NO327211B1 - Epotiloner med en modifisert sidekjede, samt fremgangsmate for fremstilling derav - Google Patents
Epotiloner med en modifisert sidekjede, samt fremgangsmate for fremstilling derav Download PDFInfo
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- NO327211B1 NO327211B1 NO19994071A NO994071A NO327211B1 NO 327211 B1 NO327211 B1 NO 327211B1 NO 19994071 A NO19994071 A NO 19994071A NO 994071 A NO994071 A NO 994071A NO 327211 B1 NO327211 B1 NO 327211B1
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- 229930013356 epothilone Natural products 0.000 title claims abstract description 16
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title description 3
- -1 Epothilone N-oxide Chemical class 0.000 claims description 8
- 150000003883 epothilone derivatives Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000004965 peroxy acids Chemical class 0.000 claims description 3
- 150000001204 N-oxides Chemical class 0.000 claims description 2
- ASQQEOXYFGEFKQ-UHFFFAOYSA-N dioxirane Chemical compound C1OO1 ASQQEOXYFGEFKQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 79
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- HESCAJZNRMSMJG-HGYUPSKWSA-N epothilone A Natural products O=C1[C@H](C)[C@H](O)[C@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C HESCAJZNRMSMJG-HGYUPSKWSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- FCCNKYGSMOSYPV-DEDISHTHSA-N (-)-Epothilone E Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(CO)sc2)/C)OC(=O)C[C@H](O)C1(C)C FCCNKYGSMOSYPV-DEDISHTHSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- FCCNKYGSMOSYPV-UHFFFAOYSA-N epothilone E Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC2OC2CC1C(C)=CC1=CSC(CO)=N1 FCCNKYGSMOSYPV-UHFFFAOYSA-N 0.000 description 2
- FCCNKYGSMOSYPV-OKOHHBBGSA-N epothilone e Chemical compound C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(CO)=N1 FCCNKYGSMOSYPV-OKOHHBBGSA-N 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- UWKQJZCTQGMHKD-UHFFFAOYSA-N 2,6-di-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=N1 UWKQJZCTQGMHKD-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
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- FFHWGQQFANVOHV-UHFFFAOYSA-N dimethyldioxirane Chemical compound CC1(C)OO1 FFHWGQQFANVOHV-UHFFFAOYSA-N 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Plural Heterocyclic Compounds (AREA)
- Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)
- Epoxy Compounds (AREA)
- Silicon Polymers (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Polyesters Or Polycarbonates (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Det er beskrevet epotiloner som er modifiserte i sidekjeden.
Description
Foreliggende oppfinnelse vedrører epotiloner med en modifisert sidekjede, samt fremgangsmåte for fremstilling derav.
Epotilonene A og B er blitt beskrevet, jfr. for eksempel DE 4 138 042,
WO 93 10 121 og WO 97 19 086.
Nevnte teknikkens stand angir at nevnte epotiloner er terapeutiske midler.
I PNAS USA, 95 (1998) 1369 -1374 er epotiloner beskrevet som nyttige terapeutiske midler. Ifølge Angew, Chem., Int. Ed., 36 (1997) 2097 - 2103 er et omfattende bibilio-tek av slike forbindelser tilveiebrakt basert på deres terapeutiske effekter.
Foreliggende oppfinnelse vedrører epotilon-N-oksid (epotilon A-N-oksid eller epotilon B-N-oksid), kjennetegnet ved at det har følgende formel:
R1, R2 = H, Z = O", R = H, CH3.
Foreliggende oppfinnelse vedrører videre fremgangsmåte for fremstilling av epotilon N-oksider ifølge krav 1, kjennetegnet ved at 3,7-ubeskyttede epotiloner A eller B blir omdannet til et N-oksid ved at N-oksideringen utføres med persyre eller et dioksiran.
