JP6723926B2 - 医薬の製造方法 - Google Patents

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Publication number

JP6723926B2

JP6723926B2 JP2016561841A JP2016561841A JP6723926B2 JP 6723926 B2 JP6723926 B2 JP 6723926B2 JP 2016561841 A JP2016561841 A JP 2016561841A JP 2016561841 A JP2016561841 A JP 2016561841A JP 6723926 B2 JP6723926 B2 JP 6723926B2

Authority

JP

Japan

Prior art keywords

chloro

fluorophenyl

methyl

solution

pyridin

Prior art date

2014-04-09

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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• 238000004519 manufacturing process Methods 0.000 title 1
• 238000000034 method Methods 0.000 claims description 84
• 150000001875 compounds Chemical class 0.000 claims description 68
• 230000008569 process Effects 0.000 claims description 20
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
• JESRNIJXVIFVOV-UHFFFAOYSA-N 2-methylpyrazol-3-amine Chemical compound CN1N=CC=C1N JESRNIJXVIFVOV-UHFFFAOYSA-N 0.000 claims description 18
• 239000003795 chemical substances by application Substances 0.000 claims description 17
• RAEXTEKKMYSCEX-UHFFFAOYSA-N CS(=O)(=O)C1=NC=CC(=N1)C1=CC(NC=C1)=O Chemical compound CS(=O)(=O)C1=NC=CC(=N1)C1=CC(NC=C1)=O RAEXTEKKMYSCEX-UHFFFAOYSA-N 0.000 claims description 14
• 125000000217 alkyl group Chemical group 0.000 claims description 14
• 239000003960 organic solvent Substances 0.000 claims description 14
• FRSBDALHVZFPHT-UHFFFAOYSA-N 2-chloro-1-(4-chloro-3-fluorophenyl)ethanone Chemical compound FC1=CC(C(=O)CCl)=CC=C1Cl FRSBDALHVZFPHT-UHFFFAOYSA-N 0.000 claims description 12
• 238000002360 preparation method Methods 0.000 claims description 11
• ATHKVJCNHIGEBV-UHFFFAOYSA-N 1-(4-chloro-3-fluorophenyl)-2-hydroxyethanone Chemical compound OCC(=O)C1=CC=C(Cl)C(F)=C1 ATHKVJCNHIGEBV-UHFFFAOYSA-N 0.000 claims description 10
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
• 101001110310 Lentilactobacillus kefiri NADP-dependent (R)-specific alcohol dehydrogenase Proteins 0.000 claims description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
• ZNGGAPYUQROFJC-QMMMGPOBSA-N (1r)-1-(4-chloro-3-fluorophenyl)ethane-1,2-diol Chemical compound OC[C@H](O)C1=CC=C(Cl)C(F)=C1 ZNGGAPYUQROFJC-QMMMGPOBSA-N 0.000 claims description 6
• AGYWDGVTLKNTBS-UHFFFAOYSA-N 4-bromo-1-chloro-2-fluorobenzene Chemical compound FC1=CC(Br)=CC=C1Cl AGYWDGVTLKNTBS-UHFFFAOYSA-N 0.000 claims description 6
• 239000000010 aprotic solvent Substances 0.000 claims description 6
• 235000019253 formic acid Nutrition 0.000 claims description 6
• 239000003880 polar aprotic solvent Substances 0.000 claims description 6
• 239000007800 oxidant agent Substances 0.000 claims description 5
• HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 5
• 235000019254 sodium formate Nutrition 0.000 claims description 5
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
• KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 claims description 4
• 229910052736 halogen Inorganic materials 0.000 claims description 4
• 150000002367 halogens Chemical class 0.000 claims description 4
• 150000002901 organomagnesium compounds Chemical class 0.000 claims description 4
• 239000004280 Sodium formate Substances 0.000 claims description 3
• 125000003545 alkoxy group Chemical group 0.000 claims description 3
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
• YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 3
• OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 claims description 2
• 239000000243 solution Substances 0.000 description 136
• ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical group CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 114
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 93
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 92
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 92
• 238000006243 chemical reaction Methods 0.000 description 82
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 78
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
• 239000000203 mixture Substances 0.000 description 62
• 235000002639 sodium chloride Nutrition 0.000 description 49
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 46
• 239000007787 solid Substances 0.000 description 45
• 239000002904 solvent Substances 0.000 description 44
• -1 aryl sulfonic acid Chemical compound 0.000 description 43
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
• 239000012044 organic layer Substances 0.000 description 36
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 35
• SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical class [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 35
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 34
• 150000003839 salts Chemical class 0.000 description 33
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
• 238000003756 stirring Methods 0.000 description 28
• 238000004128 high performance liquid chromatography Methods 0.000 description 27
• 238000000634 powder X-ray diffraction Methods 0.000 description 27
• UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 25
• 239000002002 slurry Substances 0.000 description 25
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 24
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 23
• 239000000523 sample Substances 0.000 description 22
• 239000000126 substance Substances 0.000 description 22
• 239000002585 base Substances 0.000 description 21
• 239000003153 chemical reaction reagent Substances 0.000 description 21
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
• 229940077388 benzenesulfonate Drugs 0.000 description 19
• 238000000113 differential scanning calorimetry Methods 0.000 description 19
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
• SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 17
• 229940092714 benzenesulfonic acid Drugs 0.000 description 17
• 230000015572 biosynthetic process Effects 0.000 description 17
• 239000012458 free base Substances 0.000 description 17
• 239000000543 intermediate Substances 0.000 description 17
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 17
• 239000011780 sodium chloride Substances 0.000 description 17
• 239000000725 suspension Substances 0.000 description 17
• KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 16
• 239000000546 pharmaceutical excipient Substances 0.000 description 16
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 15
• 238000005481 NMR spectroscopy Methods 0.000 description 14
• 239000000047 product Substances 0.000 description 14
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
• 229910052739 hydrogen Inorganic materials 0.000 description 13
• 238000003786 synthesis reaction Methods 0.000 description 13
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• 239000008194 pharmaceutical composition Substances 0.000 description 12
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 12
• 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 11
• 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 11
• 210000004027 cell Anatomy 0.000 description 11
• 239000013078 crystal Substances 0.000 description 11
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
• 239000010410 layer Substances 0.000 description 11
• 239000012071 phase Substances 0.000 description 11
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 11
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 10
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
• YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 10
• 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 10
• 229910052757 nitrogen Inorganic materials 0.000 description 10
• LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 9
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 9
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
• 206010028980 Neoplasm Diseases 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
• 239000012065 filter cake Substances 0.000 description 9
• YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 9
• IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 9
• 230000037361 pathway Effects 0.000 description 9
• 230000002829 reductive effect Effects 0.000 description 9
• 238000010521 absorption reaction Methods 0.000 description 8
• 239000002253 acid Substances 0.000 description 8
• 125000004429 atom Chemical group 0.000 description 8
• TWSFAQBOAWKKIH-GMUIIQOCSA-N benzenesulfonic acid 1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyridin-2-one Chemical compound C1(=CC=CC=C1)S(=O)(=O)O.ClC1=C(C=C(C=C1)[C@@H](CO)N1C(C=C(C=C1)C1=NC(=NC=C1)NC1=CC=NN1C)=O)F TWSFAQBOAWKKIH-GMUIIQOCSA-N 0.000 description 8
• 238000004821 distillation Methods 0.000 description 8
• 235000019441 ethanol Nutrition 0.000 description 8
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
• 239000000843 powder Substances 0.000 description 8
• 239000011541 reaction mixture Substances 0.000 description 8
• 230000009467 reduction Effects 0.000 description 8
• 239000011734 sodium Substances 0.000 description 8
• 239000000758 substrate Substances 0.000 description 8
• 239000003826 tablet Substances 0.000 description 8
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
• BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 7
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
• 238000004458 analytical method Methods 0.000 description 7
• 239000003054 catalyst Substances 0.000 description 7
• 239000012141 concentrate Substances 0.000 description 7
• 235000008504 concentrate Nutrition 0.000 description 7
• 150000004795 grignard reagents Chemical class 0.000 description 7
• 229920001223 polyethylene glycol Polymers 0.000 description 7
• 238000010791 quenching Methods 0.000 description 7
• BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical group CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 7
• 239000003981 vehicle Substances 0.000 description 7
• MBVRZOISNGJZGC-OAQYLSRUSA-N 1-[(1s)-2-[tert-butyl(dimethyl)silyl]oxy-1-(4-chloro-3-fluorophenyl)ethyl]-4-(2-methylsulfanylpyrimidin-4-yl)pyridin-2-one Chemical compound CSC1=NC=CC(C2=CC(=O)N([C@H](CO[Si](C)(C)C(C)(C)C)C=3C=C(F)C(Cl)=CC=3)C=C2)=N1 MBVRZOISNGJZGC-OAQYLSRUSA-N 0.000 description 6
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
• GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 6
• 108010050375 Glucose 1-Dehydrogenase Proteins 0.000 description 6
• 239000007818 Grignard reagent Substances 0.000 description 6
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
• 239000002202 Polyethylene glycol Substances 0.000 description 6
• 238000005388 cross polarization Methods 0.000 description 6
• SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 6
• 238000001035 drying Methods 0.000 description 6
• 230000000694 effects Effects 0.000 description 6
• 238000002474 experimental method Methods 0.000 description 6
• 238000009472 formulation Methods 0.000 description 6
• 238000003988 headspace gas chromatography Methods 0.000 description 6
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
• 150000002576 ketones Chemical class 0.000 description 6
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
• 229950006238 nadide Drugs 0.000 description 6
• KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 6
• 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
• 239000001267 polyvinylpyrrolidone Substances 0.000 description 6
• 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
• 125000006239 protecting group Chemical group 0.000 description 6
• 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
• RZUOCXOYPYGSKL-GOSISDBHSA-N 1-[(1s)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyridin-2-one Chemical compound CN1N=CC=C1NC1=NC=CC(C2=CC(=O)N([C@H](CO)C=3C=C(F)C(Cl)=CC=3)C=C2)=N1 RZUOCXOYPYGSKL-GOSISDBHSA-N 0.000 description 5
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
• MZTDOZRNTSWXLO-GMUIIQOCSA-N C=1(C(=CC=C2C=CC=CC12)S(=O)(=O)O)S(=O)(=O)O.ClC1=C(C=C(C=C1)[C@@H](CO)N1C(C=C(C=C1)C1=NC(=NC=C1)NC1=CC=NN1C)=O)F Chemical compound C=1(C(=CC=C2C=CC=CC12)S(=O)(=O)O)S(=O)(=O)O.ClC1=C(C=C(C=C1)[C@@H](CO)N1C(C=C(C=C1)C1=NC(=NC=C1)NC1=CC=NN1C)=O)F MZTDOZRNTSWXLO-GMUIIQOCSA-N 0.000 description 5
• 102000004190 Enzymes Human genes 0.000 description 5
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• 108040008097 MAP kinase activity proteins Proteins 0.000 description 5
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• UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical compound CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 5
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 5
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• 239000004810 polytetrafluoroethylene Substances 0.000 description 5
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
• 238000000926 separation method Methods 0.000 description 5
• 238000001228 spectrum Methods 0.000 description 5
• PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 4
• 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 4
• JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
• XUWWKAZDBLFEDN-UHFFFAOYSA-N 4-(2-methylsulfanylpyrimidin-4-yl)-1h-pyridin-2-one Chemical compound CSC1=NC=CC(C2=CC(=O)NC=C2)=N1 XUWWKAZDBLFEDN-UHFFFAOYSA-N 0.000 description 4
• 240000005020 Acaciella glauca Species 0.000 description 4
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• QGKBOJYLVWQNIO-GMUIIQOCSA-N C1(=CC=C(C=C1)S(=O)(=O)O)C.ClC1=C(C=C(C=C1)[C@@H](CO)N1C(C=C(C=C1)C1=NC(=NC=C1)NC1=CC=NN1C)=O)F Chemical compound C1(=CC=C(C=C1)S(=O)(=O)O)C.ClC1=C(C=C(C=C1)[C@@H](CO)N1C(C=C(C=C1)C1=NC(=NC=C1)NC1=CC=NN1C)=O)F QGKBOJYLVWQNIO-GMUIIQOCSA-N 0.000 description 4
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
• 239000005909 Kieselgur Substances 0.000 description 4
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