[특허]Process for producing ecteinascidin compounds

[미국특허] Process for producing ecteinascidin compounds 원문보기

IPC분류정보
국가/구분	United States(US) Patent 등록
국제특허분류(IPC7판)	C07D-051/522
출원번호	US-0715541 (1996-09-18)
발명자 / 주소	Corey Elias J. Gin David
출원인 / 주소	President and Fellows of Harvard College
대리인 / 주소	Linek
인용정보	피인용 횟수 : 30 인용 특허 : 0

초록 ▼

The present invention is directed to a synthetic process for the formation of ecteinascidin compounds and related structures, such as the saframycins. In one particularly preferred embodiment, the present invention provides a synthetic route for the formation of ecteinascidin 743 (1), [ STR 1 ] an exceedingly potent and rare marine-derived antitumor agent which is slated for clinical trials. The process of this invention is enantio- and stereocontrolled, convergent and short. Also disclosed are novel process intermediates, useful not only in the total synthesis of ecteinascidin 743, but also other known ecteinascidin compounds, including derivatives and analogs thereof.

대표청구항 ▼

[ What is claimed is:] [1.] An enantio- and stereocontrolled process for the preparation of ecteinascidin 743 comprising the steps of:(a) forming an .alpha.,.beta.-unsaturated malonic ester of Formula 2, having the following structure: [ STR 45 ] as a mixture of E and Z isomers from 2-benzyloxy-3-methyl-4,5-methylenedioxybenzaldehyde and allyl 2,2-dimethoxyethyl malonate;(b) stereospecifically converting the compound of Formula 2 to the compound of Formula 3, having the following structure: [ STR 46 ] by selective allyl ester cleavage, Curtius rearrangement, and reaction of the intermediate isocyanate with benzyl alcohol;(c) converting the compound of Formula 3 into the compound of Formula 4 having the following structure: [ STR 47 ] by catalytic hydrogenation over Rh[(COD)R,R-DIPAMP].sup.+ BF.sub.4.sup.- ;(d) converting the compound of Formula 4 into the compound of Formula 5 having the following structure: [ STR 48 ] by acetal cleavage, wherein isolation and exposure of the resulting aldehyde to BF.sub.3.Et.sub.2 O and 4 .ANG. mol sieves yields the bridged lactone compound of Formula 5;(e) converting the bridged lactone compound of Formula 5 to the free amino phenol compound of Formula 6 having the following structure: [ STR 49 ] by hydrogenolysis over 10% Pd--C; (f) forming the protected .alpha.-amino ester compound of Formula 7 having the following structure: [ STR 50 ] by reacting 3,5-bis-tert-butyl-dimethyl-silyloxy-4-methoxybenzaldehyde and methyl hydrogen malonate;(g) converting the protected .alpha.-amino ester compound of Formula 7 to the chiral aldehyde 8 having the following structure: [ STR 51 ] by reduction; (h) combining the compounds of Formulae 6 and 8 to afford the monobridged pentacyclic intermediate of Formula 10, having the following structure: [ STR 52 ] as follows: reacting the compounds of Formulae 6 and 8 to give a coupled phenolic .alpha.-amino nitrile, followed by O-allylation to give the allyl ether compound of Formula 9; having the following structure: [ STR 53 ] selectively converting the lactone function in the compound of Formula 9 to a lactol by reacting the compound of Formula 9 with diisobutylaluminum hydride;desilylating the lactol compound; andcyclizing the desilylated compound to afford the pentacycle compound of Formula 10 by an internal Mannich bisannulation;(i) converting the pentacycle compound of Formula 10 to the compound of Formula 11 having the following structure: [ STR 54 ] by the selective trifluoromethane-sulfonation of the least hindered phenolic hydroxyl; followed by(1) selective silylation of the primary hydroxyl; (2) protection of the remaining phenolic group as the methoxymethyl ether; (3) double deallylation; (4) reductive N-methylation; and (5) replacement of CF.sub.3 SO.sub.3 by CH.sub.3 ;(j) oxidizing the phenol compound of Formula 11 effected position-selective angular hydroxylation to give after desilylation the dihydroxy dienone compound of Formula 12 having the following structure: [ STR 55 ] (k) forming the compound of Formula 13 having the following structure: [ STR 56 ] by esterifying the primary hydroxyl function of the compound of Formula 12 with (S)-N-allyloxycarbonyl-S-(9-fluorenylmethyl)cysteine;(l) transforming the compound of Formula 13 to the bridged lactone compound of Formula 14 having the following structure: [ STR 57 ] by; (I) first reacting the compound of Formula 13 with an in situ generated Swern reagent; (2) followed by the formation of the exendo quinone methide, (3) destruction of the excess Swern reagent; (4) addition of excess N-tert-butyl-N',N"-tetramethylguanidine to generate the 10-membered lactone bridge; and (5) addition of excess Ac.sub.2 O to acetylate the resulting phenoxide group;(m) cleaving the N-allyloxycarbonyl group of the compound of Formula 14 and oxidizing the resulting .alpha.-amino lactone to the corresponding .alpha.-keto lactone by transamination thereby forming the compound of Formula 15 having the following structure: [ STR 58 ] (n) stereospecifically forming spiro tetrahydro-isoquinoline compound by reacting the compound of Formula 15 with 2-[3-hydroxy-4-methoxy-phenyl]ethylamine;(o) followed by methoxymethyl cleavage and replacement of CN by HO to form the compound of Formula 1, ecteinascidin 743, having the following structure: [ STR 59 ]

