Triethylamine → Methyl 4,4-difluoro-1-{[(4'-fluoro-4-methylbiphenyl-3-yl)acetyl]amino}cyclohexanecarboxylate

HRID 1841888Notes

Reaction equation

HRID 1841888 reaction equation
Cl.[NH2:2][C:3]1([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH2:36][C:37](O)=[O:38])[CH:30]=2)=[CH:25][CH:24]=1.P(Cl)(Cl)(Cl)=O>O1CCCC1>[F:9][C:6]1([F:10])[CH2:7][CH2:8][C:3]([NH:2][C:37](=[O:38])[CH2:36][C:31]2[CH:30]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[CH:34]=[CH:33][C:32]=2[CH3:35])([C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH2:5]1

Participants

6

Reactant 4

HCID 8471Triethylamine2×HCID 24813Phosphorus oxychlorideHCID 58545475(4'-Fluoro-4-methylbiphenyl-3-yl)acetic acidHCID 60196672Methyl 1-amino-4,4-difluorocyclohexanecarboxylate hydrochloride

Product 1

HCID 68283296Methyl 4,4-difluoro-1-{[(4'-fluoro-4-methylbiphenyl-3-yl)acetyl]amino}cyclohexanecarboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

2.53 g (11 mmol) of the compound from Example 4A were initially charged in 50 ml of absolute tetrahydrofuran (THF). At 20° C., 3.07 ml of triethylamine were added dropwise, the mixture was stirred for 5 min and 2.44 g (10 mmol) of (4′-fluoro-4-methylbiphenyl-3-yl)acetic acid were added. After 15 min, a further 2.3 ml of triethylamine were added, followed immediately by the dropwise addition of 0.58 ml (6.2 mmol) of phosphorus oxychloride, and the mixture was stirred under reflux for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by means of flash chromatography on silica gel using the mobile phase n-hexane/ethyl acetate 1:1. This gave 2.84 g (60% of theory) of the title compound of melting point 187° C.

Workup

  1. waitAfter 15 min
  2. stirringthe mixture was stirred
  3. temperatureunder reflux for 30 min
  4. concentrationThe mixture was concentrated under reduced pressure
  5. customthe residue was purified by means of flash chromatography on silica gel using the mobile phase n-hexane/ethyl acetate 1:1

Sources & evidence

ORD record
ord-164619ac57764371a9d762a087793152
Source dataset
uspto-grants-2015_02
Patent number
US08946124B2

Reaction notes

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