87808-48-8

Step 1: Synthesis of methyl 3-fluoro-4-methylbenzoate: 3-fluoro-4-methylbenzoic acid (20 g, 130 mmol) was dissolved in thionyl chloride (80 ml) and heated to reflux for 2 hrs (the reaction was monitored by TLC until the feedstock completely disappeared). Subsequently, excess thionyl chloride was removed by distillation under reduced pressure. The residue was cooled to 0 °C and methanol (100 ml) was slowly added dropwise under stirring. After the dropwise addition, the reaction mixture was continued to be stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 3-fluoro-4-methylbenzoate as a white solid, which could be used directly in the subsequent reaction without further purification (Yield: 21 g, Yield: 96%).

[1] Organic Process Research and Development, 2008, vol. 12, # 6, p. 1137 - 1141
[2] Patent: WO2011/100433, 2011, A1. Location in patent: Page/Page column 56
[3] Patent: WO2014/102376, 2014, A1. Location in patent: Page/Page column 44-45
[4] Patent: WO2014/102377, 2014, A1. Location in patent: Page/Page column 49
[5] Patent: WO2012/80221, 2012, A1. Location in patent: Page/Page column 82