methyl 2-[(tert-butoxycarbonyl)amino]-2-(dimethoxyphosphoryl)acetate -Drug Synthesis Database

【结构式】

【分子编号】34562

【品名】methyl 2-[(tert-butoxycarbonyl)amino]-2-(dimethoxyphosphoryl)acetate

【CA登记号】

【分子式】C₁₀H₂₀NO₇P

【分子量】297.245102

【元素组成】C 40.41% H 6.78% N 4.71% O 37.68% P 10.42%

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：(XIV)

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：(II)

The condensation of 1-(benzyloxycarbonyl)piperidin-4-one with N-(tert-butoxycarbonyl)-2-phosphonoglycine trimethyl ester (II) by means of DBU in dichloromethane gives 2-[1-(benzyloxycarbonyl)piperidin-4-ylidene]-N-(tert-butoxycarbonyl)glycine methyl ester (III), which is selectively deprotected and reduced by hydrogenation with H2 over Pd/C in methanol yielding N-(tert-butoxycarbonyl)-2-(4-piperidyl)glycine methyl ester (IV). The reaction of (IV) with N,N'-di(tert-butoxycarbonyl)pyrazole-1-carboxamidine (V) by means of DIEA in dichloromethane gives the protected piperidine-1-carboxamidine (VI), which is treated with LiOH in methanol/water to obtain (VII) with a free carboxy group. The reaction of (VII) with O,N-dimethylhydroxylamine affords the hydroxamic ester (VIII), which is condensed with thiazole (IX) by means of butyllithium in THF yielding the fully protected intermediate (X). The deprotection of (X) with HCl in dioxane gives (XI) with free amino and amidino groups. The conddensation of (XI) with chiral acid (XII) by means of BOP and DIEA in acetonitrile yields amide (XIII) as a diastereomeric mixture that is resolved by preparative reverse-phase HPLC.

参考文献中间体

合成目标

【1】 Plummer, J.S.; Berryman, K.A.; Cai, C.; Cody, W.L.; DiMaio, J.; Doherty, A.M.; Edmunds, J.J.; He, J.X.; Holland, D.R.; Levesque, S.; Kent, D.R.; Narasimhan, L.S.; Rubin, J.R.; Rapundalo, S.T.; Siddiqui, M.A.; Susser, A.J.; St-Denis, Y.; Winocour, P.D.; Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications. Bioorg Med Chem Lett 1998, 8, 23, 3409.

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)	26947	benzyl 4-oxo-1-piperidinecarboxylate; N-Benzyloxycarbonyl-4-piperidone	19099-93-5	C₁₃H₁₅NO₃	详情	详情
(II)	34562	methyl 2-[(tert-butoxycarbonyl)amino]-2-(dimethoxyphosphoryl)acetate		C₁₀H₂₀NO₇P	详情	详情
(III)	34563	benzyl 4-[1-[(tert-butoxycarbonyl)amino]-2-methoxy-2-oxoethylidene]-1-piperidinecarboxylate		C₂₁H₂₈N₂O₆	详情	详情
(IV)	34564	methyl 2-[(tert-butoxycarbonyl)amino]-2-(4-piperidinyl)acetate		C₁₃H₂₄N₂O₄	详情	详情
(V)	29482	N,N-bis-Boc-1-guanylpyrazole; tert-butyl (E)-[(tert-butoxycarbonyl)amino](1H-pyrazol-1-yl)methylidenecarbamate	152120-54-2	C₁₄H₂₂N₄O₄	详情	详情
(VI)	34565	methyl 2-[(tert-butoxycarbonyl)amino]-2-(1-[[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl]-4-piperidinyl)acetate		C₂₄H₄₂N₄O₈	详情	详情
(VII)	34566	2-[(tert-butoxycarbonyl)amino]-2-(1-[[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl]-4-piperidinyl)acetic acid		C₂₃H₄₀N₄O₈	详情	详情
(VIII)	34567	tert-butyl (Z)-[(tert-butoxycarbonyl)amino](4-[1-[(tert-butoxycarbonyl)amino]-2-[methoxy(methyl)amino]-2-oxoethyl]-1-piperidinyl)methylidenecarbamate		C₂₅H₄₅N₅O₈	详情	详情
(IX)	23000	1,3-thiazole	288-47-1	C₃H₃NS	详情	详情
(X)	34568	tert-butyl (Z)-[(tert-butoxycarbonyl)amino][4-[1-[(tert-butoxycarbonyl)amino]-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1-piperidinyl]methylidenecarbamate		C₂₆H₄₁N₅O₇S	详情	详情
(XI)	34569	4-[1-amino-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1-piperidinecarboximidamide		C₁₁H₁₇N₅OS	详情	详情
(XII)	34570	(6S,8aS)-4-oxo-2-(3-phenylpropanoyl)octahydropyrrolo[1,2-a]pyrazine-6-carboxylic acid		C₁₇H₂₀N₂O₄	详情	详情
(XIII)	34571	(6S,8aS)-N-[1-[1-[amino(imino)methyl]-4-piperidinyl]-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-4-oxo-2-(3-phenylpropanoyl)octahydropyrrolo[1,2-a]pyrazine-6-carboxamide		C₂₈H₃₅N₇O₄S	详情	详情

Extended Information