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【结 构 式】 
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【分子编号】22262 【品名】4-(tert-butoxy)-4-oxobutyric acid 【CA登记号】 |
【 分 子 式 】C8H14O4 【 分 子 量 】174.19676 【元素组成】C 55.16% H 8.1% O 36.74% |
合成路线1
该中间体在本合成路线中的序号：(XII)Coupling of N-(Boc)-3-methyl-L-valine (I) with L-leucine benzyl ester (II) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-HCl (EDC) and 1-hydroxybenzotriazole (HOBt) in the presence of N-ethylmorpholine gave the N-Boc-dipeptide (III), which was deprotected with trifluoroacetic acid in CH2Cl2 to afford (IV). Subsequent coupling of (IV) with N-Fmoc-2-methyl-L-phenylalanine (V) mediated by EDC and HOBt provided the N-Fmoc-tripeptide (VI). Deprotection of the fluorenylmethoxycarbonyl group of (VI) was effected with piperidine in CH2Cl2 to yield (VII). Further coupling and deprotection cycles with N-Fmoc-O-tert-butyl-L-glutamic acid (VIII) and then with N-Fmoc-O-tert-butyl-L-aspartic acid (X) provided peptides (IX) and (XI), respectively. This latter was then coupled to mono-tert--butyl succinate (XII) to furnish (XIII).
| 【1】 Attwood, M.R.; Campbell, A.D.; Bennett, J.M.; et al.; The design and synthersis of potent inhibitors of hepatitis C virus NS3-4A proteinase. Antivir Chem Chemother 1999, 10, 5, 259. |
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (II) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
| (III) | 22253 | benzyl (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl]amino)-4-methylpentanoate | C24H38N2O5 | 详情 | 详情 | |
| (IV) | 22254 | benzyl (2S)-2-[[(2S)-2-amino-3,3-dimethylbutanoyl]amino]-4-methylpentanoate | C19H30N2O3 | 详情 | 详情 | |
| (V) | 22255 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(2-methylphenyl)propionic acid | C25H23NO4 | 详情 | 详情 | |
| (VI) | 22256 | benzyl (5S,8S,11S)-8-(tert-butyl)-1-(9H-fluoren-9-yl)-11-isobutyl-5-(2-methylbenzyl)-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oate | C44H51N3O6 | 详情 | 详情 | |
| (VII) | 22257 | benzyl (2S)-2-[((2S)-2-[[(2S)-2-amino-3-(2-methylphenyl)propanoyl]amino]-3,3-dimethylbutanoyl)amino]-4-methylpentanoate | C29H41N3O4 | 详情 | 详情 | |
| (VIII) | 22258 | (2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid | 104091-08-9 | C24H27NO6 | 详情 | 详情 |
| (IX) | 22259 | benzyl (2S,5S,8S,11S)-11-amino-5-(tert-butyl)-2-isobutyl-16,16-dimethyl-8-(2-methylbenzyl)-4,7,10,14-tetraoxo-15-oxa-3,6,9-triazaheptadecan-1-oate | C38H56N4O7 | 详情 | 详情 | |
| (X) | 22260 | (2S)-4-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid | C23H25NO6 | 详情 | 详情 | |
| (XI) | 22261 | 1-benzyl 16-(tert-butyl) (2S,5S,8S,11S,14S)-14-amino-11-[3-(tert-butoxy)-3-oxopropyl]-5-(tert-butyl)-2-isobutyl-8-(2-methylbenzyl)-4,7,10,13-tetraoxo-3,6,9,12-tetraazahexadecane-1,16-dioate | C46H69N5O10 | 详情 | 详情 | |
| (XII) | 22262 | 4-(tert-butoxy)-4-oxobutyric acid | C8H14O4 | 详情 | 详情 | |
| (XIII) | 22263 | 1-benzyl 19-(tert-butyl) (2S,5S,8S,11S,14S)-14-[2-(tert-butoxy)-2-oxoethyl]-11-[3-(tert-butoxy)-3-oxopropyl]-5-(tert-butyl)-2-isobutyl-8-(2-methylbenzyl)-4,7,10,13,16-pentaoxo-3,6,9,12,15-pentaazanonadecane-1,19-dioate | C54H81N5O13 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)Coupling of N-(Boc)-3-methyl-L-valine (I) with L-leucine benzyl ester (II) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-HCl (EDC) and 1-hydroxybenzotriazole (HOBt) in the presence of N-ethylmorpholine gave the N-Boc-dipeptide (III), which was deprotected with trifluoroacetic acid in CH2Cl2 to afford (IV). Subsequent coupling of (IV) with N-Fmoc-2-methyl-L-phenylalanine (V) mediated by EDC and HOBt provided the N-Fmoc-tripeptide (VI). Deprotection of the fluorenylmethoxycarbonyl group of (VI) was effected with piperidine in CH2Cl2 to yield (VII). Further coupling and deprotection cycles with N-Fmoc-O-tert-butyl-L-glutamic acid (VIII) and then with N-Fmoc-O-tert-butyl-L-aspartic acid (X) provided peptides (IX) and (XI), respectively. This latter was then coupled to mono-tert--butyl succinate (XII) to furnish (XIII).
| 【1】 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 |
|---|---|---|---|---|---|---|
| (I) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (II) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
| (III) | 22253 | benzyl (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl]amino)-4-methylpentanoate | C24H38N2O5 | 详情 | 详情 | |
| (IV) | 22254 | benzyl (2S)-2-[[(2S)-2-amino-3,3-dimethylbutanoyl]amino]-4-methylpentanoate | C19H30N2O3 | 详情 | 详情 | |
| (V) | 22255 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(2-methylphenyl)propionic acid | C25H23NO4 | 详情 | 详情 | |
| (VI) | 22256 | benzyl (5S,8S,11S)-8-(tert-butyl)-1-(9H-fluoren-9-yl)-11-isobutyl-5-(2-methylbenzyl)-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oate | C44H51N3O6 | 详情 | 详情 | |
| (VII) | 22257 | benzyl (2S)-2-[((2S)-2-[[(2S)-2-amino-3-(2-methylphenyl)propanoyl]amino]-3,3-dimethylbutanoyl)amino]-4-methylpentanoate | C29H41N3O4 | 详情 | 详情 | |
| (VIII) | 22258 | (2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid | 104091-08-9 | C24H27NO6 | 详情 | 详情 |
| (IX) | 22259 | benzyl (2S,5S,8S,11S)-11-amino-5-(tert-butyl)-2-isobutyl-16,16-dimethyl-8-(2-methylbenzyl)-4,7,10,14-tetraoxo-15-oxa-3,6,9-triazaheptadecan-1-oate | C38H56N4O7 | 详情 | 详情 | |
| (X) | 22260 | (2S)-4-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid | C23H25NO6 | 详情 | 详情 | |
| (XI) | 22261 | 1-benzyl 16-(tert-butyl) (2S,5S,8S,11S,14S)-14-amino-11-[3-(tert-butoxy)-3-oxopropyl]-5-(tert-butyl)-2-isobutyl-8-(2-methylbenzyl)-4,7,10,13-tetraoxo-3,6,9,12-tetraazahexadecane-1,16-dioate | C46H69N5O10 | 详情 | 详情 | |
| (XII) | 22262 | 4-(tert-butoxy)-4-oxobutyric acid | C8H14O4 | 详情 | 详情 | |
| (XIII) | 22263 | 1-benzyl 19-(tert-butyl) (2S,5S,8S,11S,14S)-14-[2-(tert-butoxy)-2-oxoethyl]-11-[3-(tert-butoxy)-3-oxopropyl]-5-(tert-butyl)-2-isobutyl-8-(2-methylbenzyl)-4,7,10,13,16-pentaoxo-3,6,9,12,15-pentaazanonadecane-1,19-dioate | C54H81N5O13 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVI)The peptide resin (XV) was then coupled with tert-butyl hydrogensuccinate (XVI) yielding resin (XVII). Further Dess-Martin oxidation of the alpha-hydroxyamide function of (XVII) gave rise to keto amide (XVIII). Finally, simultaneous cleavage from the resin and deprotection of the tert-butyl ester groups of (XVIII) by treatment with trifluoroacetic acid provided the title peptide amide.
| 【1】 Jones, P.S.; Kay, P.B.; Wilson, F.X.; Raynham, T.M.; Hurst, D.N. (Hoffmann-La Roche, Inc.); alpha-Ketoamide derivs.. US 6187905 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 47886 | tert-butyl (3S,6S,9S,12S,15S,18S)-3-amino-18-[(1S)-2-amino-1-hydroxy-2-oxoethyl]-6-[3-(tert-butoxy)-3-oxopropyl]-12-(tert-butyl)-15-isobutyl-9-(2-methylbenzyl)-4,7,10,13,16-pentaoxo-5,8,11,14,17-pentaazadocosan-1-oate | C46H77N7O11 | 详情 | 详情 | |
| (XVI) | 22262 | 4-(tert-butoxy)-4-oxobutyric acid | C8H14O4 | 详情 | 详情 | |
| (XVII) | 47887 | tert-butyl (6S,9S,12S,15S,18S,21S)-21-[(1S)-2-amino-1-hydroxy-2-oxoethyl]-6-[2-(tert-butoxy)-2-oxoethyl]-9-[3-(tert-butoxy)-3-oxopropyl]-15-(tert-butyl)-18-isobutyl-12-(2-methylbenzyl)-4,7,10,13,16,19-hexaoxo-5,8,11,14,17,20-hexaazapentacosan-1-oate | C54H89N7O14 | 详情 | 详情 | |
| (XVIII) | 47788 | (9R,10R)-9,10-dihydroxy-5-methoxy-4,8,8-trimethyl-9,10-dihydro-2H,8H-pyrano[2,3-f]chromen-2-one | C16H18O6 | 详情 | 详情 |