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

HRID 1966387노트

반응식

HRID 1966387 반응식
[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

참가 물질

6

반응물 4

HCID 8028Tetrahydrofuran2회HCID 67184N-bromobutanimide3회HCID 23666338Lithium acetate dihydrate2회HCID 469305368-(2,4-Difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylic acid2회

생성물 1

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

시약·촉매·용매 1

HCID 962Water용매3회

반응 조건

온도
55 °C

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-ae37df097f8346a89d5bab2b706e4cc5
출처 데이터셋
uspto-grants-2013_04
특허 번호
US08420649B2

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