1,2-Dichloroethane → N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)picolinamide

HRID 2094851Notes

Reaction equation

HRID 2094851 reaction equation
Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](O)=[O:23].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl>C(Cl)Cl>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:22](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 1018Picolinic acidHCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 574222641-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride

Product 1

HCID 57944963N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)picolinamideYield 60%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (example 4-1a) (400 mg, 2.1 mmol), picolinic acid (256 mg, 2.1 mmol), and HOBt (388 mg, 2.50 mmol) were mixed in DCM (7 mL). The reaction was treated with triethylamine (670 mL, 4.8 mmol) and stirred for 15 minutes at room temperature under a nitrogen atmosphere. EDC (598 mg, 3.1 mmol) was added and the reaction was stirred for an additional 4 hours. The reaction was then diluted with dichloromethane (5 mL) and washed with aqueous saturated NaHCO3 solution (5 mL, 2×) and then with aqueous saturated NaCl solution (5 mL). The organic layer was collected, dried, and filtered. Solvents were removed under vacuum. The crude product was re-suspended in EtOH (5 mL) and purified by reversed phase HPLC (5%-95% ACN in H2O: 25 minute gradient). The pure fractions were combined and concentrated to afford N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)picolinamide (372 mg, 60%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 2.21 (s, 3H), 2.44 (s, 3H), 5.05 (s, 2H), 7.49-7.47 (m, 1H), 7.59 (s, 1H), 7.93-7.88 (dt, J=14, 2 Hz, 1H), 8.07 (s, 1H), 8.24-8.21 (d, J=8 Hz, 1H), 8.61-8.56 (m, 1H), 9.83 (bs, 1H). LC/MS; [M+H] calculated for C, 15; H, 15; N, 5; O, 2; expected 297.1; found 298.3. Melting point: 135-137° C.

Workup

  1. stirringthe reaction was stirred for an additional 4 hours
  2. washwashed with aqueous saturated NaHCO3 solution (5 mL, 2×)
  3. customThe organic layer was collected
  4. customdried
  5. filtrationfiltered
  6. customSolvents were removed under vacuum
  7. custompurified by reversed phase HPLC (5%-95% ACN in H2O: 25 minute gradient)
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-0454843c222b4b36a551ee42b9a8ecdb
Source dataset
uspto-grants-2013_05
Patent number
US08445692B2

Reaction notes

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