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【结 构 式】 
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【药物名称】Asunaprevir 【化学名称】N-(tert-Butoxycarbonyl)-3-methyl-L-valyl-4(R)-(7-chloro-4-methoxyisoquinolin-1-yloxy)-N-[1(R)-[N-(cyclopropylsulfonyl)carbamoyl]-2(S)-vinylcyclopropyl]-L-prolinamide 【CA登记号】630420-16-5 【 分 子 式 】C35H46ClN5O9S 【 分 子 量 】748.286 |
【开发单位】Bristol-Myers Squibb Co. (US) 【药理作用】HCV Serine Protease NS3 Inhibitor;Treatment of Hepatitis C Virus |
合成路线1
Condensation of ethyl glycinate hydrochloride (I) with benzaldehyde in the presence of Na2SO4 and Et3N in tert-butyl methyl ether gives ethyl N-benzylideneglycinate (II), which is then cyclocondensed with trans-1,4-dibromo-2-butene (III) by means of t-BuOLi in toluene to yield ethyl 1-amino-2-vinylcyclopropanecarboxylate (IV). Alternatively, condensation of ethyl N-(diphenylmethylene)glycinate (V) also with trans-1,4-dibromo-2-butene (III) by means of t-BuOK in THF affords cyclopropanecarboxylate (IV), which is then N-protected with Boc2O at reflux to generate N-Boc derivative (VI). Enzymatic resolution of the racemate (VI) by means of acalase or savinase (proteases from Bacillus clausii) or esperase (protease from Bacillus halodurans) in DMSO at 40 °C leads to the desired ethyl (1R,2S)-N-Boc-cyclopropanecarboxylate diastereomer (VII). Hydrolysis of ethyl ester (VII) with LiOH in THF/MeOH leads to the carboxylic acid (VIII), which is then coupled with cyclopropanesulfonamide (IX) using CDI and DBU in THF to provide the sulfonamide (X). N-Deprotection of this compound by means of TFA in CH2Cl2 followed by treatment with HCl in Et2O gives amine hydrochloride (XI) .
Cyclopropanesulfonamide (IX) is prepared by amination of 3-chloropropane-1-sulfonyl chloride (XII) with t-BuNH2 in THF to provide N-tert-butyl-3-chloropropane-1-sulfonamide (XIII), which is then cyclocondensed in the presence of BuLi in THF to yield N-tert-butylcyclopropanesulfonamide (XIV). Finally, the tert-butyl group of intermediate (XIV) is removed with TFA, affording cyclopropanesulfonamide (IX), which can also be prepared by direct amination of cyclopropanesulfonyl chloride (XV) with NH3 in THF .
| 【1】 Campbell, J.A., Wang, X.A., Sin, N. et al. (Bristol-Myers Squibb Co.). Hepatitis C virus inhibitors. EP 1505963, EP 2340830, JP 2005533028, KR 2010093140, US 200410659, US 6995174, US 2011311482, WO 200309974. |
| 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) | 68241 | tert-butyl ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate | C14H22N2O5S | 详情 | 详情 | |
| (XV) | 67915 | cyclopropanesulfonyl chloride;Cyclopropylsulfonylchloride;Cyclopropylsulphonyl chloride | 139631-62-2 | C3H5ClO2S | 详情 | 详情 |
| (I) | 68234 | ethyl glycinate hydrochloride；Glycine ethyl ester hydrochloride | 623-33-6 | C4H9NO2.HCl | 详情 | 详情 |
