Dimethylformamide → tert-Butyl 4-(5-(8-morpholino-2-(quinolin-2-ylethynyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carboxylate

HRID 718605Notes

Reaction equation

HRID 718605 reaction equation
[C:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1)#[CH:2].Br[C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]=1.CN(C=O)C.CCN(C(C)C)C(C)C>[Cu]I.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.O>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:17]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]5)=[N:22][CH:23]=4)=[C:3]([C:1]#[C:2][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1

Participants

8

Reactant 4

HCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 27627562-BromoquinolineHCID 117732480tert-Butyl 4-(5-(2-ethynyl-8-morpholinoimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carboxylate

Product 1

HCID 117732479tert-Butyl 4-(5-(8-morpholino-2-(quinolin-2-ylethynyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolvent

Procedure

Compound 26a (131 mg, 0.268 mmol) and 2-bromoquinoline (558 mg, 2.68 mmol) were placed in an 8 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with argon. Dry DMF (4 mL) and DIEA (0.468 mL, 2.68 mmol) were added via syringe and then the mixture was deoxygenated by bubbling argon through the stirred solution for 5 min. CuI (2.56 mg, 0.0134 mmol) and (Ph3P)2PdCl2 (18.9 mg, 0.0268 mmol) were added and then the reaction was stirred at rt for 1 h. The reaction was poured into water (50 mL) and then the mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with water (20 mL) and brine (2×20 mL) and then dried over MgSO4 and filtered. The solution was concentrated under reduced pressure. The crude product was chromatographed on a 40 g SiO2 pre-packed column eluting with 0-60% ACN/DCM to afford compound 26b. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.97 (d, J=2.2 Hz, 1H), 8.27 (dd, J=8.9, 2.3 Hz, 1H), 8.12 (t, J=8.6 Hz, 2H), 8.04 (d, J=5.6 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.67-7.77 (m, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.49-7.59 (m, 1H), 6.81 (d, J=8.8 Hz, 1H), 6.09 (d, J=5.6 Hz, 1H), 3.98-4.07 (m, 4H), 3.88-3.98 (m, 4H), 3.61-3.70 (m, 4H), 3.51-3.61 (m, 4H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C35H36N8O3: 617.3 (M+H). Found: 617.3.

Workup

  1. customvial equipped with a stir bar
  2. customthe vial was evacuated
  3. customthe mixture was deoxygenated
  4. customby bubbling argon through the stirred solution for 5 min
  5. extractionthe mixture was extracted with EtOAc (3×30 mL)
  6. washThe combined organic extracts were washed with water (20 mL) and brine (2×20 mL)
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationThe solution was concentrated under reduced pressure
  10. customThe crude product was chromatographed on a 40 g SiO2 pre-packed column
  11. washeluting with 0-60% ACN/DCM

Sources & evidence

ORD record
ord-c50dc3499e944947b3a3b2fb7b61587a
Source dataset
uspto-grants-2015_11
Patent number
US09193736B2

Reaction notes

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