4-Fluorobenzoic Acid → HCID 178489757, compound

HRID 1911309Notes

Reaction equation

HRID 1911309 reaction equation
C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH2:36][CH2:37][C:38]2[CH:39]=[C:40]([NH2:43])[NH:41][N:42]=2)[CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1>ClCCl.CN(C=O)C>[CH3:35][O:34][C:32]1[CH:31]=[C:30]([CH2:36][CH2:37][C:38]2[CH:39]=[C:40]([NH:43][C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([F:7])=[CH:16][CH:15]=3)[NH:41][N:42]=2)[CH:29]=[C:28]([O:27][CH3:26])[CH:33]=1

Participants

7

Reactant 4

HCID 99734-Fluorobenzoic AcidHCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 178489815HCID 178489815, compound

Product 1

HCID 178489757HCID 178489757, compoundYield 3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
0 °C

Procedure

Oxalyl chloride (2M in DCM, 1.40 ml, 2.75 mmol, 1.1 eq) was added dropwise to a mixture of 4-fluorobenzoic acid (350 mg, 2.50 mmol, 1 eq) in dichloromethane (15 ml) at 0° C. containing a few drops of DMF (10 ul, 0.12 mmol, 0.05 eq) and DIPEA (937 μl, 5.25 mmol, 2.1 eq). After stirring for 60 mins at 0° C. a solution of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (742 mg, 3 mmol, 1.2 eq) in DCM (10 ml) was added dropwise over 15 mins. The mixture was maintained at 0° C. for a further 2 h, then gradually allowed to warm to room temperature overnight. The mixture was diluted with DCM (50 ml) and washed with aqueous NaHCO3 solution (50 ml). The aqueous layer was extracted with DCM (50 ml). The combined organic layers were collected and concentrated. The crude product was purified by reverse-phase prep HPLC using a 30-50% gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The desired fractions were evaporated to afford the title compound as a beige solid. (31.5 mg, 3% yield)

Workup

  1. additionwas added dropwise over 15 mins
  2. temperatureto warm to room temperature overnight
  3. washwashed with aqueous NaHCO3 solution (50 ml)
  4. extractionThe aqueous layer was extracted with DCM (50 ml)
  5. customThe combined organic layers were collected
  6. concentrationconcentrated
  7. customThe crude product was purified by reverse-phase prep HPLC
  8. customThe desired fractions were evaporated

Sources & evidence

ORD record
ord-3cb2680bcd444b5fa37ce663c45d6146
Source dataset
uspto-grants-2013_12
Patent number
US08604022B2

Reaction notes

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