2-HYDROXY-4-FLUOROPYRIDINE

To a cooled solution of HF-pyridine complex (70percent, 13.1 mL) at 0°C was slowlyadded 4-amino-2-pyridone 5 (1.85 g, 16.8 mmol). The mixture was cooled to -20°Cand tBuONO (3.0 mL, 25.2 mmol) was slowly added. The reaction mixture wasstirred at -20°C for 0.5h, then allowed to warm to r.t. for 2h and finally heated at 60°Cfor 1h. The mixture was cooled to 0°C and sat. aq. Na2CO3 was added. The aqueouslayer was extracted with ethyl acetate (5x), and the combined organic layers weredried (Na2SO4), filtered and concentrated under reduced pressure. The crude waspurified by flash chromatography on silica gel (DCM/MeOH: 95/5) to give 1a (1.14 g, 60percent) as a colorless solid.To a cooled solution of HF-pyridine complex (70percent, 13.1 mL) at 0°C was slowlyadded 4-amino-2-pyridone 5 (1.85 g, 16.8 mmol). The mixture was cooled to -20°Cand tBuONO (3.0 mL, 25.2 mmol) was slowly added. The reaction mixture wasstirred at -20°C for 0.5h, then allowed to warm to r.t. for 2h and finally heated at 60°Cfor 1h. The mixture was cooled to 0°C and sat. aq. Na2CO3 was added. The aqueouslayer was extracted with ethyl acetate (5x), and the combined organic layers weredried (Na2SO4), filtered and concentrated under reduced pressure. The crude waspurified by flash chromatography on silica gel (DCM/MeOH: 95/5) to give 1a (1.14 g, 60percent) as a colorless solid.Into a 25 mL round-bottom flask were added tert-butyl (3R)-3-ethylpiperazine-1- carboxylate(200 mg, 0.93 mmol, 1 equiv.) and To a cooled solution of HF-pyridine complex (70%, 13.1 mL) at 0C was slowlyadded 4-amino-2-pyridone 5 (1.85 g, 16.8 mmol). The mixture was cooled to -20Cand tBuONO (3.0 mL, 25.2 mmol) was slowly added. The reaction mixture wasstirred at -20C for 0.5h, then allowed to warm to r.t. for 2h and finally heated at 60Cfor 1h. The mixture was cooled to 0C and sat. aq. Na2CO3 was added. The aqueouslayer was extracted with ethyl acetate (5x), and the combined organic layers weredried (Na2SO4), filtered and concentrated under reduced pressure. The crude waspurified by flash chromatography on silica gel (DCM/MeOH: 95/5) to give 1a (1.14 g, 60%) as a colorless solid.[0257] Reference R [0258] Synthesis of 4-fluoro-l-(piperidin-4-ylmethyl)pyridin-2(17i)-one, hydrogen chloride salt [0260] Step 1 : tert-butyl 4-((4-fluoro-2-oxopyridin-l(2H)-yl)methyl)piperidine-l -carboxylate [0261] A solution of 4-fluoropyridin-2(lH)-one (1 12 mg, 0.990 mmol), tert-butyl 4- (bromomethyl)piperidine- 1 -carboxylate (276 mg, 0.990 mmol) and potassium carbonate (274 mg, 1.981 mmol) in dioxane (1981 mu) was stirred at 80 C until complete by LCMS analysis. HPLC purification afforded the title compound as a white solid.

Molecular Weight:113.09
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:113.027691913
Monoisotopic Mass:113.027691913
Topological Polar Surface Area:29.1
Heavy Atom Count:8
Complexity:171
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes