Diisopropylethylamine → 2-(Difluoromethyl)-5-{[(2-Methylpropanoyl)amino]methyl}-N-{5-Methyl-4-[4-(Trifluoromethyl)phenyl]-1h-Imidazol-2-Yl}pyridine-3-Carboxamide

HRID 241461Notes

Reaction equation

HRID 241461 reaction equation
[CH3:1][C:2]1[N:3]=[C:4]([NH2:17])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[F:18][CH:19]([F:36])[C:20]1[C:25]([C:26](O)=[O:27])=[CH:24][C:23]([CH2:29][NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CCOC(C)=O.CCOCC.CN(C=O)C>[F:36][CH:19]([F:18])[C:20]1[C:25]([C:26]([NH:17][C:4]2[NH:5][C:6]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=3)=[C:2]([CH3:1])[N:3]=2)=[O:27])=[CH:24][C:23]([CH2:29][NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])=[CH:22][N:21]=1

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 710598402-(Difluoromethyl)-5-(isobutyramidomethyl)nicotinic acidHCID 1784333994-Methyl-5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-amine

Product 1

HCID 1784332152-(Difluoromethyl)-5-{[(2-Methylpropanoyl)amino]methyl}-N-{5-Methyl-4-[4-(Trifluoromethyl)phenyl]-1h-Imidazol-2-Yl}pyridine-3-Carboxamide

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

In a thermally controlled reactor stir a mixture of 4-methyl-5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-amine (395 g, 1.63 mol, 1 equiv), 2-(difluoromethyl)-5-{[(2-methylpropanoyl)amino]methyl}pyridine-3-carboxylic acid (445.8 g, 1.63 mol, 1 equiv), DMF (3.16 L), DIPEA (856 ml, 4.91 mol, 3 equiv) and TBTU (630 g, 1.965 mol, 1.2 equiv) at an internal temperature of 75° C. for 18 hours. Cool the mixture; dilute with EtOAc (2.5 L); and wash with water (3×5 L) and brine (2×2.5 L). Extract the combined aqueous phases with EtOAc (2.5 L). Combine the organic extracts, and dry over MgSO4. Concentrate the to dryness to give a yellow semi-solid. Slurry this solid with Et2O (2.5 L) for 3 hours; collect the solids by filtration; and air dry for 16 hours then in vacuo at 50° C. for a further 48 hours to give the title product as a fine free flowing white solid (568 g, 66% yield). 1H NMR (MeOD-d4, 500 MHz): δ 8.63 (s, 1H), 8.13 (s, 1H), 7.74 (d, 2H, J=8.1 Hz), 7.67 (d, 2H, J=8.1 Hz), 7.36 (t, 1H, J=54.2 Hz), 4.47 (s, 2H), 2.52-2.45 (m, 4H), 1.13 (d, 6H, J=6.8 Hz); MS (m/z) 496 (M+1).

Workup

  1. temperatureCool the mixture
  2. washand wash with water (3×5 L) and brine (2×2.5 L)
  3. extractionExtract the combined aqueous phases with EtOAc (2.5 L)
  4. dry with materialCombine the organic extracts, and dry over MgSO4
  5. concentrationConcentrate the to dryness
  6. customto give a yellow semi-solid
  7. customfor 3 hours
  8. customcollect the solids
  9. filtrationby filtration
  10. customand air dry for 16 hours

Sources & evidence

ORD record
ord-324d25bed7944915827ae42a93aacfd9
Source dataset
uspto-grants-2014_02
Patent number
US08648200B2

Reaction notes

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