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

HRID 1253631ノート

反応式

HRID 1253631 の反応式
[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

参加物

6

反応物 4

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

生成物 1

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

試薬・触媒・溶媒 1

HCID 962Water溶媒3 回

反応条件

温度
55 °C

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-e38d0e77d6674e62bcd050754a3263f6
出典データセット
uspto-grants-2013_06
特許番号
US08455495B2

反応ノート

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