CA2971279C - Commercially viable synthesis of cantharidin and bioactive cantharidin derivatives - Google Patents
Commercially viable synthesis of cantharidin and bioactive cantharidin derivatives Download PDFInfo
- Publication number
- CA2971279C CA2971279C CA2971279A CA2971279A CA2971279C CA 2971279 C CA2971279 C CA 2971279C CA 2971279 A CA2971279 A CA 2971279A CA 2971279 A CA2971279 A CA 2971279A CA 2971279 C CA2971279 C CA 2971279C
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- Prior art keywords
- compound
- trifluoromethanesulfonate
- bis
- formula
- reaction
- Prior art date
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- DHZBEENLJMYSHQ-XCVPVQRUSA-N cantharidin Chemical compound C([C@@H]1O2)C[C@@H]2[C@]2(C)[C@@]1(C)C(=O)OC2=O DHZBEENLJMYSHQ-XCVPVQRUSA-N 0.000 title claims abstract description 142
- 229930008397 cantharidin Natural products 0.000 title claims abstract description 99
- DHZBEENLJMYSHQ-UHFFFAOYSA-N cantharidine Natural products O1C2CCC1C1(C)C2(C)C(=O)OC1=O DHZBEENLJMYSHQ-UHFFFAOYSA-N 0.000 title claims abstract description 99
- 229940095758 cantharidin Drugs 0.000 title claims abstract description 98
- 238000003786 synthesis reaction Methods 0.000 title description 35
- 230000015572 biosynthetic process Effects 0.000 title description 32
- 230000000975 bioactive effect Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 206
- 238000000034 method Methods 0.000 claims abstract description 116
- 230000008569 process Effects 0.000 claims abstract description 92
- 238000006352 cycloaddition reaction Methods 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims description 89
- 150000007517 lewis acids Chemical class 0.000 claims description 84
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 69
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 68
- 239000002841 Lewis acid Substances 0.000 claims description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 60
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 38
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 36
- 238000007254 oxidation reaction Methods 0.000 claims description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 30
- -1 copper(II) tetrafluoroborate hydrate Chemical compound 0.000 claims description 28
- 238000005984 hydrogenation reaction Methods 0.000 claims description 27
- 238000006477 desulfuration reaction Methods 0.000 claims description 25
- 230000023556 desulfurization Effects 0.000 claims description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical group [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 23
- 238000004519 manufacturing process Methods 0.000 claims description 23
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 23
- 238000006722 reduction reaction Methods 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 22
- 239000003638 chemical reducing agent Substances 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 19
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- ARUXRBUQJOYABI-UHFFFAOYSA-L cyclopentane;titanium(2+);trifluoromethanesulfonate Chemical compound [Ti+2].[CH]1[CH][CH][CH][CH]1.[CH]1[CH][CH][CH][CH]1.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F ARUXRBUQJOYABI-UHFFFAOYSA-L 0.000 claims description 18
- 239000007868 Raney catalyst Substances 0.000 claims description 17
- 239000010936 titanium Substances 0.000 claims description 17
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 17
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- UFYRWFCDYKWHJS-UHFFFAOYSA-N cyclopentane;zirconium(2+) Chemical compound [Zr+2].[CH]1[CH][CH][CH][CH]1.[CH]1[CH][CH][CH][CH]1 UFYRWFCDYKWHJS-UHFFFAOYSA-N 0.000 claims description 16
- 239000007800 oxidant agent Substances 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- MCVFFRWZNYZUIJ-UHFFFAOYSA-M lithium;trifluoromethanesulfonate Chemical compound [Li+].[O-]S(=O)(=O)C(F)(F)F MCVFFRWZNYZUIJ-UHFFFAOYSA-M 0.000 claims description 13
- 150000001266 acyl halides Chemical class 0.000 claims description 12
- UPWPDUACHOATKO-UHFFFAOYSA-K gallium trichloride Chemical compound Cl[Ga](Cl)Cl UPWPDUACHOATKO-UHFFFAOYSA-K 0.000 claims description 12
- BZQRBEVTLZHKEA-UHFFFAOYSA-L magnesium;trifluoromethanesulfonate Chemical compound [Mg+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F BZQRBEVTLZHKEA-UHFFFAOYSA-L 0.000 claims description 12
- YHBDIEWMOMLKOO-UHFFFAOYSA-I pentachloroniobium Chemical compound Cl[Nb](Cl)(Cl)(Cl)Cl YHBDIEWMOMLKOO-UHFFFAOYSA-I 0.000 claims description 12
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 12
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 claims description 12
- RBGLVWCAGPITBS-UHFFFAOYSA-L bis(trifluoromethylsulfonyloxy)tin Chemical compound [Sn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F RBGLVWCAGPITBS-UHFFFAOYSA-L 0.000 claims description 11
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 11
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 claims description 11
- PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 0.000 claims description 11
- 229910021120 PdC12 Inorganic materials 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 150000001412 amines Chemical group 0.000 claims description 10
