TW201410676A - 芳基內醯胺激酶抑制劑 - Google Patents

Info

Publication number

TW201410676A

TW201410676A TW102127296A TW102127296A TW201410676A TW 201410676 A TW201410676 A TW 201410676A TW 102127296 A TW102127296 A TW 102127296A TW 102127296 A TW102127296 A TW 102127296A TW 201410676 A TW201410676 A TW 201410676A

Authority

TW

Taiwan

Prior art keywords

amino

naphthyridin

group

oxy

alkyl

Prior art date

2012-07-31

Links

• Espacenet
• Global Dossier
• Discuss

• -1 Aryl lactam Chemical class 0.000 title claims description 199
• 229940043355 kinase inhibitor Drugs 0.000 title description 2
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
• 238000000034 method Methods 0.000 claims abstract description 421
• 239000000203 mixture Substances 0.000 claims abstract description 154
• 150000001875 compounds Chemical class 0.000 claims abstract description 125
• 102100038079 AP2-associated protein kinase 1 Human genes 0.000 claims abstract description 9
• 101710148635 AP2-associated protein kinase 1 Proteins 0.000 claims abstract description 9
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 7
• LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 claims description 124
• 229910052739 hydrogen Inorganic materials 0.000 claims description 57
• 150000003839 salts Chemical class 0.000 claims description 46
• 239000001257 hydrogen Substances 0.000 claims description 44
• 125000005843 halogen group Chemical group 0.000 claims description 43
• 125000003118 aryl group Chemical group 0.000 claims description 39
• 238000011282 treatment Methods 0.000 claims description 38
• 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 35
• 125000000217 alkyl group Chemical group 0.000 claims description 34
• 150000002431 hydrogen Chemical class 0.000 claims description 34
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 31
• 229910052757 nitrogen Inorganic materials 0.000 claims description 29
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 29
• UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 28
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
• 150000001412 amines Chemical class 0.000 claims description 25
• 201000010099 disease Diseases 0.000 claims description 25
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 25
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
• 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 23
• HPFOEWJXDNWCTH-UHFFFAOYSA-N 6h-benzo[c][2,7]naphthyridin-5-one Chemical compound C1=NC=C2C(=O)NC3=CC=CC=C3C2=C1 HPFOEWJXDNWCTH-UHFFFAOYSA-N 0.000 claims description 21
• 125000003277 amino group Chemical group 0.000 claims description 21
• 125000005605 benzo group Chemical group 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 17
• 229910052799 carbon Inorganic materials 0.000 claims description 15
• 150000002148 esters Chemical class 0.000 claims description 14
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
• 208000002193 Pain Diseases 0.000 claims description 10
• 230000000694 effects Effects 0.000 claims description 10
• 230000036407 pain Effects 0.000 claims description 10
• 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 9
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
• SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 9
• 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 8
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 8
• 201000000980 schizophrenia Diseases 0.000 claims description 8
• 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 7
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 7
• 125000006699 (C1-C3) hydroxyalkyl group Chemical group 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 208000004296 neuralgia Diseases 0.000 claims description 6
• 208000021722 neuropathic pain Diseases 0.000 claims description 6
• 229910052727 yttrium Inorganic materials 0.000 claims description 6
• XCKUSTFLSTVTCR-AWEZNQCLSA-N 8-[(2s)-2-amino-4-methylpentoxy]-2,6-dimethylbenzo[c][2,7]naphthyridin-5-one Chemical compound N1=C(C)C=C2C3=CC=C(OC[C@@H](N)CC(C)C)C=C3N(C)C(=O)C2=C1 XCKUSTFLSTVTCR-AWEZNQCLSA-N 0.000 claims description 5
• 125000003545 alkoxy group Chemical group 0.000 claims description 5
• 125000001769 aryl amino group Chemical group 0.000 claims description 5
• 125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 5
• 125000001072 heteroaryl group Chemical group 0.000 claims description 5
• 150000002576 ketones Chemical class 0.000 claims description 5
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
• 125000001424 substituent group Chemical group 0.000 claims description 5
• 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 4
• XWZXCIPLOWRHAC-UHFFFAOYSA-N 8-(2-amino-5,5,5-trifluoropentoxy)-6-methylbenzo[c][2,7]naphthyridin-5-one Chemical compound C1=NC=C2C(=O)N(C)C3=CC(OCC(N)CCC(F)(F)F)=CC=C3C2=C1 XWZXCIPLOWRHAC-UHFFFAOYSA-N 0.000 claims description 4
• JOCMZPAMMJDEEF-IBGZPJMESA-N 8-[(2s)-2-amino-4-methylpentoxy]-6-benzylbenzo[c][2,7]naphthyridin-5-one Chemical compound C=1C(OC[C@@H](N)CC(C)C)=CC=C(C2=CC=NC=C2C2=O)C=1N2CC1=CC=CC=C1 JOCMZPAMMJDEEF-IBGZPJMESA-N 0.000 claims description 4
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
• RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 claims description 4
• 229910052760 oxygen Inorganic materials 0.000 claims description 4
• 239000001301 oxygen Substances 0.000 claims description 4
• ATCROYCGFZTPSQ-LBPRGKRZSA-N 8-[(2s)-2-amino-4-methylpentoxy]-6h-benzo[c][2,7]naphthyridin-5-one Chemical compound N1=CC=C2C3=CC=C(OC[C@@H](N)CC(C)C)C=C3NC(=O)C2=C1 ATCROYCGFZTPSQ-LBPRGKRZSA-N 0.000 claims description 3
• 208000024827 Alzheimer disease Diseases 0.000 claims description 3
• 208000020925 Bipolar disease Diseases 0.000 claims description 3
• 125000004992 haloalkylamino group Chemical group 0.000 claims description 3
• 238000000338 in vitro Methods 0.000 claims description 3
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
• LOZLKDVGPQCIRZ-INIZCTEOSA-N 4,6-dimethyl-8-[(2s)-4-methyl-2-(methylamino)pentoxy]-5-oxobenzo[c][2,7]naphthyridine-9-carbonitrile Chemical compound CN1C(=O)C2=C(C)N=CC=C2C2=C1C=C(OC[C@@H](NC)CC(C)C)C(C#N)=C2 LOZLKDVGPQCIRZ-INIZCTEOSA-N 0.000 claims description 2
• GIJACGNPPUYZEJ-LBPRGKRZSA-N 4-amino-8-[(2s)-2-amino-4-methylpentoxy]-6-methylbenzo[c][2,7]naphthyridin-5-one Chemical compound N1=CC=C2C3=CC=C(OC[C@@H](N)CC(C)C)C=C3N(C)C(=O)C2=C1N GIJACGNPPUYZEJ-LBPRGKRZSA-N 0.000 claims description 2
• OOOPDKTUMJEDEK-INIZCTEOSA-N 8-[(2s)-2-amino-3-cyclobutylpropoxy]-4,6,9-trimethylbenzo[c][2,7]naphthyridin-5-one Chemical compound C([C@H](N)COC1=CC2=C(C3=CC=NC(C)=C3C(=O)N2C)C=C1C)C1CCC1 OOOPDKTUMJEDEK-INIZCTEOSA-N 0.000 claims description 2
• HRMGBYSRWUAWIG-AWEZNQCLSA-N 8-[(2s)-2-amino-4-methylpentoxy]-4,6-dimethylbenzo[c][2,7]naphthyridin-5-one Chemical compound N1=CC=C2C3=CC=C(OC[C@@H](N)CC(C)C)C=C3N(C)C(=O)C2=C1C HRMGBYSRWUAWIG-AWEZNQCLSA-N 0.000 claims description 2
• DNJVIWQGOSPTGR-LBPRGKRZSA-N 8-[(2s)-2-amino-4-methylpentoxy]-9-bromo-6-methylbenzo[c][2,7]naphthyridin-5-one Chemical compound CN1C(=O)C2=CN=CC=C2C2=C1C=C(OC[C@@H](N)CC(C)C)C(Br)=C2 DNJVIWQGOSPTGR-LBPRGKRZSA-N 0.000 claims description 2
• 208000001640 Fibromyalgia Diseases 0.000 claims description 2
• 230000001404 mediated effect Effects 0.000 claims description 2
• WMPDMMUFIRDMPA-AWEZNQCLSA-N n-[8-[(2s)-2-amino-4-methylpentoxy]-6-methyl-5-oxobenzo[c][2,7]naphthyridin-2-yl]acetamide Chemical compound N1=C(NC(C)=O)C=C2C3=CC=C(OC[C@@H](N)CC(C)C)C=C3N(C)C(=O)C2=C1 WMPDMMUFIRDMPA-AWEZNQCLSA-N 0.000 claims description 2
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