이 특허를 인용한 특허 (30) 인용/피인용 타임라인 분석

Manzanares, Ignacio; Cuevas, Carmen; Perez, Marta; Martin, Maria Jesus; Rodriguez, Alberto; Munt, Simon, Antitumoral analogs of ET-743.
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Manzanares,Ignacio; Martin,Mar��a Jes��s; Rodriguez,Alberto; Munt,Simon; Cuevas,Carmen; Perez,Marta, Antitumoral analogs of ET-743.
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Manzanares,Ignacio; Martin,Mar？a Jes？s; Rodriguez,Alberto; Munt,Simon; Cuevas,Carmen; Perez,Marta, Antitumoral analogs of et-743.
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Martinez, Valentin; Flores, Maria; Gallego, Pilar; Cuevas, Carmen; Munt, Simon; Manzanares, Ignacio, Antitumoral derivatives of ET-743.
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Martinez, Valentin; Flores, Maria; Gallego, Pilar; Cuevas, Carmen; Munt, Simon; Manzanares, Ignacio, Antitumoral derivatives of ET-743.
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Flores,Maria; Francesch,Andr？s; Gallego,Pilar; Chicharro,Jos？ Luis; Zarzuelo,Maria; Fern？ndez,Carolina; Manzanares,Ignacio, Antitumoral ecteinascidin derivatives.
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Rybak, Mary Ellen, Combination of ET-743 and a 5-fluorouracil pro-drug for cancer treatment.
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Cvitkovich, Esteban; Demetri, George Daniel; Guzman, Cecilia; Jimeno, Jose; Lazaro, Luis Lopez; Misset, Jean Louis; Twelves, Chris; Von Hoff, Daniel D., Compositions and uses of ET743 for treating cancer.
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Danishefsky, Samuel J.; Zhou, Bishan, Compounds of the saframycin-ecteinascidin series, uses, and synthesis thereof.
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Danishefsky, Samuel J.; Zhou, Bishan, Compounds of the saframycin-ecteinascidin series, uses, and synthesis thereof.
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Rinehart Kenneth L. ; Morales Jose J. ; Reid Joel ; Reymundo Isabel,ESX ; Floriano Pablo,ESX ; Gravalos Lola Garcia,ESX, ETM-775 metabolite of ecteinascidin 743.
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Gallego, Pilar; Cuevas, Carmen; Munt, Simon; Manzanares, Ignacio; Martinez, Valentin, Ecteinascidin analogs for use as antitumour agents.
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Calvo Salve, Pilar; Tobio Barreira, Maria, Formulations comprising jorumycin-, renieramycin-, safracin- or saframycin-related compounds for treating proliferative diseases.
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Cuevas, Carmen; Perez, Marta; Francesch, Andres; Fernandez, Carolina; Chicharro, Jose Luis; Gallego, Pilar; Zarzuelo, Maria; Calle, Fernando de; Manzanares, Ignacio, Hemisynthetic method and new compounds.
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Cuevas,Carmen; Perez,Marta; Francesch,Andres; Fernandez,Carolina; Chicharro,Jose Luis; Gallego,Pilar; Zarzuelo,Maria; de la Calle,Fernando; Manzanares,Ignacio, Hemisynthetic method and new compounds.
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Rinehart,Kenneth L.; Morales,Jose J.; Reid,Joel; Reymundo,Isabel; Floriano,Pablo; Gravalos,Lola Garcia, Metabolites of ecteinascidin 743.
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Rinehart, Kenneth L.; Morales, Jose J.; Reid, Joel; Reymundo, Isabel; Floriano, Pablo; Gravalos, Lola Garcia, Metabolites of ecteinascidin 743 formed by human cytochrome CYP3A4.
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Beijnen, Jacob Hendrik; Nuijen, Bastiaan; Salve, Pilar Calvo; Barreira, Maria Tobio, Pharmaceutical formulations of ecteinascidin compounds.
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Myers, Andrew G.; Plowright, Alleyn T.; Kung, Daniel W.; Lanman, Brian, Saframycins, analogues and uses thereof.
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Myers,Andrew G.; Plowright,Alleyn T., Saframycins, analogues and uses thereof.
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Rinehart Kenneth L. ; Morales Jose J., Semi-synthetic ecteinascidins.
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Barrasa, Valentin Martinez; Gallego, Pilar; Cuevas, Carmen; Munt, Simon; Manzanares, Ignacio; Menchaca, Roberto; Rodriguez, Natividad; Rodriguez, Alberto, Synthesis of naturally occurring ecteinascidins and related compounds.
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Barrasa, Valentin Martinez; Gallego, Pilar; Cuevas, Carmen; Munt, Simon; Manzanares, Ignacio; Menchaca, Roberto; Rodriguez, Natividad; Rodriguez, Alberto, Synthesis of naturally occurring ecteinascidins and related compounds.
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Corey Elias J., Synthetic analogs of ecteinascidin-743.
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Corey, Elias J., Synthetic analogs of ecteinascidin-743.
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Corey, Elias J., Synthetic analogs of ecteinascidin-743.
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Elias J. Corey, Synthetic analogs of ecteinascidin-743.
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Corey, Elias J., Synthetic process for an intermediate for ecteinascidin and phthalascidin compounds.
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Francesch,Andr��s; Fern��ndez,Carolina; Chicharro,Jos�� Luis; Gallego,Pilar; Zarzuelo,Maria; Manzanares,Ignacio; Perez,Marta; Cuevas,Carmen; Martin,Mar��a Jes{dot over (u)}s; Munt,Simon, Synthetic process for the manufacture of an ecteinaschidin compound.
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Martin López, Ma Jesús; Francesch Solloso, Andrés; Cuevas Marchante, Maria del Carmen, Synthetic process for the manufacture of ecteinascidin compounds.
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[미국특허] Process for producing ecteinascidin compounds 원문보기

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