Potassium Carbonate → 6-phenyl-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine hydrochloride

HRID 1755291Notes

Reaction equation

HRID 1755291 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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]>[ClH:1].[C:23]1([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1

Participants

10

Reactant 4

HCID 11430Potassium CarbonateHCID 66827Phenylboronic AcidHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 715343836-chloro-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine

Product 1

HCID 866826966-phenyl-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine hydrochlorideYield 78%

Reagents, catalysts & solvents 5

HCID 313Hydrochloric AcidCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 6-chloro-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (52 mg, 0.17 mmol), phenylboronic acid (31 mg, 0.25 mmol), Pd2(dba)3 (10 mg, 0.017 mmol), X-phos (32 mg, 0.067 mmol) and K2CO3 (69 mg, 0.5 mmol) in dioxane (5 mL) and water (0.5 mL) was heated to 100° C. with stirring for 4 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=180:1) to give crude product as a yellow solid. The solid 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 40% acetonitrile/60% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give a light yellow solid. This was dissolved in methanol and three drops of concentrated HCl added. The mixture was stirred for 5 minutes, then concentrated in vacuo to give the final product 6-phenyl-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine hydrochloride (46 mg, 78%) as an HCl salt. 1H NMR (300 MHz, CD3OD): δ 8.81 (s, 1H), 8.31 (s, 1H), 8.04-7.96 (m, 3H), 7.56-7.50 (m, 4 h), 6.38 (d, 1H, J=7.8 Hz), 6.20 (d, 1H, J=8.4 Hz), 3.54-3.49 (m, 4 h), 2.08-2.03 (m, 4 h). LC-MS: [M+H]+, 357.1, tR=1.912 min, HPLC: 95.34% at 214 nm, 99.67% at 254 nm, tR=7.083 min.

Workup

  1. customThe solvent was removed in vacuo
  2. customthe resulting mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=180:1)
  3. customto give crude product as a yellow solid
  4. customThe solid was 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 40% acetonitrile/60% 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-e16e9965fe634c308d61ed04dcc4defa
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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