Triethylamine → Phthalimidine

HRID 658661Notes

Reaction equation

HRID 658661 reaction equation
Cl.CC1C(CN2C=C(N)C=N2)=C(C)[O:5]N=1.Br[CH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].C(N(CC)CC)C>CN(C=O)C.O>[C:20]1(=[O:5])[C:19]2[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][NH:21]1

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 895992-(Bromomethyl)benzonitrileHCID 574222641-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride

Product 1

HCID 10199PhthalimidineYield 145.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine-hydrochloride (100 mg, 0.44 mmol), 2-(bromomethyl)benzonitrile (115 mg, 0.6 mmol), and triethylamine (0.5 mL, 3.5 mmol) in DMF (3 mL) were irradiated and stirred in the microwave reactor at 80° C. for 10 minutes. The reaction was cooled, diluted with H2O (50 mL) and extracted with ethyl acetate (3×, 30 mL). The combined organic extracts were dried over sodium sulfate and concentrated on the rotovap. The residue was dissolved in ethanol (70 mL), H2O (3 mL) and acetic acid (1 mL) and the mixture was refluxed for 2 hours. The solution was concentrated on the rotovap, taken up in methanol (3 mL) and purified by reversed phase HPLC in 3-1 mL aliquots (5 to 95% acetonitrile in H2O: 16 minute gradient). The pure fractions were combined and concentrated on the rotovap. The residue was triturated with ethyl acetate/hexanes (1/9) to afford 2-(1-(3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)isoindolin-1-one (85 mg, 61%) as a pure white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.18 (s, 3H), 2.43 (s, 3H), 4.97 (s, 2H), 5.18 (s, 2H), 7.58-7.68 (m, 3H), 7.77 (s, 1H), 8.10 (d, J=8 Hz, 1H), 8.27 (s, 1H), 9.19 (bs, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 value greater than 30 μM.

Workup

  1. temperatureThe reaction was cooled
  2. extractionextracted with ethyl acetate (3×, 30 mL)
  3. dry with materialThe combined organic extracts were dried over sodium sulfate
  4. concentrationconcentrated on the rotovap
  5. dissolutionThe residue was dissolved in ethanol (70 mL)
  6. temperatureH2O (3 mL) and acetic acid (1 mL) and the mixture was refluxed for 2 hours
  7. concentrationThe solution was concentrated on the rotovap
  8. custompurified by reversed phase HPLC in 3-1 mL aliquots (5 to 95% acetonitrile in H2O: 16 minute gradient)
  9. concentrationconcentrated on the rotovap
  10. customThe residue was triturated with ethyl acetate/hexanes (1/9)

Sources & evidence

ORD record
ord-de261467c4964c8abde5cf4beb771966
Source dataset
uspto-grants-2011_12
Patent number
US08076491B2

Reaction notes

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