HRP20010274A2 - Bicyclic nitrogen heterocycles - Google Patents

Info

Publication number

HRP20010274A2

HRP20010274A2 HR20010274A HRP20010274A HRP20010274A2 HR P20010274 A2 HRP20010274 A2 HR P20010274A2 HR 20010274 A HR20010274 A HR 20010274A HR P20010274 A HRP20010274 A HR P20010274A HR P20010274 A2 HRP20010274 A2 HR P20010274A2

Authority

HR

Croatia

Prior art keywords

mmol

evaporated

dihydro

pyrimidin

phenyl

Prior art date

1998-10-23

Links

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• Global Dossier
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• 229910052757 nitrogen Inorganic materials 0.000 title claims description 9
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title claims description 9
• 229920006395 saturated elastomer Polymers 0.000 claims description 119
• 150000001875 compounds Chemical class 0.000 claims description 99
• -1 2,6-dichlorophenyl Chemical group 0.000 claims description 64
• 238000006243 chemical reaction Methods 0.000 claims description 63
• 125000000217 alkyl group Chemical group 0.000 claims description 55
• 238000000034 method Methods 0.000 claims description 55
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
• 150000003839 salts Chemical class 0.000 claims description 32
• 125000003118 aryl group Chemical group 0.000 claims description 27
• 238000011282 treatment Methods 0.000 claims description 23
• 150000001412 amines Chemical class 0.000 claims description 16
• 229910052739 hydrogen Inorganic materials 0.000 claims description 13
• 239000001257 hydrogen Substances 0.000 claims description 13
• 239000002253 acid Substances 0.000 claims description 12
• 125000002843 carboxylic acid group Chemical group 0.000 claims description 12
• 206010052779 Transplant rejections Diseases 0.000 claims description 11
• 150000007513 acids Chemical class 0.000 claims description 11
• 125000001072 heteroaryl group Chemical group 0.000 claims description 11
• 238000011321 prophylaxis Methods 0.000 claims description 11
• 238000004519 manufacturing process Methods 0.000 claims description 10
• 230000002265 prevention Effects 0.000 claims description 10
• 239000000126 substance Substances 0.000 claims description 10
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 9
• 208000002249 Diabetes Complications Diseases 0.000 claims description 9
• 206010012655 Diabetic complications Diseases 0.000 claims description 9
• 208000006673 asthma Diseases 0.000 claims description 9
• 150000002431 hydrogen Chemical group 0.000 claims description 9
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
• 230000001900 immune effect Effects 0.000 claims description 9
• 230000002757 inflammatory effect Effects 0.000 claims description 9
• 230000000771 oncological effect Effects 0.000 claims description 9
• 239000000825 pharmaceutical preparation Substances 0.000 claims description 9
• 238000001356 surgical procedure Methods 0.000 claims description 9
• 208000015114 central nervous system disease Diseases 0.000 claims description 8
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
• 150000007514 bases Chemical class 0.000 claims description 7
• 239000003814 drug Substances 0.000 claims description 7
• 125000005002 aryl methyl group Chemical group 0.000 claims description 6
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
• 125000003545 alkoxy group Chemical group 0.000 claims description 5
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000005059 halophenyl group Chemical group 0.000 claims description 4
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
• 239000007795 chemical reaction product Substances 0.000 claims description 3
• 201000010099 disease Diseases 0.000 claims description 3
• 125000005842 heteroatom Chemical group 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
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
