CN102548406B - 合成4,5,6,7-四氯-3’,6’-二羟基-2’,4’,5’,7’-四碘-3h-螺[异苯并呋喃-1,9’-呫吨]-3-酮(玫瑰红)和有关呫吨的方法 - Google Patents
合成4,5,6,7-四氯-3’,6’-二羟基-2’,4’,5’,7’-四碘-3h-螺[异苯并呋喃-1,9’-呫吨]-3-酮(玫瑰红)和有关呫吨的方法 Download PDFInfo
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- CN102548406B CN102548406B CN201080041506.7A CN201080041506A CN102548406B CN 102548406 B CN102548406 B CN 102548406B CN 201080041506 A CN201080041506 A CN 201080041506A CN 102548406 B CN102548406 B CN 102548406B
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- chloride
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- 238000000034 method Methods 0.000 title claims abstract description 137
- 230000008569 process Effects 0.000 title abstract description 16
- 230000015572 biosynthetic process Effects 0.000 title abstract description 12
- IICCLYANAQEHCI-UHFFFAOYSA-N 4,5,6,7-tetrachloro-3',6'-dihydroxy-2',4',5',7'-tetraiodospiro[2-benzofuran-3,9'-xanthene]-1-one Chemical compound O1C(=O)C(C(=C(Cl)C(Cl)=C2Cl)Cl)=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(I)C=C21 IICCLYANAQEHCI-UHFFFAOYSA-N 0.000 title description 22
- 229930187593 rose bengal Natural products 0.000 title description 14
- 229940081623 rose bengal Drugs 0.000 title description 14
- STRXNPAVPKGJQR-UHFFFAOYSA-N rose bengal A Natural products O1C(=O)C(C(=CC=C2Cl)Cl)=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(I)C=C21 STRXNPAVPKGJQR-UHFFFAOYSA-N 0.000 title description 14
- 238000003786 synthesis reaction Methods 0.000 title description 8
- 150000003732 xanthenes Chemical class 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 154
- -1 Chloride anions Chemical class 0.000 claims abstract description 99
- 239000012535 impurity Substances 0.000 claims abstract description 76
- 239000000460 chlorine Substances 0.000 claims abstract description 71
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 53
- 239000000543 intermediate Substances 0.000 claims abstract description 40
- 238000002360 preparation method Methods 0.000 claims abstract description 31
- 239000002904 solvent Substances 0.000 claims abstract description 26
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Inorganic materials Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims abstract description 21
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 17
- 239000007800 oxidant agent Substances 0.000 claims abstract description 9
- 238000011065 in-situ storage Methods 0.000 claims abstract description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 76
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 66
- 239000011630 iodine Substances 0.000 claims description 65
- 239000000203 mixture Substances 0.000 claims description 61
- 239000000243 solution Substances 0.000 claims description 56
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 48
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 229910052794 bromium Inorganic materials 0.000 claims description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 22
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 19
- 238000005944 trans-halogenation reaction Methods 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 18
- 239000003929 acidic solution Substances 0.000 claims description 18
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical group [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 16
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 16
- 235000009518 sodium iodide Nutrition 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- 239000011734 sodium Substances 0.000 claims description 13
- 229910052708 sodium Inorganic materials 0.000 claims description 13
