Lithium diisopropylamide → (Rac)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(5,7-difluoro-quinolin-6-yl)-ethanol

HRID 1942049Notes

Reaction equation

HRID 1942049 reaction equation
[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Li+].CC([N-]C(C)C)C.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([C:28]([C:31](=[O:33])[CH3:32])=[CH:29][N:30]=2)[N:27]=1>C1COCC1>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([C:28]([C:31]([C:11]3[C:2]([F:1])=[C:3]4[C:8](=[CH:9][C:10]=3[F:12])[N:7]=[CH:6][CH:5]=[CH:4]4)([OH:33])[CH3:32])=[CH:29][N:30]=2)[N:27]=1

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 3015686Quinoline, 5,7-difluoro-HCID 132488051-(6-Chloroimidazo(1,2-b)pyridazin-3-yl)ethan-1-one

Product 1

HCID 58147518(Rac)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(5,7-difluoro-quinolin-6-yl)-ethanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 5,7-difluoro-quinoline (CAS 34522-72-0, 18.57 g, 112 mmol) in dry THF (120 mL) was added dropwise to a freshly prepared solution of LDA (n-BuLi 77 mL and diisopropylamine 18.94 mL, 123 mmol, in 500 mL THF) at −78° C. The solution was stirred at this temperature for 1 h, and then the solution of 1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)ethanone (CAS 90734-71-7, 20.0 g, 102 mmol) in 400 mL THF was added dropwise at −70° C. After stirring additional 45 min at −70 to −30° C. the RM was quenched with 1M NH4Cl, diluted with water, and extracted with EtOAc (3×). The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and then crystallized in DCM to afford the title compound as a beige solid (tR 2.94 min (conditions 1), MH+=361, 1H-NMR in DMSO-d6: 8.93 (d, 1H); 8.43 (d, 1H); 8.18 (d, 1H); 7.92 (s, 1H); 7.57 (m, 2H); 7.24 (d, 1H); 6.49 (s, 1H); 2.18 (s, 3H)).

Workup

  1. stirringAfter stirring additional 45 min at −70 to −30° C. the RM
  2. customwas quenched with 1M NH4Cl
  3. additiondiluted with water
  4. extractionextracted with EtOAc (3×)
  5. washThe organic layers were washed with brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by flash chromatography
  10. customcrystallized in DCM

Sources & evidence

ORD record
ord-8ac6b48e15bc4483976eeb86a9800ae5
Source dataset
uspto-grants-2013_03
Patent number
US08389526B2

Reaction notes

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