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【结 构 式】 
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【分子编号】68425 【品名】(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 【CA登记号】 |
【 分 子 式 】C36H44Br2N4O9 【 分 子 量 】836.575 【元素组成】C 51.69% H 5.30% Br 19.10% N 6.70% O 17.21% |
合成路线1
该中间体在本合成路线中的序号：(I)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 .
| 【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：(I)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) .
| 【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 |
|---|---|---|---|---|---|---|
| (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 |