(2S)-3-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylphenyl]-2-[(tert-butoxycarbonyl)amino]propanoic acid -Drug Synthesis Database

【结构式】

【分子编号】58616

【品名】(2S)-3-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylphenyl]-2-[(tert-butoxycarbonyl)amino]propanoic acid

【CA登记号】

【分子式】C₂₃H₂₈INO₆

【分子量】541.38293

【元素组成】C 51.03% H 5.21% I 23.44% N 2.59% O 17.73%

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：(XVII)

Synthesis of the iodo-L-phenylalanine intermediate (XVII): The condensation of catechol derivative (IX) with methyl orthoformate by means of BuLi and CSA in methanol gives the benzaldehyde dimethyl acetal (X), which is iodinated with I2 and BuLi in ethyl ether to yield the iodobenzaldehyde acetal (XI). The hydrolysis of the acetal group of (XI) by means of HCl in THF affords the 3-hydroxy benzaldehyde derivative (XII), which is treated with benzyl bromide and K2CO3 in refluxing acetonitrile to provide the benzyl protected benzaldehyde derivative (XIII). The Horner-Emmons condensation of aldehyde (XIII) with phosphonate (XIV) by means of TMG in dichloromethane gives the dehydrophenylalanine derivative (XV), which is submitted to an asymmetric hydrogenation with H2 over a chiral Rh catalyst in hot ethyl acetate to yield the L-enantiomer (XVI). Finally, the ester group of (XVI) is hydrolyzed with LiOH in methanol/water to afford the target iodo-L-phenylalanine intermediate (XVII).

参考文献中间体

合成目标

【1】 Abe, M.; Yanagisawa, A.; Tohma, S.; Kan, T.; Fukuyama, T.; Endo, A.; Total synthesis of ecteinascidin 743. J Am Chem Soc 2002, 124, 23, 6552.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IX)	58609	4-bromo-2-(methoxymethoxy)-6-methylphenyl methyl ether; 5-bromo-2-methoxy-1-(methoxymethoxy)-3-methylbenzene	C₁₀H₁₃BrO₃	详情	详情
(X)	58610	5-(dimethoxymethyl)-2-methoxy-1-(methoxymethoxy)-3-methylbenzene; 4-(dimethoxymethyl)-2-(methoxymethoxy)-6-methylphenyl methyl ether	C₁₃H₂₀O₅	详情	详情
(XI)	58611	1-(dimethoxymethyl)-2-iodo-4-methoxy-3-(methoxymethoxy)-5-methylbenzene; 4-(dimethoxymethyl)-3-iodo-2-(methoxymethoxy)-6-methylphenyl methyl ether	C₁₃H₁₉IO₅	详情	详情
(XII)	58612	3-hydroxy-2-iodo-4-methoxy-5-methylbenzaldehyde	C₉H₉IO₃	详情	详情
(XIII)	58613	3-(benzyloxy)-2-iodo-4-methoxy-5-methylbenzaldehyde	C₁₆H₁₅IO₃	详情	详情
(XIV)	34562	methyl 2-[(tert-butoxycarbonyl)amino]-2-(dimethoxyphosphoryl)acetate	C₁₀H₂₀NO₇P	详情	详情
(XV)	58614	methyl (Z)-3-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylphenyl]-2-[(tert-butoxycarbonyl)amino]-2-propenoate	C₂₄H₂₈INO₆	详情	详情
(XVI)	58615	methyl (2S)-3-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylphenyl]-2-[(tert-butoxycarbonyl)amino]propanoate	C₂₄H₃₀INO₆	详情	详情
(XVII)	58616	(2S)-3-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylphenyl]-2-[(tert-butoxycarbonyl)amino]propanoic acid	C₂₃H₂₈INO₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVII)

The condensation of the amine intermediate (VIII) with iodo-L-phenylalanine intermediate (XVII), 4-methoxyphenyl isocyanide (XVIII) and acetaldehyde (XIX) in refluxing methanol gives the adduct (XX), which is desilylated with TBAF in THF and acylated with Ac2O and pyridine to yield the acetoxy derivative (XXI). Elimination of the Mom and Boc protecting groups of (XXI) by means of TFA in dichloromethane affords the aminophenol (XXII), which is submitted to cyclization in refluxing ethyl acetate to provide the piperazinedione derivative (XXIII). The reaction of the OH group of (XXIII) with MsCl and pyridine in dichloromethane and the piperazine NH with Boc2O and DMAP in acetonitrile gives the fully protected compound (XXIV), which is reduced with NaBH4 in EtOH/dichloromethane and dehydrated by means of CSA and quinoline in refluxing toluene to yield the tetrahydropyrazinone (XXV). The cyclization of (XXV) by means of Pd2(dba)3, P(o-tol)3 and TEA in refluxing acetonitrile affords the tricyclic compound (XXVI).

