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【结 构 式】 
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【药物名称】PNU-253998 【化学名称】N-(4-Chlorobenzyl)-1-(4-morpholinyl)-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide 【CA登记号】281651-76-1 【 分 子 式 】C26H29ClN4O4 【 分 子 量 】496.99843 |
【开发单位】Pfizer (Originator) 【药理作用】Anti-Herpes Virus Drugs, ANTIINFECTIVE THERAPY, Antiviral Drugs, DNA Polymerase Inhibitors |
合成路线1
The reductocondensation of 3-bromo-4-fluorobenzaldehyde (I) with morpholine (II) by means of NaBH(OAc)3 in dichloroethane gives 4-(3-bromo-4-fluorobenzyl)morpholine (III), which is condensed with N-methoxy-N-methylacetamide (IV) by means of BuLi in THF to yield 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]ethanone (V). The reaction of (V) with an excess diethyl carbonate (VI) by means of NaH affords the 3-oxopropanoate derivative (VII), which is treated with triethyl orthoformate (VIII) and Ac2O at 150 C to provide the ethoxymethylene compound (IX). The reaction of (IX) with morpholine-4-amine (X) in ethanol gives the aminomethylene derivative (XI), which is cyclized by means of NaH in hot THF to yield the quinolone-3-carboxylate (XII). Finally, this compound is condensed with 4-chlorobenzylamine (XIII) by heating at 190 C to afford the target quinolone-3-carboxamide.
| 【1】 Pargas, R.E.M.; Tucker, J.A.; Schnute, M.E.; et al.; 1-Amino-4-oxo-1,4-dihydroquinolines with broad-spectrum antiherpetic activity. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1669. |
| 【2】 Thaisrivongs, S.; Strohbach, J.W.; Turner, S.R.; Vaillancourt, V.A.; Tucker, J.A.; Schnute, M.E. (Pharmacia Corp.); Quinolinecarboxamides as antiviral agents. EP 1140850; US 6248739; WO 0040561 . |
| 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) | 51550 | 3-Bromo-4-fluorobenzaldehyde | 77771-02-9 | C7H4BrFO | 详情 | 详情 |
| (II) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (III) | 53185 | 4-(3-bromo-4-fluorobenzyl)morpholine | n/a | C11H13BrFNO | 详情 | 详情 |
| (IV) | 17426 | N-methoxy-N-methylacetamide | 78191-00-1 | C4H9NO2 | 详情 | 详情 |
| (V) | 53186 | 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-1-ethanone | n/a | C13H16FNO2 | 详情 | 详情 |
| (VI) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (VII) | 53187 | ethyl 3-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-3-oxopropanoate | n/a | C16H20FNO4 | 详情 | 详情 |
| (VIII) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (IX) | 53188 | ethyl (Z)-3-ethoxy-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-2-propenoate | n/a | C19H24FNO5 | 详情 | 详情 |
| (X) | 35977 | 4-morpholinylamine; 4-morpholinamine | 4319-49-7 | C4H10N2O | 详情 | 详情 |
| (XI) | 53191 | ethyl (Z)-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-3-(4-morpholinylamino)-2-propenoate | n/a | C21H28FN3O5 | 详情 | 详情 |
| (XII) | 53192 | ethyl 1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | n/a | C21H27N3O5 | 详情 | 详情 |
| (XIII) | 23378 | (4-chlorophenyl)methanamine; 4-chlorobenzylamine | 104-86-9 | C7H8ClN | 详情 | 详情 |