IL111483A - Process for the preparation of etoposide phosphate and etoposide - Google Patents

Process for the preparation of etoposide phosphate and etoposide

Info

Publication number: IL111483A
Authority: IL; Israel
Prior art keywords: compound; formula; iva; benzyl; phosphate
Prior art date: 1993-11-04

Application number

IL11148394A

Other languages

English (en)

Other versions

IL111483A0 (en

Original Assignee

Bristol Myers Squibb Co

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.)

1993-11-04

Filing date

1994-11-01

Publication date

1998-12-06

1994-11-01 Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co

1994-11-01 Priority to IL12475494A priority Critical patent/IL124754A/en

1995-01-24 Publication of IL111483A0 publication Critical patent/IL111483A0/xx

1998-12-06 Publication of IL111483A publication Critical patent/IL111483A/en

Links

238000000034 method Methods 0.000 title claims description 64
LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 title abstract description 37
VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 title abstract description 30
229960005420 etoposide Drugs 0.000 title abstract description 27
229960000752 etoposide phosphate Drugs 0.000 title abstract description 26
238000002360 preparation method Methods 0.000 title description 5
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 75
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 66
229910019142 PO4 Inorganic materials 0.000 claims abstract description 36
239000002904 solvent Substances 0.000 claims abstract description 33
239000010452 phosphate Substances 0.000 claims abstract description 32
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 25
150000001875 compounds Chemical class 0.000 claims description 77
239000000203 mixture Substances 0.000 claims description 44
-1 hydroxy, phenyl Chemical group 0.000 claims description 22
125000005002 aryl methyl group Chemical group 0.000 claims description 18
238000006243 chemical reaction Methods 0.000 claims description 18
KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 16
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
239000003054 catalyst Substances 0.000 claims description 13
239000012429 reaction media Substances 0.000 claims description 12
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 11
125000006245 phosphate protecting group Chemical group 0.000 claims description 11
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 10
239000002841 Lewis acid Substances 0.000 claims description 9
150000007517 lewis acids Chemical class 0.000 claims description 9
238000004519 manufacturing process Methods 0.000 claims description 9
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
238000010992 reflux Methods 0.000 claims description 8
229910052736 halogen Inorganic materials 0.000 claims description 7
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
238000001816 cooling Methods 0.000 claims description 6
150000002367 halogens Chemical class 0.000 claims description 6
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
230000010933 acylation Effects 0.000 claims description 5
238000005917 acylation reaction Methods 0.000 claims description 5
125000000217 alkyl group Chemical group 0.000 claims description 5
239000013078 crystal Substances 0.000 claims description 5
150000002148 esters Chemical class 0.000 claims description 5
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
125000003545 alkoxy group Chemical group 0.000 claims description 4
125000001118 alkylidene group Chemical group 0.000 claims description 4
229910052739 hydrogen Inorganic materials 0.000 claims description 4
239000001257 hydrogen Substances 0.000 claims description 4
239000003960 organic solvent Substances 0.000 claims description 4
239000011541 reaction mixture Substances 0.000 claims description 4
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 3
229910000510 noble metal Inorganic materials 0.000 claims description 3
RQKYHDHLEMEVDR-UHFFFAOYSA-N oxo-bis(phenylmethoxy)phosphanium Chemical compound C=1C=CC=CC=1CO[P+](=O)OCC1=CC=CC=C1 RQKYHDHLEMEVDR-UHFFFAOYSA-N 0.000 claims description 3
125000001424 substituent group Chemical group 0.000 claims description 3
125000004432 carbon atom Chemical group C* 0.000 claims description 2
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
YNLAOSYQHBDIKW-UHFFFAOYSA-M diethylaluminium chloride Chemical compound CC[Al](Cl)CC YNLAOSYQHBDIKW-UHFFFAOYSA-M 0.000 claims description 2
239000011592 zinc chloride Substances 0.000 claims description 2
235000005074 zinc chloride Nutrition 0.000 claims description 2
JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 2
238000010438 heat treatment Methods 0.000 claims 5
HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 3
GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 claims 2
LJDZFAPLPVPTBD-UHFFFAOYSA-N nitroformic acid Chemical class OC(=O)[N+]([O-])=O LJDZFAPLPVPTBD-UHFFFAOYSA-N 0.000 claims 2
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims 1
241000357437 Mola Species 0.000 claims 1
125000003158 alcohol group Chemical group 0.000 claims 1
YTFJQDNGSQJFNA-UHFFFAOYSA-N benzyl dihydrogen phosphate Chemical group OP(O)(=O)OCC1=CC=CC=C1 YTFJQDNGSQJFNA-UHFFFAOYSA-N 0.000 claims 1
229910052796 boron Inorganic materials 0.000 claims 1
229910052751 metal Inorganic materials 0.000 claims 1
239000002184 metal Substances 0.000 claims 1
229910052763 palladium Inorganic materials 0.000 claims 1
VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims 1
VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims 1
125000005270 trialkylamine group Chemical group 0.000 claims 1
238000010792 warming Methods 0.000 claims 1
238000005859 coupling reaction Methods 0.000 abstract description 25
QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 abstract description 16
102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 abstract description 12
108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 abstract description 12
230000008878 coupling Effects 0.000 abstract description 9
238000010168 coupling process Methods 0.000 abstract description 9
125000006239 protecting group Chemical group 0.000 abstract description 9
238000005984 hydrogenation reaction Methods 0.000 abstract description 8
239000007787 solid Substances 0.000 description 25
239000000243 solution Substances 0.000 description 25
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
238000002425 crystallisation Methods 0.000 description 12
230000008025 crystallization Effects 0.000 description 12
238000006366 phosphorylation reaction Methods 0.000 description 12
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 11
238000003756 stirring Methods 0.000 description 11
230000026731 phosphorylation Effects 0.000 description 10
101150041968 CDC13 gene Proteins 0.000 description 9
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 9
239000012453 solvate Substances 0.000 description 9
235000000346 sugar Nutrition 0.000 description 9
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
239000000047 product Substances 0.000 description 8
238000004128 high performance liquid chromatography Methods 0.000 description 7
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
238000010511 deprotection reaction Methods 0.000 description 6
235000021317 phosphate Nutrition 0.000 description 6
125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 6
150000003839 salts Chemical class 0.000 description 6
FOVRGQUEGRCWPD-UHFFFAOYSA-N (5aR)-9t-beta-D-Glucopyranosyloxy-5t-(4-hydroxy-3,5-dimethoxy-phenyl)-(5ar,8at)-5,8,8a,9-tetrahydro-5aH-furo[3',4';6,7]naphtho[2,3-d][1,3]dioxol-6-on Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(OC3C(C(O)C(O)C(CO)O3)O)C3C2C(OC3)=O)=C1 FOVRGQUEGRCWPD-UHFFFAOYSA-N 0.000 description 5
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
YVCVYCSAAZQOJI-JHQYFNNDSA-N 4'-demethylepipodophyllotoxin Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YVCVYCSAAZQOJI-JHQYFNNDSA-N 0.000 description 5
238000005481 NMR spectroscopy Methods 0.000 description 5
125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
239000000725 suspension Substances 0.000 description 5
FOVRGQUEGRCWPD-BRLGUANISA-N (5s,5ar,8ar,9r)-9-(4-hydroxy-3,5-dimethoxyphenyl)-5-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-5a,6,8a,9-tetrahydro-5h-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one Chemical class COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 FOVRGQUEGRCWPD-BRLGUANISA-N 0.000 description 4
YCCILVSKPBXVIP-UHFFFAOYSA-N 2-(4-hydroxyphenyl)ethanol Chemical compound OCCC1=CC=C(O)C=C1 YCCILVSKPBXVIP-UHFFFAOYSA-N 0.000 description 4
ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
239000002253 acid Substances 0.000 description 4
230000015572 biosynthetic process Effects 0.000 description 4
229930182478 glucoside Natural products 0.000 description 4
150000003512 tertiary amines Chemical class 0.000 description 4
DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 3
102000004190 Enzymes Human genes 0.000 description 3
108090000790 Enzymes Proteins 0.000 description 3
239000007983 Tris buffer Substances 0.000 description 3
229910052784 alkaline earth metal Inorganic materials 0.000 description 3
239000002585 base Substances 0.000 description 3
150000001735 carboxylic acids Chemical class 0.000 description 3
230000015556 catabolic process Effects 0.000 description 3
