BR9807742B1 - n-àxidos de epotilâneos a e b, e processo para sua preparaÇço. - Google Patents
n-àxidos de epotilâneos a e b, e processo para sua preparaÇço. Download PDFInfo
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- BR9807742B1 BR9807742B1 BRPI9807742-2A BR9807742A BR9807742B1 BR 9807742 B1 BR9807742 B1 BR 9807742B1 BR 9807742 A BR9807742 A BR 9807742A BR 9807742 B1 BR9807742 B1 BR 9807742B1
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- Prior art keywords
- formula
- oxide
- meoh
- epothylene
- ddd
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- 238000000034 method Methods 0.000 title claims description 20
- 238000002360 preparation method Methods 0.000 title claims description 5
- 150000001204 N-oxides Chemical class 0.000 claims description 14
- 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 claims description 12
- 229930013356 epothilone Natural products 0.000 claims description 8
- 150000004965 peroxy acids Chemical class 0.000 claims description 4
- ASQQEOXYFGEFKQ-UHFFFAOYSA-N dioxirane Chemical compound C1OO1 ASQQEOXYFGEFKQ-UHFFFAOYSA-N 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- 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 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 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 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 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
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-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
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- FFHWGQQFANVOHV-UHFFFAOYSA-N dimethyldioxirane Chemical compound CC1(C)OO1 FFHWGQQFANVOHV-UHFFFAOYSA-N 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
- 239000010931 gold Substances 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 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
- 239000011780 sodium chloride Substances 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
- 239000007858 starting material 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
- 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
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- -1 Epothilone N-oxide Chemical class 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 238000010934 O-alkylation reaction Methods 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229910000071 diazene Inorganic materials 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000001465 metallisation Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- QDNCLIPKBNMUPP-UHFFFAOYSA-N trimethyloxidanium Chemical compound C[O+](C)C QDNCLIPKBNMUPP-UHFFFAOYSA-N 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
Landscapes
- 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)
- Polyesters Or Polycarbonates (AREA)
- Epoxy Compounds (AREA)
- Silicon Polymers (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)
Description
Relatório Descritivo da Patente de Invenção para "N-ÓXIDOS DEEPOTILÔNEOS A E Β, E PROCESSO PARA SUA PREPARAÇÃO".
Os epotilôneos AeB foram descritos, cf., por exemplo, a paten-te DE 4 138 042, pedido de patente internacional WO 93 10 121 e pedido depatente internacional WO 97 19 086.
A técnica mencionada sugere os ditos epotilôneos como agen-tes terapêuticos. Em PNAS USA, 95 (1998) 1369 - 1374, os epotilôneos sãodescritos como agentes terapêuticos úteis. De acordo com Angew. Chem.,Int. Ed., 36 (1997) 2097 - 2103, proporciona-se uma extensa biblioteca des-ses compostos, com base nos seus efeitos terapêuticos.
A invenção refere-se então a um processo para a preparação deepotilôneos que são modificados na posição 16,17, em cujo processo osmateriais de partida são epotilôneos AeB 3,7-protegidos ou desprotegidos e:a) esses são hidrogenados na dupla-ligação 16,17 ou
b) submetidos a uma reação de adição com halogênio na dupla-ligação 16,17 ou
c) epoxidizados na dupla-ligação 16,17 e, se apropriado, o epó-xido resultante é reduzido para produzir o 16-álcool.
O processo de acordo com a invenção pode ser caracterizadopelo fato de que:
- no processo (a), a hidrogenação é influenciada com diimina ouhidrogênio e um catalisador metálico heterogêneo ou homogêneo ou
- no processo (c), a epoxidação é influenciada com um perácidoou um dioxirano.
Além do mais, a invenção refere-se à preparação de N-óxidosde epotilôneos 2,3-insaturados, em que:
(i) os epotilôneos A ou B 3,7-protegidos são convertidos em umN-óxido, de uma maneira conhecida de per se e, o 3-substituinte é eliminadopor uma base para produzir a dupla-ligação 2,3 ou
(ii) os epotilôneos A ou B 7-protegidos ou 7-desprotegidos, quetêm uma dupla-ligação na posição 2,3, são convertidos em um N-óxido, deuma maneira conhecida de per se e, se apropriado, o N-óxido resultante éEste processo de acordo com a invenção pode ser caracteriza-do pelo fato de que a N-oxidação é feita com perácido ou um dioxirano e re-agentes eletrofílicos de alquila, arila ou heteroarila, em particular, iodeto demetila ou tetrafluoborato de trimetiloxônio, são usados para a O-alquilaçãoopcional.
