Hydrochloric Acid → 2-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)isoindolin-1-one

HRID 658662Notes

Reaction equation

HRID 658662 reaction equation
[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#N)[CH:10]=[N:9]2)=[C:5]([CH3:23])[O:4][N:3]=1.Cl.C[OH:26]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[CH2:14][C:15]4[C:16](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH:10]=[N:9]2)=[C:5]([CH3:23])[O:4][N:3]=1

Participants

4

Reactant 3

HCID 313Hydrochloric AcidHCID 887MethanolHCID 574224122-((1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-ylamino)methyl)benzonitrile

Product 1

HCID 574224132-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)isoindolin-1-oneYield 50%

Procedure

2-((1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-ylamino)methyl)benzonitrile (example 9-2) (30 mg, 0.14 mmol) was stirred in a mixture of MeOH/2N aqueous NaOH (5 mL) at 100° C. for 30 minutes in the microwave reactor. The reaction was acidified with 1N aqueous HCl (100 mL) and extracted with ethyl acetate (3×, 70 mL). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was dissolved in MeOH (3 mL) and purified by reversed phase HPLC in 2-1.5 mL aliquots (5 to 95% acetonitrile in H2O: 16 minute gradient). The pure fractions were combined and concentrated to afford 2-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)isoindolin-1-one (21 mg, 50%) as a pure white solid. 1H NMR (DMSO-d6, 400 MHz): δ 2.15 (s, 3H), 2.41 (s, 3H), 4.81 (s, 2H), 5.17 (s, 2H), 7.48-7.50 (m, 1H), 7.51-7.52 (m, 2H), 7.72 (d, J=7.2 Hz, 1H), 7.75 (s, 1H), 8.20 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 11 μM.

Workup

  1. extractionextracted with ethyl acetate (3×, 70 mL)
  2. dry with materialThe combined organic extracts were dried over sodium sulfate
  3. concentrationconcentrated
  4. dissolutionThe residue was dissolved in MeOH (3 mL)
  5. custompurified by reversed phase HPLC in 2-1.5 mL aliquots (5 to 95% acetonitrile in H2O: 16 minute gradient)
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-1df1a21e94f64fbe809aa9b86ebcece6
Source dataset
uspto-grants-2011_12
Patent number
US08076491B2

Reaction notes

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