Preparation of 2,6-difluoro-4-iodopyridine_Industrial additives

Preparation background and overview of 2,6-difluoro-4-iodopyridine

2,6-difluoro-4-iodopyridine can be used as a pharmaceutical synthesis intermediate. 2,6-difluoropyridine can be used as the reaction raw material, and the intermediate 3-chloro can be generated under the action of n-butyllithium and iodine. Hydroxypyridine-iodo-2,6-difluoropyridine is further reacted to prepare 2,6-difluoro-4-iodopyridine.

Preparation of 2,6-difluoro-4-iodopyridine

Step 1 of the preparation of 2,6-difluoro-4-iodopyridine:

Add n-butyllithium (7.5 mL, 12 mmol, 1.6 M in hexanes) dropwise to diisopropylamine (1.7 mL, 12 mmol) in TH IV at -78°C under nitrogen protection. To the solution in sodium borate F (10 mL), after 20 minutes, add 2,6-difluoropyridine (1.1 mL, 12 mmol) dropwise, after another 1 hour, maintain -78°C, and add iodine (3.2 g, 13.5 mmol) in THF (5 mL). The solution was allowed to warm to room temperature over 1 hour, washed with 10% aqueous Na2SO3 (10 mL), and extracted with ethyl acetate (50 mL). The organic extract was dried (Na₂SO₄), concentrated in vacuo, and the residue was recrystallized from petroleum ether to obtain 3-iodo-2,6-difluoropyridine ( 2.72g, 94%), colorless crystals, yield (2.72g, 94%), melting point 38-40°C.

Preparation of 2,6-difluoro-4-iodopyridine Step 2:

Under nitrogen protection, at -78°C, add n-butyllithium (6.5 mL, 10.4 mmol, 1.6 M hexane solution) dropwise to 50 ml of diisopropylamine (1.5 mL, 4.8 mmol). of THF (5 mL) solution. After 20 minutes, a solution of 3-iodo-2,6-difluoropyridine (2.46 g, 10.4 mmol) in THF (12 mL) was added dropwise to the mixture via cannula. After maintaining the reaction at -78°C for 10 hours, THF (5 mL) and H₂O (0.51 g, 28 mmol) were added, and the mixture was warmed to room temperature within 1 hour. The mixture was washed with 10% Na₂SO₃ aqueous solution (10 mL) and extracted with ethyl acetate (150 mL). The organic extracts were dried (Na₂SO₄), concentrated in vacuo and the residue purified by chromatography (with 5:95 ethyl acetate/petroleum ether; Rf = 0.6 elution), 2,6-difluoro-4-iodopyridine (1.72g, 70%) was obtained as colorless crystals, yield (1.72g, 70%), melting point 80-82°C.

References

[1] Cheng D , Croft L , Abdi M , et al. Synthetic Entries to Substituted Bicyclic Pyridones[J]. Organic Letters, 2007, 9(25):5175-5178.