CA1341262C - A new process of the synthesis of 3',4'-anhydrovinblastine, vinblastine and vincristine - Google Patents
A new process of the synthesis of 3',4'-anhydrovinblastine, vinblastine and vincristine Download PDFInfo
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- CA1341262C CA1341262C CA000543832A CA543832A CA1341262C CA 1341262 C CA1341262 C CA 1341262C CA 000543832 A CA000543832 A CA 000543832A CA 543832 A CA543832 A CA 543832A CA 1341262 C CA1341262 C CA 1341262C
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- Prior art keywords
- formula
- alkyl
- process according
- enamine
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- Prior art date
- 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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- 238000000034 method Methods 0.000 title claims abstract description 55
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 title claims abstract description 41
- 229960003048 vinblastine Drugs 0.000 title claims abstract description 32
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 title claims abstract description 31
- 230000008569 process Effects 0.000 title claims abstract description 28
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 title claims abstract description 8
- 229960004528 vincristine Drugs 0.000 title claims abstract description 8
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 title claims abstract description 8
- FFRFGVHNKJYNOV-DOVUUNBWSA-N 3',4'-Anhydrovinblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C=C(C2)CC)N2CCC2=C1NC1=CC=CC=C21 FFRFGVHNKJYNOV-DOVUUNBWSA-N 0.000 title claims 2
- 230000015572 biosynthetic process Effects 0.000 title description 23
- 238000003786 synthesis reaction Methods 0.000 title description 14
- 150000002081 enamines Chemical class 0.000 claims abstract description 71
- 239000000543 intermediate Substances 0.000 claims abstract description 56
- -1 alkaloid compounds Chemical class 0.000 claims abstract description 19
- 230000001590 oxidative effect Effects 0.000 claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 claims abstract description 14
- JXLYSJRDGCGARV-PJXZDTQASA-N Leurosidine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-PJXZDTQASA-N 0.000 claims abstract description 9
- JXLYSJRDGCGARV-KSNABSRWSA-N ac1l29ym Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-KSNABSRWSA-N 0.000 claims abstract description 9
- 230000009466 transformation Effects 0.000 claims abstract description 9
- 229930013930 alkaloid Natural products 0.000 claims abstract description 7
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000000539 dimer Substances 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 14
- GKWYINOZGDHWRA-UHFFFAOYSA-N catharanthine Natural products C1C(CC)(O)CC(CC2C(=O)OC)CN1CCC1=C2NC2=CC=CC=C12 GKWYINOZGDHWRA-UHFFFAOYSA-N 0.000 claims description 14
- 239000003638 chemical reducing agent Substances 0.000 claims description 14
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 14
- 230000000694 effects Effects 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 229960003966 nicotinamide Drugs 0.000 claims description 10
- 239000011570 nicotinamide Substances 0.000 claims description 10
- 230000003647 oxidation Effects 0.000 claims description 10
- 238000007254 oxidation reaction Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- WVTGEXAIVZDLCR-UHFFFAOYSA-N Vindoline Natural products CC1C2CN3CCCC14CCC5Nc6ccccc6C25C34 WVTGEXAIVZDLCR-UHFFFAOYSA-N 0.000 claims description 7
- 238000005273 aeration Methods 0.000 claims description 7
- CMKFQVZJOWHHDV-DYHNYNMBSA-N catharanthine Chemical compound C([C@@H]1C=C([C@@H]2[C@@]3(C1)C(=O)OC)CC)N2CCC1=C3NC2=CC=CC=C12 CMKFQVZJOWHHDV-DYHNYNMBSA-N 0.000 claims description 7
