JP5819840B2 - ブロモドメイン阻害剤としてのテトラヒドロキノリン誘導体 - Google Patents

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Publication number

JP5819840B2

JP5819840B2 JP2012537383A JP2012537383A JP5819840B2 JP 5819840 B2 JP5819840 B2 JP 5819840B2 JP 2012537383 A JP2012537383 A JP 2012537383A JP 2012537383 A JP2012537383 A JP 2012537383A JP 5819840 B2 JP5819840 B2 JP 5819840B2

Authority

JP

Japan

Prior art keywords

methyl

acetyl

tetrahydro

mmol

quinolinyl

Prior art date

2009-11-05

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 - Fee Related

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• 102000001805 Bromodomains Human genes 0.000 title description 23
• 108050009021 Bromodomains Proteins 0.000 title description 21
• 239000003112 inhibitor Substances 0.000 title description 14
• 125000000147 tetrahydroquinolinyl group Chemical class N1(CCCC2=CC=CC=C12)* 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims description 199
• -1 -CF 3 Chemical group 0.000 claims description 133
• 150000003839 salts Chemical class 0.000 claims description 118
• 229910052757 nitrogen Inorganic materials 0.000 claims description 94
• 125000000217 alkyl group Chemical group 0.000 claims description 73
• 125000001072 heteroaryl group Chemical group 0.000 claims description 44
• 125000000623 heterocyclic group Chemical group 0.000 claims description 34
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 34
• 125000003545 alkoxy group Chemical group 0.000 claims description 31
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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 30
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 25
• 125000005842 heteroatom Chemical group 0.000 claims description 24
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
• 229910052736 halogen Inorganic materials 0.000 claims description 21
• 150000002367 halogens Chemical class 0.000 claims description 21
• 229910052760 oxygen Inorganic materials 0.000 claims description 19
• 125000001424 substituent group Chemical group 0.000 claims description 19
• 229910052717 sulfur Inorganic materials 0.000 claims description 19
• 125000003118 aryl group Chemical group 0.000 claims description 18
• 235000010233 benzoic acid Nutrition 0.000 claims description 18
• 239000005711 Benzoic acid Substances 0.000 claims description 17
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 16
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 16
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 13
• 229910052739 hydrogen Inorganic materials 0.000 claims description 11
• 125000004076 pyridyl group Chemical group 0.000 claims description 11
• 206010028980 Neoplasm Diseases 0.000 claims description 10
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
• 229910052799 carbon Inorganic materials 0.000 claims description 9
• 230000001363 autoimmune Effects 0.000 claims description 8
• 230000001684 chronic effect Effects 0.000 claims description 8
• 239000003085 diluting agent Substances 0.000 claims description 8
• 230000004968 inflammatory condition Effects 0.000 claims description 8
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
• 201000011510 cancer Diseases 0.000 claims description 7
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 7
• FAWSUKOIROHXAP-NPMXOYFQSA-N 4-[(2s,4r)-1-acetyl-4-(4-chloroanilino)-2-methyl-3,4-dihydro-2h-quinolin-6-yl]benzoic acid Chemical group N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(=CC=1)C(O)=O)C(C)=O)C)C1=CC=C(Cl)C=C1 FAWSUKOIROHXAP-NPMXOYFQSA-N 0.000 claims description 6
• 125000001153 fluoro group Chemical group F* 0.000 claims description 6
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
• 238000002560 therapeutic procedure Methods 0.000 claims description 6
• 125000004429 atom Chemical group 0.000 claims description 5
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
