2,6-Lutidine → N1-(3-Fluoro-4-hydroxyphenyl)-N1-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide

HRID 1879454Notes

Reaction equation

HRID 1879454 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.N[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([F:31])[CH:25]=1.[N:32]1C(C)=CC=CC=1C>C1COCC1.O.CCOC(C)=O.CN(C=O)C>[F:31][C:26]1[CH:25]=[C:24]([N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([C:11]2([C:14]([NH2:32])=[O:16])[CH2:12][CH2:13]2)=[O:10])[CH:29]=[CH:28][C:27]=1[OH:30]

Participants

9

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 2735918Phenol, 4-amino-2-fluoro-HCID 210815301-[(4-Fluorophenyl)carbamoyl]cyclopropanecarboxylic Acid

Product 1

HCID 67297145N1-(3-Fluoro-4-hydroxyphenyl)-N1-(4-fluorophenyl)-1,1-cyclopropanedicarboxamideYield 91%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 1-{[(4-fluorophenyl)amino]carbonyl}cyclopropanecarboxylic acid (21 g, 94.17 mmol) and DMF (0.11 mL) in THF (147 mL) was added oxalyl chloride (8.37 mL, 98.88 mmol) slowly to maintain a temperature in the range of 4° C. to 15° C. The solution was stirred at room temperature for about 2 h, then slowly added to a chilled (−10° C.) solution of 4-amino-2-fluoro phenol (14.05 g, 110.65 mmol) and 2,6-lutidine (21.90 mL) in THF (147 mL) over ˜45 min. The temperature was maintained at or below 0° C. throughout the addition. The suspension was stirred for 0.5-1 h at 0° C. EtOAc (210 mL) and H2O (147 mL) were added and the layers were separated. 1N HCl (105 mL) was added to the organic portion and the layers separated. 5% NaHCO3 (105 mL) was added to the organic portion and the layers separated. The solution was dried over Na2SO4 and concentrated to dryness. EtOAc (42 mL) was added to the residue and the resulting suspension was stirred at 55° C. for 1 h and cooled to 20° C. The suspension was stirred at room temperature overnight then cooled to 0-5° C. with stirring for 2-3 h. The solid was isolated by filtration and the cake was washed with 1:2 EtOAc/heptane (21 mL). The solid was dried under reduced pressure at 55° C. to give 28.43 g of the desired product (yield: 91%).

Workup

  1. temperatureto maintain a temperature in the range of 4° C. to 15° C
  2. additionslowly added to
  3. temperatureThe temperature was maintained at or below 0° C.
  4. additionthroughout the addition
  5. stirringThe suspension was stirred for 0.5-1 h at 0° C
  6. customthe layers were separated
  7. addition1N HCl (105 mL) was added to the organic portion
  8. customthe layers separated
  9. addition5% NaHCO3 (105 mL) was added to the organic portion
  10. customthe layers separated
  11. dry with materialThe solution was dried over Na2SO4
  12. concentrationconcentrated to dryness
  13. additionEtOAc (42 mL) was added to the residue
  14. stirringthe resulting suspension was stirred at 55° C. for 1 h
  15. temperaturecooled to 20° C
  16. stirringThe suspension was stirred at room temperature overnight
  17. temperaturethen cooled to 0-5° C.
  18. stirringwith stirring for 2-3 h
  19. customThe solid was isolated by filtration
  20. washthe cake was washed with 1:2 EtOAc/heptane (21 mL)
  21. customThe solid was dried under reduced pressure at 55° C.

Sources & evidence

ORD record
ord-0ec8c9b0c6ad4268b95199cddeecf59c
Source dataset
uspto-grants-2012_11
Patent number
US08314232B2

Reaction notes

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