238000006731 degradation reaction Methods 0.000 description 3
235000019439 ethyl acetate Nutrition 0.000 description 3
125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 3
150000008131 glucosides Chemical class 0.000 description 3
239000002808 molecular sieve Substances 0.000 description 3
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
239000012044 organic layer Substances 0.000 description 3
239000000651 prodrug Substances 0.000 description 3
229940002612 prodrug Drugs 0.000 description 3
FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 3
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 3
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 2
125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 description 2
125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
125000006188 2-phenyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C(C([H])=C([H])C([H])=C1[H])C([H])([H])* 0.000 description 2
125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 description 2
125000006506 3-phenyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C([H])=C([H])C(=C1[H])C([H])([H])* 0.000 description 2
125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 2
125000006189 4-phenyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
102000002260 Alkaline Phosphatase Human genes 0.000 description 2
108020004774 Alkaline Phosphatase Proteins 0.000 description 2
241000283690 Bos taurus Species 0.000 description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
YADJFRGSGWGMNH-UHFFFAOYSA-N [chloro(phenylmethoxy)phosphoryl]oxymethylbenzene Chemical compound C=1C=CC=CC=1COP(=O)(Cl)OCC1=CC=CC=C1 YADJFRGSGWGMNH-UHFFFAOYSA-N 0.000 description 2
230000000259 anti-tumor effect Effects 0.000 description 2
239000012062 aqueous buffer Substances 0.000 description 2
239000008346 aqueous phase Substances 0.000 description 2
239000000872 buffer Substances 0.000 description 2
YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
238000004587 chromatography analysis Methods 0.000 description 2
239000012043 crude product Substances 0.000 description 2
230000001419 dependent effect Effects 0.000 description 2
230000000694 effects Effects 0.000 description 2
NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
238000001914 filtration Methods 0.000 description 2
239000012467 final product Substances 0.000 description 2
229930182470 glycoside Natural products 0.000 description 2
239000000543 intermediate Substances 0.000 description 2
125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 2
239000012452 mother liquor Substances 0.000 description 2
239000012074 organic phase Substances 0.000 description 2
239000008188 pellet Substances 0.000 description 2
OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 2
230000000865 phosphorylative effect Effects 0.000 description 2
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
238000001953 recrystallisation Methods 0.000 description 2
159000000000 sodium salts Chemical class 0.000 description 2
238000010561 standard procedure Methods 0.000 description 2
239000007858 starting material Substances 0.000 description 2
238000010626 work up procedure Methods 0.000 description 2
YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 1
229960000549 4-dimethylaminophenol Drugs 0.000 description 1
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 1
102000013563 Acid Phosphatase Human genes 0.000 description 1
108010051457 Acid Phosphatase Proteins 0.000 description 1
229910015900 BF3 Inorganic materials 0.000 description 1
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
102100032373 Coiled-coil domain-containing protein 85B Human genes 0.000 description 1
101000868814 Homo sapiens Coiled-coil domain-containing protein 85B Proteins 0.000 description 1
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
239000004367 Lipase Substances 0.000 description 1
102000004882 Lipase Human genes 0.000 description 1
108090001060 Lipase Proteins 0.000 description 1
AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
206010028980 Neoplasm Diseases 0.000 description 1
206010041067 Small cell lung cancer Diseases 0.000 description 1
208000024313 Testicular Neoplasms Diseases 0.000 description 1
206010057644 Testis cancer Diseases 0.000 description 1
241000209140 Triticum Species 0.000 description 1
235000021307 Triticum Nutrition 0.000 description 1
BHIIGRBMZRSDRI-UHFFFAOYSA-N [chloro(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(Cl)OC1=CC=CC=C1 BHIIGRBMZRSDRI-UHFFFAOYSA-N 0.000 description 1
DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
150000001241 acetals Chemical class 0.000 description 1
150000007513 acids Chemical class 0.000 description 1
