CA2963639C - Substituted aminopurine compounds, compositions thereof, and methods of treatment therewith - Google Patents

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Publication number

CA2963639C

CA2963639C CA2963639A CA2963639A CA2963639C CA 2963639 C CA2963639 C CA 2963639C CA 2963639 A CA2963639 A CA 2963639A CA 2963639 A CA2963639 A CA 2963639A CA 2963639 C CA2963639 C CA 2963639C

Authority

CA

Canada

Prior art keywords

purin

chloro

lamino

ylamino

pyran

Prior art date

2014-10-06

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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• -1 aminopurine compounds Chemical class 0.000 title claims abstract description 287
• 238000000034 method Methods 0.000 title claims abstract description 122
• 238000011282 treatment Methods 0.000 title claims description 22
• 239000000203 mixture Chemical class 0.000 title abstract description 245
• 150000001875 compounds Chemical class 0.000 claims abstract description 209
• 150000003839 salts Chemical class 0.000 claims abstract description 79
• 201000001441 melanoma Diseases 0.000 claims abstract description 31
• PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 claims description 837
• 125000000217 alkyl group Chemical group 0.000 claims description 69
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 50
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 50
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 45
• DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 claims description 34
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 33
• 229910052736 halogen Inorganic materials 0.000 claims description 29
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 28
• 210000004027 cell Anatomy 0.000 claims description 25
• 125000003118 aryl group Chemical group 0.000 claims description 24
• CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 23
• 125000001424 substituent group Chemical group 0.000 claims description 23
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
• 125000000623 heterocyclic group Chemical group 0.000 claims description 19
• 150000002367 halogens Chemical class 0.000 claims description 18
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 11
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 11
• 229910052731 fluorine Inorganic materials 0.000 claims description 11
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
• 150000001408 amides Chemical class 0.000 claims description 9
• 239000003814 drug Substances 0.000 claims description 9
• 239000003981 vehicle Substances 0.000 claims description 9
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 7
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
• 125000005936 piperidyl group Chemical group 0.000 claims description 7
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 125000001072 heteroaryl group Chemical group 0.000 claims description 6
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
• 239000008194 pharmaceutical composition Substances 0.000 claims description 6
• 230000002265 prevention Effects 0.000 claims description 6
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 6
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
• 125000005843 halogen group Chemical group 0.000 claims description 5
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 5
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 5
• 125000003566 oxetanyl group Chemical group 0.000 claims description 5
• 125000004076 pyridyl group Chemical group 0.000 claims description 5
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 4
• 108091000080 Phosphotransferase Proteins 0.000 claims description 4
• 125000003551 oxepanyl group Chemical group 0.000 claims description 4
• 102000020233 phosphotransferase Human genes 0.000 claims description 4
• BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical compound O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 claims description 4
• 102000001253 Protein Kinase Human genes 0.000 claims description 3
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
• 230000004663 cell proliferation Effects 0.000 claims description 3
• 229910052801 chlorine Inorganic materials 0.000 claims description 3
• 125000000068 chlorophenyl group Chemical group 0.000 claims description 3
• 238000000338 in vitro Methods 0.000 claims description 3
• 230000002401 inhibitory effect Effects 0.000 claims description 3
• 108060006633 protein kinase Proteins 0.000 claims description 3
• 125000005916 2-methylpentyl group Chemical group 0.000 claims description 2
• 125000005917 3-methylpentyl group Chemical group 0.000 claims description 2
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
• UHCBBWUQDAVSMS-UHFFFAOYSA-N fluoroethane Chemical group CCF UHCBBWUQDAVSMS-UHFFFAOYSA-N 0.000 claims description 2
