反应 #162534

反应方程式

1-(2-chloro-8-fluoroquinolin-3-yl)ethanone

→

(R)-1-(2-chloro-8-fluoroquinolin-3-yl)ethanol

收率 73.6%

溶剂

EtOAc

THF

—

hexanes

THF

EtOAc

反应条件

后处理

1. 1
   温度to warm to rt slowly overnight
2. 2
   其他After this time the reaction was quenched with 10 mL acetone and 100 mL of 10% Na2CO3
3. 3
   workup.ADDITIONEthyl acetate (750 mL) was added
4. 4
   其他the layers were separated
5. 5
   洗涤The organic phase was washed 3× with a 50% saturated sodium bicarbonate solution
6. 6
   干燥The organic layer was dried over MgSO4
7. 7
   过滤filtered
8. 8
   浓缩concentrated
9. 9
   浓缩The crude material was concentrated under high vacuum at 75° C.
10. 10
    其他to remove pinene
11. 11
    workup.WAIT150 mL of water for 3 h at rt
12. 12
    其他A white precipitate formed
13. 13
    过滤was filtered
14. 14
    其他dried
15. 15
    其他to afford 4.9 g of 98% ee product
16. 16
    其他to form a precipitate
17. 17
    温度at reflux
18. 18
    温度The mixture was cooled to −15° C.
19. 19
    过滤filtered
20. 20
    洗涤washed with cold 9:1 hexanes

实验过程

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).

来源