EA037067B1 - Селективные ингибиторы jak1 - Google Patents

Info

Publication number

EA037067B1

EA037067B1 EA201991700A EA201991700A EA037067B1 EA 037067 B1 EA037067 B1 EA 037067B1 EA 201991700 A EA201991700 A EA 201991700A EA 201991700 A EA201991700 A EA 201991700A EA 037067 B1 EA037067 B1 EA 037067B1

Authority

EA

Eurasian Patent Office

Prior art keywords

fluoro

methylsulfonyl

phenyl

indol

amino

Prior art date

2017-01-17

Links

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• 229940124639 Selective inhibitor Drugs 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 184
• 150000003839 salts Chemical class 0.000 claims abstract description 66
• 238000000034 method Methods 0.000 claims abstract description 41
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
• -1 3- (2 - ((2-fluoro-3- (methylsulfonyl) phenyl) amino) -5-methylpyrimidin-4-yl) -1H-indole -7-yl Chemical group 0.000 claims description 298
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 67
• 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 claims description 62
• 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 claims description 62
• QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 31
• DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 30
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 26
• 208000035475 disorder Diseases 0.000 claims description 25
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 25
• 238000011282 treatment Methods 0.000 claims description 24
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
• 229910052739 hydrogen Inorganic materials 0.000 claims description 19
• 239000001257 hydrogen Substances 0.000 claims description 17
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 15
• 229910052731 fluorine Inorganic materials 0.000 claims description 13
• 208000004631 alopecia areata Diseases 0.000 claims description 12
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
• 239000011737 fluorine Substances 0.000 claims description 11
• 239000000460 chlorine Substances 0.000 claims description 10
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
• 239000003085 diluting agent Substances 0.000 claims description 9
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
• 208000006673 asthma Diseases 0.000 claims description 8
• 229910052801 chlorine Inorganic materials 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 8
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 7
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
• 125000001153 fluoro group Chemical group F* 0.000 claims description 7
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 7
• 201000006417 multiple sclerosis Diseases 0.000 claims description 7
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
• 206010009900 Colitis ulcerative Diseases 0.000 claims description 6
• 208000011231 Crohn disease Diseases 0.000 claims description 6
