Cesium carbonate → Methyl 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate

HRID 1755301Notes

Reaction equation

Br[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[N:5]=[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=1.[CH3:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]1[N:32]=[C:31]([NH2:33])[CH:30]=[CH:29][CH:28]=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>[CH3:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]1[N:32]=[C:31]([NH:33][C:2]2[C:3]3[N:4]([CH:18]=[CH:19][N:20]=3)[N:5]=[C:6]([C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=2)[CH:30]=[CH:29][CH:28]=1

Participants

Conditions

Temperature: 100 °C

Procedure

A mixture of methyl 3-(8-bromoimidazo[1,2-b]pyridazin-6-yl)benzoate (288 mg, 0.87 mmol), 6-(2-methylpyrrolidin-1-yl)pyridin-2-amine (230 mg, 1.3 mmol), Pd2(dba)3 (50 mg, 0.087 mmol), BINAP (217 mg, 0.348 mmol), Cs2CO3 (851 mg, 2.61 mmol) and dioxane (20 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, CH2Cl2:MeOH=100:1) to give methyl 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridine-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (240 mg, 64%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.72 (s, 1H), 8.60 (s, 1H), 8.19-8.08 (m, 3H), 7.92 (s, 1H), 7.59-7.54 (m, 2H), 7.41 (t, 1H, J=8.1 Hz), 6.20 (d, 1H, J=7.5 Hz), 6.03 (d, 1H, J=8.1 Hz), 4.27-4.23 (m, 1H), 3.99 (s, 3H), 3.69-3.63 (m, 1H), 3.53-3.43 (m, 1H), 2.15-1.99 (m, 3H), 1.99 (brs, 1H), 1.21 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 429, tR=2.055 min, HPLC: 96.86% at 214 nm, 96.95% at 254 nm, tR=3.763 min.

Workup

customThe solvent was removed in vacuo
customthe resulting mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=100:1)

Sources & evidence

ORD record: ord-6927fe326a8447e7801bcf620130c427
Source dataset: uspto-grants-2015_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09169259B2

Reaction notes

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