Sodium chlorodifluoroacetate → methyl (1aRS,7bSR)-5-(2,2-dimethylpropionylamino)-1,1-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate

HRID 927949Notes

Reaction equation

HRID 927949 reaction equation
[CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([NH:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([CH:10]=[CH:11][CH2:12][O:13]2)=[CH:8][CH:7]=1)=[O:4].Cl[C:23]([F:28])([F:27])C([O-])=O.[Na+]>COCCOCCOC>[CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([NH:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([CH:10]3[C:23]([F:28])([F:27])[CH:11]3[CH2:12][O:13]2)=[CH:8][CH:7]=1)=[O:4]

Participants

4

Reactant 2

HCID 2734985Sodium chlorodifluoroacetateHCID 70983794Methyl 7-pivalamido-2H-chromene-8-carboxylate2×

Product 1

HCID 71006940methyl (1aRS,7bSR)-5-(2,2-dimethylpropionylamino)-1,1-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylateYield 56.3%

Reagents, catalysts & solvents 1

HCID 8150DiglymeSolvent

Conditions

Temperature
160 °C

Procedure

Methyl 7-(2,2-dimethylpropionylamino)-2H-chromene-8-carboxylate (Intermediate 45, 1.0 g) was dissolved in diglyme (30 mL) and the solution was heated to 160° C. Sodium chlorodifluoroacetate (4.27 g) was added in portions over 15 minutes with the final portion being washed in with diglyme (15 mL). On completion of the addition the mixture was heated at 180° C. for 15 minutes. After cooling, the mixture was poured into water and extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 2.5-15% to give methyl (1aRS,7bSR)-5-(2,2-dimethylpropionylamino)-1,1-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (0.66 g) as a colourless oil.

Workup

  1. washbeing washed in with diglyme (15 mL)
  2. additionOn completion of the addition the mixture
  3. temperaturewas heated at 180° C. for 15 minutes
  4. temperatureAfter cooling
  5. additionthe mixture was poured into water
  6. extractionextracted with ethyl acetate
  7. washwashed with water
  8. dry with materialdried (MgSO4)
  9. filtrationfiltered
  10. customThe filtrate was evaporated to dryness
  11. customthe residue was purified by chromatography on silica
  12. washeluting with a mixture of ethyl acetate and pentane with a gradient of 2.5-15%

Sources & evidence

ORD record
ord-fa111c3395f54f8c8a3b464c3738a367
Source dataset
uspto-grants-2016_03
Patent number
US09290472B2

Reaction notes

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