Potassium Carbonate → N-(6-(2-Methylpyrrolidin-1-yl)pyridin-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine

HRID 1755293Notes

Reaction equation

HRID 1755293 reaction equation
Cl[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][CH:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=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]>[CH3:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[N:13]=[C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:3]=2)[CH:17]=[CH:16][CH:15]=1

Participants

10

Reactant 4

HCID 11430Potassium CarbonateHCID 66827Phenylboronic AcidHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 715343846-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine

Product 1

HCID 71460808N-(6-(2-Methylpyrrolidin-1-yl)pyridin-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amineYield 40%

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-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (180 mg, 0.55 mmol), phenylboronic acid (102 mg, 0.83 mmol), Pd2(dba)3 (33 mg, 0.056 mmol), X-phos (105 mg, 0.22 mmol) and K2CO3 (226 mg, 1.63 mmol) in dioxane (10 mL) and water (1 mL) was heated to 100° C. with stirring for 4 h under N2. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=180:1) to give crude product. This 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 a light yellow solid (80 mg, 40%) as an HCl salt. 1H NMR (300 MHz, CD3OD): δ 8.87 (s, 1H), 8.37 (d, 1H, J=2.4 Hz), 8.10 (d, 1H, J=1.8 Hz), 8.01-7.98 (m, 2H), 7.60-7.53 (m, 4 h), 6.45 (d, 1H, J=7.8 Hz), 6.30 (d, 1H, J=8.4 Hz), 4.28-4.24 (m, 1H), 3.67-3.47 (m, 2H), 2.20-1.80 (m, 4 h), 1.20 (d, 1H, J=6.3 Hz). LC-MS: [M+H]+, 371, tR=1.97 min, HPLC: 97.57% at 214 nm, 99.43% at 254 nm, tR=7.473 min.

Workup

  1. customThe reaction mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=180:1)
  2. customto give crude product
  3. customThis was further purified by prep-HPLC (Gemini 5u C18 150×21.2 mm
  4. 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
  5. custom) to give a light yellow solid
  6. stirringThe mixture was stirred for 5 minutes
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-d4da84f1b7ee4945a9d2375f2d96c874
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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