• 229910052760 oxygen Inorganic materials 0.000 claims description 3
• 125000006850 spacer group Chemical group 0.000 claims description 3
• 229910052717 sulfur Inorganic materials 0.000 claims description 3
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
• 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
• 229940079593 drug Drugs 0.000 claims description 2
• 229910052740 iodine Inorganic materials 0.000 claims description 2
• 239000001301 oxygen Substances 0.000 claims description 2
• 238000000926 separation method Methods 0.000 claims description 2
• 239000011593 sulfur Substances 0.000 claims description 2
• 210000003169 central nervous system Anatomy 0.000 claims 1
• 208000035475 disorder Diseases 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 698
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 346
• 239000000243 solution Substances 0.000 description 305
• 239000000203 mixture Substances 0.000 description 279
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 264
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 261
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 257
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 218
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 196
• 239000007787 solid Substances 0.000 description 195
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 183
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 176
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 173
• 235000019341 magnesium sulphate Nutrition 0.000 description 173
• 239000000047 product Substances 0.000 description 151
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 143
• RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 136
• 238000001819 mass spectrum Methods 0.000 description 127
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 120
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 109
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 106
• 235000017557 sodium bicarbonate Nutrition 0.000 description 95
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 95
• 239000012074 organic phase Substances 0.000 description 89
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 81
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 78
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 78
• 239000000741 silica gel Substances 0.000 description 78
• 229910002027 silica gel Inorganic materials 0.000 description 78
• 239000007858 starting material Substances 0.000 description 68
• 238000002844 melting Methods 0.000 description 67
• 230000008018 melting Effects 0.000 description 67
• 239000003480 eluent Substances 0.000 description 65
• 238000004587 chromatography analysis Methods 0.000 description 62
• 229960000583 acetic acid Drugs 0.000 description 59
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
• 239000012071 phase Substances 0.000 description 48
• 239000002904 solvent Substances 0.000 description 41
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 40
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 38
• 238000010992 reflux Methods 0.000 description 38
• 239000000706 filtrate Substances 0.000 description 37
• 239000011541 reaction mixture Substances 0.000 description 35
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 33
• LFJGGGIWERIGNX-UHFFFAOYSA-N 4-[2-(diethylamino)ethoxy]aniline Chemical compound CCN(CC)CCOC1=CC=C(N)C=C1 LFJGGGIWERIGNX-UHFFFAOYSA-N 0.000 description 31
• 239000003921 oil Substances 0.000 description 30
• 235000019198 oils Nutrition 0.000 description 30
• 239000000725 suspension Substances 0.000 description 28
• 238000010898 silica gel chromatography Methods 0.000 description 26
• 239000012280 lithium aluminium hydride Substances 0.000 description 24
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 21
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
• HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 21
