151103-09-2

The general procedure for the synthesis of 4-(difluoromethoxy)-3-(cyclopropylmethoxy)benzaldehyde from bromomethylcyclopropane and 4-difluoromethoxy-3-hydroxybenzaldehyde was as follows: 55 g of 4-(difluoromethoxy)-3-hydroxybenzaldehyde, 42.42 g of K2CO3 (1.05 eq.), 4.86 g of KI (0.1 eq.), and 220 mL of dimethyl sulfoxide ( DMSO) were added to the reactor. The mixture was heated and stirred at 70 °C for 1 hour. Subsequently, a pre-prepared mixture of 42.65 g of bromomethylcyclopropane (1.08 eq.) and 110 mL of DMSO was slowly added dropwise for a controlled time of 1 hour. After the dropwise addition was completed, the reaction was continued at 70 °C for 3 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted by adding 375 mL of toluene and filtered to remove unreacted K2CO3. The filtrate was cooled to 0-5 °C and 375 mL of deionized water was added. The organic and aqueous phases were separated and the organic phase was washed twice with 55 mL of deionized water. Finally, the solvent was removed by distillation under reduced pressure to give 70 g (99% yield) of 4-(difluoromethoxy)-3-(cyclopropylmethoxy)benzaldehyde as a viscous pale yellow liquid.

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