General steps:
1. 3-Aminophenol (1 g, 9.16 mmol, 1.0 eq.) was dissolved in THF (35 mL) and a solution of di-tert-butyl dicarbonate (2.41 g, 11.1 mmol, 1.2 eq.) in THF (10 mL) was slowly added. The reaction mixture was refluxed overnight and the solvent was evaporated under vacuum to give a brown residue.
2. The residue was dissolved in EtOAc, washed sequentially with H2O, saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated in vacuum to give the carbamate derivative as a gray solid in quantitative yield.
3. Imidazole (1.37 g, 20.1 mmol, 2.0 eq.) was slowly added to a solution of DMF (15 ml) of the above solid (2.11 g, 10.0 mmol, 1.0 eq.) at 0 °C, followed by a solution of DMF (5 ml) of TBSCl (1.75 g, 11.6 mmol, 1.15 eq.). After stirring at room temperature overnight, the reaction mixture was partitioned between half-saturated NaHCO3 solution and AcOEt. The organic layer was washed sequentially with half-saturated and NH4Cl solution, saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated in vacuum to give the di-protected compound (2.89 g, 89%) as a white solid.
4. The above compound (500 mg, 1.54 mmol, 1.0 eq.) was dissolved in freshly distilled ether (15 ml) and a pentane [1.6 M] solution of tert-butyllithium (2.31 ml, 3.71 mmol, 2.4 eq.) was added at 40 °C and stirred for 2 hours. DMF (0.95 ml, 12.36 mmol, 8.0 eq.) was then injected and the reaction mixture was warmed to 0 °C and stirred for 1 hour. The reaction mixture was partitioned between water and ether and the aqueous layer was extracted three times with ether. The combined organic layers were washed twice with brine, dried over MgSO4 and concentrated in vacuum and purified by column chromatography (petroleum ether/ether, 99:1) to give the formylated product (239 mg, 44%) as a white powder.
5. Potassium fluoride (140.4 mg, 2.42 mmol, 2.2 eq.) was added to a solution of the above formylated product (386.2 mg, 1.099 mmol, 1.0 eq.) in DMF (30.9 ml), followed by benzyl bromide (0.17 ml, 1.43 mmol, 1.3 eq.). After stirring at room temperature overnight, the reaction mixture was diluted in water and AcOEt and the aqueous layer was extracted twice with AcOEt. The combined organic layers were sequentially washed twice with 0.5 M HCl solution, once with water, twice with LiCl (20%) solution and brine, dried over MgSO4 and then concentrated in vacuum to quantitatively obtain the O-benzyl derivative (351.3 mg) as a white powder.
6. The O-benzyl derivative (351.3 mg, 1.073 mmol, 1.0 eq.) was dissolved in ethanol (4.3 ml), diethyl malonate (0.4 ml, 2.68 mmol, 2.5 eq.), piperidine (0.26 ml, 2.7 mmol, 2.5 eq.) and acetic acid (0.006 ml, 0.107 mmol, 0.1 equivalent). After refluxing and stirring overnight, the mixture was cooled to 5 °C, the precipitate was filtered and washed with cold ethanol (20 °C) to give the quinolinone product (198 mg, 57%).
7. K2CO3 (2 eq.) and LiI (20-25 mol%) were added to a solution of quinolinone derivatives (1 eq.) in DMSO (1.5 ml/mmol), followed by alkyl halide (1.2 eq.). After reflux heating overnight, the reaction mixture was partitioned between water and DCM and the aqueous layer was extracted three times with DCM. The combined organic layers were washed with water, dried over MgSO4 and concentrated in vacuum.
8. The ester product (1 eq.) was dissolved in THF (6 ml/mmol) and a solution of LiOH (10 eq.) in water (6 ml/mmol) was added. The mixture was stirred vigorously and heated at reflux for 1 hr 40 min before THF was removed by vacuum distillation. pH was adjusted to 2 with HCl (1 M), the white precipitate was diluted in AcOEt, and the aqueous layer was extracted with AcOEt three times. The combined organic layers were washed with water, dried over MgSO4 and concentrated in vacuum, and the crude product was recrystallized from ethanol to give a sample of sufficient purity for biological tests.