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Chemical group 0.000 claims description 10
- 150000002367 halogens Chemical group 0.000 claims description 10
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 10
- 229910052763 palladium Inorganic materials 0.000 claims description 10
- 239000012279 sodium borohydride Substances 0.000 claims description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 238000006297 dehydration reaction Methods 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 7
- 229940011051 isopropyl acetate Drugs 0.000 claims description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical group CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 6
- 239000012346 acetyl chloride Substances 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 150000002466 imines Chemical class 0.000 claims description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
- 150000002923 oximes Chemical class 0.000 claims description 6
- 239000008096 xylene Substances 0.000 claims description 6
- 101100277337 Arabidopsis thaliana DDM1 gene Proteins 0.000 claims description 5
- 229910010061 TiC13 Inorganic materials 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 101150113676 chr1 gene Proteins 0.000 claims description 5
- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 claims description 5
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 5
- 150000003738 xylenes Chemical class 0.000 claims description 5
- 229910052725 zinc Inorganic materials 0.000 claims description 5
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 4
- 229910052759 nickel Inorganic materials 0.000 claims description 4
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 3
- 229910052726 zirconium Inorganic materials 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims 3
- 230000003009 desulfurizing effect Effects 0.000 claims 3
- 229910017604 nitric acid Inorganic materials 0.000 claims 3
- 229910019020 PtO2 Inorganic materials 0.000 claims 2
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 claims 2
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims 1
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 claims 1
- VDQVEACBQKUUSU-UHFFFAOYSA-M disodium;sulfanide Chemical compound [Na+].[Na+].[SH-] VDQVEACBQKUUSU-UHFFFAOYSA-M 0.000 claims 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 43
- 239000000047 product Substances 0.000 description 34
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 28
- 239000003054 catalyst Substances 0.000 description 23
- 239000000460 chlorine Substances 0.000 description 20
- 238000005698 Diels-Alder reaction Methods 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 150000003839 salts Chemical class 0.000 description 18
- MHCFAGZWMAWTNR-UHFFFAOYSA-M lithium perchlorate Chemical compound [Li+].[O-]Cl(=O)(=O)=O MHCFAGZWMAWTNR-UHFFFAOYSA-M 0.000 description 17
- 229910001486 lithium perchlorate Inorganic materials 0.000 description 17
- 239000011777 magnesium Substances 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 229910052751 metal Inorganic materials 0.000 description 14
- 239000002184 metal Substances 0.000 description 14
- 230000035484 reaction time Effects 0.000 description 14
- 150000003568 thioethers Chemical class 0.000 description 14
- 150000003462 sulfoxides Chemical class 0.000 description 13
- ZXMGHDIOOHOAAE-UHFFFAOYSA-N 1,1,1-trifluoro-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)NS(=O)(=O)C(F)(F)F ZXMGHDIOOHOAAE-UHFFFAOYSA-N 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- 150000003457 sulfones Chemical class 0.000 description 12
- 239000010949 copper Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 239000010955 niobium Substances 0.000 description 10
- 208000011580 syndromic disease Diseases 0.000 description 10
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 9
- MPCRDALPQLDDFX-UHFFFAOYSA-L Magnesium perchlorate Chemical compound [Mg+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O MPCRDALPQLDDFX-UHFFFAOYSA-L 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 9
- 229910052744 lithium Inorganic materials 0.000 description 9
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 9
- 229910052717 sulfur Inorganic materials 0.000 description 9
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 9
- 206010027145 Melanocytic naevus Diseases 0.000 description 8
- 208000003351 Melanosis Diseases 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 206010047642 Vitiligo Diseases 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 206010021198 ichthyosis Diseases 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 206010053717 Fibrous histiocytoma Diseases 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
- 208000007256 Nevus Diseases 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 6
- 201000010153 skin papilloma Diseases 0.000 description 6
- 201000004624 Dermatitis Diseases 0.000 description 5
- 206010020649 Hyperkeratosis Diseases 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- 150000001336 alkenes Chemical class 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 229940024606 amino acid Drugs 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 5