• 206010012438 Dermatitis atopic Diseases 0.000 claims description 6
• 201000004681 Psoriasis Diseases 0.000 claims description 6
• 208000024799 Thyroid disease Diseases 0.000 claims description 6
• 201000006704 Ulcerative Colitis Diseases 0.000 claims description 6
• 201000008937 atopic dermatitis Diseases 0.000 claims description 6
• 230000001363 autoimmune Effects 0.000 claims description 6
• 150000002431 hydrogen Chemical class 0.000 claims description 6
• 206010025135 lupus erythematosus Diseases 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• GIABLFVDPXIEKA-UHFFFAOYSA-N CCCC(=O)NN1CCCN(CC1)C Chemical compound CCCC(=O)NN1CCCN(CC1)C GIABLFVDPXIEKA-UHFFFAOYSA-N 0.000 claims description 4
• 239000010802 sludge Substances 0.000 claims description 4
• HCRQGSALPJKLLR-YADARESESA-N (2R)-2-[(2S)-2,4-dimethylpiperazin-1-yl]-N-[3-[2-(2-fluoro-3-methylsulfonylanilino)-5-methylpyrimidin-4-yl]-1H-indol-7-yl]butanamide Chemical compound C[C@@H]1N(CCN(C1)C)[C@@H](C(=O)NC=1C=CC=C2C(=CNC=12)C1=NC(=NC=C1C)NC1=C(C(=CC=C1)S(=O)(=O)C)F)CC HCRQGSALPJKLLR-YADARESESA-N 0.000 claims description 3
• IVRBIACRKQZTJW-HSZRJFAPSA-N (2R)-N-[3-[2-(2-fluoro-3-methylsulfonylanilino)-5-methylpyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)butanamide Chemical compound FC1=C(C=CC=C1S(=O)(=O)C)NC1=NC=C(C(=N1)C1=CNC2=C(C=CC=C12)NC([C@@H](CC)N1CCN(CC1)C)=O)C IVRBIACRKQZTJW-HSZRJFAPSA-N 0.000 claims description 3
• FWRLZLZAKAACSW-ULQDDVLXSA-N (2S)-2-[(3S,5S)-3,5-dimethylpiperazin-1-yl]-N-[3-[5-fluoro-2-(2-fluoro-3-methylsulfonylanilino)pyrimidin-4-yl]-1H-indol-7-yl]propanamide Chemical compound C[C@H]1CN(C[C@@H](N1)C)[C@H](C(=O)NC=1C=CC=C2C(=CNC=12)C1=NC(=NC=C1F)NC1=C(C(=CC=C1)S(=O)(=O)C)F)C FWRLZLZAKAACSW-ULQDDVLXSA-N 0.000 claims description 3
• WPNLVUFQGUADSS-UHFFFAOYSA-N N-(4-methyl-1,4-diazepan-1-yl)propanamide Chemical compound CCC(=O)NN1CCCN(C)CC1 WPNLVUFQGUADSS-UHFFFAOYSA-N 0.000 claims description 3
• QLSDFTJXPRAZBZ-SFHVURJKSA-N (2S)-N-[3-[2-(2-fluoro-3-methylsulfonylanilino)-5-methylpyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propanamide Chemical compound FC1=C(C=CC=C1S(=O)(=O)C)NC1=NC=C(C(=N1)C1=CNC2=C(C=CC=C12)NC([C@H](C)N1CCN(CC1)C)=O)C QLSDFTJXPRAZBZ-SFHVURJKSA-N 0.000 claims description 2
• KZBWLTMGNRKWRE-DEOSSOPVSA-N (2S)-N-[3-[2-(2-fluoro-3-methylsulfonylanilino)-5-methylpyrimidin-4-yl]-1H-indol-7-yl]-3-methoxy-2-(4-methyl-1,4-diazepan-1-yl)propanamide Chemical compound COC[C@H](N1CCCN(C)CC1)C(=O)NC1=C2NC=C(C2=CC=C1)C1=C(C)C=NC(NC2=C(F)C(=CC=C2)S(C)(=O)=O)=N1 KZBWLTMGNRKWRE-DEOSSOPVSA-N 0.000 claims description 2
• RRLNDAGZFQOBBH-QHCPKHFHSA-N (2S)-N-[3-[2-(2-fluoro-3-methylsulfonylanilino)-5-methylpyrimidin-4-yl]-1H-indol-7-yl]-3-methoxy-2-(4-methylpiperazin-1-yl)propanamide Chemical compound FC1=C(C=CC=C1S(=O)(=O)C)NC1=NC=C(C(=N1)C1=CNC2=C(C=CC=C12)NC([C@H](COC)N1CCN(CC1)C)=O)C RRLNDAGZFQOBBH-QHCPKHFHSA-N 0.000 claims description 2
• 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 description 2
