Hydrochloric Acid → (Rac)-1-(7-fluoro-quinolin-6-yl)-1-{6-[1-(2-hydroxy-ethyl)-1h-pyrazol-4-yl]-imidazo[1,2-b]pyridazin-3-yl}-ethanol

HRID 69273Notes

Reaction equation

HRID 69273 reaction equation
Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][C:23]=3[F:24])[N:20]=[CH:19][CH:18]=[CH:17]4)([OH:13])[CH3:12])=[CH:9][N:10]=2)[N:7]=1.O1CCCCC1[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Na+].[Na+].Cl>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[F:24][C:23]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[C:11]([C:8]1[N:6]2[N:7]=[C:2]([C:37]3[CH:36]=[N:35][N:34]([CH2:33][CH2:32][OH:31])[CH:38]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)([OH:13])[CH3:12]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 10340Sodium CarbonateHCID 11430Potassium CarbonateHCID 581475421-(6-Chloroimidazo[1,2-b]pyridazin-3-yl)-1-(7-fluoroquinolin-6-yl)ethanolHCID 593418191-[2-(oxan-2-yloxy)ethyl]-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Product 1

HCID 57917331(Rac)-1-(7-fluoro-quinolin-6-yl)-1-{6-[1-(2-hydroxy-ethyl)-1h-pyrazol-4-yl]-imidazo[1,2-b]pyridazin-3-yl}-ethanol

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

(rac)-1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(7-fluoro-quinolin-6-yl)-ethanol (Stage 174.1, 200 mg, 0.584 mmol) was dissolved in DME (4 mL) under argon atm. 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 171.4, 282 mg, 0.875 mmol) was added, followed by 2 M K2CO3 (0.79 mL) and PdCl2(PPh3)2 (20.5 mg, 0.029 mmol). The RM was stirred at 90° C. for 1.5 h. It was then taken into a mixture of EtOAc and 1 M Na2CO3 and extracted. The organic phase was dried on Na2SO4, filtered and evaporation of the solvent. The residue was dissolved in DCM (16 mL), 4 M HCl (dioxane, 0.438 mL, 1.751 mmol) were added at 10° C. The mixture was stirred at rt for 1 h. The solvent was evaporated and the residue was diluted with EtOAc/MeOH (95:5) and washed with 1 M Na2CO3 (1×). The aqueous phases were further extracted with EtOAc (1×). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was crystallized in DCM/Et2O to afford the title compound as a slightly yellow solid (tR 2.37 min (conditions 13), MH+=419). 1H-NMR in DMSO-d6: 8.86 (m, 1H), 8.64 (m, 2H), 8.02 (d, 1H), 7.93 (s, 1H), 7.82 (s, 1H), 7.58-7.50 (m, 2H), 7.45-7.40 (m, 2H), 6.25 (s, 1H), 4.86 (t, 1H), 4.00 (m, 2H), 3.60 (m, 2H), 2.15 (s, 3H).

Workup

  1. extractionextracted
  2. customThe organic phase was dried on Na2SO4
  3. filtrationfiltered
  4. customevaporation of the solvent
  5. dissolutionThe residue was dissolved in DCM (16 mL)
  6. stirringThe mixture was stirred at rt for 1 h
  7. customThe solvent was evaporated
  8. additionthe residue was diluted with EtOAc/MeOH (95:5)
  9. washwashed with 1 M Na2CO3 (1×)
  10. extractionThe aqueous phases were further extracted with EtOAc (1×)
  11. dry with materialThe combined organic layer was dried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe residue was crystallized in DCM/Et2O

Sources & evidence

ORD record
ord-8f5e9dbf0da34477b798ee0c14408ad1
Source dataset
uspto-grants-2014_09
Patent number
US08822468B2

Reaction notes

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