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【结 构 式】 
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【分子编号】47743 【品名】allyl (11S,11aS)-8-[3-([(11S,11aS)-10-[(allyloxy)carbonyl]-11-hydroxy-7-methoxy-2-methylene-5-oxo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy)propoxy]-11-hydroxy-7-methoxy-2-methylene-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate 【CA登记号】 |
【 分 子 式 】C39H44N4O12 【 分 子 量 】760.79812 【元素组成】C 61.57% H 5.83% N 7.36% O 25.24% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)Diamine (XVI) was protected as the bis-carbamate (XVII) by treatment with allyl chloroformate. Oxidation of the alcohol functionalities of (XVII) followed by spontaneous ring closure in the presence of tetrapropylammonium perruthenate and N-methylmorpholine-N-oxide produced the bis-pyrrolobenzodiazepine compound (XVIII). Finally, cleavage of the carbamate groups of (XVIII) with concomitant dehydration gave rise to the title compound.
| 【2】 Thurston, D.E.; Howard, P.W. (University of Portsmouth); Compounds. EP 1109812; WO 0012508 . |
| 【1】 Kelland, L.R.; Gregson, S.J.; Brooks, N.A.; Jenkins, T.C.; Thurston, D.E.; Hartley, J.A.; Howard, P.W.; Adams, L.J.; Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient cross-linking ability and potent cytotoxicity. J Med Chem 2001, 44, 5, 737. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 47741 | [2-amino-4-[3-(5-amino-4-[[(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]carbonyl]-2-methoxyphenoxy)propoxy]-5-methoxyphenyl][(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]methanone | C31H40N4O8 | 详情 | 详情 | |
| (XVII) | 47742 | allyl 5-[3-(5-[[(allyloxy)carbonyl]amino]-4-[[(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]carbonyl]-2-methoxyphenoxy)propoxy]-2-[[(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]carbonyl]-4-methoxyphenylcarbamate | C39H48N4O12 | 详情 | 详情 | |
| (XVIII) | 47743 | allyl (11S,11aS)-8-[3-([(11S,11aS)-10-[(allyloxy)carbonyl]-11-hydroxy-7-methoxy-2-methylene-5-oxo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy)propoxy]-11-hydroxy-7-methoxy-2-methylene-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate | C39H44N4O12 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)The desilylation of (XI) with HF and pyridine in THF gives the bis hydroxyethyl derivative (XII), which is submitted to an oxidative cyclization by means of oxalyl chloride and TEA in DMSO/dichloromethane, yielding the bis pyrrolobenzodiazepinone (XIII). Finally, this compound is treated with Pd(PPh3)4 and PPh3 in pyrrolidine/dichloromethane to cleave the allyloxycarbonyl protecting group and simultaneously promote the elimination of the OH groups affording the target pyrrolobenzodiazepinone.
| 【1】 Gregson, S.J.; Howard, P.W.; Corcoran, K.E.; Jenkins, T.C.; Kelland, L.R.; Thurston, D.E.; Synthesis of the first example of a C2-C3/C2'-C3'-endo unsaturated pyrrolo[2,1-c][1,4]benzodiazepine dimer. Bioorg Med Chem Lett 2001, 11, 21, 2859. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 62877 | allyl 5-[3-(5-{[(allyloxy)carbonyl]amino}-4-{[(2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methylenepyrrolidinyl]carbonyl}-2-methoxyphenoxy)propoxy]-2-{[(2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methylenepyrrolidinyl]carbonyl}-4-methoxy | C51H76N4O12Si2 | 详情 | 详情 | |
| (XII) | 47742 | allyl 5-[3-(5-[[(allyloxy)carbonyl]amino]-4-[[(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]carbonyl]-2-methoxyphenoxy)propoxy]-2-[[(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]carbonyl]-4-methoxyphenylcarbamate | C39H48N4O12 | 详情 | 详情 | |
| (XIII) | 47743 | allyl (11S,11aS)-8-[3-([(11S,11aS)-10-[(allyloxy)carbonyl]-11-hydroxy-7-methoxy-2-methylene-5-oxo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy)propoxy]-11-hydroxy-7-methoxy-2-methylene-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate | C39H44N4O12 | 详情 | 详情 |