Potassium Carbonate → Methyl 1-{[(4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl)acetyl]amino}-4,4-difluorocyclohexanecarboxylate

HRID 1466447Notes

Reaction equation

HRID 1466447 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([OH:18])=O)[CH:9]=2)=[CH:4][C:3]=1[F:19].S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+].Cl.[NH2:30][C:31]1([C:39]([O:41][CH3:42])=[O:40])[CH2:36][CH2:35][C:34]([F:38])([F:37])[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([NH:30][C:31]3([C:39]([O:41][CH3:42])=[O:40])[CH2:36][CH2:35][C:34]([F:38])([F:37])[CH2:33][CH2:32]3)=[O:18])[CH:9]=2)=[CH:4][C:3]=1[F:19]

Participants

8

Reactant 5

HCID 11430Potassium CarbonateHCID 24386Thionyl ChlorideHCID 516892Sodium BicarbonateHCID 60196672Methyl 1-amino-4,4-difluorocyclohexanecarboxylate hydrochlorideHCID 67375533(4'-Chloro-3'-fluoro-4-methylbiphenyl-3-yl)acetic acid

Product 1

HCID 86707849Methyl 1-{[(4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl)acetyl]amino}-4,4-difluorocyclohexanecarboxylate

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

6.06 g (21.7 mmol) of the compound from Example 1A were dissolved in 7.5 ml (103 mmol) of thionyl chloride. The reaction mixture was stirred at 80° C. for 1 h and then concentrated. The residue was dissolved in 30 ml of acetonitrile. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added to 5.00 g (21.8 mmol) of the compound from Example 4A. The phases were separated, the aqueous phase was extracted repeatedly with ethyl acetate and the combined organic phases were dried over sodium sulphate, filtered and concentrated. 140 ml of acetonitrile and 8.76 g (63.4 mmol) of potassium carbonate were added to the residue. With ice-cooling, the solution of the acid chloride was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was then added to ice-water and extracted repeatedly with dichloromethane, and the combined organic phases were washed repeatedly with 1N aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated. This gave 8.22 g (83% of theory) of the title compound, which were converted without further purification.

Workup

  1. concentrationconcentrated
  2. dissolutionThe residue was dissolved in 30 ml of acetonitrile
  3. customThe phases were separated
  4. extractionthe aqueous phase was extracted repeatedly with ethyl acetate
  5. dry with materialthe combined organic phases were dried over sodium sulphate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. temperatureWith ice-cooling
  9. stirringthe mixture was stirred at room temperature overnight
  10. extractionextracted repeatedly with dichloromethane
  11. washthe combined organic phases were washed repeatedly with 1N aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution
  12. dry with materialdried over sodium sulphate
  13. filtrationfiltered
  14. concentrationconcentrated
  15. customThis gave 8.22 g (83% of theory) of the title compound, which were converted without further purification

Sources & evidence

ORD record
ord-8321529d02f4463ea5600aecd23e6157
Source dataset
uspto-grants-2015_04
Patent number
US09000026B2

Reaction notes

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