(1S,2R)-methyl 1-((2R,4R)-1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】68436

【品名】(1S,2R)-methyl 1-((2R,4R)-1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate

【CA登记号】　

【分子式】C₂₄H₃₇N₃O₇

【分子量】479.5738

【元素组成】C 60.11% H 7.78% N 8.76% O 23.35%

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：(VIII)

Alcohol (VIII) is converted to the corresponding brosylate (IX) by treatment with p-bromobenzenesulfonyl chloride in the presence of DMAP and Et3N in CH2Cl2 . Subsequent displacement of the sulfonate group of compound (IX) with the quinolinol (X) in the presence of Cs2CO3 in NMP affords the ether adduct (XI) . Selective hydrolysis of diester (XI) by means of NaOH in THF/H2O generates the sodium salt (XII), which, after conversion to a mixed anhydride with i-BuOCOCl and Et3N in THF, is treated in situ with CH2N2 to give the diazoketone (XIII). Finally, reaction of diazoketone (XIII) with concentrated HBr in THF yields the α-bromoketone (I) .

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】 Llinas-Brunet, M., Bailey, M., Bhardwaj, P. et al. (Boehringer Ingelheim International GmbH & Co. KG). Hepatitis C inhibitor compounds. US 7585845.
【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.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(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
(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
(IX)	68435	(1S,2R)-methyl 1-((2R,4R)-4-(((4-bromophenyl)sulfonyl)oxy)-1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate	C₃₀H₄₀BrN₃O₉S	详情	详情
(X)	68434	methyl 8-bromo-4-hydroxy-7-methoxyquinoline-2-carboxylate	C₁₂H₁₀BrNO₄	详情	详情
(XI)	68433	methyl 8-bromo-4-(((3S,5R)-1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)-5-(((1S,2R)-1-(methoxycarbonyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-3-yl)oxy)-7-methoxyquinoline-2-carboxylate	C₃₆H₄₅BrN₄O₁₀	详情	详情
(XII)	68432	sodium 8-bromo-4-(((3S,5R)-1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)-5-(((1S,2R)-1-(methoxycarbonyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-3-yl)oxy)-7-methoxyquinoline-2-carboxylate	C₃₅H₄₂BrN₄NaO₁₀	详情	详情
(XIII)	68431	(1S,2R)-methyl 1-((2R,4S)-4-((8-bromo-2-(2-diazoacetyl)-7-methoxyquinolin-4-yl)oxy)-1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate	C₃₆H₄₃BrN₆O₉	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

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

Extended Information