[Synthesis]
1. Iodination reaction: Methyl 4-hydroxybenzoate (35.5 g, 0.233 mol) is dissolved in 200 mL of acetic acid with stirring and heated to 65°C. The reaction is carried out in the same manner as the reaction. A solution of ICI (37.8 g, 0.233 mol) dissolved in 50 mL of acetic acid was added slowly and dropwise over 40 minutes. After maintaining the reaction at 65°C for 5 hours, stirring was continued at room temperature for 16 hours. The precipitated product was collected by filtration, washed with water and dried under vacuum to give 27.5 g of the target product (99% purity by LCMS and HNMR). The mother liquor was concentrated and the residue was washed with water and dried under vacuum to give an additional 31 g of product (95% purity by LCMS and NMR). total yield of methyl 4-hydroxy-3-iodobenzoate was 58.5 g in 90.3% yield. lCMS m/z.
2. Cyanidation reaction: Methyl 4-hydroxy-3-iodobenzoate (28 g, 0.1 mol) was dissolved in 100 mL DMF, CuCN (9.92 g, 0.11 mol) and NaCN (0.49 g, 0.11 mol) were added. The system was protected by nitrogen and heated to 105 °C with stirring for 18 hours. Cooled to room temperature, filtered to remove the precipitate and the filter cake was washed with EtOAc. The organic phases were combined, diluted with 200 mL of water and extracted with EtOAc (2 x 200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Vacuum drying yielded 18 g (100% yield) of methyl 3-cyano-4-hydroxybenzoate, which was characterized by LCMS and HNMR.
3. Etherification reaction: Methyl 3-cyano-4-hydroxybenzoate (18 g, 0.11 mol) was dissolved in 100 mL DMF, 2-bromopropane (14.2 mL, 0.15 mol) and anhydrous potassium carbonate (41.9 g, 0.3 mol) were added. Under nitrogen protection, heat to 90 °C with stirring overnight. After cooling, it was diluted with 200 mL of water and extracted with CH2Cl2 (2 x 200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 20.5 g (99% yield) of methyl 3-cyano-4-isopropoxybenzoate as an oil, characterized by LCMS and HNMR.
4. Esterification reaction: Methyl 3-cyano-4-isopropoxybenzoate (20.5 g, 0.093 mol) was dissolved in 200 mL of methanol:water (6:4) mixed solvent, NaOH (5.61 g, 0.14 mol) was added, and stirred at room temperature for 2 hours. The solution was filtered through a silica gel plug and concentrated to remove the solvent. The solid was redissolved in 200 mL of CH2Cl2 and perfluorophenyl 2,α,2-trifluoroacetate (19.3 mL, 0.11 mol) and triethylamine (19.5 mL, 0.14 mol) were added. It was allowed to stand overnight and filtered, and the solids were washed with CH2Cl2. The organic phases were combined, purified on a short silica gel column and concentrated to give 29 g (83.5% yield) of perfluorophenyl 3-cyano-4-isopropoxybenzoate, which was characterized by LCMS and HNMR. |