2,4-Difluoroaniline → Pyridine-3-carboxamide, 4-chloro-N-(2,4-difluorophenyl)-

HRID 1986060Notes

Reaction equation

HRID 1986060 reaction equation
[Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:13]=1[NH2:14].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:12]=2[F:11])=[O:10])=[CH:6][N:5]=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 97092,4-DifluoroanilineHCID 81531DiisopropylethylamineHCID 8182294-Chloronicotinic acidHCID 2733179PyBroP

Product 1

HCID 587732Pyridine-3-carboxamide, 4-chloro-N-(2,4-difluorophenyl)-Yield 42.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a mixture of 4-chloronicotinic acid (Lancaster Synthesis, 0.31 g, 2.0 mmol) and 2,4-difluoroaniline (Aldrich, 0.20 mL, 2.0 mmol) in anhydrous dichloromethane (5 mL) was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP®, Novabiochem, 1.4 g, 3.0 mmol) followed by diisopropylethylamine (1.1 mL, 6.4 mmol). Anhydrous DMF (2 mL) was added to the mixture and the reaction stirred at ambient temperature. After 255 hours, the reaction mixture was partitioned between chloroform and 10% LiCl (aq). The organic layer was washed three times with 10% LiCl (aq), dried over anhydrous MgSO4, then concentrated in vacuo. Purification of the residue by flash column chromatography (SiO2, eluting with 1:1 hexane/EtOAc) afforded the desired compound (0.23 g, 42%). 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 8.78 (s, 1H), 8.66 (d, 1H, J=5.4 Hz), 7.82-7.88 (m, 1H), 7.71 (d, 1H, J=5.4 Hz), 7.37-7.43 (m, 1H), 7.14-7.19 (m, 1H);

Workup

  1. customthe reaction mixture was partitioned between chloroform and 10% LiCl (aq)
  2. washThe organic layer was washed three times with 10% LiCl (aq)
  3. dry with materialdried over anhydrous MgSO4
  4. concentrationconcentrated in vacuo
  5. customPurification of the residue
  6. washby flash column chromatography (SiO2, eluting with 1:1 hexane/EtOAc)

Sources & evidence

ORD record
ord-4c6b9f063f7346fdb53fb32d59341534
Source dataset
uspto-grants-2009_06
Patent number
US07547782B2

Reaction notes

Loading…