5-氯-2,4-二氟苯甲酸甲酯

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To solution of methyl 5-chloro-2,4-difluorobenzoate (25.9 mg, 0.125 mmol) and 3-ethoxyphenol (17.3 mg, 0.125 mmol) in dimethyl formamide (0.5 mL) was added cesium carbonate (82 mg, 0.25 mmol), the mixture was shaken at 120° C. for 16 hours, filtered and evaporated in vacuo. Water (1 mL) was added and extracted with ethyl acetate (3×1 mL), the combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in THF (0.7 mL) and to this solution was added a 1M aqueous solution of lithium hydroxide (0.7 mL) and the mixture was shaken at 30° C. for 16 hours. The reaction mixture was evaporated in vacuo, a 1M aqueous solution of hydrochloric acid (0.7 mL) was added and extracted with ethyl acetate (3×1 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. To this residue was added methanesulfonamide (28.6 mg, 0.300 mmol) and a solution of 4-dimethylaminopyridine (24.4 mg, 0.200 mmol) and EDCl (38.3 mg, 0.200 mmol) in dichloromethane (1 mL), the solution was shaken at 30° C. for 16 hours and evaporated in vacuo. The crude product was purified on a HPLC column (Sepax BR-C18 100*21.2 mm*5 μm, acetonitrile-water (0.1% trifluoroacetic acid) gradient to yield 6.2 mg (16 μmol) 5-chloro-4-(3-ethoxyphenoxy)-2-fluoro-N-(methylsulfonyl)benzamide. filtered evaporated in vacuo Water (1 mL) was added extracted with ethyl acetate (3×1 mL) the combined organic layers were dried over sodium sulphate filtered evaporated in vacuo The residue was dissolved in THF (0.7 mL) and to this solution was added a 1M aqueous solution of lithium hydroxide (0.7 mL) the mixture was shaken at 30° C. for 16 hours The reaction mixture was evaporated in vacuo a 1M aqueous solution of hydrochloric acid (0.7 mL) was added extracted with ethyl acetate (3×1 mL) The combined organic layers were dried over anhydrous sodium sulphate filtered evaporated in vacuo evaporated in vacuo The crude product was purified on a HPLC column (Sepax

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To solution of methyl 5-chloro-2,4-difluorobenzoate (25.9 mg, 0.125 mmol) and 3-ethoxyphenol (17.3 mg, 0.125 mmol) in dimethyl formamide (0.5 mL) was added cesium carbonate (82 mg, 0.25 mmol), the mixture was shaken at 120° C. for 16 hours, filtered and evaporated in vacuo. Water (1 mL) was added and extracted with ethyl acetate (3×1 mL), the combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in THF (0.7 mL) and to this solution was added a 1M aqueous solution of lithium hydroxide (0.7 mL) and the mixture was shaken at 30° C. for 16 hours. The reaction mixture was evaporated in vacuo, a 1M aqueous solution of hydrochloric acid (0.7 mL) was added and extracted with ethyl acetate (3×1 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. To this residue was added methanesulfonamide (28.6 mg, 0.300 mmol) and a solution of 4-dimethylaminopyridine (24.4 mg, 0.200 mmol) and EDCl (38.3 mg, 0.200 mmol) in dichloromethane (1 mL), the solution was shaken at 30° C. for 16 hours and evaporated in vacuo. The crude product was purified on a HPLC column (Sepax BR-C18 100*21.2 mm*5 μm, acetonitrile-water (0.1% trifluoroacetic acid) gradient to yield 6.2 mg (16 μmol) 5-chloro-4-(3-ethoxyphenoxy)-2-fluoro-N-(methylsulfonyl)benzamide. filtered evaporated in vacuo Water (1 mL) was added extracted with ethyl acetate (3×1 mL) the combined organic layers were dried over sodium sulphate filtered evaporated in vacuo The residue was dissolved in THF (0.7 mL) and to this solution was added a 1M aqueous solution of lithium hydroxide (0.7 mL) the mixture was shaken at 30° C. for 16 hours The reaction mixture was evaporated in vacuo a 1M aqueous solution of hydrochloric acid (0.7 mL) was added extracted with ethyl acetate (3×1 mL) The combined organic layers were dried over anhydrous sodium sulphate filtered evaporated in vacuo evaporated in vacuo The crude product was purified on a HPLC column (Sepax

