Synthesis
Step 3: Synthesis of methyl 4-bromophenylacetate
Sulfuric acid (56.5 mL) was slowly added dropwise to a solution of 206.6 g of 4-bromophenylacetic acid in methanol (800 mL), with the rate of dropwise acceleration being controlled to prevent violent exotherm. After the dropwise addition, the reaction mixture was heated to reflux and maintained at reflux for 2 hours. Subsequently, the device was replaced and the reflux condenser was replaced with a distillation header and approximately 400 mL of methanol was removed by distillation at atmospheric pressure. The reaction system was cooled down to 50 °C and the reaction was continued with stirring for 16 hours. Upon completion of the reaction, the mixture was cooled to room temperature, transferred to a dispensing funnel and partitioned with dichloromethane (1 L) and water (600 mL). The organic phase was separated, washed with saturated sodium bicarbonate solution and dried with anhydrous magnesium sulfate. The organic phase was concentrated under reduced pressure to give 220.1 g (98% yield) of methyl 4-bromophenylacetate as a colorless oil.
HNMR (CDCl3): δ 3.59 (s, 2H), 3.70 (s, 3H), 7.16 (d, 2H), 7.45 (d, 2H).
References
[1] Journal of Organic Chemistry, 1994, vol. 59, # 9, p. 2620 - 2622
[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 13, p. 2843 - 2866
[3] Journal of Medicinal Chemistry, 2001, vol. 44, # 17, p. 2701 - 2706
[4] Patent: US2008/21024, 2008, A1. Location in patent: Page/Page column 80
[5] Patent: WO2010/86820, 2010, A1. Location in patent: Page/Page column 41
