【结 构 式】 |
【分子编号】65420 【品名】(2S)-2-Cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valine 【CA登记号】402958-96-7 |
【 分 子 式 】C19H28N4O4 【 分 子 量 】376.45588 【元素组成】C 60.62% H 7.5% N 14.88% O 17% |
合成路线1
该中间体在本合成路线中的序号:(V)Hydrogenolysis of the benzyloxycarbonyl protecting group in N-Cbz-L-cyclohexylglycyl-L-tert-leucine methyl ester (I) in the presence of Pearlman’s catalyst in MeOH gives the free dipeptide ester (II), which is acylated with pyrazinecarboxylic acid (III) by means of DCC in dichloromethane/THF to yield the N-acyl dipeptide (IV) (1). Alkaline hydrolysis of the methyl ester (IV) followed by coupling of the resulting carboxylic acid (V) with ethyl cis-perhydrocyclopenta[c]pyrrole-1-carboxylate (VI) by means of DCC provides the acyl tripeptide ester (VII), which is then hydrolyzed to the corresponding carboxylic acid (VIII) upon treatment with NaOH in EtOH (1, 2). Coupling of L-norvaline (IX) with cyclopropylamine (X) in the presence of EDC and N-hydroxysuccinimide followed by catalytic hydrogenolysis of the N-Cbz group provides N-cyclopropyl-norvalinamide (XI) (3). Subsequent condensation of aminoamide (XI) with the N-acyl tripeptide (VIII) using either PyBOP or EDC/HOBt gives the tetrapeptide derivative (XII). Finally, oxidation of the secondary alcohol (XII) by means of Dess-Martin periodinane or NaOCl and a catalytic amount of TEMPO furnishes the title α-ketoamide (1-3). Scheme 1.
【1】 Babine, R.E., Glass, J.I., Lamar, J.E. et al. (Eli Lilly and Company). Peptidomimetic protease inhibitors. JP 2004517047, US 2005197299, WO 2002018369. |
【2】 Chen, S.-H., Lamar, J., Yip, Y. et al. P1 and P1’ optimization of [3,4]-bicycloproline P2 incorporated tetrapeptidyl α-ketoamide based HCV protease inhibitors. Lett Drug Des Discov 2005, 2(2): 118-23. |
【3】 Tanoury, G.J., Chen, M., Cochran, J.E. (Vertex Pharmaceuticals, Inc.). Processes and intermediates. WO 2007022459. |
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) | 65417 | N-Cbz-L-cyclohexylglycyl-L-tert-leucine methyl ester | C23H34N2O5 | 详情 | 详情 | |
(II) | 65418 | L-cyclohexylglycyl-L-tert-leucine methyl ester | C15H28N2O3 | 详情 | 详情 | |
(III) | 37256 | 2-pyrazinecarboxylic acid; Pyrazinoic acid | 98-97-5 | C5H4N2O2 | 详情 | 详情 |
(IV) | 65419 | (2S)-2-Cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valine methyl ester | 402958-95-6 | C20H30N4O4 | 详情 | 详情 |
(V) | 65420 | (2S)-2-Cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valine | 402958-96-7 | C19H28N4O4 | 详情 | 详情 |
(VI) | 65421 | (1S,3aR,6aS)-Octahydrocyclopenta[c]pyrrole-1-carboxylic acid ethyl ester; ethyl cis-perhydrocyclopenta[c]pyrrole-1-carboxylate | 402958-25-2 | C10H17NO2 | 详情 | 详情 |
(VII) | 65422 | (1S,3aR,6aS)-(2S)-2-Cyclohexyl-N-(pyrazinylcarbonyl)glycyl-3-methyl-L-valyloctahydrocyclopenta[c]pyrrole-1-carboxylic acid ethyl ester | 402958-97-8 | C29H43N5O5 | 详情 | 详情 |
(VIII) | 65423 | (1S,3aR,6aS)-(2S)-2-Cyclohexyl-N-(pyrazinylcarbonyl)glycyl-3-methyl-L-valyloctahydrocyclopenta[c]pyrrole-1-carboxylic acid | 402958-98-9 | C27H39N5O5 | 详情 | 详情 |
(IX) | 65424 | C14H19NO5 | 详情 | 详情 | ||
(X) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
(XI) | 65425 | (3S)-3-Amino-N-cyclopropyl-2-hydroxyhexanamide | 402960-19-4 | C9H18N2O2 | 详情 | 详情 |
(XII) | 65426 | (1S,3aR,6aS)-(2S)-2-Cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valyl-N-[(1S)-1-[2-(cyclopropylamino)-1-hydroxy-2-oxoethyl]butyl]octahydrocyclopenta[c]pyrrole-1-carboxamide | 402959-36-8 | C36H55N7O6 | 详情 | 详情 |