Eksperiment 1: Diepoksyepotilon A. ^
En oppløsning av epotilon A (5 mg, 10 ^mol) i aceton (1 ml) ble behandlet ved 0°C med dimtyldioksiran (0,4 ml, 28 ^mol, 0,07 M i aceton). Oppløsningen ble brakt til romtemperatur i løpet av noen få timer og ble omrørt i 20 timer ved denne tem-peraturen. På grunn av at TLC bekreftet at utgangsmaterialet fortsatt var til stede, ble mer dimetyldioksiran (0,25 ml, 17 famol) tilsatt, og reaksjonsblandingen ble på ny omrørt i 20 timer ved romtemperatur. Oppløsningsmidlet ble fjernet, og resten ble renset ved hjelp av PLC (0,25 x 200 x 200 mm, 10 % MeOH:CH2CI2). Følgende ble isolert: 1. 1,4 mg (27 %) diepoksyepotilon A (3:2 epimer-blanding på C16-C17). Rf 0,63 (10 % MeOH:CH2CI2); Rt: 6,79 (isomer 1) og 7,39 (isomer 2) min (RP 18, 250 x 4 mm, MeOH:H20 65:35, 1 ml/min); MS: (m/z) = 510 (M<+>); <1>H NMR (400 MHz, CDCI3, oppsamlete signaler, isomer 1): 5 = 6,96 (s, 1H, H-19), 5,48 (dd, J = 12,2 og 2.5 Hz, 1H, H-15), 4,37 (dbr, J = 10,7 Hz, 1H, H-3), 4,10 (s, 1H, H-17), 3,67 (dd, J = 5.6 og 2,5 Hz, 1H, H-7), 3,14 (qd, J = 6,6 og 2,5 Hz, 1H, H-6), 3,00 (ddd, J = 9,7, 3,6 og 2,5 Hz, 1H, H-13), 2,88 (dt, J = 8,6 og 3,6 Hz, 1H, H-12), 2,71 (s, 3H, H-21), 2,53 (dd, J = 13,7 og 11,7 Hz, 1H, H-2a), 1,41 (s, 3H, H-22), 1,27 (s, 3H, H-26), 1,17 (d, J = 6,6 Hz, 3H, H-24), 1,08 (s, 3H, H-23), 0,97 (d, J = 7,1 Hz, 3H, H-25); (isomer 2) 5 = 6,98 (s, 1H, H-19), 5,11 (dd, J = 11,7 og 2,5 Hz, 1H, H-15), 4,27 (dbr, J = 10,7 Hz, 1H, H-3), 4,14 (s, 1H, H-17), 3,06 (qd, J = 6,6 og 2,9 Hz, 1H, H-6), 2,96 (ddd, J = 9,7, 3,6 og 2,5 Hz, 1H, H-13), 2,31 (dt, J = 14,7 og 2,0 Hz, 1H, H-14a), 1,36 (s, 3H, H-22), 1,15 (d, J = 6,6 Hz, 3H, H-24), 1,14 (s, 3H, H-26), 1,07 (s, 3H, H-23). 2. 0,8 mg (16 %) epotilon A N-oksid. Rf 0,44 (10 % MeOH:CH2CI2); Rt: 4,25 min (RP 18, 250 x 4 mm, MeOH:H20 65:35, 1 ml/min); MS: (m/z) = 510 (M<+>); <1>H NMR: se metode 1.
Eksperiment 2: Dihydroepotilon A. (l£)
Palladium på trekull (5 mg, 10 %) ble tilsatt til en oppløsning av epotilon A (11 mg, 22 ^mol) i etanol (2 ml), og den svarte suspensjonen ble eksponert for en H2-atmosfære i 24 timer ved romtemperatur. På grunn av at TLC indikerte at reaksjonen ikke enda var fullført, ble en ytterligere porsjon Pd/C tilsatt, og reaksjonsblandingen ble omrørt i ytterligere 20 timer under en H2-atmosfære. Produktene ble separert ved hjelp av PLC (1 x 200 x 200 mm, 10 % MeOH:CH2CI2). Følgende ble isolert: 1. 