|
【结 构 式】 
|
【药物名称】Traxoprodil mesylate, CP-101606-27 【化学名称】(S,S)-1-(4-Hydroxyphenyl)-2-[4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol methanesulfonate trihydrate 【CA登记号】189894-57-3 【 分 子 式 】C21H35NO9S 【 分 子 量 】477.5784 |
【开发单位】Pfizer (Originator) 【药理作用】Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, NMDA Antagonists |
合成路线1
4-Hydroxypropiophenone (I) was protected as the triisopropylsilyl ether (II) and subsequently brominated with elemental bromine in CCl4. The resultant bromo ketone (III) was subsequently coupled with 4-hydroxy-4-phenylpiperidine (IV) to afford the racemic amino ketone (V). This was stereoselectively reduced with NaBH4 in EtOH yielding the threo-amino alcohol (VI). Then, desilylation of (VI) with tetrabutylammonium fluoride furnished the racemic phenol compound. Resolution into the enantiomers has been reported by formation of the corresponding D-tartaric acid salts. Finally, the title product was obtained by dissolving D-(-)-tartaric salt (VII) in water in the presence of methanesulfonic acid
| 【1】 Chenard, B.L.; et al.; (1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: A potent new neuroprotectant which blocks N-methyl-D-aspartate responses. J Med Chem 1995, 38, 16, 3138. |
| 【2】 Chenard, B.L. (Pfizer Inc.); 2-Piperidino-1-alkanol derivs. as antiischemic agents. US 5272160 . |
| 【3】 Walinsky, S.W.; Rainville, J.P.; Sinay, T.G. Jr. (Pfizer Products Inc.); Process for the preparation of the mesylate salt trihydrate of 1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol. EP 1151995 . |
| 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) | 58982 | 4'-Hydroxypropiophenone; 4-Hydroxypropiophenone; Ethyl 4-Hydroxyphenyl ktone; p-Hydroxypropiophenone; Paroxypropione | 70-70-2 | C9H10O2 | 详情 | 详情 |
| (II) | 62505 | 1-{4-[(triisopropylsilyl)oxy]phenyl}-1-propanone | C18H30O2Si | 详情 | 详情 | |
| (III) | 62506 | 2-bromo-1-{4-[(triisopropylsilyl)oxy]phenyl}-1-propanone | C18H29BrO2Si | 详情 | 详情 | |
| (IV) | 28021 | 4-phenyl-4-piperidinol; 4-Hydroxy-4-phenylpiperidine; 4-(4-Phenyl)-4-hydroxypiperidine | 40807-61-2 | C11H15NO | 详情 | 详情 |
| (V) | 62507 | 2-(4-hydroxy-4-phenyl-1-piperidinyl)-1-{4-[(triisopropylsilyl)oxy]phenyl}-1-propanone | C29H43NO3Si | 详情 | 详情 | |
| (VI) | 62508 | 1-((1S,2S)-2-hydroxy-1-methyl-2-{4-[(triisopropylsilyl)oxy]phenyl}ethyl)-4-phenyl-4-piperidinol | C29H45NO3Si | 详情 | 详情 | |
| (VII) | 62509 | 1-[(1S,2S)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]-4-phenyl-4-piperidinol | C20H25NO3 | 详情 | 详情 |
合成路线2
In a related process, the racemic piperidinyl ketone (VIII) was initially resolved employing D-tartaric acid and then subjected to a diastereoselective reduction to the (1S,2S)-alcohol (IX) employing LiBH4 in EtOH. Finally, debenzylation of (IX) by catalytic hydrogenolysis with Pd/C in EtOH and methanesulfonic acid, followed by addition of water, yielded the title compound
| 【1】 Walinsky, S.W.; Rainville, J.P.; Sinay, T.G. Jr. (Pfizer Products Inc.); Process for the preparation of the mesylate salt trihydrate of 1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol and intermediates useful therefor. EP 1149831 . |