• 208000033808 peripheral neuropathy Diseases 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims 2
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
• CGUAZCQWONVSAJ-UHFFFAOYSA-N 1-[(1-fluoro-6-methyl-5H-benzo[c][2,7]naphthyridin-8-yl)oxy]-2,4-dimethylpentan-2-amine Chemical compound NC(COC=1C=CC2=C(N(CC3=CN=CC(=C23)F)C)C1)(CC(C)C)C CGUAZCQWONVSAJ-UHFFFAOYSA-N 0.000 claims 1
• PRTTZMKZMXANFG-UHFFFAOYSA-N 2-amino-2,4-dimethylpentanenitrile Chemical compound CC(C)CC(C)(N)C#N PRTTZMKZMXANFG-UHFFFAOYSA-N 0.000 claims 1
• CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 claims 1
• NBHCBBXZBQCGBZ-UHFFFAOYSA-N 8-(2-amino-2,4-dimethylpentoxy)-7-fluoro-4,6-dimethylbenzo[c][2,7]naphthyridin-5-one Chemical compound C1=NC(C)=C2C(=O)N(C)C3=C(F)C(OCC(C)(N)CC(C)C)=CC=C3C2=C1 NBHCBBXZBQCGBZ-UHFFFAOYSA-N 0.000 claims 1
• QWYVFLDYWGJEQU-HNNXBMFYSA-N 8-[(2s)-2-amino-3-cyclopropylpropoxy]-4,6,9-trimethylbenzo[c][2,7]naphthyridin-5-one Chemical compound C([C@H](N)COC1=CC2=C(C3=CC=NC(C)=C3C(=O)N2C)C=C1C)C1CC1 QWYVFLDYWGJEQU-HNNXBMFYSA-N 0.000 claims 1
• NQXBZPJVVGIFBJ-HNNXBMFYSA-N 8-[(2s)-2-amino-4-methylpentoxy]-4,6-dimethyl-5-oxobenzo[c][2,7]naphthyridine-9-carbonitrile Chemical compound CN1C(=O)C2=C(C)N=CC=C2C2=C1C=C(OC[C@@H](N)CC(C)C)C(C#N)=C2 NQXBZPJVVGIFBJ-HNNXBMFYSA-N 0.000 claims 1
• WVWZWEDZULHZHM-HNNXBMFYSA-N 8-[(2s)-2-amino-4-methylpentoxy]-4,6-dimethyl-9-(1,3-thiazol-5-yl)benzo[c][2,7]naphthyridin-5-one Chemical compound CC(C)C[C@H](N)COC1=CC=2N(C)C(=O)C3=C(C)N=CC=C3C=2C=C1C1=CN=CS1 WVWZWEDZULHZHM-HNNXBMFYSA-N 0.000 claims 1
• KVRKKRBPFCLMMG-ZDUSSCGKSA-N 8-[(2s)-2-amino-4-methylpentoxy]-4-methyl-6h-benzo[c][2,7]naphthyridin-5-one Chemical compound N1=CC=C2C3=CC=C(OC[C@@H](N)CC(C)C)C=C3NC(=O)C2=C1C KVRKKRBPFCLMMG-ZDUSSCGKSA-N 0.000 claims 1
• YPEZYWFTKZJJJZ-AWEZNQCLSA-N 8-[(2s)-2-amino-4-methylpentoxy]-6,9-dimethylbenzo[c][2,7]naphthyridin-5-one Chemical compound CN1C(=O)C2=CN=CC=C2C2=C1C=C(OC[C@@H](N)CC(C)C)C(C)=C2 YPEZYWFTKZJJJZ-AWEZNQCLSA-N 0.000 claims 1
• ODUGXJAXPWAZJC-HNNXBMFYSA-N 8-[(2s)-2-amino-4-methylpentoxy]-6-(2-methoxyethyl)benzo[c][2,7]naphthyridin-5-one Chemical compound C1=NC=C2C(=O)N(CCOC)C3=CC(OC[C@@H](N)CC(C)C)=CC=C3C2=C1 ODUGXJAXPWAZJC-HNNXBMFYSA-N 0.000 claims 1
• APIXEYSCHSPEJC-INIZCTEOSA-N 8-[(2s)-2-amino-4-methylpentoxy]-6-(cyclopropylmethyl)benzo[c][2,7]naphthyridin-5-one Chemical compound C=1C(OC[C@@H](N)CC(C)C)=CC=C(C2=CC=NC=C2C2=O)C=1N2CC1CC1 APIXEYSCHSPEJC-INIZCTEOSA-N 0.000 claims 1
• OYOIIDJCDNWRLV-ZDUSSCGKSA-N 8-[(2s)-2-amino-4-methylpentoxy]-7-chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5-one Chemical compound C1=NC(C)=C2C(=O)N(C)C3=C(Cl)C(OC[C@@H](N)CC(C)C)=CC=C3C2=C1 OYOIIDJCDNWRLV-ZDUSSCGKSA-N 0.000 claims 1
• IBOVYPMCAGZYGE-LBPRGKRZSA-N 8-[(2s)-2-amino-4-methylpentoxy]-7-fluoro-4-methyl-6h-benzo[c][2,7]naphthyridin-5-one Chemical compound C1=NC(C)=C2C(=O)NC3=C(F)C(OC[C@@H](N)CC(C)C)=CC=C3C2=C1 IBOVYPMCAGZYGE-LBPRGKRZSA-N 0.000 claims 1
• UDYNBTZVRFJLDX-LOACHALJSA-N 8-[(2s)-2-amino-4-methylpentoxy]-9-(1-hydroxyethyl)-4,6-dimethylbenzo[c][2,7]naphthyridin-5-one Chemical compound CN1C(=O)C2=C(C)N=CC=C2C2=C1C=C(OC[C@@H](N)CC(C)C)C(C(C)O)=C2 UDYNBTZVRFJLDX-LOACHALJSA-N 0.000 claims 1
• UDIIMGJDZJDIMZ-ZDUSSCGKSA-N 8-[(2s)-2-amino-5,5-difluoropent-4-enoxy]-4,6-dimethyl-5-oxobenzo[c][2,7]naphthyridine-9-carbonitrile Chemical compound C12=CC(C#N)=C(OC[C@@H](N)CC=C(F)F)C=C2N(C)C(=O)C2=C1C=CN=C2C UDIIMGJDZJDIMZ-ZDUSSCGKSA-N 0.000 claims 1
• 239000004202 carbamide Substances 0.000 claims 1
• 125000001475 halogen functional group Chemical group 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 619
• 230000014759 maintenance of location Effects 0.000 description 360
• 235000019439 ethyl acetate Nutrition 0.000 description 270
• 239000011541 reaction mixture Substances 0.000 description 210