- 235000010265 sodium sulphite Nutrition 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 229910052700 potassium Inorganic materials 0.000 claims description 9
- XZIYJVFHFHYPHS-UHFFFAOYSA-N 4,4',5,5',6,7-hexachloro-3',6'-dihydroxy-2',7'-diiodospiro[2-benzofuran-3,9'-xanthene]-1-one Chemical compound O1C(=O)C(C(=C(Cl)C(Cl)=C2Cl)Cl)=C2C21C1=CC(I)=C(O)C(Cl)=C1OC1=C(Cl)C(O)=C(I)C=C21 XZIYJVFHFHYPHS-UHFFFAOYSA-N 0.000 claims description 8
- HFKCVAAQEVKLRR-UHFFFAOYSA-N 4,4',5,6,7-pentachloro-3',6'-dihydroxy-2',5',7'-triiodospiro[2-benzofuran-3,9'-xanthene]-1-one Chemical compound O1C(=O)C(C(=C(Cl)C(Cl)=C2Cl)Cl)=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(Cl)C(O)=C(I)C=C21 HFKCVAAQEVKLRR-UHFFFAOYSA-N 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- 230000008018 melting Effects 0.000 claims description 8
- 238000002844 melting Methods 0.000 claims description 8
- PHLREGDKKFAHDX-UHFFFAOYSA-N 2',4,5,5',6,7-hexachloro-3',6'-dihydroxy-4',7'-diiodospiro[2-benzofuran-3,9'-xanthene]-1-one Chemical compound O1C(=O)C(C(=C(Cl)C(Cl)=C2Cl)Cl)=C2C21C1=CC(Cl)=C(O)C(I)=C1OC1=C(Cl)C(O)=C(I)C=C21 PHLREGDKKFAHDX-UHFFFAOYSA-N 0.000 claims description 7
- NLTATQHSRPCJAH-UHFFFAOYSA-N 2',4,5,6,7,7'-hexachloro-3',6'-dihydroxy-4',5'-diiodospiro[2-benzofuran-3,9'-xanthene]-1-one Chemical compound O1C(=O)C(C(=C(Cl)C(Cl)=C2Cl)Cl)=C2C21C1=CC(Cl)=C(O)C(I)=C1OC1=C(I)C(O)=C(Cl)C=C21 NLTATQHSRPCJAH-UHFFFAOYSA-N 0.000 claims description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 7
- 229910052744 lithium Inorganic materials 0.000 claims description 7
- 238000012546 transfer Methods 0.000 claims description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 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 claims description 5
- XYXNTHIYBIDHGM-UHFFFAOYSA-N ammonium thiosulfate Chemical compound [NH4+].[NH4+].[O-]S([O-])(=O)=S XYXNTHIYBIDHGM-UHFFFAOYSA-N 0.000 claims description 5
- FGRVOLIFQGXPCT-UHFFFAOYSA-L dipotassium;dioxido-oxo-sulfanylidene-$l^{6}-sulfane Chemical compound [K+].[K+].[O-]S([O-])(=O)=S FGRVOLIFQGXPCT-UHFFFAOYSA-L 0.000 claims description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 claims description 5
- 239000011736 potassium bicarbonate Substances 0.000 claims description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 5
- BHZRJJOHZFYXTO-UHFFFAOYSA-L potassium sulfite Chemical compound [K+].[K+].[O-]S([O-])=O BHZRJJOHZFYXTO-UHFFFAOYSA-L 0.000 claims description 5
- 235000019252 potassium sulphite Nutrition 0.000 claims description 5
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 5
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 5
- 238000003828 vacuum filtration Methods 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 230000026030 halogenation Effects 0.000 claims description 4
- 238000005658 halogenation reaction Methods 0.000 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 4
- 150000004053 quinones Chemical class 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 3
- 239000002841 Lewis acid Substances 0.000 claims description 3
- 125000000129 anionic group Chemical group 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 2
- 230000004048 modification Effects 0.000 claims description 2
- 238000012986 modification Methods 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 12
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 4
- 239000012670 alkaline solution Substances 0.000 claims 4
- XTEGARKTQYYJKE-UHFFFAOYSA-M Chlorate Chemical class [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 claims 3
- 150000001450 anions Chemical class 0.000 claims 2
