JP4476624B2 - プラスミノゲンアクチベーターインヒビター１（ｐａｉ−１）のインヒビターとしてのナフチルベンゾフラン誘導体 - Google Patents

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Publication number

JP4476624B2

JP4476624B2 JP2003507076A JP2003507076A JP4476624B2 JP 4476624 B2 JP4476624 B2 JP 4476624B2 JP 2003507076 A JP2003507076 A JP 2003507076A JP 2003507076 A JP2003507076 A JP 2003507076A JP 4476624 B2 JP4476624 B2 JP 4476624B2

Authority

JP

Japan

Prior art keywords

benzofuran

naphthyl

pharmaceutically acceptable

compound according

mmol

Prior art date

2001-06-20

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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• 102000012335 Plasminogen Activator Inhibitor 1 Human genes 0.000 title description 32
• 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 title description 32
• 239000003112 inhibitor Substances 0.000 title description 5
• 150000001875 compounds Chemical class 0.000 claims description 193
• -1 4- (trifluoromethyl) phenyl Chemical group 0.000 claims description 74
• 150000003839 salts Chemical class 0.000 claims description 66
• 125000004432 carbon atom Chemical group C* 0.000 claims description 37
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 25
• 125000000217 alkyl group Chemical group 0.000 claims description 24
• 238000011282 treatment Methods 0.000 claims description 24
• 201000010099 disease Diseases 0.000 claims description 23
• 229910052739 hydrogen Inorganic materials 0.000 claims description 22
• 150000004702 methyl esters Chemical class 0.000 claims description 22
• 239000001257 hydrogen Substances 0.000 claims description 21
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 21
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
• 125000003118 aryl group Chemical group 0.000 claims description 16
• 150000002148 esters Chemical class 0.000 claims description 16
• 229910052736 halogen Inorganic materials 0.000 claims description 15
• 150000002367 halogens Chemical class 0.000 claims description 13
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
• 125000003107 substituted aryl group Chemical group 0.000 claims description 8
• 241000124008 Mammalia Species 0.000 claims description 7
• 208000007536 Thrombosis Diseases 0.000 claims description 7
• QAJLAJGOUHWOEW-UHFFFAOYSA-N 5-[[6-(3-pentyl-1-benzofuran-2-yl)naphthalen-2-yl]oxymethyl]-2h-tetrazole Chemical compound O1C2=CC=CC=C2C(CCCCC)=C1C(C=C1C=C2)=CC=C1C=C2OCC1=NN=NN1 QAJLAJGOUHWOEW-UHFFFAOYSA-N 0.000 claims description 6
• 125000003342 alkenyl group Chemical group 0.000 claims description 6
• 239000003527 fibrinolytic agent Substances 0.000 claims description 6
• 150000003536 tetrazoles Chemical class 0.000 claims description 6
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
• 230000003480 fibrinolytic effect Effects 0.000 claims description 5
• 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 5
• 239000008194 pharmaceutical composition Substances 0.000 claims description 5
