Dimethylformamide → N-(3-Chloro-6-fluoro-1H-indazol-5-yl)-4-[2-fluoro-4-(trifluoro-methyl)phenyl]-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxamide

HRID 734718Notes

Reaction equation

HRID 734718 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]1[C:20](O)=[O:21].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[Cl:34][C:35]1[C:43]2[C:38](=[CH:39][C:40]([F:45])=[C:41]([NH2:44])[CH:42]=2)[NH:37][N:36]=1>C(Cl)Cl.N1C=CC=CC=1.CCOC(C)=O.Cl>[Cl:34][C:35]1[C:43]2[C:38](=[CH:39][C:40]([F:45])=[C:41]([NH:44][C:20]([C:13]3[CH:12]([C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=4[F:1])[CH2:17][C:16](=[O:18])[NH:15][C:14]=3[CH3:19])=[O:21])[CH:42]=2)[NH:37][N:36]=1

Participants

9

Reactant 4

HCID 6228DimethylformamideHCID 65578Oxalyl chlorideHCID 688271204-[2-Fluoro-4-(trifluoromethyl)phenyl]-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylic acidHCID 1785072033-chloro-6-fluoro-1H-indazol-5-amine

Product 1

HCID 178429200N-(3-Chloro-6-fluoro-1H-indazol-5-yl)-4-[2-fluoro-4-(trifluoro-methyl)phenyl]-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxamideYield 8%

Reagents, catalysts & solvents 4

HCID 313Hydrochloric AcidSolventHCID 1049PyridineSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

The product from Example 21, Step 2 (1.0 g, 3.152 mmol, 1.0 equiv) and oxalyl chloride (330 μL, 3.783 mmol, 1.2 equiv) in CH2Cl2 (12.5 mL) with catalytic DMF (20 μL) was stirred at room temperature for 45 minutes. The reaction mixture was concentrated en vacuo and half was redissolved in CH2Cl2 (5 mL). This solution was added dropwise over 5 minutes to a solution of the product from Example 39, step 2 (322 mg, 1.733 mmol, 1.1 equiv) in pyridine (4 mL) at −20° C. The reaction mixture was slowly warmed to room temperature over 3 hours. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was concentrated en vacuo. The residue was purified by flash chromatography (0-80% EtOAc in Hexanes) and further purified by reverse-phase HPLC (20-90% CH3CN/H2O, 0.1TFA over 13 minutes, retention time 8.11 min) to provide 60 mg (8%) of the title compound as a white solid. MS (ES+) m/e 485 [M+H]+

Workup

  1. concentrationThe reaction mixture was concentrated en vacuo and half
  2. dissolutionwas redissolved in CH2Cl2 (5 mL)
  3. customThe phases were separated
  4. washthe organic phase was washed twice with 1N HCl, once with satd
  5. concentrationThe organic phase was concentrated en vacuo
  6. customThe residue was purified by flash chromatography (0-80% EtOAc in Hexanes)
  7. customfurther purified by reverse-phase HPLC (20-90% CH3CN/H2O, 0.1TFA over 13 minutes, retention time 8.11 min)

Sources & evidence

ORD record
ord-a89d76ddb91542ec99d1e9f520c60883
Source dataset
uspto-grants-2009_09
Patent number
US07592357B2

Reaction notes

Loading…