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With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;Cooling with ice; Inert atmosphere;
A solution of <strong>[1257535-31-1]4-bromo-2-nitro-6-(trifluoromethoxy)aniline</strong> (1 .962 g, 6.52 mmol, commercially available from, for example, Apollo Scientific) in Nu,Nu-dimethylformamide (DMF) (80 mL) was cooled with an ice/water bath to ~0 C for 10 min. Cesium carbonate (4.25 g, 13.04 mmol) was then added and stirred, and the colour changed from yellow to red. After 10 min, methyl iodide (0.408 mL, 6.52 mmol) was added and the mixture was allowed to return to rt with stirring under nitrogen for 3 h. LCMS showed -90% conversion to the desired product with no starting material remaining, and -10% formation of an impurity. The reaction mixture was partitioned using water (400 mL) and EtOAc (400 mL), and the aqueous layer re-extracted with EtOAc (2 x 400 mL). The combined organics were backwashed with water (400 mL) and then passed through a hydrophobic frit and concentrated in vacuo to give the crude product as a yellow oil. The sample was loaded in dichloromethane and purified on silica (Si) (100 g) using 100% cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the required product (1 .368 g, 67%) as an orange solid. LCMS (Method A): Rt = 1.33 min, MH+ = 314.9
67%
Intermediate 59: 4-Bromo-N-methyl-2-nitro-6-(trifluoromethoxy)aniline A solution of <strong>[1257535-31-1]4-bromo-2-nitro-6-(trifluoromethoxy)aniline</strong> (1.962 g, 6.52 mmol, commercially available from, for example, Apollo Scientific) in N,N-dimethylformamide (DMF) (80 mL) was cooled with an ice/water bath to 0 C. for 10 min. Cesium carbonate (4.25 g, 13.04 mmol) was then added and stirred, and the colour changed from yellow to red. After 10 min, methyl iodide (0.408 mL, 6.52 mmol) was added and the mixture was allowed to return to rt with stirring under nitrogen for 3 h. LCMS showed 90% conversion to the desired product with no starting material remaining, and 10% formation of an impurity. The reaction mixture was partitioned using water (400 mL) and EtOAc (400 mL), and the aqueous layer re-extracted with EtOAc (2*400 mL). The combined organics were backwashed with water (400 mL) and then passed through a hydrophobic frit and concentrated in vacuo to give the crude product as a yellow oil. The sample was loaded in dichloromethane and purified on silica (Si) (100 g) using 100% cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the required product (1.368 g, 67%) as an orange solid. LCMS (Method A): Rt=1.33 min, MH+=314.9
39%
A solution of <strong>[1257535-31-1]4-bromo-2-nitro-6-(trifluoromethoxy)aniline</strong> (1 g, 3.32 mmol, commercially available from, for example, Apollo Scientific) in DMF (40 mL) was cooled using an ice/water bath for 10 min then cesium carbonate (2.17 g, 6.64 mmol) was added. The reaction mixture was stirred for 10 min then iodomethane (0.208 mL, 3.32 mmol) was added and the mixture allowed warm to rt under nitrogen over 67 h. Further iodomethane (0.208 mL, 3.32 mmol) was added to the reaction mixture was stirred for a further 6 h then partitioned using EtOAc and water (200 mL each). The aqueous layer was re-extracted with EtOAc (2 x 200mL) then the combined organics were washed with water (200 mL) then passed through a hydrophobic frit and concentrated under reduced pressure to give the crude product as a brown gum. The material was purified by silica column chromatography, eluting with a DCM/cyclohexane solvent system (0 to 30%) to give the title product as an orange solid (404 mg, 39% yield).LCMS (Method A): Rt = 1.33 min, M+ H4+= 332.7
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