• TYOPPAUWUDNREA-UHFFFAOYSA-N n-piperazin-1-ylpropanamide Chemical compound CCC(=O)NN1CCNCC1 TYOPPAUWUDNREA-UHFFFAOYSA-N 0.000 claims 2
• MAZZDWBGKGDHRC-NTKDMRAZSA-N (2R)-2-[(2R)-2,4-dimethylpiperazin-1-yl]-N-[3-[2-(2-fluoro-3-methylsulfonylanilino)-5-methylpyrimidin-4-yl]-1H-indol-7-yl]-3-methoxypropanamide Chemical compound COC[C@@H](N1CCN(C)C[C@H]1C)C(=O)Nc1cccc2c(c[nH]c12)-c1nc(Nc2cccc(c2F)S(C)(=O)=O)ncc1C MAZZDWBGKGDHRC-NTKDMRAZSA-N 0.000 claims 1
• SOVJEVPWSAQNKB-KHCICDEESA-N (2R)-2-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-N-[3-[2-(2-fluoro-3-methylsulfonylanilino)-5-methylpyrimidin-4-yl]-1H-indol-7-yl]-3-methoxypropanamide Chemical compound C[C@@H]1CN(C[C@H](N1)C)[C@@H](C(=O)NC=1C=CC=C2C(=CNC=12)C1=NC(=NC=C1C)NC1=C(C(=CC=C1)S(=O)(=O)C)F)COC SOVJEVPWSAQNKB-KHCICDEESA-N 0.000 claims 1
• ANTDXMDPUXIDNV-SEPYTNNBSA-N (2R)-2-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-N-[3-[5-fluoro-2-(2-fluoro-3-methylsulfonylanilino)pyrimidin-4-yl]-1H-indol-7-yl]-3-methoxypropanamide Chemical compound COC[C@@H](N1C[C@@H](C)N[C@H](C)C1)C(=O)Nc1cccc2c(c[nH]c12)-c1nc(Nc2cccc(c2F)S(C)(=O)=O)ncc1F ANTDXMDPUXIDNV-SEPYTNNBSA-N 0.000 claims 1
• OEFHVDNQXRLETJ-XMMPIXPASA-N (2R)-3-ethoxy-N-[3-[2-(2-fluoro-3-methylsulfonylanilino)-5-methylpyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propanamide Chemical compound C(C)OC[C@H](C(=O)NC=1C=CC=C2C(=CNC=12)C1=NC(=NC=C1C)NC1=C(C(=CC=C1)S(=O)(=O)C)F)N1CCN(CC1)C OEFHVDNQXRLETJ-XMMPIXPASA-N 0.000 claims 1
• HIAYACPVQOBWJL-XMMPIXPASA-N (2R)-N-[3-[2-(2-fluoro-3-methylsulfonylanilino)-5-methylpyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methyl-1,4-diazepan-1-yl)butanamide Chemical compound FC1=C(C=CC=C1S(=O)(=O)C)NC1=NC=C(C(=N1)C1=CNC2=C(C=CC=C12)NC([C@@H](CC)N1CCN(CCC1)C)=O)C HIAYACPVQOBWJL-XMMPIXPASA-N 0.000 claims 1
• KZBWLTMGNRKWRE-XMMPIXPASA-N (2R)-N-[3-[2-(2-fluoro-3-methylsulfonylanilino)-5-methylpyrimidin-4-yl]-1H-indol-7-yl]-3-methoxy-2-(4-methyl-1,4-diazepan-1-yl)propanamide Chemical compound COC[C@@H](N1CCCN(C)CC1)C(=O)NC1=C2NC=C(C2=CC=C1)C1=C(C)C=NC(NC2=C(F)C(=CC=C2)S(C)(=O)=O)=N1 KZBWLTMGNRKWRE-XMMPIXPASA-N 0.000 claims 1
• RRLNDAGZFQOBBH-HSZRJFAPSA-N (2R)-N-[3-[2-(2-fluoro-3-methylsulfonylanilino)-5-methylpyrimidin-4-yl]-1H-indol-7-yl]-3-methoxy-2-(4-methylpiperazin-1-yl)propanamide Chemical compound FC1=C(C=CC=C1S(=O)(=O)C)NC1=NC=C(C(=N1)C1=CNC2=C(C=CC=C12)NC([C@@H](COC)N1CCN(CC1)C)=O)C RRLNDAGZFQOBBH-HSZRJFAPSA-N 0.000 claims 1
• WZKASYHBMKTDLZ-ZYLNGJIFSA-N (2R)-N-[3-[2-(2-fluoro-3-methylsulfonylanilino)-5-methylpyrimidin-4-yl]-1H-indol-7-yl]-3-methoxy-2-[(3S,5S)-3,4,5-trimethylpiperazin-1-yl]propanamide Chemical compound FC1=C(C=CC=C1S(=O)(=O)C)NC1=NC=C(C(=N1)C1=CNC2=C(C=CC=C12)NC([C@@H](COC)N1C[C@@H](N([C@H](C1)C)C)C)=O)C WZKASYHBMKTDLZ-ZYLNGJIFSA-N 0.000 claims 1
