tert-butyl (1S)-2-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-1-formylethylcarbamate -Drug Synthesis Database

【结构式】

【分子编号】32119

【品名】tert-butyl (1S)-2-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-1-formylethylcarbamate

【CA登记号】

【分子式】C₂₁H₃₀N₂O₆

【分子量】406.47908

【元素组成】C 62.05% H 7.44% N 6.89% O 23.62%

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：(XXIV)

Pyrrolidinone (XXVI): The selective hydrolysis of the known methyl ester (XIV) with NaOH in methanol/water gives the corresponding carboxylic acid (XV), which is coupled with the chiral oxazolidinone (XVI) by means of pivaloyl chloride and Et3N in THF to yield the amide (XVII). The regiocontrolled alkylation of (XVII) with allyl iodide and NaN(SiMe3)2 in THF affords the allyl derivative (XVIII), which is submitted to ozonolysis in dichloromethane to provide the aldehyde (XIX). The condensation of (XIX) with 2,4-dimethoxybenzylamine (XX) yields imine (XXI), which by a reductive cyclization with NaBH3CN in THF/EtOH affords pyrrolidinone (XXII). Cleavage of the oxazolidine ring of (XXII) with TsOH in hot methanol gives the amino alcohol (XXIII), which is oxidized with oxalyl chloride in DMSO to the aldehyde (XXIV). Finally, this compound is condensed with triethyl phosphonoacetate (XXV) by means of NaN(SiMe3)2 in THF to provide the desired pyrrolidinone (XXVI).

参考文献中间体

合成目标

【1】 Dragovich, P.S.; Prins, T.J.; Zhou, R.; et al.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements. J Med Chem 1999, 42, 7, 1213.
【2】 Graul, A.; Castañer, J.; AG-7088. Drugs Fut 2000, 25, 1, 9.
【3】 Meyer, M.D.; Daanen, J.F.; Ehrlich, P.P.; Ralston, J.W. (Abbott Laboratories Inc.); 3-Phenylpyrrole alpha-1 adrenergic cpds.. WO 9957122 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	32112	3-iodo-1-propene;3-iodo-propen;allyl iodide	556-56-9	C₃H₅I	详情	详情
(XIV)	32109	tert-butyl (4S)-4-(3-methoxy-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate		C₁₄H₂₅NO₅	详情	详情
(XV)	32110	3-[(4S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidin-4-yl]propionic acid		C₁₃H₂₃NO₅	详情	详情
(XVI)	14694	(S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone	90719-32-7	C₁₀H₁₁NO₂	详情	详情
(XVII)	32111	tert-butyl (4S)-4-[3-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate		C₂₃H₃₂N₂O₆	详情	详情
(XVIII)	32113	tert-butyl (4S)-4-((2S)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-pentenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate		C₂₆H₃₆N₂O₆	详情	详情
(XIX)	32114	tert-butyl (4S)-4-((2R)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-oxobutyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate		C₂₅H₃₄N₂O₇	详情	详情
(XX)	32115	(2,4-dimethoxyphenyl)methanamine; 2,4-dimethoxybenzylamine	20781-21-9	C₉H₁₃NO₂	详情	详情
(XXI)	32116	tert-butyl (4S)-4-[(2R)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-[(2,4-dimethoxybenzyl)imino]butyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate		C₃₄H₄₅N₃O₈	详情	详情
(XXII)	32117	tert-butyl (4S)-4-[[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate		C₂₄H₃₆N₂O₆	详情	详情
(XXIII)	32118	tert-butyl (1S)-2-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-1-(hydroxymethyl)ethylcarbamate		C₂₁H₃₂N₂O₆	详情	详情
(XXIV)	32119	tert-butyl (1S)-2-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-1-formylethylcarbamate		C₂₁H₃₀N₂O₆	详情	详情
(XXV)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(XXVI)	32105	ethyl (E,4S)-4-[(tert-butoxycarbonyl)amino]-5-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-2-pentenoate		C₂₅H₃₆N₂O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Oxidation of aldehyde (I) by means of sodium chlorite gave carboxylic acid (II), which was converted to the corresponding Weinreb amide (III) via activation with isobutyl chloroformate and N-methylmorpholine. Subsequent condensation of (III) with 2-lithiobenzothiazole (IV) in cold THF formed the benzothiazolyl ketone (V). In order to minimize racemization, ketone (V) was reduced to alcohol (VI) using NaBH4. After deprotection of the Boc group of (VI) with HCl in dioxan, the resulting amino alcohol (VII) was coupled with the protected dipeptide (VIII) to furnish (IX). Further acid deprotection of the Boc group of (IX) afforded amine (X).

参考文献中间体

合成目标

【1】 Zhou, R.; Dragovich, P.S.; Webber, S.E.; et al.; Structure-based design of ketone-containing, tripeptidyl human rhinovirus 3C protease inhibitors. Bioorg Med Chem Lett 2000, 10, 1, 45.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	32119	tert-butyl (1S)-2-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-1-formylethylcarbamate	C₂₁H₃₀N₂O₆	详情	详情
(II)	36592	(2S)-2-[(tert-butoxycarbonyl)amino]-3-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]propionic acid	C₂₁H₃₀N₂O₇	详情	详情
(III)	36593	tert-butyl (1S)-1-[[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]methyl]-2-[methoxy(methyl)amino]-2-oxoethylcarbamate	C₂₃H₃₅N₃O₇	详情	详情
(IV)	36594	1,3-benzothiazol-2-yllithium	C₇H₄LiNS	详情	详情
(V)	36595	tert-butyl (1S)-2-(1,3-benzothiazol-2-yl)-1-[[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]methyl]-2-oxoethylcarbamate	C₂₈H₃₃N₃O₆S	详情	详情
(VI)	36596	tert-butyl (1S)-2-(1,3-benzothiazol-2-yl)-1-[[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]methyl]-2-hydroxyethylcarbamate	C₂₈H₃₅N₃O₆S	详情	详情
(VII)	36597	(3S)-3-[(2S)-2-amino-3-(1,3-benzothiazol-2-yl)-3-hydroxypropyl]-1-(2,4-dimethoxybenzyl)-2-pyrrolidinone	C₂₃H₂₇N₃O₄S	详情	详情
(VIII)	36598	(2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(4-fluorophenyl)propionic acid	C₁₉H₂₇FN₂O₅	详情	详情
(IX)	36599	tert-butyl (1S)-1-([[(1S)-2-[((1S)-2-(1,3-benzothiazol-2-yl)-1-[[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]methyl]-2-hydroxyethyl)amino]-1-(4-fluorobenzyl)-2-oxoethyl]amino]carbonyl)-2-methylpropylcarbamate	C₄₂H₅₂FN₅O₈S	详情	详情
(X)	36600	(2S)-2-amino-N-[(1S)-2-[((1S)-2-(1,3-benzothiazol-2-yl)-1-[[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]methyl]-2-hydroxyethyl)amino]-1-(4-fluorobenzyl)-2-oxoethyl]-3-methylbutanamide	C₃₇H₄₄FN₅O₆S	详情	详情

Extended Information