Preparation of 2-fluoro-3-aldehyde-4-iodopyridine_Industrial additives

Preparation background and overview of 2-fluoro-3-aldehyde-4-iodopyridine

2-Fluoro-3-aldehyde-4-iodopyridine can be used as a pharmaceutical synthesis intermediate. 2-fluoropyridine can be used as a reaction raw material and reacted with iodine to prepare the intermediate 2-fluoro-4-iodopyridine, which can be further reacted with iodine. It is prepared by the reaction of ethyl formate and can be used to prepare the compound 2-fluoro-4-iodo-3-pyridinecarboxylic acid.

Preparation of 2-fluoro-3-aldehyde-4-iodopyridine

Preparation of 2-fluoro-3-aldehyde-4-iodopyridine 1) Synthesis of compound 2-fluoro-4-iodopyridine

Under nitrogen protection, diisopropylamine (35mL, 0.25moL) was dissolved in 100mL THF, cooled to -30°C, and n-BuLi (2.5N, 96mL, 0.24mol) was added dropwise. During the dropwise addition, the temperature was maintained at -30℃ or below. The reaction solution was stirred at -30°C for 15 minutes, then slowly raised to 0°C for 30 minutes and set aside. Under nitrogen protection, 2-fluoropyridine (CAS No. 372-48-5) (19.42g, 0.2mol) was dissolved in 100 mL of dry THF, cooled to below -70°C, dropped into the above LDA solution, and reacted at -70°C 1 hour. Iodine (61g, 0.24mol) was dissolved in 50mL of dry THF, dropped into the above reaction system, and reacted at -75°C for 1 hour. Quench with saturated ammonium chloride and stir at 25°C for 30 minutes. The hydroxypyridine was evaporated to remove THF and extracted with EtOAc (500mL*2). The organic phases were combined, washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate and concentrated to dryness to obtain crude 2-fluoro-4-iodolepidolite pyridine (30g, collected rate 67%). ¹HNMR (300MHz, DMSO-d6): δ8.37-8.43(m, 1H), 8.21-8.22(m, 1H), 7.13-7.18(m, 1H).

Preparation of 2-fluoro-3-aldehyde-4-iodopyridine 2) Synthesis of compound 2-fluoro-3-aldehyde-4-iodopyridine

Under nitrogen protection, diisopropylamine (17mL, 96.9mmoL) was dissolved in 300mL THF, cooled to -30℃, n-BuLi (46.5mL, 116mmol) was dropped in, and the temperature was maintained at -30℃ during the dropping process. the following. The reaction solution was stirred at -30°C for 15 minutes, then slowly raised to 0°C for 30 minutes and set aside. 2-Fluoro-4-iodopyridine (21.6g, 96.9mmol) was dissolved in 100 mL of dry THF, cooled to below -70°C, and the above-mentioned LDA solution was added dropwise, and reacted at -70°C for 1 hour. Ethyl formate (10 mL, 121 mol) was dropped into the above reaction system, and the temperature was slowly raised to -50°C within 1 hour. Quench with saturated ammonium chloride and stir at 25°C for 30 minutes. THF was evaporated and the reaction solution was extracted with EtOAc (300mL*2). The organic phases were combined, washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate and concentrated to dryness. Column chromatography (PE/EtOAc: 50:1 to 10:1) After purification, the product 2-fluoro-3-aldehyde-4-iodopyridine (13.0 g, yield 53%) was obtained. ¹HNMR (300MHz, DMSO-d6): δ10.15 (s, 1H), 7.97 (d, J=5.1Hz, 1H), 7.87 (d, J=5.1Hz, 1H).

Preparation and application of 2-fluoro-3-aldehyde-4-iodopyridine

For the preparation of 2-fluoro-4-iodo-3-pyridinecarboxylic acid: 2-fluoro-3-aldehyde-4-iodopyridine (13.3g, 53mmol) was dissolved in 466mL t-BuOH and 133mL water, ice Water cooling. Add isopentene (13.3g, 53mmol), Na₂HPO₄ (70g, 583mmol), and then add NaClO₂ (24g) in batches , 265 mmol), the reaction solution was stirred at 25°C for 1.5 hours. After diluting 800mL of DCM, adjust to pH=2 with 6N hydrochloric acid, separate the organic phase, and extract the aqueous phase with DCM/MeOH (20:1, 1000mL*2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and crystallized in DCM/PE (1:1) solution to obtain the product 2-fluoro-4-iodo-3-pyridinecarboxylic acid (11.5g, collected rate: 81%). ¹HNMR (300MHz, DMSO-d6): δ14.26 (brs, 1H), 8.02 (d, J＝4.2Hz, 1H), 7.94 (dd, J＝3.9, 0.6Hz, 1H ).

References

[1] WO2018157779 – A new isoindoline derivative, its pharmaceutical composition and application