• 159000000000 sodium salts Chemical class 0.000 claims description 5
• IXOJJTIEHSBORU-UHFFFAOYSA-N 1-[2-[5-chloro-6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]-1-benzofuran-3-yl]pentan-1-one Chemical compound O1C2=CC=CC=C2C(C(=O)CCCC)=C1C(C=C1C=C2)=CC=C1C(Cl)=C2OCC1=NN=NN1 IXOJJTIEHSBORU-UHFFFAOYSA-N 0.000 claims description 4
• ROHSDCNFIMAFOH-UHFFFAOYSA-N 1-[2-[5-phenyl-6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]-1-benzofuran-3-yl]pentan-1-one Chemical compound O1C2=CC=CC=C2C(C(=O)CCCC)=C1C(C=C1C=C2)=CC=C1C(C=1C=CC=CC=1)=C2OCC1=NN=NN1 ROHSDCNFIMAFOH-UHFFFAOYSA-N 0.000 claims description 4
• BJRCALOQHCTLDY-UHFFFAOYSA-N 2-[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)naphthalen-2-yl]oxy-3-phenylpropanoic acid Chemical compound O1C2=CC=CC=C2C(C(=O)CCCC)=C1C(C=C1C=C2)=CC=C1C(Br)=C2OC(C(O)=O)CC1=CC=CC=C1 BJRCALOQHCTLDY-UHFFFAOYSA-N 0.000 claims description 4
• GSFUDKCDLAJEGV-UHFFFAOYSA-N 2-[1-bromo-6-[3-(2-cyclopentylacetyl)-1-benzofuran-2-yl]naphthalen-2-yl]oxyacetic acid Chemical compound C1=CC2=C(Br)C(OCC(=O)O)=CC=C2C=C1C=1OC2=CC=CC=C2C=1C(=O)CC1CCCC1 GSFUDKCDLAJEGV-UHFFFAOYSA-N 0.000 claims description 4
• XJBAYJHTLTVEAE-UHFFFAOYSA-N 2-[1-bromo-6-[3-(2-cyclopentylethyl)-1-benzofuran-2-yl]naphthalen-2-yl]oxyacetic acid Chemical compound C1=CC2=C(Br)C(OCC(=O)O)=CC=C2C=C1C=1OC2=CC=CC=C2C=1CCC1CCCC1 XJBAYJHTLTVEAE-UHFFFAOYSA-N 0.000 claims description 4
• 239000003814 drug Substances 0.000 claims description 4
• 125000005843 halogen group Chemical group 0.000 claims description 4
• GAYZBHFSLMXJGY-UHFFFAOYSA-N 1-[2-[5-bromo-6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]-5-chloro-1-benzofuran-3-yl]pentan-1-one Chemical compound O1C2=CC=C(Cl)C=C2C(C(=O)CCCC)=C1C(C=C1C=C2)=CC=C1C(Br)=C2OCC1=NN=NN1 GAYZBHFSLMXJGY-UHFFFAOYSA-N 0.000 claims description 3
• GDOVWWPNAFFFFT-UHFFFAOYSA-N 1-[2-[5-methyl-6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]-1-benzofuran-3-yl]pentan-1-one Chemical compound O1C2=CC=CC=C2C(C(=O)CCCC)=C1C(C=C1C=C2)=CC=C1C(C)=C2OCC1=NN=NN1 GDOVWWPNAFFFFT-UHFFFAOYSA-N 0.000 claims description 3
• ZUXXIOLMGTUAPP-UHFFFAOYSA-N 1-[2-[6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]-1-benzofuran-3-yl]pentan-1-one Chemical compound O1C2=CC=CC=C2C(C(=O)CCCC)=C1C(C=C1C=C2)=CC=C1C=C2OCC1=NN=NN1 ZUXXIOLMGTUAPP-UHFFFAOYSA-N 0.000 claims description 3
• SRNBELZVNZWFDY-UHFFFAOYSA-N 1-[5-chloro-2-[6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]-1-benzofuran-3-yl]pentan-1-one Chemical compound O1C2=CC=C(Cl)C=C2C(C(=O)CCCC)=C1C(C=C1C=C2)=CC=C1C=C2OCC1=NN=NN1 SRNBELZVNZWFDY-UHFFFAOYSA-N 0.000 claims description 3
• KKXPVEAUYBUNSF-UHFFFAOYSA-N 2-[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)naphthalen-2-yl]oxyacetic acid Chemical compound BrC1=C(OCC(O)=O)C=CC2=CC(C3=C(C4=CC=CC=C4O3)C(=O)CCCC)=CC=C21 KKXPVEAUYBUNSF-UHFFFAOYSA-N 0.000 claims description 3
