Cesium carbonate → 3-(4-Chloro-2-morpholinothiazol-5-yl)-2,6-dimethyl-8-(pentan-3-yl)imidazo[1,2-b]pyridazine

HRID 1432684Notes

Reaction equation

HRID 1432684 reaction equation
[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[S:25][CH:26]=[C:27]([Cl:29])[N:28]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:29][C:27]1[N:28]=[C:24]([N:21]2[CH2:20][CH2:19][O:18][CH2:23][CH2:22]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[CH3:16]

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 534400954-(4-Chlorothiazol-2-YL)morpholineHCID 577526818-(1-Ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine

Product 1

HCID 115462553-(4-Chloro-2-morpholinothiazol-5-yl)-2,6-dimethyl-8-(pentan-3-yl)imidazo[1,2-b]pyridazineYield 106.5%

Reagents, catalysts & solvents 3

HCID 11776TriphenylphosphineCatalyst2×HCID 83717Copper iodideCatalystHCID 167845palladium(II) acetateCatalyst2×

Conditions

Temperature
120 °C

Procedure

A 20 L reactor flask under nitrogen is charged with 2900 ml of dry and degassed DMF then with 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (287 g, 0.836 mol), 2-morpholino-4-chlorothiazole (205.4 g, 1.01 mol, 1.2 equv.), Pd(OAc)2 (3.74 g, 7.91 mmol, 0.01 equiv.), triphenylphosphine (8.77 g, 33.1 mmol, 0.04 equiv.), Copper iodide (8 g, 41.59 mmol, 0.05 equiv.) and cesium carbonate (544.9 g, 1.65 mol). The reaction mixture is heated at 120° C. After 16 h at 120° C., 1.87 g of Pd(OAc)2 and 4.38 g of triphenylphosphine more is added. After 1 h, the mixture is cooled, quenched with NH4Cl solution (4300 mL) and extracted with MTBE (2900 mL), the aqueous phase is extracted twice more with 2000 ml of MTBE. The organic phases are washed with sat NaCl aq (2000 mL), then treated with charcoal 72 g in flask bottle and filtered on Celite®. The filtrate is concentrated under vacuum to afford 373.8 g (79.3%) of the title compound which is 81.4%-area HPLC analysis the rest being solvent and with no detectable Example 200 by-product.

Workup

  1. additionA 20 L reactor flask under nitrogen is charged with 2900 ml
  2. customof dry
  3. customdegassed DMF
  4. waitAfter 1 h
  5. temperaturethe mixture is cooled
  6. customquenched with NH4Cl solution (4300 mL)
  7. extractionextracted with MTBE (2900 mL)
  8. extractionthe aqueous phase is extracted twice more with 2000 ml of MTBE
  9. washThe organic phases are washed with sat NaCl aq (2000 mL)
  10. additiontreated with charcoal 72 g in flask bottle
  11. filtrationfiltered on Celite®
  12. concentrationThe filtrate is concentrated under vacuum

Sources & evidence

ORD record
ord-c31b5e8e73394118a08cdf374d1bb9b6
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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