JP5581390B2 - Ａｋｔ阻害剤 - Google Patents

Info

Publication number

JP5581390B2

JP5581390B2 JP2012535319A JP2012535319A JP5581390B2 JP 5581390 B2 JP5581390 B2 JP 5581390B2 JP 2012535319 A JP2012535319 A JP 2012535319A JP 2012535319 A JP2012535319 A JP 2012535319A JP 5581390 B2 JP5581390 B2 JP 5581390B2

Authority

JP

Japan

Prior art keywords

compound

imidazol

ethyl

tert

butyl

Prior art date

2009-10-23

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

Links

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• 239000003197 protein kinase B inhibitor Substances 0.000 title description 7
• 229940126638 Akt inhibitor Drugs 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims description 325
• -1 tetrahydropyran-4-yl Chemical group 0.000 claims description 94
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 39
• 150000003839 salts Chemical class 0.000 claims description 38
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
• 229910052739 hydrogen Inorganic materials 0.000 claims description 11
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
• HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 10
• 208000005017 glioblastoma Diseases 0.000 claims description 10
• 206010006187 Breast cancer Diseases 0.000 claims description 8
• 208000026310 Breast neoplasm Diseases 0.000 claims description 8
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 8
• 201000005202 lung cancer Diseases 0.000 claims description 8
• 208000020816 lung neoplasm Diseases 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 7
• 229910052794 bromium Inorganic materials 0.000 claims description 6
• 229910052801 chlorine Inorganic materials 0.000 claims description 5
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
• 239000003085 diluting agent Substances 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 263
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 240
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 219
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 140
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 107
• 239000000243 solution Substances 0.000 description 105
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 98
• 239000000203 mixture Substances 0.000 description 95
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 86
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 86
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 82
• 238000003756 stirring Methods 0.000 description 73
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 67
• 239000011541 reaction mixture Substances 0.000 description 61
• 229920006395 saturated elastomer Polymers 0.000 description 60
• 239000012141 concentrate Substances 0.000 description 58
• 238000006243 chemical reaction Methods 0.000 description 56
• 239000007787 solid Substances 0.000 description 56
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 53
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 50
• 239000011780 sodium chloride Substances 0.000 description 48
• 238000002360 preparation method Methods 0.000 description 47
• 229910052757 nitrogen Inorganic materials 0.000 description 43
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 42
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
• 239000010410 layer Substances 0.000 description 39
• 239000002904 solvent 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
• 238000000034 method Methods 0.000 description 34
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 33
• 239000000284 extract Substances 0.000 description 33
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 32
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 30
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 30
• 238000010898 silica gel chromatography Methods 0.000 description 27
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 25
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 24
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
• 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 23
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
• 239000000706 filtrate Substances 0.000 description 23
• 239000000725 suspension Substances 0.000 description 23
• 206010028980 Neoplasm Diseases 0.000 description 22
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 20
