ES2527176T3 - Compuestos y composiciones como inhibidores de proteína quinasa - Google Patents

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Publication number

ES2527176T3

ES2527176T3 ES10745280.7T ES10745280T ES2527176T3 ES 2527176 T3 ES2527176 T3 ES 2527176T3 ES 10745280 T ES10745280 T ES 10745280T ES 2527176 T3 ES2527176 T3 ES 2527176T3

Authority

ES

Spain

Prior art keywords

mmol

imidazol

methyl

amino

alkyl

Prior art date

2009-08-28

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.)

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 135
• 239000000203 mixture Substances 0.000 title description 123
• 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 2
• 239000003909 protein kinase inhibitor Substances 0.000 title description 2
• 150000003839 salts Chemical class 0.000 claims abstract description 57
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 36
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 29
• 150000002367 halogens Chemical class 0.000 claims abstract description 24
• 229920006395 saturated elastomer Polymers 0.000 claims abstract description 24
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 21
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 12
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 11
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 10
• 125000005843 halogen group Chemical group 0.000 claims abstract description 9
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 7
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 7
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
• 125000002619 bicyclic group Chemical group 0.000 claims abstract description 4
• 125000002950 monocyclic group Chemical group 0.000 claims abstract description 4
• 125000001424 substituent group Chemical group 0.000 claims abstract description 4
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 3
• 125000003367 polycyclic group Chemical group 0.000 claims abstract description 3
• -1 methoxy, methyl Chemical group 0.000 claims description 283
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 182
• 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 158
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 113
• OVPLZYJGTGDFNB-UHFFFAOYSA-N propan-2-yl carbamate Chemical compound CC(C)OC(N)=O OVPLZYJGTGDFNB-UHFFFAOYSA-N 0.000 claims description 54
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
• 239000003814 drug Substances 0.000 claims description 22
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 21
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
• 239000008194 pharmaceutical composition Substances 0.000 claims description 17
• 238000011282 treatment Methods 0.000 claims description 17
• 229940124597 therapeutic agent Drugs 0.000 claims description 15
• 206010028980 Neoplasm Diseases 0.000 claims description 14
• 229910052731 fluorine Inorganic materials 0.000 claims description 12
• 229910052739 hydrogen Inorganic materials 0.000 claims description 11
• 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 10
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
• 201000011510 cancer Diseases 0.000 claims description 9
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
• 201000001441 melanoma Diseases 0.000 claims description 8
• 229910052801 chlorine Inorganic materials 0.000 claims description 7
• 239000003085 diluting agent Substances 0.000 claims description 7
• 208000035475 disorder Diseases 0.000 claims description 7
• 206010009944 Colon cancer Diseases 0.000 claims description 4
• 230000001430 anti-depressive effect Effects 0.000 claims description 4
• 230000003474 anti-emetic effect Effects 0.000 claims description 4
• 239000002260 anti-inflammatory agent Substances 0.000 claims description 4
• 229940121363 anti-inflammatory agent Drugs 0.000 claims description 4
• 239000000935 antidepressant agent Substances 0.000 claims description 4
• 229940005513 antidepressants Drugs 0.000 claims description 4
• 239000002111 antiemetic agent Substances 0.000 claims description 4
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 4
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
• 230000000202 analgesic effect Effects 0.000 claims description 2
• 239000002246 antineoplastic agent Substances 0.000 claims description 2
• 229940041181 antineoplastic drug Drugs 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• 208000003200 Adenoma Diseases 0.000 claims 2
• 206010005003 Bladder cancer Diseases 0.000 claims 2
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims 2
• 201000001531 bladder carcinoma Diseases 0.000 claims 2
• 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims 2
• 201000005296 lung carcinoma Diseases 0.000 claims 2
• 208000008443 pancreatic carcinoma Diseases 0.000 claims 2
• 208000010570 urinary bladder carcinoma Diseases 0.000 claims 2
• 206010060862 Prostate cancer Diseases 0.000 claims 1
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims 1
• 208000024770 Thyroid neoplasm Diseases 0.000 claims 1
• 201000002510 thyroid cancer Diseases 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 449
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 293
• 235000019439 ethyl acetate Nutrition 0.000 description 218
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 192
• 238000006243 chemical reaction Methods 0.000 description 173
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 167
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 154
• 239000000243 solution Substances 0.000 description 146
• 238000002360 preparation method Methods 0.000 description 135
• 229910001868 water Inorganic materials 0.000 description 111
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 98
• 230000014759 maintenance of location Effects 0.000 description 98
• 239000011541 reaction mixture Substances 0.000 description 84
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 82
• 239000007787 solid Substances 0.000 description 82
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 79
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
• 238000005481 NMR spectroscopy Methods 0.000 description 77
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 72
• VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 71
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 69
• 239000000463 material Substances 0.000 description 67
• 239000012267 brine Substances 0.000 description 66
• 239000000377 silicon dioxide Substances 0.000 description 66
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 65
• 229910052681 coesite Inorganic materials 0.000 description 61
• 229910052906 cristobalite Inorganic materials 0.000 description 61
• 235000012239 silicon dioxide Nutrition 0.000 description 61
• 229910052682 stishovite Inorganic materials 0.000 description 61
• 229910052905 tridymite Inorganic materials 0.000 description 61
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 59
• 238000000034 method Methods 0.000 description 58
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 54
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 53
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 53
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 52