参考文献中间体

合成目标

【1】 Abe, M.; Yanagisawa, A.; Tohma, S.; Kan, T.; Fukuyama, T.; Endo, A.; Total synthesis of ecteinascidin 743. J Am Chem Soc 2002, 124, 23, 6552.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	58608	(1R)-2-{[tert-butyl(diphenyl)silyl]oxy}-1-[6-(methoxymethoxy)-7-methyl-1,3-benzodioxol-4-yl]-1-ethanamine; (1R)-2-{[tert-butyl(diphenyl)silyl]oxy}-1-[6-(methoxymethoxy)-7-methyl-1,3-benzodioxol-4-yl]ethylamine		C₂₈H₃₅NO₅Si	详情	详情
(XVII)	58616	(2S)-3-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylphenyl]-2-[(tert-butoxycarbonyl)amino]propanoic acid		C₂₃H₂₈INO₆	详情	详情
(XVIII)	58617	4-methoxy-N-methyleneaniline; N-(4-methoxyphenyl)-N-methyleneamine		C₈H₉NO	详情	详情
(XIX)	11974	Acetaldehyde	75-07-0	C₂H₄O	详情	详情
(XX)	58618	tert-butyl (1S)-1-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylbenzyl]-2-{{(1R)-2-{[tert-butyl(diphenyl)silyl]oxy}-1-[6-(methoxymethoxy)-7-methyl-1,3-benzodioxol-4-yl]ethyl}[2-(4-methoxyanilino)-1-methyl-2-oxoethyl]amino}-2-oxoethylcarbamate		C₆₁H₇₂IN₃O₁₂Si	详情	详情
(XXI)	58619	(2R)-2-{{(2S)-3-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylphenyl]-2-[(tert-butoxycarbonyl)amino]propanoyl}[2-(4-methoxyanilino)-1-methyl-2-oxoethyl]amino}-2-[6-(methoxymethoxy)-7-methyl-1,3-benzodioxol-4-yl]ethyl acetate		C₄₇H₅₆IN₃O₁₃	详情	详情
(XXII)	58620	(2R)-2-{{(2S)-2-amino-3-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylphenyl]propanoyl}[2-(4-methoxyanilino)-1-methyl-2-oxoethyl]amino}-2-(6-hydroxy-7-methyl-1,3-benzodioxol-4-yl)ethyl acetate		C₄₀H₄₄IN₃O₁₀	详情	详情
(XXIII)	58621	(2R)-2-{(3S)-3-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylbenzyl]-6-methyl-2,5-dioxopiperazinyl}-2-(6-hydroxy-7-methyl-1,3-benzodioxol-4-yl)ethyl acetate		C₃₃H₃₅IN₂O₉	详情	详情
(XXIV)	58622	tert-butyl (2S)-4-((1R)-2-(acetyloxy)-1-{7-methyl-6-[(methylsulfonyl)oxy]-1,3-benzodioxol-4-yl}ethyl)-2-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylbenzyl]-5-methyl-3,6-dioxo-1-piperazinecarboxylate		C₃₉H₄₅IN₂O₁₃S	详情	详情
(XXV)	58623	tert-butyl (2S)-4-((1R)-2-(acetyloxy)-1-{7-methyl-6-[(methylsulfonyl)oxy]-1,3-benzodioxol-4-yl}ethyl)-2-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylbenzyl]-5-methyl-3-oxo-3,4-dihydro-1(2H)-pyrazinecarboxylate		C₃₉H₄₅IN₂O₁₂S	详情	详情
(XXVI)	58624	tert-butyl (1R,9S)-11-((1R)-2-(acetyloxy)-1-{7-methyl-6-[(methylsulfonyl)oxy]-1,3-benzodioxol-4-yl}ethyl)-3-(benzyloxy)-4-methoxy-5-methyl-12-methylene-10-oxo-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-triene-13-carboxylate		C₃₉H₄₄N₂O₁₂S	详情	详情

Extended Information