JP4187652B2 - ニューロペプチドｙアンタゴニストとしてのキノリン誘導体 - Google Patents

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Publication number

JP4187652B2

JP4187652B2 JP2003532058A JP2003532058A JP4187652B2 JP 4187652 B2 JP4187652 B2 JP 4187652B2 JP 2003532058 A JP2003532058 A JP 2003532058A JP 2003532058 A JP2003532058 A JP 2003532058A JP 4187652 B2 JP4187652 B2 JP 4187652B2

Authority

JP

Japan

Prior art keywords

methyl

quinolin

pyrrolidin

benzonitrile

alkyl

Prior art date

2001-09-28

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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• 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title claims description 12
• 101710151321 Melanostatin Proteins 0.000 title claims description 11
• URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 title description 8
• 239000005557 antagonist Substances 0.000 title description 3
• 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 title description 2
• 102400000064 Neuropeptide Y Human genes 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 285
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 176
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 127
• 238000000034 method Methods 0.000 claims description 94
• 125000000217 alkyl group Chemical group 0.000 claims description 87
• -1 pyrrolidinylcarbonyl Chemical group 0.000 claims description 62
• 239000001257 hydrogen Substances 0.000 claims description 42
• 229910052739 hydrogen Inorganic materials 0.000 claims description 42
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 39
• 125000000623 heterocyclic group Chemical group 0.000 claims description 37
• 229910052736 halogen Inorganic materials 0.000 claims description 33
• 150000002367 halogens Chemical class 0.000 claims description 33
• 125000003545 alkoxy group Chemical group 0.000 claims description 30
• 238000006243 chemical reaction Methods 0.000 claims description 29
• 229910052757 nitrogen Inorganic materials 0.000 claims description 29
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
• 150000003839 salts Chemical class 0.000 claims description 26
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 24
• 125000003118 aryl group Chemical group 0.000 claims description 22
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
• 229940086609 Lipase inhibitor Drugs 0.000 claims description 21
• 208000008589 Obesity Diseases 0.000 claims description 21
• 238000004519 manufacturing process Methods 0.000 claims description 21
• 235000020824 obesity Nutrition 0.000 claims description 21
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 20
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 18
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 18
• AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical group CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 claims description 18
• 230000002265 prevention Effects 0.000 claims description 18
• 125000001424 substituent group Chemical group 0.000 claims description 18
• 150000001412 amines Chemical class 0.000 claims description 17
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
• 229960001243 orlistat Drugs 0.000 claims description 17
• 239000003814 drug Substances 0.000 claims description 15
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 14
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 13
• 208000030814 Eating disease Diseases 0.000 claims description 13
• 208000019454 Feeding and Eating disease Diseases 0.000 claims description 13
• 208000001647 Renal Insufficiency Diseases 0.000 claims description 13
