CA1341262C - Nouveau procede de synthese de 3',4'-anhydrovinblastine de la vinblastine et de la vincristine - Google Patents

Nouveau procede de synthese de 3',4'-anhydrovinblastine de la vinblastine et de la vincristine Download PDF

Info

Publication number: CA1341262C
Authority: CA; Canada
Prior art keywords: formula; alkyl; process according; enamine; represented
Prior art date: 1987-08-06
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.): Expired - Fee Related

Application number

CA000543832A

Other languages

English (en)

Inventor

Camille A. Boulet

James P. Kutney

Michael Mchugh

Hiroki Tsukamoto

Jun Nakano

Lewis S.L. Choi

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

University of British Columbia

Original Assignee

University of British Columbia

Priority date (The priority date 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 date listed.)

1987-08-06

Filing date

1987-08-06

Publication date

2001-06-26

1987-08-06 Application filed by University of British Columbia filed Critical University of British Columbia

1987-08-06 Priority to CA000543832A priority Critical patent/CA1341262C/fr

1988-08-02 Priority to US07/228,821 priority patent/US5047528A/en

1988-08-03 Priority to SE8802813A priority patent/SE467875B/sv

1988-08-03 Priority to DE3826412A priority patent/DE3826412A1/de

1988-08-04 Priority to IL8734788A priority patent/IL87347A/en

1988-08-05 Priority to FR888810637A priority patent/FR2622888B1/fr

1988-08-05 Priority to NL8801966A priority patent/NL8801966A/nl

1988-08-05 Priority to IT8821678A priority patent/IT1227155B/it

1988-08-05 Priority to AU20512/88A priority patent/AU617342B2/en

1988-08-05 Priority to BE8800908A priority patent/BE1003228A4/fr

1988-08-05 Priority to ZA885765A priority patent/ZA885765B/xx

1988-08-05 Priority to CH2974/88A priority patent/CH676711A5/de

1988-08-06 Priority to CN 88104941 priority patent/CN1027266C/zh

1988-08-06 Priority to JP63196999A priority patent/JPH0613532B2/ja

1988-08-08 Priority to GB8818765A priority patent/GB2215331B/en

1988-08-08 Priority to HU884126A priority patent/HU208829B/hu

2001-06-26 Application granted granted Critical

2001-06-26 Publication of CA1341262C publication Critical patent/CA1341262C/fr

2018-06-26 Anticipated expiration legal-status Critical

Status Expired - Fee Related legal-status Critical Current

Links

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 And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)

CA000543832A 1987-01-22 1987-08-06 Nouveau procede de synthese de 3',4'-anhydrovinblastine de la vinblastine et de la vincristine Expired - Fee Related CA1341262C (fr)

Priority Applications (16)

Application Number	Priority Date	Filing Date	Title
CA000543832A CA1341262C (fr)	1987-08-06	1987-08-06	Nouveau procede de synthese de 3',4'-anhydrovinblastine de la vinblastine et de la vincristine
US07/228,821 US5047528A (en)	1987-01-22	1988-08-02	Process of synthesis of vinblastine and vincristine
SE8802813A SE467875B (sv)	1987-08-06	1988-08-03	Foerfarande foer framstaellning av vinblastin och vinkristin.
DE3826412A DE3826412A1 (de)	1987-08-06	1988-08-03	Verfahren fuer die synthese von vinblastin und vincristin
IL8734788A IL87347A (en)	1987-08-06	1988-08-04	Process for the synthesis of vinblastine and vincristine
AU20512/88A AU617342B2 (en)	1987-01-22	1988-08-05	Process for the synthesis of dimer alkaloid compounds
NL8801966A NL8801966A (nl)	1987-08-06	1988-08-05	Werkwijze voor de bereiding van vinblastine en vincristine.
IT8821678A IT1227155B (it)	1987-08-06	1988-08-05	Procedimento di sintesi di vinblastina e vincristina.
FR888810637A FR2622888B1 (fr)	1987-01-22	1988-08-05	Procede perfectionne de synthese de la vinblastine et de la vincristine
BE8800908A BE1003228A4 (fr)	1987-08-06	1988-08-05	Procede de synthese de la vinblastine et de la vincristine
ZA885765A ZA885765B (en)	1987-08-06	1988-08-05	Process for the synthesis of vinblastine and vincristine
CH2974/88A CH676711A5 (fr)	1987-08-06	1988-08-05
JP63196999A JPH0613532B2 (ja)	1987-08-06	1988-08-06	二量体の生成方法
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
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 (fr)	1987-08-06	1987-08-06	Nouveau procede de synthese de 3',4'-anhydrovinblastine de la vinblastine et de la vincristine

Publications (1)

Publication Number	Publication Date
CA1341262C true CA1341262C (fr)	2001-06-26

Family

ID=4136214

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA000543832A Expired - Fee Related CA1341262C (fr)	1987-01-22	1987-08-06	Nouveau procede de synthese de 3',4'-anhydrovinblastine de la vinblastine et de la vincristine

Country Status (12)