0,5 mg (5 %) dihydroepotilon A. Rf 0,60 (10 % MeOH:CH2CI2); Rt: 10,80 min (RP 18, 250 x 4 mm, MeOH:H20 65:35, 1 ml/min); MS: (m/z) = 496 (M<+>), 478, 407, 308; <1>H NMR (400 Mhz, CDCI3, oppsamlete signaler): 5 = 7,05 (d, J = 6,6 Hz, 1H, OH), 6,77 (s, 1H, H-19), 5,23 (dd, J = 12,4 og 2,3 Hz, 1H, H-15), 4,42 (ddd, J = 11,7, 6,6 og 3,0 Hz, 1H, H-3), 3,70 (ddd, J = 5, 3 og 2 Hz, 1H, H-7), 312 (qd, J = 6,6 og 3,0 Hz, 1H, H-6), 3,07 (d, J = 12,7 Hz, 1H, H-17a), 2,96 ddd, = 9,7, 3,6 og 2,0 Hz, 1H, H-13), 2,91, (ddd, J = 9,7, 3,6 og 2,6 Hz, 1H, H-12), 2,68 (s, 3H, H-21), 2,51 (dd, J
= 13,7 og 11,7 Hz, 1H, H-2a), 2,24 (d, J = 12,7 Hz, 1H, H-17b), 2,19 (m, 1H, H-16), 2,13 (dd, J = 13,7 og 3,0 Hz, 1H, H-2b); 1,35 (s, 3H, H-22), 1,15 (d, J = 6,6 Hz, 3H, H-24), 1,09 (s, 3H, H-23), 0,99 (d, J = 7,1 Hz, 3H, H-25), 0,93 (d, J = 6,6 Hz, 3H, H-26). 2. 8 mg (72 %) 15-deoksydihydroepotilonsyre. Rf 0,10 (10 % MeOH:CH2CI2).
Eksperiment 3: 16-hydroksyepotiloner A. (IbJ
Palladium på trekull (10 mg, 10 %) ble tilsatt til en oppløsning av diepoksyepotilon A (7 mg, 14 ^mol), 1:1 epimerblanding på C-16) i etanol (2 ml), og den svarte suspensjonen eksponert for en H2-atmosfære i 24 timer ved romtemperatur. På grunn av at TLC indikerte at reaksjonen enda ikke var fullført, ble en ytterligere porsjon Pd/C tilsatt, og reaksjonsblandingen ble omrørt i ytterligere 80 timer under en H2-atmosfære. Produktene ble separert ved hjelp av PLC (1 x 200 x 200 mm, 10 % MeOH:CH2CI2). Følgende ble isolert:
1. 3 mg (43 %) 16-hydroksyepotilon A (isomer 1).
Rf 0,38 (10 % MeOH:CH2CI2); Rt: 6.65 (RP 18, 250 x 4 mm, MeOH:H20 65:35, 1 ml/min); <1>H NMR (400 MHz, CDCI3, oppsamlete signaler): 5 = 6,85 (s, 1H, H-19), 5,02 (dd, J = 11,7 og 2,0 Hz, 1H, H-15), 4,38 (dbr, J = 11,2 Hz, 1H, H-3), 3,67 (dd, J = 4 og 3 Hz, 1H, H-7), 3,14 (qd, J = 6,8 og 3,0 Hz, 1H, H-6), 2,95 (d, J = 15,3 Hz, 1H, H-17a), 2,89 (d, J = 15,3 Hz, 1H, H-17b), 2,89 (ddd, J = 10,2, 3,6 og 2,0 Hz, 1H, H-13), 2,81 (ddd, J = 9,7, 3,6 og 2,5 Hz, 1H, H-12), 2,70 (s, 3H, H-21), 2,53 (dd, J = 15,8 og 11,7 Hz, 1H, H-2a), 2,14 (dd, J = 15,8 og 2,0 Hz, 1H, H-2b), 2,08 (dt, J = 14,3og2,0 Hz, 1H, H-14a), 1,39 (s, 3H, H-22), 1,25 (s, 3H, H-26), 1,19 (d, J = 6,6 Hz, 3H, H-24), 1,05 (s, 3H, H-23), 0,99 (d, J = 7,1 Hz, 3H, H-25).
2. 3 mg (43 %) 16-hydroksyepotilon A (isomer 2).
