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【结 构 式】

【分子编号】27445

【品名】(2S)-2-([[(3S,6S,9S,12S)-6-benzyl-12-[(tert-butoxycarbonyl)amino]-9-(1H-indol-3-ylmethyl)-5,8,11,14-tetraoxo-1,4,7,10-tetraazacyclotetradecan-3-yl]carbonyl]amino)-4-methylpentanoic acid

【CA登记号】

【 分 子 式 】C38H49N7O9

【 分 子 量 】747.84884

【元素组成】C 61.03% H 6.6% N 13.11% O 19.25%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(X)

The solid phase method for the synthesis of peptides is here used starting with a phenylacetamidomethyl resin coupled with boc-protected-L-leucine (I), which was coupled successively with protected L-2,3-diaminopropionic acid (II) yielding dipeptide (III), with protected L-phenylalanine (IV), yielding tripeptide (V), with protected L-tryptophan (VI) yielding tetrapeptide (VII), and with protected L-aspartic acid (VIII), yielding pentapeptide (IX). The cyclization of (IX) by selective deprotection of the side chains of diaminopropionic acid and aspartic acid with piperidine in DMF, followed by cyclization by means of PyBop and DIEA in DMF affords the cyclic pentapeptide (X).

1 Lombardi, A.; D'Agostino, B.; Filippelli, A.; Pedone, C.; Matera, M.G.; Falciani, M.; De Rosa, M.; Rossi, F.; Pavone, V.; Neuronorm is a potent and water soluble neurokinin A receptor antagonist. Bioorg Med Chem Lett 1998, 8, 13, 1735.
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) 26057 L-Leucine 61-90-5 C6H13NO2 详情 详情
(II) 27439 (2S)-2-[(tert-butoxycarbonyl)amino]-3-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid C23H26N2O6 详情 详情
(III) 27440 (2S)-2-[((2S)-2-[(tert-butoxycarbonyl)amino]-3-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)amino]-4-methylpentanoic acid C29H37N3O7 详情 详情
(IV) 12874 (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine 13734-34-4 C14H19NO4 详情 详情
(V) 27441 (6S,9S,12S)-6-benzyl-9-([[(9H-fluoren-9-ylmethoxy)carbonyl]amino]methyl)-12-isobutyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid C38H46N4O8 详情 详情
(VI) 25478 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1-formyl-1H-indol-3-yl)propionic acid C17H20N2O5 详情 详情
(VII) 27442 (6S,9S,12S,15S)-9-benzyl-12-([[(9H-fluoren-9-ylmethoxy)carbonyl]amino]methyl)-6-[(1-formyl-1H-indol-3-yl)methyl]-15-isobutyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecan-16-oic acid C50H56N6O10 详情 详情
(VIII) 27443 (2S)-2-[(tert-butoxycarbonyl)amino]-4-(9H-fluoren-9-ylmethoxy)-4-oxobutyric acid C23H25NO6 详情 详情
(IX) 27444 (6S,9S,12S,15S,18S)-12-benzyl-15-([[(9H-fluoren-9-ylmethoxy)carbonyl]amino]methyl)-6-[2-(9H-fluoren-9-ylmethoxy)-2-oxoethyl]-9-[(1-formyl-1H-indol-3-yl)methyl]-18-isobutyl-2,2-dimethyl-4,7,10,13,16-pentaoxo-3-oxa-5,8,11,14,17-pentaazanonadecan-19-oic acid C68H71N7O13 详情 详情
(X) 27445 (2S)-2-([[(3S,6S,9S,12S)-6-benzyl-12-[(tert-butoxycarbonyl)amino]-9-(1H-indol-3-ylmethyl)-5,8,11,14-tetraoxo-1,4,7,10-tetraazacyclotetradecan-3-yl]carbonyl]amino)-4-methylpentanoic acid C38H49N7O9 详情 详情

合成路线2

该中间体在本合成路线中的序号:(X)

The deprotection of the Boc-amino group of the aspartic acid of (X) allows its condensation with the protected S-(tetra-O-acetyl-beta-D-galactopyranosyl)-L-cysteine (XI) affording the monocyclic hexapeptide (XII), which is treated first with HF, SMe2, p-cresol, and p-thiocresol to eliminate the solid phase resin and the Boc protecting group of the cysteine residue, and then cyclized by means of PyBop to afford the bicyclic hexapeptide (XIII). Finally, this compound is treated with sodium methoxide (c>5 mM) for more than 5 h. to give a mixture of the already known galactopyranosyl-hexapaptide Neuronorm (XIV) and the target compound (the dehydroalanyl derivative), which were separated by RP-HPLC.

1 Lombardi, A.; D'Agostino, B.; Nastri, F.; D'Andrea, L.D.; Filippelli, A.; Rossi, F.; Pavone, V.; A novel super-potent neurokinin A receptor antagonist containing dehydroalanine. Bioorg Med Chem Lett 1998, 8, 10, 1153.
2 Lombardi, A.; D'Agostino, B.; Filippelli, A.; Pedone, C.; Matera, M.G.; Falciani, M.; De Rosa, M.; Rossi, F.; Pavone, V.; Neuronorm is a potent and water soluble neurokinin A receptor antagonist. Bioorg Med Chem Lett 1998, 8, 13, 1735.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 27445 (2S)-2-([[(3S,6S,9S,12S)-6-benzyl-12-[(tert-butoxycarbonyl)amino]-9-(1H-indol-3-ylmethyl)-5,8,11,14-tetraoxo-1,4,7,10-tetraazacyclotetradecan-3-yl]carbonyl]amino)-4-methylpentanoic acid C38H49N7O9 详情 详情
(XI) 27446 (2R)-2-[(tert-butoxycarbonyl)amino]-3-([(2S,3R,4S,5R,6R)-3,4,5-tris(acetoxy)-6-[(acetoxy)methyl]tetrahydro-2H-pyran-2-yl]sulfanyl)propionic acid C22H33NO13S 详情 详情
(XII) 27447 (2S)-2-([[(3S,6S,9S,12S)-6-benzyl-12-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-([(2S,3R,4S,5R,6R)-3,4,5-tris(acetoxy)-6-[(acetoxy)methyl]tetrahydro-2H-pyran-2-yl]sulfanyl)propanoyl]amino]-9-(1H-indol-3-ylmethyl)-5,8,11,14-tetraoxo-1,4,7,10-tetraazacyclotetradecan-3-yl]carbonyl]amino)-4-methylpentanoic acid C55H72N8O19S 详情 详情
(XIII) 27448 (2R,3R,4S,5R,6S)-3,5-bis(acetoxy)-2-[(acetoxy)methyl]-6-([[(1S,4S,7S,10S,13R,16S)-4-benzyl-7-(1H-indol-3-ylmethyl)-16-isobutyl-3,6,9,12,15,18,21-heptaoxo-2,5,8,11,14,17,20-heptaazabicyclo[8.8.4]docos-13-yl]methyl]sulfanyl)tetrahydro-2H-pyran-4-yl acetate C50H62N8O16S 详情 详情
(XIV) 27449 (1S,4S,7S,10S,13R,16S)-4-benzyl-7-(1H-indol-3-ylmethyl)-16-isobutyl-13-([[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]sulfanyl]methyl)-2,5,8,11,14,17,20-heptaazabicyclo[8.8.4]docosane-3,6,9,12,15,18,21-heptone C42H54N8O12S 详情 详情
Extended Information