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 20
• YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 19
• NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 18
• 239000013058 crude material Substances 0.000 description 17
• 238000001914 filtration Methods 0.000 description 17
• NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 16
• AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 16
• 235000019270 ammonium chloride Nutrition 0.000 description 16
• IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 16
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
• 238000010533 azeotropic distillation Methods 0.000 description 15
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
• 238000005406 washing Methods 0.000 description 15
• DKMQAOXNQQCNNM-UHFFFAOYSA-N 3-(2,6-dichlorophenyl)-1-methyl-7-methylsulfonyl-4h-pyrimido[4,5-d]pyrimidin-2-one Chemical compound C1C2=CN=C(S(C)(=O)=O)N=C2N(C)C(=O)N1C1=C(Cl)C=CC=C1Cl DKMQAOXNQQCNNM-UHFFFAOYSA-N 0.000 description 14
• JPOJBQLUJAIHHL-UHFFFAOYSA-N 1h-pyrimido[4,5-d]pyrimidin-2-one Chemical compound N1=CN=C2NC(=O)N=CC2=C1 JPOJBQLUJAIHHL-UHFFFAOYSA-N 0.000 description 13
• JDMFXJULNGEPOI-UHFFFAOYSA-N 2,6-dichloroaniline Chemical compound NC1=C(Cl)C=CC=C1Cl JDMFXJULNGEPOI-UHFFFAOYSA-N 0.000 description 13
• 239000007864 aqueous solution Substances 0.000 description 13
• 150000004945 aromatic hydrocarbons Chemical class 0.000 description 13
• 239000012299 nitrogen atmosphere Substances 0.000 description 13
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 12
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
• 239000010410 layer Substances 0.000 description 12
• 230000003647 oxidation Effects 0.000 description 12
• 238000007254 oxidation reaction Methods 0.000 description 12
• FYPDTUFSUFLWTO-UHFFFAOYSA-N 3-(2,6-dichlorophenyl)-7-methylsulfonyl-1-phenyl-4h-pyrimido[4,5-d]pyrimidin-2-one Chemical compound C12=NC(S(=O)(=O)C)=NC=C2CN(C=2C(=CC=CC=2Cl)Cl)C(=O)N1C1=CC=CC=C1 FYPDTUFSUFLWTO-UHFFFAOYSA-N 0.000 description 11
• 239000012230 colorless oil Substances 0.000 description 11
• 125000004122 cyclic group Chemical class 0.000 description 11
• AOPBDRUWRLBSDB-UHFFFAOYSA-N 2-bromoaniline Chemical compound NC1=CC=CC=C1Br AOPBDRUWRLBSDB-UHFFFAOYSA-N 0.000 description 10
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 10
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
• PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• 239000012279 sodium borohydride Substances 0.000 description 10
• 229910000033 sodium borohydride Inorganic materials 0.000 description 10
• WFNLHDJJZSJARK-UHFFFAOYSA-N 2-chloro-6-methylaniline Chemical compound CC1=CC=CC(Cl)=C1N WFNLHDJJZSJARK-UHFFFAOYSA-N 0.000 description 9
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
• 238000010828 elution Methods 0.000 description 9
• SNNHLSHDDGJVDM-UHFFFAOYSA-N ethyl 4-chloro-2-methylsulfanylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(SC)N=C1Cl SNNHLSHDDGJVDM-UHFFFAOYSA-N 0.000 description 9
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
• SOSKTLIORVPIQK-UHFFFAOYSA-N 3-(2,6-difluorophenyl)-1-methyl-7-methylsulfonyl-4h-pyrimido[4,5-d]pyrimidin-2-one Chemical compound C1C2=CN=C(S(C)(=O)=O)N=C2N(C)C(=O)N1C1=C(F)C=CC=C1F SOSKTLIORVPIQK-UHFFFAOYSA-N 0.000 description 8
• ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 8
• CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 8
• OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
• 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 8
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 8
• 239000007788 liquid Substances 0.000 description 8
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
• 239000012312 sodium hydride Substances 0.000 description 8
• 229910000104 sodium hydride Inorganic materials 0.000 description 8
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