• ZBPITDNNHOZZKP-UHFFFAOYSA-N 2-[1-bromo-6-(3-pentyl-1-benzofuran-2-yl)naphthalen-2-yl]oxyacetic acid Chemical compound BrC1=C(OCC(O)=O)C=CC2=CC(C3=C(C4=CC=CC=C4O3)CCCCC)=CC=C21 ZBPITDNNHOZZKP-UHFFFAOYSA-N 0.000 claims description 3
• MTJFCIIDAQCXHQ-UHFFFAOYSA-N 2-[1-bromo-6-[3-(3,3-dimethylbutanoyl)-1-benzofuran-2-yl]naphthalen-2-yl]oxyacetic acid Chemical compound BrC1=C(OCC(O)=O)C=CC2=CC(C3=C(C4=CC=CC=C4O3)C(=O)CC(C)(C)C)=CC=C21 MTJFCIIDAQCXHQ-UHFFFAOYSA-N 0.000 claims description 3
• YBCYPFGPKUKYKH-UHFFFAOYSA-N 2-[1-chloro-6-(3-pentanoyl-1-benzofuran-2-yl)naphthalen-2-yl]oxyacetic acid Chemical compound ClC1=C(OCC(O)=O)C=CC2=CC(C3=C(C4=CC=CC=C4O3)C(=O)CCCC)=CC=C21 YBCYPFGPKUKYKH-UHFFFAOYSA-N 0.000 claims description 3
• LSFUNZSHLQEMQY-UHFFFAOYSA-N 2-[1-methyl-6-(3-pentanoyl-1-benzofuran-2-yl)naphthalen-2-yl]oxy-3-phenylpropanoic acid Chemical compound O1C2=CC=CC=C2C(C(=O)CCCC)=C1C(C=C1C=C2)=CC=C1C(C)=C2OC(C(O)=O)CC1=CC=CC=C1 LSFUNZSHLQEMQY-UHFFFAOYSA-N 0.000 claims description 3
• KMYZMZRQCOUXCL-UHFFFAOYSA-N 2-[1-phenyl-6-(3-phenyl-1-benzofuran-2-yl)naphthalen-2-yl]oxyacetic acid Chemical compound OC(=O)COC1=CC=C2C=C(C3=C(C4=CC=CC=C4O3)C=3C=CC=CC=3)C=CC2=C1C1=CC=CC=C1 KMYZMZRQCOUXCL-UHFFFAOYSA-N 0.000 claims description 3
• ZIGSNVGQWSWNHV-UHFFFAOYSA-N 2-[4-bromo-6-[3-(3-methylbutanoyl)-1-benzofuran-2-yl]naphthalen-2-yl]oxyacetic acid Chemical compound C1=C(OCC(O)=O)C=C(Br)C2=CC(C3=C(C4=CC=CC=C4O3)C(=O)CC(C)C)=CC=C21 ZIGSNVGQWSWNHV-UHFFFAOYSA-N 0.000 claims description 3
• SQWABVRSODAVEX-UHFFFAOYSA-N 2-[6-(3-benzoyl-1-benzofuran-2-yl)naphthalen-2-yl]oxyacetic acid Chemical compound C1=CC2=CC(OCC(=O)O)=CC=C2C=C1C=1OC2=CC=CC=C2C=1C(=O)C1=CC=CC=C1 SQWABVRSODAVEX-UHFFFAOYSA-N 0.000 claims description 3
• RHBUDCNKVWPXAA-UHFFFAOYSA-N 2-[6-(3-pentanoyl-1-benzofuran-2-yl)-1-[4-(trifluoromethyl)phenyl]naphthalen-2-yl]oxyacetic acid Chemical compound O1C2=CC=CC=C2C(C(=O)CCCC)=C1C(C=C1C=CC=2OCC(O)=O)=CC=C1C=2C1=CC=C(C(F)(F)F)C=C1 RHBUDCNKVWPXAA-UHFFFAOYSA-N 0.000 claims description 3
• ZQFRYDYKEOYUNS-UHFFFAOYSA-N 2-[6-(3-pentanoyl-1-benzofuran-2-yl)naphthalen-2-yl]oxyacetic acid Chemical compound C1=C(OCC(O)=O)C=CC2=CC(C3=C(C4=CC=CC=C4O3)C(=O)CCCC)=CC=C21 ZQFRYDYKEOYUNS-UHFFFAOYSA-N 0.000 claims description 3
• RCLVYHIXCSLQDS-UHFFFAOYSA-N 2-[6-(3-pentyl-1-benzofuran-2-yl)naphthalen-2-yl]oxyacetic acid Chemical compound C1=C(OCC(O)=O)C=CC2=CC(C3=C(C4=CC=CC=C4O3)CCCCC)=CC=C21 RCLVYHIXCSLQDS-UHFFFAOYSA-N 0.000 claims description 3
• CJSQHIFLZRAIEE-UHFFFAOYSA-N 2-[6-(5-chloro-3-pentanoyl-1-benzofuran-2-yl)naphthalen-2-yl]oxyacetic acid Chemical compound C1=C(OCC(O)=O)C=CC2=CC(C3=C(C4=CC(Cl)=CC=C4O3)C(=O)CCCC)=CC=C21 CJSQHIFLZRAIEE-UHFFFAOYSA-N 0.000 claims description 3
• QPYMFRMUFAADMV-UHFFFAOYSA-N 2-[6-[3-(2-cyclopentylacetyl)-1-benzofuran-2-yl]naphthalen-2-yl]oxyacetic acid Chemical compound C1=CC2=CC(OCC(=O)O)=CC=C2C=C1C=1OC2=CC=CC=C2C=1C(=O)CC1CCCC1 QPYMFRMUFAADMV-UHFFFAOYSA-N 0.000 claims description 3
