Preparation method of ethyl 4-amino-3-methoxybenzoate_Kain Industrial Additive

Background and overview^[1]

4-Amino-3-methoxybenzoic acid ethyl ester can be used as a pharmaceutical synthesis intermediate. If 4-amino-3-methoxyethyl benzoate is inhaled, move the patient to fresh air; if skin contact occurs, remove contaminated clothing and rinse the skin thoroughly with soap and water. If discomfort occurs, Seek medical attention; if eye contact occurs, separate eyelids, rinse with running water or saline, and seek medical attention immediately; if ingested, rinse mouth immediately, do not induce vomiting, and seek medical attention immediately.

Preparation^[1]

4-Amino-3-methoxybenzoic acid ethyl ester was prepared as follows: 22 liters of a container equipped with an electric heating mantle, a thermocouple probe, an overhead mechanical stirrer, a water-cooled condenser, a nitrogen bubbler and an addition funnel. 3-neck RBF was filled with 4-amino-3-methoxybenzoic acid (1.0 kg, 5.98 mol, 1.0 equiv) and ethanol (200 proof) (10.0 L, 10 vol). Without external cooling, sulfuric acid (1.17kg, 0.64L, 12.0mol, 2.0eq) was slowly added over 1 hour, the slurry initially thickened, and eventually all solids dissolved to form a dark solution. Exothermic addition brought the temperature to -45°C; the solution was then refluxed with additional heating and held at reflux overnight. The HPLC sample was removed, showing 5% of the starting benzoic acid remaining. Switch the reflux head and distill out 2.5L. The reaction mixture was cooled to 6 °C in an ice bath and the pH was slowly adjusted to 12 by adding an aqueous solution of sodium hydroxide (50 wt%, 1.03 kg, 681 ml, 12.9 mol, 2.15 equiv). Keep the temperature below 20°C. After stirring for 30 minutes, an additional amount of water (4.0 L) was added and stirred at approximately 100 °C. 10°C for 30 minutes. The solid was filtered, washed thoroughly with water (4.0 L), and dried under vacuum at 65 °C overnight. The yield of ethyl 4-amino-3-methoxybenzoate was 1.04kg (89.1%) as a light brown solid.

m.p.=83-87℃ (DSC); 1HNMR (300MHz, CDCl3) δ7.56 (1H, dd, J=7.9, 1.5Hz), 7.47 (1H, dJ=1.5Hz), 6.66 (1H, d , J=7.9Hz), 4.33 (2H, t, J=7.2Hz), 4.27 (1H, brs), 3.90 (3H), 1.37 (3H, t, J=7.2Hz).

Main reference materials

[1](WO2014128094)ASYMMETRICSYNTHESISOFASUBSTITUTEDPYRROLIDINE-2-CARBOXAMIDE