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To solution of methyl 5-chloro-2,4-difluorobenzoate (25.9 mg, 0.125 mmol) and 3-ethoxyphenol (17.3 mg, 0.125 mmol) in dimethyl formamide (0.5 mL) was added cesium carbonate (82 mg, 0.25 mmol), the mixture was shaken at 120° C. for 16 hours, filtered and evaporated in vacuo. Water (1 mL) was added and extracted with ethyl acetate (3×1 mL), the combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in THF (0.7 mL) and to this solution was added a 1M aqueous solution of lithium hydroxide (0.7 mL) and the mixture was shaken at 30° C. for 16 hours. The reaction mixture was evaporated in vacuo, a 1M aqueous solution of hydrochloric acid (0.7 mL) was added and extracted with ethyl acetate (3×1 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. To this residue was added methanesulfonamide (28.6 mg, 0.300 mmol) and a solution of 4-dimethylaminopyridine (24.4 mg, 0.200 mmol) and EDCl (38.3 mg, 0.200 mmol) in dichloromethane (1 mL), the solution was shaken at 30° C. for 16 hours and evaporated in vacuo. The crude product was purified on a HPLC column (Sepax BR-C18 100*21.2 mm*5 μm, acetonitrile-water (0.1% trifluoroacetic acid) gradient to yield 6.2 mg (16 μmol) 5-chloro-4-(3-ethoxyphenoxy)-2-fluoro-N-(methylsulfonyl)benzamide. filtered evaporated in vacuo Water (1 mL) was added extracted with ethyl acetate (3×1 mL) the combined organic layers were dried over sodium sulphate filtered evaporated in vacuo The residue was dissolved in THF (0.7 mL) and to this solution was added a 1M aqueous solution of lithium hydroxide (0.7 mL) the mixture was shaken at 30° C. for 16 hours The reaction mixture was evaporated in vacuo a 1M aqueous solution of hydrochloric acid (0.7 mL) was added extracted with ethyl acetate (3×1 mL) The combined organic layers were dried over anhydrous sodium sulphate filtered evaporated in vacuo evaporated in vacuo The crude product was purified on a HPLC column (Sepax

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 5-chloro-2,4-difluorobenzoic acid (2.8 g, 15 mmol) in a solution of HCl in methanol (4 M, 10 mL) was stirred at 60° C. for 4 hours. The reaction was cooled down and the solvent was evaporated to afford the title compound, which was used for the next step without further purification. The reaction was cooled down the solvent was evaporated

反应条件: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of methyl 5-chloro-2,4-difluorobenzoate (2.2 g, 10.7 mmol), tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (2.0 g, 10.7 mmol) and potassium carbonate (4.43 g, 32.1 mmol) in DMF (30 mL) was stirred at 30° C. for 16 h. The mixture was quenched by water and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column (eluting with petroleum ether/ethyl acetate, from 20/1 to 3/1) to give tert-butyl 3-((2-chloro-5-fluoro-4-(methoxycarbonyl)phenoxy)methyl)azetidine-1-carboxylate (1.2 g, 30%) as a pale yellow oil. LCMS (ESI) m/z: 318.0 [M-56+H]. The mixture was quenched by water extracted with EtOAc (50 mL×3) The combined organic layers were washed with brine dried over anhydrous sodium sulfate filtered concentrated The resulting residue was purified by silica gel column (eluting with petroleum ether/ethyl acetate, from 20/1 to 3/1)