|
【结 构 式】 
|
【药物名称】 【化学名称】3-[5-(Piperazin-1-ylcarbonyl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 【CA登记号】335672-25-8 【 分 子 式 】C21H19N5O2 【 分 子 量 】373.41788 |
【开发单位】Merck & Co. (Originator) 【药理作用】ONCOLYTIC DRUGS, Angiogenesis Inhibitors, VEGFR-2 (FLK-1/KDR) Inhibitors |
合成路线1
Treatment of 2-chloroquinoline-3-carboxylic acid (I) with oxalyl chloride affords acid chloride (II), which is subsequently coupled with methyl 3,4-diaminobenzoate (III) to yield amide (IV). Intramolecular cyclization of amino amide (IV) with Burgess reagent in refluxing THF produces the benzimidazole (V). Then, acidic hydrolysis of both methyl ester and chloroquinoline functions of (V) gives rise to the carboxylic acid (VI). Coupling of (VI) with N-Boc-piperazine (VII) furnishes amide (VIII). The N-Boc protecting group of (VIII) is finally removed by treatment with trifluoroacetic acid in CH2Cl2.
| 【1】 Hungate, R.W.; Fraley, M.E.; Hambaugh, S.R. (Merck & Co., Inc.); Tyrosine kinase inhibitors. JP 2003512353; US 6479512; WO 0128993 . |
| 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) | 61948 | 2-chloro-3-quinolinecarboxylic acid | C10H6ClNO2 | 详情 | 详情 | |
| (II) | 61950 | 2-chloro-3-quinolinecarbonyl chloride | C10H5Cl2NO | 详情 | 详情 | |
| (III) | 34921 | 3-cyanobenzoyl chloride | 1711-11-1 | C8H4ClNO | 详情 | 详情 |
| (IV) | 61951 | methyl 3-amino-4-{[(2-chloro-3-quinolinyl)carbonyl]amino}benzoate | C18H14ClN3O3 | 详情 | 详情 | |
| (V) | 61952 | methyl 2-(2-chloro-3-quinolinyl)-1H-benzimidazole-5-carboxylate | C18H12ClN3O2 | 详情 | 详情 | |
| (VI) | 61953 | 2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-benzimidazole-5-carboxylic acid | C17H11N3O3 | 详情 | 详情 | |
| (VII) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (VIII) | 61954 | tert-butyl 4-{[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-benzimidazol-5-yl]carbonyl}-1-piperazinecarboxylate | C26H27N5O4 | 详情 | 详情 |