Uses
Methyl 4-acetamido-2-methoxybenzoate (Metoclopramide EP Impurity D) is an impurity of bromopride (B686645), which is an antiemetic.
Synthesis
To a solution of methyl 4-amino-2-methoxybenzoate (501 mg, 2.77 mmol) in anhydrous ethanol (8 mL) was slowly added acetic anhydride (0.42 mL, 4.44 mmol, 1.6 equiv). The resulting clarified solution was heated to 60-65 °C and the reaction was maintained at this temperature with stirring for 2 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature and the solvent was subsequently removed using a rotary evaporator. The residue was washed sequentially with deionized water (10 mL) and saturated sodium bicarbonate solution (10 mL) and then extracted with ethyl acetate (20 mL in two portions of 10 mL each). The organic phases were combined, washed sequentially with deionized water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, the organic phase was concentrated under reduced pressure to give methyl 4-acetamido-2-methoxybenzoate (545 mg, 88% yield) as a white solid. The product was characterized by 1H NMR (400 MHz, DMSO-d6): δ 2.07 (s, 3H, AcNH-4), 3.74 (s, 3H, OMe-2 or COOMe), 3.77 (s, 3H, COOMe or OMe-2), 7.19 (br d, J = 8.8 Hz, 1H, H-5), 10.22 (s, 1H, NH ). Ref: J. Med. Chem. 2007, 50(15), 3561-3572.
References
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3561 - 3572
[2] Patent: WO2011/123890, 2011, A1. Location in patent: Page/Page column 118-119
[3] Patent: WO2015/26792, 2015, A1. Location in patent: Paragraph 0542
[4] Archiv der Pharmazie, 1980, vol. 313, # 4, p. 297 - 300
[5] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 7, p. 2311 - 2315