Rf 0,31 (10 % MeOH:CH2CI2); Rt: 6,10 min (RP 18, 250 x 4 mm, MeOH:H20 65:35, 1 ml/min); <1>H NMR (300 MHz, CDCI3, oppsamlete signaler): 5 = 6,85 (s, 1H, H-19), 5,21 (dd, J = 11,3 og 1,9 Hz, 1H, H-15), 4,42 (dbr, J = 10,5 Hz, 1H, H-3), 3,71 (sbr, 1H, H-7), 3,21 (d, J = 14,3 Hz, 1H, H-17a), 3,13 (qd, J =6,8 og 3,0 Hz, 1H, H-6), 3,09 (dt, J = 9,8 og 3,4 Hz, 1H, H-13), 2,87 (dt, J = 9,4 og 3,0 Hz, 1H, H-12), 2,73 (d, J = 14,3 Hz, 1H, H-17b), 2,68 (s, 3H, H-21), 2,63 (dd, J = 16,6 og 11,7 Hz, 1H, H-2a), 2,27 (dt, J = 14,7 og 2,3 Hz, 1H, H-14a), 2,24 (dd, J = 16,6 og 2,6 Hz, 1H, H-2b), 1,39 (s, 3H, H-22), 1,22 (s, 3H, H-26), 1,19 (d, J = 6,8 Hz, 3H, H-24), 1,05 (s,3H, H-23), 0,99 (d, J = 7,2 Hz, 3H, H-25).
Epotilon A N-oksid (2a): 100 mg 70 % m-klorperbenzosyre i 0,5 ml diklormetan ble tilsatt til 100 mg epotilon A i 1 ml diklormetan. Etter at blandingen var blitt omrørt i 6 timer ved romtemperatur, ble den fortynnet med diklormetan og ekstrahert ved risting med natriumsulfitt-oppløsning for å ødelegge persyre i overskudd og med natrium-bikarbonat-oppløsning. Oppløsningsmidlet blir avdampet i vakuum, og resten separert ved preparativ HPLC på en Nucleosil RP-18-kolonne (250 x 20 mm, elueringsmiddel/vann 60:40). Utbytte var 60 mg farveløs olje.
Rf = 0,60 (silica gel TLC aluminiumfolie, elueringsmiddel diklormetan/metanol 9:1); ESI-MS (neg. ioner m/z 510;
UV (metanol): lamda maks. 240 nm;
<13>C NMR (CDCI3): C-1 170,5, C-2 39,9, C-3 70,8, C-4 55,1, C-5 221,4, C-6 40,9, C-7 72,9, C-8 37,6, C-9 31,8, C-10 22,8, C-11 28.0, C-12 58,0,
C-13 55,8, C-14 32,2, C-15 75,5, C-16 144,5, C-17 111,4, C-18 143,4, C-19 110,3, C-20 145,6, C-21 13,5, C-22 15,4, C-23 23,3, C-24 12,0, C-25 16,5, C-27 18,2 ppm;
1H NMR(CDCI3):2a-H2,12dd, 2b-H 2,47 dd, 3-H 4,55 dd, 3-OH 6,48 bredde, 6-H 3,25 dq, 7-H 3,72 dd, 8-H 1,81 m, 9a-H 1,34 m, 9b-H 1,56 m, 10-H2 1,48 m, 11a-H 1,27 m, 11b-H 1,87 m, 12-H 2,92 ddd, 13-H 2,98 m; 14a-H 1,67 ddd, 14b-H 2,23 d, 15-H 5,33 d, 17-H 6,82 s, 19-H 7,09 s, 21-H3 2,61 s, 22-H3 1,02 s, 23-H3 1,42 s, 24-H3 1,18 d, 25-H3 0,99 d, 27-H3 2,04 s ppm.
21-Acetoksyepotilon A (= 21-acetylepotilon E) (3a):
0,05 ml 2,6-di-tert-butylpyridin og 0,1 ml eddiksyre anhydrid blir tilsatt til 50 mg epotilon A N-oksid (2a) i 0,5 ml diklormetan. Etter at blandingen er blitt oppvarmet ved 75°C i 15 minutter, blir oppløsningsmiddel og reagenser avdampet i vakuum og resten separert ved preparativ HPLC på Nucleosil RP-18 (250 x 20 mm, elueringsmiddel/vann 60:40). Utbytte 30 mg farveløs olje.
Rr 0,50 (silica gel TLC aluminiumfolie, elueringsmiddel diklormetan/metanol 95:5); ESI-MS (neg. ioner) m/z 552;
UV (metanol); lamda maks. 210, 250 nm ;
<1>H NMR (CDCI3> signaler forskjellige med hensyn på 2a): 15-H 5,45 dd, 17-H
6,60 s, 19-H 7,15 s, 21-H2 5,35 s, CH3CO 2,15 s ppm.
