Sodium Iodide → HCID 12043784, compound

A solution of potassium hydroxide (4.35 g, 77.65 mmol) in water (50 ml) was added to a solution of 1-acetoxy-8-[(3S,4S)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]octane (7.31 g, 15.53 ml) in ethanol (100 ml), and the resulting mixture was heated with stirring under reflux for 12 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then evaporated to remove the solvent. The residue was dissolved in dichloromethane (100 ml), and triethylamine (4.33 ml, 31.06 mmol) and methanesulfonyl chloride (1.8 ml, 23.29 mmol) were added to the solution followed by stirring for 1 hour and 30 minutes at 5° C. After the reaction was completed, water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then evaporated to remove the solvent. Sodium iodide (11.6 g, 77.65 mmol) was added to a solution of the residue in acetone (200 ml), followed by heating under reflux for 3 hours. After the reaction mixture was filtered and concentrated under reduced pressure, water was added to the residue, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then evaporated to remove the solvent. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10) to give 1-iodo-8-[(3S,4S)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]octane (4.0 g, 7.42 mmol). Sodium hydride (0.62 g, 15.58 mmol) was added to a solution of separately prepared dimethyl 2-(4,4,5,5,5-pentafluoropentyl)malonate (4.33 g, 14.85 mmol) in tetrahydrofuran (40 ml) followed by stirring for 30 minutes at 0° C. A solution of 1-iodo-8-[(3S,4S)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]octane in tetrahydrofuran (40 ml) was added to the resulting mixture followed by stirring for 24 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/30) to give dimethyl 2-{8-[(3S,4S)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]octyl}-2-(4,4,5,5,5-pentafluoropentyl)malonate (3.7 g, Yield 71%) as a foamy oil.

1. temperaturethe resulting mixture was heated
2. temperatureunder reflux for 12 hours
3. concentrationAfter the reaction mixture was concentrated under reduced pressure, water
4. additionwas added to the residue, which
5. extractionwas then extracted with ethyl acetate
6. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
7. customevaporated
8. customto remove the solvent
9. dissolutionThe residue was dissolved in dichloromethane (100 ml)
10. stirringby stirring for 1 hour and 30 minutes at 5° C
11. extractionwas then extracted with dichloromethane
12. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
13. customevaporated
14. customto remove the solvent
15. temperatureby heating
16. temperatureunder reflux for 3 hours
17. filtrationAfter the reaction mixture was filtered
18. concentrationconcentrated under reduced pressure, water
19. additionwas added to the residue, which
20. extractionwas then extracted with ethyl acetate
21. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
22. customevaporated
23. customto remove the solvent
24. customThe residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10)

ORD record

ord-7d7aa4a4f10d4b1283e8aaef3abd6a4e

Source dataset

uspto-grants-2003_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06610733B2