Hydrochloric Acid → (5-Bromo-2-fluorophenyl)(1-hydroxy-4-methoxycyclohexyl)methanone

HRID 1965034Notes

Reaction equation

HRID 1965034 reaction equation
[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([F:26])=[C:16]([CH:18]([O:21][Si](C)(C)C)C#N)[CH:17]=1.[CH3:27][O:28][CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.Cl>C(#N)C.C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([F:26])=[C:16]([C:18]([C:32]2([OH:35])[CH2:33][CH2:34][CH:29]([O:28][CH3:27])[CH2:30][CH2:31]2)=[O:21])[CH:17]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 5350284-MethoxycyclohexanoneHCID 2733832Lithium HexamethyldisilazideHCID 581975642-(5-Bromo-2-fluorophenyl)-2-((trimethylsilyl)oxy)acetonitrile2×

Product 1

HCID 67979505(5-Bromo-2-fluorophenyl)(1-hydroxy-4-methoxycyclohexyl)methanoneYield 18.6%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolvent

Procedure

LiHMDS (1.0 M, 165 mL, 165 mmol) was added dropwise to a solution of 2-(5-bromo-2-fluorophenyl)-2-((trimethylsilyl)oxy)acetonitrile (Intermediate 12 Step 1, 45.80 g, 150 mmol) in acetonitrile (250 mL) at −78° C. The reaction mixture was stirred for 1.5 h and a solution of 4-methoxycyclohexanone (Lee, C. K.; Lee, I.-S. H.; Noland, W. E. Heterocycles, 2007, 71, 419-428) (20.3 g, 150 mmol) in THF (30 mL) was added slowly and the stirring at −78° C. was continued for 3 h. 1M HCl aq. (300 mL) was added at −78° C., and the mixture was allowed to warm slowly to r.t. and stirred overnight. The phases were separated and the aqueous layer was extracted with EtOAc (2×500 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford 57 g of the crude material. A portion of the crude product (30 g) was purified by flash chromatography using a gradient of 0 to 50% EtOAc in EtOAc in hexanes to afford 9.24 g of the title compound.

Workup

  1. waitthe stirring at −78° C. was continued for 3 h
  2. stirringstirred overnight
  3. customThe phases were separated
  4. extractionthe aqueous layer was extracted with EtOAc (2×500 mL)
  5. dry with materialThe combined extracts were dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto afford 57 g of the crude material
  9. customA portion of the crude product (30 g) was purified by flash chromatography

Sources & evidence

ORD record
ord-b190c2d6f75d4fbebf828795032378c9
Source dataset
uspto-grants-2013_04
Patent number
US08415483B2

Reaction notes

Loading…