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 180
• 239000000243 solution Substances 0.000 description 178
• 230000002829 reductive effect Effects 0.000 description 168
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 162
• 238000004128 high performance liquid chromatography Methods 0.000 description 155
• 239000007787 solid Substances 0.000 description 137
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 122
• 238000005481 NMR spectroscopy Methods 0.000 description 108
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 95
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 92
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 89
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 79
• 238000006243 chemical reaction Methods 0.000 description 75
• 239000012044 organic layer Substances 0.000 description 75
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 65
• 239000011734 sodium Substances 0.000 description 65
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 64
• 239000012267 brine Substances 0.000 description 56
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 56
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 50
• 238000000746 purification Methods 0.000 description 49
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 45
• 239000000047 product Substances 0.000 description 43
• 239000000543 intermediate Substances 0.000 description 41
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 41
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 40
• 239000012043 crude product Substances 0.000 description 39
• 239000002904 solvent Substances 0.000 description 39
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
• 239000010410 layer Substances 0.000 description 36
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 35
• 229910052938 sodium sulfate Inorganic materials 0.000 description 35
• 235000011152 sodium sulphate Nutrition 0.000 description 35
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 32
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 31
• 239000005909 Kieselgur Substances 0.000 description 31
• 239000000463 material Substances 0.000 description 31
• 125000006239 protecting group Chemical group 0.000 description 29
• 238000003786 synthesis reaction Methods 0.000 description 29
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 29
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 28
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 28
• 239000002585 base Substances 0.000 description 27
• 239000000706 filtrate Substances 0.000 description 26
• OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 25
• 239000002253 acid 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
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 20
• IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 20
• 239000012071 phase Substances 0.000 description 20
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 19
• 239000003921 oil Substances 0.000 description 19
• 235000019198 oils Nutrition 0.000 description 19
• 229920006395 saturated elastomer Polymers 0.000 description 19
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
• 239000003153 chemical reaction reagent Substances 0.000 description 18
• 238000001816 cooling Methods 0.000 description 18
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
• 239000003208 petroleum Substances 0.000 description 17
• 229910000104 sodium hydride Inorganic materials 0.000 description 17
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 16
• 238000002953 preparative HPLC Methods 0.000 description 16
• 239000000725 suspension Substances 0.000 description 16
• OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 15
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