1-(6-Chloroimidazo(1,2-b)pyridazin-3-yl)ethan-1-one → 1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethanol

HRID 1959725Notes

Reaction equation

HRID 1959725 reaction equation
[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:12].[Li]CCCC.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28](=[O:30])[CH3:29])=[CH:26][N:27]=2)[N:24]=1>C1COCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([C:10]3[C:2]([F:1])=[C:3]4[C:7](=[CH:8][C:9]=3[F:11])[N:6]([CH3:12])[N:5]=[CH:4]4)([OH:30])[CH3:29])=[CH:26][N:27]=2)[N:24]=1

Participants

5

Reactant 3

HCID 132488051-(6-Chloroimidazo(1,2-b)pyridazin-3-yl)ethan-1-one2×HCID 579174794,6-Difluoro-1-methyl-1H-indazole2×HCID 178418339Butyllithium

Product 1

HCID 581475291-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethanolYield 41%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 4,6-difluoro-1-methyl-1H-indazole (intermediate P) (600 mg, 3.57 mmol) in anhydrous THF (20 mL) at −78° C. was added n-BuLi (1.6M solution in hexane, 2.56 mL, 4.1 mmol). The solution was stirred at this temperature for 1 h and then a solution of 1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethanone (intermediate M) (698 mg, 3.57 mmol) in anhydrous THF (10 mL) was added dropwise. The resulting solution was stirred at this temperature for 3 h and allowed to warm to it slowly and stirred overnight. The reaction mixture was quenched with water, extracted with EtOAc three times. The organic layers were combined and washed with brine, dried over Na2SO4. The crude was purified by flash chromatography (DCM:MeOH=95:5) to give 530 mg (41%) of the title compound as yellow oil. 1H-NMR (400 MHz, CDCl3) ppm 8.05 (d, 1H), 8.0 (s, 1H), 7.85 (s, 1H), 7.1 (d, 1H), 6.85 (d, 1H), 4.0 (s, 3H), 2.3 (s, 3H). LCMS (method B): [MH]+=363.9, tR=2.15 min.

Workup

  1. stirringThe resulting solution was stirred at this temperature for 3 h
  2. temperatureto warm to it slowly
  3. stirringstirred overnight
  4. customThe reaction mixture was quenched with water
  5. extractionextracted with EtOAc three times
  6. washwashed with brine
  7. dry with materialdried over Na2SO4
  8. customThe crude was purified by flash chromatography (DCM:MeOH=95:5)

Sources & evidence

ORD record
ord-931cb39f17c54458bd65d2d8bb5c6e5a
Source dataset
uspto-grants-2013_04
Patent number
US08410264B2

Reaction notes

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