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【结 构 式】 
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【药物名称】RWJ-51204 【化学名称】5-(Ethoxymethyl)-7-fluoro-N-(2-fluorophenyl)-3-oxo-1,2,3,5-tetrahydropyrido[1,2-a]benzimidazole-4-carboxamide 【CA登记号】205701-85-5 【 分 子 式 】C21H19F2N3O3 【 分 子 量 】399.40068 |
【开发单位】R.W. Johnson (Originator) 【药理作用】Anxiolytics, PSYCHOPHARMACOLOGIC DRUGS, GABA(A) BZ Site Receptor Partial Agonists |
合成路线1
Michael addition of acrylonitrile (II) to 4-fluoro-2-nitroaniline (I) in the presence of Triton B provided nitrile (III). The nitro group of (III) was then reduced to the amine (IV) by hydrogenation over Pd/C. Further cyclization of amine (IV) with ethyl (ethoxycarbonyl)acetimidate (V) furnished the benzimidazole (VI). Diester (VII) (prepared by refluxing the nitrile (VI) with ethanolic HCl), was submitted to Dieckmann cyclization in the presence of NaOEt to produce the pyridobenzimidazole (VIII). Reaction of the ester group of (VIII) with 2-fluoroaniline (IX) in boiling xylene yielded the corresponding anilide (X), which was finally alkylated with ethoxymethyl chloride (XI) in the presence of NaH and crown ether.
| 【1】 Sanfilippo, P.J.; Reitz, A.B.; Kordik, C.P.; Dubinsky, B.; Rosenthal, D.I.; Vaidya, A.H.; Jordan, A.D.; Wu, W.-N.; Potential anxiolytic agents. Part 4: Novel orally-active N(5)-substituted pyrido[1,2-a]benzimidazoles with high GABA-A receptor affinity. Bioorg Med Chem Lett 2002, 12, 17, 2381. |
| 【2】 Cohen, J.H.; et al.; Process research for the synthesis of RWJ-51204, a novel anxiolytic agent. Org Process Res Dev 1999, 3, 4, 260. |
| 【3】 Reitz, A.B.; Jordan, A.D.; Sanfilippo, P.J.; Scott, M.K. (Ortho-McNeil Pharmaceutical, Inc.); 5-Heteroatom-containing alkyl substd.-3-oxo-pyrido(1,2-a)benzimidazole-4-carboxamide derivs. useful in treating central nervous system disorders. EP 0935598; US 5817668; WO 9815553 . |
| 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) | 22288 | 4-fluoro-2-nitrophenylamine; 4-fluoro-2-nitroaniline | 364-78-3 | C6H5FN2O2 | 详情 | 详情 |
| (III) | 22290 | 3-(4-fluoro-2-nitroanilino)propanenitrile | C9H8FN3O2 | 详情 | 详情 | |
| (IV) | 22291 | 3-(2-amino-4-fluoroanilino)propanenitrile | C9H10FN3 | 详情 | 详情 | |
| (VI) | 22293 | ethyl 2-[1-(2-cyanoethyl)-5-fluoro-1H-benzimidazol-2-yl]acetate | C14H14FN3O2 | 详情 | 详情 | |
| (VII) | 22294 | ethyl 3-[2-(2-ethoxy-2-oxoethyl)-5-fluoro-1H-benzimidazol-1-yl]propanoate | C16H19FN2O4 | 详情 | 详情 | |
| (VIII) | 22295 | ethyl 7-fluoro-3-oxo-1,2,3,5-tetrahydropyrido[1,2-a]benzimidazole-4-carboxylate | C14H13FN2O3 | 详情 | 详情 | |
| (IX) | 22296 | 2-fluorophenylamine; 2-fluoroaniline | 348-54-9 | C6H6FN | 详情 | 详情 |
| (X) | 22297 | 7-fluoro-N-(2-fluorophenyl)-3-oxo-1,2,3,5-tetrahydropyrido[1,2-a]benzimidazole-4-carboxamide | C18H13F2N3O2 | 详情 | 详情 |