1,2-Dichloroethane → 4-(4-fluorophenyl)-N-1H-indazol-5-yl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxamide

HRID 227693Notes

Reaction equation

HRID 227693 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]([C:14]([O:16]C)=O)=[CH:12][NH:11][C:10](=[O:18])[NH:9]2)=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2.C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O.C(OCC)(=O)C.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]([C:14]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[CH:23]4)=[O:16])=[CH:12][NH:11][C:10](=[O:18])[NH:9]2)=[CH:6][CH:7]=1

Participants

9

Reactant 4

HCID 111,2-DichloroethaneHCID 8471TriethylamineHCID 880121H-Indazol-5-amineHCID 57755876Methyl 4-(4-fluorophenyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

Product 1

HCID 111755614-(4-fluorophenyl)-N-1H-indazol-5-yl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxamide

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

The product of Step b above (258 mg, 1.09 mmol, 1 equiv) was combined with 5-aminoindazole (303 mg, 2.28 mmol, 1.2 equiv) and EDC (437 mg, 2.28 mmol, 1.2 equiv) in a round bottom flask. DMF (4.5 mL) was added, followed by DMAP (30 mg) and triethylamine (0.318 mL, 2.28 mmol, 1.2 equiv). The reaction mixture was heated to 80° C. for 2 hours. The reaction was cooled to room temperature and poured into a separatory funnel containing ethyl acetate and water. The layers were separated, and the organic layer was washed with 1M HCl (2×), satd. NaHCO3 (1×), and satd. NaCl (1×). The organic extracts were dried over Na2SO4, filtered and concentrated to a yellow solid. One-fourth of the residue was further purified by reverse-phase HPLC (0-80% CH3CN/H2O/0.1% TFA over 10 minutes, retention time 6.26 min) to provide 9 mg of the product as a colorless solid. NMR 1H NMR (400 MHz, DMSO-D6) 5 ppm 12.92 (br s, 1H), 9.56 (s, 1H), 9.12 (dd, J=1.6, 5.9 Hz, 1H), 8.04 (t, J=1.3 Hz, 1H), 7.97 (s, 1H), 7.43 (d, J=1.3 Hz, 2H), 7.40 (d, J=5.8 Hz, 1H), 7.34 (m, 2H), 7.17 (t, J=9.1 Hz, 2H), 5.45 (d, J=3.1 Hz, 1H) MS m/z 352 [M+H]+

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. additionpoured into a separatory funnel
  3. customThe layers were separated
  4. washthe organic layer was washed with 1M HCl (2×)
  5. dry with materialThe organic extracts were dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated to a yellow solid
  8. customOne-fourth of the residue was further purified by reverse-phase HPLC (0-80% CH3CN/H2O/0.1% TFA over 10 minutes, retention time 6.26 min)

Sources & evidence

ORD record
ord-1167c407c59642289e1685a624c43912
Source dataset
uspto-grants-2009_07
Patent number
US07560467B2

Reaction notes

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