• PXXDOEMDQBOWHE-UHFFFAOYSA-N 4-[1-acetyl-2-methyl-4-(4-methylanilino)-3,4-dihydro-2h-quinolin-6-yl]benzoic acid Chemical compound C12=CC(C=3C=CC(=CC=3)C(O)=O)=CC=C2N(C(C)=O)C(C)CC1NC1=CC=C(C)C=C1 PXXDOEMDQBOWHE-UHFFFAOYSA-N 0.000 claims description 4
• 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 4
• 125000002883 imidazolyl group Chemical group 0.000 claims description 4
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
• VXXFVFXAKOHQIA-IFXJQAMLSA-N 1-[(2s,4r)-4-[(5-fluoropyridin-2-yl)amino]-2-methyl-6-(4-methylimidazol-1-yl)-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)N1C=C(C)N=C1)C(C)=O)C)C1=CC=C(F)C=N1 VXXFVFXAKOHQIA-IFXJQAMLSA-N 0.000 claims description 3
• XBTDPNSDSQVSBA-CCLHPLFOSA-N 1-[(2s,4r)-4-[(5-fluoropyridin-2-yl)amino]-2-methyl-6-[4-(piperidin-1-ylmethyl)phenyl]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(CN2CCCCC2)=CC=1)C(C)=O)C)C1=CC=C(F)C=N1 XBTDPNSDSQVSBA-CCLHPLFOSA-N 0.000 claims description 3
• 125000005037 alkyl phenyl group Chemical group 0.000 claims description 3
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
• XLHWPLMXJZZFLM-UHFFFAOYSA-N 1-[2-methyl-4-(4-methylanilino)-6-[4-(morpholine-4-carbonyl)phenyl]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound C12=CC(C=3C=CC(=CC=3)C(=O)N3CCOCC3)=CC=C2N(C(C)=O)C(C)CC1NC1=CC=C(C)C=C1 XLHWPLMXJZZFLM-UHFFFAOYSA-N 0.000 claims description 2
• LIBBMGDUMSQEGE-UHFFFAOYSA-N 1-[2-methyl-6-[1-[2-(methylamino)ethyl]pyrazol-4-yl]-4-(pyridin-2-ylamino)-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound C1=NN(CCNC)C=C1C1=CC=C(N(C(C)CC2NC=3N=CC=CC=3)C(C)=O)C2=C1 LIBBMGDUMSQEGE-UHFFFAOYSA-N 0.000 claims description 2
• YYAUJNXXEJJJEY-UHFFFAOYSA-N 1-[2-methyl-6-[1-[2-(methylamino)ethyl]pyrazol-4-yl]-4-(pyrimidin-2-ylamino)-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound C1=NN(CCNC)C=C1C1=CC=C(N(C(C)CC2NC=3N=CC=CN=3)C(C)=O)C2=C1 YYAUJNXXEJJJEY-UHFFFAOYSA-N 0.000 claims description 2
• VLQJGBRQPMWAOG-UHFFFAOYSA-N 1-[4-[(5-fluoropyridin-2-yl)amino]-2-methyl-6-[4-(methylaminomethyl)phenyl]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound C1=CC(CNC)=CC=C1C1=CC=C(N(C(C)CC2NC=3N=CC(F)=CC=3)C(C)=O)C2=C1 VLQJGBRQPMWAOG-UHFFFAOYSA-N 0.000 claims description 2
• LNIGKABMKQPEJP-UHFFFAOYSA-N 1-[4-anilino-2-methyl-6-[3-(morpholin-4-ylmethyl)phenyl]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound C12=CC(C=3C=C(CN4CCOCC4)C=CC=3)=CC=C2N(C(C)=O)C(C)CC1NC1=CC=CC=C1 LNIGKABMKQPEJP-UHFFFAOYSA-N 0.000 claims description 2
• HHLPOWRWLBEWKR-UHFFFAOYSA-N 1-[4-anilino-2-methyl-6-[4-(piperidin-1-ylmethyl)phenyl]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound C12=CC(C=3C=CC(CN4CCCCC4)=CC=3)=CC=C2N(C(C)=O)C(C)CC1NC1=CC=CC=C1 HHLPOWRWLBEWKR-UHFFFAOYSA-N 0.000 claims description 2
• NXGNKWNCNDHXEW-UHFFFAOYSA-N 1-[6-[1-(2-hydroxyethyl)triazol-4-yl]-2-methyl-4-(pyridin-2-ylamino)-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound C12=CC(C=3N=NN(CCO)C=3)=CC=C2N(C(C)=O)C(C)CC1NC1=CC=CC=N1 NXGNKWNCNDHXEW-UHFFFAOYSA-N 0.000 claims description 2
• UQXYDLCFKSSUMO-UHFFFAOYSA-N 1-[6-[1-(2-hydroxyethyl)triazol-4-yl]-2-methyl-4-[(3-methylpyridin-2-yl)amino]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound C12=CC(C=3N=NN(CCO)C=3)=CC=C2N(C(C)=O)C(C)CC1NC1=NC=CC=C1C UQXYDLCFKSSUMO-UHFFFAOYSA-N 0.000 claims description 2
• HIKJEYPUVIOESF-UHFFFAOYSA-N 1-[6-[1-(2-hydroxyethyl)triazol-4-yl]-2-methyl-4-[(4-methylpyridin-2-yl)amino]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound C12=CC(C=3N=NN(CCO)C=3)=CC=C2N(C(C)=O)C(C)CC1NC1=CC(C)=CC=N1 HIKJEYPUVIOESF-UHFFFAOYSA-N 0.000 claims description 2
• AGRHDPJTLMEWON-UHFFFAOYSA-N 1-[6-[1-(2-hydroxyethyl)triazol-4-yl]-2-methyl-4-[(5-methylpyridin-2-yl)amino]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound C12=CC(C=3N=NN(CCO)C=3)=CC=C2N(C(C)=O)C(C)CC1NC1=CC=C(C)C=N1 AGRHDPJTLMEWON-UHFFFAOYSA-N 0.000 claims description 2
