(1S,2R)-1-((2R,4S)-1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylic acidtripeptide carbamate -Drug Synthesis Database

【结构式】

【分子编号】68429

【品名】(1S,2R)-1-((2R,4S)-1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylic acidtripeptide carbamate

【CA登记号】　

【分子式】C₂₃H₃₅N₃O₇

【分子量】465.54692

【元素组成】C 59.34% H 7.58% N 9.03% O 24.06%

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：(VI)

Cyclization of the α-bromoketone (I) with N-isobutyrylthiourea (II) in i-PrOH at 75 °C produces the thiazole derivative (III), which upon methyl ester hydrolysis using LiOH in H2O/MeOH/THF gives directly BI-201335 .
In an alternative method, the methyl ester precursor (III) is obtained by condensation of the dipeptide derivative (IV) with methyl 1(R)-amino-2(S)-vinylcyclopropanecarboxylate tosylate salt (Va) by means of EDC, HOBt and DIEA in DMF .
In a different strategy, the tripeptide carbamate (VI) is coupled with the chloroquinoline derivative (VII) by means of t-BuOK in DMSO to afford BI-201335 .

参考文献中间体

合成目标

【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】 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	CAS号	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
(I)	68425	(1S,2R)-methyl 1-((2R,4S)-4-((8-bromo-2-(2-bromoacetyl)-7-methoxyquinolin-4-yl)oxy)-1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate		C₃₆H₄₄Br₂N₄O₉	详情	详情
(II)	68424	N-isobutyrylthiourea;N-(aminothioxomethyl)-2-methyl-Propanamide;Isobutyrylthiourea	6965-58-8	C₅H₁₀N₂OS	详情	详情
(III)	68426	(1S,2R)-methyl 1-((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-carboxamido)-2-vinylcyclopropanecarboxylate		C₄₁H₅₁BrN₆O₉S	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

合成路线2

该中间体在本合成路线中的序号：(VI)

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