|
【结 构 式】 
|
【药物名称】 【化学名称】N-Cyclohexyl-N-methyl-L-leucyl-4-O-(benzyl)-L-tyrosine tert-butylamide 【CA登记号】 【 分 子 式 】C33H49N3O3 【 分 子 量 】535.77678 |
【开发单位】Elan (Originator), Pfizer (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Non-Opioid Analgesics, Stroke, Treatment of, Calcium Channel Blockers |
合成路线1
The precursor amino acid derivatives were obtained as follows: The condensation of N-Boc-O-benzyltyrosine (I) with tert-butylamine using O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) gave amide (II). Subsequent deprotection of the Boc group of (II) by means of trifluoroacetic acid provided O-benzyltyrosine tert-butyl amide (III). N-Methyl leucine benzyl ester (IV) was alkylated with 3-bromocyclohexene (V), yielding the cyclohexenyl amine (VI). Hydrogenation of the olefinic double bond of (VI) with concomitant benzyl ester hydrogenolysis in the presence of Pd/C furnished N-cyclohexyl-N-methylleucine (VII). The title dipeptide was finally obtained by HBTU-promoted coupling of amino acids (III) and (VII).
| 【1】 Ryder, T.R.; Hu, L.-Y.; Rafferty, M.F.; et al.; N,N-dialkyl-dipeptidylamines as novel N-type calcium channel blockers. Bioorg Med Chem Lett 1999, 9, 6, 907. |
| 【2】 Szoke, B.G.; Rafferty, M.F.; Silva, D.F.; Song, Y.; Malone, T.C.; Hu, L.-Y.; Urge, L.; Nadasdi, L.; Ryder, T.R. (Neurex Corp.; Pfizer Inc.); Substd. peptidylamine calcium channel blockers. WO 9854123 . |
| 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) | 30396 | (2S)-3-[4-(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)amino]propionic acid | 54784-43-9 | C21H25NO5 | 详情 | 详情 |
| (II) | 30797 | tert-butyl (1S)-1-[4-(benzyloxy)benzyl]-2-(tert-butylamino)-2-oxoethylcarbamate | C25H34N2O4 | 详情 | 详情 | |
| (III) | 30798 | (2S)-2-amino-3-[4-(benzyloxy)phenyl]-N-(tert-butyl)propanamide | C20H26N2O2 | 详情 | 详情 | |
| (IV) | 30799 | benzyl (2S)-4-methyl-2-(methylamino)pentanoate | C14H21NO2 | 详情 | 详情 | |
| (V) | 30800 | 3-bromo-1-cyclohexene | 1521-51-3 | C6H9Br | 详情 | 详情 |
| (VI) | 30801 | benzyl (2S)-2-[2-cyclohexen-1-yl(methyl)amino]-4-methylpentanoate | C20H29NO2 | 详情 | 详情 | |
| (VII) | 30802 | (2S)-2-[cyclohexyl(methyl)amino]-4-methylpentanoic acid | C13H25NO2 | 详情 | 详情 |
合成路线2
Alternatively, the compound was prepared using polymer-supported resins. Dialkyl leucine (VII) was first treated with isobutyl chloroformate and morpholine resin, tyrosine derivative (III) was added, and was then treated with isocyanate resin and tris(2-aminomethyl)amine resin. Filtration of the insoluble resins provided a solution of pure dipeptide derivative.
| 【1】 Szoke, B.G.; Rafferty, M.F.; Silva, D.F.; Song, Y.; Malone, T.C.; Hu, L.-Y.; Urge, L.; Nadasdi, L.; Ryder, T.R. (Neurex Corp.; Pfizer Inc.); Substd. peptidylamine calcium channel blockers. WO 9854123 . |