• LWAJDCIIKOGJNS-UHFFFAOYSA-N 1-[6-[1-(2-hydroxyethyl)triazol-4-yl]-2-methyl-4-[(6-methylpyridin-2-yl)amino]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound C12=CC(C=3N=NN(CCO)C=3)=CC=C2N(C(C)=O)C(C)CC1NC1=CC=CC(C)=N1 LWAJDCIIKOGJNS-UHFFFAOYSA-N 0.000 claims description 2
• NWUSBAWGHMHOSL-UHFFFAOYSA-N 4-[1-acetyl-2-methyl-4-[(5-methylpyridin-2-yl)amino]-3,4-dihydro-2h-quinolin-6-yl]benzoic acid Chemical compound C12=CC(C=3C=CC(=CC=3)C(O)=O)=CC=C2N(C(C)=O)C(C)CC1NC1=CC=C(C)C=N1 NWUSBAWGHMHOSL-UHFFFAOYSA-N 0.000 claims description 2
• LCALSMKRLRQSEW-UHFFFAOYSA-N 4-[1-acetyl-2-methyl-4-[3-(trifluoromethyl)anilino]-3,4-dihydro-2h-quinolin-6-yl]benzoic acid Chemical compound C12=CC(C=3C=CC(=CC=3)C(O)=O)=CC=C2N(C(C)=O)C(C)CC1NC1=CC=CC(C(F)(F)F)=C1 LCALSMKRLRQSEW-UHFFFAOYSA-N 0.000 claims description 2
• XPUCQJSAUFPNIJ-UHFFFAOYSA-N 4-[1-acetyl-2-methyl-4-[4-(trifluoromethyl)anilino]-3,4-dihydro-2h-quinolin-6-yl]benzoic acid Chemical compound C12=CC(C=3C=CC(=CC=3)C(O)=O)=CC=C2N(C(C)=O)C(C)CC1NC1=CC=C(C(F)(F)F)C=C1 XPUCQJSAUFPNIJ-UHFFFAOYSA-N 0.000 claims description 2
• HFOKQPIWNDBDIS-UHFFFAOYSA-N 4-[1-acetyl-4-(4-chloro-n-ethylanilino)-2-methyl-3,4-dihydro-2h-quinolin-6-yl]-n-methylbenzamide Chemical compound C=1C=C(Cl)C=CC=1N(CC)C(C1=C2)CC(C)N(C(C)=O)C1=CC=C2C1=CC=C(C(=O)NC)C=C1 HFOKQPIWNDBDIS-UHFFFAOYSA-N 0.000 claims description 2
• FKMXTZHFWDLVLJ-UHFFFAOYSA-N 4-[1-acetyl-4-(4-cyanoanilino)-2-methyl-3,4-dihydro-2h-quinolin-6-yl]benzoic acid Chemical compound C12=CC(C=3C=CC(=CC=3)C(O)=O)=CC=C2N(C(C)=O)C(C)CC1NC1=CC=C(C#N)C=C1 FKMXTZHFWDLVLJ-UHFFFAOYSA-N 0.000 claims description 2
• QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 2
• 229940095102 methyl benzoate Drugs 0.000 claims description 2
• 125000001425 triazolyl group Chemical group 0.000 claims description 2
• BVXAFKJVGMEQRF-RBISFHTESA-N 1-[(2s,4r)-2-methyl-4-[(5-methylpyridin-2-yl)amino]-6-[4-(piperidin-1-ylmethyl)phenyl]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(CN2CCCCC2)=CC=1)C(C)=O)C)C1=CC=C(C)C=N1 BVXAFKJVGMEQRF-RBISFHTESA-N 0.000 claims 1
• SAXUXMSUABSPPF-KDYSTLNUSA-N 1-[(2s,4r)-2-methyl-6-[4-(piperidin-1-ylmethyl)phenyl]-4-(pyridin-2-ylamino)-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(CN2CCCCC2)=CC=1)C(C)=O)C)C1=CC=CC=N1 SAXUXMSUABSPPF-KDYSTLNUSA-N 0.000 claims 1
• OPPYCJBWBQERQN-CCLHPLFOSA-N 1-[(2s,4r)-4-[(5-chloropyridin-2-yl)amino]-2-methyl-6-[4-(piperidin-1-ylmethyl)phenyl]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(CN2CCCCC2)=CC=1)C(C)=O)C)C1=CC=C(Cl)C=N1 OPPYCJBWBQERQN-CCLHPLFOSA-N 0.000 claims 1
• ZYWTWMAXCZSRSE-YCRPNKLZSA-N 1-[(2s,4r)-6-(6-aminopyridin-3-yl)-4-anilino-2-methyl-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=NC(N)=CC=1)C(C)=O)C)C1=CC=CC=C1 ZYWTWMAXCZSRSE-YCRPNKLZSA-N 0.000 claims 1
• RQAYPLLPEGHEDZ-UHFFFAOYSA-N 1-[4-anilino-2-methyl-6-[1-[2-(methylamino)ethyl]pyrazol-4-yl]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound C1=NN(CCNC)C=C1C1=CC=C(N(C(C)CC2NC=3C=CC=CC=3)C(C)=O)C2=C1 RQAYPLLPEGHEDZ-UHFFFAOYSA-N 0.000 claims 1
• FAWSUKOIROHXAP-UHFFFAOYSA-N 4-[1-acetyl-4-(4-chloroanilino)-2-methyl-3,4-dihydro-2h-quinolin-6-yl]benzoic acid Chemical compound C12=CC(C=3C=CC(=CC=3)C(O)=O)=CC=C2N(C(C)=O)C(C)CC1NC1=CC=C(Cl)C=C1 FAWSUKOIROHXAP-UHFFFAOYSA-N 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 582
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 445
• 239000000543 intermediate Substances 0.000 description 255
• 239000000203 mixture Substances 0.000 description 252
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 214
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 162
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 157
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 146
• 238000000034 method Methods 0.000 description 137
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 130