Além do mais, este processo de acordo com a invenção podeser caracterizado pelo fato de que um N-óxido resultante é submetido a umareação de Katada, em particular como descrita em Houben-Weyl, volumeE7b, página 646.
Além do mais, este processo de acordo com a invenção podeser caracterizado pelo fato de que a reação de Katada é feita com um deri-vado de ácido carboxílico ativado, em particular anidrido carboxílico ou clo-reto de ácido carboxílico.
Além do mais, este processo de acordo com a invenção podeser caracterizado pelo fato de que a reação de Katada é conduzida com ani-drido acético e, se apropriado, os 21-acetoepotilôneos obtidos são clivadosde uma maneira conhecida de per se, para produzir 21-hidroxiepotilôneos Aou B (epotilôneos EeF, respectivamente).
Além do mais, este processo de acordo com a invenção podeser caracterizado pelo fato de que o processo de clivagem opcional é reali-zado hidrolítica ou enzimaticamente.
Além do mais, a invenção refere-se a um processo para a pre-paração de epotilôneos, que são modificados na posição C19, em cujo pro-cesso os epotilôneos A ou B 3,7-protegidos ou desprotegidos são metaladosna posição C19 e capturados com reagentes eletrofílicos, de uma maneiraconhecida de per se, como epotilôneos substituídos por alquila, arila, hete-roarila, oxigênio ou enxofre, que são modificados na posição C19.
Este processo de acordo com a invenção pode ser caracteriza-do pelo fato de que a metalação é feita usando butil-lítio.
Além do mais, a invenção refere-se a um processo para a pre-paração de epotilôneos que são modificados na posição C27, em cujo pro-cesso o grupo alila (C17, C16 e C27) é substituído de uma maneira conheci-da de per se no C27-grupo metila por um heteroátomo.
Este processo de acordo com a invenção pode. ser caracteriza-do pelo fato de que o C27-grupo metila é substituído por um átomo de bro-mo, em particular com a ajuda de N-bromossuccinimida e, se apropriado, obrometo resultante é convertido em um C27-composto hidróxi.
Finalmente, a invenção refere-se a compostos preparados peloprocesso de acordo com a invenção.
Experimento 1: Diepoxiepotilõneo A. (1a)
Uma solução de epotilôneo A (5 mg, 10 μηποίβε) em acetona (1ml) foi tratada a 0°C com dimetildioxirano (0,4 ml, 28 μηποίβε, 0,07 M emacetona). A solução foi colocada na temperatura ambiente durante umaspoucas horas e foi agitada por 20 horas nesta temperatura. Uma vez que aTLC confirmou que o material de partida ainda estava presente, mais dime-tildioxirano (0,25 ml, 17 μη-ioles) foi adicionado e a mistura reacional foi no-vãmente agitada por 20 horas à temperatura ambiente. O solvente foi remo-vido e o resíduo foi purificado por meio de PLC (0,25 χ 200 χ 200 mm, 10%de MeOHiCH2Cb). Foram isolados os seguintes:
1. 1,4 mg (27%) de diepoxiepotilõneo A (mistura de epímeros3:2 em C16-C17). Rf 0,63 (10% MeOH:CH2CI2); Rf: 6,79 (isômero 1) e 7,39(isômero 2) min (RP 18, 250 χ 4 mm, Me0H:H20 65:35, 1 ml/min); MS: (m/z)= 510 (M+); 1H RMN (400 M3Hz, CDCI3, sinais selecionados, isômero 1): δ =6,96 (s, 1 Η, H-19), 5,48 (dd, J = 12,2 e 2,5 Hz, 1H, H-15), 4,37 (dbr, J = 10,7Hz, 1H, H-3), 4,10 (s, 1H, H-17),3,67 (dd, J = 5,6 e 2,5 Hz, 1H, H-7), 3,14(qd, J = 6,6 e 2,5 Hz, 1H, H-6), 3,00 (ddd, J = 9,7, 3,6 e 2,5 Hz, 1H, H-13),2,88 (dt, J = 8,6 e 3,6 Hz, 1H, H-12), 2,71 (s, 3H, H-21), 2,53 (dd, J = 13,7 e11,7 Hz, 1H, H-2a), 1,41 (s, 3H, H-22), 1,27 (s, 3H, H-26), 1,17 (d, J = 6,6Hz, 3H, H-24), 1,08 (s, 3H, H-23), 0,97 (d, J = 7,1 Hz, 3H, H-25); (isômero 2)δ = 6,98 (s, 1H, H-19), 5,11 (dd, J = 11,7 e 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 e 2,9 Hz, 1H, H-6),2,96 (ddd, J = 9,7, 3,6 e 2,5 Hz, 1H, H-13), 2,31 (dt, J = 14,7 e 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%) de N-óxido de epotilôneo A. Rf 0,44 (10% Me-OH: CH2CI2); Rf: 4,25 min (RP 18, 250 χ 4 mm, MeOHiH2O 65:35, 1 ml/min);MS: (m/z) = 510 (M+); 1H RMN: consultar o processo 1.
