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 456089Notes

Reaction equation

HRID 456089 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-oneHCID 579174794,6-Difluoro-1-methyl-1H-indazoleHCID 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 (600 mg, 3.57 mmol) in 20 mL of anhydrous THF 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 hour and then a solution of 1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethanone (698 mg, 3.57 mmol) in 10 mL of anhydrous THF was added at −78° C. dropwise. The resulting solution was stirred at this temperature for 3 hours and slowly warmed up to room temperature and stirred overnight. The reaction mixture was quenched with water, extracted with EtOAc for three times. The organic layers were combined and washed with brine, dried over Na2SO4. The crude product was purified with flash chromatography (CH2Cl2:MeOH 95:5) to give the title compound as a yellow oil (530 mg, 41%). 1H-NMR (400 MHz, CDCl3) δ 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 hours
  2. stirringstirred overnight
  3. customThe reaction mixture was quenched with water
  4. extractionextracted with EtOAc for three times
  5. washwashed with brine
  6. dry with materialdried over Na2SO4
  7. customThe crude product was purified with flash chromatography (CH2Cl2:MeOH 95:5)

Sources & evidence

ORD record
ord-b2c1e479889948428eb15c3f492ae508
Source dataset
uspto-grants-2013_07
Patent number
US08497368B2

Reaction notes

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