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【结 构 式】 
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【药物名称】BI-201335 【化学名称】N-(Cyclopentyloxycarbonyl)-3-methyl-L-valyl-4(R)-[8-bromo-2-[2-(isobutyrylamino)thiazol-4-yl]-7-methoxyquinolin-4-yloxy]-N-[1(R)-carboxy-2(S)-vinylcyclopropyl]-L-prolinamide 【CA登记号】 【 分 子 式 】C40H49BrN6O9S 【 分 子 量 】869.821 |
【开发单位】Boehringer Ingelheim Pharma GmbH & Co. KG (DE) 【药理作用】Treatment of Hepatitis C Virus;Serine Protease NS3/Non-Structural Protein 4A (NS4A) Inhibitor |
合成路线1
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
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 |
合成路线3
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) .
| 【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4
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) .
| 【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 | 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 | |
| (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 |
合成路线5
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) .
| 【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 |
合成路线6
ortho-Metalation of N-Boc-m-anisidine (XXXII) with BuLi in cold THF, followed by bromination with perfluorooctyl bromide, gives N-Boc-2-bromo-3-methoxyaniline (XXXIII), which by Boc group cleavage with HCl in diglyme at 100 °C provides 2-bromo-3-methoxyaniline hydrochloride (XXXIV). Friedel–Crafts acylation of bromoanisidine (XXXIV) with acetonitrile (XXXV) in the presence of BCl3 and AlCl3 in chlorobenzene at 100 °C affords 2’-amino-3’-bromo-4’-methoxyacetophenone (XXXVI) , which is then coupled with the acid chloride (XXXVII) [prepared by chlorination of 2-isobutyrylaminothiazole-4-carboxylic acid (XXXVIII) with either (COCl)2 in DMF/THF or SOCl2 in NMP by means of Et3N and DMAP in THF to provide the corresponding carboxamide (XXXIX) . Intramolecular cyclocondensation of the ketoamide (XXXIX) in the presence of either t-BuOK in DME at 80-85 °C or KOH in t-BuOH yields the quinolinol (XL), which is then chlorinated with POCl3 in dioxane at 75 °C to obtain the 4-chloroquinoline derivative (VII) .
| 【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. |
| 【2】 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. |
| 【3】 Patel, N., Senanayake, C.H., Wei, X., Yee, N.K. (Boehringer Ingelheim Pharma GmbH & Co. KG). Process for preparing sulfonyl quinolines. EP 2408768, WO 2010107965. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 68430 | N-(4-(8-bromo-4-chloro-7-methoxyquinolin-2-yl)thiazol-2-yl)isobutyramide | C17H15BrClN3O2S | 详情 | 详情 | |
| (XXXII) | 68452 | tert-butyl (3-methoxyphenyl)carbamate | C12H17NO3 | 详情 | 详情 | |
| (XXXIII) | 68453 | tert-butyl (2-bromo-3-methoxyphenyl)carbamate | C12H16BrNO3 | 详情 | 详情 | |
| (XXXIV) | 68454 | 2-bromo-3-methoxyaniline hydrochloride | C7H8BrNO.HCl | 详情 | 详情 | |
| (XXXV) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (XXXVI) | 68455 | 1-(2-amino-3-bromo-4-methoxyphenyl)ethanone;2’-amino-3’-bromo-4’-methoxyacetophenone | 923289-30-9 | C9H10BrNO2 | 详情 | 详情 |
| (XXXVII) | 68456 | 2-isobutyramidothiazole-4-carbonyl chloride | C8H9ClN2O2S | 详情 | 详情 | |
| (XXXVIII) | 68457 | 2-isobutyramidothiazole-4-carboxylic acid | C8H10N2O3S | 详情 | 详情 | |
| (XXXIX) | 68458 | N-(6-acetyl-2-bromo-3-methoxyphenyl)-2-isobutyramidothiazole-4-carboxamide | C17H18BrN3O4S | 详情 | 详情 | |
| (XL) | 68459 | N-(4-(8-bromo-4-hydroxy-7-methoxyquinolin-2-yl)thiazol-2-yl)isobutyramide | C17H16BrN3O3S | 详情 | 详情 |