42753-75-3

67-56-1

89-57-6

42753-75-3

In a 5-liter four-necked flask equipped with a reflux condenser, a dropping funnel, a thermometer casing, and a mechanical stirrer, methanol (3500 mL) and 5-aminosalicylic acid (500 g, 3.26 mol) were added and stirring was turned on. The reaction temperature was controlled in the range of 35-40 °C and thionyl chloride (600 mL, 8.16 mol) was added slowly dropwise for about 2 hours. After the dropwise addition, the reaction mixture was heated and refluxed for 15-16 hours, during which the reaction mixture gradually changed to a brown dilute slurry. The progress of the reaction was monitored by thin layer chromatography (TLC) until the residue of 5-aminosalicylic acid was below 1.0% (based on TLC analysis). Subsequently, the following post-treatment was carried out: first, about 2000 mL of methanol was removed by distillation at atmospheric pressure, and then the remaining methanol was azeotropically distilled (3 × 1000 mL) with water at reduced pressure (200-250 mmHg) to obtain a slurry. The slurry was poured into water (3500 mL) and the pH was adjusted first to 5.0 with 25% (w/v) NaOH solution (750 mL) and then to 7.0-7.5 with 20% (w/v) Na2CO3 solution (300 mL).The precipitated solid of methyl 5-amino salicylate was filtered and washed with water (2 x 1000 mL). The filter cake was dried to constant weight at 65 °C under reduced pressure (250 mmHg) to give 490 g of product in 90% yield. Melting point: 93-95°C. Reference: EP 0291159. 1H-NMR (CDCl3) data: δ 3.92 ppm (3H, s, Ar-COOCH3); 6.85 ppm (2H, m, Ar-H); 7.16 ppm (1H, d, J=2.73 Hz, Ar-H). Mass spectral data: m/z 167 (M+), 135, 107, 79.