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【结 构 式】 
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【分子编号】37890 【品名】(2,3-difluorophenyl)[3-(isopropylamino)-4-nitrophenyl]methanone 【CA登记号】 |
【 分 子 式 】C16H14F2N2O3 【 分 子 量 】320.2956464 【元素组成】C 60% H 4.41% F 11.86% N 8.75% O 14.99% |
合成路线1
该中间体在本合成路线中的序号：(V)Treatment of 2,4-difluoronitrobenzene (I) with isopropylamine in the presence of K2CO3 in THF afforded 2-isopropylamino-4-fluoronitrobenzene (II). Subsequent condensation of (II) with 2,3-difluorophenylacetonitrile (III) by means of potassium tert-butoxide, followed by oxidative treatment of the intermediate nitrile (IV) with H2O2 generated benzophenone (V). The nitro group of (V) was then reduced by hydrogenation over Raney Nickel yielding diamine (VI), which was cyclized to benzimidazole (VII) upon treatment with cyanogen bromide. Addition of the lithium anion of N-methyl-N-(trimethylsilyl)acetamide to (VII) gave beta-hydroxyamide (VIII). Finally, acid promoted dehydration of (VIII) furnished the corresponding alpha,beta-unsaturated amide.
| 【1】 Jungheim, L.N.; Shepherd, T.A.; Spitzer, W.A.; Tebbe, M.J. (Eli Lilly and Company); Anti-viral cpds.. EP 0906097; WO 9746237 . |
| 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) | 32036 | 2,4-difluoro-1-nitrobenzene | 446-35-5 | C6H3F2NO2 | 详情 | 详情 |
| (II) | 37887 | 5-fluoro-N-isopropyl-2-nitroaniline; N-(5-fluoro-2-nitrophenyl)-N-isopropylamine | C9H11FN2O2 | 详情 | 详情 | |
| (III) | 37888 | 2-(2,3-difluorophenyl)acetonitrile | 145689-34-5 | C8H5F2N | 详情 | 详情 |
| (IV) | 37889 | 2-(2,3-difluorophenyl)-2-[3-(isopropylamino)-4-nitrophenyl]acetonitrile | C17H15F2N3O2 | 详情 | 详情 | |
| (V) | 37890 | (2,3-difluorophenyl)[3-(isopropylamino)-4-nitrophenyl]methanone | C16H14F2N2O3 | 详情 | 详情 | |
| (VI) | 37891 | [4-amino-3-(isopropylamino)phenyl](2,3-difluorophenyl)methanone | C16H16F2N2O | 详情 | 详情 | |
| (VII) | 37892 | (2-amino-1-isopropyl-1H-benzimidazol-6-yl)(2,3-difluorophenyl)methanone | C17H15F2N3O | 详情 | 详情 | |
| (VIII) | 37894 | 3-(2-amino-1-isopropyl-1H-benzimidazol-6-yl)-3-(2,3-difluorophenyl)-3-hydroxy-N-methylpropanamide | C20H22F2N4O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Treatment of 2,4-difluoronitrobenzene (I) with isopropylamine in the presence of K2CO3 in THF afforded 2-isopropylamino-4-fluoronitrobenzene (II). Subsequent condensation of (II) with 2,3-difluorophenylacetonitrile (III) by means of potassium tert-butoxide, followed by oxidative treatment of the intermediate nitrile (IV) with H2O2 generated benzophenone (V). The nitro group of (V) was then reduced by hydrogenation over Raney Nickel yielding diamine (VI), which was cyclized to benzimidazole (VII) upon treatment with cyanogen bromide. Addition of the lithium anion of bis(trimethylsilyl)acetamide to (VII) gave beta-hydroxyamide (VIII). Finally, acid promoted dehydration of (VIII) furnished the corresponding alpha,beta-unsaturated amide, which was isoalted as the hydrochloride salt.
| 【1】 Jungheim, L.N.; Shepherd, T.A.; Spitzer, W.A.; Tebbe, M.J. (Eli Lilly and Company); Anti-viral cpds.. EP 0906097; WO 9746237 . |
| 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) | 32036 | 2,4-difluoro-1-nitrobenzene | 446-35-5 | C6H3F2NO2 | 详情 | 详情 |
| (II) | 37887 | 5-fluoro-N-isopropyl-2-nitroaniline; N-(5-fluoro-2-nitrophenyl)-N-isopropylamine | C9H11FN2O2 | 详情 | 详情 | |
| (III) | 37888 | 2-(2,3-difluorophenyl)acetonitrile | 145689-34-5 | C8H5F2N | 详情 | 详情 |
| (IV) | 37889 | 2-(2,3-difluorophenyl)-2-[3-(isopropylamino)-4-nitrophenyl]acetonitrile | C17H15F2N3O2 | 详情 | 详情 | |
| (V) | 37890 | (2,3-difluorophenyl)[3-(isopropylamino)-4-nitrophenyl]methanone | C16H14F2N2O3 | 详情 | 详情 | |
| (VI) | 37891 | [4-amino-3-(isopropylamino)phenyl](2,3-difluorophenyl)methanone | C16H16F2N2O | 详情 | 详情 | |
| (VII) | 37892 | (2-amino-1-isopropyl-1H-benzimidazol-6-yl)(2,3-difluorophenyl)methanone | C17H15F2N3O | 详情 | 详情 | |
| (VIII) | 37893 | 3-(2-amino-1-isopropyl-1H-benzimidazol-6-yl)-3-(2,3-difluorophenyl)-3-hydroxypropanamide | C19H20F2N4O2 | 详情 | 详情 |