• 238000000746 purification Methods 0.000 description 20
• 239000000908 ammonium hydroxide Substances 0.000 description 19
• 239000012044 organic layer Substances 0.000 description 19
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 18
• 108091008611 Protein Kinase B Proteins 0.000 description 18
• 239000002585 base Substances 0.000 description 18
• 230000015572 biosynthetic process Effects 0.000 description 18
• 210000004027 cell Anatomy 0.000 description 18
• 238000010626 work up procedure Methods 0.000 description 18
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
• 239000008346 aqueous phase Substances 0.000 description 16
• JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 16
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
• 229910000147 aluminium phosphate Inorganic materials 0.000 description 15
• 230000005764 inhibitory process Effects 0.000 description 15
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 15
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 14
• 239000013078 crystal Substances 0.000 description 14
• 239000003814 drug Substances 0.000 description 14
• 230000000694 effects Effects 0.000 description 14
• 238000003786 synthesis reaction Methods 0.000 description 14
• HGBDGFXWZDTFEB-SCSAIBSYSA-N (5r)-4-chloro-5-methyl-6,8-dihydro-5h-pyrido[2,3-d]pyrimidin-7-one Chemical compound C1=NC(Cl)=C2[C@H](C)CC(=O)NC2=N1 HGBDGFXWZDTFEB-SCSAIBSYSA-N 0.000 description 13
• 201000011510 cancer Diseases 0.000 description 13
• 238000004587 chromatography analysis Methods 0.000 description 13
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
• 238000003556 assay Methods 0.000 description 12
• 238000001727 in vivo Methods 0.000 description 12
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 12
• 239000003921 oil Substances 0.000 description 12
• DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 12
• JYUQEWCJWDGCRX-UHFFFAOYSA-N tert-butyl 4-formylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C=O)CC1 JYUQEWCJWDGCRX-UHFFFAOYSA-N 0.000 description 12
• 238000011282 treatment Methods 0.000 description 12
• XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 11
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 11
• XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 11
• 238000001914 filtration Methods 0.000 description 11
• 235000017557 sodium bicarbonate Nutrition 0.000 description 11
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
• 0 Cc(nc(C(CC1)CCN1C1=C2C=CC=CC=CC=C/C=C/[C@@]2NC=N1)[n]1CCN(*)IC)c1I Chemical compound Cc(nc(C(CC1)CCN1C1=C2C=CC=CC=CC=C/C=C/[C@@]2NC=N1)[n]1CCN(*)IC)c1I 0.000 description 10
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
• RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 10
• 150000002576 ketones Chemical class 0.000 description 10
• IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 10
• 229940124597 therapeutic agent Drugs 0.000 description 10
• FSNGFFWICFYWQC-UHFFFAOYSA-N 1-(2-chloroethyl)pyrrolidine;hydron;chloride Chemical compound Cl.ClCCN1CCCC1 FSNGFFWICFYWQC-UHFFFAOYSA-N 0.000 description 9
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
• 150000001412 amines Chemical group 0.000 description 9
• 235000019270 ammonium chloride Nutrition 0.000 description 9
• 239000003153 chemical reaction reagent Substances 0.000 description 9
• UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
• 239000001257 hydrogen Substances 0.000 description 9
• 239000012071 phase Substances 0.000 description 9
• 238000010992 reflux Methods 0.000 description 9
• UTUVUXYKFFKIKP-UHFFFAOYSA-N tert-butyl 4-(1h-imidazol-2-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC=CN1 UTUVUXYKFFKIKP-UHFFFAOYSA-N 0.000 description 9
• ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 8
• ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 8
• 150000001299 aldehydes Chemical class 0.000 description 8
• 239000012298 atmosphere Substances 0.000 description 8
• 239000012065 filter cake Substances 0.000 description 8
• 238000010438 heat treatment Methods 0.000 description 8
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
• 239000002002 slurry Substances 0.000 description 8
• 238000005406 washing Methods 0.000 description 8
• VNMXIOWPBADSIC-UHFFFAOYSA-N 1-(oxan-4-yl)ethanone Chemical compound CC(=O)C1CCOCC1 VNMXIOWPBADSIC-UHFFFAOYSA-N 0.000 description 7
