Cesium carbonate → N-(6-(2-methylpiperidin-1-yl)pyridin-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine

HRID 1755310Notes

Reaction equation

HRID 1755310 reaction equation
Br[C:2]1[C:3]2[N:4]([CH:14]=[CH:15][N:16]=2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:24]1[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][CH:25]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CO.Cl.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].O1CCOCC1>[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:24]1[N:29]=[C:28]([NH:30][C:2]2[C:3]3[N:4]([CH:14]=[CH:15][N:16]=3)[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:7]=2)[CH:27]=[CH:26][CH:25]=1

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 665204986-(2-Methylpiperidin-1-yl)pyridin-2-amineHCID 717440288-Bromo-6-phenylimidazo[1,2-B]pyridazine

Product 1

HCID 71525435N-(6-(2-methylpiperidin-1-yl)pyridin-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amineYield 10.2%

Reagents, catalysts & solvents 4

HCID 313Hydrochloric AcidCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 8-bromo-6-phenylimidazo[1,2-b]pyridazine (125 mg, 0.46 mmol), 6-(2-methylpiperidin-1-yl)pyridin-2-amine (144 mg, 0.75 mmol), Pd2(dba)3 (29 mg, 0.05 mmol), BINAP (125 mg, 0.2 mmol), Cs2CO3 (489 mg, 1.5 mmol) and dioxane (10 mL) was heated to 100° C. with stirring for 16 h under N2. The solution was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give crude product which was further purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give a light yellow solid. This was dissolved in methanol, three drops of concentrated HCl was added, and the mixture was stirred for 5 minutes, then concentrated in vacuo to give N-(6-(2-methylpiperidin-1-yl)pyridin-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine (18 mg, 10%) as an HCl salt. 1H NMR (300 MHz, CD3OD): δ 8.99 (s, 1H), 8.44 (s, 1H), 8.20 (s, 1H), 8.05-7.98 (m, 3H), 7.60 (brs, 3H), 7.46-7.28 (m, 2H), 4.12 (brs, 1H), 3.92-3.81 (m, 1H), 3.65-3.56 (m, 1H), 2.07-1.66 (m, 6H), 1.17 (d, 3H, J=5.7 Hz). LC-MS: [M+H]+, 385, tR=2.081 min, HPLC: 99.49% at 214 nm, 99.48% at 254 nm, tR=3.588 min.

Workup

  1. customThe solution was removed in vacuo
  2. customthe resulting mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1)
  3. customto give crude product which
  4. customwas further purified by prep-HPLC (Gemini 5u C18 150×21.2 mm
  5. waitgradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min
  6. custom) to give a light yellow solid
  7. stirringthe mixture was stirred for 5 minutes
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-cea5ab167840450aa24c31bd67929429
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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