• 239000010410 layer Substances 0.000 description 52
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 50
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical group CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 42
• 238000003818 flash chromatography Methods 0.000 description 42
• 238000000746 purification Methods 0.000 description 42
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 37
• 239000003921 oil Substances 0.000 description 35
• 238000000605 extraction Methods 0.000 description 33
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
• 238000005160 1H NMR spectroscopy Methods 0.000 description 31
• RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 31
• 235000017557 sodium bicarbonate Nutrition 0.000 description 29
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 29
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 28
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 28
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 26
• 235000019341 magnesium sulphate Nutrition 0.000 description 26
• 239000000047 product Substances 0.000 description 26
• 239000007858 starting material Substances 0.000 description 26
• 101100381978 Mus musculus Braf gene Proteins 0.000 description 25
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 25
• 239000000706 filtrate Substances 0.000 description 25
• 239000000543 intermediate Substances 0.000 description 25
• 239000012044 organic layer Substances 0.000 description 25
• 229910000029 sodium carbonate Inorganic materials 0.000 description 25
• 235000017550 sodium carbonate Nutrition 0.000 description 25
• KKVYYGGCHJGEFJ-UHFFFAOYSA-N 1-n-(4-chlorophenyl)-6-methyl-5-n-[3-(7h-purin-6-yl)pyridin-2-yl]isoquinoline-1,5-diamine Chemical compound N=1C=CC2=C(NC=3C(=CC=CN=3)C=3C=4N=CNC=4N=CN=3)C(C)=CC=C2C=1NC1=CC=C(Cl)C=C1 KKVYYGGCHJGEFJ-UHFFFAOYSA-N 0.000 description 24
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
• 239000007864 aqueous solution Substances 0.000 description 24
• 210000003050 axon Anatomy 0.000 description 24
• 239000012074 organic phase Substances 0.000 description 23
• 244000257039 Duranta repens Species 0.000 description 22
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 22
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 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 20
• RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 18
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
• 229910052757 nitrogen Inorganic materials 0.000 description 18
• 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 16
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 15
• 238000004128 high performance liquid chromatography Methods 0.000 description 15
• 241001459693 Dipterocarpus zeylanicus Species 0.000 description 14
• 229910052786 argon Inorganic materials 0.000 description 14
• 239000000725 suspension Substances 0.000 description 14
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 13
• 108091000080 Phosphotransferase Proteins 0.000 description 13
• 244000180577 Sambucus australis Species 0.000 description 13
• 235000018734 Sambucus australis Nutrition 0.000 description 13
• XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 13
• 102000020233 phosphotransferase Human genes 0.000 description 13
• 239000002904 solvent Substances 0.000 description 13
• 238000003756 stirring Methods 0.000 description 13
• BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 12
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 12
• 229910052799 carbon Inorganic materials 0.000 description 12
• 239000003795 chemical substances by application Substances 0.000 description 12
• 238000012360 testing method Methods 0.000 description 12
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
• 235000019270 ammonium chloride Nutrition 0.000 description 11
• 239000008346 aqueous phase Substances 0.000 description 11
• 239000002585 base Substances 0.000 description 11
• 238000010992 reflux Methods 0.000 description 11
• BHRDAUOXWKBEKC-UHFFFAOYSA-N 2-[[4-bromo-5-(2-chloropyrimidin-4-yl)-2-cyclopropylimidazol-1-yl]methoxy]ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCN1C(C2CC2)=NC(Br)=C1C1=CC=NC(Cl)=N1 BHRDAUOXWKBEKC-UHFFFAOYSA-N 0.000 description 10
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 10
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• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 10
• 235000011114 ammonium hydroxide Nutrition 0.000 description 10
• 239000000460 chlorine Substances 0.000 description 10
• 201000010099 disease Diseases 0.000 description 10
• LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 10
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 10
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
• 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 9
• AXHRGVJWDJDYPO-UHFFFAOYSA-N 2-bromo-1h-imidazole Chemical compound BrC1=NC=CN1 AXHRGVJWDJDYPO-UHFFFAOYSA-N 0.000 description 9
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
• 230000015572 biosynthetic process Effects 0.000 description 9
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 9
• 229910052794 bromium Inorganic materials 0.000 description 9
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
• 239000013058 crude material Substances 0.000 description 9
• UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
• 239000000499 gel Substances 0.000 description 9
• HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 9
• BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 9
• 239000012071 phase Substances 0.000 description 9
• 239000000741 silica gel Substances 0.000 description 9
• 229910002027 silica gel Inorganic materials 0.000 description 9
• 229910000104 sodium hydride Inorganic materials 0.000 description 9
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
• OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 8
• 239000004480 active ingredient Substances 0.000 description 8
• ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 8
• 230000000694 effects Effects 0.000 description 8
• 239000012065 filter cake Substances 0.000 description 8
• 150000003840 hydrochlorides Chemical class 0.000 description 8
• NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 8
• 102000009929 raf Kinases Human genes 0.000 description 8
• 108010077182 raf Kinases Proteins 0.000 description 8
• MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 8
• 238000003786 synthesis reaction Methods 0.000 description 8
• UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 7
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 7
• 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 7
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
• 239000002253 acid Substances 0.000 description 7
• 125000001246 bromo group Chemical group Br* 0.000 description 7
• 239000003153 chemical reaction reagent Substances 0.000 description 7
• FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 7
• 239000012458 free base Substances 0.000 description 7
• 238000010438 heat treatment Methods 0.000 description 7
• 230000005855 radiation Effects 0.000 description 7
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