4-Methylmorpholine → Ethyl 2-(6-chloro-4-(isopropylamino)nicotinamido)-3-oxobutanoate

HRID 595408Notes

Reaction equation

HRID 595408 reaction equation
[Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH:14]2[CH2:17]C[CH2:15]2)[C:5]([C:6]([O:8]CC)=O)=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:24][CH:25]([C:31](=[O:33])[CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27].CN1CCOCC1>C(Cl)Cl.CN(C=O)C.C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH:14]([CH3:15])[CH3:17])[C:5]([C:6]([NH:24][CH:25]([C:31](=[O:33])[CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:8])=[CH:4][N:3]=1

Participants

9

Reactant 4

HCID 79724-MethylmorpholineHCID 65578Oxalyl chlorideHCID 13282896Ethyl 2-amino-3-oxobutanoateHCID 89689654Ethyl 6-chloro-4-(cyclobutylamino)nicotinate

Product 1

HCID 89689546Ethyl 2-(6-chloro-4-(isopropylamino)nicotinamido)-3-oxobutanoate

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

A stirred solution of 6-chloro-4-(isopropylamino)nicotinic acid (2) in DCM (15 mL) was cooled to 0° C., oxalyl chloride (2 equiv) was added, followed by addition of 2 drops of DMF. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to remove excess of oxalyl chloride. The acyl chloride, generated in-situ was dissolved in THF and added dropwise to a cool, stirred solution of ethyl 2-amino-3-oxobutanoate (1.1 equiv.) and NMM (5 equiv.) in THF. The reaction temperature was slowly brought to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc and washed with water, followed by brine solution. The EtOAc layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by column chromatography through silica gel and EtOAc: Pet. Ether as eluent to afford the title compound, ethyl 2-(6-chloro-4-(isopropylamino)nicotinamido)-3-oxobutanoate.

Workup

  1. concentrationThe reaction mixture was concentrated
  2. customto remove excess of oxalyl chloride
  3. dissolutionin-situ was dissolved in THF
  4. additionadded dropwise to a cool
  5. customwas slowly brought to room temperature
  6. stirringstirred overnight
  7. washwashed with water
  8. customThe EtOAc layer was collected
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe crude material obtained
  13. customwas purified by column chromatography through silica gel and EtOAc

Sources & evidence

ORD record
ord-c3669fc7dc7844b1b9e451f4f7af9d69
Source dataset
uspto-grants-2016_01
Patent number
US09242975B2

Reaction notes

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