Iodine → [2-((2R,6S)-2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-phenyl]-methanol

HRID 577805Notes

Reaction equation

HRID 577805 reaction equation
[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])[CH2:3]1.[BH4-].[Na+].II>C1COCC1>[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:10]=2[CH2:11][OH:12])[CH2:5]1

Participants

5

Reactant 3

HCID 807IodineHCID 4311764Sodium borohydrideHCID 673575112-((2R,6S)-2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-benzoic acid2×

Product 1

HCID 67376655[2-((2R,6S)-2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-phenyl]-methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred and ice-bath cooled solution of 2-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-benzoic acid (Intermediate 1, 27.0 g, 99.6 mmol) in THF (250 mL) was added sodium borohydride (12.56 g, 358.6 mmol) in small portions, followed by iodine (32.5 g, 139.4 mmol) in THF (250 mL). The addition was carried out such that the temperature maintained below 10° C. The mixture brought to room temperature and refluxed for 12 hours. It was cooled and then quenched with methanol (250 mL). Solvents were evaporated and the residue treated with 2M NaOH (500 mL) for 2 hours. The aqueous layer extracted with ethyl acetate (3×150 mL), and the combined organic phases were washed with water and brine before being dried (Na2SO4) and concentrated to give the title compound as a gummy solid. MS (ES) MH+: 257.2 for C13H17F2NO2

Workup

  1. additionThe addition
  2. temperaturemaintained below 10° C
  3. custombrought to room temperature
  4. temperaturerefluxed for 12 hours
  5. temperatureIt was cooled
  6. customquenched with methanol (250 mL)
  7. customSolvents were evaporated
  8. additionthe residue treated with 2M NaOH (500 mL) for 2 hours
  9. extractionThe aqueous layer extracted with ethyl acetate (3×150 mL)
  10. washthe combined organic phases were washed with water and brine
  11. dry with materialbefore being dried (Na2SO4)
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-0444590fbc2d4cd68acf83834a4f96f9
Source dataset
uspto-grants-2015_05
Patent number
US09040528B2

Reaction notes

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