反応 #2329018

反応方程式

2-chloro-4-fluorobenzonitrile

trans 1,3-cyclohexanediol

NaH

→

title compound

収率 9.2%

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

収率 9.2%

溶媒

THF

THF

反応条件

後処理

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

実験手順

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).

出典