• 206010003246 arthritis Diseases 0.000 claims description 13
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
• 206010012601 diabetes mellitus Diseases 0.000 claims description 13
• 235000014632 disordered eating Nutrition 0.000 claims description 13
• 201000006370 kidney failure Diseases 0.000 claims description 13
• 229910052760 oxygen Inorganic materials 0.000 claims description 13
• 239000001301 oxygen Chemical group 0.000 claims description 13
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 12
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
• 125000005842 heteroatom Chemical group 0.000 claims description 12
• 239000008194 pharmaceutical composition Substances 0.000 claims description 12
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
• ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 11
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 11
• 229910052717 sulfur Chemical group 0.000 claims description 11
• 239000011593 sulfur Chemical group 0.000 claims description 11
• 102100028427 Pro-neuropeptide Y Human genes 0.000 claims description 10
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
• MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 8
• SELLRXHGEKIKKL-UHFFFAOYSA-N [4-(azepan-1-yl)-2-methylquinolin-7-yl]methanol Chemical compound C=12C=CC(CO)=CC2=NC(C)=CC=1N1CCCCCC1 SELLRXHGEKIKKL-UHFFFAOYSA-N 0.000 claims description 8
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 6
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
• OFCMJTXCXQZZHQ-UHFFFAOYSA-N (2,6-dimethyl-4-pyrrolidin-1-ylquinolin-7-yl)methanol Chemical compound C=12C=C(C)C(CO)=CC2=NC(C)=CC=1N1CCCC1 OFCMJTXCXQZZHQ-UHFFFAOYSA-N 0.000 claims description 5
• FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical group C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims description 5
• FBJUQLXTVWMSMQ-UHFFFAOYSA-N 4-[(2,6-dimethyl-4-pyrrolidin-1-ylquinolin-7-yl)methylamino]benzonitrile Chemical compound C=12C=C(C)C(CNC=3C=CC(=CC=3)C#N)=CC2=NC(C)=CC=1N1CCCC1 FBJUQLXTVWMSMQ-UHFFFAOYSA-N 0.000 claims description 5
• ZETVYJWZAJSNLN-UHFFFAOYSA-N 4-[(2-methyl-4-pyrrolidin-1-ylquinolin-7-yl)methylamino]-2-(trifluoromethyl)benzonitrile Chemical compound C=12C=CC(CNC=3C=C(C(C#N)=CC=3)C(F)(F)F)=CC2=NC(C)=CC=1N1CCCC1 ZETVYJWZAJSNLN-UHFFFAOYSA-N 0.000 claims description 5
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
• CHRSSSYOZYZOFK-UHFFFAOYSA-N 2-[(2-methyl-4-pyrrolidin-1-ylquinolin-7-yl)methoxy]benzonitrile Chemical compound C=12C=CC(COC=3C(=CC=CC=3)C#N)=CC2=NC(C)=CC=1N1CCCC1 CHRSSSYOZYZOFK-UHFFFAOYSA-N 0.000 claims description 4
• XATCREPNDSEOGK-UHFFFAOYSA-N 2-chloro-4-[(2-methyl-4-pyrrolidin-1-ylquinolin-7-yl)methoxy]benzonitrile Chemical compound C=12C=CC(COC=3C=C(Cl)C(C#N)=CC=3)=CC2=NC(C)=CC=1N1CCCC1 XATCREPNDSEOGK-UHFFFAOYSA-N 0.000 claims description 4
• SNRXFJAQZXURJY-UHFFFAOYSA-N 2-methyl-7-(pyridin-4-yloxymethyl)-4-pyrrolidin-1-ylquinoline Chemical compound C=12C=CC(COC=3C=CN=CC=3)=CC2=NC(C)=CC=1N1CCCC1 SNRXFJAQZXURJY-UHFFFAOYSA-N 0.000 claims description 4
• FQMBNIOZTFMQEB-UHFFFAOYSA-N 4-[(2-methyl-4-pyrrolidin-1-ylquinolin-7-yl)methoxy]-2-(trifluoromethyl)benzonitrile Chemical compound C=12C=CC(COC=3C=C(C(C#N)=CC=3)C(F)(F)F)=CC2=NC(C)=CC=1N1CCCC1 FQMBNIOZTFMQEB-UHFFFAOYSA-N 0.000 claims description 4
• VORUYQGEUJBGHH-UHFFFAOYSA-N 4-[(2-methyl-4-pyrrolidin-1-ylquinolin-7-yl)methoxy]benzene-1,2-dicarbonitrile Chemical compound C=12C=CC(COC=3C=C(C(C#N)=CC=3)C#N)=CC2=NC(C)=CC=1N1CCCC1 VORUYQGEUJBGHH-UHFFFAOYSA-N 0.000 claims description 4