230000006978 adaptation Effects 0.000 description 1
239000003513 alkali Substances 0.000 description 1
229910052783 alkali metal Inorganic materials 0.000 description 1
125000003118 aryl group Chemical group 0.000 description 1
230000001580 bacterial effect Effects 0.000 description 1
229910052794 bromium Inorganic materials 0.000 description 1
125000001246 bromo group Chemical group Br* 0.000 description 1
239000007853 buffer solution Substances 0.000 description 1
244000309466 calf Species 0.000 description 1
201000011510 cancer Diseases 0.000 description 1
229910052799 carbon Inorganic materials 0.000 description 1
150000001768 cations Chemical class 0.000 description 1
239000003153 chemical reaction reagent Substances 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
125000001309 chloro group Chemical group Cl* 0.000 description 1
238000011281 clinical therapy Methods 0.000 description 1
238000011109 contamination Methods 0.000 description 1
238000000354 decomposition reaction Methods 0.000 description 1
230000030609 dephosphorylation Effects 0.000 description 1
238000006209 dephosphorylation reaction Methods 0.000 description 1
LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 1
125000006575 electron-withdrawing group Chemical group 0.000 description 1
230000002255 enzymatic effect Effects 0.000 description 1
YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 1
HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
238000000605 extraction Methods 0.000 description 1
239000000706 filtrate Substances 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
125000001153 fluoro group Chemical group F* 0.000 description 1
150000002338 glycosides Chemical class 0.000 description 1
125000005843 halogen group Chemical group 0.000 description 1
229910001385 heavy metal Inorganic materials 0.000 description 1
230000007062 hydrolysis Effects 0.000 description 1
238000006460 hydrolysis reaction Methods 0.000 description 1
239000012535 impurity Substances 0.000 description 1
238000011065 in-situ storage Methods 0.000 description 1
210000004347 intestinal mucosa Anatomy 0.000 description 1
229910052740 iodine Inorganic materials 0.000 description 1
125000002346 iodo group Chemical group I* 0.000 description 1
238000002955 isolation Methods 0.000 description 1
235000019421 lipase Nutrition 0.000 description 1
229910001486 lithium perchlorate Inorganic materials 0.000 description 1
238000003760 magnetic stirring Methods 0.000 description 1
229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
230000007935 neutral effect Effects 0.000 description 1
238000005580 one pot reaction Methods 0.000 description 1
239000008194 pharmaceutical composition Substances 0.000 description 1
150000002989 phenols Chemical class 0.000 description 1
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
230000001376 precipitating effect Effects 0.000 description 1
239000002243 precursor Substances 0.000 description 1
150000003138 primary alcohols Chemical class 0.000 description 1
OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
238000000746 purification Methods 0.000 description 1
238000011084 recovery Methods 0.000 description 1
238000000926 separation method Methods 0.000 description 1
208000000587 small cell lung carcinoma Diseases 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
239000011734 sodium Substances 0.000 description 1
239000011877 solvent mixture Substances 0.000 description 1
239000000126 substance Substances 0.000 description 1
150000008163 sugars Chemical class 0.000 description 1
239000006228 supernatant Substances 0.000 description 1
229960001278 teniposide Drugs 0.000 description 1
NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
201000003120 testicular cancer Diseases 0.000 description 1
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
238000003828 vacuum filtration Methods 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/44—Preparation of O-glycosides, e.g. glucosides
- C12P19/60—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
Engineering & Computer Science (AREA)
Health & Medical Sciences (AREA)
General Health & Medical Sciences (AREA)
Biotechnology (AREA)
Genetics & Genomics (AREA)
Biochemistry (AREA)
Molecular Biology (AREA)
Zoology (AREA)
Wood Science & Technology (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Bioinformatics & Cheminformatics (AREA)
General Engineering & Computer Science (AREA)
Microbiology (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Pharmacology & Pharmacy (AREA)
Animal Behavior & Ethology (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Saccharide Compounds (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)
Enzymes And Modification Thereof (AREA)

