GENERAL STEPS: Methyl 4-hydroxybenzoate (35.5 g, 0.233 mol) was dissolved in 200 mL of acetic acid, stirred and heated to 65°C. 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. The reaction mixture was stirred at 65°C for 5 hours, followed by 16 hours at room temperature. 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 the target product (95% purity analyzed by LCMS and HNMR).The total yield of methyl 4-hydroxy-3-iodobenzoate was 58.5 g in 90.3% yield.LCMS m/z 278.
Synthesis of methyl 3-cyano-4-hydroxybenzoate 3: Methyl 4-hydroxy-3-iodobenzoate 2 (28 g, 0.1 mol) was dissolved in 100 mL of DMF and CuCN (9.92 g, 0.11 mol) and NaCN (0.49 g, 0.11 mol) were added. After the system was displaced with nitrogen, it was heated to 105 °C and stirred for 18 hours. It was cooled to room temperature, filtered to remove the precipitate and the filter cake was washed with EtOAc. The combined organic phases were diluted with 200 mL of water and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried with sodium sulfate, filtered and concentrated to dryness. Vacuum drying gave 18 g (100% yield) of product 3, which was characterized by LCMS and HNMR.
Synthesis of methyl 3-cyano-4-isopropoxybenzoate 4: Methyl 3-cyano-4-hydroxybenzoate 3 (18 g, 0.11 mol) was dissolved in 100 mL of DMF and 2-bromopropane (14.2 mL, 0.15 mol) and anhydrous potassium carbonate (41.9 g, 0.3 mol) were added. After the system was displaced with nitrogen, it was heated to 90 °C and stirred overnight. Cooled to room temperature, the reaction mixture was diluted with 200 mL of water and extracted with CH2Cl2 (2 x 200 mL). The organic layers were combined, dried with sodium sulfate, filtered and concentrated to dryness to give 20.5 g (99% yield) of the oily product 4, which was characterized by LCMS and HNMR.
Synthesis of perfluorophenyl 3-cyano-4-isopropoxybenzoate 6: Methyl 3-cyano-4-isopropoxybenzoate 4 (20.5 g, 0.093 mol) was dissolved in 200 mL of a mixed methanol-water solvent of 6:4, NaOH (5.61 g, 0.14 mol) was added, and stirred for 2 h at room temperature. The solution was filtered through a silica gel plug and the solvent was removed under vacuum. The solid was redissolved in 200 mL of CH2Cl2 and perfluorophenyl 2,α,2-trifluoroacetate 5 (19.3 mL, 0.11 mol) and triethylamine (19.5 mL, 0.14 mol) were added. After standing overnight, the solution was filtered and the solid was washed with CH2Cl2. The combined organic phases were purified on a short silica gel column and concentrated to dryness to give 29 g (83.5% yield) of product 6, which was characterized by LCMS and HNMR.
