Sodium hydride → HCID 59203868, compound

HRID 2241836Notes

Reaction equation

HRID 2241836 reaction equation
[C@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][C@H:3]([OH:7])[CH2:2]1.[H-].[Na+].[Cl:11][C:12]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>O1CCCC1>[Cl:11][C:12]1[CH:19]=[C:18]([O:7][C@@H:3]2[CH2:4][CH2:5][CH2:6][C@@H:1]([OH:8])[CH2:2]2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 1090002-Chloro-4-fluorobenzonitrileHCID 6432541HCID 6432541, compound

Product 1

HCID 59203868HCID 59203868, compoundYield 9.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

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).

Workup

  1. temperaturecooled in an ice/acetone bath
  2. customThe cold bath was removed
  3. stirringto stir at room temperature overnight
  4. customThe reaction was quenched with approximately 10 mL 5% citric acid
  5. customthe THF was removed by rotovap
  6. additionEthyl acetate was added
  7. customthe layers were separated
  8. extractionThe aqueous layer was extracted twice more with ethyl acetate
  9. washThe combined organic layers were washed twice with brine
  10. dry with materialdried over magnesium sulfate
  11. filtrationfiltered
  12. customThe resulting product was triturated with hexane
  13. customthe hexane decanted off
  14. customThe crude product was chromatographed with an ethyl acetate hexane gradient (10% ethyl acetate to 50% ethyl acetate)
  15. customthe solvent removed
  16. customThe results of two such runs

Sources & evidence

ORD record
ord-76276b93699f4e34b2fadc91494b5460
Source dataset
uspto-grants-2010_03
Patent number
US07670613B2

Reaction notes

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