Ammonium Chloride → Ethyl 2-(6-chloropyridazin-3-yl)-2,2-difluoroacetate

HRID 1925135Notes

Reaction equation

HRID 1925135 reaction equation
[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([F:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[B-](F)(F)(F)[F:26].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.[NH4+].[Cl-]>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([F:26])([F:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 2724933SelectfluorHCID 2733832Lithium HexamethyldisilazideHCID 46941482Ethyl 2-(6-chloropyridazin-3-yl)-2-fluoroacetate

Product 1

HCID 46941483Ethyl 2-(6-chloropyridazin-3-yl)-2,2-difluoroacetateYield 52.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of ethyl 2-(6-chloropyridazin-3-yl)-2-fluoroacetate (36.6 g, 167 mmol) in anhydrous THF (500 mL) was added lithium hexamethyldisilazide (201 ml, 201 mmol) drop-wise at −78° C. After 15 minutes, a solution of Selectfluor (71.2 g, 201 mmol) in DMF (183 mL) was added drop-wise. Upon complete addition, the reaction was allowed to warm to ambient temperature over a 30 min period. Saturated NH4Cl (70 mL) was then added, and THF was removed via rotary evaporation. The resulting residue was diluted with water (500 mL), extracted with Et2O (3×100 mL), dried with MgSO4, filtered, and concentrated to dryness. The resulting material was purified via MPLC (Hex:EtOAc, 8:2) to provide ethyl 2-(6-chloropyridazin-3-yl)-2,2-difluoroacetate 45D (20.8 g, 88 mmol, 52.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (t, J=7.07 Hz, 3 H) 4.38 (q, J=7.07 Hz, 2 H) 8.26 (d, J=9.09 Hz, 1 H) 8.33 (d, J=8.84 Hz, 1 H). ESI-MS:m/z 237.1 (M+H)+.

Workup

  1. additionUpon complete addition
  2. customTHF was removed via rotary evaporation
  3. additionThe resulting residue was diluted with water (500 mL)
  4. extractionextracted with Et2O (3×100 mL)
  5. dry with materialdried with MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated to dryness
  8. customThe resulting material was purified via MPLC (Hex:EtOAc, 8:2)

Sources & evidence

ORD record
ord-4910a37971514e8e891eaa4dd84e79c7
Source dataset
uspto-grants-2012_05
Patent number
US08178534B2

Reaction notes

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