Water → HCID 178502532, compound

HRID 1484515Notes

Reaction equation

HRID 1484515 reaction equation
[CH3:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[O:19][C:20]([F:23])([F:22])[F:21].[C:24]([O:28][CH3:29])(=[O:27])[NH:25][NH2:26].O.C([O-])([O-])=O.[K+].[K+]>O=P(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:29][O:28][C:24]([NH:25][N:26]=[C:14]([NH:13][C:10]1[CH:11]=[N:12][C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([CH3:1])=[C:3]([O:19][C:20]([F:23])([F:22])[F:21])[CH:4]=2)=[CH:8][CH:9]=1)[CH3:15])=[O:27]

Participants

7

Reactant 4

HCID 962WaterHCID 11430Potassium Carbonate2×HCID 80519Methyl carbazate2×HCID 118021636HCID 118021636, compound2×

Product 1

HCID 178502532HCID 178502532, compoundYield 59.1%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 24813Phosphorus oxychlorideSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of N-{6-[4-methyl-3-(trifluoromethoxy)phenoxy]pyridin-3-yl}acetamide (Intermediate 32, 500 mg, 1.53 mmol) in 2.2 mL of POCl3, methyl carbazate (152 mg) was added. The resulting mixture was heated at 60° C. for 7 hrs and overnight at room temperature. After additional heating for 5 hrs, further methyl carbazate (30 mg, 0.2 equiv) was added. The mixture was cooled to 0° C. and water was cautiously added, followed by a saturated solution of K2CO3 and then solid K2CO3 until pH=8 was reached. Ethyl acetate (50 mL) was then added and phases were separated. The aqueous phase was then back-extracted with ethyl acetate (2×50 mL). The combined organics were dried over Na2SO4, filtered and concentrated to give 520 mg of crude as orange foam which was purified by silica flash-chromatography, eluant cyclohexane/ethyl acetate, gradient from 50/50 to 20/80 v/v giving the title compound (360 mg) as white foam.

Workup

  1. temperatureAfter additional heating for 5 hrs
  2. temperatureThe mixture was cooled to 0° C.
  3. customphases were separated
  4. extractionThe aqueous phase was then back-extracted with ethyl acetate (2×50 mL)
  5. dry with materialThe combined organics were dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto give 520 mg of crude as orange foam which
  9. customwas purified by silica flash-chromatography, eluant cyclohexane/ethyl acetate, gradient from 50/50 to 20/80 v/v

Sources & evidence

ORD record
ord-5b1a76f1313243eca5c5fb4ef5e6c556
Source dataset
uspto-grants-2016_08
Patent number
US09422252B2

Reaction notes

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