| (II) | 68235 | (E)-ethyl 2-(benzylideneamino)acetate;2-(benzylideneamino)acetic acid ethyl ester；ethyl N-benzylideneglycinate；Benzylideneglycine ethyl ester；N-Benzylideneglycineethyl ester；ethyl(benzylideneamino)acetate | 40682-54-0 | C11H13NO2 | 详情 | 详情 |
| (III) | 18349 | (E)-1,4-dibromo-2-butene；trans-1,4-dibromo-2-butene | 821-06-7 | C4H6Br2 | 详情 | 详情 |
| (IV) | 68236 | ethyl 1-amino-2-vinylcyclopropanecarboxylate | 787548-29-2 | C8H13NO2 | 详情 | 详情 |
| (V) | 68237 | ethyl N-(diphenylmethylene)glycinate；(Benzhydrylideneamino)aceticacid methyl ester;Benzophenoneimine glycine methyl ester;Methyl2-[(diphenylmethylene)amino]acetate;Methyl 3-aza-4,4-diphenylbut-3-enoate;Methyl N-(diphenylmethylene)glycinate;Methyl[(diphenylmethylene)amino]acetate;N-(Diphenylmethylene)glycine methyl ester;N-Diphenylmethylideneglycine methyl ester | 81167-39-7 | C16H15NO2 | 详情 | 详情 |
| (VI) | 68238 | ethyl 1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylate | 681807-59-0 | C13H21NO4 | 详情 | 详情 |
| (VII) | 68239 | ethyl (1R,2S)－1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylate | 213316-49-5 | C13H21NO4 | 详情 | 详情 |
| (VIII) | 68240 | (1R,2S)-1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylic acid | 213316-50-8 | C11H17NO4 | 详情 | 详情 |
| (IX) | 68242 | cyclopropanesulfonamide；Cyclopropanesulfonyl amide | 154350-29-5 | C3H7NO2S | 详情 | 详情 |
| (XI) | 68243 | tert-butyl ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate hydrochloride | C14H22N2O5S.HCl | 详情 | 详情 | |
| (XII) | 39225 | g-Chloropropanesulfonyl chloride;3-Chloropropansulfonyl chloride;1-Chloro-3-propanesulfonylchloride;3-Chloropropanesulfonyl chloride;3-chloro-1-propanesulfonyl chloride;3-chloropropane-1-sulfonyl chloride | 1633-82-5 | C3H6Cl2O2S | 详情 | 详情 |
| (XIII) | 68244 | N-tert-butyl-(3-chloro)propylsulfonamide;N-tert-butyl-3-chloropropane-1-sulfonamide;3-Chloro-N-(1,1-dimethylethyl)-1-propanesulfonamide;1-Propanesulfonamide,3-chloro-N-(1,1-dimethylethyl)- | 63132-85-4 | C7H16ClNO2S | 详情 | 详情 |
| (XIV) | 68245 | N-(tert-butyl)cyclopropanesulfonamide;N-tert-butylcyclopropanesulfonamide;N-(tert-butyl)cyclopropanesulfonamide | C7H15NO2S | 详情 | 详情 |
合成路线2
Coupling of primary amine (XI) with 1-(tert-butoxycarbonyl)-4(R)-hydroxy-L-proline (XVI) by means of HATU and DIEA in CH2Cl2 gives dipeptide (XVII), which is treated with TFA in CH2Cl2 to provide the deprotected dipeptide (XVIII). Condensation of peptide (XVIII) with N-(tert-butoxycarbonyl)-3-methyl-L-valine (XIX) using HATU and DIEA in CH2Cl2 affords tripeptide (XX), which is finally condensed with 1,7-dichloro-4-methoxyisoquinoline (XXI) in the presence of LaCl3 and t-BuOK in DMF (1).
1,7-Dichloro-4-methoxyisoquinoline (XXI) is obtained by cyclization of 3-(4-chlorophenyl)-3-methoxyacrylic acid (XXII) with (PhO)2PON3 by means of of Et3N in benzene, resulting in 7-chloro-4-methoxyisoquinolin-1(2H)-one (XXIII), which is then chlorinated with POCl3 in refluxing DMF .
