Potassium Carbonate → tert-Butyl 4-(5-(2-(2-ethoxy-2-oxoethyl)-8-morpholinoimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carboxylate

HRID 718610Notes

Reaction equation

HRID 718610 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][CH:15]=[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:11]3=[N:10][C:9]=2[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:9]1[N:10]=[C:11]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[N:13][N:12]2[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([N:45]2[CH2:44][CH2:43][N:42]([C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])[CH2:47][CH2:46]2)=[N:7][CH:6]=1)[CH3:28]

Participants

4

Reactant 3

HCID 11430Potassium CarbonateHCID 143452tert-Butyl piperazine-1-carboxylateHCID 117728649Ethyl 2-(3-(6-chloropyridin-3-yl)-8-morpholinoimidazo[1,2-b]pyridazin-2-yl)acetate

Product 1

HCID 117732483tert-Butyl 4-(5-(2-(2-ethoxy-2-oxoethyl)-8-morpholinoimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carboxylate

Conditions

Temperature
130 °C

Procedure

Compound 28d (854 mg, 2.13 mmol), K2CO3 (323 mg, 2.34 mmol), Cu powder (27.0 mg, 0.425 mmol), and 1-(tert-butoxycarbonyl)piperazine (435 mg, 2.34 mmol) were placed in a 40 mL vial equipped with a stir bar. The vessel was evacuated and backflushed with argon and then dry DMF (4 mL) was added via syringe. The reaction was heated to 130° C. and stirred for 3 d. The solvent was removed under reduced pressure and then the residue was partitioned between water (50 mL) and DCM (70 mL). The organic phase was separated and then the aqueous layer was extracted with DCM (2×20 mL). The organic extracts were combined and washed with brine (2×30 mL), and then dried over Na2SO4 and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 40 g SiO2 pre-packed column eluting with 0-80% ACN/DCM to afford compound 28e. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.42 (d, J=1.7 Hz, 1H), 7.97 (d, J=5.6 Hz, 1H), 7.83 (dd, J=8.8, 2.4 Hz, 1H), 6.78 (d, J=9.0 Hz, 1H), 6.06 (d, J=5.6 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.94-4.01 (m, 4H), 3.87-3.94 (m, 4H), 3.83 (s, 2H), 3.59-3.67 (m, 4H), 3.50-3.59 (m, 4H), 1.50 (s, 9H), 1.25 (t, J=7.1 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H37N7O5: 552.3 (M+H). Found: 552.2.

Workup

  1. customvial equipped with a stir bar
  2. customThe vessel was evacuated
  3. additiondry DMF (4 mL) was added via syringe
  4. customThe solvent was removed under reduced pressure
  5. customthe residue was partitioned between water (50 mL) and DCM (70 mL)
  6. customThe organic phase was separated
  7. extractionthe aqueous layer was extracted with DCM (2×20 mL)
  8. washwashed with brine (2×30 mL)
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. customThe solvent was removed under reduced pressure
  12. customThe crude product was chromatographed on a 40 g SiO2 pre-packed column
  13. washeluting with 0-80% ACN/DCM

Sources & evidence

ORD record
ord-915834fb2ccb40688806f1c7314364c8
Source dataset
uspto-grants-2015_11
Patent number
US09193736B2

Reaction notes

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