• YRGQRXMURUGZDN-UHFFFAOYSA-N 4-[(2-methyl-4-pyrrolidin-1-ylquinolin-7-yl)methoxy]benzonitrile Chemical compound C=12C=CC(COC=3C=CC(=CC=3)C#N)=CC2=NC(C)=CC=1N1CCCC1 YRGQRXMURUGZDN-UHFFFAOYSA-N 0.000 claims description 4
• BZCCJWGPBJXSFD-UHFFFAOYSA-N 4-[(2-methyl-4-pyrrolidin-1-ylquinolin-7-yl)methylamino]benzonitrile Chemical compound C=12C=CC(CNC=3C=CC(=CC=3)C#N)=CC2=NC(C)=CC=1N1CCCC1 BZCCJWGPBJXSFD-UHFFFAOYSA-N 0.000 claims description 4
• RVEDDNXDVZBQNM-UHFFFAOYSA-N 4-[[4-(azepan-1-yl)-2-methylquinolin-7-yl]methoxy]benzonitrile Chemical compound C=12C=CC(COC=3C=CC(=CC=3)C#N)=CC2=NC(C)=CC=1N1CCCCCC1 RVEDDNXDVZBQNM-UHFFFAOYSA-N 0.000 claims description 4
• UXMOAHLHPOHSPS-QFIPXVFZSA-N 4-[[4-[(3s)-3-ethoxypyrrolidin-1-yl]-2,6-dimethylquinolin-7-yl]methoxy]benzonitrile Chemical compound C1[C@@H](OCC)CCN1C1=CC(C)=NC2=CC(COC=3C=CC(=CC=3)C#N)=C(C)C=C12 UXMOAHLHPOHSPS-QFIPXVFZSA-N 0.000 claims description 4
• BUGFCSYGBDDVKK-UHFFFAOYSA-N C(CCC)(=O)N.CC1=NC2=CC(=CC=C2C(=C1)N1CCCC1)C(=O)O Chemical compound C(CCC)(=O)N.CC1=NC2=CC(=CC=C2C(=C1)N1CCCC1)C(=O)O BUGFCSYGBDDVKK-UHFFFAOYSA-N 0.000 claims description 4
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
• LGQODQYMJCBWSG-HNNXBMFYSA-N [4-[(3s)-3-ethoxypyrrolidin-1-yl]-2,6-dimethylquinolin-7-yl]methanol Chemical compound C1[C@@H](OCC)CCN1C1=CC(C)=NC2=CC(CO)=C(C)C=C12 LGQODQYMJCBWSG-HNNXBMFYSA-N 0.000 claims description 4
• 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 4
• 239000013543 active substance Substances 0.000 claims description 4
• 125000001246 bromo group Chemical group Br* 0.000 claims description 4
• 201000010099 disease Diseases 0.000 claims description 4
• 150000004678 hydrides Chemical class 0.000 claims description 4
• 125000002346 iodo group Chemical group I* 0.000 claims description 4
• 125000004076 pyridyl group Chemical group 0.000 claims description 4
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
• OSHRLFZAABJWIA-UHFFFAOYSA-N 4-[(2,6-dimethyl-4-pyrrolidin-1-ylquinolin-7-yl)methoxy]benzonitrile Chemical compound C=12C=C(C)C(COC=3C=CC(=CC=3)C#N)=CC2=NC(C)=CC=1N1CCCC1 OSHRLFZAABJWIA-UHFFFAOYSA-N 0.000 claims description 3
• 229940127470 Lipase Inhibitors Drugs 0.000 claims description 3
• 125000005112 cycloalkylalkoxy group Chemical group 0.000 claims description 3
• 239000007787 solid Substances 0.000 description 141
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 129
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 65
• 238000007429 general method Methods 0.000 description 48
• KALINDFRXWSFSG-UHFFFAOYSA-N (2-methyl-4-pyrrolidin-1-ylquinolin-7-yl)methanol Chemical compound C=12C=CC(CO)=CC2=NC(C)=CC=1N1CCCC1 KALINDFRXWSFSG-UHFFFAOYSA-N 0.000 description 47
• 239000000243 solution Substances 0.000 description 46
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 44
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
• 239000002904 solvent Substances 0.000 description 39
• 239000012267 brine Substances 0.000 description 37
• 239000000203 mixture Substances 0.000 description 37
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 37
• 239000012044 organic layer Substances 0.000 description 35
• 229910004298 SiO 2 Inorganic materials 0.000 description 30
• 239000011541 reaction mixture Substances 0.000 description 27
• 238000001816 cooling Methods 0.000 description 25
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 24
• XJALNDJLTTXUGN-UHFFFAOYSA-N (4-chloro-2-methylquinolin-7-yl)methanol Chemical compound C1=CC(CO)=CC2=NC(C)=CC(Cl)=C21 XJALNDJLTTXUGN-UHFFFAOYSA-N 0.000 description 23
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
