【结 构 式】 |
【药物名称】 【化学名称】N-(2,6-Difluorophenyl)-6,7-difluoro-3-oxo-1,2,3,5-tetrahydropyrido[1,2-a]benzimidazole-4-carboxamide 【CA登记号】 【 分 子 式 】C18H11F4N3O2 【 分 子 量 】377.30087 |
【开发单位】Johnson & Johnson (Originator) 【药理作用】Anxiolytics, PSYCHOPHARMACOLOGIC DRUGS, GABA(A) Receptor Agonists |
合成路线1
Addition of acrylonitrile (II) to 3,4-difluoro-2-nitroaniline (I) gave the anilinopropionitrile (III). Subsequent hydrogenation of the nitro group of (III) over Pd/C led to the phenylenediamine (IV), which was condensed with carbethoxyacetimidate-HCl (V) to produce the benzimidazole (VI). After conversion of the nitrile group of (VI) to ester (VII) with ethanolic HCl, Dieckmann condensation using NaOEt furnished the cyclic ketoester (VIII). Finally, reaction of (VIII) with 2,6-difluoroaniline (IX) in xylene yielded the target carboxamide.
【1】 Maryanoff, B.E.; et al.; Potential anxiolytic agents. Pyrido[1, 2-a]benzimidazoles: A new structural class of ligands for the benzodiazepine binding site on GABA-A receptors. J Med Chem 1995, 38, 1, 16. |
【2】 Nortey, S.O.; Sanfilippo, P.J.; Dubinsky, B.; Maryanoff, B.E.; McComsey, D.F.; Reitz, A.B.; Shank, R.P.; McNally, J.J.; Potential anxiolytic agents. 3. Novel A-ring modified pyrido[1,2-a]benzimidazoles. Bioorg Med Chem Lett 1999, 9, 11, 1547. |
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) | 31347 | 3,4-difluoro-2-nitrophenylamine; 3,4-difluoro-2-nitroaniline | C6H4F2N2O2 | 详情 | 详情 | |
(II) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
(III) | 31348 | 3-(3,4-difluoro-2-nitroanilino)propanenitrile | C9H7F2N3O2 | 详情 | 详情 | |
(IV) | 31349 | 3-(2-amino-3,4-difluoroanilino)propanenitrile | C9H9F2N3 | 详情 | 详情 | |
(V) | 17929 | ethyl 3-ethoxy-3-iminopropanoate | 2318-25-4 | C7H13NO3 | 详情 | 详情 |
(VI) | 31350 | ethyl 2-[1-(2-cyanoethyl)-4,5-difluoro-1H-benzimidazol-2-yl]acetate | C14H13F2N3O2 | 详情 | 详情 | |
(VII) | 31351 | ethyl 3-[2-(2-ethoxy-2-oxoethyl)-4,5-difluoro-1H-benzimidazol-1-yl]propanoate | C16H18F2N2O4 | 详情 | 详情 | |
(VIII) | 31352 | ethyl 6,7-difluoro-3-oxo-1,2,3,5-tetrahydropyrido[1,2-a]benzimidazole-4-carboxylate | C14H12F2N2O3 | 详情 | 详情 | |
(IX) | 17933 | 2,6-Difluorophenylamine; 2,6-Difluoroaniline | 5509-65-9 | C6H5F2N | 详情 | 详情 |