Hydrochloric Acid → 10-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid

Temperature

0 °C

A solution of potassium hydroxide (22.35 g, 398.4 mmol) in water (70 ml) was added to a solution of dimethyl 2-{8-[(3S,4S)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]octyl}-2-(4,4,5,5,5-pentafluoropentyl)malonate (7.0 g, 9.96 mmol) in ethanol (140 ml), followed by heating under reflux for 15 hours. The reaction mixture was adjusted to pH 4 by addition of hydrochloric acid at 0° C. and then concentrated under reduced pressure. Water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, a solution of boron tribromide in dichloromethane (1N, 59.76 ml, 59.76 mmol) was added to a solution of the residue in dichloromethane (100 ml) at −78° C. The resulting mixture was stirred and warmed to 0° C. over 3 hours. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, toluene (50 ml) was added to the residue, followed by heating under reflux for 72 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate/dichloromethane=5/1/1) to give 10-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid (3.4 g, Yield 57.8%).

1. temperatureby heating
2. temperatureunder reflux for 15 hours
3. concentrationconcentrated under reduced pressure
4. additionWater was added to the residue, which
5. extractionwas then extracted with ethyl acetate
6. washThe organic layer was washed with water
7. dry with materialdried over anhydrous magnesium sulfate
8. distillationAfter distilling off the solvent
9. extractionwas then extracted with dichloromethane
10. washThe organic layer was washed with saturated aqueous sodium chloride
11. dry with materialdried over anhydrous magnesium sulfate
12. distillationAfter distilling off the solvent, toluene (50 ml)
13. additionwas added to the residue
14. temperatureby heating
15. temperatureunder reflux for 72 hours
16. additionWater was added to the reaction mixture, which
17. extractionwas then extracted with ethyl acetate
18. washThe organic layer was washed with saturated aqueous sodium chloride
19. dry with materialdried over anhydrous magnesium sulfate
20. distillationAfter distilling off the solvent
21. customthe residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate/dichloromethane=5/1/1)

ORD record

ord-2007552770a147bcaf425138bfab5a7a

Source dataset

uspto-grants-2003_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06610733B2