Hexane → (3S)-2-(2,4-Difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-1-butene

Temperature

8 °C

A mechanically stirred mixture of methyl triphenylphosphonium bromide (169.2 g, 0.474 moles) in 350 ml of dry tetrahydrofuran was cooled to 8° C. A solution of lithium bis (trimethylsilyl) amide (84.8 g, 0.507 moles) in 500 ml tetrahydrofuran was added to the above mixture at a rate so that the temperature of the mixture remained at 23° C. After stirring for 1 hour at room temperature the contents were cooled to 31 70° C. and stirred for 1/2 hour. Then a solution of compound 4a, (2S)-2',4'-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone, (100 g, 0.370 moles) in 250 ml of tetrahydrofuran was added slowly to maintain the temperature of the mixture below -70° C. The resulting mixture was stirred at 7° C. for 17 hours. Added 65 ml of ethyl acetate to the above mixture followed by the addition of 3.9 L of hexane and allowed to stand for 15 minutes. The solid was removed by suction-filtration and washed thoroughly with 650 ml of hexane. The filtrate was washed with 1:1 mixture of methanol: water (2×1300 ml) and brine (1300 ml) then dried over MgSO4. The solvent was evaporated to give the title compound 5a as an oil (91.5 g, 92%).

1. customremained at 23° C
2. temperaturewere cooled to 31 70° C.
3. stirringstirred for 1/2 hour
4. temperatureto maintain the temperature of the mixture below -70° C
5. stirringThe resulting mixture was stirred at 7° C. for 17 hours
6. waitto stand for 15 minutes
7. customThe solid was removed by suction-filtration
8. washwashed thoroughly with 650 ml of hexane
9. washThe filtrate was washed with 1:1 mixture of methanol
10. dry with materialwater (2×1300 ml) and brine (1300 ml) then dried over MgSO4
11. customThe solvent was evaporated

ORD record

ord-3ac3d67601fe4734a3ef47e2ef598e99

Source dataset

uspto-grants-2000_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06133485