Cesium carbonate → 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine

HRID 1432733Notes

Reaction equation

HRID 1432733 reaction equation
[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[Cl:21][C:22]1[N:23]=[C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[S:25][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:21][C:22]1[N:23]=[C:24]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[S:25][C:26]=1[C:13]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]2=[N:15][C:14]=1[C:16]([F:19])([F:18])[F:17]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 11776TriphenylphosphineHCID 534400954-(4-Chlorothiazol-2-YL)morpholineHCID 688423458-(1-Ethyl-propyl)-3-iodo-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine

Product 1

HCID 579329793-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazineYield 4%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
130 °C

Procedure

In a dry 25 mL round bottom flask, 8-(1-ethyl-propyl)-3-iodo-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine (250 mg, 0.630 mmol), 4-(4-chloro-thiazol-2-yl)-morpholine (194 mg, 0.945 mmol), and Cs2CO3 (410 mg, 1.26 mmol) are dissolved in DMF. The mixture is degassed with bubbling nitrogen for 15 minutes. Then, Pd2(dba)3 (18 mg, 0.032 mmol) and PPh3 (33 mg, 0.126 mmol) are added. The reaction mixture is heated to 130° C. overnight. The reaction is cooled to room temp., quenched with a solution of NH4Cl sat? (20 mL), and extracted with Et2O (3×50 mL). The combined organic extracts are washed with brine (30 mL), dried with Na2SO4, filtered and concentrated. The residue is purified via reverse phase HPLC with a 30-80% gradient of CH3CN in 10 mM NH4HCO3/H2O/5% CH3CN (pH 10.0) to give the title compound (11 mg, 0.023 mmol, 4%). 1H-NMR (CDCl3), δ 0.86 (t, J=7.3 Hz, 6H), 1.84 (m, 4H), 2.55 (s, 3H), 3.31 (m, 1H), 3.54 (dd, J=5.2, 4H), 3.84 (dd, J=5.2 Hz, 4H), 6.82 (s, 1H) ppm. ES-MS (m/z): calcd for C20H23ClF3N5OS (M+H)+: 473.95; found: 474.2.

Workup

  1. customThe mixture is degassed with bubbling nitrogen for 15 minutes
  2. temperatureThe reaction is cooled to room temp.
  3. customquenched with a solution of NH4Cl
  4. extraction(20 mL), and extracted with Et2O (3×50 mL)
  5. washThe combined organic extracts are washed with brine (30 mL)
  6. dry with materialdried with Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue is purified via reverse phase HPLC with a 30-80% gradient of CH3CN in 10 mM NH4HCO3/H2O/5% CH3CN (pH 10.0)

Sources & evidence

ORD record
ord-ba19ee5eb2954105931ecfc94e870de5
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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