97.8% |
Stage #1: 7-Fluoro-1H-[1,8]naphthyridin-2-one; 4-benzyloxy-butan-1-ol With tetrabutylammomium bromide In tetrahydrofuran at 25℃; for 0.5h;
Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 30℃; for 4h;
Stage #3: With hydrogenchloride In tetrahydrofuran; water at 30℃; for 0.5h; |
A85
[0889] A first intermediate compound, 7-(4-benzyloxybutoxy)-[1,8]naphthyridin-2-one, was produced according to the reaction summarized below, as follows. 7-Fluoro-1H-[1,8]naphthyridin-2-one (210 g, 1.28 moles), tetrabutylammonium bromide (20 g, 0.064 mole), 4-benzyloxybutanol (235.8 mL, 1.34 mole), and THF (2.5 L) were charged to a 12 L three-neck round bottom flask equipped with a mechanical stirrer, an addition funnel, and inerted with nitrogen (g). The suspension was stirred at 25° C. for 30 minutes. An ice bath was used to cool the reaction mixture and 1 M potassium tert-butoxide in THF (2.87 L, 2.87 mole) was added via addition funnel at a rate to keep the internal temperature below 30° C. Upon complete addition, the thick slurry became a solution and was stirred at 25° C. for 4 hours or until the reaction was complete by LC/MS analysis. 1 N HCl (1.6 L, 1.6 mole) was added slowly to keep the reaction temperature below 30° C. and stirred for 30 minutes. THF was removed using a rotoevaporator and 7 L of ethyl acetate was added to form a biphasic mixture. The mixture was transferred to a separatory funnel, where the aqueous layer was collected and reextracted with 1 L of ethyl acetate. The ethyl acetate layers were combined, filtered through Celite, washed with water, then with brine, and collected. MgSO4 was added, then filtered, and product was concentrated under vacuum to a yellow solid (405 g, 1.25 mole, 97.8%). MS: APCI: M+1: 325.1 (Exact Mass: 324.15). 1H NMR (CDCl3). |