|
【结 构 式】 
|
【分子编号】25485 【品名】N-(Tert-butoxycarbonyl)-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide; N-(Tert-butoxycarbonyl)-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide 【CA登记号】 |
【 分 子 式 】C97H102N14O18S 【 分 子 量 】1784.02644 【元素组成】C 65.31% H 5.76% N 10.99% O 16.14% S 1.8% |
合成路线1
该中间体在本合成路线中的序号：(XII)The peptide was synthesized by a solid-phase method using a p-methylbenzhydrylamine resin to which N1-Boc-N6-Fmoc-L-lysine (I) was coupled giving (II). To this solid phase the following protected amino acids Nalpha-Boc-N1-formyl-L-tryptophan (III), Nalpha-Boc-Nomega-Tos-L-arginine (V), Nalpha-Boc-D-(2-naphthyl)alanine (VII), Nalpha-Boc-Npi-L-histidine (IX) and Nalpha-Boc-Ogamma-Fm-L-aspartic acid (XI) were sequentially coupled yielding resins (IV), (VI), (VIII), (X) and (XII).
| 【1】 Al-Obeidi, F.A.; Sharma, S.D.; de L. Castrucci, A.; Kesterson, R.A.; Lu, D.; Hadley, M.E.; Cone, R.D.; Hruby, V.J.; Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J Med Chem 1995, 38, 18, 3454. |
| 【2】 Hadley, M.E.; Hruby, V.J.; Sharma, S.D. (University of Arizona); Peptides having potent antagonist and agonist bioactivities at melanocortin receptors. US 5731408 . |
| 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) | 25476 | (2S)-2-[(tert-butoxycarbonyl)amino]-6-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]hexanoic acid | 84624-27-1 | C26H32N2O6 | 详情 | 详情 |
| (II) | 25477 | 9H-fluoren-9-ylmethyl (5S)-6-amino-5-[(tert-butoxycarbonyl)amino]-6-oxohexylcarbamate | C26H33N3O5 | 详情 | 详情 | |
| (III) | 25478 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1-formyl-1H-indol-3-yl)propionic acid | C17H20N2O5 | 详情 | 详情 | |
| (IV) | 25479 | 9H-fluoren-9-ylmethyl (5S)-6-amino-5-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(1-formyl-1H-indol-3-yl)propanoyl]amino]-6-oxohexylcarbamate | C38H43N5O7 | 详情 | 详情 | |
| (V) | 19064 | (2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid | C18H28N4O6S | 详情 | 详情 | |
| (VI) | 25480 | tert-butyl (1S,4S,7S)-7-(aminocarbonyl)-15-(9H-fluoren-9-yl)-4-[(1-formyl-1H-indol-3-yl)methyl]-1-[3-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]propyl]-2,5,13-trioxo-14-oxa-3,6,12-triazapentadec-1-ylcarbamate | C51H61N9O10S | 详情 | 详情 | |
| (VII) | 23498 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid | C18H21NO4 | 详情 | 详情 | |
| (VIII) | 25481 | tert-butyl (1R,4S,7S,10S)-10-(aminocarbonyl)-18-(9H-fluoren-9-yl)-7-[(1-formyl-1H-indol-3-yl)methyl]-4-[3-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]propyl]-1-(2-naphthylmethyl)-2,5,8,16-tetraoxo-17-oxa-3,6,9,15-tetraazaoctadec-1-ylcarbamate | C64H72N10O11S | 详情 | 详情 | |
| (IX) | 25482 | (2S)-3-[1-[(benzyloxy)methyl]-1H-imidazol-5-yl]-2-[(tert-butoxycarbonyl)amino]propionic acid | 83468-83-1 | C19H25N3O5 | 详情 | 详情 |
| (X) | 25483 | 9H-fluoren-9-ylmethyl (5S,8S,11S,14R,17S)-17-amino-5-(aminocarbonyl)-18-[1-[(benzyloxy)methyl]-1H-imidazol-5-yl]-8-[(1-formyl-1H-indol-3-yl)methyl]-11-[3-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]propyl]-14-(2-naphthylmethyl)-7,10,13,16-tetraoxo-6,9,12,15-tetraazaoctadec-1-ylcarbamate | C73H79N13O11S | 详情 | 详情 | |
| (XI) | 25484 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-4-oxobutyric acid | C24H25NO8 | 详情 | 详情 | |
| (XII) | 25485 | N-(Tert-butoxycarbonyl)-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide; N-(Tert-butoxycarbonyl)-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide | C97H102N14O18S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The coupling sequences were continued with Nalpha-Boc-L-norleucine (XIII) to afford resin (XIV). Elimination of the Fmoc and OFm protecting groups of (XIV) was performed with piperidine in NMP allowing the formation of the lactam ring by cyclization with BOP and DIEA in NMP providing the macrocyclic lactam (XV).
| 【1】 Al-Obeidi, F.A.; Sharma, S.D.; de L. Castrucci, A.; Kesterson, R.A.; Lu, D.; Hadley, M.E.; Cone, R.D.; Hruby, V.J.; Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J Med Chem 1995, 38, 18, 3454. |
| 【2】 Hadley, M.E.; Hruby, V.J.; Sharma, S.D. (University of Arizona); Peptides having potent antagonist and agonist bioactivities at melanocortin receptors. US 5731408 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 25485 | N-(Tert-butoxycarbonyl)-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide; N-(Tert-butoxycarbonyl)-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide | C97H102N14O18S | 详情 | 详情 | |
| (XIII) | 20398 | (2S)-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C11H21NO4 | 详情 | 详情 | |
| (XIV) | 25486 | N-(Tert-butoxycarbonyl)-D-norleucyl-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide; N-(Tert-butoxycarbonyl)-D-norleucyl-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide | C103H113N15O19S | 详情 | 详情 | |
| (XV) | 25487 | tert-butyl (1S)-1-([[(3S,6S,9R,12S,15S,23S)-23-(aminocarbonyl)-12-([1-[(benzyloxy)methyl]-1H-imidazol-5-yl]methyl)-3-[(1-formyl-1H-indol-3-yl)methyl]-6-[3-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]propyl]-9-(2-naphthylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexaazacyclotricosan-15-yl]amino]carbonyl)pentylcarbamate | C73H91N15O14S | 详情 | 详情 |