Diisopropylamine → 5-((R)-1-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid

Participants

Reaction Conditions

Reaction Steps

n-Butyllithium (2.5 M in hexanes; 7.23 mL, 18.07 mmol) was added dropwise to a solution of diisopropylamine (2.55 mL, 18.07 mmol) in 8 mL of THF at −40° C. The mixture was stirred for 1 h at −40° C. This solution was cannulated into a 3-necked 250-mL round-bottomed flask that contained a solution of tert-butyl(3S)-4-((1R)-1-(6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate (4.87 g, 15.06 mmol) in 60 mL of THF at −78° C. After 15 min at −78° C., triisopropyl borate (Aldrich; 6.92 mL, 30.1 mmol) was added, and the resulting mixture was stirred at −78° C. for 15 min and then allowed to warm to ambient temperature. The reaction mixture was subsequently treated with 1 M NaOH (80 mL) and allowed to stir for 20 min. The aqueous layer was separated and the organic layer was discarded. The aqueous layer was treated with 10% HCl (aq) until a pH of about 5 to 6 was achieved. The resulting mixture was diluted with EtOAc (20 mL) and the mixture was extracted with 8:2 EtOAc/MeOH (200 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give (5-((1R)-1-((2S)-4-(tert-butoxycarbonyl)-2-methyl-1-piperazinyl)ethyl)-2-fluoro-3-pyridinyl)boronic acid (5.01 g, 13.64 mmol, 91% yield) as an off-white solid. m/z (ESI, +ve) 368.1 (M+H)−.

Provenance & Evidence