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【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%

与该中间体有关的原料药合成路线共 1 条

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
Extended Information