Morpholine → 8-(1-Ethyl-propyl)-2,6-dimethyl-3-(3-methyl-4-morpholin-4-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine

HRID 1432698Notes

Reaction equation

HRID 1432698 reaction equation
Br[C:2]1[C:3]([CH3:23])=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])[S:5][CH:6]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.CN(C1C=CC=CC=1C1C=CC=CC=1)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CCOC(C)=O.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]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:4]3[S:5][CH:6]=[C:2]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:3]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]

Participants

7

Reactant 4

HCID 8083MorpholineHCID 2733832Lithium HexamethyldisilazideHCID 57932970HCID 57932970, compoundHCID 866200962-dicyclohexylphosphino-biphenyl 2'-(N,N-dimethyl-amino)biphenyl

Product 1

HCID 579330038-(1-Ethyl-propyl)-2,6-dimethyl-3-(3-methyl-4-morpholin-4-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazineYield 16%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
65 °C

Procedure

To a flask containing 3-(4-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 0.76 mmol), morpholine (0.10 mL, 1.15 mmol), Pd2(dba)3 (0.035 g, 0.038 mmol), and 2-dicyclohexylphosphino-biphenyl-2′-(N,N-dimethyl-amino)biphenyl (0.018 g, 0.046 mmol) is added 1 M LiHMDS (1.9 mL, 1.91 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (30 mL), washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (15%-30% EtOAc gradient), dissolved in Et2O (20 mL) and extracted with 1 M HCl (2×30 mL). The aqueous layer is washed with Et2O (20 mL), made basic with 5 M NaOH (15 mL), extracted with EtOAc (2×20 mL), the combined organic layers washed with brine (40 mL), dried over MgSO4, filtered and concentrated to furnish the title compound (0.047 g, 0.12 mmol, 16%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.73-1.91 (m, 4H), 2.01 (s, 3H), 2.45 (s, 3H), 2.49 (s, 3H), 2.99-3.05 (m, 4H), 3.28-3.37 (m, 1H), 3.84-3.88 (m, 4H), 6.65 (s, 1H), 6.71 (s, 1H). LC/MS (m/z): calcd. for C22H30N4OS (M+H)+: 399.2; found: 399.2.

Workup

  1. washwashed with water (20 mL), brine (20 mL)
  2. dry with materialdried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue is purified by ISCO (15%-30% EtOAc gradient)
  6. dissolutiondissolved in Et2O (20 mL)
  7. extractionextracted with 1 M HCl (2×30 mL)
  8. washThe aqueous layer is washed with Et2O (20 mL)
  9. extractionextracted with EtOAc (2×20 mL)
  10. washthe combined organic layers washed with brine (40 mL)
  11. dry with materialdried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-e7cb6cf431774b3f935d4f625791390e
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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