Lithium Hexamethyldisilazide → (3S,5R,6R)-3-Allyl-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one

Temperature

-10 °C

(3S,5R,6R)-6-(4-Chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one and (3R,5R,6R)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one (18 g, 51.0 mmol, Example 4, Step D) was added to an oven dried 500 mL round-bottom flask. The solid was dissolved in anhydrous toluene and concentrated to remove adventitious water. 3-Bromoprop-1-ene (11.02 mL, 127 mmol, passed neat through basic alumina prior to addition) in tetrahydrofuran (200 mL) was added and the reaction vessel was evacuated and refilled with argon three times. Lithium bis(trimethylsilyl)amide (1.0 M, 56.1 mL, 56.1 mmol) was added dropwise at −40° C. (dry ice/acetonitrile bath) and stirred under argon. The reaction was allowed to gradually warm to −10° C. and stirred at −10° C. for 3 hours. The reaction was quenched with saturated ammonium chloride (10 mL), concentrated, and the crude product was diluted in water (150 mL) and diethyl ether (200 mL). The layers were separated and the aqueous layer was washed twice more with diethyl ether (200 mL/each). The combined organic layer was washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to a residue. The residue was purified by flash chromatography (2×330 g silica gel columns, gradient elution of 0% to 30% acetone in hexanes) to provide the title compound as a white solid. The product can alternatively be crystallized from a minimum of hexanes in dichloromethane. Enantiomeric excess was determined to be 87% by chiral SFC (90% CO2, 10% methanol (20 mM ammonia), 5.0 mL/min, 100 bar (10,000 kPa), 40° C., 5 minute method, Phenomenex Lux-2 (Phenomenex, Torrance, Calif.) (100 mm×4.6 mm, 5 μm column), retention times: 1.62 min. (minor) and 2.17 min. (major)). The purity could be upgraded to >98% through recrystallization in hexanes and dichloromethane.

1. customdried 500 mL round-bottom flask
2. dissolutionThe solid was dissolved in anhydrous toluene
3. concentrationconcentrated
4. customto remove adventitious water
5. additionto addition) in tetrahydrofuran (200 mL)
6. additionwas added
7. customthe reaction vessel was evacuated
8. additionrefilled with argon three times
9. stirringstirred at −10° C. for 3 hours
10. customThe reaction was quenched with saturated ammonium chloride (10 mL)
11. concentrationconcentrated
12. additionthe crude product was diluted in water (150 mL)
13. customThe layers were separated
14. washthe aqueous layer was washed twice more with diethyl ether (200 mL/each)
15. washThe combined organic layer was washed with brine (100 mL)
16. dry with materialdried over magnesium sulfate
17. filtrationfiltered
18. concentrationconcentrated under reduced pressure to a residue
19. customThe residue was purified by flash chromatography (2×330 g silica gel columns, gradient elution of 0% to 30% acetone in hexanes)

ORD record

ord-f272ce275eb342bb87cd9cd9819be315

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08952036B2