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【结 构 式】 
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【药物名称】CP-465022 【化学名称】(+)-(aS)-3-(2-Chlorophenyl)-2-[(E)-2-[6-(diethylaminomethyl)pyridin-2-yl]vinyl]-6-fluoroquinazolin-4(3H)-one 【CA登记号】199655-36-2 (racemate) 【 分 子 式 】C26H24ClFN4O 【 分 子 量 】462.95878 |
【开发单位】Pfizer (Originator) 【药理作用】Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, AMPA Antagonists |
合成路线1
Hydrogenation of 2-nitro-5-fluorobenzoic acid (I), followed by in situ condensation with acetic anhydride produced benzoxazinone (II). Subsequent reaction of (III) with 2-chloroaniline (III) in refluxing AcOH furnished quinazolinone (IV). Treatment of (IV) with 2,6-pyridinedicarboxaldehyde (V) in the presence of ZnCl2 and Ac2O gave rise to the pyridinylvinyl derivative (VI). The title amine was finally obtained by reductive amination of aldehyde (VI) with diethylamine using NaBH(OAc)3). The two atropisomers were separated by means of preparative chiral HPLC.
| 【1】 Ewing, F.E.; Welch, W.M.; Huang, J.; et al.; Atropisomeric quinazolin-4-one derivatives are potent noncompetitive alpha-amino-3-hydroxy-5-ethyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. Bioorg Med Chem Lett 2001, 11, 2, 177. |
| 【2】 Elliott, M.L.; Welch, W.M. Jr. (Pfizer Inc.); Novel 2,3 disubstd.-4(3H)-quinazolinones. EP 0901487; JP 1999514663; WO 9743276 . |
| 【3】 Welch, W.M. Jr.; DeVries, K.M. (Pfizer Inc.); Atropisomers of 3-aryl-4(3H)-quinazolinones and their use as AMPA-receptor antagonists. EP 0968194; JP 2000509731; WO 9838173 . |
| 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) | 31962 | 2-Nitro-5-fluorobenzoic acid; 5-Fluoro-2-nitrobenzoic acid | 320-98-9 | C7H4FNO4 | 详情 | 详情 |
| (II) | 38462 | 6-fluoro-2-methyl-4H-3,1-benzoxazin-4-one | C9H6FNO2 | 详情 | 详情 | |
| (III) | 35804 | 2-chloroaniline; 2-chlorophenylamine | 95-51-2 | C6H6ClN | 详情 | 详情 |
| (IV) | 38463 | 3-(2-chlorophenyl)-6-fluoro-2-methyl-4(3H)-quinazolinone | C15H10ClFN2O | 详情 | 详情 | |
| (V) | 38464 | 2,6-pyridinedicarbaldehyde | 5431-44-7 | C7H5NO2 | 详情 | 详情 |
| (VI) | 38465 | 6-[(E)-2-[3-(2-chlorophenyl)-6-fluoro-4-oxo-3,4-dihydro-2-quinazolinyl]ethenyl]-2-pyridinecarbaldehyde | C22H13ClFN3O2 | 详情 | 详情 |