-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】N-[1(S)-[N-[1(S)-[N-[1(S)-(1,3-Benzothiazol-2-yl)carbonyl-2-[2-oxopyrrolidin-3(S)-yl]ethyl]carbamoyl]-2-(4-fluorophenyl)ethyl]carbamoyl]-2-methylpropyl]-5-methylisoxazole-3-carboxamide

【CA登记号】

【分子式】C₃₃H₃₅FN₆O₆S

【分子量】662.7459

【开发单位】Agouron (Originator)

【药理作用】ANTIINFECTIVE THERAPY, Anti-Rhinovirus Drugs, Antiviral Drugs, HRV 3C Protease Inhibitors

合成路线1 合成路线2

合成路线1

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

【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

合成路线2

The coupling of (X) with 5-methylisoxazole-3-carbonyl chloride (XI), yielded amide (XII). The alcohol group of (XII) was then oxidized to ketone (XIV) employing Dess-Martin periodinane (XIII). Finally, the 2,4-dimethoxybenzyl group (DMB) of (XIV) was cleaved by treatment with DDQ in hot acetonitrile.

参考文献中间体

【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	CAS号	分子式	供应商	用于合成
(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
(XI)	32107	5-methyl-3-isoxazolecarbonyl chloride		C₅H₄ClNO₂	详情	详情
(XII)	36601	N-[(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-methylpropyl]-5-methyl-3-isoxazolecarboxamide		C₄₂H₄₇FN₆O₈S	详情	详情
(XIII)	18845	Dess-Martin periodinane; 1,1,1-Triacetoxy-1,2-benziodoxol-3(1H)-one	87413-09-0	C₁₃H₁₃IO₈	详情	详情
(XIV)	36602	N-[(1S)-1-([[(1S)-2-[((1S)-2-(1,3-benzothiazol-2-yl)-1-[[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]methyl]-2-oxoethyl)amino]-1-(4-fluorobenzyl)-2-oxoethyl]amino]carbonyl)-2-methylpropyl]-5-methyl-3-isoxazolecarboxamide		C₄₂H₄₅FN₆O₈S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)