methyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate -Drug Synthesis Database

【结构式】

【分子编号】62534

【品名】methyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate

【CA登记号】

【分子式】C₁₄H₂₇NO₅

【分子量】289.37212

【元素组成】C 58.11% H 9.4% N 4.84% O 27.65%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IX)

Activation of N-Boc-D-allo-isoleucine (VII) with carbonyl diimidazole, followed by condensation with the lithium enolate of methyl acetate provided keto ester (VIII). Keto group reduction in (VIII) by means of KBH4 led to the isostatine derivative (IX), which was further hydrolyzed to acid (X) with NaOH in aqueous dioxane. Silylation of hydroxy acid (X) at both the alcohol and carboxyl groups employing tert-butyldimethylsilyl chloride and imidazole, followed by selective desilylation of the carboxyl group with NaOH afforded the protected amino hydroxy acid (XI)

参考文献中间体

合成目标

【1】 Jou, G.; Gonzalez, I.; Albericio, F.; Lloyd-Williams, P.; Giralt, E.; Total synthesis of dehydrodidemnin B. Use of uronium and phosphonium salt coupling reagents in peptide synthesis in solution. J Org Chem 1997, 62, 2, 354.
【2】 Giralt Lledo, E.; Albericio Palomera, F.; Lloyd-Williams, P.; Gonzalez Valcarcel, I.; Jou Prat, G.; Gomez Gonzalez, A.; Manzanares Secades, I. (PharmaMar, SA); Process for the preparation of didemnine A. ES 2102322 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VII)	50775	(2R,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid	C₁₁H₂₁NO₄	详情	详情
(VIII)	62533	methyl (4R,5S)-4-[(tert-butoxycarbonyl)amino]-5-methyl-3-oxoheptanoate	C₁₄H₂₅NO₅	详情	详情
(IX)	62534	methyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate	C₁₄H₂₇NO₅	详情	详情
(X)	52722	(3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoic acid	C₁₃H₂₅NO₅	详情	详情
(XI)	50802	(3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-methylheptanoic acid	C₁₉H₃₉NO₅Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XLI)

For the synthesis of the other peptidic moiety (L), removal of the N-Boc group from the isostatine derivative (XLI) by means of trifluoroacetic acid gave amino ester (XLII), which was coupled with N-Boc-L-threonine benzyl ether (III) to afford dipeptide (XLIII). Boc group removal in (XLIII) with HCl provided peptide (XLIV), which was coupled with N-Boc-N-methyl-D-leucine (XXVII) to yield tripeptide (XLV). Saponification of the methyl ester group of (XLV) with NaOH provided acid (XLVI). Sequential protection of the alcohol hydroxyl of (XLVI) as the tert-butyldimethylsilyl ether, and esterification of the carboxyl group with trichloroethanol led to the fully protected tripeptide (XLVII). The benzyl ether group of (XLVII) was then removed by catalytic hydrogenolysis to furnish alcohol (XLVIII)

参考文献中间体

合成目标

【1】 Jou, G.; Gonzalez, I.; Albericio, F.; Lloyd-Williams, P.; Giralt, E.; Total synthesis of dehydrodidemnin B. Use of uronium and phosphonium salt coupling reagents in peptide synthesis in solution. J Org Chem 1997, 62, 2, 354.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(III)	50782	(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid	C₁₆H₂₃NO₅	详情	详情
(XXVII)	50788	(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid	C₁₂H₂₃NO₄	详情	详情
(XLI)	62534	methyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate	C₁₄H₂₇NO₅	详情	详情
(XLII)	62550	methyl (3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoate	C₉H₁₉NO₃	详情	详情
(XLIII)	62551	methyl (3S,4R,5S)-4-({(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butanoyl}amino)-3-hydroxy-5-methylheptanoate	C₂₅H₄₀N₂O₇	详情	详情
(XLIV)	62552	methyl (3S,4R,5S)-4-{[(2S,3R)-2-amino-3-(benzyloxy)butanoyl]amino}-3-hydroxy-5-methylheptanoate	C₂₀H₃₂N₂O₅	详情	详情
(XLV)	62553	methyl (6R,9S,12R,13S)-9-[(1R)-1-(benzyloxy)ethyl]-13-hydroxy-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate	C₃₂H₅₃N₃O₈	详情	详情
(XLVI)	62554	(6R,9S,12R,13S)-9-[(1R)-1-(benzyloxy)ethyl]-13-hydroxy-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oic acid	C₃₁H₅₁N₃O₈	详情	详情
(XLVII)	50787	2,2,2-trichloroethyl (6R,9S,12R,13S)-9-[(1R)-1-(benzyloxy)ethyl]-13-[[tert-butyl(dimethyl)silyl]oxy]-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate	C₃₉H₆₆Cl₃N₃O₈Si	详情	详情
(XLVIII)	50784	2,2,2-trichloroethyl (6R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-9-[(1R)-1-hydroxyethyl]-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate	C₃₂H₆₀Cl₃N₃O₈Si	详情	详情

Extended Information