IL11148394A 1993-11-04 1994-11-01 Process for the preparation of etoposide phosphate and etoposide IL111483A (en)

Priority Applications (1)

Application Number	Priority Date	Filing Date	Title
IL12475494A IL124754A (en)	1993-11-04	1994-11-01	Process for the preparation of etoposide phosphate and etoposide

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US08/145,517 US5459248A (en)	1993-11-04	1993-11-04	Process of preparing etoposide phosphate and etoposide

Publications (2)

Publication Number	Publication Date
IL111483A0 IL111483A0 (en)	1995-01-24
IL111483A true IL111483A (en)	1998-12-06

Family

ID=22513464

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL11148394A IL111483A (en)	1993-11-04	1994-11-01	Process for the preparation of etoposide phosphate and etoposide

Country Status (20)

Country	Link
US (2)	US5459248A (de)
EP (1)	EP0652226B1 (de)
JP (2)	JP2801152B2 (de)
KR (1)	KR100351325B1 (de)
CN (4)	CN1046290C (de)
AT (1)	ATE193018T1 (de)
AU (1)	AU692472B2 (de)
CA (1)	CA2133594C (de)
CY (1)	CY2201B1 (de)
DE (1)	DE69424504T2 (de)
DK (1)	DK0652226T3 (de)
ES (1)	ES2146247T3 (de)
FI (1)	FI115913B (de)
GR (1)	GR3034213T3 (de)
HK (1)	HK1003302A1 (de)
HU (1)	HU221969B1 (de)
IL (1)	IL111483A (de)
PT (1)	PT652226E (de)
SG (1)	SG50571A1 (de)
TW (1)	TW420687B (de)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5459248A (en) *	1993-11-04	1995-10-17	Bristol-Myers Squibb Company	Process of preparing etoposide phosphate and etoposide
ES2191733T3 (es) *	1995-12-04	2003-09-16	Nippon Kayaku Kk	Procedimiento para producir etoposido.
US6207673B1 (en)	1997-03-12	2001-03-27	The University Of North Carolina At Chapel Hill	Covalent conjugates of topoisomerase I and topoisomerase II inhibitors
JP4698775B2 (ja) *	1997-06-02	2011-06-08	ブリストル−マイヤーズスクイブカンパニー	エトポシドの製造方法
EP1117671A2 (de)	1998-09-10	2001-07-25	Phytogen Life Sciences Inc.	Verfahren zur herstellung von dem antineoplastischen wirkstoff etoposid
AU775373B2 (en)	1999-10-01	2004-07-29	Immunogen, Inc.	Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents
JP3983546B2 (ja) *	2000-04-19	2007-09-26	塩野義製薬株式会社	スルホンアミド誘導体の製造方法およびその結晶
US20030082618A1 (en) *	2001-10-15	2003-05-01	Guangshan Li	Methods for detecting genetic aberrations
US20150246137A1 (en) *	2012-09-27	2015-09-03	The University Of North Carolina At Chapel Hill	Lipid coated nanoparticles containing agents having low aqueous and lipid solubilities and methods thereof
CN113121618A (zh) *	2021-04-07	2021-07-16	梯尔希（南京）药物研发有限公司	两种依托泊苷杂质的制备方法

