Diisopropylethylamine → 6-[6-((R)-3-fluoro-pyrrolidin-1-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline

HRID 69181Notes

Reaction equation

HRID 69181 reaction equation
Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.Cl.[F:23][C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.[F-].[K+].C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1.CCOC(C)=O>[F:23][C@@H:24]1[CH2:28][CH2:27][N:26]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)=[CH:9][N:10]=3)[N:7]=2)[CH2:25]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 522689Potassium FluorideHCID 2759162(3R)-3-fluoropyrrolidine hydrochlorideHCID 579174466-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline

Product 1

HCID 579174286-[6-((R)-3-fluoro-pyrrolidin-1-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
170 °C

Procedure

6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline (Example 14, 100 mg, 0.339 mmol), (R)-(−)-3-fluoropyrrolidine hydrochloride (220 mg, 1.696 mmol) and KF (99 mg, 1.696 mmol) were suspended in NMP (1.5 mL). N-Ethyldiisopropylamine (296 μL, 1.696 mmol) was then added and the RM was stirred at 170° C. for 4 h. The mixture was diluted with EtOAc and extracted with 1 M HCl (3×). The aqueous layer was washed with TBME (2×) and then adjusted to pH 10 with 2 M NaOH. The solution was extracted with DCM (3×). The organic layer was washed with water (2×), dried over sodium, filtered and concentrated. The residue was purified by flash chromatography (Flashmaster) and triturated in DCM to afford the title compound as a yellow foam (tR 4.14 min (conditions 4), MH+=348.5, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.29 (m, 1H); 7.93 (m, 2H); 7.81 (d, 1H); 7.76 (m, 1H); 7.49 (dd, 1H); 7.43 (s, 1H); 6.81 (d, 1H); 5.46 (m, 1H); 4.38 (s, 2H); 3.62 (m, 4H); 2.20 (m, 2H)).

Workup

  1. extractionextracted with 1 M HCl (3×)
  2. washThe aqueous layer was washed with TBME (2×)
  3. extractionThe solution was extracted with DCM (3×)
  4. washThe organic layer was washed with water (2×)
  5. dry with materialdried over sodium
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by flash chromatography (Flashmaster)
  9. customtriturated in DCM

Sources & evidence

ORD record
ord-43277f780dbf4530b750279af485185a
Source dataset
uspto-grants-2014_09
Patent number
US08822468B2

Reaction notes

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