- CXBGOBGJHGGWIE-IYJDUVQVSA-N vindoline Chemical compound CN([C@H]1[C@](O)([C@@H]2OC(C)=O)C(=O)OC)C3=CC(OC)=CC=C3[C@]11CCN3CC=C[C@]2(CC)[C@@H]13 CXBGOBGJHGGWIE-IYJDUVQVSA-N 0.000 claims description 7
- 150000004075 acetic anhydrides Chemical class 0.000 claims description 6
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 6
- 239000012346 acetyl chloride Substances 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 150000001204 N-oxides Chemical class 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 230000008878 coupling Effects 0.000 claims description 5
- 238000010168 coupling process Methods 0.000 claims description 5
- 238000005859 coupling reaction Methods 0.000 claims description 5
- LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical group C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 235000000346 sugar Nutrition 0.000 claims description 4
- AGNTUUNJYRDJCW-UHFFFAOYSA-N 1-[(1-benzyl-4H-pyridin-3-yl)methylamino]pyrrolidine-2-carboxamide Chemical compound C1CC(N(C1)NCC2=CN(C=CC2)CC3=CC=CC=C3)C(=O)N AGNTUUNJYRDJCW-UHFFFAOYSA-N 0.000 claims description 3
- WJNYVKCAEHASOF-UHFFFAOYSA-N 1-benzyl-4h-pyridine-3-carbonitrile Chemical compound C1=CCC(C#N)=CN1CC1=CC=CC=C1 WJNYVKCAEHASOF-UHFFFAOYSA-N 0.000 claims description 3
- 238000006062 fragmentation reaction Methods 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- JIJVOHRWYUICGU-UHFFFAOYSA-N 1-benzhydryl-4h-pyridine-3-carboxamide Chemical compound C1=CCC(C(=O)N)=CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 JIJVOHRWYUICGU-UHFFFAOYSA-N 0.000 claims description 2
- RFURHRKBOOHVBM-UHFFFAOYSA-N dimethyl 2-(3-carbamoyl-4h-pyridin-1-yl)butanedioate Chemical compound COC(=O)CC(C(=O)OC)N1C=CCC(C(N)=O)=C1 RFURHRKBOOHVBM-UHFFFAOYSA-N 0.000 claims description 2
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- 150000007942 carboxylates Chemical class 0.000 claims 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 238000007865 diluting Methods 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 1
- 230000001131 transforming effect Effects 0.000 claims 1
- 230000009467 reduction Effects 0.000 abstract description 28
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 150000003797 alkaloid derivatives Chemical group 0.000 abstract description 4
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- 241000208328 Catharanthus Species 0.000 abstract description 2
- 241000863480 Vinca Species 0.000 abstract description 2
- 230000000719 anti-leukaemic effect Effects 0.000 abstract description 2
- 230000000118 anti-neoplastic effect Effects 0.000 abstract description 2
- 230000000840 anti-viral effect Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- 238000006722 reduction reaction Methods 0.000 description 44
- 239000000243 solution Substances 0.000 description 31
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 26
- 239000000047 product Substances 0.000 description 23
- 238000004007 reversed phase HPLC Methods 0.000 description 14
- 229910052786 argon Inorganic materials 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000012298 atmosphere Substances 0.000 description 11
- 238000010790 dilution Methods 0.000 description 10
- 239000012895 dilution Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 230000006872 improvement Effects 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 150000002431 hydrogen Chemical class 0.000 description 7
