Example 1: Preparation of 2,3-dihydroxybenzoic acid
1. To a stirred solution of 2,3-dimethoxybenzoic acid (100 g; 0.549 mol) in dichloromethane (500 mL) was added a catalytic amount of DMF (2 mL), and thionyl chloride (130.6 g; 1.102 mol) was slowly added at 30-35 °C, and the reaction was stirred for 2 hours. The progress of the reaction was monitored by TLC (feedstock residue ≤5%). If the reaction was not completed, thionyl chloride (9.8 g; 0.823 mol) was added. 2.
2. Upon completion of the reaction, the reaction solution was slowly added to ammonia solution (580 mL) pre-cooled to -5 °C, keeping the temperature below 15 °C. The reaction solution was then stirred at 30-35 °C. Subsequently, the reaction was stirred at 30-35 °C for 30 min.
3. Separate the organic phase and concentrate by distillation at atmospheric pressure at less than 50 °C. Add toluene (100 mL) and azeotropically dehydrate to a moisture content of <0.5%.
4. Dissolve the resulting benzamide compound in toluene (500 mL), add POCl3 (126.3 g; 0.824 mol), and raise the temperature to 80-85°C for 1-2 hours (HPLC monitor to benzamide residue ≤ 1.0%). POCl3 (10.1 g; 0.06 mol) was supplemented as necessary.
5. After the reaction solution was cooled to 30-35 °C, ice water (1000 mL, 0-5 °C) was slowly added. After partitioning, the organic phase was washed with 8% NaHCO3 solution, azeotropically dehydrated to ≤0.2% water (110-115 °C), concentrated to 1/3 of the original volume, cooled to 40 °C and then further cooled to 30-35 °C. The reaction solution was then dried in a separate reaction vial.
6. In another reaction flask, toluene (160 mL) was mixed with triethylamine (199.7 g; 1.977 mol) at 30-35 °C and stirred for 10 min. AlCl3 (52.7 g x 5; 1.977 mol at 10 min intervals) was added in batches and the temperature was controlled to ≤ 50 °C. After warming to 70-75 °C, the solution obtained in step 5 was added slowly (30 min) and the reaction was maintained for 8 h (HPLC monitoring: 2,3-dimethoxybenzyl cyanide ≤ 0.25%, 3-methoxy-2-hydroxybenzyl cyanide ≤ 0.2%). Triethylamine (27.7 g; 0.27 mol) and AlCl3 (36.6 g; 0.27 mol) were supplemented as necessary.
7. The reaction solution was cooled to 30-35 °C and quenched with pre-cooled aqueous HCl (water 500 mL + concentrated HCl 500 mL, 15 °C). stirred for 30 min at 25-30 °C and the solids were filtered. The aqueous layer was extracted with MIBK (320 mL) and the organic phases were combined after diatomaceous earth filtration. The aqueous layer was again extracted with MIBK (320+160 mL), the combined organic phases were washed with 20% NaCl solution and azeotropically dehydrated to ≤0.2% moisture (110 °C).
8. Cooled to 30 ℃ and sequentially filtered through 0.45 μm/1 μm filter membrane, added 1% EDTA solution (400mL) stirred for 30 minutes, 10 μm filter cloth filtration. The residue after concentration of the organic phase was treated with dichloromethane (400 mL), and the solid obtained was filtered and dried in vacuum at 60-65°C for 6 h. 2,3-dihydroxybenzonitrile was obtained (56 g, yield 75.4%, HPLC purity 99.81%; impurity A:0.05%, impurity B:0.07%).
