CN102143950A - 合成取代的异喹啉的方法 - Google Patents
合成取代的异喹啉的方法 Download PDFInfo
- Publication number
- CN102143950A CN102143950A CN2009801349958A CN200980134995A CN102143950A CN 102143950 A CN102143950 A CN 102143950A CN 2009801349958 A CN2009801349958 A CN 2009801349958A CN 200980134995 A CN200980134995 A CN 200980134995A CN 102143950 A CN102143950 A CN 102143950A
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- China
- Prior art keywords
- compound
- formula
- phenyl
- acid
- iodide
- Prior art date
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- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 59
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 150000002537 isoquinolines Chemical class 0.000 title 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 99
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 93
- 150000001875 compounds Chemical class 0.000 claims description 71
- 239000002253 acid Substances 0.000 claims description 27
- 239000003795 chemical substances by application Substances 0.000 claims description 27
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 claims description 24
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 20
- 229910052740 iodine Inorganic materials 0.000 claims description 19
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 239000011630 iodine Substances 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 16
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 15
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- -1 sulfydryl Chemical group 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 13
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 12
- 238000006198 methoxylation reaction Methods 0.000 claims description 12
- 229910052763 palladium Inorganic materials 0.000 claims description 12
- 239000011591 potassium Substances 0.000 claims description 12
- 229910052700 potassium Inorganic materials 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 239000004348 Glyceryl diacetate Substances 0.000 claims description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 10
- 238000006555 catalytic reaction Methods 0.000 claims description 10
- 235000019443 glyceryl diacetate Nutrition 0.000 claims description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 10
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 239000003444 phase transfer catalyst Substances 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 7
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 7
- 239000000908 ammonium hydroxide Substances 0.000 claims description 7
- UZKWTJUDCOPSNM-UHFFFAOYSA-N butyl vinyl ether Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- AIDQCFHFXWPAFG-UHFFFAOYSA-N n-formylformamide Chemical compound O=CNC=O AIDQCFHFXWPAFG-UHFFFAOYSA-N 0.000 claims description 6
- 125000004825 2,2-dimethylpropylene group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[*:1])C([H])([H])[*:2] 0.000 claims description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 claims description 5
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 5
- 230000001035 methylating effect Effects 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 238000010306 acid treatment Methods 0.000 claims description 4
- 238000004176 ammonification Methods 0.000 claims description 4
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
- KYLUAQBYONVMCP-UHFFFAOYSA-N (2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P KYLUAQBYONVMCP-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 7
- 238000010129 solution processing Methods 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 8
- MZWRTCSTQRDWGM-UHFFFAOYSA-N 1-chloro-4-methoxyisoquinoline Chemical class C1=CC=C2C(OC)=CN=C(Cl)C2=C1 MZWRTCSTQRDWGM-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 43
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- 238000003756 stirring Methods 0.000 description 32
- 239000000047 product Substances 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 239000010410 layer Substances 0.000 description 21
- 239000007787 solid Substances 0.000 description 21
- 238000010791 quenching Methods 0.000 description 20
- 238000005406 washing Methods 0.000 description 20
- 230000000171 quenching effect Effects 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 18
- 239000012535 impurity Substances 0.000 description 17
- 239000012065 filter cake Substances 0.000 description 16
