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【结 构 式】 
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【分子编号】36564 【品名】(2S)-2-[[(benzyloxy)carbonyl]amino]-4-(tert-butoxy)-4-oxobutyric acid 【CA登记号】 |
【 分 子 式 】C16H21NO6 【 分 子 量 】323.34588 【元素组成】C 59.43% H 6.55% N 4.33% O 29.69% |
合成路线1
该中间体在本合成路线中的序号：(I)Esterification of N-(benzyloxycarbonyl)-L-aspartic acid beta-tert-butyl ester (I) by means of diazomethane provided the alpha-methyl ester (II), which was subsequently sulfenylated using (2,4-dinitrophenyl)-(4-methoxybenzyl)disulfide (III) in the presence of n-BuLi to furnish the (2R,3R)-sulfide (IV) as the major isomer. Reduction of the methyl ester group of (IV) with DIBAL, followed by Wittig-Horner reaction of a postulated aldehyde aluminoxyacetal intermediate with neopentyl diethoxyphosphoryl methanesulfonate produced the alpha,beta-unsaturated sulfonate ester (V). Reduction of the double bond of (V) employing [(PPh3)CuH]6 in neutral medium afforded the saturated ester (VI) with only a small epimerization at the C2 position. The tert-butyl ester of (VI) was then deprotected with trifluoroacetic acid yielding the free acid (VII).
| 【1】 Davis, C.; Bischoff, L.; Meudal, H.; et al.; Investigation of subsite preferences in aminopeptidase A (EC 3.4.11.7) led to the design of the first highly potent and selective inhibitors of this enzyme. J Med Chem 1999, 42, 25, 5197. |
| 【2】 Fournie-Zaluski, M.-C.; Roques, B.; David, C.; Bischoff, L.; Llorens-Cortes, C. (CNRS (Centre National de la Recherche Scientifique); INSERM (Institut National de la Sante et de la Recherche Medicale)); Tripeptide cpds. useful as selective inhibitors of aminopeptidase A and corresponding pharmaceutical compsns.. FR 2788526; WO 0043414 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40723 | neopentyl (diethoxyphosphoryl)methanesulfonate | C10H23O6PS | 详情 | 详情 | ||
| (I) | 36564 | (2S)-2-[[(benzyloxy)carbonyl]amino]-4-(tert-butoxy)-4-oxobutyric acid | C16H21NO6 | 详情 | 详情 | |
| (II) | 36565 | 4-(tert-butyl) 1-methyl (2S)-2-[[(benzyloxy)carbonyl]amino]butanedioate | C17H23NO6 | 详情 | 详情 | |
| (III) | 36566 | 1-[(4-methoxybenzyl)disulfanyl]-2,4-dinitrobenzene; 2,4-dinitrophenyl 4-methoxybenzyl disulfide | C14H12N2O5S2 | 详情 | 详情 | |
| (IV) | 36567 | 4-(tert-butyl) 1-methyl (2R,3S)-2-[[(benzyloxy)carbonyl]amino]-3-[(4-methoxybenzyl)sulfanyl]butanedioate | C25H31NO7S | 详情 | 详情 | |
| (V) | 36568 | tert-butyl (2S,3R,4E)-3-[[(benzyloxy)carbonyl]amino]-2-[(4-methoxybenzyl)sulfanyl]-5-[(neopentyloxy)sulfonyl]-4-pentenoate | C30H41NO8S2 | 详情 | 详情 | |
| (VI) | 36569 | tert-butyl (2S,3R)-3-[[(benzyloxy)carbonyl]amino]-2-[(4-methoxybenzyl)sulfanyl]-5-[(neopentyloxy)sulfonyl]pentanoate | C30H43NO8S2 | 详情 | 详情 | |
| (VII) | 36570 | (2S,3R)-3-[[(benzyloxy)carbonyl]amino]-2-[(4-methoxybenzyl)sulfanyl]-5-[(neopentyloxy)sulfonyl]pentanoic acid | C26H35NO8S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIX)The Fmoc protecting group of resin (XI) was removed by treatment with piperidine in DMF to give (XII). This was subsequently coupled with N-Fmoc-3-methyl-L-valine (XIII) to provide, after Fmoc deprotection with piperidine, the dipeptide resin (XIV). Further coupling and deprotection cycles with N-Fmoc-3-(2-methylphenyl)-L-alanine (XV) and N-Fmoc-D-valine (XVII) yielded resins (XVI) and (XVIII), respectively. Resin (XVIII) was then coupled with N-(benzyloxycarbonyl)-L-aspartic acid beta-tert-butyl ester (XIX), and the title compound was finally deprotected and liberated from the resin by means of trifluoroacetic acid in CH2Cl2.
| 【1】 Dunsdon, R.M.; et al.; Solid phase synthesis of aminoboronic acids: Potent inhibitors of the hepatitis C virus NS3 proteinase. Bioorg Med Chem Lett 2000, 10, 14, 1577. |
| 【2】 Attwood, M.R.; Hurst, D.N.; Jones, P.S.; Kay, P.B.; Raynham, T.M.; Wilson, F.X. (F. Hoffmann-La Roche AG); Antiviral peptide derivs.. JP 2000508344; WO 9822496 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 43348 | 9H-fluoren-9-ylmethyl (1S)-1-[([1-[4-(5-amino-3-methyl-5-oxopentyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl]propyl]amino)carbonyl]-3-methylbutylcarbamate | C35H50BN3O6 | 详情 | 详情 | |
| (XII) | 43349 | (2S)-2-amino-N-[1-[4-(5-amino-3-methyl-5-oxopentyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl]propyl]-4-methylpentanamide | C20H40BN3O4 | 详情 | 详情 | |
| (XIII) | 43350 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3,3-dimethylbutyric acid | 132684-60-7 | C21H23NO4 | 详情 | 详情 |
| (XIV) | 43351 | (2S)-2-[[(2S)-2-amino-3,3-dimethylbutanoyl]amino]-N-[1-[4-(5-amino-3-methyl-5-oxopentyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl]propyl]-4-methylpentanamide | C26H51BN4O5 | 详情 | 详情 | |
| (XV) | 22255 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(2-methylphenyl)propionic acid | C25H23NO4 | 详情 | 详情 | |
| (XVI) | 43352 | (2S)-N-[1-[4-(5-amino-3-methyl-5-oxopentyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl]propyl]-2-[((2S)-2-[[(2S)-2-amino-3-(2-methylphenyl)propanoyl]amino]-3,3-dimethylbutanoyl)amino]-4-methylpentanamide | C36H62BN5O6 | 详情 | 详情 | |
| (XVII) | 43354 | (2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylbutyric acid | C20H21NO4 | 详情 | 详情 | |
| (XVIII) | 43353 | (2S)-2-[((2S)-2-[[(2S)-2-[[(2R)-2-amino-3-methylbutanoyl]amino]-3-(2-methylphenyl)propanoyl]amino]-3,3-dimethylbutanoyl)amino]-N-[1-[4-(5-amino-3-methyl-5-oxopentyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl]propyl]-4-methylpentanamide | C41H71BN6O7 | 详情 | 详情 | |
| (XIX) | 36564 | (2S)-2-[[(benzyloxy)carbonyl]amino]-4-(tert-butoxy)-4-oxobutyric acid | C16H21NO6 | 详情 | 详情 |