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【结 构 式】 
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【分子编号】64823 【品名】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 【CA登记号】 |
【 分 子 式 】C25H31Cl3N2O8 【 分 子 量 】593.88792 【元素组成】C 50.56% H 5.26% Cl 17.91% N 4.72% O 21.55% |
合成路线1
该中间体在本合成路线中的序号：(X)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.
| 【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 | CAS号 | 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
该中间体在本合成路线中的序号：(X)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.
| 【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 | CAS号 | 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 |