Sodium Carbonate → HCID 86682725, compound

HRID 1755363Notes

Reaction equation

HRID 1755363 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][CH:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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].[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:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25]([F:36])([F:35])[F:24])[CH:3]=2)[CH:17]=[CH:16][CH:15]=1

Participants

8

Reactant 4

HCID 10340Sodium CarbonateHCID 27343872-(Trifluoromethyl)benzeneboronic 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 86682725HCID 86682725, compoundYield 26.2%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 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 (0.10 g, 0.305 mmol), 2-(trifluoromethyl)phenylboronic acid (64 mg, 0.335 mmol), Pd2(dba)3 (0.035 g, 0.061 mmol), X-phos (0.058 g, 0.122 mmol) and Na2CO3 (0.097 g, 0.915 mmol) in dioxane (20 mL) and water (5 mL) was heated to 100° C. for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:10) and the residue 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: 30% acetonitrile/70% 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). The fractions containing product were acidified by the addition of concentrated HCl then concentrated to afford N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-8-amine hydrochloride (38 mg, 26%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.88 (s, 1H), 8.84 (s, 1H), 8.52 (s, 1H), 8.27 (s, 1H), 7.94-7.66 (m, 4 h), 7.48 (t, 1H, J=7.5 Hz), 6.67 (d, 1H, J=7.5 Hz), 6.08 (d, 1H, J=8.1 Hz), 3.95-3.91 (m, 1H), 3.37-3.28 (m, 1H), 3.09-3.02 (m, 1H), 1.92-1.83 (m, 3H), 1.49-1.41 (m, 1H), 0.78 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 439, tR=1.91 min, HPLC: 98.98% at 214 nm, 99.36% at 254 nm, tR=6.99 min.

Workup

  1. concentrationthen concentrated in vacuo
  2. customThe residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:10)
  3. customthe residue was further purified by Prep-HPLC (Gemini 5u C18 150×21.2 mm
  4. additionThe fractions containing product
  5. additionwere acidified by the addition of concentrated HCl
  6. concentrationthen concentrated

Sources & evidence

ORD record
ord-82cafbe59bc04065ae8ec3d7b0c3d121
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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