Pyridine → 4'-Fluoro-biphenyl-4-carboxylic acid {2-[methyl-(1-methyl-piperidin-4-yl)-amino]-benzooxazol-5-yl}-amide

HRID 1174935Notes

Reaction equation

HRID 1174935 reaction equation
C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[CH3:23][N:24]([CH:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)[C:25]1[O:26][C:27]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:28]=2[N:29]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH3:23][N:24]([CH:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)[C:25]1[O:26][C:27]2[CH:33]=[CH:32][C:31]([NH:34][C:20]([C:17]3[CH:16]=[CH:15][C:14]([C:11]4[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=4)=[CH:19][CH:18]=3)=[O:22])=[CH:30][C:28]=2[N:29]=1

Participants

7

Reactant 4

HCID 1049PyridineHCID 65578Oxalyl chlorideHCID 27826894-(4-Fluorophenyl)benzoic acidHCID 59558009N2-Methyl-N2-(1-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine

Product 1

HCID 115470744'-Fluoro-biphenyl-4-carboxylic acid {2-[methyl-(1-methyl-piperidin-4-yl)-amino]-benzooxazol-5-yl}-amideYield 38.1%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent2×

Procedure

Add oxalyl chloride (0.16 mL, 1.82 mmol) and 3 drops of DMF to a stirring suspension of 4′-fluoro-biphenyl-4-carboxylic acid (0.197 g, 0.910 mmol) in CH2Cl2 (2.0 mL). Stir the reaction mixture at room temperature for 2 h, Concentrate the mixture in vacuo, add n-hexane, re-concentrate, and re-dissolve in CH2Cl2. Add the resultant 4′-fluoro-biphenyl-4-carbonyl chloride solution to a mixture of rac-N2-methyl-N2-(1-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine (0.158 g, 0.607 mmol) and pyridine (0.05 mL) in CH2Cl2 (10 mL). Shake the reaction mixture overnight at room temperature. Wash the mixture with saturated NaHCO3 (2×20 mL), dry the organic phase over Na2SO4, filter, and concentrate the mixture in vacuo. Subject the residue to silica gel flash column chromatography (3×4 g columns, eluting with 5% 2N NH3 in MeOH/CH2Cl2) to yield the desired product as a white solid (0.106 g, 38%). mass spectrum (m/e): 459.0 (M+1), 457.0 (M−1). 1H NMR (400 MHz, CDCl3): δ 7.95-7.90 (m, 3H), 7.63 (d, J=8.0 Hz, 2H), 7.60-7.54 (m, 2H), 7.52 (d, J=1.2 Hz, 1H), 7.36 (dd, J=8.8, 1.6 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.18-7.11 (m, 2H), 4.21-4.11 (m, 1H), 3.07 (s, 3H), 2.97 (d, J=11.6 Hz, 2H), 2.32 (s, 3B), 2.21-2.12 (m, 2H), 2.00-1.88 (m, 2H), 1.83-1.75 (m, 2H).

Workup

  1. concentrationConcentrate the mixture in vacuo
  2. additionadd n-hexane
  3. concentrationre-concentrate
  4. dissolutionre-dissolve in CH2Cl2
  5. additionAdd the resultant 4′-fluoro-biphenyl-4-carbonyl chloride solution
  6. customthe reaction mixture overnight
  7. customat room temperature
  8. washWash the mixture with saturated NaHCO3 (2×20 mL)
  9. dry with materialdry the organic phase over Na2SO4
  10. filtrationfilter
  11. concentrationconcentrate the mixture in vacuo
  12. washto silica gel flash column chromatography (3×4 g columns, eluting with 5% 2N NH3 in MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-58d22802a05e408ba1472a4ec0554c32
Source dataset
uspto-grants-2010_11
Patent number
US07838543B2

Reaction notes

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