2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid;N-(cyclopentyloxycarbonyl)-3-methyl-L-valine -Drug Synthesis Database

【结构式】

【分子编号】68442

【品名】2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid;N-(cyclopentyloxycarbonyl)-3-methyl-L-valine

【CA登记号】　

【分子式】C₁₂H₂₁NO₄

【分子量】243.30308

【元素组成】C 59.24% H 8.7% N 5.76% O 26.3%

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：(XVIII)

Tripeptide derivative (VIII) is obtained by coupling of N-Boc-4(R)-hydroxy-L-proline (XIV) with methyl 1(R)-amino-2(S)-vinylcyclopropanecarboxylate (Vb) by means of TBTU and DIEA in DMF to afford amide (XV). Subsequent Mitsunobu condensation of alcohol (XV) with p-nitrobenzoic acid (PNBA) in the presence of PPh3 and DEAD in THF gives the fully protected dipeptide (XVI), from which the N-Boc group is removed by treatment with HCl in dioxane, yielding the corresponding amine (XVII) . Coupling of dipeptide ester (XVII) with N-(cyclopentyloxycarbonyl)-3-methyl-L-valine (XVIII) [prepared by condensation of cyclopentyl succinimidyl carbonate (XX) with 3-methyl-L-valine (XIX) by means of Et3N in THF/H2O in the presence of TBTU and DIEA in CH2Cl2 provides tripeptide derivative (XXI), which by selective hydrolysis of the PNB ester (XXI) by means of LiOH in H2O/THF produces the tripeptide derivative (VIII) .

参考文献中间体

合成目标

【3】 Bhardwaj, P., Forgione, P., Goudreau, N. et al. (Boehringer Ingelheim International GmbH). Hepatitis C inhibitor compounds. EP 1654261, JP 2006528937, JP 2010043129, US 2005020503, US 2011177030, US 8067438, WO 2004103996.
【1】 Llinas-Brunet, M., Bailey, M.D., Goudreau, N. et al. Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335). J Med Chem 2010, 53(17): 6466-76.
【2】 Llinas-Brunet, M., Bailey, M., Bhardwaj, P. et al. (Boehringer Ingelheim International GmbH & Co. KG). Hepatitis C inhibitor compounds. US 7585845.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Vb)	68460	(1R,2R)-methyl 1-amino-2-vinylcyclopropanecarboxylate		C₇H₁₁NO₂	详情	详情
(VIII)	68436	(1S,2R)-methyl 1-((2R,4R)-1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate		C₂₄H₃₇N₃O₇	详情	详情
(XIV)	16094	(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid;1-(tert-butoxycarbonyl)-4®-hydroxy-L-proline;(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid	16094	C₁₀H₁₇NO₅	详情	详情
(XV)	68440	(4S)-tert-butyl 4-hydroxy-2-(((1R,2S)-1-(methoxycarbonyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidine-1-carboxylate		C₁₇H₂₆N₂O₆	详情	详情
(XVI)	68441	(2S,4R)-tert-butyl 2-(((1R,2S)-1-(methoxycarbonyl)-2-vinylcyclopropyl)carbamoyl)-4-((4-nitrobenzyl)oxy)pyrrolidine-1-carboxylate		C₂₄H₃₁N₃O₈	详情	详情
(XVII)	68439	(1R,2S)-methyl 1-((2R,4R)-4-((4-nitrobenzyl)oxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate hydrochloride		C₁₉H₂₃N₃O₆.HCl	详情	详情
(XVIII)	68442	2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid;N-(cyclopentyloxycarbonyl)-3-methyl-L-valine		C₁₂H₂₁NO₄	详情	详情
(XIX)	28445	(2S)-2-amino-3,3-dimethylbutyric acid		C₆H₁₃NO₂	详情	详情
(XX)	68443	cyclopentyl succinimidyl carbonate;N-(Cyclopentyloxycarbonyloxy)succinimide;1-[[(cyclopentyloxy)carbonyl]oxy]-2,5-Pyrrolidinedione	128595-07-3	C₁₀H₁₃NO₅	详情	详情
(XXI)	68437	(1R,2S)-methyl 1-((2S,4R)-1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)-4-((4-nitrobenzyl)oxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate		C₃₁H₄₂N₄O₉	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVIII)

Coupling of 4(R)-hydroxy-L-proline methyl ester hydrochloride (XXII) with N-(cyclopentyloxycarbonyl)-3-methyl-L-valine (XVIII) by means of EDC, HOBt and DIEA in DMF affords the dipeptide derivative (XXIII), which is then subjected to methyl ester hydrolysis with LiOH in H2O/MeOH/THF to yield dipeptide carbamate (XXIV) (isolated as solvate with MTBE). Subsequent condensation of compound (XXIV) with the chloroquinoline (VII) using t-BuOK in DMSO gives rise to the key intermediate (IV) .
Coupling of the dipeptide carbamate (XXIV) with methyl 1(R)-amino-2(S)-vinylcyclopropanecarboxylate tosylate salt (Va) by means of EDC, HOBt and DIEA in DMF leads to the tripeptide ester (XXV), which by hydrolysis with LiOH in H2O/MeOH/THF provides the carboxylic acid intermediate (VI) .

参考文献中间体

合成目标

【1】 Berkenbusch, T., Busacca, C.A., Jaeger, B., Varsolona, R.J. (Boehringer Ingelheim Pharma GmbH & Co. KG). Crystalline forms of a 2-thiazolyl-4-quinolinyl-oxy derivative, a potent HCV inhibitor. CN 102159571, EP 2331538, JP 2012502910, KR 2011059841, US 2010093792, WO 2010033444.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(Va)	68428	methyl 1(R)-amino-2(S)- vinylcyclopropanecarboxylate tosylate salt;(1R,2S)-methyl 1-amino-2-vinylcyclopropanecarboxylate 4-methylbenzenesulfonate	C₇H₁₁NO₂.C₇H₈O₃S	详情	详情
(IV)	68427	(2R,4S)-4-((8-bromo-2-(2-isobutyramidothiazol-4-yl)-7-methoxyquinolin-4-yl)oxy)-1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acid	C₃₄H₄₂BrN₅O₈S	详情	详情
(VI)	68429	(1S,2R)-1-((2R,4S)-1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylic acidtripeptide carbamate	C₂₃H₃₅N₃O₇	详情	详情
(VII)	68430	N-(4-(8-bromo-4-chloro-7-methoxyquinolin-2-yl)thiazol-2-yl)isobutyramide	C₁₇H₁₅BrClN₃O₂S	详情	详情
(XVIII)	68442	2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid;N-(cyclopentyloxycarbonyl)-3-methyl-L-valine	C₁₂H₂₁NO₄	详情	详情
(XXII)	68444	4(R)-hydroxy-L-proline methyl ester hydrochloride;(2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride	C₆H₁₁NO₃.HCl	详情	详情
(XXIII)	68447	(2S,4R)-methyl 1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate	C₁₈H₃₀N₂O₆	详情	详情
(XXIV)	68446	(2S,4R)-1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid	C₁₇H₂₈N₂O₆	详情	详情
(XXV)	68445	(1R,2S)-methyl 1-((2S,4R)-1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate	C₂₄H₃₇N₃O₇	详情	详情

Extended Information