Epotilon E (3b): 1 dråpe konsentrert ammoniumoppløsning blir tilsatt til 10 mg 21-acetoksyepotilon A (3a) i 0,5 ml metanol, og blandingen oppvarmes i 1 time ved 40°C og avdampes til tørrhet i vakuum. Resten blir separert ved preparativ TLC. Utbytte 6 mg, identisk med en autentisk prøve av epotilon E.
Eksperiment 4: 19-metylepotilon A. ( 4b)
En oppløsning av epotilon A (15 mg, 30 ^mol) i THF (1 ml) ble behandlet ved
-90°C med n-butyllitium (100 ul, 160 ^mol, 1,6 M i heksan). Oppløsningen ble øyeblikkelig farvet gylden oransje. Etter at reaksjonsoppløsningen var blitt omrørt i 15 minutter ved -90°C, ble den behandlet med metyliodid (100 ^l, 1,6 mmol). Den resulterende svakt grønn-gule oppløsning ble varmet til -30°C og stoppet med buffer pH = 7,0 (2 ml). Emulsjonen ble brakt til pH 6 med 0,1 N saltsyre. Etter at blandingen var blitt mettet med fast NaCI, ble den vandige fasen ekstrahert med CH2CI2 (2 x 5 ml) og etylacetat (5 ml), kombinerte organiske faser ble tørket over MgS04 og filtrert, og oppløsningsmidlet ble fjernet på en Rotavap. Rensingen ble utført ved PLC (1 x 200 x 200 nm, 10 % MeOH:CH2CI2) og HPLC (RP 18, 250 x 16 mm, MeOH:H20 65:35). Følgende ble isolert: 1. 2,5 mg (17 %) 19-metylepotilon A. Rf 0,50 (10 % MeOH:CH2CI2); 11,70 min (RP 18, 250 x 4 mm, MeOH:H20 65:35, 1 ml/min); MS: (m/z) = 508 (M<+>), 420, 320; <1>H NMR (300 MHz, CDCI3), oppsamlete signaler): 5 = 6,41 (s, 1H, H-17), 5,46 (dd, J = 9,0 og 2,3 Hz, 1H, H-15), 4,15 (dd, J = 10,5 og 3,0 Hz, 1H, H-3), 3,77 (dd, J = 8 og 4 Hz, 1H, H-7), 3,20 (qd, J = 6,8 og 4,5 Hz, 1H, H-6), 3,04 (dt, J = 7,5 og 3,8 Hz, 1H, H-13), 2,91 (dt, J = 7,5 og 3,8 Hz, 1H, H-12), 2,61 (s, 3H, H-21), 2,51 (dd, J = 14,4 og 10,5 Hz, 1H, H-2a), 2,38 (dd, J = 14,4 og 3,0 Hz, 1H, H-2b), 2,32 (s, 3H, H-27), 2,15 (ddd, J = 15,1, 3,8 og 3,0 Hz, 1H, H-14a), 2,01 (d, J = 1,5Hz, 3H, H-26), 1,91 (dt, J = 15,1 og 8,8 Hz, 1H, H-14b); 1,34 (s, 3H, H-22), 1,16 (d, J = 6,8 Hz, 3H, H-24), 1,10 (s, 3H, H-23), 1,00 (d, J = 6,6Hz, 3H, H-25).
