Boron trifluoride etherate → HCID 90074338, compound

Temperature

-70 °C

n-Butyllithium (2.5 M solution in hexanes, 131 mL, 328 mmol) was added drop-wise over approximately 9 minutes to a −70° C. solution of ethynyl(trimethyl)silane (46.3 mL, 328 mmol) in tetrahydrofuran (1 L), and the reaction mixture was stirred at −70° C. for 30 minutes. A solution of (1S)—N,N-dibenzyl-1-[(2R)-oxiran-2-yl]ethanamine (C37, see J. Barluenga et al., J. Org. Chem. 1995, 60, 6696-6699) (79.6 g, 298 mmol) in tetrahydrofuran (250 mL) was added; the reaction mixture, which had warmed as a result of the addition, was recooled to approximately −65° C., and boron trifluoride diethyl etherate (37.6 mL, 298 mmol) was added. The reaction mixture was then stirred for 1.5 hours at −70° C. Saturated aqueous ammonium chloride solution (200 mL) was added, and the mixture was allowed to warm to room temperature. The organic layer was washed with saturated aqueous sodium chloride solution, and the aqueous layer from the quenched reaction was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in methanol (500 mL), treated with potassium carbonate (206 g, 1.49 mol) and stirred at room temperature for 18 hours. After filtration through Celite and rinsing with ethyl acetate, the crude product solution was concentrated in vacuo, dissolved in diethyl ether (1 L), washed with water (250 mL) and with saturated aqueous sodium chloride solution (75 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. After seeding with a small sample of solid product, heptane (60 mL) was added, and the mixture was vigorously stirred for 5 minutes, then filtered; the isolated solid was rinsed with heptane (50 mL) to afford the product as a pale orange solid. Yield: 37.3 g, 127 mmol, 43%. 1H NMR (400 MHz, CDCl3) δ 7.22-7.36 (m, 10H), 4.53 (s, 1H), 3.84 (d, J=13.1 Hz, 2H), 3.63 (ddd, J=9.5, 5.8, 4.0 Hz, 1H), 3.34 (d, J=13.3 Hz, 2H), 2.80 (dq, J=9.4, 6.6 Hz, 1H), 2.46 (ddd, half of ABXY pattern, J=17.0, 4.0, 2.6 Hz, 1H), 2.21 (ddd, half of ABXY pattern, J=17.0, 6.0, 2.6 Hz, 1H), 1.86 (dd, J=2.7, 2.5 Hz, 1H), 1.07 (d, J=6.8 Hz, 3H).

1. temperaturethe reaction mixture, which had warmed as
2. customa result of the addition
3. customwas recooled to approximately −65° C.
4. stirringThe reaction mixture was then stirred for 1.5 hours at −70° C
5. temperatureto warm to room temperature
6. washThe organic layer was washed with saturated aqueous sodium chloride solution
7. customthe aqueous layer from the quenched reaction
8. extractionwas extracted with ethyl acetate
9. dry with materialThe combined organic layers were dried over magnesium sulfate
10. filtrationfiltered
11. concentrationconcentrated in vacuo
12. dissolutionThe residue was dissolved in methanol (500 mL)
13. stirringstirred at room temperature for 18 hours
14. filtrationAfter filtration through Celite
15. washrinsing with ethyl acetate
16. concentrationthe crude product solution was concentrated in vacuo
17. dissolutiondissolved in diethyl ether (1 L)
18. washwashed with water (250 mL) and with saturated aqueous sodium chloride solution (75 mL)
19. dry with materialdried over magnesium sulfate
20. filtrationfiltered
21. concentrationconcentrated under reduced pressure
22. additionwas added
23. stirringthe mixture was vigorously stirred for 5 minutes
24. filtrationfiltered
25. washthe isolated solid was rinsed with heptane (50 mL)

ORD record

ord-48fad174afbb43d4ac8866b59ca28b51

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08916564B2