【结 构 式】 |
【药物名称】PD-151307 【化学名称】Perhydroazepin-1-ylcarbonyl-L-leucyl-4-O-(benzyl)-L-tyrosine tert-butyl ester 【CA登记号】 【 分 子 式 】C33H47N3O5 【 分 子 量 】565.75964 |
【开发单位】Neurex (Originator), Pfizer (Originator) 【药理作用】Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, N-Type Calcium Channel Blockers |
合成路线1
By condensation of N-(perhydroazepin-1-ylcarbonyl)-L-leucine (V) with 4-O-benzyl-L-tyrosine tert-butyl ester (VIII) by means of HOBT and diisopropylethylamine in DMF. The two peptide intermediates (V) and (VIII) have been obtaines a follows: L-Leucine fragment (V): The carbonatation of perhydroazepine (I) with CO2 and pyridine followed by reaction with SOCl2 gives perhydroazepin-1-ylcarbonyl chloride (II), which is condensed with L-leucine benzyl ester (III) yielding the N-acylated leucine ester (IV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in THF to afford the target intermediate (V). Tyrosine fragment (VIII): By esterification of 4-O-benzyl-L-tyrosine (VI) with isobutylene (VII) by means of sulfuric acid in dioxane.
【1】 Malone, T.; et al.; Identification and SAR studies of PD 151307, a novel N-type calcium channel blocker. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 122. |
【2】 Roth, B.D.; Connor, D.T.; Malone, T.C.; Hamilton, H.W.; Rafferty, M.F.; Hu, L.-Y.; Cody, W.L.; He, J.X.; Nadasdi, L.; Brogley, L.; Urge, L.; Silva, D.F.; Song, Y.; Szoke, B.G.; Booth, R.J.; Lescosky, J. (Neurex Corp.; Pfizer Inc.); Peptidyl calcium channel blockers. US 6423689 . |
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) | 18672 | azepane | 111-49-9 | C6H13N | 详情 | 详情 |
(II) | 26713 | 1-azepanecarbonyl chloride | C7H12ClNO | 详情 | 详情 | |
(III) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
(IV) | 26714 | benzyl (2S)-2-[(1-azepanylcarbonyl)amino]-4-methylpentanoate | C20H30N2O3 | 详情 | 详情 | |
(V) | 26715 | (2S)-2-[(1-azepanylcarbonyl)amino]-4-methylpentanoic acid | C13H24N2O3 | 详情 | 详情 | |
(VI) | 26716 | (2S)-2-amino-3-[4-(benzyloxy)phenyl]propionic acid | 16652-64-5 | C16H17NO3 | 详情 | 详情 |
(VII) | 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 |
(VIII) | 26717 | tert-butyl (2S)-2-amino-3-[4-(benzyloxy)phenyl]propanoate | C20H25NO3 | 详情 | 详情 |