Synthesis
The general procedure for the synthesis of 2-chloro-4-fluoro-5-nitrobenzoic acid from 2-chloro-4-fluorobenzoic acid was as follows: 50 g of concentrated sulfuric acid and 0.8 g of the catalyst prepared in Example 1 were added to a reaction flask, followed by the addition of 10 g of 2-chloro-4-fluorobenzoic acid in batches. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was cooled to 0°C in an ice bath, and then 5 g of fuming nitric acid was added slowly and dropwise, controlling the reaction temperature between -5 and 8°C. The reaction was continued for 5 to 8 hours until the content of 2-chloro-4-fluorobenzoic acid was less than 0.5%. The reaction mixture was slowly poured into 80 g of crushed ice and the solid product was collected by filtration. The filter cake was washed with 30 g of ice water and subsequently air-dried at 65 °C to give 12.0 g of the white solid product 2-chloro-4-fluoro-5-nitrobenzoic acid in 97.1% yield and 97.2% purity. The isomer of formula (II) was 1.1% by weight.
References
[1] Patent: CN106866684, 2017, A. Location in patent: Paragraph 0131-0132; 0204-0205
[2] Patent: CN106905161, 2017, A. Location in patent: Paragraph 0014; 0015; 0016; 0017
[3] Farmaco, 2004, vol. 59, # 6, p. 463 - 471
[4] Synthesis, 1987, # 10, p. 883 - 887
[5] Patent: US2002/45550, 2002, A1
