Potassium Carbonate → HCID 89522441, compound

HRID 1755284Notes

Reaction equation

HRID 1755284 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=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:22]1([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1

Participants

10

Reactant 4

HCID 11430Potassium CarbonateHCID 66827Phenylboronic AcidHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 86682692HCID 86682692, compound

Product 1

HCID 89522441HCID 89522441, compoundYield 37%

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-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (157 mg, 0.5 mmol), phenylboronic acid (92 mg, 0.75 mmol), Pd2(dba)3 (29 mg, 0.05 mmol), X-phos (96 mg, 0.2 mmol) and K2CO3 (208 mg, 1.5 mmol) in dioxane (10 mL) and water (1 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, petroleum ether:ethyl acetate=3:1) to give crude product (135 mg) 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. The mixture was dissolved in methanol then three drops of concentrated HCl were added and the mixture was stirred for 5 minutes, then concentrated in vacuo to give the final product 6-phenyl-N-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine hydrochloride (65 mg, 37%) as a HCl salt. 1H NMR (300 MHz, CD3OD): δ 9.40 (s, 1H), 8.48 (d, 1H, J=2.1 Hz), 8.21 (d, 1H, J=2.4 Hz), 8.12-8.06 (m, 3H), 7.61-7.56 (m, 4 h), 7.48 (d, 1H, J=8.4 Hz). LC-MS: 356, [M+H]+, tR=1.822 min, HPLC: 100% at 214 nm, 99.96% at 254 nm, tR=7.247 min.

Workup

  1. customThe solvent 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 (135 mg) 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-d3ed514b88cc4e1a9c729c04705e1fd5
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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