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【结 构 式】 
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【分子编号】25178 【品名】2-amino-4,5-dichloro-3-fluorophenylamine 【CA登记号】 |
【 分 子 式 】C6H5Cl2FN2 【 分 子 量 】195.0229832 【元素组成】C 36.95% H 2.58% Cl 36.36% F 9.74% N 14.36% |
合成路线1
该中间体在本合成路线中的序号：(IV)Fluorination of 4,5-dichloro-2-nitroaniline (I) with 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoborate) (II) gave fluoroaniline (III). The nitro group of (III) was then reduced by hydrogenation over Raney-Ni to afford phenylenediamine (IV). This was cyclized with isopropyl isothiocyanate in the presence of 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate as the desulfurizing agent to yield benzimidazole (V). Coupling with 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose (VI) using trimethylsilyl triflate and N,O-bis(trimethylsilyl)acetamide produced a mixture of regioisomeric ribofuranosyl benzimidazoles (VII) and (VIII), which were separated by column chromatography. Finally, deprotection of the acetate esters from the major isomer (VII) with Na2CO3 provided the title compound.
| 【1】 Chamberlain, S.D.; Koszalka, G.W.; Chan, J.H.; Townsend, L.B.; Tidwell, J.H.; Drach, J.C.; Freeman, G.A. (Glaxo Wellcome plc; University of Michigan); Benzimidazole derivs.. EP 0970100; WO 9835977 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 28919 | 2-isothiocyanatopropane | 2253-73-8 | C4H7NS | 详情 | 详情 | |
| (I) | 25175 | 4,5-dichloro-2-nitroaniline | 6641-64-1 | C6H4Cl2N2O2 | 详情 | 详情 |
| (II) | 25176 | 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane | C6H13FN2O | 详情 | 详情 | |
| (III) | 25177 | 3,4-dichloro-2-fluoro-6-nitroaniline | C6H3Cl2FN2O2 | 详情 | 详情 | |
| (IV) | 25177 | 3,4-dichloro-2-fluoro-6-nitroaniline | C6H3Cl2FN2O2 | 详情 | 详情 | |
| (IV) | 25178 | 2-amino-4,5-dichloro-3-fluorophenylamine | C6H5Cl2FN2 | 详情 | 详情 | |
| (V) | 25178 | 2-amino-4,5-dichloro-3-fluorophenylamine | C6H5Cl2FN2 | 详情 | 详情 | |
| (VI) | 25179 | 5,6-dichloro-4-fluoro-N-isopropyl-1H-benzimidazol-2-amine | C10H10Cl2FN3 | 详情 | 详情 | |
| (VII) | 25180 | (2R,3R,4R,5R)-4-(acetoxy)-2-[5,6-dichloro-4-fluoro-2-(isopropylamino)-1H-benzimidazol-1-yl]-5-methyltetrahydro-3-furanyl acetate | C19H22Cl2FN3O5 | 详情 | 详情 | |
| (VIII) | 25181 | (2R,3R,4R,5R)-4-(acetoxy)-2-[5,6-dichloro-7-fluoro-2-(isopropylamino)-1H-benzimidazol-1-yl]-5-methyltetrahydro-3-furanyl acetate | C19H22Cl2FN3O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Fluorination of 4,5-dichloro-2-nitroaniline (I) with 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoborate) (II) gave fluoroaniline (III). The nitro group of (III) was then reduced by hydrogenation over Raney-Ni to afford phenylenediamine (IV). This was cyclized with isopropyl isothiocyanate in the presence of 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate as the desulfurizing agent to yield benzimidazole (V). Coupling with 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose (VI) using trimethylsilyl triflate and N,O-bis(trimethylsilyl)acetamide produced a mixture of regioisomeric ribofuranosyl benzimidazoles (VII) and (VIII), which were separated by column chromatography. Finally, deprotection of the acetate esters from the major isomer (VII) with Na2CO3 provided the title compound.
| 【1】 Chamberlain, S.D.; Koszalka, G.W.; Chan, J.H.; Townsend, L.B.; Tidwell, J.H.; Drach, J.C.; Freeman, G.A. (Glaxo Wellcome plc; University of Michigan); Benzimidazole derivs.. EP 0970100; WO 9835977 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 28919 | 2-isothiocyanatopropane | 2253-73-8 | C4H7NS | 详情 | 详情 | |
| (I) | 25175 | 4,5-dichloro-2-nitroaniline | 6641-64-1 | C6H4Cl2N2O2 | 详情 | 详情 |
| (II) | 25176 | 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane | C6H13FN2O | 详情 | 详情 | |
| (III) | 25177 | 3,4-dichloro-2-fluoro-6-nitroaniline | C6H3Cl2FN2O2 | 详情 | 详情 | |
| (IV) | 25177 | 3,4-dichloro-2-fluoro-6-nitroaniline | C6H3Cl2FN2O2 | 详情 | 详情 | |
| (IV) | 25178 | 2-amino-4,5-dichloro-3-fluorophenylamine | C6H5Cl2FN2 | 详情 | 详情 | |
| (V) | 25178 | 2-amino-4,5-dichloro-3-fluorophenylamine | C6H5Cl2FN2 | 详情 | 详情 | |
| (VI) | 25179 | 5,6-dichloro-4-fluoro-N-isopropyl-1H-benzimidazol-2-amine | C10H10Cl2FN3 | 详情 | 详情 | |
| (VII) | 25180 | (2R,3R,4R,5R)-4-(acetoxy)-2-[5,6-dichloro-4-fluoro-2-(isopropylamino)-1H-benzimidazol-1-yl]-5-methyltetrahydro-3-furanyl acetate | C19H22Cl2FN3O5 | 详情 | 详情 | |
| (VIII) | 25181 | (2R,3R,4R,5R)-4-(acetoxy)-2-[5,6-dichloro-7-fluoro-2-(isopropylamino)-1H-benzimidazol-1-yl]-5-methyltetrahydro-3-furanyl acetate | C19H22Cl2FN3O5 | 详情 | 详情 |