8-benzyloxy-2-chloroquinoline

Synthesis

Step IB: Preparation of 8-(benzyloxy)-2-chloroquinoline: 8-(benzyloxy)quinolin-2(1H)-one (26.5 g, 105 mmol) and dichloroethane (DCE, 105 mL) were added to the reaction flask. Oxalyl chloride (18.4 mL, 211 mmol) was added dropwise under stirring, followed by N,N-dimethylformamide (DMF, 0.5 mL) as a catalyst. The reaction mixture was heated to 85 °C and the reaction was stirred at this temperature overnight. Upon completion of the reaction, the mixture was cooled to room temperature and concentrated on a rotary evaporator to give an oily crude product. Dichloromethane (DCM, 300 mL) was added to the crude product and the organic layer was washed with saturated sodium bicarbonate solution (300 mL). The organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated to give the oil. Purification by recrystallization from toluene afforded 28.4 g of the target product 8-(benzyloxy)-2-chloroquinoline in quantitative yield. Step 2B: Preparation of 8-(benzyloxy)-2-chloroquinoline: 8-(benzyloxy)quinolin-2(1H)-one (26.5 g, 105 mmol) and ethylene dichloride (DCE, 105 mL) were added to the reaction flask. Oxalyl chloride (18.4 mL, 211 mmol) was added dropwise under stirring, followed by N,N-dimethylformamide (DMF, 0.5 mL) as a catalyst. The reaction mixture was heated to 85 °C and the reaction was stirred at this temperature overnight. Upon completion of the reaction, the mixture was cooled to room temperature and concentrated on a rotary evaporator to give an oily crude product. Dichloromethane (DCM, 300 mL) was added to the crude product and the organic layer was washed with saturated sodium bicarbonate solution (300 mL). The organic layer was separated, dried with anhydrous sodium sulfate, filtered and concentrated to give the oil. Purification by recrystallization from toluene afforded 28.4 g of the target product 8-(benzyloxy)-2-chloroquinoline in quantitative yield.

References

[1] Patent: WO2008/124323, 2008, A1. Location in patent: Page/Page column 50; 57
[2] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 1, p. 78 - 83
[3] Patent: WO2014/100730, 2014, A1. Location in patent: Paragraph 00348
[4] Patent: WO2004/2490, 2004, A2. Location in patent: Page/Page column 42
[5] Patent: WO2004/2992, 2004, A1. Location in patent: Page 51