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

HRID 1466448Notes

Reaction equation

HRID 1466448 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.[Cl: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>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH2:36][C:37]([NH:2][C:3]3([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]3)=[O:38])[CH:30]=2)=[CH:27][CH:28]=1

Participants

6

Reactant 4

HCID 8471Triethylamine2×HCID 24813Phosphorus oxychlorideHCID 60196672Methyl 1-amino-4,4-difluorocyclohexanecarboxylate hydrochlorideHCID 66707678(4'-Chloro-4-methylbiphenyl-3-yl)acetic acid

Product 1

HCID 68283315Methyl 1-{[(4'-chloro-4-methylbiphenyl-3-yl)acetyl]amino}-4,4-difluorocyclohexanecarboxylate

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). 3.07 ml of triethylamine were added dropwise at 20° C., the mixture was stirred for 5 min, and 2.61 g (10 mmol) of (4′-chloro-4-methylbiphenyl-3-yl)acetic acid (EP 2029531 A1 and US 2009/298828 A1) 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 3.6 g (73% of theory) of the title compound of melting point 186° 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-4d1f7ebf41134155a26bdda57d627d62
Source dataset
uspto-grants-2015_04
Patent number
US09000026B2

Reaction notes

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