-5-hydroxy-4-methylanilino)quinazolin-7-yl]-2-methoxyacetamide Chemical compound N=1C=NC2=CC(NC(=O)COC)=CC=C2C=1NC1=CC(O)=C(C)C=C1F NWEVEWXSLYZWJA-UHFFFAOYSA-N 0.000 claims description 6
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
• YMMYOYOZKAMGGJ-UHFFFAOYSA-N 2-[4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazolin-7-yl]oxyethyl acetate Chemical compound N1=CN=C2C=C(OCCOC(C)=O)C(OC)=CC2=C1NC1=CC(O)=C(C)C=C1F YMMYOYOZKAMGGJ-UHFFFAOYSA-N 0.000 claims description 5
• KJHZBMRRZLEZEY-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-(2-pyrrolidin-1-ylethoxy)quinazolin-4-yl]amino]phenol Chemical compound N1=CN=C2C=C(OCCN3CCCC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F KJHZBMRRZLEZEY-UHFFFAOYSA-N 0.000 claims description 5
• MLPJQRZMIKCLAE-UHFFFAOYSA-N 2-chloro-5-[(6,7-dimethoxyquinazolin-4-yl)amino]-4-fluorophenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC(O)=C(Cl)C=C1F MLPJQRZMIKCLAE-UHFFFAOYSA-N 0.000 claims description 5
• 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 5
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 5
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
• JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 5
• CLSDZDFPIGPTBE-UHFFFAOYSA-N 2,4-difluoro-5-[[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino]phenol Chemical compound C=12C=C(OC)C(OCCOC)=CC2=NC=NC=1NC1=CC(O)=C(F)C=C1F CLSDZDFPIGPTBE-UHFFFAOYSA-N 0.000 claims description 4
• SPBPKQJZKCGMNA-UHFFFAOYSA-N 2-bromo-5-[(6,7-dimethoxyquinazolin-4-yl)amino]-4-fluorophenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC(O)=C(Br)C=C1F SPBPKQJZKCGMNA-UHFFFAOYSA-N 0.000 claims description 4
• UCSSQROSBFPVKH-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino]phenol Chemical compound C=12C=C(OC)C(OCCOC)=CC2=NC=NC=1NC1=CC(O)=C(Cl)C=C1F UCSSQROSBFPVKH-UHFFFAOYSA-N 0.000 claims description 4
• PKPDNFNJEGKHGS-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinazolin-4-yl]amino]phenol Chemical compound N1=CN=C2C=C(OCCN3CCN(C)CC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F PKPDNFNJEGKHGS-UHFFFAOYSA-N 0.000 claims description 4
• WKHGVOGOGAFWKY-UHFFFAOYSA-N 2-chloro-5-[[7-(2-cyclopentyloxyethoxy)-6-methoxyquinazolin-4-yl]amino]-4-fluorophenol Chemical compound N1=CN=C2C=C(OCCOC3CCCC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F WKHGVOGOGAFWKY-UHFFFAOYSA-N 0.000 claims description 4
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 4
• QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 4
• SOIKJFMWXGNLOF-UHFFFAOYSA-N 4-fluoro-5-[[7-(2-hydroxyethoxy)-6-methoxyquinazolin-4-yl]amino]-2-methylphenol Chemical compound N1=CN=C2C=C(OCCO)C(OC)=CC2=C1NC1=CC(O)=C(C)C=C1F SOIKJFMWXGNLOF-UHFFFAOYSA-N 0.000 claims description 4
• KXAGMEUPTWULJN-UHFFFAOYSA-N 4-fluoro-5-[[7-(2-methoxyethylamino)quinazolin-4-yl]amino]-2-methylphenol Chemical compound N=1C=NC2=CC(NCCOC)=CC=C2C=1NC1=CC(O)=C(C)C=C1F KXAGMEUPTWULJN-UHFFFAOYSA-N 0.000 claims description 4
• BGPMVNFAGBHYEC-UHFFFAOYSA-N 5-(6,7-dimethoxyquinazolin-4-yl)oxy-2-methylphenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1OC1=CC=C(C)C(O)=C1 BGPMVNFAGBHYEC-UHFFFAOYSA-N 0.000 claims description 4
• FHZCSNTVCRCIKT-UHFFFAOYSA-N 5-[(6,7-dimethoxyquinazolin-4-yl)amino]-2,4-difluorophenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC(O)=C(F)C=C1F FHZCSNTVCRCIKT-UHFFFAOYSA-N 0.000 claims description 4
• 125000004193 piperazinyl group Chemical group 0.000 claims description 4
• 230000001603 reducing effect Effects 0.000 claims description 4
• UEUPJXFRYBVXCU-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-(2-morpholin-4-ylethoxy)quinazolin-4-yl]amino]phenol Chemical compound N1=CN=C2C=C(OCCN3CCOCC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F UEUPJXFRYBVXCU-UHFFFAOYSA-N 0.000 claims description 3
• PDFCFEZKAPFQOW-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-(2-thiomorpholin-4-ylethoxy)quinazolin-4-yl]amino]phenol Chemical compound N1=CN=C2C=C(OCCN3CCSCC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F PDFCFEZKAPFQOW-UHFFFAOYSA-N 0.000 claims description 3
