Cesium carbonate → (R)-N-(6-(2-methylpyrrolidin-1-yl)pyridine-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine

HRID 1755323Notes

Reaction equation

HRID 1755323 reaction equation
Br[C:2]1[C:3]2[N:4]([CH:14]=[CH:15][N:16]=2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]1[N:28]=[C:27]([NH2:29])[CH:26]=[CH:25][CH:24]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]1[N:28]=[C:27]([NH:29][C:2]2[C:3]3[N:4]([CH:14]=[CH:15][N:16]=3)[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:7]=2)[CH:26]=[CH:25][CH:24]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 717440288-Bromo-6-phenylimidazo[1,2-B]pyridazineHCID 86682708(R)-6-(2-methylpyrrolidin-1-yl)pyridin-2-amine

Product 1

HCID 71525710(R)-N-(6-(2-methylpyrrolidin-1-yl)pyridine-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amineYield 35.1%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
100 °C

Procedure

A mixture of 8-bromo-6-phenylimidazo[1,2-b]pyridazine (166 mg, 0.6 mmol), (R)-6-(2-methylpyrrolidin-1-yl)pyridin-2-amine (160 mg, 0.9 mmol), Pd2(dba)3 (36 mg, 0.06 mmol), BINAP (152 mg, 0.24 mmol), Cs2CO3 (593 mg, 1.8 mmol) and dioxane (10 mL) was heated to 100° C. with stirring for 16 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 (R)—N-(6-(2-methylpyrrolidin-1-yl)pyridine-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine (78 mg, 35%) as a white solid. 1H NMR (300 MHz, DMSO): δ 8.76 (s, 1H), 7.95-7.87 (m, 3H), 7.55-7.35 (m, 5H), 6.23 (d, 1H, J=7.5 Hz), 6.02 (d, 1H, J=8.1 Hz), 4.22-4.18 (m, 1H), 3.57-3.53 (m, 1H), 3.41-3.36 (m, 1H), 2.09-1.98 (m, 3H), 1.72 (brs, 1H), 1.16 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 371, tR=1.994 min, HPLC: 99.27% at 214 nm, 99.26% at 254 nm, tR=4.72 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)

Sources & evidence

ORD record
ord-1753ae26e73042468daa9ebe6e739bc7
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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