Water → methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate

Participants

Reaction Conditions

Reaction Steps

0.138 g of tetrakis(triphenylphosphine)palladium, 0.046 g of cuprous iodide, and 0.42 cm3 of 1-bromo-3,5-difluorobenzene were added to a mixture, stirred at a temperature in the region of 20° C. under an inert atmosphere, of 0.95 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine -3-carboxylate in 9.5 cm3 of triethylamine. The mixture was heated at a temperature in the region of 80° C. for 3 hours. After cooling to approximately 20° C., the reaction mixture was taken up in 30 cm3 of ethyl acetate and 30 cm3 of water and stirred for 5 minutes. The organic phase was separated by settling, while the aqueous layer was extracted with 2 times 30 cm3 of ethyl acetate. The organic extracts were combined, washed with 3 times 30 cm3 of water, dried over sodium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm; diameter 2.3 cm; 40 g), elution was carried out with pure ethyl acetate. 2 fractions of 100 cm3 were first collected and then 20-cm3 fractions were obtained. Fractions 8 to 40 were combined and evaporated under the above conditions. 0.967 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate was obtained in the form of a foam with an orange color.

Provenance & Evidence