反应详情

温度

95 °C

To a stirring solution of 5-bromo-3-methylpicolinic acid (10000 g, 1 equiv, 46.29 moles) in ethanol (50 L) at 0° C. was added sulfuric acid (2.52 L, 1 equiv, 46.29 moles) over 1 h. Following addition of sulfuric acid, the mixture was heated at 95° C. for 20 h. Reaction progress was monitored by using TLC and LCMS. After 20 hours, LCMS showed 12.61% unreacted SM, at RT-0.67 ((M−1)−215.92) and 86.95% product at RT-2.04 ((M+1)−244.2). The reaction mass heated for additional 6 h and LCMS analysis following the additional heating showed 10.07% unreacted SM, at RT-0.7 and 89.93% product at RT-2.08 ((M+1)−244.2. The reaction was stopped by concentrating the reaction mixture under reduced pressure to remove as much solvent as possible. To the residue was added dichloromethane (DCM), (25 L) and the reaction mixture was poured into ice cold water (20 L). The organic (DCM) layer was separated from the aqueous layer and the latter was further extracted twice with DCM (10 L). The combined organic layers were washed with saturated sodium bicarbonate solution (30 L), dried over sodium sulfate, and concentrated under reduced pressure to obtain a brown oil. This brown oil was used in the next step without further purification. Yield: 10.1 Kg, (89.4%); MS (ESI) m/z 244.2 [M+1]+; LCMS purity: 99.11%; 1H NMR (400 MHz, DMSO-d6) δ: 8.61 (s, 1H), 8.13 (s, 1H), 4.29 (q, 2H), 2.44 (s, 1H), 1.28 (t, 3H).

1. customReaction progress
2. customat RT
3. customat RT
4. temperatureThe reaction mass heated for additional 6 h
5. temperatureadditional heating
6. customat RT
7. customat RT
8. concentrationby concentrating the reaction mixture under reduced pressure
9. customto remove as much solvent as possible
10. additionTo the residue was added dichloromethane (DCM), (25 L)
11. additionthe reaction mixture was poured into ice cold water (20 L)
12. customThe organic (DCM) layer was separated from the aqueous layer
13. extractionthe latter was further extracted twice with DCM (10 L)
14. washThe combined organic layers were washed with saturated sodium bicarbonate solution (30 L)
15. dry with materialdried over sodium sulfate
16. concentrationconcentrated under reduced pressure
17. customto obtain a brown oil
18. customThis brown oil was used in the next step without further purification