Methanesulfonic Acid → Methyl 2-[2-(tetrahydropyran-2-yloxy)-phenyl]-3-fluoromethoxy-acrylate

HRID 378656Notes

Reaction equation

HRID 378656 reaction equation
[H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[CH2:21])[C:17]([O:19][CH3:20])=[O:18].C([O:24][CH3:25])=O.CS(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+].BrC[F:39]>CN(C)C=O>[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[CH:21][O:24][CH2:25][F:39])[C:17]([O:19][CH3:20])=[O:18]

Participants

8

Reactant 6

HCID 6395Methanesulfonic AcidHCID 7865Methyl formateHCID 11430Potassium CarbonateHCID 24758Sodium hydrideHCID 61108BromofluoromethaneHCID 18328184HCID 18328184, compound

Product 1

HCID 53774316Methyl 2-[2-(tetrahydropyran-2-yloxy)-phenyl]-3-fluoromethoxy-acrylateYield 75%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
2.5 °C

Procedure

1.5 g of 80% strength sodium hydride in mineral oil are added in portions at 20° C. with stirring to a solution of 12.5 g (60 mmol) of methyl 2-[2-(tetrahydropyran-2-yloxy)-phenyl]-acrylate and 30 g of methyl formate in 150 ml of dry dimethylformamide in a three-necked flask having an attached condenser. After approximately one hour, the exothermic reaction commences with foaming. The temperature is kept at 40° C. for 3 hours. The mixture is cooled to 0-5° C. and treated successively with 4.8 g (0.05 mol) of methanesulphonic acid and in portions with 13.8 g (0.1 mol) of potassium carbonate. The temperature of the cooling fluid in the condenser, as well as the temperature of the reaction mixture, is then adjusted to 0° C. Using a syringe, 6.8 g (0.06 mol) of bromofluoromethane are added and the mixture is stirred overnight at 0-5° C. The reaction mixture is stirred for a further 24 hours without cooling. The temperature of the cooling fluid is kept at approximately 0° C. The mixture is concentrated, the residue is taken up using ethyl acetate, the solution is washed with water, and the organic phase is dried over sodium sulphate and concentrated again. The residue is chromatographed on silica gel using hexane/acetone (7:3). 11.6 g (75% of theory) of methyl 2-[2-(tetrahydropyran-2-yloxy)-phenyl]-3-fluoromethoxy-acrylate are obtained.

Workup

  1. customthe exothermic reaction commences with foaming
  2. waitThe temperature is kept at 40° C. for 3 hours
  3. customis then adjusted to 0° C
  4. stirringThe reaction mixture is stirred for a further 24 hours
  5. temperaturewithout cooling
  6. customis kept at approximately 0° C
  7. concentrationThe mixture is concentrated
  8. washthe solution is washed with water
  9. dry with materialthe organic phase is dried over sodium sulphate
  10. concentrationconcentrated again
  11. customThe residue is chromatographed on silica gel

Sources & evidence

ORD record
ord-a1a8a350e10844c4ae6d1bad7bb1a436
Source dataset
uspto-grants-2000_02
Patent number
US06031107

Reaction notes

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