Cesium carbonate → Methyl 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate

HRID 1755314Notes

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:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[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:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH:7]=2)[CH:30]=[CH:29][CH:28]=1

Participants

Conditions

Temperature: 100 °C

Procedure

A mixture of methyl 4-(8-bromoimidazo[1,2-b]pyridazin-6-yl)benzoate (208 mg, 0.63 mmol), 6-(2-methylpyrrolidin-1-yl)pyridin-2-amine (168 mg, 0.95 mmol), Pd2(dba)3 (37 mg, 0.063 mmol), BINAP (157 mg, 0.252 mmol), Cs2CO3 (616 mg, 1.89 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, CH2Cl2:MeOH=30:1) to give methyl 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo [1,2-b]pyridazin-6-yl)benzoate (120 mg, 45%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.81 (s, 1H), 8.09-7.98 (m, 5H), 7.59 (d, 1H, J=1.5 Hz), 7.42 (t, 1H, J=8.4 Hz), 6.27 (d, 1H, J=7.5 Hz), 6.08 (d, 1H, J=8.1 Hz), 4.29-4.21 (m, 1H), 3.96 (s, 3H), 3.62-3.58 (m, 1H), 3.43-3.40 (m, 1H), 2.16-2.12 (m, 3H), 1.78-75 (m, 1H), 1.19 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 429, tR=1.989 min, HPLC: 94.6% at 214 nm, 96.8% at 254 nm, tR=5.255 min.

Workup

customThe solvent was removed in vacuo
customthe resulting mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=30:1)

Sources & evidence

ORD record: ord-316ea919af234cc5910ad28bc0324d99
Source dataset: uspto-grants-2015_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09169259B2

Reaction notes

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