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
