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【结 构 式】 
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【分子编号】33752 【品名】4-nitrophenyl (E)-3-(4-methoxyphenyl)-2-propenoate 【CA登记号】 |
【 分 子 式 】C16H13NO5 【 分 子 量 】299.28296 【元素组成】C 64.21% H 4.38% N 4.68% O 26.73% |
合成路线1
该中间体在本合成路线中的序号：(III)The hydrolysis of DU-86 (I) with NaOMe gives tetracyclic compound (II), which is acylated with the 4-nitrophenyl cinnamate (III) and NaH yielding the adduct (IV). The opening of the cyclopropane ring of (IV) with HBr in acetonitrile affords the aromatic phenol (V), which is activated with 4-nitrophenyl chloroformate (VI) and TEA to provide the activated anhydride (VII). Finally, this compound is condensed with 4-(1-piperidinyl)piperidine-1-amine (VIII), and treated with HBr to furnish the target hydrobromide.
| 【1】 Amishiro, N.; Nagamura, S.; Saito, H.; Kobayashi, E.; Okamoto, A.; Gomi, K. (Kyowa Hakko Kogyo Co., Ltd.); DC-89 deriv.. EP 0702014; US 5670492; WO 9526964 . |
| 【2】 Nagamura, S.; Murakata, C.; Amishiro, N.; et al.; Synthesis and antitumor activity of duocarmycin derivatives: Modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups. Bioorg Med Chem 2000, 8, 2, 381. |
| 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) | 40881 | methyl (3bR,4aS)-2-methyl-8-oxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C26H25N3O7 | 详情 | 详情 | |
| (II) | 38365 | methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C14H14N2O3 | 详情 | 详情 | |
| (III) | 33752 | 4-nitrophenyl (E)-3-(4-methoxyphenyl)-2-propenoate | C16H13NO5 | 详情 | 详情 | |
| (IV) | 40882 | methyl (3bR,4aS)-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C24H22N2O5 | 详情 | 详情 | |
| (V) | 40883 | methyl (8S)-8-(bromomethyl)-4-hydroxy-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C24H23BrN2O5 | 详情 | 详情 | |
| (VI) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (VII) | 40884 | methyl (8S)-8-(bromomethyl)-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-4-[[(4-nitrophenoxy)carbonyl]oxy]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C31H26BrN3O9 | 详情 | 详情 | |
| (VIII) | 40885 | C10H21N3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The hydrolysis of DU-86 (I) with NaOMe gives tetracyclic compound (II), which is acylated with the 4-nitrophenyl cinnamate (III) and NaH yielding the adduct (IV). The opening of the cyclopropane ring of (IV) with HBr in acetonitrile affords the aromatic phenol (V), which is activated with 4-nitrophenyl chloroformate (VI) and TEA to provide the activated anhydride (VII). Finally, this compound is condensed with 4-methylpiperazine-1-amine (VIII), and treated with HBr to furnish the target hydrobromide.
| 【1】 Amishiro, N.; Nagamura, S.; Saito, H.; Kobayashi, E.; Okamoto, A.; Gomi, K. (Kyowa Hakko Kogyo Co., Ltd.); DC-89 deriv.. EP 0702014; US 5670492; WO 9526964 . |
| 【2】 Nagamura, S.; Murakata, C.; Amishiro, N.; et al.; Synthesis and antitumor activity of duocarmycin derivatives: Modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups. Bioorg Med Chem 2000, 8, 2, 381. |
| 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) | 40881 | methyl (3bR,4aS)-2-methyl-8-oxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C26H25N3O7 | 详情 | 详情 | |
| (II) | 38365 | methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C14H14N2O3 | 详情 | 详情 | |
| (III) | 33752 | 4-nitrophenyl (E)-3-(4-methoxyphenyl)-2-propenoate | C16H13NO5 | 详情 | 详情 | |
| (IV) | 40882 | methyl (3bR,4aS)-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C24H22N2O5 | 详情 | 详情 | |
| (V) | 40883 | methyl (8S)-8-(bromomethyl)-4-hydroxy-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C24H23BrN2O5 | 详情 | 详情 | |
| (VI) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (VII) | 40884 | methyl (8S)-8-(bromomethyl)-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-4-[[(4-nitrophenoxy)carbonyl]oxy]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C31H26BrN3O9 | 详情 | 详情 | |
| (VIII) | 40886 | 4-methyl-1-piperidinamine; 4-methyl-1-piperidinylamine | 19107-42-7 | C6H14N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)Decarboxylation of (IX) in refluxing bromobenzene yielded (X), which was converted to the 3-bromoindole (XI) by reaction with N-bromosuccinimide in the presence of silicagel. Desilylation of (XI) with tetrabutylammonium fluoride gave phenol (XII), and further intramolecular cyclization of (XII) with simultaneous amide hydrolysis by treatment with NaOMe produced the cyclopropyl cyclohexadienone (XIII). Finally, the 4-methoxycinnamoyl group was introduced in (XIII) by condensation with the 4-nitrophenyl ester (XIV) in the presence of NaH at -20 C.
| 【1】 Okabe, M.; Tamaoki, T.; Saito, H.; Okamoto, A.; Amishiro, N.; Murakata, C.; Synthesis and antitumor activity of duocarmycin derivatives: Modification of segment-A of A-ring pyrrole compounds. J Med Chem 1999, 42, 15, 2946-60. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 33747 | (8S)-8-(bromomethyl)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylic acid | C31H38BrN3O7Si | 详情 | 详情 | |
| (X) | 33748 | [(1S)-1-(bromomethyl)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-methyl-1,6-dihydropyrrolo[3,2-e]indol-3(2H)-yl](5,6,7-trimethoxy-1H-indol-2-yl)methanone | C30H38BrN3O5Si | 详情 | 详情 | |
| (XI) | 33749 | [(1S)-8-bromo-1-(bromomethyl)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-methyl-1,6-dihydropyrrolo[3,2-e]indol-3(2H)-yl](5,6,7-trimethoxy-1H-indol-2-yl)methanone | C30H37Br2N3O5Si | 详情 | 详情 | |
| (XII) | 33750 | [(1S)-8-bromo-1-(bromomethyl)-5-hydroxy-7-methyl-1,6-dihydropyrrolo[3,2-e]indol-3(2H)-yl](5,6,7-trimethoxy-1H-indol-2-yl)methanone | C24H23Br2N3O5 | 详情 | 详情 | |
| (XIII) | 33751 | (3bR,4aS)-3-bromo-2-methyl-4,4a,5,6-tetrahydrocyclopropa[c]pyrrolo[3,2-e]indol-8(1H)-one | C12H11BrN2O | 详情 | 详情 | |
| (XIV) | 33752 | 4-nitrophenyl (E)-3-(4-methoxyphenyl)-2-propenoate | C16H13NO5 | 详情 | 详情 |