【结 构 式】 |
【药物名称】APC-6336 【化学名称】2-[2-(5-Carbamoyl-1H-benzimidazol-2-ylmethyl)-1-methyl-1H-benzimidazol-6-ylcarboxamido]-3-phosphonopropionic acid 【CA登记号】263870-19-5 【 分 子 式 】C21H21N6O7P 【 分 子 量 】500.41132 |
【开发单位】Bristol-Myers Squibb (Originator), Celera (Originator) 【药理作用】Anti-Hepatitis C Virus Drugs, Anti-Hepatitis Virus Drugs, ANTIINFECTIVE THERAPY, Antiviral Drugs, HCV NS3 Protease Inhibitors |
合成路线1
The reduction of 3,4-dinitrobenzoic acid amide (I) with H2 over Pd/C in methanol gives 3,4-diaminobenzoic acid (II), which is cyclized with 3-ethoxy-3-iminopropionic acid ethyl ester (IV) (obtained by reaction of cyanacetic acid ethyl ester (III) with ethanolic HCl) in hot acetic acid to yield 2-(5-carbamoyl-1H-benzimidazol-2-yl)acetic acid ethyl ester (V). The reaction of 3-methoxy-4-nitrobenzoic acid (VII) with aqueous methylamine in a sealed tube at 100 C gives 3-(methylamino)-4-nitrobenzoic acid (VIII), which is reduced with H2 over Pd/C in methanol/THF to yield 4-amino-3-(methylamino)benzoic acid (VI). The cyclization of (VI) with (V) by means of 1,3-dimethylperhydropyrimidin-2-one (DMPU) at 190 C affords the substituted bis-benzimidazolylmethyl (IX). The reaction of (IX) with 2-amino-3-phosponopropionic acid tris-trimethylsilyl ester (X) (prepared by esterification of 2-amino-3-phosphonopropionic acid (XI) with N-methyl-N-(trimethylsilyl)trifluoroacetamide (XII)) by means of (PyBroP) in DMF provides the carboxamide (XIII). Finally, the cleavage of the trimethylsilyl ester groups by means of TFA furnishes the target phosphonic acid.
【1】 Rice, K.; Wang, V.R.; Hataye, J.M.; Shelton, E.J.; Spender, J.R. (Celera Genomics); Novel cpds. and compsns. for treating hepatitis C infections. WO 0020400 . |
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) | 55559 | 3,4-dinitrobenzamide | C7H5N3O5 | 详情 | 详情 | |
(II) | 55560 | 3,4-diaminobenzamide | C7H9N3O | 详情 | 详情 | |
(III) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
(IV) | 17929 | ethyl 3-ethoxy-3-iminopropanoate | 2318-25-4 | C7H13NO3 | 详情 | 详情 |
(V) | 55561 | ethyl 2-[5-(aminocarbonyl)-1H-benzimidazol-2-yl]acetate | C12H13N3O3 | 详情 | 详情 | |
(VI) | 14729 | 4-amino-3-(methylamino)benzoic acid | C8H10N2O2 | 详情 | 详情 | |
(VII) | 21085 | 3-methoxy-4-nitrobenzoic acid;4-Nitro-3-methoxybenzoic acid | 5081-36-7 | C8H7NO5 | 详情 | 详情 |
(VIII) | 14728 | 3-(methylamino)-4-nitrobenzoic acid | C8H8N2O4 | 详情 | 详情 | |
(IX) | 55562 | 2-{[5-(aminocarbonyl)-1H-benzimidazol-2-yl]methyl}-1-methyl-1H-benzimidazole-6-carboxylic acid | C18H15N5O3 | 详情 | 详情 | |
(X) | 55563 | 3-{bis[(trimethylsilyl)oxy]phosphoryl}alanine | C9H24NO5PSi2 | 详情 | 详情 | |
(XI) | 55565 | DL-2-Amino-3-phosphonopropionic acid; 2-Amino-3-phosphonopropionic acid | 20263-06-3 | C3H8NO5P | 详情 | 详情 |
(XII) | 21859 | 2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)acetamide | C6H12F3NOSi | 详情 | 详情 | |
(XIII) | 55564 | N-[(2-{[5-(aminocarbonyl)-1H-benzimidazol-2-yl]methyl}-1-methyl-1H-benzimidazol-6-yl)carbonyl]-3-{bis[(trimethylsilyl)oxy]phosphoryl}alanine | C27H37N6O7PSi2 | 详情 | 详情 |