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