Dimethylformamide → 5-bromo-6-chloro-N-(4-(1,1-difluoroethoxy)phenyl)nicotinamide

HRID 73797Notes

Reaction equation

HRID 73797 reaction equation
C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[C:9]([Cl:17])=[N:10][CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=O.CN(C=O)C.CCN(C(C)C)C(C)C.[F:32][C:33]([F:43])([O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH3:34]>C(Cl)Cl.C1COCC1.CCCCCC>[Br:7][C:8]1[C:9]([Cl:17])=[N:10][CH:11]=[C:12]([CH:16]=1)[C:13]([NH:40][C:39]1[CH:41]=[CH:42][C:36]([O:35][C:33]([F:32])([F:43])[CH3:34])=[CH:37][CH:38]=1)=[O:15]

Participants

9

Reactant 5

HCID 6228DimethylformamideHCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 2854335-Bromo-6-chloropyridine-3-carboxylic acidHCID 68195912Benzenamine, 4-(1,1-difluoroethoxy)-

Product 1

HCID 867026295-bromo-6-chloro-N-(4-(1,1-difluoroethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8058HexaneSolvent

Procedure

Oxalyl chloride (653 μL, 7.46 mmol) was added to a mixture of 5-bromo-6-chloronicotinic acid (1.2 g, 4.97 mmol) and DMF (20 μL, 0.258 mmol) in DCM (40 mL) under nitrogen atmosphere and the RM was stirred for 2 h at RT. The solvent was evaporated, the residue was dissolved in DCM (10 mL) and evaporated again to dryness. The residue was dissolved in THF (30 mL), DIPEA (1.737 mL, 9.95 mmol) was added and the RM was cooled down to −15° C. 4-(1,1-difluoroethoxy)aniline (Stage 30.3, 0.932 g, 5.22 mmol) in THF (10 mL) was added dropwise in 15 min. period and the RM was stirred for 1 h at RT. The solvent was evaporated off under reduced pressure and the residue was diluted with EtOAc (100 mL), treated with citric acid 10% (60 mL) and extracted with EtOAc. The combined extracts were washed with sat. aq. Na2CO3 (50 mL) and brine (2×50 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was suspended in n-hexane, filtered and dried to give the title product as a beige solid. HPLC (Condition 5) tR=7.3 min, UPLC-MS (Condition 3) tR=1.16 min, m/z=391/393 [M+H]+.

Workup

  1. customThe solvent was evaporated
  2. dissolutionthe residue was dissolved in DCM (10 mL)
  3. customevaporated again to dryness
  4. dissolutionThe residue was dissolved in THF (30 mL)
  5. temperaturethe RM was cooled down to −15° C
  6. stirringthe RM was stirred for 1 h at RT
  7. customThe solvent was evaporated off under reduced pressure
  8. additionthe residue was diluted with EtOAc (100 mL)
  9. additiontreated with citric acid 10% (60 mL)
  10. extractionextracted with EtOAc
  11. washThe combined extracts were washed with sat. aq. Na2CO3 (50 mL) and brine (2×50 mL)
  12. dry with materialdried over Na2SO4
  13. customthe solvent was evaporated off under reduced pressure
  14. customto give the crude product which
  15. filtrationfiltered
  16. customdried

Sources & evidence

ORD record
ord-4d7b8e4564de4fda824523e6578c81bc
Source dataset
uspto-grants-2014_09
Patent number
US08829195B2

Reaction notes

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