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【结 构 式】 
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【药物名称】DW-2143 【化学名称】1-[1-(4-Aminobenzoyl)indolin-5-ylsulfonyl]-4-phenylimidazolidin- 2-one 【CA登记号】 【 分 子 式 】C24H22N4O4S 【 分 子 量 】462.53134 |
【开发单位】Dong-Wha 【药理作用】ONCOLYTIC DRUGS，MISCELLANEOUS ANTINEOPLASTIC AGENTS |
合成路线1
The bromination of styrene (II) with N-bromosuccinimide in the presence of cyanamide (I) provided 2-bromo-1-phenylethylcyanamide (III). Further addition of MeOH to (III) in the presence of HCl, followed by Na2CO3-promoted cyclization, produced the methoxyimidazoline (IV). Acylation of indoline (V) with trifluoroacetic anhydride and pyridine gave amide (VI) and subsequent chlorosulfonation yielded sulfonyl cloride (VII). This acid chloride was coupled to imidazoline (IV) in the presence of NaHCO3 in aqueous acetone to furnish a mixture of sulfonyl imidazolines (VIII) and (IX). The major isomer (IX) was isolated by column chromatography, and then, hydrolysis with HCl in MeOH at r.t. provided imidazolidinone (X). The trifluoroacetamide group of (X) was further hydrolyzed by treatment with NaOH in aqueous MeOH to give (XI). Subsequent condensation of (XI) with 4-nitrobenzoyl chloride (XII) in the presence of pyridine yielded 4-nitrobenzamide (XIII), which was finally reduced to the aminobenzamide by hydrogenation using Raney-nickel as the catalyst.
| 【1】 Jung, S.-H.; Lee, H.S.; Song, J.S.; Kim, H.M.; Han, S.B.; Lee, C.W.; Lee, M.; Choi, D.R.; Lee, J.A.; Chung, Y.H.; Yoon, S.J.; Moon, E.Y.; Hwang, H.S.; Seong, S.K.; Lee, D.K.; Synthesis and antitumor activity of 4-phenyl-1-arylsulfonyl imidazolidinones. Bioorg Med Chem Lett 1998, 8, 12, 1547. |
| 【2】 Yoon, S.J.; Chung, Y.H.; Lee, M.S.; Choi, D.R.; Lee, J.A.; Lee, H.S.; Yun, H.R.; Lee, D.K.; Moon, E.Y.; Hwang, H.S.; Choi, C.H.; Jung, S.H. (Dong-Wha Pharmaceuticals Industry Co. Ltd); Arylsulfonylimidazolone derivs. as an antitumor agent. EP 1021437; JP 2000505096; US 5929103; WO 9807719 . |
| 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) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (II) | 19649 | 1-vinylbenzene | 100-42-5 | C8H8 | 详情 | 详情 |
| (III) | 19650 | 2-bromo-1-phenylethylcyanamide | C9H9BrN2 | 详情 | 详情 | |
| (IV) | 19651 | methyl 5-phenyl-4,5-dihydro-1H-imidazol-2-yl ether; 2-methoxy-5-phenyl-4,5-dihydro-1H-imidazole | C10H12N2O | 详情 | 详情 | |
| (V) | 19652 | indoline | 496-15-1 | C8H9N | 详情 | 详情 |
| (VI) | 19653 | 1-(2,3-dihydro-1H-indol-1-yl)-2,2,2-trifluoro-1-ethanone | C10H8F3NO | 详情 | 详情 | |
| (VII) | 19654 | 1-(2,2,2-trifluoroacetyl)-5-indolinesulfonyl chloride | C10H7ClF3NO3S | 详情 | 详情 | |
| (VIII) | 19655 | 2,2,2-trifluoro-1-[5-[(2-methoxy-5-phenyl-4,5-dihydro-1H-imidazol-1-yl)sulfonyl]-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C20H18F3N3O4S | 详情 | 详情 | |
| (IX) | 19656 | 2,2,2-trifluoro-1-[5-[(2-methoxy-4-phenyl-4,5-dihydro-1H-imidazol-1-yl)sulfonyl]-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C20H18F3N3O4S | 详情 | 详情 | |
| (X) | 19657 | 4-phenyl-1-[[1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]sulfonyl]-2-imidazolidinone | C19H16F3N3O4S | 详情 | 详情 | |
| (XI) | 19658 | 1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-4-phenyl-2-imidazolidinone | C17H17N3O3S | 详情 | 详情 | |
| (XII) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (XIII) | 19660 | 1-[[1-(4-nitrobenzoyl)-2,3-dihydro-1H-indol-5-yl]sulfonyl]-4-phenyl-2-imidazolidinone | C24H20N4O6S | 详情 | 详情 |
合成路线2
A synthesis of the (S)-enantiomer of the target compound has also been reported, starting from (S)-1-phenylethanolamine (XIV). Treatment with phenyl chloroformate (XV) and NaHCO3 yielded carbamate (XVI). Subsequent reaction of (XVI) with methanesulfonyl chloride and Et3N provided mesylate (XVII). The sulfonamide (XVIII) was prepared from sulfonyl chloride (VII) by treatment with ammonia gas in CH2Cl2. Condensation of this sulfonamide with mesylate (XVII) in the presence of NaH produced the chiral imidazolidinone (XIX). Finally, the target compound was obtained by condensation with 4-nitrobenzoyl chloride (XII), followed by reduction with H2 in the presence of Raney-Ni.
| 【1】 Jung, S.-H.; Lee, H.S.; Song, J.S.; Kim, H.M.; Han, S.B.; Lee, C.W.; Lee, M.; Choi, D.R.; Lee, J.A.; Chung, Y.H.; Yoon, S.J.; Moon, E.Y.; Hwang, H.S.; Seong, S.K.; Lee, D.K.; Synthesis and antitumor activity of 4-phenyl-1-arylsulfonyl imidazolidinones. Bioorg Med Chem Lett 1998, 8, 12, 1547. |
| 【2】 Yoon, S.J.; Chung, Y.H.; Lee, M.S.; Choi, D.R.; Lee, J.A.; Lee, H.S.; Yun, H.R.; Lee, D.K.; Moon, E.Y.; Hwang, H.S.; Choi, C.H.; Jung, S.H. (Dong-Wha Pharmaceuticals Industry Co. Ltd); Arylsulfonylimidazolone derivs. as an antitumor agent. EP 1021437; JP 2000505096; US 5929103; WO 9807719 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 19654 | 1-(2,2,2-trifluoroacetyl)-5-indolinesulfonyl chloride | C10H7ClF3NO3S | 详情 | 详情 | |
| (XII) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (XIV) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (XV) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
| (XVI) | 19663 | phenyl (1S)-2-hydroxy-1-phenylethylcarbamate | C15H15NO3 | 详情 | 详情 | |
| (XVII) | 19664 | (2S)-2-[(phenoxycarbonyl)amino]-2-phenylethyl methanesulfonate | C16H17NO5S | 详情 | 详情 | |
| (XVIII) | 19665 | 1-(2,2,2-trifluoroacetyl)-5-indolinesulfonamide | C10H9F3N2O3S | 详情 | 详情 | |
| (XIX) | 19666 | (4S)-1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-4-phenyl-2-imidazolidinone | C17H17N3O3S | 详情 | 详情 | |
| (XX) | 19667 | (4S)-1-[[1-(4-nitrobenzoyl)-2,3-dihydro-1H-indol-5-yl]sulfonyl]-4-phenyl-2-imidazolidinone | C24H20N4O6S | 详情 | 详情 |