Potassium Hydroxide → 5-fluoro-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine

Participants

Reaction Conditions

Reaction Steps

A solution of 3-fluoro-5-hydroxypyridine (500 mg, 4.43 mmol, as prepared in step 10f below) in dimethylformamide (20 mL) was treated with ground KOH (400 mg, 7.10 mmol) and stirred for 30 minutes at 80° C. To this mixture was rapidly added the 1-(t-butyloxycarbonyl)-(2S)-p-toluene-sulfonyloxymethylazetidine (1.05 g, 4.39 mmol, as prepared in Step 10b below) dissolved in dimethylformamide (5 mL) and the reaction mixture was subsequently stirred for 16 h at 80° C. The mixture was concentrated to remove the dimethylformamide and the resultant residue diluted with water and extracted with EtOAc (3×). The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo. This material was purified by flash chromatography (silica gel; hexane/EtOAc, 10:1) to give 5-fluoro-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (692 mg, 56%): 1H NMR (CDCl3, 300 MHz) δ1.40 (s, 9H), 2.30 (m, 2H), 3.92 (m, 2H), 4.16 (m, 1H), 4.40 (m, 1H), 4.54 (m, 1H), 7.05 (m, 1H), 8.20 (m, 2H); MS (CI/NH3) m/z: 283 (M+H)+. To 5-fluoro-3-(1-Boc-(2S)-azetidinylmethoxy)pyridine from above (320 mg, 1.14 mmol) was added HCl/Et2O in methylene chloride at 0° C., and the solution was stirred for 2 h. The solvent was removed and the residue was recrystallized from EtOH/Et2O to afford the title compound (250 mg): mp 165-167° C.; [α]D25 27.8 (c 0.56, MeOH); 1H NMR (D2O, 300 MHz) δ2.70 (m, 2H), 4.10 (m, 2H), 4.50 (d, J=4.5 Hz, 2H), 5.01 (m, 1H), 7.80 (tt, J=3 Hz, 1H), 8.42 (dd, J=3, 6 Hz, 2H); MS (CI/NH3) m/z 183 (M+H)+, 200 (M+NH4)+.

Provenance & Evidence