|
【结 构 式】 
|
【分子编号】63274 【品名】(5S,8S,14S)-14-benzyl-5-[4-(benzyloxy)benzyl]-8-(1-methyl-1-sulfanylethyl)-3,6,9,12-tetraoxo-1-phenyl-2-oxa-4,7,10,13-tetraazapentadecan-15-oic acid 【CA登记号】 |
【 分 子 式 】C40H44N4O8S 【 分 子 量 】740.87752 【元素组成】C 64.85% H 5.99% N 7.56% O 17.28% S 4.33% |
合成路线1
该中间体在本合成路线中的序号：(IX)The title compound is prepared by solid-phase peptide synthesis starting from N-Fmoc-L-phenylalanine attached to Wang resin (I). Deprotection of (I) with piperidine in NMP removes the N-Fmoc group, yielding the phenylalanine resin (II). Coupling of (II) with N-trityl glycine (III) in the presence of PyBOP and HOBt, followed by acidic cleavage of the N-trityl group furnishes the dipeptide derivative (IV). To this is assembled N-Fmoc-S-trityl-D-penicillamine (V), followed by deprotection with piperidine in NMP, to produce resin (VI). Subsequent coupling of (VI) with N-Cbz-O-benzyl-L-tyrosine (VII) leads to the protected tetrapeptide (VIII). Removal of the S-trityl protecting group of (VIII) employing trifluoroacetic acid provides thiol (IX).
| 【1】 Rew, Y.; Malkmus, S.; Svensson, C.; Yaksh, T.L.; Chung, N.N.; Schiller, P.W.; Cassel, J.A.; DeHaven, R.; Goodman, M.; Synthesis and biological activities of cyclic lanthionine enkephalin analogues: delta-Opioid receptor selective ligands. J Med Chem 2002, 45, 17, 3746. |
| 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) | 19030 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine | 35661-40-6 | C24H21NO4 | 详情 | 详情 |
| (II) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (III) | 63269 | 2-(tritylamino)acetic acid | C21H19NO2 | 详情 | 详情 | |
| (IV) | 63270 | (2S)-2-[(2-aminoacetyl)amino]-3-phenylpropanoic acid | C11H14N2O3 | 详情 | 详情 | |
| (V) | 63271 | (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-methyl-3-(tritylsulfanyl)butanoic acid | C39H35NO4S | 详情 | 详情 | |
| (VI) | 63272 | (2S)-2-[(2-{[(2S)-2-amino-3-methyl-3-(tritylsulfanyl)butanoyl]amino}acetyl)amino]-3-phenylpropanoic acid | C35H37N3O4S | 详情 | 详情 | |
| (VII) | 27842 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(benzyloxy)phenyl]propionic acid | C24H23NO5 | 详情 | 详情 | |
| (VIII) | 63273 | (5S,8S,14S)-14-benzyl-5-[4-(benzyloxy)benzyl]-8-[1-methyl-1-(tritylsulfanyl)ethyl]-3,6,9,12-tetraoxo-1-phenyl-2-oxa-4,7,10,13-tetraazapentadecan-15-oic acid | C59H58N4O8S | 详情 | 详情 | |
| (IX) | 63274 | (5S,8S,14S)-14-benzyl-5-[4-(benzyloxy)benzyl]-8-(1-methyl-1-sulfanylethyl)-3,6,9,12-tetraoxo-1-phenyl-2-oxa-4,7,10,13-tetraazapentadecan-15-oic acid | C40H44N4O8S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)Treatment of N-trityl-D-serine benzyl ester (X) with I2/PPh3 gives rise to the iodoalanine derivative (XI). Thiol (IX) is then alkylated by iodide (XI) in the presence of Cs2CO3 to furnish thioether (XII). Simultaneous cleavage from the resin and removal of the N-trityl group in (XII) employing trifluoroacetic acid leads to the linear pentapeptide derivative (XIII). This is then cyclized to (XIV) in the presence of DPPA and NaHCO3 in dilute DMF solution. The Cbz and benzyl protecting groups of (XIV) are finally removed by HBr in AcOH to provide the title compound.
| 【1】 Rew, Y.; Malkmus, S.; Svensson, C.; Yaksh, T.L.; Chung, N.N.; Schiller, P.W.; Cassel, J.A.; DeHaven, R.; Goodman, M.; Synthesis and biological activities of cyclic lanthionine enkephalin analogues: delta-Opioid receptor selective ligands. J Med Chem 2002, 45, 17, 3746. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 63274 | (5S,8S,14S)-14-benzyl-5-[4-(benzyloxy)benzyl]-8-(1-methyl-1-sulfanylethyl)-3,6,9,12-tetraoxo-1-phenyl-2-oxa-4,7,10,13-tetraazapentadecan-15-oic acid | C40H44N4O8S | 详情 | 详情 | |
| (X) | 63275 | benzyl (2R)-3-hydroxy-2-(tritylamino)propanoate | C29H27NO3 | 详情 | 详情 | |
| (XI) | 63276 | benzyl (2S)-3-iodo-2-(tritylamino)propanoate | C29H26INO2 | 详情 | 详情 | |
| (XII) | 63277 | (5S,8S,14S)-14-benzyl-5-[4-(benzyloxy)benzyl]-8-(1-{[(2S)-3-(benzyloxy)-3-oxo-2-(tritylamino)propyl]sulfanyl}-1-methylethyl)-3,6,9,12-tetraoxo-1-phenyl-2-oxa-4,7,10,13-tetraazapentadecan-15-oic acid | C69H69N5O10S | 详情 | 详情 | |
| (XIII) | 63278 | (5S,8S,14S)-8-(1-{[(2S)-2-amino-3-(benzyloxy)-3-oxopropyl]sulfanyl}-1-methylethyl)-14-benzyl-5-[4-(benzyloxy)benzyl]-3,6,9,12-tetraoxo-1-phenyl-2-oxa-4,7,10,13-tetraazapentadecan-15-oic acid | C50H55N5O10S | 详情 | 详情 | |
| (XIV) | 63279 | benzyl (3S,6S,12S)-6-benzyl-12-({(2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)phenyl]propanoyl}amino)-13,13-dimethyl-5,8,11-trioxo-1-thia-4,7,10-triazacyclotridecane-3-carboxylate | C50H53N5O9S | 详情 | 详情 |