Experimento 2: Diidroepotilõneo A. (1c)
Paládio em carvão (5 mg, 10%) foi adicionado a uma solução deepotilôneo A (11 mg, 22 μηιοίβε) em etanol (2 ml) e a suspensão preta foiexposta a uma atmosfera de H2 por 24 horas à temperatura ambiente. Umavez que a TLC indicou que a resina ainda não estava completa, uma outraparte de Pd/C foi adicionada e a mistura reacional foi agitada por mais 20horas sob uma atmosfera de H2. Os produtos foram separados por meio dePLC (1 χ 200 χ 200 mm, 10% de MeOH:CH2CI2). Foram isolados os seguintes:
1. 0,5 mg (5%) de diidroepotilõneo A. Rf 0,60 (10% Me-OH:CH2CI2); Rf: 10,80 min (RP 18, 250 χ 4 mm, Me0H:H20 65,35, 1 ml/min);MS: (m/z) = 496 (M+), 478, 407, 308; 1H RMN (400MHz, CDCI3, sinais sele-cionados): δ = 7,05 (d, J = 6,6 Hz, 1H, OH), 6,77 (s, 1H, H-19), 5,23 (dd, J =12,4 e 2,3 Hz, 1H, H-15), 4,42 (ddd, J = 11,7, 6,6 e 3,0 Hz, 1H, H-3), 3,70(ddd, J = 5,3 e 2 Hz, 1H, H-7), 3,12 (qd, J = 6,6 e 3,0 Hz1 1H, H-6), 3,07 (d, J= 12,7 Hz, 1H, H-17a), 2,96 (ddd, J = 9,7, 3,6 e 2,0 Hz, 1H, H-13), 2,91 (ddd,J = 9,7, 3,6 e 2,6 Hz, 1H, H-12), 2,68 (s, 3H, H-21), 2,51 (dd, J = 13,7 e 11,7Hz, 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 e 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%) de ácido 15-deoxidiidroepotilônico. Rf 0,10 (10%MeOH:CH2CI2).
Experimento 3: 16-Hidroxiepotilõneo A. (1b)
Paládio em carvão (10 mg, 10%) foi adicionado a uma soluçãode diepoxiepotilôneo A (7 mg, 14 μιηοΙβε), mistura de epímeros 1:1 em C-16) em etanol (2 ml) e a suspensão preta foi exposta a uma atmosfera de H2por 24 horas à temperatura ambiente. Uma vez que a TLC indicou que aresina ainda não estava completa, uma outra parte de Pd/C foi adicionada ea mistura reacional foi agitada por mais 80 horas sob uma atmosfera de H2.Os produtos foram separados por meio de PLC (1 χ 200 χ 200 mm, 10% deMeOH:CH2CI2). Foram isolados os seguintes:
1. 3 mg (43%) de 16-hidroxiepotilôneo A (isômero 1). Rf 0,38(10% MeOHiCH2CI2); Rf: 6,65 min (RP 18, 250 χ 4 mm, MeOHiH2O 65:35, 1ml/min); 1H RMN (400 MHz, CDCI3, sinais selecionados): δ = 6,85 (s, 1H, H-19), 5,02 (dd, J = 11,7 e 2,0 Hz, 1 Η, H-15), 4,38 (dbr, J = 11,2 Hz, 1H1 H-3),3,67 (dd, J = 4 e 3 Hz, 1H, H-7), 3,14 (qd, J = 6,8 e 3,0 Hz, 1H, H-6), 2,95 (d,J = 15,3 Hz, 1 Η, H-17a), 2,89 (d, J = 15,3 Hz1 1H, H-17b), 2,89 (ddd, J =10,2, 3,6 e 2,0 Hz, 1H, H-13), 2,81 (ddd, J = 9,7, 3,6 e 2,5 Hz, 1H, H-12),2.70 (s, 3H, H-21), 2,53 (dd, J = 15,8 e 11,7 Hz, 1H, H-2a), 2,14 (dd, J =15,8 e 2,0 Hz, 1H, H-2b), 2,08 (dt, J = 14,3 e 2,0 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%) de 16-hidroxiepotilôneo A (isômero 2). Rf 0,31(10% MeOH:CH2CI2); Rf: 6,10 min (RP 18, 250 χ 4 mm, Me0H:H20 65:35, 1ml/min); 1H RMN (300 MHz, CDCI3, sinais selecionados): δ = 6,85 (s, 1H, H-19), 5,21 (dd, J = 11,3 e 1,9 Hz, 1H, H-15), 4,42 (dbr, J = 10,5 Hz, 1H, H-3),