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 124
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 123
• 238000002360 preparation method Methods 0.000 description 118
• 230000014759 maintenance of location Effects 0.000 description 112
• 235000002639 sodium chloride Nutrition 0.000 description 106
• 239000007787 solid Substances 0.000 description 98
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 97
• 239000000243 solution Substances 0.000 description 97
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 94
• MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 83
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 75
• 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 74
• 239000012074 organic phase Substances 0.000 description 70
• GTCAXTIRRLKXRU-UHFFFAOYSA-N carbamic acid methyl ester Natural products COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 69
• 239000010410 layer Substances 0.000 description 69
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 60
• 239000012267 brine Substances 0.000 description 59
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 57
• 239000000377 silicon dioxide Substances 0.000 description 55
• 239000002904 solvent Substances 0.000 description 54
• ZEMZPXWZVTUONV-UHFFFAOYSA-N 2-(2-dicyclohexylphosphanylphenyl)-n,n-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 ZEMZPXWZVTUONV-UHFFFAOYSA-N 0.000 description 51
• 235000019439 ethyl acetate Nutrition 0.000 description 51
• 239000011734 sodium Substances 0.000 description 51
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 47
• 235000019253 formic acid Nutrition 0.000 description 47
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
• 238000006243 chemical reaction Methods 0.000 description 39
• 229920006395 saturated elastomer Polymers 0.000 description 38
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 37
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 36
• 239000008346 aqueous phase Substances 0.000 description 34
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 33
• UXRDAJMOOGEIAQ-CKOZHMEPSA-N [(8r,9s,10r,13s,14s,17r)-17-acetyl-10,13-dimethyl-16-methylidene-3-oxo-1,2,8,9,11,12,14,15-octahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1=CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC(=C)[C@](OC(=O)C)(C(C)=O)[C@@]1(C)CC2 UXRDAJMOOGEIAQ-CKOZHMEPSA-N 0.000 description 31
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
• 238000003756 stirring Methods 0.000 description 30
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 30
• 239000003607 modifier Substances 0.000 description 29
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
• 229910021529 ammonia Inorganic materials 0.000 description 28
• 239000000706 filtrate Substances 0.000 description 28
• 239000000725 suspension Substances 0.000 description 28
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
• 239000000843 powder Substances 0.000 description 26
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 24
• 238000003818 flash chromatography Methods 0.000 description 24
• 239000008194 pharmaceutical composition Substances 0.000 description 24
• 239000000741 silica gel Substances 0.000 description 24
• 229910002027 silica gel Inorganic materials 0.000 description 24
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 23
• VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 22
• 239000002244 precipitate Substances 0.000 description 22
• 239000011541 reaction mixture Substances 0.000 description 22
• 201000010099 disease Diseases 0.000 description 21
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
• OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 20
• 238000001819 mass spectrum Methods 0.000 description 20
• 239000000047 product Substances 0.000 description 20
• 238000010992 reflux Methods 0.000 description 20
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