Potassium Carbonate → Isobutyl 4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenylcarbamate

HRID 1991246Notes

Reaction equation

HRID 1991246 reaction equation
[O:1]=[S:2]1(=[O:17])[CH2:7][CH2:6][N:5]([C:8]2[C:14]([F:15])=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[F:16])[CH2:4][CH2:3]1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+].Cl[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31]>>[O:17]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]2[C:14]([F:15])=[CH:13][C:11]([NH:12][C:30](=[O:31])[O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:10][C:9]=2[F:16])[CH2:4][CH2:3]1

Participants

4

Reactant 3

HCID 11430Potassium CarbonateHCID 62365Isobutyl chloroformateHCID 698536734-(1,1-Dioxido-4-thiomorpholinyl)-3,5-difluoroaniline tetrahydrofuran

Product 1

HCID 9925157Isobutyl 4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenylcarbamate

Conditions

Temperature
45 °C

Procedure

To a 400 L glass-lined reactor containing the 4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluoroaniline/tetrahydrofuran solutions (Step 3, 12.6 kg, 48 moles, 1.0 eq) is added a 47% potassium carbonate solution (14.1 kg, 48 moles, 1.0 eq). The mixture is heated to approximately 45° C., and isobutyl chloroformate (7.2 kg, 53 moles, 1.1 eq) is added while maintaining a reaction temperature between 45° C. and 55° C. The reaction is stirred at 45°-55° C. Once complete, the reaction is quenched by slowly adding water (45 L) over 15 minutes. The reaction mixture is cooled to 25° C. and the phases are separated. The tetrahydrofuran solution is swapped to an isopropanol (150 L)/water (50 L) suspension, and the slurry is slowly cooled to 5° C. The yellow slurry is then filtered and the cake washed with cold isopropanol (2×30 L). The yellow solids are dried with 60° C. nitrogen to give the title compound, 1H NMR (CDCl3) δ 7.02 (m, 2H), 6.81 (s, 1H), 3.95 (d, 2H), 3.60 (m, 4H), 3.17 (m, 4H), 1.97 (m, 1H), 0.94 (d, 6H).

Workup

  1. temperaturewhile maintaining a reaction temperature between 45° C. and 55° C
  2. customOnce complete, the reaction is quenched by slowly adding water (45 L) over 15 minutes
  3. temperatureThe reaction mixture is cooled to 25° C.
  4. customthe phases are separated
  5. temperaturethe slurry is slowly cooled to 5° C
  6. filtrationThe yellow slurry is then filtered
  7. washthe cake washed with cold isopropanol (2×30 L)
  8. customThe yellow solids are dried with 60° C. nitrogen

Sources & evidence

ORD record
ord-6cdbe3e2e6ab464294c023d3ad70cd25
Source dataset
uspto-grants-2010_01
Patent number
US07645781B2

Reaction notes

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