HCID 57707761, compound → (R)-1-(2-Chloro-8-fluoroquinolin-3-yl)ethanol

Temperature

-55 °C

In a round bottomed flask was dissolved (+)-dip-chloride(tm) (17.5 g, 540 mmol, 2.2 eq) in anhydrous THF (200 mL) and the solution was cooled to −55° C. (using a dry ice/MeCN bath). To this solution was added 1-(2-chloro-8-fluoroquinolin-3-yl)ethanone (5.50 g, 24.5 mmol) as a solution in THF (50 mL). The reaction was allowed to warm to rt slowly overnight. After this time the reaction was quenched with 10 mL acetone and 100 mL of 10% Na2CO3 and allowed to stir for 2 h at rt. Ethyl acetate (750 mL) was added and the layers were separated. The organic phase was washed 3× with a 50% saturated sodium bicarbonate solution and once with brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was concentrated under high vacuum at 75° C. to remove pinene. The residue was slurried in 150 mL of hexanes and 150 mL of water for 3 h at rt. A white precipitate formed and was filtered and dried to afford 4.9 g of 98% ee product. The solid was dissolved in 25 mL of boiling EtOAc and 25 mL of hot hexanes was added to form a precipitate at reflux. The mixture was cooled to −15° C., filtered, and washed with cold 9:1 hexanes:EtOAc to afford (R)-1-(2-chloro-8-fluoroquinolin-3-yl)ethanol (4.07 g, 73% yield). Chiral HPLC (10% IPA in hexanes, chiralcel AD-H shows product to be >99.9% ee. Desired enantiomer elutes at 9.6 min, undesired enantiomer elutes at 8.1 min. 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (br s), 7.64 (br d, J=8.2 Hz, 1H), 7.50 (td, J=7.8, 4.7 Hz, 1H), 7.41 (ddd, J=10.2, 7.8, 1.2 Hz, 1H), 5.40 (qd, J=5.9, 0.8 Hz, 1H), 2.22 (br s, 1H), 1.62 (d, J=6.3 Hz, 3H). Mass Spectrum (ESI) m/e=226.0 (M+1).

1. temperatureto warm to rt slowly overnight
2. customAfter this time the reaction was quenched with 10 mL acetone and 100 mL of 10% Na2CO3
3. additionEthyl acetate (750 mL) was added
4. customthe layers were separated
5. washThe organic phase was washed 3× with a 50% saturated sodium bicarbonate solution
6. dry with materialThe organic layer was dried over MgSO4
7. filtrationfiltered
8. concentrationconcentrated
9. concentrationThe crude material was concentrated under high vacuum at 75° C.
10. customto remove pinene
11. wait150 mL of water for 3 h at rt
12. customA white precipitate formed
13. filtrationwas filtered
14. customdried
15. customto afford 4.9 g of 98% ee product
16. customto form a precipitate
17. temperatureat reflux
18. temperatureThe mixture was cooled to −15° C.
19. filtrationfiltered
20. washwashed with cold 9:1 hexanes

ORD record

ord-9c9266611b424d9587e892c3005147a6

Source dataset

uspto-grants-2014_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08716290B2