Boron trifluoride etherate → HCID 118621161, compound

Boron trifluoride diethyl etherate (2.97 mL, 24.1 mmol) was added drop-wise to a solution of rel-(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C18) (1.67 g, 9.99 mmol) in toluene (150 mL) at an internal temperature of −72.5° C. The reaction mixture was stirred at −73° C. to −76° C. for 30 minutes, then treated with 2,4-difluoro-1-iodobenzene (98%, 1.37 mL, 11.2 mmol) in one portion. While the reaction temperature was maintained below −73° C., n-butyllithium (2.5 M in hexanes, 4.24 mL, 10.6 mmol) was added in a drop-wise manner over 15 minutes. The reaction mixture was stirred at −73° C. to −75° C. for 1 hour, then was quenched with saturated aqueous ammonium chloride solution (350 mL) at −74° C. and allowed to warm to room temperature. The resulting mixture was extracted with ethyl acetate (400 mL), and the aqueous layer was extracted with additional ethyl acetate (250 mL and 100 mL); the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 30% ethyl acetate in heptane) afforded the product as a white solid after azeotroping twice with dichloromethane. Yield: 2.16 g, 7.68 mmol, 77%. GCMS m/z 281 [M+]. 1H NMR (400 MHz, CDCl3) δ 7.88-7.98 (m, 1H), 6.84-6.93 (m, 1H), 6.79 (ddd, J=11.9, 8.6, 2.4 Hz, 1H), 6.34 (br s, 1H), 4.04 (br d, J=12.7 Hz, 1H), 3.83 (d, J=12.5 Hz, 1H), 3.72 (d, J=7.0 Hz, 1H), 3.54 (dd, J=6.8, 5.1 Hz, 1H), 2.99-3.08 (m, 1H), 2.86-2.95 (m, 1H), 1.99 (br dd, J=13.8, 6.8 Hz, 1H), 1.56-1.68 (m, 1H), 0.88-1.00 (m, 1H), 0.51-0.64 (m, 2H), 0.37-0.47 (m, 1H), 0.24-0.33 (m, 1H).

1. temperatureWhile the reaction temperature was maintained below −73° C.
2. stirringThe reaction mixture was stirred at −73° C. to −75° C. for 1 hour
3. customwas quenched with saturated aqueous ammonium chloride solution (350 mL) at −74° C.
4. extractionThe resulting mixture was extracted with ethyl acetate (400 mL)
5. extractionthe aqueous layer was extracted with additional ethyl acetate (250 mL and 100 mL)
6. dry with materialthe combined organic layers were dried over sodium sulfate
7. filtrationfiltered
8. concentrationconcentrated in vacuo

ORD record

ord-3a5985b583ed4d02b6c358f8d19693ec

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09403846B2