Dimethylformamide → 4-Chloro-2-{[2-(2-chloro-3,6-difluoro-phenyl)-acetyl]-methyl-amino}-6-methyl-nicotinic acid ethyl ester

HRID 878392Notes

Reaction equation

HRID 878392 reaction equation
C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([F:15])[C:9]=1[CH2:16][C:17]([OH:19])=O.CN(C)C=O.[CH2:25]([O:27][C:28](=[O:39])[C:29]1[C:34]([Cl:35])=[CH:33][C:32]([CH3:36])=[N:31][C:30]=1[NH:37][CH3:38])[CH3:26]>ClCCl.N1C=CC=CC=1>[CH2:25]([O:27][C:28](=[O:39])[C:29]1[C:34]([Cl:35])=[CH:33][C:32]([CH3:36])=[N:31][C:30]=1[N:37]([C:17](=[O:19])[CH2:16][C:9]1[C:10]([F:15])=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[Cl:7])[CH3:38])[CH3:26]

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 65578Oxalyl chlorideHCID 27735662-Chloro-3,6-difluorobenzeneacetic acidHCID 669300704-Chloro-6-methyl-2-methylamino-nicotinic acid ethyl ester

Product 1

HCID 669300034-Chloro-2-{[2-(2-chloro-3,6-difluoro-phenyl)-acetyl]-methyl-amino}-6-methyl-nicotinic acid ethyl esterYield 39.7%

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 6344DichloromethaneSolvent3×

Procedure

Oxalyl chloride (0.19 ml) was added dropwise to a solution of (2-chloro-3,6-difluoro-phenyl)-acetic acid (373 mg) in dichloromethane (5 ml) at ambient temperature. A drop of N,N-dimethylformamide (“DMF”) was added to initiate the reaction. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated to give a colourless oil which was dissolved in dichloromethane (5 ml). The mixture was added dropwise to a slurry of 4-chloro-6-methyl-2-methylamino-nicotinic acid ethyl ester (Example 4.1) (413 mg) and pyridine (0.16 ml) in dichloromethane (5 ml). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between dichloromethane and water. The phases were separated and the organic layer was concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:4) to give 4-chloro-2-{[2-(2-chloro-3,6-difluoro-phenyl)-acetyl]-methyl-amino}-6-methyl-nicotinic acid ethyl ester as a yellow solid (299 mg). 1H NMR (400 MHz, CDCl3): 7.32 (bs, 1H), 7.00-7.05 (m, 1H), 6.90-6.96 (m, 1H), 4.43-4.45 (m, 2H), 3.66 (s, 2H), 3.24 (m, 3H), 2.60 (s, 3H), 1.37-1.40 (t, 3H) ppm.

Workup

  1. customthe reaction
  2. concentrationThe reaction mixture was concentrated
  3. customto give a colourless oil which
  4. stirringThe reaction mixture was stirred at ambient temperature for 16 hours
  5. customThe reaction mixture was partitioned between dichloromethane and water
  6. customThe phases were separated
  7. concentrationthe organic layer was concentrated
  8. customThe residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:4)

Sources & evidence

ORD record
ord-c29f31f60ce74a1ea1c44c2103d2eac5
Source dataset
uspto-grants-2015_03
Patent number
US08987455B2

Reaction notes

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