【结 构 式】 |
【药物名称】NPS-1392 【化学名称】(-)-3,3-Bis(3-fluorophenyl)-2(R)-methylpropan-1-amine hydrochloride 【CA登记号】200427-53-8, 170018-66-3 (free base), 186495-92-1 (monoHI) 【 分 子 式 】C16H18ClF2N 【 分 子 量 】297.77836 |
【开发单位】NPS Pharmaceuticals (Originator) 【药理作用】Cerebrovascular Diseases, Treatment of, Ischemic Stroke, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, NMDA Antagonists |
合成路线1
Horner-Emmons condensation of 3,3'-difluorobenzophenone (I) with diethyl (cyanomethyl)phosphonate provided 3,3-bis(3-fluorophenyl)acrylonitrile (II). The olefinic double bond of (II) was then reduced using catalytic hydrogenation to give (III). After deprotonation of (III) with either lithium diisopropylamide or lithium hexamethyldisilazide at -78 C, alkylation with iodomethane afforded the racemic alpha-methyl nitrile (IV). Isolation of the required (R)-enantiomer (V) was accomplished by means of chiral HPLC. Finally, reduction of the nitrile group of (V) with borane-dimethyl sulfide complex provided the title amine, which was isolated as the hydrochloride salt.
【1】 Moe, S.T.; Shimizu, S.M.; Smith, D.L.; et al.; Synthesis, biological activity, and absolute stereochemical assignment NPS 1392: A potent and stereoselective NMDA receptor antagonist. Bioorg Med Chem Lett 1999, 9, 14, 1915. |
【2】 Moe, S.T.; Mueller, A.L. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. WO 9856752 . |
【3】 Moe, S.T.; Mueller, A.L.; Vanwagenen, B.C.; Barmore, R.M.; Delmar, E.G.; Artman, L.D.; Balandrin, M.F.; Smith, D.L. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. WO 9746511 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
10045 | Diethyl cyanomethylphosphonate | 2537-48-6 | C6H12NO3P | 详情 | 详情 | |
(I) | 35077 | bis(3-fluorophenyl)methanone | 345-70-0 | C13H8F2O | 详情 | 详情 |
(II) | 35078 | 3,3-bis(3-fluorophenyl)acrylonitrile | C15H9F2N | 详情 | 详情 | |
(III) | 35079 | 3,3-bis(3-fluorophenyl)propanenitrile | C15H11F2N | 详情 | 详情 | |
(IV) | 35080 | 3,3-bis(3-fluorophenyl)-2-methylpropanenitrile | C16H13F2N | 详情 | 详情 | |
(V) | 35081 | (2R)-3,3-bis(3-fluorophenyl)-2-methylpropanenitrile | C16H13F2N | 详情 | 详情 |