4-[2-(Dimethylamino)ethoxy]benzaldehyde

Uses

4-[2-(Dimethylamino)ethoxy]benzaldehyde is used in preparation of cyclosporin A analogs as NTCP inhibitors.

Synthesis

First, 80 g of p-hydroxybenzaldehyde, 128 g of potassium carbonate, 150 mL of DMF and 10 mL of isopropyl were mixed and stirred. Subsequently, 101 g of 2-(dimethylamino)chloroethane hydrochloride was added to the mixture, followed by 80 g of triethylamine. The reaction mixture was stirred at 80°C for 2 hours. Upon completion of the reaction, the reaction solution was cooled to room temperature, poured into 700 mL of water and extracted with 500 mL of chloroform. 300 mL of 2 mol-L-1 sulfuric acid was added to the chloroform layer for extraction. To the aqueous phase, 200 mL of 20% sodium hydroxide solution was added under ice water bath conditions, followed by extraction with 1000 mL of ethyl acetate. The organic phase was dried with anhydrous sodium sulfate and the ethyl acetate was recovered under reduced pressure. The fractions with boiling points of 142-144 °C/0.533 kPa were collected by distillation under reduced pressure to give 110.2 g of 4-(2-dimethylaminoethoxy)benzaldehyde in 86.3% yield. 100 g of 4-(2-dimethylaminoethoxy)benzaldehyde was dissolved in 150 mL of methanol and 26.5 g of sodium borohydride was slowly added under ice bath conditions, and the progress of the reaction was monitored by TLC until the reaction was complete. Excess sodium borohydride was quenched by addition of ammonium chloride. After removing methanol under reduced pressure, 300 mL of water was added to the crude product and extracted with 200 mL of ethyl acetate. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by distillation under reduced pressure to give 87.9 g of colorless liquid in 87% yield.

References

[1] Patent: CN106518706, 2017, A. Location in patent: Paragraph 0009
[2] Patent: WO2006/51079, 2006, A1. Location in patent: Page/Page column 5
[3] Patent: WO2015/91531, 2015, A1. Location in patent: Page/Page column 52
[4] Patent: WO2015/86693, 2015, A1. Location in patent: Page/Page column 65
[5] Patent: WO2012/79154, 2012, A1. Location in patent: Page/Page column 76; 77