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

HRID 718595Notes

Reaction equation

HRID 718595 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:24]4[N:25]=[CH:26][CH:27]=[C:28]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[C:23]4=[N:22][C:21]=3[C:35]([OH:37])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[NH2:53][C:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[N:55]=1>O.CN(C=O)C.C(Cl)Cl>[O:32]1[CH2:31][CH2:30][N:29]([C:28]2[C:23]3[N:24]([C:20]([C:17]4[CH:16]=[CH:15][C:14]([N:11]5[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]5)=[N:19][CH:18]=4)=[C:21]([C:35](=[O:37])[NH:53][C:54]4[CH:63]=[CH:62][C:61]5[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=5)[N:55]=4)[N:22]=3)[N:25]=[CH:26][CH:27]=2)[CH2:34][CH2:33]1

Participants

8

Reactant 4

HCID 113792-AminoquinolineHCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 1177284223-(6-(4-(tert-Butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-8-morpholinoimidazo[1,2-b]pyridazine-2-carboxylic acid

Product 1

HCID 117732470tert-Butyl 4-(5-(8-morpholino-2-(quinolin-2-ylcarbamoyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

Compound 20c (258 mg, 0.506 mmol) was placed in a 20 mL vial equipped with a stir bar and then DCM (4 mL) and DMF (10 μL) were added. Oxalyl chloride (66.2 μL, 0.759 mmol) was added dropwise via syringe and the reaction was stirred for 20 min. The solvent was removed under reduced pressure. The residue was dissolved in DCM (25 mL) and then DIEA (440 μL, 2.53 mmol) and 2-aminoquinoline (87.5 mg, 0.607 mmol) were added sequentially. The reaction was stirred at rt for 16 h and then poured into water (20 mL) and separated. The aqueous layer was extracted with DCM (3×10 mL) and the combined organic layers were dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude residue was chromatographed on a 12 g SiO2 pre-packed column eluting with 0-100% EtOAc/DCM to afford compound 20d. 1H-NMR (400 MHz, CDCl3) δ (ppm): 9.99 (s, 1H), 8.59-8.64 (m, 2H), 8.16 (d, J=9.0 Hz, 1H), 8.06 (d, J=5.6 Hz, 1H), 7.96 (dd, J=8.8, 2.4 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.65-7.71 (m, 1H), 7.42-7.48 (m, 1H), 6.79 (d, J=8.8 Hz, 1H), 6.15 (d, J=5.9 Hz, 1H), 4.04-4.10 (m, 4H), 3.98-4.04 (m, 4H), 3.63-3.70 (m, 4H), 3.54-3.60 (m, 4H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C34H37N9O4: 636.3 (M+H). Found: 636.4.

Workup

  1. customvial equipped with a stir bar
  2. customThe solvent was removed under reduced pressure
  3. dissolutionThe residue was dissolved in DCM (25 mL)
  4. stirringThe reaction was stirred at rt for 16 h
  5. customseparated
  6. extractionThe aqueous layer was extracted with DCM (3×10 mL)
  7. dry with materialthe combined organic layers were dried over MgSO4
  8. filtrationfiltered
  9. customThe solvent was removed under reduced pressure
  10. customThe crude residue was chromatographed on a 12 g SiO2 pre-packed column
  11. washeluting with 0-100% EtOAc/DCM

Sources & evidence

ORD record
ord-e6b99400ef7f420b9434ca069dc57049
Source dataset
uspto-grants-2015_11
Patent number
US09193736B2

Reaction notes

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