• 238000004587 chromatography analysis Methods 0.000 description 21
• 150000002148 esters Chemical class 0.000 description 21
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
• 229920006395 saturated elastomer Polymers 0.000 description 18
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
• 238000001914 filtration Methods 0.000 description 16
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
• 239000006260 foam Substances 0.000 description 14
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
• 230000015572 biosynthetic process Effects 0.000 description 13
• 238000003786 synthesis reaction Methods 0.000 description 13
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
• 235000019270 ammonium chloride Nutrition 0.000 description 12
• 239000000460 chlorine Substances 0.000 description 12
• 230000002829 reductive effect Effects 0.000 description 12
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 12
• AEKVBBNGWBBYLL-UHFFFAOYSA-N 4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1 AEKVBBNGWBBYLL-UHFFFAOYSA-N 0.000 description 11
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
• 238000003818 flash chromatography Methods 0.000 description 11
• 235000017557 sodium bicarbonate Nutrition 0.000 description 10
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
• 239000000725 suspension Substances 0.000 description 10
• MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical compound C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 description 9
• HNLMDHLGHYLXHV-UHFFFAOYSA-N 4-[(4-chloro-2-methylquinolin-7-yl)methoxy]benzonitrile Chemical compound C=1C2=NC(C)=CC(Cl)=C2C=CC=1COC1=CC=C(C#N)C=C1 HNLMDHLGHYLXHV-UHFFFAOYSA-N 0.000 description 9
• ZBTRVXHNFXDKAA-UHFFFAOYSA-N ClC1=CC(=NC2=CC(=C(C=C12)C)CO)C.ClC1=CC(=NC2=CC(=C(C=C12)C)COC1=CC=C(C#N)C=C1)C Chemical compound ClC1=CC(=NC2=CC(=C(C=C12)C)CO)C.ClC1=CC(=NC2=CC(=C(C=C12)C)COC1=CC=C(C#N)C=C1)C ZBTRVXHNFXDKAA-UHFFFAOYSA-N 0.000 description 9
• MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
• 239000002585 base Substances 0.000 description 9
• 239000003054 catalyst Substances 0.000 description 9
• 239000002244 precipitate Substances 0.000 description 9
• APXLGOWXMOSNNJ-UHFFFAOYSA-N (4-chloro-2-methylquinolin-7-yl)methanol 4-[(4-chloro-2-methylquinolin-7-yl)methoxy]-2-(trifluoromethyl)benzonitrile Chemical compound ClC1=CC(=NC2=CC(=CC=C12)CO)C.ClC1=CC(=NC2=CC(=CC=C12)COC1=CC(=C(C#N)C=C1)C(F)(F)F)C APXLGOWXMOSNNJ-UHFFFAOYSA-N 0.000 description 8
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 8
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
• NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 8
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
• 108020003175 receptors Proteins 0.000 description 8
• 102000005962 receptors Human genes 0.000 description 8
• 239000012312 sodium hydride Substances 0.000 description 8
• 229910000104 sodium hydride Inorganic materials 0.000 description 8
• 229910052938 sodium sulfate Inorganic materials 0.000 description 8
• 235000011152 sodium sulphate Nutrition 0.000 description 8
• HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 description 7
• 229910052794 bromium Inorganic materials 0.000 description 7
• 238000006880 cross-coupling reaction Methods 0.000 description 7
• 239000000706 filtrate Substances 0.000 description 7
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
• HOSOQDOSOGQBPQ-UHFFFAOYSA-N 4-chloro-2-methylquinoline-7-carbaldehyde Chemical compound C1=CC(C=O)=CC2=NC(C)=CC(Cl)=C21 HOSOQDOSOGQBPQ-UHFFFAOYSA-N 0.000 description 6
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