6-Chloro-5-fluoro-nicotinic acid synthesis
- Product Name:6-Chloro-5-fluoro-nicotinic acid
- CAS Number:38186-86-6
- Molecular formula:C6H3ClFNO2
- Molecular Weight:175.54
34552-15-3
38186-86-6
2-Chloro-3-fluoro-5-methylpyridine (512 mg, 3.5 mmol) was used as starting material and dissolved in a solvent mixture of pyridine (2.5 mL) and water (2.5 mL). Potassium permanganate (1.1 g, 6.9 mmol) was added to this solution in batches and after the first addition, the reaction mixture was heated to 100 °C and stirred for 1 hour. Subsequently, additional potassium permanganate (totaling 3.3 g, 20.7 mmol) was added in two batches over a period of 2 hours. During the reaction, if solids accumulate in the condenser, it can be washed with water and pyridine. After continued stirring at 100 °C for 1 h, the reaction mixture was cooled to room temperature. The reaction was quenched with saturated aqueous Na2S2O3 and stirred for 30 minutes. The reaction mixture was filtered and the filtrate was acidified to pH 2 with 1.5 M HCl. The aqueous phase was extracted with EtOAc (3×), the organic phases were combined and washed with brine (1×), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by rapid chromatography on silica gel, using a gradient elution of 90% to 70% petroleum ether-EtOAc to afford 5-fluoro-6-chloronicotinic acid as a white solid (300 mg, 49% yield).
34552-15-3
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$10.00/1g
38186-86-6
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$25.00/100mg
Yield:38186-86-6 49%
Reaction Conditions:
with pyridine;potassium permanganate;water at 100; for 4 h;
Steps:
6-Chloro-5-fluoronicotinic acid
To a solution of 2-chloro-3-fluoro-5-methylpyridine (512 mg, 3.S2mmol) in pyridine (2.5 mL) and water (2.5 mL) was added one portion of potassium permanganate (1.1 g, 6.9 mmol). The reaction mixture was heated to 100 °C. Two more equal portion of potassium permanganate (for a total of 3.3 g, 20.7 mmol) were added afterrespectively 1 h and 2 h of stirring at 100 °C. When needed, the solid accumulated in the condenser were washed down with water and pyridine. After another 1 h of stirring at 100 °C, the reaction mixture was cooled down to room temperature. The reaction mixture was quenched with saturated aqueous Na2S2O3 and stirred 30 minutes. The mixture was filtered, then acidified to pH 2 with HC1 5 M. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (lx), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 90% to 70% PE-EtOAc gradient to give the title compound as a white solid (300 mg, 49%).
References:
REINMÜLLER, Viktoria WO2018/154118, 2018, A2 Location in patent:Page/Page column 106; 107