3.71 (sbr, 1 Η, H-7), 3,21 (d, J = 14,3 Hz, 1H, H-17a), 3,13 (qd, J = 6,8 e 3,0Hz1 1 Η, H-6), 3,09 (dt, J = 9,8 e 3,4 Hz, 1H, H-13), 2,87 (dt, J = 9,4 e 3,0 Hz,1H, H-12), 2,73 (d, J = 14,3 Hz1 1H, H-17b), 2,68 (s, 3H, H-21), 2,63 (dd, J =16,6 e 11,7 Hz, 1H, H-2a), 2,27 (dt, J = 14,7 e 2,3 Hz, 1H, H-14a), 2,24 (dd,J = 16,6 e 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 Hz1 3H, H-25).
N-óxido de epotilôneo A (2a): 100 mg de ácido m-cloroperbenzóico 70% em 0,5 ml de diclorometano foram adicionados a 100mg de epotilôneo A em 1 ml de diclorometano. Após a mistura ter sido agi-tada por 6 horas à temperatura ambiente, é diluída com diclorometano eextraída por sacudimento, sucessivamente, com solução de sulfito de sódio,para destruir o excesso de perácido, e com bicarbonato de sódio. O sol-vente é evaporado a vácuo e o resíduo é separado por HPLC preparativaem uma coluna Nucleosil RP-18 (250 χ 20 mm, eluente metanol/água60:40). Rendimento de 60 mg de óleo incolor.
Rf = 0,60 (TLC em sílica gel, folha de alumínio, eluente dicloro-metano/metanol 9:1);
ESI-MS (íons neg.) m/z 510;
1JV (methanol): Iamda máx. 240 nm;
13C RMN (CDCI3): C-1 170,5, C-2 39,9, C-3 70,8, C-4 55,1, C-5221,4, 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-1258,0, 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-2516,5, C-27 18,2 ppm;
1H RMN (CDCI3): 2a-H 2,12 dd, 2b-H 2,47 dd, 3-H 4,55 dd, 3-OH6,48 amplo, 6-H 3,25 dq, 7-H 3,72 dd, 8-H 1,81 m, 9a-H 1,34 m, 9b-H 1,56m, IO-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, 15H- 5,33 d, 17-H 6,82 s, 19-H 7,09 s, 21-H32,61 s, 22-H3 1,02 s, 23-H3 1,42, 24-H3 1,18 d, 25-H3 0,99 d, 27-H3 2,04 sppm.
21-Acetoxiepotilõneo A (= 21-acetilepotilôneo E) (3a):
0,05 ml de 2,6-di-terc-butilpiridina e 0,1 ml de anidrido acéticosão adicionados a 50 mg de N-óxido de epotilôneo A (2a) em 0,5 ml de di-clorometano. Após a mistura ter sido aquecida a 75°C por 15 minutos, o sol-vente e os reagentes são evaporados a vácuo e o resíduo é separado porHPLC preparativa em Nucleosil RP-18 (250 χ 20 mm, eluente metanol/água60:40). Rendimento de 30 mg de óleo incolor.
Rf = 0,50 (TLC em sílica gel, folha de alumínio, eluente dicloro-metano/metanol 95:5);
ESI-MS (íons neg.) m/z 552;
UV (methanol): Iamda máx. 210, 250 nm;
1H RMN (CDCI3, sinais diferentes em relação a 2a): 15-H 5,45dd, 17-H 6,60 s, 19-H 7,15 s, 21-H2 5,35 s, CH3CO 2,15 s ppm.
