UTA-6026, -Drug Synthesis Database

【结构式】

【药物名称】UTA-6026

【化学名称】4-[(11aS)-7-Methoxy-5-oxo-2,3,5,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yloxy]-N-[2-[(7bR,8aS)-7-methyl-4-oxo-1,2,4,5,8,8a-hexahydrocyclopropa[c]pyrrolo[3,2-e]indol-2-ylcarbonyl]-1H-indol-5-yl]butyramide

【CA登记号】349665-44-7 (error in CA)

【分子式】C₃₈H₃₆N₆O₆

【分子量】672.74722

【开发单位】Arizona Cancer Center (Originator), University of Arizona (Originator), University of Texas System (Originator)

【药理作用】ONCOLYTIC DRUGS, DNA-Intercalating Drugs

合成路线1 合成路线2

合成路线1

Vanillic acid (I) was alkylated with ethyl bromobutyrate (II) to afford ether (III). The ester function of (III) was then subjected to saponification, yielding diacid (IV). Nitration of (IV) gave the nitro compound (V). Selective esterification of the aliphatic carboxyl group of (V) was achieved employing p-toluenesulfonic acid in methanol, and the resultant mono-acid was further converted to the corresponding acid chloride (VI) upon treatment with oxalyl chloride. Coupling of acid chloride (VI) with (S)-pyrrolidine-2-carbaldehyde diethyl dithioketal (VII) provided amide (VIII). After the reduction of the nitro group of (VIII) by means of SnCl2, the resultant amino compound (IX) was protected as the N-Fmoc derivative (X). Thioketal deprotection of (X) with concomitant cyclization in the presence of HgCl2 and CaCO3 gave rise to the pyrrolobenzodiazepinone system (XI). The methyl ester of (XI) was then hydrolyzed under acidic conditions to furnish acid (XII).

参考文献中间体

【1】 Zhou, Q.; et al.; Design and synthesis of a novel DNA-DNA interstrand adenine-guanine cross-linking agent. J Am Chem Soc 2001, 123, 20, 4865.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	17786	4-hydroxy-3-methoxybenzoic acid; Vanillic acid	121-34-6	C₈H₈O₄	详情	详情
(II)	11263	ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate	2969-81-5	C₆H₁₁BrO₂	详情	详情
(III)	52255	4-{[4-(ethyloxy)-4-oxobutyl]oxy}-3-(methyloxy)benzoic acid		C₁₄H₁₈O₆	详情	详情
(IV)	52256	4-[(3-carboxypropyl)oxy]-3-(methyloxy)benzoic acid		C₁₂H₁₄O₆	详情	详情
(V)	52257	4-[(3-carboxypropyl)oxy]-5-(methyloxy)-2-nitrobenzoic acid		C₁₂H₁₃NO₈	详情	详情
(VI)	52258	methyl 4-{[4-(chlorocarbonyl)-2-(methyloxy)-5-nitrophenyl]oxy}butanoate		C₁₃H₁₄ClNO₇	详情	详情
(VII)	52259	2-[bis(ethylsulfanyl)methyl]pyrrolidine; ethyl (ethylsulfanyl)(2-pyrrolidinyl)methyl sulfide		C₉H₁₉NS₂	详情	详情
(VIII)	52260	methyl 4-{[4-({2-[bis(ethylsulfanyl)methyl]-1-pyrrolidinyl}carbonyl)-2-(methyloxy)-5-nitrophenyl]oxy}butanoate		C₂₂H₃₂N₂O₇S₂	详情	详情
(IX)	52261	methyl 4-{[5-amino-4-({2-[bis(ethylsulfanyl)methyl]-1-pyrrolidinyl}carbonyl)-2-(methyloxy)phenyl]oxy}butanoate		C₂₂H₃₄N₂O₅S₂	详情	详情
(X)	52263	methyl 4-{[4-({2-[bis(ethylsulfanyl)methyl]-1-pyrrolidinyl}carbonyl)-5-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-2-(methyloxy)phenyl]oxy}butanoate		C₃₇H₄₄N₂O₇S₂	详情	详情
(XI)	52262	9H-fluoren-9-ylmethyl 11-hydroxy-7-(methyloxy)-8-{[4-(methyloxy)-4-oxobutyl]oxy}-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate		C₃₃H₃₄N₂O₈	详情	详情
(XII)	52264	4-{[10-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-11-hydroxy-7-(methyloxy)-5-oxo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy}butanoic acid		C₃₂H₃₂N₂O₈	详情	详情

合成路线2

Acid (XII) was coupled with the indolyl amine (XIII) by means of EDC to give amide (XIV). Finally, simultaneous removal of the Fmoc protecting group of (XIV) and cyclization of its seco-cyclopropapyrroloindole moiety were accomplished in one step by treatment with tetrabutylammonium fluoride in DMF, producing the target compound.

参考文献中间体

【1】 Zhou, Q.; et al.; Design and synthesis of a novel DNA-DNA interstrand adenine-guanine cross-linking agent. J Am Chem Soc 2001, 123, 20, 4865.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XII)	52264	4-{[10-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-11-hydroxy-7-(methyloxy)-5-oxo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy}butanoic acid	C₃₂H₃₂N₂O₈	详情	详情
(XIII)	52265	(5-amino-1H-indol-2-yl)[1-(chloromethyl)-5-hydroxy-8-methyl-1,6-dihydropyrrolo[3,2-e]indol-3(2H)-yl]methanone	C₂₁H₁₉ClN₄O₂	详情	详情
(XIV)	52266	9H-fluoren-9-ylmethyl 8-({4-[(2-{[1-(chloromethyl)-5-hydroxy-8-methyl-1,6-dihydropyrrolo[3,2-e]indol-3(2H)-yl]carbonyl}-1H-indol-5-yl)amino]-4-oxobutyl}oxy)-11-hydroxy-7-(methyloxy)-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10	C₅₃H₄₉ClN₆O₉	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)