- 239000002360 explosive Substances 0.000 description 5
- 239000011968 lewis acid catalyst Substances 0.000 description 5
- 229910003002 lithium salt Inorganic materials 0.000 description 5
- 159000000002 lithium salts Chemical class 0.000 description 5
- 229910052749 magnesium Inorganic materials 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 208000010305 Epidermal Cyst Diseases 0.000 description 4
- 208000002927 Hamartoma Diseases 0.000 description 4
- 208000003367 Hypopigmentation Diseases 0.000 description 4
- 206010068489 Idiopathic guttate hypomelanosis Diseases 0.000 description 4
- 208000005890 Neuroma Diseases 0.000 description 4
- 206010057041 Poikiloderma Diseases 0.000 description 4
- 206010040868 Skin hypopigmentation Diseases 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 150000001262 acyl bromides Chemical class 0.000 description 4
- 150000001267 acyl iodides Chemical class 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 208000001119 benign fibrous histiocytoma Diseases 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000013058 crude material Substances 0.000 description 4
- 201000010305 cutaneous fibrous histiocytoma Diseases 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 4
- 238000002845 discoloration Methods 0.000 description 4
- 206010016629 fibroma Diseases 0.000 description 4
- 201000000284 histiocytoma Diseases 0.000 description 4
- 208000000069 hyperpigmentation Diseases 0.000 description 4
- 230000003810 hyperpigmentation Effects 0.000 description 4
- QSZMZKBZAYQGRS-UHFFFAOYSA-N lithium;bis(trifluoromethylsulfonyl)azanide Chemical compound [Li+].FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F QSZMZKBZAYQGRS-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 230000000750 progressive effect Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 208000001126 Keratosis Diseases 0.000 description 3
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 3
- 241001481669 Meloidae Species 0.000 description 3
- 241000269799 Perca fluviatilis Species 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical class [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 3
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 229910001425 magnesium ion Inorganic materials 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 150000002739 metals Chemical class 0.000 description 3
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
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- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical group C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 description 1
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Classifications
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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
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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 ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D497/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Rheumatology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Hematology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Ophthalmology & Optometry (AREA)
- Otolaryngology (AREA)
- Cardiology (AREA)
- Communicable Diseases (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Saccharide Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201462093396P | 2014-12-17 | 2014-12-17 | |
| US62/093,396 | 2014-12-17 | ||
| PCT/US2015/066487 WO2016100732A2 (en) | 2014-12-17 | 2015-12-17 | Commercially viable synthesis of cantharidin and bioactive cantharidin derivatives |
Publications (2)
| Publication Number | Publication Date |
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| JP6898241B2 (ja) | 2015-01-20 | 2021-07-07 | ヴェリカ ファーマシューティカルズ, インコーポレイテッドVerrica Pharmaceuticals, Inc. | 医薬品グレードカンタリジンの定量および調製 |
| CN106674248B (zh) * | 2016-12-17 | 2019-02-26 | 重庆市中药研究院 | 一种斑蝥素的合成工艺 |
| JP7280870B2 (ja) | 2017-06-06 | 2023-05-24 | ヴェリカ ファーマシューティカルズ インコーポレーテッド | 皮膚障害の処置 |
| USD900312S1 (en) | 2017-06-15 | 2020-10-27 | Verrica Pharmaceuticals, Inc. | Applicator |
| JP7497980B2 (ja) | 2017-06-15 | 2024-06-11 | ヴェリカ ファーマシューティカルズ インコーポレーテッド | 体表面の障害の処置のためのデバイスおよび方法 |
| EP4339199A3 (en) * | 2017-10-04 | 2024-05-15 | Verrica Pharmaceuticals, Inc. | Synthesis of cantharidin |
| US20210393570A1 (en) * | 2017-10-31 | 2021-12-23 | Université de Bourgogne | Therapeutical compositions for use in the treatment of non-malignant conditions associated with phosphatidylinositol-3-kinase activation: overgrowth spectrum, cutaneous capillary malformations and seborrheic keratoses |
| CN113455515A (zh) * | 2021-06-24 | 2021-10-01 | 广东省农业科学院果树研究所 | 斑蝥素在制备防治柑橘采后绿霉菌的农药杀菌剂的应用 |
| KR20240012182A (ko) | 2022-07-20 | 2024-01-29 | 고려대학교 산학협력단 | 칸타리딘을 유효성분으로 포함하는 교모세포종 예방 또는 치료용 조성물 |
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| JP6810693B2 (ja) | 2021-01-06 |
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| JP2021073173A (ja) | 2021-05-13 |
| KR102528106B1 (ko) | 2023-05-03 |
| CN114106013A (zh) | 2022-03-01 |
| BR112017013029B1 (pt) | 2022-12-06 |
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