[2-(trimethylsilyl)ethoxy]methyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutanoate -Drug Synthesis Database

【结构式】

【分子编号】50746

【品名】[2-(trimethylsilyl)ethoxy]methyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutanoate

【CA登记号】

【分子式】C₁₅H₃₁NO₆Si

【分子量】349.49978

【元素组成】C 51.55% H 8.94% N 4.01% O 27.47% Si 8.04%

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：(III)

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】 Li, W.-R.; et al.; Total synthesis and structural investigations of didemnins A, B, and C. J Am Chem Soc 1990, 112, 21, 7659.

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)	50745	N-BOC-L-threonine; Boc-Threonine; N-tert-Butoxycarbonyl-L-threonine; N-(tert-Butoxycarbonyl)-L-threonine; BOC-L-Threonine	2592-18-9	C₉H₁₇NO₅	详情	详情
(II)	27243	[2-(chloromethoxy)ethyl](trimethyl)silane	76513-69-4	C₆H₁₅ClOSi	详情	详情
(III)	50746	[2-(trimethylsilyl)ethoxy]methyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutanoate		C₁₅H₃₁NO₆Si	详情	详情
(IV)	39328	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid		C₁₇H₁₇NO₅	详情	详情
(V)	50747	(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid		C₁₉H₂₁NO₅	详情	详情
(VI)	50748	(2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-[[(2S)-3-(4-methoxyphenyl)-2-(methylamino)propanoyl]oxy]butyric acid		C₂₀H₃₀N₂O₇	详情	详情
(VII)	50749	(2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)-2-pyrrolidinecarboxylic acid		C₁₉H₂₆N₂O₅	详情	详情
(VIII)	50750	(2S,3R)-3-[[(2S)-2-[[[(2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)pyrrolidinyl]carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy]-2-[(tert-butoxycarbonyl)amino]butyric acid		C₃₉H₅₄N₄O₁₁	详情	详情
(IX)	22838	(2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoic acid		C₁₄H₁₉NO₄	详情	详情
(X)	29552	methyl (2S)-2-pyrrolidinecarboxylate	2133-40-6	C₆H₁₁NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The modified tyrosine building block (II) was prepared by alkylation of N-Cbz-L-tyrosine (I) at both the phenolic OH and the NH groups employing dimethyl sulfate under phase-transfer conditions. N-Boc-L-Threonine benzyl ether (III) was converted to the corresponding (triethylsilyl)ethoxymethyl ester, and the O-benzyl group was subsequently removed by catalytic hydrogenolysis to afford (IV). Coupling between the tyrosine (II) and threonine (IV) derivatives using DCC and DMAP gave rise to the protected didepsipeptide (V). The SEM protecting group was then cleaved by means of HF in acetonitrile, yielding intermediate (VI)

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
(I)	39328	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid	C₁₇H₁₇NO₅	详情	详情
(II)	50747	(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid	C₁₉H₂₁NO₅	详情	详情
(III)	50782	(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid	C₁₆H₂₃NO₅	详情	详情
(IV)	50746	[2-(trimethylsilyl)ethoxy]methyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutanoate	C₁₅H₃₁NO₆Si	详情	详情
(V)	62532	[2-(trimethylsilyl)ethoxy]methyl (2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoate	C₃₄H₅₀N₂O₁₀Si	详情	详情
(VI)	52709	(2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoic acid	C₂₈H₃₆N₂O₉	详情	详情

Extended Information