Epotilôneo E (3b): 1 gota de solução de amônia concentrada éadicionada a 10 mg de 21-acetoxiepotilôneo A (3a) em 0,5 ml de metanol ea mistura é aquecida por 1 hora a 40°C e é evaporada a seco em vácuo. Oresíduo é separado por TLC preparativa. Rendimento 6 mg, idêntico a umaamostra autêntica de epotilôneo E.
Experimento 4: 19-Metilepotilòneo A. (4b)
Uma solução de epotilôneo A (15 mg, 30 μπιοίβε) em THF (1 ml)foi tratada a -90°C com n-butil-lítio (100 μΙ, 160 μηηοΙβ5, 1,6 M em hexano).
A solução ficou imediatamente laranja-ouro. Após a solução ter sido agitadapor 15 minutos a -90°C, foi tratada com iodeto de metila (100 μΙ, 1,6 mmo-les). A solução amarelo-esverdeada clara resultante foi aquecida a -30°C etemperada com tampão a pH = 7,0 (2 ml). A emulsão foi colocada em pH 6com ácido clorídrico a 0,1 N. Após a mistura ter sido saturada com NaCI só-lido, a fase aquosa foi extraída com CH2Cb (2x5 ml) e acetato de etila (5ml), as fases orgânicas combinadas foram secas sobre MgSO4 e filtradas eo solvente foi removido em um Rotavap. A purificação foi feita por PLC (1 χ200 χ 200 mm, 10% de MeOH;CH2CI2) e HPLC (RP 18, 250 χ 16 mm, Me-OH:H2O 65:35). Foram isolados os seguintes:
1. 2,5 mg (17%) de 19-metilepotilôneo A. Rf 0,50 (10% Me-OH:CH2CI2); R,: 11,70 min (RP 18, 250 χ 4 mm, Me0H:H20 65:35, 1 ml/min);MS: (m/z) = 508 (M+), 420, 320; 1H RMN (300 MHz, CDCI3, sinais seleciona-dos): δ = 6,41 (s, 1 Η, H-17), 5,46 (dd, J = 9,0 e 2,3 Hz, 1H, H-15), 4,15 (dd, J= 10,5 e 3,0 Hz, 1H, H-3), 3,77 (dd, J = 8 e 4 Hz, 1H, H-7), 3,20 (qd, J = 6,8e 4,5 Hz, 1H, H-6), 3,04 (dt, J = 7,5 e 3,8 Hz, 1H, H-13), 2,91 (dt, J = 7,5 and3,8 Hz, 1 Η, H-12), 2,61 (s, 3H, H-21), 2,51 (dd, J = 14,4 e 10,5 Hz, 1H, H-2a), 2,38 (dd, J = 14,4 e 3,0 Hz, 1H, H-2b), 2,32 (s, 3H, H-27), 2,15 (ddd, J =15,1, 3,8 e 3,0 Hz, 1H, H-14a), 2,01 (d, J = 1,5 Hz, 3H, H-26), 1,91 (dt, J =15,1 e 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 = 6,8 Hz, 3H, H-25).
