Water → 5-Propyl-2-(4-(4-chlorophenyl)-3,5-difluorophenyl)-1,3-dioxane

Temperature

-60 °C

5-Propyl-2-(3,5-difluorophenyl)-1,3-dioxane (5.0 g; 20.6 mmol), which had been synthesized in Step 1 of Example 1, was dissolved in THF (50 ml), and the solution was cooled to -60° C. in a nitrogen atmosphere. A solution (16.1 ml; 25.8 mmol) of 1.60M n-butyl lithium in hexane was added dropwise thereto so that the temperature of the mixture did not exceed -55° C. The mixture was stirred for 50 minutes with the temperature being maintained below -55° C. Subsequently, a solution (51.6 ml; 25.8 mmol) of 0.5M zinc chloride in THF was added dropwise so that the temperature of the mixture did not exceed -50° C. Thereafter, the mixture was warmed to room temperature and stirred for 30 minutes. Tetrakistriphenylphosphine palladium (0.5 g) and 1-bromo-4-chlorobenzene (4.94 g; 25.8 mmol) were added, and the mixture was refluxed for 3 hours. Water (100 ml) was added to the resultant reaction mixture, and the material produced was extracted with toluene. The extract was sequentially washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and saturated brine and dried over magnesium sulfate. Subsequently, the solvent was evaporated. The residue was purified by column chromatography (eluent: toluene). The solvent was evaporated, and the residue was recrystallized twice from heptane, to thereby obtain 4.10 g (11.6 mmol) of 5-propyl-2-(4-(4-chlorophenyl)-3,5-difluorophenyl)-1,3-dioxane. The yield of this compound from 5-propyl-2-(3,5-difluorophenyl)-1,3-dioxane was 56.3%.

1. customdid not exceed -55° C
2. temperaturebeing maintained below -55° C
3. customdid not exceed -50° C
4. temperatureThereafter, the mixture was warmed to room temperature
5. stirringstirred for 30 minutes
6. temperaturethe mixture was refluxed for 3 hours
7. customreaction mixture
8. customthe material produced
9. extractionwas extracted with toluene
10. washThe extract was sequentially washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and saturated brine
11. dry with materialdried over magnesium sulfate
12. customSubsequently, the solvent was evaporated
13. customThe residue was purified by column chromatography (eluent: toluene)
14. customThe solvent was evaporated
15. customthe residue was recrystallized twice from heptane

ORD record

ord-ce3499d974cd4ddf9258fc4dcd1b8457

Source dataset

uspto-grants-1999_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05858272