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【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
Extended Information