• MVYGSFKMASDTCN-UHFFFAOYSA-N 4-fluoro-5-[[6-methoxy-7-(2-methylsulfinylethoxy)quinazolin-4-yl]amino]-2-methylphenol Chemical compound N1=CN=C2C=C(OCCS(C)=O)C(OC)=CC2=C1NC1=CC(O)=C(C)C=C1F MVYGSFKMASDTCN-UHFFFAOYSA-N 0.000 claims description 3
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 3
• 125000001246 bromo group Chemical group Br* 0.000 claims description 3
• 239000003795 chemical substances by application Substances 0.000 claims description 3
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
• VJINORGYVPPLAU-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-(2-piperidin-1-ylethoxy)quinazolin-4-yl]amino]phenol Chemical compound N1=CN=C2C=C(OCCN3CCCCC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F VJINORGYVPPLAU-UHFFFAOYSA-N 0.000 claims description 2
• ICSJRTHEPBTIHO-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino]phenol Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F ICSJRTHEPBTIHO-UHFFFAOYSA-N 0.000 claims description 2
• MQBJLYQZTQLXJP-UHFFFAOYSA-N 4-fluoro-5-[[7-(2-methoxyethoxy)quinazolin-4-yl]amino]-2-methylphenol Chemical compound N=1C=NC2=CC(OCCOC)=CC=C2C=1NC1=CC(O)=C(C)C=C1F MQBJLYQZTQLXJP-UHFFFAOYSA-N 0.000 claims description 2
• 125000004423 acyloxy group Chemical group 0.000 claims description 2
• 125000003282 alkyl amino group Chemical group 0.000 claims description 2
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
• OHUQJWOIRKREPF-UHFFFAOYSA-N n-(4-bromo-2,6-difluorophenyl)-6,7-dimethoxyquinazolin-4-amine Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=C(F)C=C(Br)C=C1F OHUQJWOIRKREPF-UHFFFAOYSA-N 0.000 claims description 2
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims 10
• 125000004103 aminoalkyl group Chemical group 0.000 claims 3
• 125000003709 fluoroalkyl group Chemical group 0.000 claims 3
• XDUSWBSGDKRQAF-UHFFFAOYSA-N 4-(3-chlorophenoxy)-6,7-dimethoxyquinazoline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1OC1=CC=CC(Cl)=C1 XDUSWBSGDKRQAF-UHFFFAOYSA-N 0.000 claims 1
• DLSREUWBAOWMKZ-UHFFFAOYSA-N 4-(3-chlorophenyl)sulfanyl-6,7-dimethoxyquinazoline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1SC1=CC=CC(Cl)=C1 DLSREUWBAOWMKZ-UHFFFAOYSA-N 0.000 claims 1
• VFCGGDJQUYSDNZ-UHFFFAOYSA-N 4-(3-chlorophenyl)sulfanyl-6,7-dimethylquinazoline Chemical class C=12C=C(C)C(C)=CC2=NC=NC=1SC1=CC=CC(Cl)=C1 VFCGGDJQUYSDNZ-UHFFFAOYSA-N 0.000 claims 1
• 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 1
• IKLSIDTUVXSHJB-UHFFFAOYSA-N 6,7-dimethoxy-4-(3,4,5-trimethoxyphenoxy)quinazoline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1OC1=CC(OC)=C(OC)C(OC)=C1 IKLSIDTUVXSHJB-UHFFFAOYSA-N 0.000 claims 1
• FGMVWDJVELFKJI-UHFFFAOYSA-N 6,7-dimethoxy-4-(3-methoxyphenyl)sulfanylquinazoline Chemical compound COC1=CC=CC(SC=2C3=CC(OC)=C(OC)C=C3N=CN=2)=C1 FGMVWDJVELFKJI-UHFFFAOYSA-N 0.000 claims 1
• RNCVPFCGSMNPPO-UHFFFAOYSA-N 6,7-dimethoxy-n-(3,4,5-trimethoxyphenyl)quinazolin-4-amine Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC(OC)=C(OC)C(OC)=C1 RNCVPFCGSMNPPO-UHFFFAOYSA-N 0.000 claims 1
• 239000006187 pill Substances 0.000 claims 1
• 230000008569 process Effects 0.000 abstract description 32
• 230000000694 effects Effects 0.000 abstract description 27
• 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 abstract description 19
• 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 abstract description 19
• 238000011282 treatment Methods 0.000 abstract description 14
• 206010028980 Neoplasm Diseases 0.000 abstract description 10
• 229920006395 saturated elastomer Polymers 0.000 abstract description 7
• 201000011510 cancer Diseases 0.000 abstract description 6
• 201000010099 disease Diseases 0.000 abstract description 6
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
• 239000008194 pharmaceutical composition Substances 0.000 abstract description 4
