Dimethylformamide → 1-Chloro-3-methyl-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide

HRID 1803592Notes

Reaction equation

HRID 1803592 reaction equation
O=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)C(=O)N[NH:3]1.P(Cl)(Cl)([Cl:18])=O.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26].CCN(CC)CC.[CH3:39][N:40]([CH:42]=[O:43])C>S(Cl)(Cl)=O.O>[F:21][C:22]([F:30])([F:31])[C:23]1[CH:24]=[C:25]([NH:26][C:12]([C:8]2[CH:9]=[C:10]3[C:11](=[CH:6][CH:7]=2)[C:2]([Cl:18])=[N:3][N:40]([CH3:39])[C:42]3=[O:43])=[O:14])[CH:27]=[CH:28][CH:29]=1

Participants

8

Reactant 5

HCID 6228DimethylformamideHCID 73753-(Trifluoromethyl)anilineHCID 8471TriethylamineHCID 24813Phosphorus oxychlorideHCID 3090561,4-Dioxo-1,2,3,4-tetrahydrophthalazine-6-carboxylic acid

Product 1

HCID 597431211-Chloro-3-methyl-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 24386Thionyl ChlorideSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of 1,4-dioxo-1,2,3,4-tetrahydro-phthalazine-6-carboxylic acid (2.5 g, 9.14 mmol), in thionyl chloride (25 mL) was refluxed for 3 hours. Phosphorous oxychloride (25 mL) was added and the reaction refluxed for an additional 15 hours. The solution was concentrated under vacuum and treated 3 times with toluene in order to remove the excess thionyl chloride. The crude residue was dissolved in DMF (15 mL) and added dropwise to a 0° C. solution of 3-(trifluoromethyl)aniline (1.71 mL, 13.71 mmol), DMF (15 mL) and NEt3 (3.82 mL, 27.42 mmol). The reaction was then heated to 85° C. for 1 h. The reaction was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers were washed with water (×3), sat.aq. NH4Cl, brine and dried (Na2SO4). Column chromatography (Hex/EtOAc) afforded 1-chloro-3-methyl-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (17 mg) as a white solid, 1H NMR (400 MHz, d6-DMSO) δ: 3.73 (s, 3H), 7.51 (d, 1H), 7.64 (t, 1H), 8.10 (d, 1H), 8.17 (d, 1H), 8.27 (s, 1H), 8.54 (dd, 1H), 8.93 (d, 1H), 11.03 (s, 1H) ppm; m/z (M+1) 382.09; and 4-chloro-2-methyl-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (156 mg) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ: 3.72 (s, 3H), 7.52 (d, 1H), 7.65 (t, 1H), 8.08 (d, 1H), 8.25 (s, 1H), 8.46 (s, 2H), 8.53 (m, 1H), 11.02 (s, 1H) ppm; m/z (M+1) 382.09.

Workup

  1. temperaturethe reaction refluxed for an additional 15 hours
  2. concentrationThe solution was concentrated under vacuum
  3. additiontreated 3 times with toluene in order
  4. customto remove the excess thionyl chloride
  5. dissolutionThe crude residue was dissolved in DMF (15 mL)
  6. temperatureThe reaction was cooled to room temperature
  7. extractionextracted with EtOAc
  8. washThe combined organic layers were washed with water (×3)
  9. dry with materialNH4Cl, brine and dried (Na2SO4)

Sources & evidence

ORD record
ord-4ec1030b9d084241b65aadd54cb6a4a8
Source dataset
uspto-grants-2013_01
Patent number
US08349836B2

Reaction notes

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