M-Phenylenediamine → 6-(3-Aminophenylamino)-8-(cyclopropyl(4-methoxybenzyl)amino) imidazo[1,2-b]pyridazine-3-carbonitrile

HRID 889453Notes

Reaction equation

HRID 889453 reaction equation
Cl[C:2]1[CH:3]=[C:4]([N:13]([CH:23]2[CH2:25][CH2:24]2)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[C:26]1([NH2:33])[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cu]I.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].COCCOCCOC>[NH2:32][C:28]1[CH:27]=[C:26]([NH:33][C:2]2[CH:3]=[C:4]([N:13]([CH:23]3[CH2:25][CH2:24]3)[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=2)[CH:31]=[CH:30][CH:29]=1

Participants

8

Reactant 4

HCID 7935M-PhenylenediamineHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 593137576-Chloro-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carbonitrile

Product 1

HCID 593140256-(3-Aminophenylamino)-8-(cyclopropyl(4-methoxybenzyl)amino) imidazo[1,2-b]pyridazine-3-carbonitrileYield 9.2%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8150DiglymeSolvent

Conditions

Temperature
125 °C

Procedure

A 1-dram vial was charged with 1-methoxy-2-(2-methoxyethoxy)ethane (1.5 mL) and purged for 10 min with argon. The vessel was then charged with 1G (0.100 g, 0.28 mmol), benzene-1,3-diamine (0.037 g, 0.34 mmol), cesium carbonate (0.368 g, 1.13 mmol), copper(I) iodide (0.027 g, 0.14 mmol), Xantphos (0.033 g, 0.057 mmol), and Pd2(dba)3 (0.026 g, 0.028 mmol) in one portion. The resulting suspension was heated to 125° C. overnight. The suspension was filtered through a medium-porosity frit, and the solid was washed with THF. The filtrate was diluted with EtOAc and water, and the layers were separated. The aqueous phase was extracted three times with EtOAc. The organics were then combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was dissolved in DMF and purified via preparatory HPLC using a YMC ODS C-18 column (30×250 mm), 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 60 min, flow rate 25 mL/min, monitoring at 220 nm. Rt=53.697 min. The appropriate fractions were concentrated and lyophilized to dryness, affording 3A (11 mg, 9% yield). HPLC: Rt=3.68 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). MS (ES): m/z=426.0 [M+H]+.

Workup

  1. custompurged for 10 min with argon
  2. filtrationThe suspension was filtered through a medium-porosity frit
  3. washthe solid was washed with THF
  4. additionThe filtrate was diluted with EtOAc and water
  5. customthe layers were separated
  6. extractionThe aqueous phase was extracted three times with EtOAc
  7. dry with materialdried over anhydrous sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. dissolutionThe crude residue was dissolved in DMF
  11. custompurified via preparatory HPLC
  12. customB=100, gradient time 60 min, flow rate 25 mL/min
  13. concentrationThe appropriate fractions were concentrated

Sources & evidence

ORD record
ord-423161535e284b4cb4adf225d550c26a
Source dataset
uspto-grants-2012_08
Patent number
US08252795B2

Reaction notes

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