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【结 构 式】 
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【药物名称】PNU-183792 【化学名称】N-(4-Chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide 【CA登记号】282536-25-8 【 分 子 式 】C23H24ClN3O3 【 分 子 量 】425.91903 |
【开发单位】Pfizer (Originator) 【药理作用】Anti-Cytomegalovirus Drugs, Anti-Herpes Virus Drugs, ANTIINFECTIVE THERAPY, Anti-Varicella Zoster Virus Drugs, Antiviral Drugs, DNA Polymerase Inhibitors |
合成路线1
The 4-hydroxyquinoline (III) was synthesized via Gould-Jacobs reaction from 4-iodoaniline (I) and diethyl ethoxymethylenemalonate (II). Displacement of the ethyl ester group with 4-chlorobenzylamine (IV) at 180 C furnished the chlorobenzyl amide (V). Subsequent palladium-catalyzed carbonylation of iodide (V) provided the methyl carboxylate (VI), which was further reduced to alcohol (VII) using LiAlH4. Methylation of the hydroxyquinoline (VII) with iodomethane gave rise to the N-methyl quinolone (VIII). After conversion of the alcohol function of (VIII) to the corresponding mesylate (IX), displacement with morpholine (X) yielded the target morpholinomethyl quinolone.
| 【1】 Turner, S.R.; Strohbach, J.W.; Scott, A.; Schnute, M.E.; Vaillancourt, V.A.; Thaisrivongs, S. (Pharmacia Corp.); 4-Oxo-1,4-dihydro-3-quinolinecarboxamides as antiviral agents. EP 1140851; WO 0040563 . |
| 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) | 26393 | 4-iodoaniline; 4-iodophenylamine | 540-37-4 | C6H6IN | 详情 | 详情 |
| (II) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (III) | 44988 | ethyl 4-hydroxy-6-iodo-3-quinolinecarboxylate | C12H10INO3 | 详情 | 详情 | |
| (IV) | 23378 | (4-chlorophenyl)methanamine; 4-chlorobenzylamine | 104-86-9 | C7H8ClN | 详情 | 详情 |
| (V) | 44989 | N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide | C17H12ClIN2O2 | 详情 | 详情 | |
| (VI) | 49889 | methyl 3-[[(4-chlorobenzyl)amino]carbonyl]-4-hydroxy-6-quinolinecarboxylate | C19H15ClN2O4 | 详情 | 详情 | |
| (VII) | 49890 | N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide | C18H15ClN2O3 | 详情 | 详情 | |
| (VIII) | 49891 | N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide | C19H17ClN2O3 | 详情 | 详情 | |
| (IX) | 49892 | (3-[[(4-chlorobenzyl)amino]carbonyl]-1-methyl-4-oxo-1,4-dihydro-6-quinolinyl)methyl methanesulfonate | C20H19ClN2O5S | 详情 | 详情 | |
| (X) | 10338 | 1-[(4S,5S)-5-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(trityloxy)-1-ethanone | C33H42O5Si | 详情 | 详情 |