- 229920000642 polymer Polymers 0.000 claims 2
- 238000005406 washing Methods 0.000 claims 2
- 239000003637 basic solution Substances 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- 239000002516 radical scavenger Substances 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 abstract description 12
- 238000006192 iodination reaction Methods 0.000 abstract description 11
- 230000026045 iodination Effects 0.000 abstract description 10
- 238000001914 filtration Methods 0.000 abstract description 8
- OQWNURCMRMGIJZ-UHFFFAOYSA-N C1C(C=CC=C2)=C2OC2=CC=CC=C12.I Chemical compound C1C(C=CC=C2)=C2OC2=CC=CC=C12.I OQWNURCMRMGIJZ-UHFFFAOYSA-N 0.000 abstract description 6
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 238000004587 chromatography analysis Methods 0.000 abstract description 2
- 238000000605 extraction Methods 0.000 abstract description 2
- 239000002547 new drug Substances 0.000 abstract description 2
- 239000000376 reactant Substances 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000007787 solid Substances 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 23
- 238000005481 NMR spectroscopy Methods 0.000 description 22
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- 239000003814 drug Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 14
- 229910052799 carbon Inorganic materials 0.000 description 12
- 229910052731 fluorine Inorganic materials 0.000 description 11
- 239000000725 suspension Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 229910052736 halogen Inorganic materials 0.000 description 8
- 150000002367 halogens Chemical class 0.000 description 8
- 150000002596 lactones Chemical group 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- 238000002955 isolation Methods 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- AUHHYELHRWCWEZ-UHFFFAOYSA-N tetrachlorophthalic anhydride Chemical compound ClC1=C(Cl)C(Cl)=C2C(=O)OC(=O)C2=C1Cl AUHHYELHRWCWEZ-UHFFFAOYSA-N 0.000 description 7
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 239000003086 colorant Substances 0.000 description 5
- IINNWAYUJNWZRM-UHFFFAOYSA-L erythrosin B Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(I)C(=O)C(I)=C2OC2=C(I)C([O-])=C(I)C=C21 IINNWAYUJNWZRM-UHFFFAOYSA-L 0.000 description 5
- 239000000463 material Substances 0.000 description 5
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- 238000011282 treatment Methods 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000008030 elimination Effects 0.000 description 4
- 238000003379 elimination reaction Methods 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000004808 supercritical fluid chromatography Methods 0.000 description 4
- MLMLMXDCMFGFMG-UHFFFAOYSA-N 2',4,5,6,7-pentachloro-3',6'-dihydroxy-4',5',7'-triiodospiro[2-benzofuran-3,9'-xanthene]-1-one Chemical compound O1C(=O)C(C(=C(Cl)C(Cl)=C2Cl)Cl)=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(Cl)C=C21 MLMLMXDCMFGFMG-UHFFFAOYSA-N 0.000 description 3
- SWZVJOLLQTWFCW-UHFFFAOYSA-N 2-chlorobenzene-1,3-diol Chemical compound OC1=CC=CC(O)=C1Cl SWZVJOLLQTWFCW-UHFFFAOYSA-N 0.000 description 3
- AFQUMYICNSZTNS-UHFFFAOYSA-N 4,5,6,7-tetrabromo-3',6'-dihydroxy-2',4',5',7'-tetraiodospiro[2-benzofuran-3,9'-xanthene]-1-one Chemical compound O1C(=O)C(C(=C(Br)C(Br)=C2Br)Br)=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(I)C=C21 AFQUMYICNSZTNS-UHFFFAOYSA-N 0.000 description 3
- DDXCXUMXVNCVSV-UHFFFAOYSA-N 4,5,6,7-tetrachloro-3',6'-dihydroxy-2',4',7'-triiodospiro[2-benzofuran-3,9'-xanthene]-1-one Chemical compound O1C(=O)C(C(=C(Cl)C(Cl)=C2Cl)Cl)=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C2C=C(I)C(O)=C1 DDXCXUMXVNCVSV-UHFFFAOYSA-N 0.000 description 3
