3-Bromoanisole → HCID 22397834, compound

HRID 1860698Notes

Reaction equation

HRID 1860698 reaction equation
Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:25]2([OH:28])[CH2:26][CH2:27][N:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)[CH:7]=[CH:6][CH:5]=1

Participants

5

Reactant 3

HCID 169713-BromoanisoleHCID 192201-Benzyl-4-piperidoneHCID 178418339Butyllithium

Product 1

HCID 22397834HCID 22397834, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

3-Bromoanisole (50.0 g, 0.264 mol) was dissolved in 150 mL of THF and then chilled to −78° C. n-Butyllithium (1.6M, 175 mL, 0.276 mol) was then added while maintaining the reaction temperature at −70° C. or below. After complete addition, the reaction mixture was stirred for an additional 60 min. 1-Benzyl-4-piperidone in 150 mL of THF was then added at such a rate as to maintain the reaction temperature at −70° C. or below. The reaction was stirred at −70° C. for an additional 15 min, then the dry ice-acetone bath was removed, and the reaction was allowed to come to room temperature. Brine (400 mL) was added, and the organic layer was separated and washed with an additional 300 mL of brine. The organic layer was separated, dried (K2CO3), and concentrated in vacuo. 6N HCl (250 mL) was added to the oily residue which was then washed with EtOAc. The aqueous layer was separated, basified with 50% NaOH, and extracted with EtOAc. The EtOAc layer was separated, dried (K2CO3), and concentrated in vacuo to give 75.7 g of 4-(3-methoxyphenyl)-1-benzyl-4-piperidinol as an orange oil. A sample was chromatographed on silica gel using hexane/EtOAc (7:3) mixtures as the eluent to afford a yellow oil which was dissolved in ether and treated with ethereal hydrochloric acid to give 4-(3-methoxyphenyl)-1-benzyl-4-piperidinol hydrochloride as a white solid (mp 195-197° C.). 1H NMR (CDCl3) (free base) δ (ppm) 1.64-1.75 (m, 2H), 2.09-2.21 (m, 2H), 2.41-2.51 (m, 2H), 2.71-2.80 (m, 2H), 3.51 (s, 2H), 3.80 (s, 3H), 6.77-6.81 (m, 1H), 7.06-7.09 (m, 2H), 7.23-7.35 (m, 6H). Anal. Calcd for C19H23NO2 HCl.½H2O: C, 66.56; H, 7.06; N, 4.09. Found: C, 66.41; H, 7.31; N, 4.33.

Workup

  1. additionwas then added
  2. temperaturewhile maintaining the reaction temperature at −70° C. or below
  3. additionAfter complete addition
  4. temperatureto maintain the reaction temperature at −70° C. or below
  5. stirringThe reaction was stirred at −70° C. for an additional 15 min
  6. customthe dry ice-acetone bath was removed
  7. customto come to room temperature
  8. additionBrine (400 mL) was added
  9. customthe organic layer was separated
  10. washwashed with an additional 300 mL of brine
  11. customThe organic layer was separated
  12. dry with materialdried (K2CO3)
  13. concentrationconcentrated in vacuo
  14. addition6N HCl (250 mL) was added to the oily residue which
  15. washwas then washed with EtOAc
  16. customThe aqueous layer was separated
  17. extractionextracted with EtOAc
  18. customThe EtOAc layer was separated
  19. dry with materialdried (K2CO3)
  20. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-cb0e0700957446fab727f310f2caacba
Source dataset
uspto-grants-2003_03
Patent number
US06531481B2

Reaction notes

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