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【结 构 式】 
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【分子编号】47735 【品名】(2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylenepyrrolidine; tert-butyl(dimethyl)silyl [(2S)-4-methylenepyrrolidinyl]methyl ether 【CA登记号】 |
【 分 子 式 】C12H25NOSi 【 分 子 量 】227.42214 【元素组成】C 63.38% H 11.08% N 6.16% O 7.04% Si 12.35% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The pyrrolidine intermediate (VIII) has been obtained as follows: Protection of trans-4-hydroxy-L-proline (I) with allyl chloroformate gave carbamate (II). Following esterification of (II) with MeOH and H2SO4, the methyl ester (III) was reduced to diol (IV) by using LiBH4 in THF. Selective silylation of the primary alcohol of (IV) was achieved with TBDMS chloride the presence of DBU to furnish the silyl ether (V). Oxidation of (V) to ketone (VI) was carried out either under Swern conditions or by means of tetrapropylammonium perruthenate (TPAP) in the presence of N-methylmorpholine-N-oxide. Subsequent Wittig reaction of ketone (VI) with methylene triphenylphosphorane provided olefin (VII). The allyloxycarbonyl protecting group of (VII) was then removed by palladium-catalyzed hydrostannolysis with tributyltin hydride to yield the pyrrolidine intermediate (VIII).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 47730 | (2S,4R)-1-[(allyloxy)carbonyl]-4-hydroxy-2-pyrrolidinecarboxylic acid | C9H13NO5 | 详情 | 详情 | |
| (III) | 42200 | 1-allyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C10H15NO5 | 详情 | 详情 | |
| (IV) | 47731 | allyl (2S,4R)-4-hydroxy-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C9H15NO4 | 详情 | 详情 | |
| (V) | 47732 | allyl (2S,4R)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-hydroxy-1-pyrrolidinecarboxylate | C15H29NO4Si | 详情 | 详情 | |
| (VI) | 47733 | allyl (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-oxo-1-pyrrolidinecarboxylate | C15H27NO4Si | 详情 | 详情 | |
| (VII) | 47734 | allyl (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylene-1-pyrrolidinecarboxylate | C16H29NO3Si | 详情 | 详情 | |
| (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 |
合成路线2
该中间体在本合成路线中的序号：(VIII)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 |