Diisopropyl Ether → (3aR,5R,7aS)-5-[(Benzyloxy)methyl]-7a-(2,4-difluorophenyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole

Temperature

-73.5 °C

Boron trifluoride diethyl etherate (60.1 mL, 474 mmol) was added to a solution of C4 (50.0 g, 202 mmol) in a 1:1 mixture of toluene and diisopropyl ether (2 L) at an internal temperature of −76° C. The reaction was stirred at this temperature for 30 minutes, then treated with 2,4-difluoro-1-iodobenzene (27.1 mL, 226 mmol). While the reaction temperature was maintained at −76 to −71° C., n-butyllithium (2.5 M in hexanes, 85.7 mL, 214 mmol) was slowly added. The reaction mixture was stirred at −76° C. for 1.5 hours, then quenched with saturated aqueous ammonium chloride solution (1 L) and partitioned between water (1 L) and ethyl acetate (750 mL). After the mixture warmed to room temperature, the aqueous layer was extracted with ethyl acetate (3×250 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (550 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 70% ethyl acetate in heptane) gave the product as a yellow oil. Yield: 48.14 g, 133.2 mmol, 66%. 1H NMR (400 MHz, CDCl3) δ 7.94 (ddd, J=9, 9, 7 Hz, 1H), 7.28-7.40 (m, 5H), 6.87-6.93 (m, 1H), 6.80 (ddd, J=12.0, 8.6, 2.4 Hz, 1H), 4.60 (AB quartet, JAB=12.1 Hz, ΔνAB=21.4 Hz, 2H), 4.14 (br dd, J=12.8, 1.3 Hz, 1H), 3.82-3.90 (m, 2H), 3.72 (d, J=7.2 Hz, 1H), 3.54-3.60 (m, 2H), 3.50 (dd, half of ABX pattern, J=10.3, 4.1 Hz, 1H), 3.04-3.13 (m, 1H), 1.86 (ddd, J=14.0, 7.0, 2.0 Hz, 1H), 1.49-1.61 (m, 1H).

1. stirringThe reaction mixture was stirred at −76° C. for 1.5 hours
2. customquenched with saturated aqueous ammonium chloride solution (1 L)
3. custompartitioned between water (1 L) and ethyl acetate (750 mL)
4. temperatureAfter the mixture warmed to room temperature
5. extractionthe aqueous layer was extracted with ethyl acetate (3×250 mL)
6. washthe combined organic layers were washed with saturated aqueous sodium chloride solution (550 mL)
7. dry with materialdried over sodium sulfate
8. filtrationfiltered
9. concentrationconcentrated in vacuo

ORD record

ord-7b69edaf06c54380ae05bda9a1654827

Source dataset

uspto-grants-2014_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08865706B2