Hydrochloric Acid → 4-Hydroxy-1-(3-methylbutyl)-3-(8-methyl-1,1-dioxido-4h-[1,3]oxazolo[5,4-h][1,2,4]benzothiadiazin-3-yl)-1,8-naphthyridin-2(1h)-one

Participants

Reaction Conditions

Reaction Steps

To a solution of the product of Example 12A (16.7 mg, 0.0714 mmol) and the product of Example 352F (23.1 mg, 0.0714 mmol) in anhydrous tetrahydrofuran (2 mL) at 0° C. was added sodium hydride (60%, 11.4 mg, 0.286 mmol) under a nitrogen atmosphere. The reaction was heated at reflux for 3 hours, cooled to 0° C., and treated with glacial acetic acid (0.165 mL). The resulting yellow solution was heated at reflux for 2 hours, cooled to 0° C., diluted with water (5 mL), and acidified with 1N aqueous hydrochloric acid to pH 3. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound as a yellow solid (20 mg, 60%). MS (ESI−) m/z 466 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 0.99 (d, J=6.25 Hz, 6 H) 1.58 (m, 2 H) 1.71 (m, 1 H) 2.73 (s, 3H) 4.50 (m, 2 H) 7.50 (dd, J=7.72, 4.41 Hz, 1 H) 7.64 (d, J=8.82 Hz, 1 H) 8.10 (d, J=8.82 Hz, 1 H) 8.57 (dd, J=7.91, 2.02 Hz, 1 H) 8.89 (dd, J=4.60, 2.02 Hz, 1 H) 14.18 (s, 1 H). A suspension of the product of Example 352G (14.6 mg, 0.0312 mmol) in anhydrous tetrahydrofuran (3 mL) and distilled water (1 mL) was treated with 0.998 N aqueous sodium hydroxide (0.0313 mL, 0.0312 mmol) and the yellow solution mixed for 15 minutes. The solvent was removed under reduced pressure and the residue dried to afford the sodium salt of Example 352G (15 mg, 98%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.25 Hz, 6 H) 1.48 (m, 2 H) 1.65 (m, 1 H) 2.67 (s, 3 H) 4.30 (m, J=8.82, 6.25 Hz, 2 H) 7.13 (dd, J=7.91, 4.60 Hz, 1 H) 7.21 (d, J=8.82 Hz, 1 H) 7.86 (d, J=8.82 Hz, 1 H) 8.38 (dd, J=8.09, 1.47 Hz, 1 H) 8.53 (m, J=2.94 Hz, 1 H) 16.09 (s, 1 H).

Provenance & Evidence