2. omtrent 50 % epotilon A
Eksperiment 5: 19-bromepotilon A. ( 4a)
En løsning av epotilon A (25 mg, 50 ^mol) i THF (2,5 ml) ble behandlet ved
-90°C med n-butyllitium (160 ul, 225 ^mol, 1,6 M heksan). Oppløsningen ble øyeblikkelig gylden oransje. Etter at blandingen var blitt omrørt i 15 minutter ved -90°C, ble N-bromsuksinimid (27 mg, 150 ^mol), oppløst i THF (0,5 ml), tilsatt. Oppløsningen ble sakte avfarvet. Reaksjonsblandingen som nå hadde en svakt brunaktig farve, ble varmet til -30°C og brakt til pH 6,5 med 0,1 N saltstyre (1 ml). Etter at blandingen var blitt mettet med fast NaCI, ble den vandige fasen ekstrahert med CH2CI2 (2x5 ml) og etylacetat (5 ml), kombinerte organiske faser ble tørket over MgS04 og filtrert, og oppløsningsmidlet ble fjernet på en Rotavap. Rensing ble utført ved PLC (1 x 200 x 200 nm, 10 % MeOH:CH2CI2) og HPLC (RP 18, 250 x 16 nm, MeOH:H20 65:35). Følgende ble isolert: 1. 2,6 mg (9%) 19-bromepotilon A. Rf 0,53 (10 % MeOH:CH2CI2); Rt: 20,78 min (RP18, 250 x 4 nm, MEOH:H20 65:35, 1 ml/min); MS: (m/z) = 574 og 572 (M<+>), 556, 554, 468, 466, 386, 384, 341; <1>H NMR (300 MHz, CDCI3,
oppsamlete signaler): 8 = 6,43 (s, 1H, H-17), 5,46 (dd, J = 6,7 og 2,3 Hz, 1H, H-15), 4,13 (ddd, J = 9,4, 6,0 og 3,8 Hz, 1H, H-3), 3,80 (dd, J = 8 og 4 Hz, 1H, H-7), 3,38 (d, J = 6,0 Hz, 1H, OH), 3,22 (qd, J = 6,8 og 5,3 Hz, 1H, H-6), 3,05 (dt, J = 8,3 og 4,1 Hz, 1H, H-13), 2,91 (dt, J = 7,5 og 3,7 Hz, 1H, H-12), 2,66 (s, 3H, H-21), 2,55 (dd, J = 14,7 og 9,4 Hz, 1H, H-2a), 2,47 (dd, J = 14,7 og 3,8 Hz, 1H, H-2b), 2,16 (d, J = 1,1 Hz, 3H, H-26), 2,14 (dt, J = 14,7 og 3,8 Hz, 1H, H-14a), 1,90 (dt, J = 15 og 8,3 Hz, 1H, H-14b);
1,34 (2, 3H, H-22), 1,17 (d, J = 6,8 Hz, 3H, H-24), 1,11 (s, 3H, H-23), 1,01 (d, J = 6,8 Hz, 3H, H-25).
2. omtrent 60 % epotilon A
Syntese-eksemplene 1a til 5a
Claims (2)
1. Epotilon-N-oksid (epotilon A-N-oksid eller epotilon B-N-oksid), karakterisert ved at det har følgende formel:
R1, R2 = H, Z = O", R = H, CH3.
2. Fremgangsmåte for fremstilling av epotilon N-oksider ifølge krav 1, karakterisert ved at 3,7-ubeskyttede epotiloner A eller B blir omdannet til et N-oksid ved at N-oksideringen utføres med persyre eller et dioksiran.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19707505 | 1997-02-25 | ||
| PCT/EP1998/001060 WO1998038192A1 (de) | 1997-02-25 | 1998-02-25 | Seitenkettenmodifizierte epothilone |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO994071D0 NO994071D0 (no) | 1999-08-24 |
| NO994071L NO994071L (no) | 1999-10-21 |
| NO327211B1 true NO327211B1 (no) | 2009-05-11 |
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ID=7821415
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO19994071A NO327211B1 (no) | 1997-02-25 | 1999-08-24 | Epotiloner med en modifisert sidekjede, samt fremgangsmate for fremstilling derav |
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| DE (2) | DE19880193D2 (no) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4138042C2 (de) * | 1991-11-19 | 1993-10-14 | Biotechnolog Forschung Gmbh | Epothilone, deren Herstellungsverfahren sowie diese Verbindungen enthaltende Mittel |
| PT873341E (pt) * | 1995-11-17 | 2004-02-27 | Biotechnolog Forschung Mbh Gbf | Derivados de epotilona preparacao e utilizacao |
| US6441186B1 (en) * | 1996-12-13 | 2002-08-27 | The Scripps Research Institute | Epothilone analogs |
| HU228851B1 (en) * | 1997-02-25 | 2013-06-28 | Biotechnolog Forschung Gmbh | Process for preparing epothilones with a modified side chain and compounds prepared by this process |
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1998
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