Diisopropyl Ether → (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid

Participants

Reaction Conditions

Reaction Steps

A solution of 1.7 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylate in 17 cm3 of dioxane to which had been added 2.58 cm3 of 5N aqueous sodium hydroxide solution was stirred for 15 hours at a temperature in the region of 60° C. After cooling to a temperature in the region of 20° C., the reaction mixture was 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 3 cm; 50 g), elution was carried out with a dichloromethane/methanol (90/10 by volume) mixture, and first a fraction of 200 cm3 was collected, followed by 23-cm3 fractions. Fractions 3 to 21 were combined and then concentrated as above. A foam was obtained, which product was subjected to a second purification by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm; diameter 3 cm; 70 g), elution was carried out with a dichloromethane/methanol (95/5 by volume) mixture, and first a fraction of 250 cm3 was collected, then a fraction of 100 cm3 was collected, followed by 20-cm3 fractions. Fractions 1 to 17 were combined and then concentrated as above. A foam was obtained, which product was taken up in dichloromethane and then in 20 cm3 of a 50/50 mixture of diisopropyl ether and pentane. The crystallized product formed was filtered off, washed with 2 times 10 cm3 of a diisopropyl ether/pentane (50/50 by volume) mixture and then 2 times 10 cm3 of pentane, and dried in the air. 0.524 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid was obtained in the form of a solid with a cream color melting at approximately 97° C.

Provenance & Evidence