• LAGOGXVTWHRRQZ-UHFFFAOYSA-N 2-[6-[3-(3,3-dimethylbutanoyl)-1-benzofuran-2-yl]naphthalen-2-yl]oxyacetic acid Chemical compound C1=C(OCC(O)=O)C=CC2=CC(C3=C(C4=CC=CC=C4O3)C(=O)CC(C)(C)C)=CC=C21 LAGOGXVTWHRRQZ-UHFFFAOYSA-N 0.000 claims description 3
• HDYRFLFOMDPGQT-UHFFFAOYSA-N 5-[[1-methyl-6-(3-pentyl-1-benzofuran-2-yl)naphthalen-2-yl]oxymethyl]-2h-tetrazole Chemical compound O1C2=CC=CC=C2C(CCCCC)=C1C(C=C1C=C2)=CC=C1C(C)=C2OCC1=NN=NN1 HDYRFLFOMDPGQT-UHFFFAOYSA-N 0.000 claims description 3
• FDEMZMDJNCQRGX-UHFFFAOYSA-N [2-[5-bromo-6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]-1-benzofuran-3-yl]-phenylmethanone Chemical compound C1=CC2=CC(C3=C(C4=CC=CC=C4O3)C(=O)C=3C=CC=CC=3)=CC=C2C(Br)=C1OCC1=NN=NN1 FDEMZMDJNCQRGX-UHFFFAOYSA-N 0.000 claims description 3
• 125000005024 alkenyl aryl group Chemical group 0.000 claims description 3
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 3
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• 238000002360 preparation method Methods 0.000 claims description 3
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
• UEWNJOGCIKIMKV-UHFFFAOYSA-N 1-[2-[5-bromo-6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]-1-benzofuran-3-yl]pentan-1-one Chemical compound O1C2=CC=CC=C2C(C(=O)CCCC)=C1C(C=C1C=C2)=CC=C1C(Br)=C2OCC1=NN=NN1 UEWNJOGCIKIMKV-UHFFFAOYSA-N 0.000 claims description 2
• YUDAZDZELHZKAG-UHFFFAOYSA-N 2-[1-bromo-6-(5-chloro-3-pentanoyl-1-benzofuran-2-yl)naphthalen-2-yl]oxyacetic acid Chemical compound BrC1=C(OCC(O)=O)C=CC2=CC(C3=C(C4=CC(Cl)=CC=C4O3)C(=O)CCCC)=CC=C21 YUDAZDZELHZKAG-UHFFFAOYSA-N 0.000 claims description 2
• PVBZXRNDBMTFCC-UHFFFAOYSA-N 2-[1-methyl-6-(3-pentanoyl-1-benzofuran-2-yl)naphthalen-2-yl]oxyacetic acid Chemical compound CC1=C(OCC(O)=O)C=CC2=CC(C3=C(C4=CC=CC=C4O3)C(=O)CCCC)=CC=C21 PVBZXRNDBMTFCC-UHFFFAOYSA-N 0.000 claims description 2
• FDQBGIKIDBWUMY-UHFFFAOYSA-N 2-[6-(3-pentanoyl-1-benzofuran-2-yl)-1-phenylnaphthalen-2-yl]oxyacetic acid Chemical compound O1C2=CC=CC=C2C(C(=O)CCCC)=C1C(C=C1C=CC=2OCC(O)=O)=CC=C1C=2C1=CC=CC=C1 FDQBGIKIDBWUMY-UHFFFAOYSA-N 0.000 claims description 2
• DMPFULRNBDUSCQ-UHFFFAOYSA-N 2-[6-(3-pentanoyl-1-benzofuran-2-yl)naphthalen-2-yl]oxy-3-phenylpropanoic acid Chemical compound O1C2=CC=CC=C2C(C(=O)CCCC)=C1C(C=C1C=C2)=CC=C1C=C2OC(C(O)=O)CC1=CC=CC=C1 DMPFULRNBDUSCQ-UHFFFAOYSA-N 0.000 claims description 2
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
• 125000004494 ethyl ester group Chemical group 0.000 claims 24
• ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims 2
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims 1
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 233
• 238000000034 method Methods 0.000 description 207
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 169
• 239000007787 solid Substances 0.000 description 107
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 105
• 230000008569 process Effects 0.000 description 83
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 75
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 75
• 238000001819 mass spectrum Methods 0.000 description 73
