Sodium Carbonate → HCID 86682727, compound

HRID 1755369Notes

Reaction equation

HRID 1755369 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[C@@H:22]([CH3:23])[CH2:21][CH2:20][C@@H:19]3[CH3:24])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=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.[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]>[CH3:24][C@H:19]1[CH2:20][CH2:21][C@H:22]([CH3:23])[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:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:3]=2)[CH:17]=[CH:16][CH:15]=1

Participants

8

Reactant 4

HCID 10340Sodium CarbonateHCID 66827Phenylboronic AcidHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 86682728HCID 86682728, compound

Product 1

HCID 86682727HCID 86682727, compoundYield 9%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 6-chloro-N-(6-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.668 g, 1.95 mmol), phenylboronic acid (0.261 g, 2.14 mmol), Pd2(dba)3 (0.224 g, 0.39 mmol), X-phos (0.372 g, 0.78 mmol) and Na2CO3 (0.62 g, 5.85 mmol) in dioxane (30 mL) and water (10 mL) was heated to 90° C. for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was 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). The fractions containing product were acidified by the addition of concentrated HCl and concentrated in vacuo to afford N-(6-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)pyridin-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine (57 mg, 9% over two steps) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 8.87 (s, 1H), 8.35 (s, 1H), 7.95-7.92 (m, 3H), 7.59-7.47 (m, 4 h), 6.48 (d, 1H, J=7.8 Hz), 6.17 (d, 1H, J=8.1 Hz), 4.23 (s, 2H), 2.25 (s, 2H), 1.64-1.62 (m, 2H), 1.09 (s, 3H), 1.07 (s, 3H). LC-MS: [M+H]+, 385, tR=2.023 min, HPLC: 96.85% at 214 nm, 96.97% at 254 nm, tR=8.147 min.

Workup

  1. concentrationthen concentrated in vacuo
  2. customThe residue was purified by Prep-HPLC (Gemini 5u C18 150×21.2 mm
  3. additionThe fractions containing product
  4. additionwere acidified by the addition of concentrated HCl
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-edaf555be68643c2903611bb640336e6
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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