• 230000005764 inhibitory process Effects 0.000 claims description 2
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
• 102000006835 Lamins Human genes 0.000 claims 23
• 108010047294 Lamins Proteins 0.000 claims 23
• 210000005053 lamin Anatomy 0.000 claims 23
• 101100086716 Caenorhabditis elegans ran-3 gene Proteins 0.000 claims 6
• 229940035339 tri-chlor Drugs 0.000 claims 2
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
• 101100080643 Caenorhabditis elegans ran-4 gene Proteins 0.000 claims 1
• 238000004519 manufacturing process Methods 0.000 claims 1
• 206010028980 Neoplasm Diseases 0.000 abstract description 21
• 201000011510 cancer Diseases 0.000 abstract description 10
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 208
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 204
• 230000000694 effects Effects 0.000 description 173
• 239000000243 solution Substances 0.000 description 166
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 159
• 238000006243 chemical reaction Methods 0.000 description 148
• 238000005160 1H NMR spectroscopy Methods 0.000 description 112
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 86
• 239000007787 solid Substances 0.000 description 85
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 76
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 75
• 239000002904 solvent Substances 0.000 description 75
• 238000000746 purification Methods 0.000 description 73
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 72
• 239000011541 reaction mixture Substances 0.000 description 66
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 64
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 55
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
• 238000010626 work up procedure Methods 0.000 description 54
• 101150041968 CDC13 gene Proteins 0.000 description 50
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 50
• 125000004545 purin-9-yl group Chemical group N1=CN=C2N(C=NC2=C1)* 0.000 description 50
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 48
• FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 47
• GDLOOQFSFHLRKT-UHFFFAOYSA-N 1-methylcyclohexane-1-carboxamide Chemical compound NC(=O)C1(C)CCCCC1 GDLOOQFSFHLRKT-UHFFFAOYSA-N 0.000 description 47
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 47
• 229910052938 sodium sulfate Inorganic materials 0.000 description 46
• 235000011152 sodium sulphate Nutrition 0.000 description 46
• NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 43
• 239000007832 Na2SO4 Substances 0.000 description 42
• 239000000706 filtrate Substances 0.000 description 42
• 150000003254 radicals Chemical group 0.000 description 41
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 37
• 239000012044 organic layer Substances 0.000 description 34
• 239000000725 suspension Substances 0.000 description 29
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
• 238000010898 silica gel chromatography Methods 0.000 description 27
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
• JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 26
• 229910052739 hydrogen Inorganic materials 0.000 description 25
• 239000012043 crude product Substances 0.000 description 24
• 239000003921 oil Substances 0.000 description 24
• 235000019198 oils Nutrition 0.000 description 24
• 238000003756 stirring Methods 0.000 description 24
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 22
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
• 239000001257 hydrogen Substances 0.000 description 21
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 21
• 239000011347 resin Substances 0.000 description 21
• 229920005989 resin Polymers 0.000 description 21
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 20
• 238000004440 column chromatography Methods 0.000 description 19
• 239000000741 silica gel Substances 0.000 description 19
• 229910002027 silica gel Inorganic materials 0.000 description 19
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
• 229910052763 palladium Inorganic materials 0.000 description 17
• 230000002829 reductive effect Effects 0.000 description 17
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
• 238000005481 NMR spectroscopy Methods 0.000 description 16
• 239000007821 HATU Substances 0.000 description 15
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 15
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 15
• 239000012074 organic phase Substances 0.000 description 15
• 239000000047 product Substances 0.000 description 15
• 230000037396 body weight Effects 0.000 description 14
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
• 239000010410 layer Substances 0.000 description 13
• 229910052727 yttrium Inorganic materials 0.000 description 13
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
