Potassium Hydroxide → 2-(1-(Tert-butoxycarbonylamino)ethyl)-6-fluoro-3-(pyridin-2-yl)quinoline-4-carboxylic acid

Participants

Reaction Conditions

Reaction Steps

(S)-tert-Butyl 3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate (910 g, 3.44 mol, 1.0 equiv) and 5-fluoroisatin (597 g, 3.62 mol, 1.05 equiv) were dissolved in ethanol/H2O (1:1, 6.0 L each). To this solution was added KOH pellets (609 g, 10.84 mol, 3.15 equiv). The reaction mixture was then heated at 82° C. (internal temperature) overnight. The reaction was monitored using LCMS. Upon completion, the reaction mixture was cooled and evaporated in vacuo to remove ethanol. The aq layer was then washed with DCM (3×4.0 L) and acidified using concd HCl to pH 4. (The acidification procedure was carried out in the following way: The aq layer was taken in a wide mouth flask assembled with mechanical stirrer and pH meter and the flask was cooled using ice-water bath. To this cooled solution was slowly added conc. HCl. To suppress the heat and fumes, small portions of crushed ice was periodically added inside the solution. A yellow solid precipitated out during the addition of conc. HCl). The resultant yellow solid was filtered immediately, thoroughly washed with water (3×1.0 L), triturated with methanol (3×1.0 L), (Note: the product solubility in methanol is very low) then with hexanes (2.0 L), and dried under high vacuum at 60° C. to obtain 2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-(pyridin-2-yl)quinoline-4-carboxylic acid as a creamy white solid: 1H NMR (300 MHz, DMSO-d6): δ 1.10 (s, 2H), 1.21 (d, J=6.3 Hz, 3H), 1.30 (s, 7H), 4.82-4.89 (m, 1H), 7.10 (d, J=7.5 Hz, 1H), 7.45-7.49 (m, 1H), 7.56-7.61 (m, 2H), 7.76-7.83 (td, J=3.0 Hz, 1H), 7.93-7.99 (td, J=2.0 Hz, 1H), 8.16-8.21 (m, 1H), 8.71 (d, J=4.8 Hz, 1H); LC-MS (ESI) m/z 412.2 [M+H]+.

Provenance & Evidence