4-ethoxy-2-fluorophenol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 56.3 g 4-ethoxy-fluorophenol in 200 ml THF was treated with 84.0 ml pentamethyl-diethylentriamine, cooled to −78° C., then slowly treated with 251 ml 1.6 M n-butyllithium solution in hexane. The reaction mixture was stirred at −78° C. for 3 hrs and then slowly treated with 89.7 ml trimethyl borate. After stirring for 15 min at −78° C., the solution was warmed up to r.t., stirred for an additional 2 hrs and cooled to 0° C. To the mixture were then added dropwise 63.2 ml acetic acid. After stirring for 30 min, 68.3 ml 30% aqueous hydrogen peroxide solution were added slowly. The reaction mixture was warmed up to r.t., stirred overnight and subsequently treated with 200 ml saturated sodium sulfite solution. The mixture was diluted with water and extracted with hexanes. The organic layer was washed with water and brine, dried over MgSO4, filtrated and concentrated to give 60.3 g 5-ethoxy-2-fluoro-phenol as a light brown liquid which was used for the next step without further purification. After stirring for 15 min at −78° C. the solution was warmed up to r.t. stirred for an additional 2 hrs cooled to 0° C After stirring for 30 min The reaction mixture was warmed up to r.t. stirred overnight extracted with hexanes The organic layer was washed with water and brine dried over MgSO4 filtrated concentrated

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-ethoxy-2-fluoro-phenol (Intermediate 5; 125 mg, 0.801 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 270 mg, 0.801 mmol), and potassium carbonate (244 mg, 1.761 mmol) in 4 mL of dimethylformamide was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, the precipitate was filtered and the filtrate was extracted with ethyl acetate three times and the combined organic extracts were washed with saturated brine, and dried over sodium sulfate. The mixture was filtered, concentrated and purified by flash silica gel chromatography (4% methanol in dichloromethane) to afford 4-[4-(4-ethoxy-2-fluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (141 mg, 39%) as a white solid. Mass spectrum M+H-Boc=358. the precipitate was filtered the filtrate was extracted with ethyl acetate three times the combined organic extracts were washed with saturated brine dried over sodium sulfate The mixture was filtered concentrated purified by flash silica gel chromatography (4% methanol in dichloromethane)

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

Procedure: 10% Palladium-on-carbon (26 mg, 0.11 mmol) was added to a solution of 1-benzyloxy-4-ethoxy-2-fluoro-benzene (260 mg, 1.06 mmol) in ethyl acetate (20 mL). The reaction mixture was shaken under hydrogen (30 psi) overnight. The reaction mixture was filtered through celite and a pad of silica gel, which was washed with 40% ethyl acetate/hexane. The solvent was removed to give 4-ethoxy-2-fluoro-phenol (155 mg, 94%) as a white solid which was used directly in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 1.25 (t, 3H, J=6.9 Hz), 3.89 (q, 2H, J=6.9 Hz), 6.52-6.56 (m, 1H), 6.71-6.85 (m, 2H), 9.21 (s, 1H). The reaction mixture was filtered through celite a pad of silica gel, which was washed with 40% ethyl acetate/hexane The solvent was removed

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 56.3 g 4-ethoxy-fluorophenol in 200 ml THF was treated with 84.0 ml pentamethyl-diethylentriamine, cooled to −78° C., then slowly treated with 251 ml 1.6 M n-butyllithium solution in hexane. The reaction mixture was stirred at −78° C. for 3 hrs and then slowly treated with 89.7 ml trimethyl borate. After stirring for 15 min at −78° C., the solution was warmed up to r.t., stirred for an additional 2 hrs and cooled to 0° C. To the mixture were then added dropwise 63.2 ml acetic acid. After stirring for 30 min, 68.3 ml 30% aqueous hydrogen peroxide solution were added slowly. The reaction mixture was warmed up to r.t., stirred overnight and subsequently treated with 200 ml saturated sodium sulfite solution. The mixture was diluted with water and extracted with hexanes. The organic layer was washed with water and brine, dried over MgSO4, filtrated and concentrated to give 60.3 g 5-ethoxy-2-fluoro-phenol as a light brown liquid which was used for the next step without further purification. After stirring for 15 min at −78° C. the solution was warmed up to r.t. stirred for an additional 2 hrs cooled to 0° C After stirring for 30 min The reaction mixture was warmed up to r.t. stirred overnight extracted with hexanes The organic layer was washed with water and brine dried over MgSO4 filtrated concentrated