• 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 4
• 239000004480 active ingredient Substances 0.000 abstract description 3
• 125000005647 linker group Chemical group 0.000 abstract description 2
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 2
• 125000000547 substituted alkyl group Chemical group 0.000 abstract 1
• 239000000203 mixture Substances 0.000 description 188
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 183
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 144
• 238000001704 evaporation Methods 0.000 description 118
• 230000008020 evaporation Effects 0.000 description 118
• 238000001914 filtration Methods 0.000 description 94
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 92
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 89
• 239000007787 solid Substances 0.000 description 83
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 79
• 239000000243 solution Substances 0.000 description 78
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 76
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 74
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 72
• 239000002904 solvent Substances 0.000 description 72
• 239000007858 starting material Substances 0.000 description 62
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 54
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
• 238000010992 reflux Methods 0.000 description 50
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 46
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
• 239000000047 product Substances 0.000 description 34
• 125000004356 hydroxy functional group Chemical group O* 0.000 description 31
• 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 31
• 238000004440 column chromatography Methods 0.000 description 29
• 239000011541 reaction mixture Substances 0.000 description 27
• 239000003039 volatile agent Substances 0.000 description 26
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 23
• 239000012267 brine Substances 0.000 description 23
• 235000017557 sodium bicarbonate Nutrition 0.000 description 23
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 23
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
• 239000000284 extract Substances 0.000 description 22
• 239000002244 precipitate Substances 0.000 description 22
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
• 239000000706 filtrate Substances 0.000 description 21
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
• 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 18
• 239000003054 catalyst Substances 0.000 description 18
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
• 239000012265 solid product Substances 0.000 description 17
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 16
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 16
• 239000012074 organic phase Substances 0.000 description 16
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
• 239000000725 suspension Substances 0.000 description 14
• 238000012360 testing method Methods 0.000 description 13
• 230000008728 vascular permeability Effects 0.000 description 13
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
• ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 12
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
• 239000002585 base Substances 0.000 description 12
• 238000003556 assay Methods 0.000 description 11
• 210000004027 cell Anatomy 0.000 description 11
• 239000003701 inert diluent Substances 0.000 description 11
• 239000012442 inert solvent Substances 0.000 description 11
• 239000002198 insoluble material Substances 0.000 description 11
• 238000005191 phase separation Methods 0.000 description 11
• 239000005909 Kieselgur Substances 0.000 description 10
• 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 10
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
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