【结 构 式】 |
【分子编号】23498 【品名】(2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid 【CA登记号】 |
【 分 子 式 】C18H21NO4 【 分 子 量 】315.36908 【元素组成】C 68.55% H 6.71% N 4.44% O 20.29% |
合成路线1
该中间体在本合成路线中的序号:(XX)The amino acid Boc-(2-naphthyl)-D-alanine (XX) were added to intermediate (XIX), yielding the peptide resin (XXI). When the integration of amino acids was completed, the peptide resin (XXI) was deprotected with TFA, acetylated with acetic anhydride and finally treated with ammonia in methanol in order to eliminate the resin matrix and form the final amide group.
【1】 Robinson, J.3rd; Morgans, D.J.; Bingenheimer, W.; Arzeno, H.B.; Temporary serine protection in solid phase synthesis of LH-RH analogs. Int J Pept Protein Res 1993, 41, 4, 342. |
【2】 Castaner, J.; Leeson, P.; Rabasseda, X.; Ganirelix Acetate. Drugs Fut 1999, 24, 4, 393. |
【3】 Nestor, J.J. Jr.; McClure, N.L. (Syntex (USA), Inc.); Temporary minimal protection synthesis of LH-RH analogs. EP 0443532; JP 1992211096; US 5212288 . |
【4】 Vickery, B.H. (Syntex (USA), Inc.); LHRH antagonist analogs and 19-nor-progestational steroids for therapy. EP 0301850 . |
【5】 Nestor, J.J. Jr.; Vickery, B.H. (Syntex (USA), Inc.); Nonapeptide and decapeptide analogs of LHRH as LHRH antagonists. EP 0277829; JP 1988201199; US 4801577 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XIX) | 23497 | (2R)-2-[([(2S)-1-[(2S,5S,8R,11S,14S,17R,20R)-20-(4-chlorobenzyl)-2,8-bis(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-11-(4-hydroxybenzyl)-14-(hydroxymethyl)-5-isobutyl-24,24-dimethyl-4,7,10,13,16,19,22-heptaoxo-17-(3-pyridinylmethyl)-23-oxa-3,6, | C70H107ClN16O14 | 详情 | 详情 | |
(XX) | 23498 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid | C18H21NO4 | 详情 | 详情 | |
(XXI) | 23499 | (2R)-2-[([(2S)-1-[(2S,5S,8R,11S,14S,17R,20R,23R)-20-(4-chlorobenzyl)-2,8-bis(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-11-(4-hydroxybenzyl)-14-(hydroxymethyl)-5-isobutyl-27,27-dimethyl-23-(2-naphthylmethyl)-4,7,10,13,16,19,22,25-octaoxo-17-(3- | C83H118ClN17O15 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XII)Methylation of N-Boc-D-phenylalanine (VIII) with methyl iodide and NaH afforded the N-methyl amino acid (IX). After coupling with methylamine in the presence of EDC and HOBt, the Boc protecting group of the resulting amide (X) was removed by treatment with trifluoroacetic acid to give (XI). The N-methyl amino acid (XIII), prepared by methylation of N-Boc-naphthylalanine (XII), was then coupled to amine (XI) by means of EDC and HOAt to yield dipeptide amide (XIV). A further treatment of (XIV) with trifluoroacetic acid removed the Boc protecting group to yield (XV), which was then coupled with amino acid (VII) in the presence of EDC and HOAt yielding (XVI). Finally, deprotection of the Boc-tripeptide (XVI) with trifluoroacetic acid provided the title compound.
【1】 Hansen, T.K.; Ankersen, M.; Hansen, B.S.; Raun, K.; Nielsen, K.K.; Lau, J.; Peschke, B.; Lundt, B.F.; Thogersen, H.; Johansen, N.L.; Madsen, K.; Andersen, P.H.; Novel orally active growth hormone secretagogues. J Med Chem 1998, 41, 19, 3705. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VII) | 22191 | (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid | C12H21NO4 | 详情 | 详情 | |
(VIII) | 22184 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid | C14H19NO4 | 详情 | 详情 | |
(IX) | 22185 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-phenylpropionic acid | 37553-65-4 | C15H21NO4 | 详情 | 详情 |
(X) | 27231 | tert-butyl (1R)-1-benzyl-2-(methylamino)-2-oxoethyl(methyl)carbamate | C16H24N2O3 | 详情 | 详情 | |
(XI) | 27232 | (2R)-N-methyl-2-(methylamino)-3-phenylpropanamide | C11H16N2O | 详情 | 详情 | |
(XII) | 23498 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid | C18H21NO4 | 详情 | 详情 | |
(XIII) | 22189 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2-naphthyl)propionic acid | 147577-61-5 | C19H23NO4 | 详情 | 详情 |
(XIV) | 27233 | tert-butyl (1R)-2-[[(1R)-1-benzyl-2-(methylamino)-2-oxoethyl](methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl(methyl)carbamate | C30H37N3O4 | 详情 | 详情 | |
(XV) | 27234 | (2R)-N-[(1R)-1-benzyl-2-(methylamino)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propanamide | C25H29N3O2 | 详情 | 详情 | |
(XVI) | 27235 | tert-butyl (E)-5-[[(1R)-2-[[(1R)-1-benzyl-2-(methylamino)-2-oxoethyl](methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl](methyl)amino]-1,1-dimethyl-5-oxo-3-pentenylcarbamate | C37H48N4O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(VII)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4
该中间体在本合成路线中的序号:(XXIV)The coupling of resin (XXIII) with N-Boc-D-(2-naphthyl)alanine (XXIV) as before gave, after the corresponding deprotection cycle with trifluoroacetic acid, resin (XXV). The peptide resin (XXV) was acetylated with Ac2O and finally deprotected and cleaved from the resin by treatment with HF to provide the target peptide.
