Tetrahydrofuran → 3-bromo-8-(2,4-difluorophenyl)-1-methylpyrido[3,2-d]pyridazin-2(1H)-one

HRID 1966387Notes

Reaction equation

HRID 1966387 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:18]([CH3:19])[C:17](=[O:20])[C:16](C(O)=O)=[CH:15][C:11]=2[CH:12]=[N:13][N:14]=1.C1COCC1.O.O.C([O-])(=O)C.[Li+].C1C(=O)N([Br:43])C(=O)C1>O>[Br:43][C:16]1[C:17](=[O:20])[N:18]([CH3:19])[C:10]2[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:14][N:13]=[CH:12][C:11]=2[CH:15]=1

Participants

6

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 67184N-bromobutanimide3×HCID 23666338Lithium acetate dihydrate2×HCID 469305368-(2,4-Difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylic acid2×

Product 1

HCID 469305373-bromo-8-(2,4-difluorophenyl)-1-methylpyrido[3,2-d]pyridazin-2(1H)-one

Reagents, catalysts & solvents 1

HCID 962WaterSolvent3×

Conditions

Temperature
55 °C

Procedure

To a suspension of 8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylic acid (7) (1.00 g, 3.15 mmol) in 10:1 THF:H2O (11 mL), stirred at 55° C., was added lithium acetate dihydrate (67 mg, 0.66 mmol). The mixture was stirred at 55° C. and treated with NBS (1.51 g, 8.48 mmol) in three equal portions at 30 min intervals. After addition of NBS was complete, the reaction mixture was stirred an additional 1 h at 55° C. In a separate flask, a suspension of 8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylic acid (7) (0.92 g, 2.89 mmol) in 10:1 THF:H2O (10 mL) stirred at 55° C. was treated with lithium acetate dihydrate (62 mg, 0.61 mmol) followed by NBS (1.39 g, 7.80 mmol) under the same conditions. Upon complete reaction, the two reaction mixtures were combined, diluted with water, and extracted with CH2Cl2. The combined organic layers were washed with 20% THF in water, dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography [eluting with a gradient of 10-40% B in A where the eluents were: A=CH2Cl2; B=1:49.5:49.5 MeOH:EtOAc:CH2Cl2] to give 3-bromo-8-(2,4-difluorophenyl)-1-methylpyrido[3,2-d]pyridazin-2(1H)-one as a yellow solid. MS (ESI, pos. ion) m/z: 350, 352 (M+1, M+3).

Workup

  1. stirringthe reaction mixture was stirred an additional 1 h at 55° C
  2. customUpon complete reaction
  3. customthe two reaction mixtures
  4. extractionextracted with CH2Cl2
  5. washThe combined organic layers were washed with 20% THF in water
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe resulting residue was purified by silica gel chromatography [
  10. washeluting with a gradient of 10-40% B in A where the eluents

Sources & evidence

ORD record
ord-ae37df097f8346a89d5bab2b706e4cc5
Source dataset
uspto-grants-2013_04
Patent number
US08420649B2

Reaction notes

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