反应详情

温度

60 °C

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.

1. temperatureAfter cooling to a temperature in the region of 20° C.
2. concentrationthe reaction mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C
3. customThe residue obtained
4. customwas purified by chromatography under a nitrogen pressure of 50 kPa
5. washon a column of silica gel (particle size 20-45 μm; diameter 3 cm; 50 g), elution
6. customfirst a fraction of 200 cm3 was collected
7. concentrationconcentrated as above
8. customA foam was obtained
9. customwhich product was subjected to a second purification by chromatography under a nitrogen pressure of 50 kPa
10. washon a column of silica gel (particle size 20-45 μm; diameter 3 cm; 70 g), elution
11. customfirst a fraction of 250 cm3 was collected
12. customa fraction of 100 cm3 was collected
13. concentrationconcentrated as above
14. customA foam was obtained
15. customThe crystallized product formed
16. filtrationwas filtered off
17. washwashed with 2 times 10 cm3 of a diisopropyl ether/pentane (50/50 by volume) mixture
18. dry with material2 times 10 cm3 of pentane, and dried in the air