• 239000008096 xylene Substances 0.000 description 8
• KQCMTOWTPBNWDB-UHFFFAOYSA-N 2,4-dichloroaniline Chemical compound NC1=CC=C(Cl)C=C1Cl KQCMTOWTPBNWDB-UHFFFAOYSA-N 0.000 description 7
• ODUZJBKKYBQIBX-UHFFFAOYSA-N 2,6-difluoroaniline Chemical compound NC1=C(F)C=CC=C1F ODUZJBKKYBQIBX-UHFFFAOYSA-N 0.000 description 7
• KUABOYVOOBOICM-UHFFFAOYSA-N 2-methyl-4-(methylamino)pyrimidine-5-carbothialdehyde Chemical compound CNC1=NC(C)=NC=C1C=S KUABOYVOOBOICM-UHFFFAOYSA-N 0.000 description 7
• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 7
• GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 7
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
• 239000011780 sodium chloride Substances 0.000 description 7
• UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 6
• DGNQWZHSZZRVKY-UHFFFAOYSA-N 3-cyclohexyl-1-methyl-7-methylsulfonyl-4h-pyrimido[4,5-d]pyrimidin-2-one Chemical compound C1C2=CN=C(S(C)(=O)=O)N=C2N(C)C(=O)N1C1CCCCC1 DGNQWZHSZZRVKY-UHFFFAOYSA-N 0.000 description 6
• MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 description 6
• XMFVPJWFIPAVTG-UHFFFAOYSA-N 6-(2,6-dichlorophenyl)-2-methylsulfonyl-5,8-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound O=C1NC2=NC(S(=O)(=O)C)=NC=C2CN1C1=C(Cl)C=CC=C1Cl XMFVPJWFIPAVTG-UHFFFAOYSA-N 0.000 description 6
• ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
• KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 6
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
• 239000002585 base Substances 0.000 description 6
• 238000001816 cooling Methods 0.000 description 6
• VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 6
• 238000001665 trituration Methods 0.000 description 6
• TVMWJKHBIUODJN-UHFFFAOYSA-N 2-[2-[3-[7-anilino-3-(2,6-dichlorophenyl)-2-oxo-4h-pyrimido[4,5-d]pyrimidin-1-yl]phenyl]ethyl]isoindole-1,3-dione Chemical compound ClC1=CC=CC(Cl)=C1N1C(=O)N(C=2C=C(CCN3C(C4=CC=CC=C4C3=O)=O)C=CC=2)C2=NC(NC=3C=CC=CC=3)=NC=C2C1 TVMWJKHBIUODJN-UHFFFAOYSA-N 0.000 description 5
• HIWFKHBQWGOMAQ-UHFFFAOYSA-N 4-[3-(2-hydroxyethyl)anilino]-2-methylsulfanylpyrimidine-5-carbaldehyde Chemical compound CSC1=NC=C(C=O)C(NC=2C=C(CCO)C=CC=2)=N1 HIWFKHBQWGOMAQ-UHFFFAOYSA-N 0.000 description 5
• 125000003277 amino group Chemical group 0.000 description 5
• 239000008346 aqueous phase Substances 0.000 description 5
• 239000000969 carrier Substances 0.000 description 5
• 239000006071 cream Substances 0.000 description 5
• 238000002425 crystallisation Methods 0.000 description 5
• 230000008025 crystallization Effects 0.000 description 5
• LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 5
• KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 5
• 229910000027 potassium carbonate Inorganic materials 0.000 description 5
• 238000000746 purification Methods 0.000 description 5
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 5
• RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 4
• PDDICYMOFZWURN-UHFFFAOYSA-N 2-[3-[[5-[(2,6-dichloroanilino)methyl]-2-methylsulfanylpyrimidin-4-yl]amino]phenyl]ethanol Chemical compound C=1C=CC(CCO)=CC=1NC1=NC(SC)=NC=C1CNC1=C(Cl)C=CC=C1Cl PDDICYMOFZWURN-UHFFFAOYSA-N 0.000 description 4
• VNJOEUSYAMPBAK-UHFFFAOYSA-N 2-methylbenzenesulfonic acid;hydrate Chemical compound O.CC1=CC=CC=C1S(O)(=O)=O VNJOEUSYAMPBAK-UHFFFAOYSA-N 0.000 description 4
• SQZBBRFSAWJTEM-UHFFFAOYSA-N 3-(2-bromophenyl)-1-[3-(2-hydroxyethyl)phenyl]-7-methylsulfanyl-4h-pyrimido[4,5-d]pyrimidin-2-one Chemical compound C12=NC(SC)=NC=C2CN(C=2C(=CC=CC=2)Br)C(=O)N1C1=CC=CC(CCO)=C1 SQZBBRFSAWJTEM-UHFFFAOYSA-N 0.000 description 4
• BHVAESQUGJJBRK-UHFFFAOYSA-N 3-(2-bromophenyl)-1-[3-(2-hydroxyethyl)phenyl]-7-methylsulfonyl-4h-pyrimido[4,5-d]pyrimidin-2-one Chemical compound C12=NC(S(=O)(=O)C)=NC=C2CN(C=2C(=CC=CC=2)Br)C(=O)N1C1=CC=CC(CCO)=C1 BHVAESQUGJJBRK-UHFFFAOYSA-N 0.000 description 4
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