反应 #2329018

反应方程式

2-chloro-4-fluorobenzonitrile

trans 1,3-cyclohexanediol

NaH

→

title compound

收率 9.2%

(1R,3R)-2-Chloro-4-(3-hydroxy-cyclohexyloxy)-benzonitrile

收率 9.2%

溶剂

THF

THF

反应条件

后处理

1. 1
   温度cooled in an ice/acetone bath
2. 2
   其他The cold bath was removed
3. 3
   workup.STIRRINGto stir at room temperature overnight
4. 4
   其他The reaction was quenched with approximately 10 mL 5% citric acid
5. 5
   其他the THF was removed by rotovap
6. 6
   workup.ADDITIONEthyl acetate was added
7. 7
   其他the layers were separated
8. 8
   萃取The aqueous layer was extracted twice more with ethyl acetate
9. 9
   洗涤The combined organic layers were washed twice with brine
10. 10
    干燥dried over magnesium sulfate
11. 11
    过滤filtered
12. 12
    其他The resulting product was triturated with hexane
13. 13
    其他the hexane decanted off
14. 14
    其他The crude product was chromatographed with an ethyl acetate hexane gradient (10% ethyl acetate to 50% ethyl acetate)
15. 15
    其他the solvent removed
16. 16
    其他The results of two such runs

实验过程

A commercial mixture of cis/trans 1,3-cyclohexanediol (7.77 g, 66.9 mmol) was dissolved in 50 mL anhydrous THF (tetrahydrofuran), under a nitrogen atmosphere, and cooled in an ice/acetone bath. NaH (60% suspension in oil, 2.69 g, 6.725 mmol) was then added and the solution stirred approximately 10 min. Then a solution of 2-chloro-4-fluorobenzonitrile (1.06 gms, 6.79 mmol)(in 20 mL anhydrous THF was added in a slow, steady stream (not dropwise). The cold bath was removed, and allowed to stir at room temperature overnight. The reaction was quenched with approximately 10 mL 5% citric acid and the THF was removed by rotovap. off. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate and the organic layers were combined. The combined organic layers were washed twice with brine, then dried over magnesium sulfate, filtered and rotovapped. The resulting product was triturated with hexane, and the hexane decanted off. The crude product was chromatographed with an ethyl acetate hexane gradient (10% ethyl acetate to 50% ethyl acetate), and the desired fractions were combined, and the solvent removed. The results of two such runs were combined, and submitted for preparative reverse phase HPLC. The title compound (0.1575 g) was returned. HNMR (CDCl3, ppm) 7.5 (1H, d, J=8.8 Hz), 6.96 (1H, s), 6.82 (1H, d, J=8.8 Hz), 4.8-4.6 (1H, m), 4.2-4.1 (1H, m), 2.1-1.4 (9H, m).

来源