- 239000002002 slurry Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- 150000002576 ketones Chemical class 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000012544 monitoring process Methods 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 125000005843 halogen group Chemical group 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 210000003739 neck Anatomy 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 230000032683 aging Effects 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 230000002378 acidificating effect Effects 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 241000711549 Hepacivirus C Species 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000006210 lotion Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000012266 salt solution Substances 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 3
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000002051 biphasic effect Effects 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000012456 homogeneous solution Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 229960000329 ribavirin Drugs 0.000 description 3
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000008247 solid mixture Substances 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 241000863032 Trieres Species 0.000 description 2
- 150000001409 amidines Chemical class 0.000 description 2
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
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- 239000012074 organic phase Substances 0.000 description 2
- 230000006320 pegylation Effects 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 2
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- 238000001291 vacuum drying Methods 0.000 description 2
- 239000006200 vaporizer Substances 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- FSBZFVCIKUIIMT-UHFFFAOYSA-N 5-chloro-2-methylbenzamide Chemical compound CC1=CC=C(Cl)C=C1C(N)=O FSBZFVCIKUIIMT-UHFFFAOYSA-N 0.000 description 1
- JLRCBNLADGATRC-UHFFFAOYSA-N COC(c(c1c2)ccc2Cl)=CNC1=O Chemical compound COC(c(c1c2)ccc2Cl)=CNC1=O JLRCBNLADGATRC-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N Cc(cccc1)c1C(O)=O Chemical compound Cc(cccc1)c1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- FZEBWIMPBAGUJA-UHFFFAOYSA-N O=C(c(cn1)c(ccc(Cl)c2)c2c1Cl)I Chemical compound O=C(c(cn1)c(ccc(Cl)c2)c2c1Cl)I FZEBWIMPBAGUJA-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- WONCHGDEGMFLPR-UHFFFAOYSA-N [Cl-].[NH4+].CC(CCCCCCC)P(CCCCCCCC)CCCCCCCC Chemical compound [Cl-].[NH4+].CC(CCCCCCC)P(CCCCCCCC)CCCCCCCC WONCHGDEGMFLPR-UHFFFAOYSA-N 0.000 description 1
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000002521 alkyl halide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229940054066 benzamide antipsychotics Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000001680 brushing effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002084 enol ethers Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- SWLQAGBBUFCESY-UHFFFAOYSA-N ethyl-di(propan-2-yl)azanium;bromide Chemical compound Br.CCN(C(C)C)C(C)C SWLQAGBBUFCESY-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 244000052637 human pathogen Species 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- ZRLVQFQTCMUIRM-UHFFFAOYSA-N potassium;2-methylbutan-2-olate Chemical compound [K+].CCC(C)(C)[O-] ZRLVQFQTCMUIRM-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 238000009991 scouring Methods 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000013595 supernatant sample Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- OKBQUWUVZGPEQZ-UHFFFAOYSA-N tributyl(hexadecyl)phosphanium Chemical compound CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC OKBQUWUVZGPEQZ-UHFFFAOYSA-N 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Epidemiology (AREA)
- Catalysts (AREA)
Abstract
Description
名称 | 克 |
5-氯-2-甲基苯甲酸 | 20.00 |
草酰氯 | 14.88 |
二甲基甲酰胺 | 0.21 |
氢氧化铵 | 96.50 |
2-甲基四氢呋喃 | 171.76 |
2-甲基四氢呋喃-双相淬冷剂 | 85.88 |
水-MeTHF洗液 | 100.00 |
名称 | 克 |
起始酰胺 | 19.58 |
甲胺、1,1-二甲氧基-N,N-二甲基- | 15.13 |
叔戊醇钾 | 122.42 |
甲苯 | 341.16 |
N-甲基吡咯烷酮 | 151.11 |
水 | 146.85 |
氯化氢 | 23.89 |
庚烷 | 66.92 |
甲醇 | 7.77 |
名称 | 当量 | 克 |
起始物 | 1.00 | 15.00 |
亚碘酰苯二乙酸盐 | 1.10 | 30.19 |
甲磺酸 | 1.00 | 8.05 |
甲醇 | 88.75 | 237.51 |
名称 | 当量 | 克 |
起始羟基异喹啉 | 1.00 | 10.00 |
磷酰氯 | 3.00 | 21.94 |
乙腈 | n/a | 39.16 |
水-反相淬冷剂 | n/a | 200.00 |
磷酸三钾,N-水合物 | 100.24 | |
四氢呋喃 | 101.90 | |
甲苯 | 30.49 | |
四氢呋喃-碳滤饼洗涤液 | 49.62 | |
庚烷-溶剂转换及滤饼洗涤液 | 314.46 |
名称 | 克 |
2-溴-5-氯苯甲酸甲酯 | 1000.00 |
丁基乙烯醚 | 802.92 |
乙腈 | 3916.50 |
