-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】(11aS)-8-[6-[1(S)-(Chloromethyl)-5-hydroxy-2,3-dihydro-1H-benzo[e]indol-3-yl]-6-oxohexyloxy]-7-methoxy-2,3,5,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one

【CA登记号】

【分子式】C₃₂H₃₄ClN₃O₅

【分子量】576.09788

【开发单位】University of Auckland (Originator)

【药理作用】Oncolytic Drugs, DNA-Damaging Drugs

合成路线1 合成路线2

合成路线1

4-Benzyloxy-5-methoxy-2-nitrobenzoic acid (I) is treated with oxalyl chloride to provide the corresponding acid chloride (II), which is subsequently coupled with (S)-2-pyrrolidinemethanol (III) to give amide (IV). Hydrogenation of (IV) over Pd/C removes the benzyl protecting group and reduces the nitro substituent to the amino benzamide (V). Reaction of the aniline (V) with allyl chloroformate affords the carbamate (VI). The phenolic hydroxyl of (VI) is alkylated with trichloroethyl 6-bromohexanoate (VII) to yield (VIII). Dess-Martin oxidation of the primary alcohol group of (VIII) with concomitant intramolecular cyclization leads to the desired pyrrolobenodiazepine (X) together with the overoxidized dione (IX), which can be separated by column chromatography.

参考文献中间体

【1】 Tercel, M.; Stribbling, S.M.; Sheppard, H.; Siim, B.G.; Wu, K.; Pullen, S.M.; Botting, K.J.; Wilson, W.R.; Denny, W.A.; Unsymmetrical DNA cross-linking agents: Combination of the CBI and PBD pharmacophores. J Med Chem 2003, 46, 11, 2132.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	64815	4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid	C₁₅H₁₃NO₆	详情	详情
(II)	64816	4-(benzyloxy)-5-methoxy-2-nitrobenzoyl chloride	C₁₅H₁₂ClNO₅	详情	详情
(III)	64118	(2S)pyrrolidinylmethanol	C₅H₁₁NO	详情	详情
(IV)	64817	[4-(benzyloxy)-5-methoxy-2-nitrophenyl][(2S)-2-(hydroxymethyl)pyrrolidinyl]methanone	C₂₀H₂₂N₂O₆	详情	详情
(V)	64818		C₁₃H₁₈N₂O₄	详情	详情
(VI)	64819	allyl 5-hydroxy-2-{[(2S)-2-(hydroxymethyl)pyrrolidinyl]carbonyl}-4-methoxyphenylcarbamate	C₁₇H₂₂N₂O₆	详情	详情
(VII)	64820	2,2,2-trichloroethyl 6-bromohexanoate	C₈H₁₂BrCl₃O₂	详情	详情
(VIII)	64821	2,2,2-trichloroethyl 6-(5-{[(allyloxy)carbonyl]amino}-4-{[(2S)-2-(hydroxymethyl)pyrrolidinyl]carbonyl}-2-methoxyphenoxy)hexanoate	C₂₅H₃₃Cl₃N₂O₈	详情	详情
(IX)	64822	allyl (11aS)-7-methoxy-5,11-dioxo-8-{[6-oxo-6-(2,2,2-trichloroethoxy)hexyl]oxy}-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate	C₂₅H₂₉Cl₃N₂O₈	详情	详情
(X)	64823	allyl (11aS)-11-hydroxy-7-methoxy-5-oxo-8-{[6-oxo-6-(2,2,2-trichloroethoxy)hexyl]oxy}-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate	C₂₅H₃₁Cl₃N₂O₈	详情	详情

合成路线2

Cleavage of the trichloroethyl ester of (X) using Zn/HCO2H gives the carboxylic acid (XI). The N-Boc benzindole derivative (XII) is deprotected under acidic conditions to the amine (XIII), which is subsequently coupled with acid (XI) to yield the amide (XIV). Finally, palladium catalyzed cleavage of the N-Alloc group of (XIV) with concomitant dehydration leads to the desired compound.

参考文献中间体

【1】 Tercel, M.; Stribbling, S.M.; Sheppard, H.; Siim, B.G.; Wu, K.; Pullen, S.M.; Botting, K.J.; Wilson, W.R.; Denny, W.A.; Unsymmetrical DNA cross-linking agents: Combination of the CBI and PBD pharmacophores. J Med Chem 2003, 46, 11, 2132.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(X)	64823	allyl (11aS)-11-hydroxy-7-methoxy-5-oxo-8-{[6-oxo-6-(2,2,2-trichloroethoxy)hexyl]oxy}-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate	C₂₅H₃₁Cl₃N₂O₈	详情	详情
(XI)	64824	6-({(11aS)-10-[(allyloxy)carbonyl]-11-hydroxy-7-methoxy-5-oxo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl}oxy)hexanoic acid	C₂₃H₃₀N₂O₈	详情	详情
(XII)	64825	tert-butyl (1S)-1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benzo[e]indole-3-carboxylate	C₁₈H₂₀ClNO₃	详情	详情
(XIII)	64826	(1S)-1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indol-5-ol	C₁₃H₁₂ClNO	详情	详情
(XIV)	64827	allyl (11aS)-8-({6-[(1S)-1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benzo[e]indol-3-yl]-6-oxohexyl}oxy)-11-hydroxy-7-methoxy-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate	C₃₆H₄₀ClN₃O₈	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)