• 102000004190 Enzymes Human genes 0.000 description 7
• 108090000790 Enzymes Proteins 0.000 description 7
• 101000669921 Homo sapiens Rho-associated protein kinase 2 Proteins 0.000 description 7
• 108091000080 Phosphotransferase Proteins 0.000 description 7
• 102100039314 Rho-associated protein kinase 2 Human genes 0.000 description 7
• 229940088598 enzyme Drugs 0.000 description 7
• 239000003112 inhibitor Substances 0.000 description 7
• 239000002609 medium Substances 0.000 description 7
• DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 7
• 102000020233 phosphotransferase Human genes 0.000 description 7
• 238000000926 separation method Methods 0.000 description 7
• JYUKMAIZDJIQSG-UHFFFAOYSA-N tert-butyl 4-(4,5-diiodo-1h-imidazol-2-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(I)=C(I)N1 JYUKMAIZDJIQSG-UHFFFAOYSA-N 0.000 description 7
• DMHCUTUEDFHEFC-UHFFFAOYSA-N tert-butyl 4-[5-(oxan-4-yl)-1h-imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C2CCOCC2)=CN1 DMHCUTUEDFHEFC-UHFFFAOYSA-N 0.000 description 7
• LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 7
• OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
• DPGSPRJLAZGUBQ-UHFFFAOYSA-N 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(C=C)OC1(C)C DPGSPRJLAZGUBQ-UHFFFAOYSA-N 0.000 description 6
• HBLHDCLWIHODIX-UHFFFAOYSA-N 4-[4-(oxan-4-yl)-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidine Chemical compound C1CCCN1CCN1C=C(C2CCOCC2)N=C1C1CCNCC1 HBLHDCLWIHODIX-UHFFFAOYSA-N 0.000 description 6
• HGBDGFXWZDTFEB-UHFFFAOYSA-N 4-chloro-5-methyl-6,8-dihydro-5h-pyrido[2,3-d]pyrimidin-7-one Chemical compound C1=NC(Cl)=C2C(C)CC(=O)NC2=N1 HGBDGFXWZDTFEB-UHFFFAOYSA-N 0.000 description 6
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
• 239000002253 acid Substances 0.000 description 6
• DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical group CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 6
• 238000001816 cooling Methods 0.000 description 6
• 238000001514 detection method Methods 0.000 description 6
• GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 6
• 239000012458 free base Substances 0.000 description 6
• 238000004128 high performance liquid chromatography Methods 0.000 description 6
• 239000000543 intermediate Substances 0.000 description 6
• BKTSPYPORGPMQE-UHFFFAOYSA-N methyl 3-(4,6-dichloropyrimidin-5-yl)butanoate Chemical compound COC(=O)CC(C)C1=C(Cl)N=CN=C1Cl BKTSPYPORGPMQE-UHFFFAOYSA-N 0.000 description 6
• XLADYKVTZFVWDT-UHFFFAOYSA-N methyl 3-(4-hydroxy-6-oxo-1h-pyrimidin-5-yl)butanoate Chemical compound COC(=O)CC(C)C1=C(O)N=CN=C1O XLADYKVTZFVWDT-UHFFFAOYSA-N 0.000 description 6
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 6
• BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
• 229910000029 sodium carbonate Inorganic materials 0.000 description 6
• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 5
• KGEDUCGWJNIMDD-UHFFFAOYSA-N 5,5,5-trifluoro-2-oxopentanal Chemical compound FC(F)(F)CCC(=O)C=O KGEDUCGWJNIMDD-UHFFFAOYSA-N 0.000 description 5
• SQKDYZDLBBSUKS-UHFFFAOYSA-N 5,5,5-trifluoropentanal Chemical compound FC(F)(F)CCCC=O SQKDYZDLBBSUKS-UHFFFAOYSA-N 0.000 description 5
• USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 5
• 239000005695 Ammonium acetate Substances 0.000 description 5
• KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 5
• 101000779418 Homo sapiens RAC-alpha serine/threonine-protein kinase Proteins 0.000 description 5
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
• 230000002378 acidificating effect Effects 0.000 description 5
• 235000019257 ammonium acetate Nutrition 0.000 description 5
• 229940043376 ammonium acetate Drugs 0.000 description 5
• 238000004458 analytical method Methods 0.000 description 5
• 231100000673 dose–response relationship Toxicity 0.000 description 5
• 238000003821 enantio-separation Methods 0.000 description 5
• 150000002148 esters Chemical class 0.000 description 5
• 238000005755 formation reaction Methods 0.000 description 5
• 238000009472 formulation Methods 0.000 description 5
• 238000005259 measurement Methods 0.000 description 5
• 238000010791 quenching Methods 0.000 description 5
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