3-Methoxy-5-(5-methyl-1h-tetrazol-1-yl)aniline → 8-((1-(2-hydroxyethyl)-1H-pyrazol-3-yl)amino)-6-((3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)phenyl)amino)imidazo[1,2-b]pyridazine-3-carbonitrile

HRID 889463Notes

Reaction equation

HRID 889463 reaction equation
[Si]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:18]3[N:19]([C:24]([C:27]#[N:28])=[CH:25][N:26]=3)[N:20]=[C:21](Cl)[CH:22]=2)=[N:12]1)(C(C)(C)C)(C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[C:36]([N:38]2[C:42]([CH3:43])=[N:41][N:40]=[N:39]2)[CH:37]=1)[NH2:34].C(P(C(C)(C)C)C1(C)CC1(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].CO>[OH:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:18]3[N:19]([C:24]([C:27]#[N:28])=[CH:25][N:26]=3)[N:20]=[C:21]([NH:34][C:33]3[CH:35]=[C:36]([N:38]4[C:42]([CH3:43])=[N:41][N:40]=[N:39]4)[CH:37]=[C:31]([O:30][CH3:29])[CH:32]=3)[CH:22]=2)=[N:12]1

Participants

8

Reactant 4

HCID 31552523-Methoxy-5-(5-methyl-1h-tetrazol-1-yl)anilineHCID 21909131Di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphaneHCID 23676156Sodium t-butoxideHCID 866413848-((1-(2-((tert-butyl(dimethyl)silyl)oxy)ethyl)-1H-pyrazol-3-yl)amino)-6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile

Product 1

HCID 593139378-((1-(2-hydroxyethyl)-1H-pyrazol-3-yl)amino)-6-((3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)phenyl)amino)imidazo[1,2-b]pyridazine-3-carbonitrileYield 3.84%

Reagents, catalysts & solvents 3

HCID 61538Palladium, di-mu-chlorobis(eta3-2-propenyl)di-CatalystHCID 887MethanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A suspension of 12A (39 mg, 0.093 mmol), 3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)aniline (28.7 mg, 0.14 mmol), and di-tert-butyl (1-methyl-2,2-diphenylcyclopropyl) phosphine (6.58 mg, 0.019 mmol) in toluene (0.75 mL) was purged with nitrogen. Allylpalladium (II) chloride dimer (3.41 mg, 9.3 μmol) and sodium tert-butoxide (10.76 mg, 0.11 mmol) were added, and the reaction mixture was purged with nitrogen and heated at 100° C. After 15 minutes, the reaction mixture was concentrated, suspended in water (50 mL), extracted with 10% isopropanol/dichloromethane (3×25 mL), dried over Na2SO4, and concentrated. The crude was purified with silica gel chromatography (stepwise gradient, 20 to 50% ethyl acetate/hexanes to neat ethyl acetate). The fractions were concentrated, dissolved in dichloromethane (2 mL) and treated with TFA (2 mL). After 3 hours, the reaction mixture was concentrated, purified using reverse phase HPLC, and lyophilized with 1.0 N HCl to isolate Example 12, (2.1 mg, 3.84% yield) as a tan solid. HPLC: Rt=1.65 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 10-90% aqueous methanol containing 0.1% TFA, 2 min. gradient, flow rate=5 mL/min., detection at 254 nm). MS (ES): m/z=473.06 [M+H]+. 1H NMR (500 MHz, methanol-d3) δ ppm 8.03 (1H, s), 7.86 (1H, s), 7.61 (1H, d, J=1.83 Hz), 7.51 (1H, s), 7.47 (1H, s), 6.68-6.89 (1H, m), 6.13 (1H, d, J=2.29 Hz), 4.23 (2H, t, J=5.27 Hz), 3.97 (2H, t, J=5.27 Hz), 3.94 (3H, s), 2.69 (3H, s).

Workup

  1. customwas purged with nitrogen
  2. customthe reaction mixture was purged with nitrogen
  3. concentrationthe reaction mixture was concentrated
  4. extractionextracted with 10% isopropanol/dichloromethane (3×25 mL)
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated
  7. customThe crude was purified with silica gel chromatography (stepwise gradient, 20 to 50% ethyl acetate/hexanes to neat ethyl acetate)
  8. concentrationThe fractions were concentrated
  9. dissolutiondissolved in dichloromethane (2 mL)
  10. additiontreated with TFA (2 mL)
  11. waitAfter 3 hours
  12. concentrationthe reaction mixture was concentrated
  13. custompurified
  14. customto isolate Example 12, (2.1 mg, 3.84% yield) as a tan solid

Sources & evidence

ORD record
ord-d5427389ca6340cf8c903fed3718a2fd
Source dataset
uspto-grants-2012_08
Patent number
US08252795B2

Reaction notes

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