TWI571471B - 螺環芳基磷氧化物和芳基磷硫化物 - Google Patents

Info

Publication number

TWI571471B

TWI571471B TW104121403A TW104121403A TWI571471B TW I571471 B TWI571471 B TW I571471B TW 104121403 A TW104121403 A TW 104121403A TW 104121403 A TW104121403 A TW 104121403A TW I571471 B TWI571471 B TW I571471B

Authority

TW

Taiwan

Prior art keywords

compound

amino

title compound

shown below

mmol

Prior art date

2014-07-04

Links

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• -1 aryl phosphorous sulfides Chemical class 0.000 title description 129
• 125000003118 aryl group Chemical group 0.000 title description 22
• 150000001875 compounds Chemical class 0.000 claims description 476
• 238000002360 preparation method Methods 0.000 claims description 95
• 206010028980 Neoplasm Diseases 0.000 claims description 48
• 229910052757 nitrogen Inorganic materials 0.000 claims description 42
• 150000003839 salts Chemical class 0.000 claims description 42
• 125000005842 heteroatom Chemical group 0.000 claims description 38
• 229910052717 sulfur Inorganic materials 0.000 claims description 31
• 125000000217 alkyl group Chemical group 0.000 claims description 28
• 229910052739 hydrogen Inorganic materials 0.000 claims description 27
• 229910052760 oxygen Inorganic materials 0.000 claims description 27
• 102100033793 ALK tyrosine kinase receptor Human genes 0.000 claims description 26
• 229910052799 carbon Inorganic materials 0.000 claims description 19
• 125000001072 heteroaryl group Chemical group 0.000 claims description 15
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 11
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
• 229910052736 halogen Inorganic materials 0.000 claims description 10
• 229910052740 iodine Inorganic materials 0.000 claims description 10
• 229910052731 fluorine Inorganic materials 0.000 claims description 9
• 150000002367 halogens Chemical class 0.000 claims description 9
• 229910052794 bromium Inorganic materials 0.000 claims description 8
• 229910052801 chlorine Inorganic materials 0.000 claims description 8
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
• 125000001183 hydrocarbyl group Chemical group 0.000 claims description 8
• 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 7
• 230000035772 mutation Effects 0.000 claims description 7
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 6
• 201000011510 cancer Diseases 0.000 claims description 6
• 239000003112 inhibitor Substances 0.000 claims description 5
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
• 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 3
• 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 3
• YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims description 3
• 229910052698 phosphorus Inorganic materials 0.000 claims description 3
• 101000605639 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Proteins 0.000 claims description 2
• 101000686031 Homo sapiens Proto-oncogene tyrosine-protein kinase ROS Proteins 0.000 claims description 2
• 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 2
• 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 claims description 2
• 102100038332 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Human genes 0.000 claims description 2
• 102100023347 Proto-oncogene tyrosine-protein kinase ROS Human genes 0.000 claims description 2
• 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 2
• 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 claims description 2
• 108091008605 VEGF receptors Proteins 0.000 claims description 2
• 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 2
• 231100000599 cytotoxic agent Toxicity 0.000 claims description 2
• 239000002619 cytotoxin Substances 0.000 claims description 2
• 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 2
• 101710112752 Cytotoxin Proteins 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 308
• 238000000034 method Methods 0.000 description 214
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 145
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 142
• 235000019439 ethyl acetate Nutrition 0.000 description 140
• 239000011541 reaction mixture Substances 0.000 description 109
• 239000000203 mixture Substances 0.000 description 106
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 97
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
• WQAWEUZTDVWTDB-UHFFFAOYSA-N dimethyl(oxo)phosphanium Chemical compound C[P+](C)=O WQAWEUZTDVWTDB-UHFFFAOYSA-N 0.000 description 78
• 239000013078 crystal Substances 0.000 description 67
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 66
• 238000006243 chemical reaction Methods 0.000 description 63
• 239000000243 solution Substances 0.000 description 63
• 238000005481 NMR spectroscopy Methods 0.000 description 59
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
• 239000007787 solid Substances 0.000 description 42
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
• 238000004809 thin layer chromatography Methods 0.000 description 40
• 239000003921 oil Substances 0.000 description 34
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
• OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 31
• 125000001424 substituent group Chemical group 0.000 description 30
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
• 239000012044 organic layer Substances 0.000 description 27
• 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 26
• PHFHJCOYBQFRBG-UHFFFAOYSA-N 2-methoxy-5-(6-methyl-6-azaspiro[3.4]octan-2-yl)aniline Chemical group COC1=C(N)C=C(C=C1)C1CC2(C1)CN(CC2)C PHFHJCOYBQFRBG-UHFFFAOYSA-N 0.000 description 24
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
• DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 21
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
• 125000004429 atom Chemical group 0.000 description 19
• 239000002585 base Substances 0.000 description 19
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 17
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 17
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
• QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 15
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
• 239000002253 acid Substances 0.000 description 14
• 239000003208 petroleum Substances 0.000 description 14
• 125000004432 carbon atom Chemical group C* 0.000 description 13
• 239000001257 hydrogen Substances 0.000 description 13
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
• 210000004027 cell Anatomy 0.000 description 12
• 238000002474 experimental method Methods 0.000 description 12
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
• 239000002146 L01XE16 - Crizotinib Substances 0.000 description 10
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
• 229910052796 boron Inorganic materials 0.000 description 10
• KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 10
• 229960005061 crizotinib Drugs 0.000 description 10
• 125000000623 heterocyclic group Chemical group 0.000 description 10
• 239000012074 organic phase Substances 0.000 description 10
• CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 10
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
• 241001465754 Metazoa Species 0.000 description 9
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 9
• 241000699670 Mus sp. Species 0.000 description 9
• 239000012043 crude product Substances 0.000 description 9
• 239000000706 filtrate Substances 0.000 description 9
• 125000004433 nitrogen atom Chemical group N* 0.000 description 9
• 230000002829 reductive effect Effects 0.000 description 9
• 239000002904 solvent Substances 0.000 description 9
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
• WLKUSVNHZXUEFO-UHFFFAOYSA-N 4-fluoro-2-methoxy-1-nitrobenzene Chemical compound COC1=CC(F)=CC=C1[N+]([O-])=O WLKUSVNHZXUEFO-UHFFFAOYSA-N 0.000 description 8
• 101150023956 ALK gene Proteins 0.000 description 8
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
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• 208000002154 non-small cell lung carcinoma Diseases 0.000 description 8
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• 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 8
• RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 8
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
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• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
• 210000000349 chromosome Anatomy 0.000 description 7
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• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
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• 239000011734 sodium Substances 0.000 description 7
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• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
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• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 4
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