Country	Link
JP (1)	JPH0613532B2 (fr)
AU (1)	AU617342B2 (fr)
BE (1)	BE1003228A4 (fr)
CA (1)	CA1341262C (fr)
CH (1)	CH676711A5 (fr)
DE (1)	DE3826412A1 (fr)
GB (1)	GB2215331B (fr)
HU (1)	HU208829B (fr)
IT (1)	IT1227155B (fr)
NL (1)	NL8801966A (fr)
SE (1)	SE467875B (fr)
ZA (1)	ZA885765B (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
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
KR940005016B1 (ko) *	1990-11-30	1994-06-09	후지레비오 가부시끼가이샤	1,4-디히드로피리딘 유도체 및 그의 제조방법
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)

* Cited by examiner, † Cited by third party
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 (fr) *	1987-01-22	2001-06-26	James P. Kutney	Procede pour la synthese de 3',4'-anhydrovinblastine, de la vinblastine et de la vincristine

1987
- 1987-08-06 CA CA000543832A patent/CA1341262C/fr 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 BE BE8800908A patent/BE1003228A4/fr not_active IP Right Cessation
- 1988-08-05 CH CH2974/88A patent/CH676711A5/de 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 IT IT8821678A patent/IT1227155B/it active
- 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 HU HU884126A patent/HU208829B/hu not_active IP Right Cessation
- 1988-08-08 GB GB8818765A patent/GB2215331B/en not_active Expired - Lifetime

Also Published As

Publication number	Publication date
JPH01151590A (ja)	1989-06-14
BE1003228A4 (fr)	1992-02-04
SE8802813L (sv)	1989-02-07
HUT50351A (en)	1990-01-29
HU208829B (en)	1994-01-28
AU2051288A (en)	1989-02-09
ZA885765B (en)	1989-09-27
AU617342B2 (en)	1991-11-28
NL8801966A (nl)	1989-03-01
GB8818765D0 (en)	1988-09-07
GB2215331A (en)	1989-09-20
JPH0613532B2 (ja)	1994-02-23
GB2215331B (en)	1992-01-02
SE8802813D0 (sv)	1988-08-03
DE3826412A1 (de)	1989-02-16
IT1227155B (it)	1991-03-19
CH676711A5 (fr)	1991-02-28
SE467875B (sv)	1992-09-28
IT8821678A0 (it)	1988-08-05

Legal Events

Date	Code	Title	Description
2007-06-26	MKLA	Lapsed

Publication	Publication Date	Title
US4144237A (en)	1979-03-13	Synthetic vinblastine and vincristine derivatives
Trimurtulu et al.	1994	Alkaloids from the antarctic sponge Kirkpatrickia varialosa. Part 2: Variolin A and N (3′)-methyl tetrahydrovariolin B
JP3606872B2 (ja)	2005-01-05	ニチニチソウからの抗有糸分裂性の２成分アルカロイド誘導体
CA1042428A (fr)	1978-11-14	Derives amides de la vlb et de la leurocristine
JPS6314783A (ja)	1988-01-21	２−ハロゲン化エルゴリン誘導体の製法
Fukuda et al.	1999	Directed C-7 lithiation of 1-(2, 2-diethylbutanoyl) indoles
US5047528A (en)	1991-09-10	Process of synthesis of vinblastine and vincristine
CA1341261C (fr)	2001-06-26	Procede pour la synthese de 3',4'-anhydrovinblastine, de la vinblastine et de la vincristine
AU617342B2 (en)	1991-11-28	Process for the synthesis of dimer alkaloid compounds
US4191688A (en)	1980-03-04	Amides of leurosine, leuroformine, desacetylleurosine and desacetylleuroformine
US4096148A (en)	1978-06-20	Oxazolidinedione derivatives of Vinca alkaloids
IE42385B1 (en)	1980-07-30	Novel amide derivatives of dimeric alkaloids
Bourlot et al.	1994	A Convenient Synthesis of 1, 2-Dihydro-3H-indol-3-ones and 1, 2-Dihydro-2H-indol-2-ones by Baeyer-Villiger Oxidation
USRE37449E1 (en)	2001-11-13	Process of synthesis of 3′,4′-anhydrovinblastine, vinblastine and vincristine
US4143041A (en)	1979-03-06	4'-Deoxyvincristine and related compounds
US4430269A (en)	1984-02-07	12'-Iodo derivatives of dimeric indole-dihydroindole alkaloids, and process for preparing them
US4160767A (en)	1979-07-10	Vinca alkaloid intermediates
IL87347A (en)	1994-05-30	Process for the synthesis of vinblastine and vincristine
USRE30561E (en)	1981-03-31	Vinca alkaloid intermediates
EP0001920B1 (fr)	1983-05-25	Dérivés de la vincaleucoblastine, leur méthode de préparation, compositions pharmaceutiques les contenant et ces dérivés pour utilisation comme agents antimitotiques
USRE30560E (en)	1981-03-31	Oxazolidinedione derivatives of Vinca alkaloids
CA1114816A (fr)	1981-12-22	Dimeres pontes d'alcaloides de catharantus
US4122081A (en)	1978-10-24	5'-Hydroxyleurosine and related compounds
US4159269A (en)	1979-06-26	Preparation of oxazolidinedione derivatives of Vinca alkaloids
CA1088527A (fr)	1980-10-28	4'-desoxyvincristine et composes apparentes