Synthesis
Step B: Synthesis of 4-amino-2,3-difluoro-5-nitrobenzoic acid; To a suspension of 2,3,4-trifluoro-5-nitrobenzoic acid (167.2 g, 0.756 mol, 1.0 equiv) in 400 mL of distilled water was slowly added concentrated ammonium hydroxide solution (28% NH3, 340 g, 380 mL, 4.23 mol, 5.6 equiv), and the reaction temperature was controlled to be below 6.0 °C over 2-2.5 h. After addition, stirring was continued for 50 min, followed by slowly warming the reaction mixture to room temperature. equiv), and the reaction temperature was controlled to be below 6.0 °C for 2-2.5 h. After addition, stirring was continued for 50 min, after which the reaction mixture was slowly warmed up to room temperature and maintained for 3-4 h. The reaction progress was monitored by HPLC. The progress of the reaction was monitored by HPLC and when the conversion was >90%, the reaction mixture was cooled in an ice-water bath and the pH was adjusted to 2 by slow dropwise addition of concentrated hydrochloric acid (350 mL). Stirring was continued for 1 h under ice-bath conditions, followed by filtration. The filter cake was washed with 1 L of distilled water and 350 mL of methyl tert-butyl ether (MTBE), and dried in an oven at 48°C overnight to obtain 134.9 g of yellow solid product.HPLC purity analysis showed that the purity at 220 nm and 254 nm was 83.6% and 96.96%, respectively. The MTBE filtrate was combined, concentrated by rotary evaporation and dried under vacuum overnight to give a second batch of 9.9 g of yellow solid product with HPLC purities of 81.1% (220 nm) and 95.40% (254 nm), respectively. 4-Amino-2,3-difluoro-5-nitrobenzoic acid was obtained in a total yield of 144.8 g in 88%. -129.0; 13C NMR (100 MHz, DMSO-d6) δ 106 (qd, J = 10 Hz), 126 (CH), 128 (C), 140 (CF, dd, J = 241, 16 Hz), 140.8 (C, dd, J = 12, 4 Hz), 153 (CF, dd, J = 263, 11 Hz), 164 ( COOH).IR (cm-1): 3494, 3383, 1697, 1641, 1280.Mass spectrum (APCI-) m/z: 217 (M-1).
References
[1] Patent: US2004/116710, 2004, A1. Location in patent: Page 6; 16
[2] Patent: WO2007/76245, 2007, A2. Location in patent: Page/Page column 18-19
[3] Patent: US2003/232869, 2003, A1. Location in patent: Page 9; 16
[4] Patent: WO2013/142182, 2013, A2. Location in patent: Page/Page column 21; 22
[5] Patent: WO2007/2092, 2007, A1. Location in patent: Page/Page column 50
