Ethyl Acetate → N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamide

HRID 1752985Notes

Reaction equation

HRID 1752985 reaction equation
[F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:8]=2[C:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[CH:13]=2)=[O:10])=[C:4]([CH3:29])[CH:3]=1.C(OCC)(=O)C.N12CCN(CC1)CC2.[Cl:44][C:45](OCCl)=O>O.CN(C=O)C>[Cl:44][CH2:45][N:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:24])[F:25])=[CH:22][C:7]=2[O:6][C:5]2[CH:27]=[CH:28][C:2]([F:1])=[CH:3][C:4]=2[CH3:29])=[CH:13][C:14]1=[O:18]

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 9237DabcoHCID 62754Chloromethyl chloroformate2×HCID 867284852-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide

Product 1

HCID 118126598N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamideYield 87%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6228DimethylformamideSolvent

Procedure

To a 50 liter jacketed glass reactor fitted with an N2 inlet and a mechanical stirrer, and with a jacket temperature set at 20° C., was added 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (9a, 2482.0 g, 6.11 moles, 1.0 eq) under nitrogen. Ethyl acetate (25 liters) was added with stirring at 100 rpm followed by 1,4-diazabicyclo [2.2.2] octane (DABCO) (342.6 g, 3.05 moles, 0.5 eq) and DMF (1.25 liters, Sigma-Aldrich). Chloromethyl chloroformate (815 ml, 9.16 moles, 1.5 eq) was then added over 30 minutes. When the addition of chloromethyl chloroformate was complete, the jacket temperature was ramped up to 60° C. over 30 minutes. The resulting yellow-slurry was stirred for 3 hours at about 60° C., at which time the reaction was judged to be complete by HPLC analysis. The jacket temperature was ramped down to 15° C. over 20 minutes before quenching the reaction by slow addition of water (500 ml) over 10 minutes. Additional water was added, and the mixture stirred at 115 rpm for 15 minutes. Stirring was stopped, the aqueous layer was discarded, and the organic layer washed with water (5 liters), followed by a saturated solution of NaHCO3 (137 g) in water (620 ml). The organic layer was seeded with 5 g of N-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (7), and the resulting slurry was partially concentrated (removed 18.5 liters of organics) in the rotovap (40° C., vacuum). The resulting suspension was stored at room temperature under nitrogen atmosphere overnight, during which time additional material crystallized out of solution. The remaining solvent was chased with heptanes adding more heptanes as needed to maintain the volume at 10 liters. The thick suspension was stirred on the rotovap at room temperature for 45 minutes, and then the solids were collected by filtration. The off-white solid was washed with heptanes (2.5 liters), then dried in vacuo (40° C., full house vacuum) to give 2409 g (87%) of N-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide as an off-white crystalline solid.

Workup

  1. customfitted with an N2 inlet and a mechanical stirrer
  2. customset at 20° C.
  3. stirringThe resulting yellow-slurry was stirred for 3 hours at about 60° C., at which time the reaction
  4. waitThe jacket temperature was ramped down to 15° C. over 20 minutes
  5. custombefore quenching
  6. customthe reaction
  7. stirringthe mixture stirred at 115 rpm for 15 minutes
  8. stirringStirring
  9. washthe organic layer washed with water (5 liters)
  10. concentrationthe resulting slurry was partially concentrated
  11. custom(removed 18.5 liters of organics) in the rotovap (40° C., vacuum)
  12. waitThe resulting suspension was stored at room temperature under nitrogen atmosphere overnight, during which time additional material
  13. customcrystallized out of solution
  14. temperatureto maintain the volume at 10 liters
  15. stirringThe thick suspension was stirred on the rotovap at room temperature for 45 minutes
  16. filtrationthe solids were collected by filtration
  17. washThe off-white solid was washed with heptanes (2.5 liters)
  18. customdried in vacuo (40° C., full house vacuum)

Sources & evidence

ORD record
ord-1e25a2ccdfeb4605b8c99e17b845ad4b
Source dataset
uspto-grants-2015_10
Patent number
US09163042B2

Reaction notes

Loading…