Application examples of 2-chloro-3-bromo-5-fluoropyridine_Industrial additives

Background and overview of application examples of 2-chloro-3-bromo-5-fluoropyridine

2-Chloro-3-bromo-5-fluoropyridine is a pharmaceutical intermediate, which can be used to prepare tert-butyl 2-(2-chloro-5-fluoropyridin-3-yl)-tetrahydropyrrole- 1-formate ester, which is then used to prepare imidazo[1,2-b]pyridazine macrocyclic kinase inhibitors; 2-chloro-3-bromo-5-fluoropyridine can also be used to prepare 2-chloro-5- Fluoropyridin-3-ylboronic acid is used in the preparation of pyrazolo[1,5-a]pyrimidinylcarboxamide compounds for treating medical disorders in patients.

Application examples of 2-chloro-3-bromo-5-fluoropyridine

Application examples of 2-chloro-3-bromo-5-fluoropyridine Application 1,

The method for preparing tert-butyl 2-(2-chloro-5-fluoropyridin-3-yl)-tetrahydropyrrole-1-carboxylate with 2-chloro-3-bromo-5-fluoropyridine is as follows :

Under nitrogen protection, 1-tert-butoxycarbonyl-pyrrolidine (9.42g, 55.0mmol) was dissolved in anhydrous THF (120mL). Add sec-butyllithium tetrahydrofuran solution (55.0mL, 1.0M, 55.0mmol) at -40°C. After the dripping is completed, react at -40°C for 10 minutes. Then add dropwise a THF solution (33.0) containing 1mol/L zinc chloride. mL, 33.0 mmol), after the dripping was completed, it was raised to room temperature and continued to stir for 30 minutes. Add 2-chloro-3-bromo-5-fluoropyridine (10.5g, 50.0mmol), palladium acetate (560mg, 2.50mmol) and tri-tert-butylphosphine tetrafluoroborate (910mg, 3.10mmol) under nitrogen protection. After stirring at room temperature for 16 hours, the mixture was extracted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Column chromatography (directly elute with petroleum ether/ethyl acetate = 10/1, and then eluate containing the product under reduced pressure to remove the solvent), purify to obtain tert-butyl 2-(2-chloro5-fluoropyridine) -3-yl)-tetrahydropyrrole-1-carboxylic acid (3.80g, 12.6mmol, yield 25%). Characterize the prepared compounds: MS (ESI) m/z=301 (M+1)⁺

Application 2.

The tetrahydrofuran titanium chloride method used to prepare 2-chloro-5-fluoropyridin-3-ylboronic acid is as follows:

To a solution of n-BuLi/THF (1.45mL, 2.5mol/L) in THF (5mL), 3-bromo-2-chloro-5-fluoropyridine (630mg, 3.0mmol) was added dropwise at -78°C. A solution in THF (5 mL). The reaction mixture was stirred at -78°C for an additional 30 minutes, then B(OiPr)₃ (677 mg, 3.6 mmol) was added in THF (2 mL). The mixture was stirred at -78°C for an additional 2 h and quenched with 5% aqueous NaOH (10 mL). The mixture was acidified to pH 1-2 with dilute aqueous HCl and quenched with EA (60 mL x 3). The combined organic phases were dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuo to afford 2-chloro-5-fluoropyridin-3-ylboronic acid (1.5 g, crude) as a gray oil which was used in the next step without further purification. LC-MS m/z:176.1[M+H]⁺. t=0.64min.

References

[1] [Invented in China] CN201811574262.3 An imidazo[1,2-b]pyridazine macrocyclic kinase inhibitor

[2] [Invented in China] CN201780034861.3 Pyrazolo[1,5-a]pyrimidinylcarboxamide compounds and their uses in the treatment of medical conditions