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【结 构 式】 
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【分子编号】47741 【品名】[2-amino-4-[3-(5-amino-4-[[(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]carbonyl]-2-methoxyphenoxy)propoxy]-5-methoxyphenyl][(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]methanone 【CA登记号】 |
【 分 子 式 】C31H40N4O8 【 分 子 量 】596.68076 【元素组成】C 62.4% H 6.76% N 9.39% O 21.45% |
合成路线1
该中间体在本合成路线中的序号：(XVI)Reaction of 1,3-diiodopropane (X) with two equivalents of vanillic acid (IX) in the presence of NaOH produced diacid (XI). Nitration of (XI) to give (XII) was carried out with concentrated HNO3 at -10 C. Dinitro diacid (XII) was then converted to the corresponding acid chloride (XIII) by treatment with oxalyl chloride. Coupling of acid chloride (XIII) with pyrrolidine (VIII) gave the bis-amide (XIV). After desilylation of (XIV) with tetrabutylammonium fluoride, the resultant bis-nitro-alcohol (XV) was reduced by means of SnCl2 to the diamine (XVI).
| 【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 |
|---|---|---|---|---|---|---|
| (VIII) | 47735 | (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylenepyrrolidine; tert-butyl(dimethyl)silyl [(2S)-4-methylenepyrrolidinyl]methyl ether | C12H25NOSi | 详情 | 详情 | |
| (IX) | 17786 | 4-hydroxy-3-methoxybenzoic acid; Vanillic acid | 121-34-6 | C8H8O4 | 详情 | 详情 |
| (X) | 42364 | 1,3-diiodopropane | 627-31-6 | C3H6I2 | 详情 | 详情 |
| (XI) | 47736 | 4-[3-(4-carboxy-2-methoxyphenoxy)propoxy]-3-methoxybenzoic acid | C19H20O8 | 详情 | 详情 | |
| (XII) | 47737 | 4-[3-(4-carboxy-2-methoxy-5-nitrophenoxy)propoxy]-5-methoxy-2-nitrobenzoic acid | C19H18N2O12 | 详情 | 详情 | |
| (XIII) | 47738 | 4-[3-[4-(chlorocarbonyl)-2-methoxy-5-nitrophenoxy]propoxy]-5-methoxy-2-nitrobenzoyl chloride | C19H16Cl2N2O10 | 详情 | 详情 | |
| (XIV) | 47739 | [(2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylenepyrrolidinyl][4-[3-(4-[[(2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylenepyrrolidinyl]carbonyl]-2-methoxy-5-nitrophenoxy)propoxy]-5-methoxy-2-nitrophenyl]methanone | C43H64N4O12Si2 | 详情 | 详情 | |
| (XV) | 47740 | [(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl][4-[3-(4-[[(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]carbonyl]-2-methoxy-5-nitrophenoxy)propoxy]-5-methoxy-2-nitrophenyl]methanone | C31H36N4O12 | 详情 | 详情 | |
| (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 |
合成路线2
该中间体在本合成路线中的序号：(XVI)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 |