• VNPHSNSQFXKHNW-HSZRJFAPSA-N (2R)-N-[3-[5-fluoro-2-(2-fluoro-3-methylsulfonylanilino)pyrimidin-4-yl]-1H-indol-7-yl]-3-methoxy-2-(4-methyl-1,4-diazepan-1-yl)propanamide Chemical compound COC[C@@H](N1CCCN(C)CC1)C(=O)NC1=C2NC=C(C2=CC=C1)C1=C(F)C=NC(NC2=C(F)C(=CC=C2)S(C)(=O)=O)=N1 VNPHSNSQFXKHNW-HSZRJFAPSA-N 0.000 claims 1
• JNUZADQZHYFJGW-JOCHJYFZSA-N (2R)-N-[3-[5-fluoro-2-(2-fluoro-3-methylsulfonylanilino)pyrimidin-4-yl]-1H-indol-7-yl]-3-methoxy-2-(4-methylpiperazin-1-yl)propanamide Chemical compound FC=1C(=NC(=NC=1)NC1=C(C(=CC=C1)S(=O)(=O)C)F)C1=CNC2=C(C=CC=C12)NC([C@@H](COC)N1CCN(CC1)C)=O JNUZADQZHYFJGW-JOCHJYFZSA-N 0.000 claims 1
• XGULBHANUDZVLI-LLJLJFOGSA-N (2R)-N-[3-[5-fluoro-2-(2-fluoro-3-methylsulfonylanilino)pyrimidin-4-yl]-1H-indol-7-yl]-3-methoxy-2-[(3S,5S)-3,4,5-trimethylpiperazin-1-yl]propanamide Chemical compound FC=1C(=NC(=NC=1)NC1=C(C(=CC=C1)S(=O)(=O)C)F)C1=CNC2=C(C=CC=C12)NC([C@@H](COC)N1C[C@@H](N([C@H](C1)C)C)C)=O XGULBHANUDZVLI-LLJLJFOGSA-N 0.000 claims 1
• MAZZDWBGKGDHRC-DVECYGJZSA-N (2S)-2-[(2R)-2,4-dimethylpiperazin-1-yl]-N-[3-[2-(2-fluoro-3-methylsulfonylanilino)-5-methylpyrimidin-4-yl]-1H-indol-7-yl]-3-methoxypropanamide Chemical compound COC[C@H](N1CCN(C)C[C@H]1C)C(=O)Nc1cccc2c(c[nH]c12)-c1nc(Nc2cccc(c2F)S(C)(=O)=O)ncc1C MAZZDWBGKGDHRC-DVECYGJZSA-N 0.000 claims 1
• SOVJEVPWSAQNKB-IECBHUPTSA-N (2S)-2-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-N-[3-[2-(2-fluoro-3-methylsulfonylanilino)-5-methylpyrimidin-4-yl]-1H-indol-7-yl]-3-methoxypropanamide Chemical compound COC[C@H](N1C[C@@H](C)N[C@H](C)C1)C(=O)Nc1cccc2c(c[nH]c12)-c1nc(Nc2cccc(c2F)S(C)(=O)=O)ncc1C SOVJEVPWSAQNKB-IECBHUPTSA-N 0.000 claims 1
• PUOCMFXCTMHFMA-QZMQVMSPSA-N (2S)-2-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-N-[3-[5-fluoro-2-(2-fluoro-3-methylsulfonylanilino)pyrimidin-4-yl]-1H-indol-7-yl]butanamide Chemical compound CC[C@H](N1C[C@@H](C)N[C@H](C)C1)C(=O)Nc1cccc2c(c[nH]c12)-c1nc(Nc2cccc(c2F)S(C)(=O)=O)ncc1F PUOCMFXCTMHFMA-QZMQVMSPSA-N 0.000 claims 1
• AXCUQYSFMVWWKV-LJAQVGFWSA-N (2S)-N-[3-[2-(2-fluoro-3-methylsulfonylanilino)-5-methylpyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)-3-phenylmethoxypropanamide Chemical compound C(C1=CC=CC=C1)OC[C@@H](C(=O)NC=1C=CC=C2C(=CNC=12)C1=NC(=NC=C1C)NC1=C(C(=CC=C1)S(=O)(=O)C)F)N1CCN(CC1)C AXCUQYSFMVWWKV-LJAQVGFWSA-N 0.000 claims 1
• IVRBIACRKQZTJW-QHCPKHFHSA-N (2S)-N-[3-[2-(2-fluoro-3-methylsulfonylanilino)-5-methylpyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)butanamide Chemical compound FC1=C(C=CC=C1S(=O)(=O)C)NC1=NC=C(C(=N1)C1=CNC2=C(C=CC=C12)NC([C@H](CC)N1CCN(CC1)C)=O)C IVRBIACRKQZTJW-QHCPKHFHSA-N 0.000 claims 1
• CVHTUKRJGWQVLQ-RLSLOFABSA-N (2S)-N-[3-[2-(2-fluoro-3-methylsulfonylanilino)-5-methylpyrimidin-4-yl]-1H-indol-7-yl]-2-[(3S,5S)-3,4,5-trimethylpiperazin-1-yl]butanamide Chemical compound FC1=C(C=CC=C1S(=O)(=O)C)NC1=NC=C(C(=N1)C1=CNC2=C(C=CC=C12)NC([C@H](CC)N1C[C@@H](N([C@H](C1)C)C)C)=O)C CVHTUKRJGWQVLQ-RLSLOFABSA-N 0.000 claims 1
