【结 构 式】 |
【药物名称】NU-1085 【化学名称】2-(4-Hydroxyphenyl)-1H-benzimidazole-4-carboxamide 【CA登记号】188106-83-4 【 分 子 式 】C14H11N3O2 【 分 子 量 】253.26267 |
【开发单位】University of Newcastle upon Tyne (Originator), Agouron (Codevelopment) 【药理作用】Antineoplastic Enhancing Agents, Modulators of the Therapeutic Activity of Antineoplastic Agents, ONCOLYTIC DRUGS, Poly(ADP-ribose)polymerase-1 (PARP-1) Inhibitors |
合成路线1
Regioselective ring opening of 3-nitrophthalic anhydride (I) with ammonia yielded amide (II), which was subjected to a Hofmann degradation with Br2 and KOH to afford 3-nitroanthranilic acid (III). Esterification of (III) to ster (IV) using MeOH/HCl, followed by reduction of the nitro group by catalytic hydrogenation, gave methyl 2,3-diaminobenzoate (V). Alternatively, diamino ester (V) was prepared by reduction of nitro acid (III), followed by catalytic esterification. Methyl 2,3-diaminobenzoate (V) was then selectively acylated at the 3-amino group with 4-methoxybenzoyl chloride (VI) producing amide (VII), which was cyclized to the benzimidazole (VIII) upon refluxing in HOAc. The corresponding amide (IX) was obtained by reaction of ester (VIII) with liquid ammonia at 100 C in a pressure vessel. Finally, the methyl ether group of (IX) was cleaved to the title phenol by treatment with boron tribromide.
【1】 Wood, M.D.; Taylor, S.G.; Reavill, C.; et al.; Pharmacological actions of a novel, high-affinity, and selective human dopamine D3 receptor antagonist, SB-277011-A. J Pharmacol Exp Ther 2000, 294, 3, 1154. |
【2】 Griffin, R.J.; Calvert, A.H.; Newell, D.R.; Curtain, J.N.; Golding, B.T. (University of Newcastle upon Tyne); Benzimidazole cpds.. US 6100283 . |
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) | 46407 | 4-nitro-2-benzofuran-1,3-dione;3-nitrophthalic anhydride | 641-70-3 | C8H3NO5 | 详情 | 详情 |
(II) | 46408 | 2-(aminocarbonyl)-3-nitrobenzoic acid | C8H6N2O5 | 详情 | 详情 | |
(III) | 46409 | 2-amino-3-nitrobenzoic acid | C7H6N2O4 | 详情 | 详情 | |
(IV) | 46410 | methyl 2-amino-3-nitrobenzoate | C8H8N2O4 | 详情 | 详情 | |
(V) | 18889 | methyl 2,3-diaminobenzoate | C8H10N2O2 | 详情 | 详情 | |
(VI) | 22671 | 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride | 100-07-2 | C8H7ClO2 | 详情 | 详情 |
(VII) | 46411 | methyl 2-amino-3-[(4-methoxybenzoyl)amino]benzoate | C16H16N2O4 | 详情 | 详情 | |
(VIII) | 46412 | methyl 2-(4-methoxyphenyl)-1H-benzimidazole-4-carboxylate | C16H14N2O3 | 详情 | 详情 | |
(IX) | 46413 | 2-(4-methoxyphenyl)-1H-benzimidazole-4-carboxamide | C15H13N3O2 | 详情 | 详情 |