- QCPFFGGFHNZBEP-UHFFFAOYSA-N 4,5,6,7-tetrachloro-3',6'-dihydroxyspiro[2-benzofuran-3,9'-xanthene]-1-one Chemical compound O1C(=O)C(C(=C(Cl)C(Cl)=C2Cl)Cl)=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 QCPFFGGFHNZBEP-UHFFFAOYSA-N 0.000 description 3
- JQVAPEJNIZULEK-UHFFFAOYSA-N 4-chlorobenzene-1,3-diol Chemical compound OC1=CC=C(Cl)C(O)=C1 JQVAPEJNIZULEK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000005708 Sodium hypochlorite Substances 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 239000002537 cosmetic Substances 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 229940011411 erythrosine Drugs 0.000 description 3
- 239000004174 erythrosine Substances 0.000 description 3
- 235000012732 erythrosine Nutrition 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Veterinary Medicine (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Virology (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pyrane Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24370109P | 2009-09-18 | 2009-09-18 | |
| US61/243,701 | 2009-09-18 | ||
| PCT/US2010/049341 WO2011035161A1 (en) | 2009-09-18 | 2010-09-17 | Process for the synthesis of 4,5,6,7-tetrachloro-3',6'-dihydroxy-2',4',5'7'-tetraiodo-3h-spiro[isobenzofuran-1,9'-xanthen]-3-one (rose bengal) and related xanthenes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102548406A CN102548406A (zh) | 2012-07-04 |
| CN102548406B true CN102548406B (zh) | 2015-04-08 |
Family
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Family Applications (1)
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| CA2828940C (en) | 2011-03-10 | 2024-04-16 | Provectus Pharmaceuticals, Inc. | Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer |
| US9470610B2 (en) * | 2013-10-22 | 2016-10-18 | The United States Of America As Represented By The Secretary Of The Air Force | Methods for using rose bengal for detection of oxidative decomposition of contaminants |
| JP7015232B2 (ja) * | 2018-11-21 | 2022-02-02 | 東レ・ファインケミカル株式会社 | 高純度のフルオレセイン類化合物の製造方法 |
| WO2020173891A1 (en) * | 2019-02-26 | 2020-09-03 | F. Hoffmann-La Roche Ag | Process for the preparation of (6s)-3-[(4s)-4-cyano-2-oxo-pyrrolidin-1-yl]-6-methyl-n-(3,4,5-trifluorophenyl)-6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine-5-carboxamide |
| JP7512409B6 (ja) | 2020-03-26 | 2024-07-23 | プロヴェクタス ファーマテック，インク． | 腫瘍学及びウイルス学におけるハロゲン化キサンテンの新規の使用 |
| US11938182B2 (en) | 2020-03-26 | 2024-03-26 | Provectus Pharmatech, Inc. | Halogenated xanthenes as vaccine adjuvants |
| US20240325341A1 (en) * | 2023-03-29 | 2024-10-03 | Provectus Pharmatech, Inc. | Anti-bacterial effect of halogenated fluoresceins against colistin-resistant gram-negative bacteria |
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2011035161A1 (en) | 2011-03-24 |
| CA2771988A1 (en) | 2011-03-24 |
| HK1172212A1 (zh) | 2013-04-19 |
| EP2464225A1 (en) | 2012-06-20 |
| KR101494055B1 (ko) | 2015-02-16 |
| US9422260B2 (en) | 2016-08-23 |
| HK1172501A1 (en) | 2013-04-26 |
| JP5671040B2 (ja) | 2015-02-18 |
| JP2013505261A (ja) | 2013-02-14 |
| US20130274322A1 (en) | 2013-10-17 |
| US8530675B2 (en) | 2013-09-10 |
| CN102548406A (zh) | 2012-07-04 |
| EP2464225B1 (en) | 2015-09-16 |
| MX2012003063A (es) | 2012-07-25 |
| US20110071217A1 (en) | 2011-03-24 |
| KR20120091088A (ko) | 2012-08-17 |
| EP2464225A4 (en) | 2013-03-27 |
| ES2548575T3 (es) | 2015-10-19 |
| EP2464225B8 (en) | 2017-08-23 |
| CA2771988C (en) | 2016-07-05 |
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