2. aproximadamente 50% de epotilôneo A
Experimento 5: 19-Bromoepotilòneo A. (4a)
Uma solução de epotilôneo A (25 mg, 50 moles) em THF (2,5 ml)foi tratada a -90°C com n-butil-lítio (160 μΙ, 225 μηποίβε, 1,6 M em hexano).A solução ficou imediatamente laranja-ouro. Após a solução ter sido agitadapor 15 minutos a -90°C, adicionou-se N-bromossuccinimida (27 mg, 150 μmoles) dissolvida em THF (0,5 ml). A solução ficou imediatamente descob-rida. A mistura reacional, então de cor marrom-claro, foi aquecida a -30°C ecolocada em pH 6,5 com ácido clorídrico a 0,1 N (1 ml). Após a mistura tersido saturada com NaCI sólido, a fase aquosa foi extraída com CH2CI2 (2x5ml) e acetato de etila (5 ml), as fases orgânicas combinadas foram secassobre MgSO4 e filtradas e o solvente foi removido em um Rotavap. A purifi-cação foi feita por PLC (1 χ 200 χ 200 mm, 10% de MeOHiCH2CI2) e HPLC(RP 18, 250 χ 16 mm, MeOHiH2O 65:35). Foram isolados os seguintes:
1. 2,6 mg (9%) de 19-bromoepotilôneo A. Rf 0,53 (10% Me-OH:CH2CI2); Rf: 20,78 min (RP 18, 250 χ 4 mm, Me0H:H20 65:35, 1 ml/min);
MS: (m/z) = 574 e 572 (M+), 556, 554, 468, 466, 386, 384, 341; 1H RMN (300MHz, CDCI3, sinais selecionados): δ = 6,43 (s, 1H, H-17), 5,46 (dd, J = 8,7 e2,3 Hz, 1H, H-15), 4,13 (ddd, J = 9,4, 6,0 e 3,8 Hz, 1H, H-3), 3,80 (dd, J = 8e 4 Hz, 1H, H-7), 3,38 (d, J = 6,0 Hz, 1H, OH), 3,22 (qd, J = 6,8 e 5,3 Hz,1 Η, H-6), 3,05 (dt, J = 8,3 and 4,1 Hz, 1H, H-13), 2,91 (dt, J = 7,5 e 3,7 Hz,1H, H-12), 2,66 (s, 3H, H-21), 2,55 (dd, J = 14,7 e 9,4 Hz, 1H, H-2a), 2,47(dd, J = 14,7 e 3,8 Hz, 1H, H-2b), 2,16 (d, J = 1,1 Hz, 3H, H-26), 2,14 (dt, J =14,7 e 3,8 Hz, 1H, H-14a), 1,90 (dt, J = 15 e 8,3 Hz, 1H, H-14b); 1,34 (s, 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. aproximadamente 60% de epotilôneo AExemplos de Síntese 1a a 5a
<formula>formula see original document page 10</formula>
la R1, R2 = Η, X, Y= -O-, R = H
b R1, R2 H, X = OH Y = H, R = H
c R1, R2 = Η, X = H Y = H, R = H
<formula>formula see original document page 10</formula>
2a R1, R=H, Z = O-, R = H
b R1, R2 = Η, Z = OCH3 BF4", R = H
<formula>formula see original document page 10</formula>
3a R1, R2 = H, R3 = acetyl, R = H
b R1, R2, R3 = H, R = H<formula>formula see original document page 11</formula>
4a R1, R2 = H, V = Br, R = Hb V = CH3, R1, R2 Η, R = H
<formula>formula see original document page 33</formula>
5a R1, R2 = Η, W = OH, R = H
Claims (3)
1. N-óxido de epotilôneo (N-óxido de epotilôneo A), caracteriza-do pelo fato de que apresenta a seguinte fórmula: <formula>formula see original document page 12</formula>na qual,R1 e R2 são H;Z é O; eRé H.
2. N-óxido de epotilôneo (N-óxido de epotilôneo B), caracteriza-do pelo fato de que apresenta a seguinte fórmula: <formula>formula see original document page 12</formula>na qual,R1 e R2 são H;Z é CT; eRé Me.
3. Processo para a preparação de N-óxido de epotilôneo, comodefinido na reivindicação 1 ou 2, caracterizado pelo fato de que os epotilô-neos A ou B, 3,7-protegidos ou desprotegidos, são convertidos em um N-óxido, sendo que a N-oxidação é feita com perácido ou um dioxirano.
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| DE19707505.3 | 1997-02-25 | ||
| DE19707505 | 1997-02-25 | ||
| PCT/EP1998/001060 WO1998038192A1 (de) | 1997-02-25 | 1998-02-25 | Seitenkettenmodifizierte epothilone |
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| DE4138042C2 (de) * | 1991-11-19 | 1993-10-14 | Biotechnolog Forschung Gmbh | Epothilone, deren Herstellungsverfahren sowie diese Verbindungen enthaltende Mittel |
| DK1186606T4 (da) * | 1995-11-17 | 2011-12-05 | Biotechnolog Forschung Gmbh | Epothilonderivater, deres fremstilling og anvendelse |
| US6441186B1 (en) * | 1996-12-13 | 2002-08-27 | The Scripps Research Institute | Epothilone analogs |
| EP1201666A3 (de) * | 1997-02-25 | 2003-03-05 | Gesellschaft für biotechnologische Forschung mbH (GBF) | Seitenkettenmodifizierte Epothilone |
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