【结 构 式】 |
【药物名称】 【化学名称】N-[3-[2-Amino-3-cyano-6-(2-hydroxyphenyl)pyridin-4-yl]phenyl]-3-(1-piperidinyl)propionamide hydrochloride 【CA登记号】433958-84-0, 433957-88-1 (free base), 433958-92-0 (trifluoroacetate) 【 分 子 式 】C26H28ClN5O2 【 分 子 量 】477.99836 |
【开发单位】Bayer (Originator) 【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Antiinflammatory Drugs, IKK-2 (IKK-beta) Inhibitors |
合成路线1
2'-Hydroxyacetophenone (I) is protected as the silyl ether (II) employing t-butyldimethylsilyl chloride and imidazole. Condensation of acetophenone (II) with 3-nitrobenzaldehyde (III) and malononitrile in the presence of ammonium acetate gives rise to the cyanopyridine (IV). The nitro group of (IV) is then reduced to the corresponding amine (V) by catalytic hydrogenation over Pd/C. 3-Piperidinylpropionic acid (VI) is then activated as the acid chloride (VII) upon treatment with oxalyl chloride. Subsequent coupling of acid chloride (VII) with amine (V) furnishes amide (VIII). Finally, desilylation of (VIII) by means of either tetrabutylammonium fluoride or HCl in dioxane leads to the title compound. (1,2)
【1】 Murata, T.; Shimada, M.; Sakakibara, S.; Yoshino, T.; Kadono, H.; Masuda, T.; Shimazaki, M.; Shintani, T.; Fuchikami, K.; Sakai, K.; Inbe, H.; Takeshita, K.; Niki, T.; Umeda, M.; Bacon, K.B.; Ziegelbauer, K.B.; Lowinger, T.B.; Discovery of novel and selective IKK-beta serine-threonine protein kinase inhibitors. Part 1. Bioorg Med Chem Lett 2003, 13, 5, 913. |
【2】 Yoshida, N.; Masuda, T.; Sakakibara, S.; Murata, T.; Yoshino, T.; Umeda, M.; Shimada, M.; Lowinger, T.B.; Komura, H.; Shintani, T.; Ziegelbauer, K.B.; Fuchikami, K.; Ikegami, Y.; Shimazaki, M. (Bayer AG); 4-Aryl pyridine derivs.. EP 1339687; JP 2002193938; WO 0244153 . |
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) | 29654 | 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone | 118-93-4 | C8H8O2 | 详情 | 详情 |
(II) | 64006 | 1-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-ethanone | C14H22O2Si | 详情 | 详情 | |
(III) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
(IV) | 64007 | 2-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-(3-nitrophenyl)nicotinonitrile | C24H26N4O3Si | 详情 | 详情 | |
(V) | 64008 | 2-amino-4-(3-aminophenyl)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)nicotinonitrile | C24H28N4OSi | 详情 | 详情 | |
(VI) | 64010 | 3-(1-piperidinyl)propanoic acid | C8H15NO2 | 详情 | 详情 | |
(VII) | 64011 | 3-(1-piperidinyl)propanoyl chloride | C8H14ClNO | 详情 | 详情 | |
(VIII) | 64009 | N-{3-[2-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-cyano-4-pyridinyl]phenyl}-3-(1-piperidinyl)propanamide | C32H41N5O2Si | 详情 | 详情 |