Iodine → (2R)-1-(2,5-Difluorophenyl)-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-one

HRID 379647Notes

Reaction equation

HRID 379647 reaction equation
[Mg].II.Br[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[F:12].[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][C@H:20]([CH3:29])[C:21](N1CCOCC1)=[O:22].[NH4+].[Cl-]>C1COCC1.O>[F:12][C:6]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=1[C:21](=[O:22])[C@H:20]([O:19][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1)[CH3:29]

Participants

8

Reactant 5

HCID 807Iodine2×HCID 25517Ammonium ChlorideHCID 678622-Bromo-1,4-difluorobenzene2×HCID 5462224MagnesiumHCID 10977653(2R)-1-morpholino-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-one

Product 1

HCID 10199306(2R)-1-(2,5-Difluorophenyl)-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-oneYield 98.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
52.5 °C

Procedure

A mixture of magnesium (7.25 g, 0.298 mol) and iodine (catalytic amount) and 1-bromo-2,5-difluorobenzene (20.0 g, 0.178 mol) in THF (250ml ) was vigously stirred. The color of iodine was disappeared and the inner temperature rose up to 65° C. To this mixture was added additional 1-bromo-2,5-difluorobenzene (30.0 g, 0.267 mol) dropwise to maintain the inner temperature from 50 to 55° C. over 45min. The resulting mixture was stirred at 55° C. for 30min. then at r.t. for 1 hr. The mixture was cooled down to −5° C. To this mixture was added a solution of 4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (52.5 g, 0.216 mol ) in THF (150ml) dropwise over 40min. And the resulting mixture was stirred at r.t. for 4hrs. The reaction mixture was cooled down to 5° C. and saturated NH4Cl aq. (100ml) was added carefully. The whole was diluted with H2O (600ml) and extracted with EtOAc (400 ml+200 ml×2). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (n-hexane: EtOAc=10:1˜5:1) to give (2R)-2′,5′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (47.3 g, 81% ) as pale yellow syrup.

Workup

  1. customrose up to 65° C
  2. stirringThe resulting mixture was stirred at 55° C. for 30min.
  3. temperatureThe mixture was cooled down to −5° C
  4. stirringAnd the resulting mixture was stirred at r.t. for 4hrs
  5. temperatureThe reaction mixture was cooled down to 5° C.
  6. extractionextracted with EtOAc (400 ml+200 ml×2)
  7. dry with materialThe combined organic layer was dried over Na2SO4
  8. concentrationconcentrated in vacuo
  9. customThe residue was chromatographed on silica gel (n-hexane: EtOAc=10:1˜5:1)

Sources & evidence

ORD record
ord-66395d86b59b4abfbbf2224b95c3671c
Source dataset
uspto-grants-2001_10
Patent number
US06300353B1

Reaction notes

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