Pd(OAc)2 | 27.00 |
三-邻-甲苯基膦 | 243.99 |
二异丙基乙胺 | 621.64 |
甲苯 | 4356.00 |
水 | 1000.00 |
5%w/v碳酸钾 | 2000.00 |
磷酸 | 3556.00 |
半盐水水溶液 | 1000.00 |
磷酸 | 1778.00 |
甲苯 | 2178.00 |
甲苯 | 1742.40 |
甲苯 | 871.20 |
萃取 | 甲苯中的分析 | 酸性层中的分析 |
1 | 943.8g 55.4% | 564.1g 33.1% |
2 | 205.9g 12.1% | 403.6g 23.7% |
3 | 171.3g 10.0% | 246.6g 14.5% |
4 | 103.8g 6.1% | 156.9g 9.2% |
5 | 60.7g 3.6% | 98.4g 5.8% |
分析(g) | 产率(%) | |
合并的有机萃取物1-5 | 1598.4 | 93.8 |
H3PO4主要层 | 98.4 | 5.8 |
Wshd有机萃取物1-5 | 1477.1 | 86.7 |
H3PO4洗液 | 58.7 | 3.4 |
萃取以后的H3PO4洗液 | 32.7 | 1.9 |
H3PO4洗液的甲苯萃取物 | 29.1 | 1.7 |
所需产物 | 1488.1 | 87.3 |
名称 | 克 |
起始酮 | 1000.00 |
溴 | 676.41 |
甲苯 | 8712.00 |
溴 | 150.31 |
溴(若需要) | 75.16 |
碳酸钾 | 649.98 |
水 | 3000.00 |
水 | 1500.00 |
氯化钠(半盐水) | 1710.00 |
名称 | 克 |
起始溴化物 | 10.00 |
二甲酰胺钠 | 4.89 |
四-N-丁基溴化铵 | 1.11 |
乙腈 | 62.66 |
四氢呋喃 | 17.72 |
甲醇 | 23.75 |
水(淬冷系统) | 100.00 |
甲基叔丁基醚(50∶50份数比的洗涤液) | 7.42 |
乙腈 | 7.83 |
乙腈 | 3.45 |
乙酸(淬冷系统) | 1.26 |
水(滤饼洗涤液) | 40.00 |
甲醇(50∶50部分比的MTBE∶MeOH洗涤液) | 7.92 |
甲基叔丁基醚(滤饼洗液) | 37.08 |
名称 | 克 |
起始醇 | 483.60 |
甲磺酸 | 2376.08 |
甲醇 | 2680.06 |
甲醇 | 197.92 |
氢氧化铵 | 3094.46 |
水 | 5000.00 |
时间(h) | SM(AP) | 产物(AP) |
2.5 | 86 | 13 |
24 | 14 | 84 |
46.5 | 3.7 | 95.1 |
添加体积(L) | 时间 | 温度(℃) |
0 | 12:01 | 1.6 |
1 | 12:11 | 22.3 |
3 | 12:38 | 27.0 |
4 | 12:48 | 28.3 |
5.1 | 13:03 | 25.4 |
Claims (31)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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CN201410655091.2A CN104447548B (zh) | 2008-09-04 | 2009-08-27 | 合成取代的异喹啉的方法 |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US9408808P | 2008-09-04 | 2008-09-04 | |
US61/094088 | 2008-09-04 | ||
US12/547158 | 2009-08-25 | ||
US12/547,158 US8207341B2 (en) | 2008-09-04 | 2009-08-25 | Process or synthesizing substituted isoquinolines |
PCT/US2009/055132 WO2010027889A2 (en) | 2008-09-04 | 2009-08-27 | Process for synthesizing substituted isoquinolines |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN201410655091.2A Division CN104447548B (zh) | 2008-09-04 | 2009-08-27 | 合成取代的异喹啉的方法 |
Publications (2)
Publication Number | Publication Date |
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CN102143950A true CN102143950A (zh) | 2011-08-03 |
CN102143950B CN102143950B (zh) | 2014-12-17 |
Family
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CN201410655091.2A Expired - Fee Related CN104447548B (zh) | 2008-09-04 | 2009-08-27 | 合成取代的异喹啉的方法 |
CN200980134995.8A Expired - Fee Related CN102143950B (zh) | 2008-09-04 | 2009-08-27 | 合成取代的异喹啉的方法 |
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Country Status (9)
Country | Link |
---|---|
US (3) | US8207341B2 (zh) |
EP (2) | EP3037416A1 (zh) |
JP (2) | JP5656838B2 (zh) |
KR (2) | KR101648595B1 (zh) |
CN (2) | CN104447548B (zh) |
AR (1) | AR073278A1 (zh) |
ES (1) | ES2554619T3 (zh) |
TW (1) | TWI441811B (zh) |
WO (1) | WO2010027889A2 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN108794397A (zh) * | 2017-12-14 | 2018-11-13 | 南京卡文迪许生物工程技术有限公司 | 一种罗沙司他的合成方法及其中间体化合物 |
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CN114805204B (zh) * | 2022-04-01 | 2023-09-15 | 云南师范大学 | 一种制备4-碘异喹啉-1(2h)-酮类化合物的方法 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN108794397A (zh) * | 2017-12-14 | 2018-11-13 | 南京卡文迪许生物工程技术有限公司 | 一种罗沙司他的合成方法及其中间体化合物 |
CN109956870A (zh) * | 2017-12-14 | 2019-07-02 | 南京卡文迪许生物工程技术有限公司 | 一种罗沙司他的合成方法及其中间体化合物 |
US11465970B2 (en) | 2017-12-14 | 2022-10-11 | Nanjing Cavendish Bio-Engineering Tech. Co., LTD. | Method for synthesis of Roxadustat and intermediate compounds thereof |
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ES2554619T3 (es) | 2015-12-22 |
TWI441811B (zh) | 2014-06-21 |
US8207341B2 (en) | 2012-06-26 |
EP3037416A1 (en) | 2016-06-29 |
CN104447548A (zh) | 2015-03-25 |
KR101648595B1 (ko) | 2016-08-16 |
US20120220774A1 (en) | 2012-08-30 |
JP5656838B2 (ja) | 2015-01-21 |
KR20160005792A (ko) | 2016-01-15 |
EP2326624A2 (en) | 2011-06-01 |
EP2326624B1 (en) | 2015-10-07 |
US20130123503A1 (en) | 2013-05-16 |
KR101680000B1 (ko) | 2016-11-28 |
CN104447548B (zh) | 2017-10-24 |
WO2010027889A3 (en) | 2010-04-22 |
JP2014159459A (ja) | 2014-09-04 |
JP2012515711A (ja) | 2012-07-12 |
CN102143950B (zh) | 2014-12-17 |
TW201014827A (en) | 2010-04-16 |
AR073278A1 (es) | 2010-10-28 |
JP5714744B2 (ja) | 2015-05-07 |
US20100056792A1 (en) | 2010-03-04 |
KR20110082516A (ko) | 2011-07-19 |
WO2010027889A2 (en) | 2010-03-11 |
US8877929B2 (en) | 2014-11-04 |
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