methyl 8-bromo-4-hydroxy-7-methoxyquinoline-2-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】68434

【品名】methyl 8-bromo-4-hydroxy-7-methoxyquinoline-2-carboxylate

【CA登记号】　

【分子式】C₁₂H₁₀BrNO₄

【分子量】312.12

【元素组成】C 46.18% H 3.23% Br 25.60% N 4.49% O 20.50%

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：(X)

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：(X)

Sandmeyer reaction of 2-amino-3-nitrophenol (XXVI) using NaNO2 and HBr in the presence of CuBr in H2O/dioxane gives 2-bromo-3-nitrophenol (XXVII), which by O-alkylation with MeI in the presence of Cs2CO3 in DMF affords the methyl ether (XXVIII). Subsequent reduction of the nitro derivative (XXVIII) with Fe powder in refluxing AcOH/EtOH provides 2-bromo-3-methoxyaniline (XXIX) . Addition of aniline (XXIX) to dimethyl acetylene dicarboxylate (XXX) in refluxing MeOH produces the amino diester (XXXI), which by cyclization at 240 °C in diphenyl ether affords the quinoline (X) .

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	CAS号	分子式	供应商	用于合成
(X)	68434	methyl 8-bromo-4-hydroxy-7-methoxyquinoline-2-carboxylate		C₁₂H₁₀BrNO₄	详情	详情
(XXVI)	41985	2-amino-3-nitrophenol	603-85-0	C₆H₆N₂O₃	详情	详情
(XXVII)	68448	2-bromo-3-nitrophenol	101935-40-4	C₆H₄BrNO₃	详情	详情
(XXVIII)	68449	2-bromo-1-methoxy-3-nitrobenzene;2-Bromo-3-nitroanisole	67853-37-6	C₇H₆BrNO₃	详情	详情
(XXIX)	68451	2-bromo-3-methoxyaniline		C₇H₈BrNO	详情	详情
(XXX)	24551	Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester	762-42-5	C₆H₆O₄	详情	详情
(XXXI)	68450	dimethyl 2-((2-bromo-3-methoxyphenyl)amino)maleate		C₁₃H₁₄BrNO₅	详情	详情

Extended Information