【1】 Stalewski, J.; Galyean, R.; Jiang, G.; et al.; GnRH antagonists: A new generation of long acting analogues incorporating p-ureido-phenylalanines at positions 5 and 6. J Med Chem 2001, 44, 3, 453. |
【2】 Jiang, G.; Semple, G. (Ferring BV Group Holding); GnRH antagonists being modified in positions 5 and 6. WO 9846634 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XXIII) | 46759 | benzyl (5S,8S,11R,14S,17S,20R,23R)-23-amino-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-17-[(benzyloxy)methyl]-11-(4-[[(tert-butylamino)carbonyl]amino]benzyl)-24-(4-chlorophenyl)-14-[4-([[(4R)-2,6-dioxohexahydro-4-pyrimidinyl]carbonyl]amino)benzyl]-8-isobutyl-7,10,13,16,19,22-hexaoxo-20-(3-pyridinylmethyl)-6,9,12,15,18,21-hexaazatetracos-1-yl(isopropyl)carbamate | C86H110ClN17O16 | 详情 | 详情 | |
(XXIV) | 23498 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid | C18H21NO4 | 详情 | 详情 | |
(XXV) | 46758 | benzyl (5S,8S,11R,14S,17S,20R,23R,26R)-26-amino-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-17-[(benzyloxy)methyl]-11-(4-[[(tert-butylamino)carbonyl]amino]benzyl)-23-(4-chlorobenzyl)-14-[4-([[(4R)-2,6-dioxohexahydro-4-pyrimidinyl]carbonyl]amino)benzyl]-8-isobutyl-27-(2-naphthyl)-7,10,13,16,19,22,25-heptaoxo-20-(3-pyridinylmethyl)-6,9,12,15,18,21,24-heptaazaheptacos-1-yl(isopropyl)carbamate | C99H121ClN18O17 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(XIX)Coupling/deprotection cycles with N-Boc-D-(3-pyridyl)alanine (XV), N-Boc-D-4-chlorophenylalanine (XVII) and N-Boc-D-(2-naphthyl)alanine (XIX) furnished the peptide resins (XVI), (XVIII) and (XX).
【1】 Rivier, J.E.; et al.; Gonadotropin-releasing hormone antagonists: Novel members of the azaline B family. J Med Chem 1995, 38, 14, 2649. |
【2】 Rivier, J.E.F.; Porter, J.S.; Hoeger, C.A.; Jiang, G.; Rivier, C.L. (The Salk Institute for Biological Studies); GnRH antagonists. EP 0804471; JP 1998500397; US 5506207; WO 9525741 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XIV) | 51381 | benzyl (5S,8S,11R,14S,17S)-17-amino-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-11,14-bis(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]benzyl)-8-isobutyl-7,10,13,16-tetraoxo-20-phenyl-19-oxa-6,9,12,15-tetraazaicos-1-yl(isopropyl)carbamate | C89H101N11O14 | 详情 | 详情 | |
(XV) | 23494 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(3-pyridinyl)propionic acid | C13H18N2O4 | 详情 | 详情 | |
(XVI) | 51382 | benzyl (5S,8S,11R,14S,17S,20R)-20-amino-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-17-[(benzyloxy)methyl]-11,14-bis(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]benzyl)-8-isobutyl-7,10,13,16,19-pentaoxo-21-(3-pyridinyl)-6,9,12,15,18-pentaazahenicos-1-yl(isopropyl)carbamate | C97H109N13O15 | 详情 | 详情 | |
(XVII) | 23496 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-chlorophenyl)propionic acid | C14H18ClNO4 | 详情 | 详情 | |
(XVIII) | 51583 | 4-(2-ethyl-5-nitro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole | C14H15N3O2 | 详情 | 详情 | |
(XIX) | 23498 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid | C18H21NO4 | 详情 | 详情 | |
(XX) | 51384 | benzyl (5S,8S,11R,14S,17S,20R,23R,26R)-26-amino-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-17-[(benzyloxy)methyl]-23-(4-chlorobenzyl)-11,14-bis(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]benzyl)-8-isobutyl-27-(2-naphthyl)-7,10,13,16,19,22,25-heptaoxo-20-(3-pyridinylmethyl)-6,9,12,15,18,21,24-heptaazaheptacos-1-yl(isopropyl)carbamate | C119H128ClN15O17 | 详情 | 详情 |