Trifluoroacetic acid → 6-((5-Cyano-2-methoxyphenyl)amino)-8-((2,2,2-trifluoroethyl)amino)imidazo[1,2-b]pyridazine-3-carbonitrile

HRID 889460Notes

Reaction equation

HRID 889460 reaction equation
Cl[C:2]1[CH:3]=[C:4]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:23]#[N:24].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+].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].O>[C:23]([C:22]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:20]([NH:19][C:2]2[CH:3]=[C:4]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=2)[CH:21]=1)#[N:24]

Participants

9

Reactant 5

HCID 6422Trifluoroacetic acidHCID 21909131Di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphaneHCID 224525573-Amino-4-methoxybenzonitrileHCID 23676156Sodium t-butoxideHCID 866413826-Chloro-8-((2,2,2-trifluoroethyl)amino)imidazo[1,2-b]pyridazine-3-carbonitrile

Product 1

HCID 593138006-((5-Cyano-2-methoxyphenyl)amino)-8-((2,2,2-trifluoroethyl)amino)imidazo[1,2-b]pyridazine-3-carbonitrileYield 5.4%

Reagents, catalysts & solvents 3

HCID 61538Palladium, di-mu-chlorobis(eta3-2-propenyl)di-CatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 9A (100 mg, 0.36 mmol), 3-amino-4-methoxybenzonitrile (108 mg, 0.73 mmol) and di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (25.6 mg, 0.073 mmol) in toluene (1 mL) was purged with nitrogen. Allylpalladium (II) chloride dimer (13.3 mg, 0.036 mmol) and sodium tert-butoxide (41.8 mg, 0.435 mmol) were added, and the reaction mixture was purged with nitrogen and heated at 100° C. After 20 minutes, the reaction mixture was cooled to room temperature, diluted with DCM, and filtered through CELITE®. The filtrate was concentrated under reduced pressure, dissolved in DMSO/methanol, and purified by reverse phase HPLC (PHENOMENEX® Luna Axia 5 micron 30×250 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in (Solvent A=10% MeOH-90% H2O-0.1% TFA) in 15 min.) to obtain Example 9, (9.9 mg, 0.020 mmol, 5.4% yield) as a light yellow solid. HPLC: Rt=0.95 min. (BEH C18 2.1×50 mm, 1.7 u, 0 to 100 B in 1 min. with 0.5 min. hold time, flow rate=1 mL/min., detection at 254 nm, Solvent A: 100% water/0.1% TFA; Solvent B: 100% ACN1/0.1% TFA). MS (ES): m/z=388.3 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.76 (1H, d, J=1.94 Hz), 8.67 (1H, s), 8.23 (1H, s), 8.03-8.12 (1H, m), 7.41-7.55 (1H, m), 7.24 (1H, d, J=8.32 Hz), 6.75 (1H, s), 4.06-4.17 (2H, m), 4.00 (3H, s).

Workup

  1. customwas purged with nitrogen
  2. customthe reaction mixture was purged with nitrogen
  3. temperaturethe reaction mixture was cooled to room temperature
  4. additiondiluted with DCM
  5. filtrationfiltered through CELITE®
  6. concentrationThe filtrate was concentrated under reduced pressure
  7. dissolutiondissolved in DMSO/methanol
  8. custompurified by reverse phase HPLC (PHENOMENEX® Luna Axia 5 micron 30×250 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in (Solvent A=10% MeOH-90% H2O-0.1% TFA) in 15 min.)
  9. customto obtain Example 9, (9.9 mg, 0.020 mmol, 5.4% yield) as a light yellow solid

Sources & evidence

ORD record
ord-f41dadc0b40b45cfa21dd51eac0139c7
Source dataset
uspto-grants-2012_08
Patent number
US08252795B2

Reaction notes

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