-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】Cyclo[dehydroalanine-L-aspartyl-L-tryptophyl-Lphenylalanyl-[2(S),3-diaminopropionyl]-L-leucine] C-4.2-N-3.5-lactam

【CA登记号】

【分子式】C₃₆H₄₂N₈O₇

【分子量】698.78554

【开发单位】Univ. Napoli ?Federico II?, Naples (IT); Seconda Univ. Napoli, Naples (IT)

【药理作用】RESPIRATORY DRUGS, ASTHMA THERAPY

合成路线1 合成路线2

合成路线1

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).

参考文献中间体

【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

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.

参考文献中间体

【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	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

Drug NewChemical Entity Original Patent(1)