methyl 3-chloro-4-fluorobenzoate

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 3-chloro-4-fluorobenzoate (23.6 mg, 0.125 mmol) and 2-piperidin-1-ylpyrimidin-5-ol (Preparation 10, 22.4 mg 0.125 mmol) in pyridine (0.5 mL) were added cesium carbonate (122 mg, 0.375 mmol) and copper powder (16 mg, 0.25 mmol) and the reaction mixture was shaken at 120° C. for 16 hours. The reaction mixture was filtered and evaporated in vacuo. Water (1 mL) was added and the mixture extracted with EtOAc (3×1 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was dissolved in tetrahydrofuran (0.7 mL), aqueous lithium hydroxide solution (0.7 mL of a 1M solution, 0.7 mmol) was added and the reaction shaken at 30° C. for 16 hours. The reaction was evaporated in vacuo and a 1 M aqueous solution of hydrochloric acid (0.7 mL) was added. The mixture was extracted three times with EtOAc (3×1 mL), the combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting residue, methanesulfonamide (11.9 mg, 0.125 mmol), DMAP (45.8 mg, 0.375 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55 mg, 0.28 mmol) were dissolved in dichloromethane (1 mL) and shaken at 30° C. for 16 hours before evaporation in vacuo. The residue purified on a HPLC column (YMC-pack ODS-AQ 150*30 mm*5 μm, acetonitrile-water (0.1% trifluoroacetic acid) gradient) to afford the title compound (5.23 mg, 12.7 μmol). The reaction mixture was filtered evaporated in vacuo Water (1 mL) was added the mixture extracted with EtOAc (3×1 mL) The combined organic layers were dried over magnesium sulfate filtered evaporated in vacuo The residue was dissolved in tetrahydrofuran (0.7 mL) aqueous lithium hydroxide solution (0.7 mL of a 1M solution, 0.7 mmol) was added the reaction shaken at 30° C. for 16 hours The reaction was evaporated in vacuo a 1 M aqueous solution of hydrochloric acid (0.7 mL) was added The mixture was extracted three times with EtOAc (3×1 mL) the combined organic layers were dried over magnesium sulfate filtered evaporated in vacuo shaken at 30° C. for 16 hours before evaporation in vacuo The residue purified on a HPLC column (YMC-pack ODS-AQ 150*30 mm*5 μm, acetonitrile-water (0.1% trifluoroacetic acid) gradient)