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US2666778A (en) *	1950-05-10	1954-01-19	George M Steinberg	Method for the synthesis of organic phosphates
NL6613143A (de) *	1965-09-21	1967-03-22
EP0111058B1 (de) *	1982-11-26	1987-11-04	Nippon Kayaku Kabushiki Kaisha	Verfahren zur Herstellung von 4'-Demethyl-epipodophylotoxin-beta-D-ethyliden-glucosid und Acylderivate davon
JPS60246393A (ja) *	1984-05-22	1985-12-06	Nippon Kayaku Co Ltd	エトポシドの新規製造法
JPS62209089A (ja) *	1986-03-08	1987-09-14	Kuraray Co Ltd	ドリシルグリコピラノシルクロロホスフエイト誘導体およびその製造方法
US4904768A (en) *	1987-08-04	1990-02-27	Bristol-Myers Company	Epipodophyllotoxin glucoside 4'-phosphate derivatives
NZ225599A (en) *	1987-08-04	1991-09-25	Bristol Myers Co	Antibody-enzyme conjugates and combinations with prodrugs for the treatment of tumour cells
US4888419A (en) *	1987-08-31	1989-12-19	Bristol-Myers Company	3'-demethoxyepipodophyllotoxin glucoside derivatives
US5036055A (en) *	1989-06-07	1991-07-30	Bristol-Myers Company	Acylated derivatives of etoposide
US5066645A (en) *	1989-09-01	1991-11-19	Bristol-Myers Company	Epipodophyllotoxin altroside derivatives
US5081234A (en) *	1990-04-30	1992-01-14	Bristol-Myers Squibb Co.	4'-demethylepipodophyllotoxin glycosides
CA2041280A1 (en) *	1990-05-10	1991-11-11	Yosuke Sawada	Arylsulfatase
CN1025918C (zh) *	1990-06-07	1994-09-14	国家医药管理局上海医药工业研究院	抗肿瘤药表鬼臼毒吡喃糖甙的合成新工艺
US4997931A (en) *	1990-06-11	1991-03-05	Bristol-Myers Squibb Company	Epipodophyllotoxin glycosides
TW260671B (de) *	1991-04-29	1995-10-21	Bristol Myers Squibb Co
US5648474A (en) *	1991-10-08	1997-07-15	Bristol-Myers Squibb	Crystalline etoposide 4'-phosphate diethanolate
JPH07632B2 (ja) *	1991-12-23	1995-01-11	ブリストル−マイヤーズスクイブカンパニー	エトポシド４’−ホスフェート二ナトリウム塩の安定な六水和物
JP3061476B2 (ja) *	1992-04-24	2000-07-10	日本化薬株式会社	エトポシド燐酸エステルの製造法
US5375555A (en) *	1992-10-06	1994-12-27	Dolan; George D.	Non-furling flag fasteners
US5459248A (en) *	1993-11-04	1995-10-17	Bristol-Myers Squibb Company	Process of preparing etoposide phosphate and etoposide

1993
- 1993-11-04 US US08/145,517 patent/US5459248A/en not_active Expired - Lifetime
1994
- 1994-10-03 TW TW083109134A patent/TW420687B/zh active
- 1994-10-04 CA CA002133594A patent/CA2133594C/en not_active Expired - Fee Related
- 1994-11-01 IL IL11148394A patent/IL111483A/en not_active IP Right Cessation
- 1994-11-01 FI FI945149A patent/FI115913B/fi active IP Right Grant
- 1994-11-02 KR KR1019940029032A patent/KR100351325B1/ko not_active Expired - Fee Related
- 1994-11-02 JP JP6269821A patent/JP2801152B2/ja not_active Expired - Fee Related
- 1994-11-03 SG SG1996005289A patent/SG50571A1/en unknown
- 1994-11-03 AU AU77627/94A patent/AU692472B2/en not_active Ceased
- 1994-11-03 HU HU9403157A patent/HU221969B1/hu not_active IP Right Cessation
- 1994-11-03 DE DE69424504T patent/DE69424504T2/de not_active Expired - Fee Related
- 1994-11-03 PT PT94308115T patent/PT652226E/pt unknown
- 1994-11-03 EP EP94308115A patent/EP0652226B1/de not_active Expired - Lifetime
- 1994-11-03 DK DK94308115T patent/DK0652226T3/da active
- 1994-11-03 ES ES94308115T patent/ES2146247T3/es not_active Expired - Lifetime
- 1994-11-03 AT AT94308115T patent/ATE193018T1/de not_active IP Right Cessation
- 1994-11-04 CN CN94118214A patent/CN1046290C/zh not_active Expired - Fee Related
1995
- 1995-06-07 US US08/483,429 patent/US5688926A/en not_active Expired - Lifetime
1997
- 1997-11-12 JP JP31075697A patent/JP3810906B2/ja not_active Expired - Fee Related
- 1997-11-27 CN CN97123031A patent/CN1061047C/zh not_active Expired - Fee Related
- 1997-11-27 CN CN97123032A patent/CN1056378C/zh not_active Expired - Fee Related
- 1997-11-27 CN CN97123033A patent/CN1058017C/zh not_active Expired - Fee Related
1998
- 1998-03-23 HK HK98102432D patent/HK1003302A1/en not_active IP Right Cessation
2000
- 2000-08-17 GR GR20000401898T patent/GR3034213T3/el not_active IP Right Cessation
- 2000-11-02 CY CY0000053A patent/CY2201B1/xx unknown