• 239000000243 solution Substances 0.000 description 72
• 238000000921 elemental analysis Methods 0.000 description 62
• 238000005259 measurement Methods 0.000 description 62
• 235000019439 ethyl acetate Nutrition 0.000 description 59
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 57
• 239000000203 mixture Substances 0.000 description 53
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 48
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
• 238000003818 flash chromatography Methods 0.000 description 43
• 238000000746 purification Methods 0.000 description 41
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 40
• 239000003480 eluent Substances 0.000 description 38
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 30
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
• 239000002904 solvent Substances 0.000 description 27
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 26
• 239000011541 reaction mixture Substances 0.000 description 24
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 22
• 229910000024 caesium carbonate Inorganic materials 0.000 description 22
• 239000012267 brine Substances 0.000 description 21
• 239000012071 phase Substances 0.000 description 21
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 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
• 238000004128 high performance liquid chromatography Methods 0.000 description 19
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
• 125000001072 heteroaryl group Chemical group 0.000 description 18
• 244000166102 Eucalyptus leucoxylon Species 0.000 description 17
• 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 17
• ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 16
• NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 16
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
• 235000019270 ammonium chloride Nutrition 0.000 description 15
• 238000006243 chemical reaction Methods 0.000 description 15
• 238000002425 crystallisation Methods 0.000 description 15
• 230000008025 crystallization Effects 0.000 description 15
• 239000012074 organic phase Substances 0.000 description 14
• REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 13
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 13
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 13
• FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 13
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 13
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
• 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 12
• 238000001035 drying Methods 0.000 description 12
• PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 12
• 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 11
• 229960000583 acetic acid Drugs 0.000 description 11
• 230000005764 inhibitory process Effects 0.000 description 11
• 239000000047 product Substances 0.000 description 11
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