(2R,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid -Drug Synthesis Database

【结构式】

【分子编号】50775

【品名】(2R,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid

【CA登记号】

【分子式】C₁₁H₂₁NO₄

【分子量】231.29208

【元素组成】C 57.12% H 9.15% N 6.06% O 27.67%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

Protection of the carboxyl group of Boc-L-threonine (I) with [2-(chloromethoxy)ethyl]trimethylsilane (SEM-Cl) (II) by means of Li2CO3 affords protected threonine (III). Separately, Z-L-tyrosine (IV) is treated with dimethyl sulfate and KOH in THF with tetrabutylammonium hydrogen sulfate as a catalyst to furnish N,O-dimethyl-L-tyrosine (V), which is then converted into secondary amine (VI) by coupling with protected threonine (III) either by means of 2,4,6-trichlorobenzoyl chloride in THF and DMAP in benzene or with isopropenyl chloroformate, Et3N and DMAP, followed by elimination of the carbobenzyloxy group by hydrogenation over Pd/C. Coupling of Z-L-leucine (IX) to L-proline methyl ester (X) by means of DCC, HOBt and NMM in CH2Cl2, followed by hydrolysis with LiOH, affords Z-leucylproline (VII), which is then coupled to amine (VI) by means of BOPCl and Et3N in CH2Cl2, and then subjected to deprotection with hydrofluoric acid in acetonitrile affording intermediate (VIII).

参考文献中间体

合成目标

【1】 Hamada, Y.; Shioiri, T.; Anti-tumor active cyclic peptide derived from marine organism: Synthesis, conformation and bioactivity. Kagaku Zokan 1990, 118, 31.
【2】 Harris, B.D.; et al.; Synthetic studies of didemnins. II. Approaches to statine diastereomers. Tetrahedron Lett 1987, 28, 25, 2837.
【3】 Hamada, Y.; et al.; Efficient total synthesis of didemnins A and B. J Am Chem Soc 1989, 111, 2, 669.

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)	50775	(2R,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid		C₁₁H₂₁NO₄	详情	详情
(II)	44205	(2-ethoxy-2-oxoethyl)lithium		C₄H₇LiO₂	详情	详情
(III)	50776	ethyl (4R,5S)-4-[(tert-butoxycarbonyl)amino]-5-methyl-3-oxoheptanoate		C₁₅H₂₇NO₅	详情	详情
(IV)	50777	tert-butyl (1R,2S)-1-formyl-2-methylbutylcarbamate		C₁₁H₂₁NO₃	详情	详情
(V)	50778	ethyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate		C₁₅H₂₉NO₅	详情	详情
(VI)	50779	2,2,2-trichloro-1-ethanol		C₂H₃Cl₃O	详情	详情
(VII)	50780	2,2,2-trichloroethyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate		C₁₅H₂₆Cl₃NO₅	详情	详情
(VIII)	50781	2,2,2-trichloroethyl (3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoate		C₁₀H₁₈Cl₃NO₃	详情	详情
(IX)	50782	(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid		C₁₆H₂₃NO₅	详情	详情
(X)	50783	2,2,2-trichloroethyl (3S,4R,5S)-4-[[(2S,3R)-2-amino-3-(benzyloxy)butanoyl]amino]-3-hydroxy-5-methylheptanoate		C₂₁H₃₁Cl₃N₂O₅	详情	详情
(XI)	50788	(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid		C₁₂H₂₃NO₄	详情	详情
(XII)	31819	(2R)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid	16937-99-8	C₁₁H₂₁NO₄	详情	详情
(XIII)	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
(XIV)	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
(XV)	50747	(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid		C₁₉H₂₁NO₅	详情	详情
(XVI)	39328	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid		C₁₇H₁₇NO₅	详情	详情
(XVII)	50785	2,2,2-trichloroethyl (5S,8R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-5-(4-methoxybenzyl)-4,8-dimethyl-9-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-3,6,10-trioxo-1-phenyl-2,7-dioxa-4,11-diazapentadecan-15-oate		C₄₆H₇₁Cl₃N₄O₁₀Si	详情	详情
(XVIII)	50786	(5S,8R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-5-(4-methoxybenzyl)-4,8-dimethyl-9-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-3,6,10-trioxo-1-phenyl-2,7-dioxa-4,11-diazapentadecan-15-oic acid		C₄₄H₇₀N₄O₁₀Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

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3

该中间体在本合成路线中的序号：(VII)

A modification of the previous synthetic methods was further reported. The protected isostatine (XI) was prepared by a related procedure utilizing benzyl ester protected intermediates instead of the methyl ester analogues. After activation of N-Boc-D-allo-isoleucine (VII) with carbonyl diimidazole, condensation with the lithium enolate of benzyl acetate yielded keto ester (LIV). Reduction of the keto group of (LIV), followed by silylation of the resultant alcohol (LV) and benzyl group hydrogenolysis led to the amino hydroxy acid derivative (XI)

参考文献中间体

合成目标

【1】 Edge, A. (Diacrin, Inc.); Method for improving graft acceptance in a recipient by administration of a cytokine profile altering agent. WO 0051630 .

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
(XI)	50802	(3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-methylheptanoic acid	C₁₉H₃₉NO₅Si	详情	详情
(LIV)	62561	benzyl (4R,5S)-4-[(tert-butoxycarbonyl)amino]-5-methyl-3-oxoheptanoate	C₂₀H₂₉NO₅	详情	详情
(LV)	62562	benzyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate	C₂₀H₃₁NO₅	详情	详情

Extended Information