Preparation of 2,3-dibromo-5-fluoropyridine_Industrial additives

Preparation background and overview of 2,3-dibromo-5-fluoropyridine

2,3-Dibromo-5-fluoropyridine is an organic intermediate that can be prepared from 5-fluoro-pyridin-2-ylamine by bromination to prepare 3-bromo-5-fluoro-pyridine-2 -based amine, and then prepare 2,3-dibromo-5-fluoropyridine through diazotization reaction.

Preparation of 2,3-dibromo-5-fluoropyridine

Preparation step 1 of 2,3-dibromo-5-fluoropyridine: 3-bromo-5-fluoro-pyridin-2-ylamine:

NBS (10 g, 56.2 mmol) was slowly added to a solution of 5-fluoro-pyridin-2-ylamine (55) (12.4 g, 56.2 mmol) in MeCN (200 mL). The reaction mixture was stirred at RT overnight. At the end, the solution was filtered and the filtrate was concentrated to obtain a residue, which was purified by silica gel chromatography (10% to 20% EtOAc in petroleum ether) to obtain 3-bromo-5-fluoro-pyridine- as a yellow solid. 2-ylamine (56) (5.2 g, 27.2 mmol, 31% yield). ESI-MS(M+1): 191, calculated for C5H4BrFN2 190.

Preparation step 2 of 2,3-dibromo-5-fluoropyridine: 2,3-dibromo-5-fluoropyridine:

Dissolve 3-bromo-5-fluoro-pyridin-2-ylamine (56) (1.91 g, 0.01 mol) in 48% hydrobromic acid (30 mL) at 60°C. After cooling to -5°C, bromine (3.24g, 0.02mol) was added dropwise within 5min. A solution of sodium nitrite (1.01 g, 0.02 mol) in water (3 mL) was then added at a rate that maintained the temperature of the reaction mixture between -5°C and 0°C. When finished, bring the temperature to 25°C. The bromine was reduced with excess solid sodium sulfite and the reaction mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (30 mL), brine (30 mL), dried over Na₂SO₄ and filtered. The filtrate was evaporated in vacuo from the calcium carbonate and the residue was purified by silica gel flash column chromatography (10% to 20% EtOAc in petroleum ether) to afford 2,3-dibromo-5-fluoropyridine (1.27 g, 5.0 mmol, 50% yield).

References

[1] [China invention, China invention authorization] CN201180034741.6 Non-dichromated pyridine saturated nitrogen heterocyclic compound that can be used as a PDE10 inhibitor