• 239000012230 colorless oil Substances 0.000 description 12
• 208000035475 disorder Diseases 0.000 description 12
• 229920006395 saturated elastomer Polymers 0.000 description 12
• 239000003826 tablet Substances 0.000 description 12
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
• 239000012267 brine Substances 0.000 description 11
• 239000012299 nitrogen atmosphere Substances 0.000 description 11
• 239000003208 petroleum Substances 0.000 description 11
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
• 241001465754 Metazoa Species 0.000 description 10
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
• SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
• 201000010099 disease Diseases 0.000 description 10
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• PVTTZZSJLBWJDF-UHFFFAOYSA-N ClC1=C(C(=CC(=C1)Cl)F)N=C=S Chemical compound ClC1=C(C(=CC(=C1)Cl)F)N=C=S PVTTZZSJLBWJDF-UHFFFAOYSA-N 0.000 description 9
• 239000008346 aqueous phase Substances 0.000 description 9
• 239000002775 capsule Substances 0.000 description 9
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 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
• 241000699670 Mus sp. Species 0.000 description 8
• 239000002253 acid Substances 0.000 description 8
• 125000004429 atom Chemical group 0.000 description 8
• 125000004432 carbon atom Chemical group C* 0.000 description 8
• 150000003857 carboxamides Chemical class 0.000 description 8
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
• 150000002431 hydrogen Chemical class 0.000 description 8
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 8
• 229920002472 Starch Polymers 0.000 description 7
• 239000003638 chemical reducing agent Substances 0.000 description 7
• 239000007822 coupling agent Substances 0.000 description 7
• VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 7
• 238000009472 formulation Methods 0.000 description 7
• 235000019698 starch Nutrition 0.000 description 7
• DSXVZIOQROMOEF-UHFFFAOYSA-N 1,3,5-trichloro-2-isothiocyanatobenzene Chemical compound ClC1=CC(Cl)=C(N=C=S)C(Cl)=C1 DSXVZIOQROMOEF-UHFFFAOYSA-N 0.000 description 6
• WNDSHZVSXJQYSU-UHFFFAOYSA-N 1-chloro-2-fluoro-4-isothiocyanato-3-methylbenzene Chemical compound ClC1=C(C(=C(C=C1)N=C=S)C)F WNDSHZVSXJQYSU-UHFFFAOYSA-N 0.000 description 6
• UQOKRDJILZMZKU-UHFFFAOYSA-N 2-nitropyrimidine Chemical compound [O-][N+](=O)C1=NC=CC=N1 UQOKRDJILZMZKU-UHFFFAOYSA-N 0.000 description 6
• LLJSSSLSNWIKDE-UHFFFAOYSA-N 3,5-dichloro-4-isothiocyanatobenzonitrile Chemical compound ClC1=CC(C#N)=CC(Cl)=C1N=C=S LLJSSSLSNWIKDE-UHFFFAOYSA-N 0.000 description 6
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
• 238000003556 assay Methods 0.000 description 6
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 6
• 239000003054 catalyst Substances 0.000 description 6
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 6
• CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 6
• 239000003085 diluting agent Substances 0.000 description 6
• 239000000284 extract Substances 0.000 description 6
• 238000010348 incorporation Methods 0.000 description 6
• 230000000155 isotopic effect Effects 0.000 description 6
• 238000010992 reflux Methods 0.000 description 6
• 239000008107 starch Substances 0.000 description 6
• ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 6
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 5
• INUSQTPGSHFGHM-UHFFFAOYSA-N 2,4-dichloro-5-nitropyrimidine Chemical compound [O-][N+](=O)C1=CN=C(Cl)N=C1Cl INUSQTPGSHFGHM-UHFFFAOYSA-N 0.000 description 5
• ZEDOBEHSBNTVKR-UHFFFAOYSA-N 2-chloro-6-fluoro-3-methylaniline Chemical compound CC1=CC=C(F)C(N)=C1Cl ZEDOBEHSBNTVKR-UHFFFAOYSA-N 0.000 description 5
• OYFCZVXGUPBDPD-UHFFFAOYSA-N 5-chloro-1,3-difluoro-2-isothiocyanatobenzene Chemical compound FC1=CC(Cl)=CC(F)=C1N=C=S OYFCZVXGUPBDPD-UHFFFAOYSA-N 0.000 description 5
• ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 5
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 5
• XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 5
• 125000003710 aryl alkyl group Chemical group 0.000 description 5
• 150000007942 carboxylates Chemical class 0.000 description 5
• RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 5
• 125000005842 heteroatom Chemical group 0.000 description 5
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
• DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 5
• MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
• 229910052757 nitrogen Inorganic materials 0.000 description 5
• 239000003960 organic solvent Substances 0.000 description 5
• 238000011160 research Methods 0.000 description 5
• 239000000126 substance Substances 0.000 description 5
• 208000024891 symptom Diseases 0.000 description 5
• 238000004809 thin layer chromatography Methods 0.000 description 5
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