| 【1】 Campbell, J.A., Wang, X.A., Sin, N. et al. (Bristol-Myers Squibb Co.). Hepatitis C virus inhibitors. EP 1505963, EP 2340830, JP 2005533028, KR 2010093140, US 200410659, US 6995174, US 2011311482, WO 200309974. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 68243 | tert-butyl ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate hydrochloride | C14H22N2O5S.HCl | 详情 | 详情 | |
| (XVI) | 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 |
| (XVII) | 68248 | (2S,4R)-tert-butyl 2-(((1S,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate | C19H29N3O7S | 详情 | 详情 | |
| (XVIII) | 68247 | (2S,4R)-N-((1S,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-4-hydroxypyrrolidine-2-carboxamide 2,2,2-trifluoroacetate | C14H21N3O5S.C2HF3O2 | 详情 | 详情 | |
| (XIX) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (XX) | 68246 | tert-butyl (1-((2S,4R)-2-(((1S,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate | C25H40N4O8S | 详情 | 详情 | |
| (XXI) | 68249 | 1,7-dichloro-4-methoxyisoquinoline | C10H7Cl2NO | 详情 | 详情 | |
| (XXII) | 68250 | 3-(4-chlorophenyl)-3-methoxyacrylic acid | C10H9ClO3 | 详情 | 详情 | |
| (XXIII) | 68251 | 7-chloro-4-methoxyisoquinolin-1(2H)-one | C10H8ClNO2 | 详情 | 详情 |
合成路线3
Alternatively, condensation of 1,7-dichloro-4-methoxyisoquinoline (XXI) with 1-(tert-butoxycarbonyl)-4(R)-hydroxy-L-proline (XVI) in the presence of t-BuOK in DMSO gives 1-(tert-butoxycarbonyl)-4(R)-[(7-chloro-4-methoxyisoquinolin-1-yl)oxy]-L-proline (XXIV), which is then coupled with 1(R)-amino-2(S)-vinylcyclopropanecarboxamide (XI) by means of EDC, HOBt and DIEA , or HATU and DIEA in CH2Cl2 , to yield the corresponding dipeptide derivative (XXV). NBoc cleavage by means of HCl in i-PrOH (1) or refluxing MeOH provides amine hydrochloride (XXVI), which is finally condensed with N-(tert-butoxycarbonyl)-3-methyl-L-valine (XIX) using HATU and DIEA in .
| 【1】 Perrone, R.K., Wang, C., Ying, W., Song, A.I. (Bristol-Myers Squibb Co.).Crystalline forms of N-(tert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-((7-cholor-4-methoxy-1-isoquino linyl)oxy)-N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-L-prolinamide. CN 101903371, EP 2231639, JP 2011507869, KR 2010099703, WO 2009085659. |
| 【2】 Sun, L.Q., Wang, A.X., Chen, J. et al. Design and optimization of a series of potent and novel HCV NS3 protease inhibitors leading to the discovery of BMS-650032. 241st ACS Natl Meet (March 27-30, Anaheim) 2011, Abst MEDI 73. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 68243 | tert-butyl ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate hydrochloride | C14H22N2O5S.HCl | 详情 | 详情 | |
| (XVI) | 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 |
| (XIX) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (XXI) | 68249 | 1,7-dichloro-4-methoxyisoquinoline | C10H7Cl2NO | 详情 | 详情 | |
| (XXIV) | 68254 | 1-(tert-butoxycarbonyl)-4(R)-[(7-chloro-4-methoxyisoquinolin-1-yl)oxy]-L-proline;(2S,4R)-1-(tert-butoxycarbonyl)-4-((7-chloro-4-methoxyisoquinolin-1-yl)oxy)pyrrolidine-2-carboxylic acid | C20H23ClN2O6 | 详情 | 详情 | |
| (XXV) | 68253 | (2S,4R)-tert-butyl 4-((7-chloro-4-methoxyisoquinolin-1-yl)oxy)-2-(((1S,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidine-1-carboxylate | C29H35ClN4O8S | 详情 | 详情 | |
| (XXVI) | 68252 | (2S,4R)-4-((7-chloro-4-methoxyisoquinolin-1-yl)oxy)-N-((1S,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)pyrrolidine-2-carboxamide hydrochloride | C24H27ClN4O6S.HCl | 详情 | 详情 |