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【结 构 式】 
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【分子编号】67764 【品名】(E)-butyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate dihydrochloride 【CA登记号】 |
【 分 子 式 】C19H25N3O2.2HCl 【 分 子 量 】400.348 【元素组成】C 57.00% H 6.80% Cl 17.71% N 10.50% O 7.99% |
合成路线1
该中间体在本合成路线中的序号：(II)Chlorination of carboxylic acid (I) with SOCl2 in the presence of NMP in THF/toluene, followed by condensation of the resulting acid chloride with the amine HCl (II) or its free base using DIEA in THF, provides the carboxamide (IVa) . Alternatively, condensation of carboxylic acid (I) with the amino esters (IIIa) or (IIIb) by means of HATU and Et3N or DIEA in DMSO affords the corresponding carboxamides (IVb) or (IVc) . Finally, butyl (IVa) ,methyl (IVb) or ethyl (IVc) esters are hydrolyzed with aqueous NaOH in THF/MeOH at 67 °C or DMSO , and then treated with aqueous NaOH in THF .
| 【1】 Boecher, W., Haefner, C., Kukolj, G. (Boehringer Ingelheim Pharma GmbH & Co. KG). Combination therapy for treating HCV infection. CN 103228278, EP 2621495, JP 2013540112, KR 2013116245, US 2012135949, WO 2012041771. |
| 【2】 Brickl, R.-S., Chen, S., Chung, J. et al. (Boehringer Ingelheim Pharma GmbH & Co. KG). Solid state forms of a potent HCV inhibitor. CN 103153987, EP 2621921, JP 2013543495, KR 2013108326, US 2012122887, US 8598183, US 2014057928, WO 2012044520. 3. Mensa, F., Nehmiz, G. (Boehringer Ingelheim Pharma GmbH & Co. KG). Oral combination therapy for treating HCV infection in specific patient subgenotype populations. WO 2013147749. |
| 【3】 Mensa, F. (Boehringer Ingelheim Pharma GmbH & Co. KG). Oral combination therapy for treating HCV infection in specific patient sub-population. WO 2013147750. |
| 【4】 LaPlante, S.R., Boes, M., Brochu, C. et al. Conformation-based restrictions and scaffold replacements in the design of hepatitis C virus polymerase inhibitors. Discovery of deleobuvir (BI 207127). J Med Chem 2014, 57(5): 1845-54. |
| 【5】 Mensa, F., Nehmiz, G. (Boehringer Ingelheim Pharma GmbH & Co. KG). Oral combination therapy for treating HCV infection in specific patient subgenotype populations. WO 2013147749. |
| 【6】 Tsantrizos, Y.S., Chabot, C., Beaulieu, P. et al. (Boehringer Ingelheim Pharma GmbH & Co. KG). Viral polymerase inhibitors. CN 102911161, CN 103304541, CN 103319464, CN 103333162, EP 1718608, EP 2626354, JP 2007523094, JP 2010195818, JP 2010280740, KR 2012091276, US 2005222236, US 8030309, WO 2005080388. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 67765 | (E)-methyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate | C16H19N3O2 | 详情 | 详情 | |
| (IIIb) | 67766 | (E)-ethyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate | C17H21N3O2 | 详情 | 详情 | |
| (IVa) | 67769 | (E)-butyl 3-(2-(1-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido)cyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate | C38H41BrN6O3 | 详情 | 详情 | |
| (IVb) | 67768 | (E)-methyl 3-(2-(1-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido)cyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate | C35H35BrN6O3 | 详情 | 详情 | |
| (IVc) | 67767 | (E)-ethyl 3-(2-(1-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido)cyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate | C36H37BrN6O3 | 详情 | 详情 | |
| (I) | 67763 | 2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxylic acid | C19H18BrN3O2 | 详情 | 详情 | |
| (II) | 67764 | (E)-butyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate dihydrochloride | C19H25N3O2.2HCl | 详情 | 详情 | |
| (V) | 67770 | (E)-3-(2-(1-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido)cyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylic acid | C34H33BrN6O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Jones oxidation of 2-fluoro-4-methyl-1-nitrobenzene (XVIII) with CrO3 and H2SO4, followed by acetylation with Ac2O in AcOH yields the gemdiacetate (XIX), which by deacetylation with HCl in AcOH at 115 °C provides 3-fluoro-4-nitrobenzaldehyde (XX). Horner-Wadsworth-Emmons reaction of aldehyde (XX) with ethyl (diethoxyphosphoryl)acetate (XXI) using NaH in THF affords the unsaturated ester (XXII), which by fluoride substitution with methylamine (XXIII) in DMSO provides the nitro-aniline derivative (XXIVa) . Alternatively, condensation of 2,4-dichloro-1-nitrobenzene (XXV) with methylamine (XXIII) using Et3N in DMSO or THF yields 5-chloro-N-methyl-2-nitroaniline (XXVI), which is then subjected to Heck coupling with ethyl acrylate (XXVIIa), methyl acrylate (XXVIIb) or butyl acrylate (XXVIIa) in the presence of Pd(OAc)2, LiCl and DIEA in DMAc at 110 °C , or Pd2dba3, t-Bu3P and (c-Hex)2NMe at 110 °C to give the corresponding arylacrylates (XXIVa), (XXIVb) or (XXIVc). Reduction of the nitro group in compounds (XXIVa), (XXIVb) or (XXIVc) by means of SnCl2.2H2O in EtOH at 80 °C , H2 over Raney-Ni in toluene/MeOH or Na2S2O4 and K2CO3 in EtOH/H2O produces the corresponding diaminophenylacrylates (XXVIIIa) , (XXVIIIb) or (XXVIIIc) , which are finally condensed with 1-aminocyclo-butanecarboxylic acid hydrochloride (XXIX) in CH2Cl2 to provide the benzimidazole intermediates (IIIa) , (IIIb) or (XXX), the free base of intermediate (II) .
