Background and overview[1]
3-Amino-5-hydroxybenzoic acid can be used as a pharmaceutical synthesis intermediate. If 3-amino-5-hydroxybenzoic acid is inhaled, move the patient to fresh air; if there is skin contact, take off contaminated clothing, rinse the skin thoroughly with soap and water, and seek medical attention if you feel unwell; if the eye contact If exposed to sunlight, 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]
The preparation of 3-amino-5-hydroxybenzoic acid is as follows:
Preparation of 3,5-dinitrobenzoic acid (compound 5A)
Under ice bath, 15 mL of concentrated nitric acid was added dropwise to a solution of benzoic acid (6.1 g, 50 mmol) in concentrated sulfuric acid (30 mL), and stirred at room temperature for 15 hours. Heat to 100°C and continue stirring for 4 hours. Cool to room temperature, add 10 mL of concentrated nitric acid dropwise, heat to 100°C, continue stirring for 3 hours, and continue stirring for 3 hours after reaching 135°C. Cool to room temperature, pour the reaction solution into a mixture of 80g ice and 80g water, continue stirring for 30 minutes, filter, and wash the filter cake with water to remove sulfuric acid to obtain 5g of crude compound 5A with a yield of 50%.
Preparation of 3-methoxy-5-nitrobenzoic acid (compound 5B)
At -78°C, n-butyllithium (24 mL, 60 mmol) was added dropwise to methanol, and stirring continued for 15 minutes. Methanol is removed by rotary evaporation to obtain lithium methoxide. Dissolve lithium methoxide in hexamethylphosphoric triamide (50 mL), add compound 5A (2.5 g, 11.8 mmol), stir at room temperature for 18 hours, heat to 80°C and continue stirring for 6 hours. Cool to room temperature, pour the reaction solution into a mixture of ice and 6NH2SO4, extract with diethyl ether (3×300mL), dry over anhydrous sodium sulfate, filter, and remove the solvent to obtain 2g of crude compound 5B, with a yield of 87%.
Preparation of 3-hydroxy-5-nitrobenzoic acid (compound 5C)
At -10°C, boron tribromide (1.26 mL, 13 mmol) was dropped into a solution of compound 5B (860 mg, 4.36 mmol) in dichloromethane (20 mL), and the reaction was carried out at room temperature for 15 hours. Cool with ice water, add 10 mL of water, continue stirring for 30 minutes, extract with ethyl acetate (3 × 50 mL), wash with saturated brine, dry with anhydrous sodium sulfate, filter, and remove the solvent to obtain the crude compound 5C, which is directly put into the next step.
Preparation of 3-amino-5-hydroxybenzoic acid (compound 5D)
Compound 5C was dissolved in methanol (20 mL), and hydrogenated under normal pressure for 2 hours under Pd/C catalysis. Filter through diatomaceous earth to remove Pd/C, and spin off the methanol to obtain the crude product of compound 8D 3-amino-5-hydroxybenzoic acid.
Main reference materials
[1] (CN104045552) Medicinal compounds as neuroprotective agents
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