Also Published As

Publication number	Publication date
JP3810906B2 (ja)	2006-08-16
PT652226E (pt)	2000-09-29
KR100351325B1 (ko)	2002-10-31
JP2801152B2 (ja)	1998-09-21
CA2133594A1 (en)	1995-05-05
AU692472B2 (en)	1998-06-11
US5688926A (en)	1997-11-18
CN1061047C (zh)	2001-01-24
CN1189500A (zh)	1998-08-05
DE69424504D1 (de)	2000-06-21
HU221969B1 (hu)	2003-03-28
CN1106016A (zh)	1995-08-02
EP0652226A1 (de)	1995-05-10
JPH07196680A (ja)	1995-08-01
DE69424504T2 (de)	2000-09-21
GR3034213T3 (en)	2000-12-29
CY2201B1 (en)	2002-11-08
ATE193018T1 (de)	2000-06-15
FI945149A0 (fi)	1994-11-01
HK1003302A1 (en)	1998-10-23
HU9403157D0 (en)	1994-12-28
HUT72461A (en)	1996-04-29
CN1046290C (zh)	1999-11-10
IL111483A0 (en)	1995-01-24
FI945149L (fi)	1995-05-05
JPH10152499A (ja)	1998-06-09
CN1189499A (zh)	1998-08-05
CN1056378C (zh)	2000-09-13
KR950014128A (ko)	1995-06-15
FI115913B (fi)	2005-08-15
EP0652226B1 (de)	2000-05-17
US5459248A (en)	1995-10-17
CN1058017C (zh)	2000-11-01
DK0652226T3 (da)	2000-08-07
SG50571A1 (en)	1998-07-20
ES2146247T3 (es)	2000-08-01
AU7762794A (en)	1995-05-18
CA2133594C (en)	1999-02-23
CN1189497A (zh)	1998-08-05
TW420687B (en)	2001-02-01

Legal Events

Date	Code	Title
1999-06-20	FF	Patent granted
1999-10-28	KB	Patent renewed
2001-04-30	KB	Patent renewed
2005-02-20	KB	Patent renewed
2010-02-14	MM9K	Patent not in force due to non-payment of renewal fees

Publication	Publication Date	Title
EP0180415B1 (de)	1990-01-31	6-0-Methylerythromycinderivat
HUP0102670A2 (hu)	2002-02-28	Kapszulázott, reakcióképes komponenseket tartalmazó fogápoló készítmény
CA2133594C (en)	1999-02-23	Process of preparing etoposide phosphate and etoposide
US5036055A (en)	1991-07-30	Acylated derivatives of etoposide
PL182790B1 (pl)	2002-02-28	Sposób wytwarzania antybiotyków antracyklinowych
AU630501B2 (en)	1992-10-29	Epiopodophyllotoxin altroside derivatives
EP0683788B1 (de)	1997-08-27	3'-azaridino-anthracyclin-derivate
IL124754A (en)	1998-12-06	Process for the preparation of etoposide phosphate and etoposide
HK1003302B (en)	2001-02-23	Process of preparing etoposide phosphate and etoposide
EP1140962B1 (de)	2007-02-21	Oleandomycin-derivate
US4767847A (en)	1988-08-30	Nobamycin its analogs and process therefore
HU221982B1 (hu)	2003-03-28	Glükopiranóz intermedier etopozid-foszfát és etopozid szintéziséhez
EP0986569B1 (de)	2003-09-24	Verfahren zur herstellung von etoposid
CA2062510A1 (en)	1992-10-30	Process for the preparation of 4'-demethylepipodophyllotoxin gluoside 4'-phosphates
PL83131B1 (de)	1975-12-31
HK1025576B (en)	2004-01-21	Process for preparing etoposide