Dimethylformamide → 4,4-Difluoro-4-(4'-methoxy-biphenyl-4-yl)-butyric Acid

HRID 23758Notes

Reaction equation

HRID 23758 reaction equation
[F:1][C:2]([F:23])([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:3](N(OC)C)=O.F[C:25](F)(C1C=CC(C2C=CC(OC)=CC=2)=CC=1)[C:26]([OH:28])=[O:27].C(Cl)(=O)C(Cl)=O.CN(C)C=O.Cl.CNOC.C(N(CC)CC)C>ClCCl.C(#N)C.C(O)(C)(C)C.C1COCC1.O>[F:23][C:2]([F:1])([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1)[CH2:3][CH2:25][C:26]([OH:28])=[O:27]

Participants

12

Reactant 6

HCID 6228DimethylformamideHCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 22575053HCID 22575053, compoundHCID 22575057HCID 22575057, compound

Product 1

HCID 98395084,4-Difluoro-4-(4'-methoxy-biphenyl-4-yl)-butyric Acid

Reagents, catalysts & solvents 5

HCID 962WaterSolvent2×HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolventHCID 6386tert-ButanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

2,2-Difluoro-N-methoxy-2-(4′-methoxy-biphenyl-4-yl)-N-methyl-acetamide. To a solution of difluoro-(4′-methoxy-biphenyl-4-yl)-acetic acid (3.74 g, 13.4 mmol) in dichloromethane (40 mL) and acetonitrile (40 mL) is added oxalyl chloride (2.40 mL, 27.5 mmol) followed by N,N-dimethylformamide (1.05 mL, 13.6 mmol). This mixture is stirred at room temperature for 45 min and added over 10 min to a solution of N,O-dimethylhydroxylamine hydrochloride (5.23 g, 53.6 mmol) and triethylamine (11.2 mL, 80.4 mmol) in t-butanol (40 mL), THF (80 mL), and water (30 mL) at 0° C. The resulting mixture is stirred for 4 hours while warming from 0° C. to room temperature. The reaction is diluted with water and the layers separated. The organic layer is washed in succession with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified by column chromatography (silica gel, 20-30% EtOAc/hexanes) to give the desired product as a pale yellow solid.

Workup

  1. stirringThe resulting mixture is stirred for 4 hours
  2. temperaturewhile warming from 0° C. to room temperature
  3. customthe layers separated
  4. washThe organic layer is washed in succession with saturated aqueous NaHCO3 and brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe crude product is purified by column chromatography (silica gel, 20-30% EtOAc/hexanes)

Sources & evidence

ORD record
ord-7a500e444eb1402490c18621fa4f138b
Source dataset
uspto-grants-2005_02
Patent number
US06852751B2

Reaction notes

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