- 239000012279 sodium borohydride Substances 0.000 description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000010626 work up procedure Methods 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 239000005515 coenzyme Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 150000001340 alkali metals Chemical class 0.000 description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000000935 solvent evaporation Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KGUMNRYFUFLBGA-UHFFFAOYSA-N 1,4-dihydropyridine-3-carboxamide Chemical class NC(=O)C1=CNC=CC1 KGUMNRYFUFLBGA-UHFFFAOYSA-N 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- LEDCFITVWDCVCB-UHFFFAOYSA-N methyl 2-(3-carbamoyl-4h-pyridin-1-yl)-3-methylbutanoate Chemical compound COC(=O)C(C(C)C)N1C=CCC(C(N)=O)=C1 LEDCFITVWDCVCB-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000006213 oxygenation reaction Methods 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- GHPYJLCQYMAXGG-WCCKRBBISA-N (2R)-2-amino-3-(2-boronoethylsulfanyl)propanoic acid hydrochloride Chemical compound Cl.N[C@@H](CSCCB(O)O)C(O)=O GHPYJLCQYMAXGG-WCCKRBBISA-N 0.000 description 1
- QUIJMHDIAFOPRK-UHFFFAOYSA-N 1-cyclooctylazocane Chemical compound C1CCCCCCC1N1CCCCCCC1 QUIJMHDIAFOPRK-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 241001661930 Aspidosperma Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 101100134922 Gallus gallus COR5 gene Proteins 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 239000007987 MES buffer Substances 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241001246918 Tabernanthe iboga Species 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002432 hydroperoxides Chemical class 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910052754 neon Inorganic materials 0.000 description 1
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Priority Applications (16)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000543832A CA1341262C (en) | 1987-08-06 | 1987-08-06 | A new process of the synthesis of 3',4'-anhydrovinblastine, vinblastine and vincristine |
| US07/228,821 US5047528A (en) | 1987-01-22 | 1988-08-02 | Process of synthesis of vinblastine and vincristine |
| DE3826412A DE3826412A1 (de) | 1987-08-06 | 1988-08-03 | Verfahren fuer die synthese von vinblastin und vincristin |
| SE8802813A SE467875B (sv) | 1987-08-06 | 1988-08-03 | Foerfarande foer framstaellning av vinblastin och vinkristin. |
| IL8734788A IL87347A (en) | 1987-08-06 | 1988-08-04 | Process for the synthesis of vinblastine and vincristine |
| BE8800908A BE1003228A4 (fr) | 1987-08-06 | 1988-08-05 | Procede de synthese de la vinblastine et de la vincristine |
| AU20512/88A AU617342B2 (en) | 1987-01-22 | 1988-08-05 | Process for the synthesis of dimer alkaloid compounds |
| IT8821678A IT1227155B (it) | 1987-08-06 | 1988-08-05 | Procedimento di sintesi di vinblastina e vincristina. |
| CH2974/88A CH676711A5 (da) | 1987-08-06 | 1988-08-05 | |
| NL8801966A NL8801966A (nl) | 1987-08-06 | 1988-08-05 | Werkwijze voor de bereiding van vinblastine en vincristine. |
| ZA885765A ZA885765B (en) | 1987-08-06 | 1988-08-05 | Process for the synthesis of vinblastine and vincristine |
| FR888810637A FR2622888B1 (fr) | 1987-01-22 | 1988-08-05 | Procede perfectionne de synthese de la vinblastine et de la vincristine |
| CN 88104941 CN1027266C (zh) | 1987-08-06 | 1988-08-06 | 生物碱化合物类二聚物的合成方法 |
| JP63196999A JPH0613532B2 (ja) | 1987-08-06 | 1988-08-06 | 二量体の生成方法 |
| GB8818765A GB2215331B (en) | 1987-08-06 | 1988-08-08 | Improvements in or relating to the synthesis of vinblastine and vincristine and related compounds |
| HU884126A HU208829B (en) | 1987-08-06 | 1988-08-08 | Process for synthetizing dimeric alkaloid compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000543832A CA1341262C (en) | 1987-08-06 | 1987-08-06 | A new process of the synthesis of 3',4'-anhydrovinblastine, vinblastine and vincristine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1341262C true CA1341262C (en) | 2001-06-26 |
Family
ID=4136214