Similarly, intermediate (II) can be obtained by condensation of the diaminophenylacrylate (XXVIIIc) with N-Boc-1-aminocyclobutanecarboxylic acid (XXXI) using DCC in toluene, followed by N-deprotection and cyclization of the resulting amino amide (XXXII) with HCl in BuOH at 75 °C .
| 【1】 Boecher, W., Haefner, C., Kukolj, G. (Boehringer Ingelheim Pharma GmbH & Co. KG). Combination therapy for treating HCV infection. CN 103228278, EP 2621495, JP 2013540112, KR 2013116245, US 2012135949, WO 2012041771. |
| 【2】 Brickl, R.-S., Chen, S., Chung, J. et al. (Boehringer Ingelheim Pharma GmbH & Co. KG). Solid state forms of a potent HCV inhibitor. CN 103153987, EP 2621921, JP 2013543495, KR 2013108326, US 2012122887, US 8598183, US 2014057928, WO 2012044520. |
| 【3】 Mensa, F., Nehmiz, G. (Boehringer Ingelheim Pharma GmbH & Co. KG). Oral combination therapy for treating HCV infection in specific patient subgenotype populations. WO 2013147749. |
| 【4】 Mensa, F. (Boehringer Ingelheim Pharma GmbH & Co. KG). Oral combination therapy for treating HCV infection in specific patient sub-population. WO 2013147750. |
| 【5】 LaPlante, S.R., Boes, M., Brochu, C. et al. Conformation-based restrictions and scaffold replacements in the design of hepatitis C virus polymerase inhibitors. Discovery of deleobuvir (BI 207127). J Med Chem 2014, 57(5): 1845-54. |
| 【6】 Tsantrizos, Y.S., Chabot, C., Beaulieu, P. et al. (Boehringer Ingelheim Pharma GmbH & Co. KG). Viral polymerase inhibitors. CN 102911161, CN 103304541, CN 103319464, CN 103333162, EP 1718608, EP 2626354, JP 2007523094, JP 2010195818, JP 2010280740, KR 2012091276, US 2005222236, US 8030309, WO 2005080388. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIVa) | 67786 | (E)-ethyl 3-(3-(methylamino)-4-nitrophenyl)acrylate | C12H14N2O4 | 详情 | 详情 | |
| (XXIVb) | 67787 | (E)-methyl 3-(3-(methylamino)-4-nitrophenyl)acrylate | C11H12N2O4 | 详情 | 详情 | |
| (XXIVc) | 67788 | (E)-butyl 3-(3-(methylamino)-4-nitrophenyl)acrylate | C14H18N2O4 | 详情 | 详情 | |
| (XXVIIa) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (XXVIIb) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (XXVIIc) | 67789 | butyl acrylate | C7H12O2 | 详情 | 详情 | |
| (XXVIIIa) | 67791 | (E)-ethyl 3-(4-amino-3-(methylamino)phenyl)acrylate | C12H16N2O2 | 详情 | 详情 | |
| (XXVIIIb) | 67792 | (E)-methyl 3-(4-amino-3-(methylamino)phenyl)acrylate | C11H14N2O2 | 详情 | 详情 | |
| (XXVIIIc) | 67790 | (E)-butyl 3-(4-amino-3-(methylamino)phenyl)acrylate | C14H20N2O2 | 详情 | 详情 | |
| (IIIa) | 67765 | (E)-methyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate | C16H19N3O2 | 详情 | 详情 | |
| (IIIb) | 67766 | (E)-ethyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate | C17H21N3O2 | 详情 | 详情 | |
| (II) | 67764 | (E)-butyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate dihydrochloride | C19H25N3O2.2HCl | 详情 | 详情 | |
| (XVIII) | 39366 | 2-fluoro-4-methyl-1-nitrobenzene | 446-34-4 | C7H6FNO2 | 详情 | 详情 |
| (XIX) | 67783 | (3-fluoro-4-nitrophenyl)methylene diacetate | C11H10FNO6 | 详情 | 详情 | |
| (XX) | 67784 | 3-fluoro-4-nitrobenzaldehyde | C7H4FNO3 | 详情 | 详情 | |
| (XXI) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (XXII) | 67785 | (E)-ethyl 3-(3-fluoro-4-nitrophenyl)acrylate | C11H10FNO4 | 详情 | 详情 | |
| (XXIII) | 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 |
| (XXV) | 21787 | 2,4-dichloro-1-nitrobenzene | 611-06-3 | C6H3Cl2NO2 | 详情 | 详情 |
| (XXVI) | 46715 | 5-chloro-N-methyl-2-nitroaniline; N-(5-chloro-2-nitrophenyl)-N-methylamine | 35966-84-8 | C7H7ClN2O2 | 详情 | 详情 |
| (XXIX) | 67793 | 1-aminocyclo-butanecarboxylic acid hydrochloride | 98071-16-0 | C5H9NO2.HCl | 详情 | 详情 |
| (XXX) | 67794 | (E)-butyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate | C19H25N3O2 | 详情 | 详情 | |
| (XXXI) | 67795 | 1-((tert-butoxycarbonyl)amino)cyclobutanecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
| (XXXII) | 67796 | (E)-butyl 3-(4-amino-3-(1-((tert-butoxycarbonyl)amino)-N-methylcyclobutanecarboxamido)phenyl)acrylate | C24H35N3O5 | 详情 | 详情 |