Sodium Carbonate → HCID 86682724, compound

HRID 1755360Notes

Reaction equation

HRID 1755360 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.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.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].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=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

Participants

8

Reactant 4

HCID 10340Sodium CarbonateHCID 27343222-Chlorophenylboronic acidHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 715343846-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine

Product 1

HCID 86682724HCID 86682724, compoundYield 40.2%

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 (0.15 g, 0.456 mmol), 2-chlorophenylboronic acid (0.078 g, 0.5 mmol), Pd2(dba)3 (0.058 g, 0.1 mmol), X-phos (0.095 g, 0.2 mmol) and Na2CO3 (0.145 g, 1.368 mmol) in dioxane (20 mL) and water (5 mL) was heated to 100° C. for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate petroleum ether=1:20) and then further 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: 35% acetonitrile/65% water (0.1% TFA VAT) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA VAT) in a linear fashion over 9 min). The fractions containing product were acidified by the addition of concentrated HCl and concentrated to afford 6-(2-chlorophenyl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine hydrochloride (81 mg, 40%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.67 (s, 1H), 8.42 (d, 1H, J=1.8 Hz), 8.17 (d, 1H, J=1.8 Hz), 7.66-7.48 (m, 5H), 6.48 (d, 1H, J=7.5 Hz), 6.34 (d, 1H, J=8.4 Hz), 4.26-4.22 (m, 1H), 3.63-3.57 (m, 1H), 3.44-3.38 (m, 1H), 2.17-2.04 (m, 3H), 1.76-1.38 (m, 1H), 1.09 (d, 3H, J=6.3 Hz) LC-MS: [M+H]+, 405, tR=1.971 min, HPLC: 98.88% at 214 nm, 98.93% at 254 nm, tR=7.63 min.

Workup

  1. concentrationthen concentrated in vacuo
  2. customThe residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate petroleum ether=1:20)
  3. customfurther purified by Prep-HPLC (Gemini 5u C18 150×21.2 mm
  4. additionThe fractions containing product
  5. additionwere acidified by the addition of concentrated HCl
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-9f4350edd92d460fab12733ec00ce653
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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