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000543832A Expired - Fee Related CA1341262C (en) | 1987-01-22 | 1987-08-06 | A new process of the synthesis of 3',4'-anhydrovinblastine, vinblastine and vincristine |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JPH0613532B2 (da) |
| AU (1) | AU617342B2 (da) |
| BE (1) | BE1003228A4 (da) |
| CA (1) | CA1341262C (da) |
| CH (1) | CH676711A5 (da) |
| DE (1) | DE3826412A1 (da) |
| GB (1) | GB2215331B (da) |
| HU (1) | HU208829B (da) |
| IT (1) | IT1227155B (da) |
| NL (1) | NL8801966A (da) |
| SE (1) | SE467875B (da) |
| ZA (1) | ZA885765B (da) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5047528A (en) * | 1987-01-22 | 1991-09-10 | University Of Bristish Columbia | Process of synthesis of vinblastine and vincristine |
| USRE37449E1 (en) | 1987-02-06 | 2001-11-13 | University Of British Columbia | Process of synthesis of 3′,4′-anhydrovinblastine, vinblastine and vincristine |
| US5432279A (en) * | 1989-03-04 | 1995-07-11 | Mitsui Petrochemical Industries, Inc. | Process for the preparation of binary indole alkaloids |
| CA2056799C (en) * | 1990-11-30 | 2002-01-01 | Hiroshi Ikawa | 1,4-dihydropyridine derivatives and methods of producing the same |
| JP3010151U (ja) * | 1994-04-26 | 1995-04-25 | スミ子 片山 | 切込みのついた筒形食器収納ケース。 |
| FR2779146B1 (fr) * | 1998-06-02 | 2002-01-18 | Roowin | Nouveaux derives de vinca-alcaloides et procedes de preparation |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4279817A (en) * | 1975-05-30 | 1981-07-21 | The United States Of America As Represented By The Department Of Health & Human Services | Method for producing dimer alkaloids |
| HU195513B (en) * | 1984-10-16 | 1988-05-30 | Richter Gedeon Vegyeszet | Process for producing stable solutions of alkaloides with bis-indole skeleton |
| AU590873B2 (en) * | 1985-03-12 | 1989-11-23 | University Of Vermont And State Agricultural College, The | Synthesis of vinblastine and vincristine type compounds |
| CA1341261C (en) * | 1987-01-22 | 2001-06-26 | James P. Kutney | Process for the synthesis of 3',4'-anhydrovinblastine, vinblastine and vincristine |
-
1987
- 1987-08-06 CA CA000543832A patent/CA1341262C/en not_active Expired - Fee Related
-
1988
- 1988-08-03 SE SE8802813A patent/SE467875B/sv not_active IP Right Cessation
- 1988-08-03 DE DE3826412A patent/DE3826412A1/de not_active Ceased
- 1988-08-05 CH CH2974/88A patent/CH676711A5/de not_active IP Right Cessation
- 1988-08-05 IT IT8821678A patent/IT1227155B/it active
- 1988-08-05 BE BE8800908A patent/BE1003228A4/fr not_active IP Right Cessation
- 1988-08-05 NL NL8801966A patent/NL8801966A/nl not_active Application Discontinuation
- 1988-08-05 ZA ZA885765A patent/ZA885765B/xx unknown
- 1988-08-05 AU AU20512/88A patent/AU617342B2/en not_active Ceased
- 1988-08-06 JP JP63196999A patent/JPH0613532B2/ja not_active Expired - Lifetime
- 1988-08-08 GB GB8818765A patent/GB2215331B/en not_active Expired - Lifetime
- 1988-08-08 HU HU884126A patent/HU208829B/hu not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CH676711A5 (da) | 1991-02-28 |
| GB8818765D0 (en) | 1988-09-07 |
| NL8801966A (nl) | 1989-03-01 |
| AU2051288A (en) | 1989-02-09 |
| HU208829B (en) | 1994-01-28 |
| IT1227155B (it) | 1991-03-19 |
| SE8802813D0 (sv) | 1988-08-03 |
| JPH0613532B2 (ja) | 1994-02-23 |
| HUT50351A (en) | 1990-01-29 |
| GB2215331B (en) | 1992-01-02 |
| SE8802813L (sv) | 1989-02-07 |
| BE1003228A4 (fr) | 1992-02-04 |
| ZA885765B (en) | 1989-09-27 |
| IT8821678A0 (it) | 1988-08-05 |
| JPH01151590A (ja) | 1989-06-14 |
| DE3826412A1 (de) | 1989-02-16 |
| GB2215331A (en) | 1989-09-20 |
| SE467875B (sv) | 1992-09-28 |
| AU617342B2 (en) | 1991-11-28 |
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Legal Events
| Date | Code | Title | Description |
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| MKLA | Lapsed |