• CJUARKYQFZUURR-QFIPXVFZSA-N (2S)-N-[3-[5-fluoro-2-(2-fluoro-3-methylsulfonylanilino)pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)butanamide Chemical compound FC=1C(=NC(=NC=1)NC1=C(C(=CC=C1)S(=O)(=O)C)F)C1=CNC2=C(C=CC=C12)NC([C@H](CC)N1CCN(CC1)C)=O CJUARKYQFZUURR-QFIPXVFZSA-N 0.000 claims 1
• VNPHSNSQFXKHNW-QHCPKHFHSA-N (2S)-N-[3-[5-fluoro-2-(2-fluoro-3-methylsulfonylanilino)pyrimidin-4-yl]-1H-indol-7-yl]-3-methoxy-2-(4-methyl-1,4-diazepan-1-yl)propanamide Chemical compound COC[C@H](N1CCCN(C)CC1)C(=O)NC1=C2NC=C(C2=CC=C1)C1=C(F)C=NC(NC2=C(F)C(=CC=C2)S(C)(=O)=O)=N1 VNPHSNSQFXKHNW-QHCPKHFHSA-N 0.000 claims 1
• JMGMJHPZBLVBPW-UHFFFAOYSA-N N-[4-(2-hydroxyethyl)piperazin-1-yl]propanamide Chemical compound C(CC)(=O)NN1CCN(CC1)CCO JMGMJHPZBLVBPW-UHFFFAOYSA-N 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 228
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 164
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 156
• 239000000543 intermediate Substances 0.000 description 134
• 239000011541 reaction mixture Substances 0.000 description 133
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 128
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 114
• 239000000203 mixture Substances 0.000 description 112
• 239000007787 solid Substances 0.000 description 91
• 238000005160 1H NMR spectroscopy Methods 0.000 description 60
• 235000019439 ethyl acetate Nutrition 0.000 description 60
• 239000000243 solution Substances 0.000 description 59
• 239000012071 phase Substances 0.000 description 58
• 238000005481 NMR spectroscopy Methods 0.000 description 54
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 50
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 48
• PAQZWJGSJMLPMG-UHFFFAOYSA-N propylphosphonic anhydride Substances CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 45
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 42
• 108010058846 Ovalbumin Proteins 0.000 description 41
• 229940092253 ovalbumin Drugs 0.000 description 41
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 40
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 38
• 239000011734 sodium Substances 0.000 description 35
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 28
• 239000000047 product Substances 0.000 description 28
• 239000012044 organic layer Substances 0.000 description 27
• 239000012074 organic phase Substances 0.000 description 27
• 238000002953 preparative HPLC Methods 0.000 description 27
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
• 239000002904 solvent Substances 0.000 description 25
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
• 230000002401 inhibitory effect Effects 0.000 description 24
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
• 239000003480 eluent Substances 0.000 description 22
• 239000012299 nitrogen atmosphere Substances 0.000 description 21
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 19
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