Sodium Carbonate → N-(6-(2-Methylpyrrolidin-1-yl)pyridin-2-yl)-6-(1,2,3,4-tetrahydroquinolin-7-yl)imidazo[1,2-b]pyridazin-8-amine hydrochloride

HRID 1755382Notes

Reaction equation

HRID 1755382 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.CC1(C)C(C)(C)OB([C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][CH2:38][NH:39]3)=[CH:34][CH:33]=2)O1.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:32]3[CH:41]=[C:40]4[C:35]([CH2:36][CH2:37][CH2:38][NH:39]4)=[CH:34][CH:33]=3)[CH:3]=2)[CH:17]=[CH:16][CH:15]=1

Participants

8

Reactant 4

HCID 10340Sodium CarbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 594187157-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinolineHCID 715343846-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine

Product 1

HCID 86682735N-(6-(2-Methylpyrrolidin-1-yl)pyridin-2-yl)-6-(1,2,3,4-tetrahydroquinolin-7-yl)imidazo[1,2-b]pyridazin-8-amine hydrochloride

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 (300 mg, 0.91 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinoline (354 mg, 1.37 mmol), Pd2(dba)3 (105 mg, 0.18 mmol), X-phos (172 mg, 0.36 mmol) and Na2CO3 (290 mg, 2.73 mmol) in dioxane (5 mL) and water (5 mL) was heated to 100° C. for 15 h then concentrated in vacuo and purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=1:1) to afford the desired product as its free base. 1 mL HCl was added to the residue and the mixture stirred for 5 min. The mixture was then concentrated to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(1,2,3,4-tetrahydroquinolin-7-yl)imidazo[1,2-b]pyridazin-8-amine hydrochloride (25 mg, 6%). 1H NMR (300 MHz, DMSO): δ 10.74 (s, 1H), 9.14 (s, 1H), 8.55 (s, 1H), 8.30 (s, 1H), 7.51 (t, 1H, J=7.8 Hz), 7.35-7.19 (m, 3H), 6.67 (d, 1H, J=7.8 Hz), 6.16 (d, 1H, J=8.1 Hz), 4.23-4.20 (m, 2H), 3.65-3.58 (m, 1H), 3.42-3.38 (m, 3H), 2.83-2.79 (m, 2H), 2.10-1.91 (m, 5H), 1.72-1.70 (m, 1H), 1.13 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 426, tR=1.923 min, HPLC: 99.64% at 214 nm, 99.62% at 254 nm, tR=6.052 min.

Workup

  1. concentrationthen concentrated in vacuo
  2. custompurified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=1:1)

Sources & evidence

ORD record
ord-30f68cf6d8d34fedad27a99d13bcba0c
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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