Boronic Acid → 2-Fluoro-5-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)benzonitrile

HRID 2239881Notes

Reaction equation

HRID 2239881 reaction equation
Cl[C:2]1[CH:3]=[C:4]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[F:35])#[N:28].P([O-])([O-])([O-])=O.[K+].[K+].[K+].B(O)O>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[Fe+2].[Pd]>[F:35][C:34]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]([N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)=[CH:30][C:29]=1[C:27]#[N:28]

Participants

9

Reactant 4

HCID 61668Boronic AcidHCID 62657Potassium Phosphate, TribasicHCID 27579643-Cyano-4-fluorophenylboronic acidHCID 596245586-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine

Product 1

HCID 684836932-Fluoro-5-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)benzonitrile

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 129828017Ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane;iron(2+);(2,3,4,5-tetraphenylcyclopenta-1,4-dien-1-yl)benzeneCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

To a vial was added 6-chloro-N-(4-methoxybenzyl)-N-phenyl imidazo[1,2-b]pyridazin-8-amine (150 mg, 0.411 mmol) from (1a), 3-cyano-4-fluorophenylboronic acid (74.6 mg, 0.452 mmol), potassium phosphate (174 mg, 0.822 mmol), tris(dibenzylideneacetone)dipalladium (2.0 mg, 0.002 mmol) and 1,2,3,4,5-pentaphenyl-1′-(di-t-butylphosphino)ferrocene (CTC-Q-Phos) (5.8 mg, 0.008 mmol) in toluene (2 mL) under nitrogen. The solution was heated to 100° C. for 10 hours. After checking the reaction solution which showed no reaction, more palladium reagent (2.0 mg), ligand (5.8 mg) and boronic acid (74.6 mg) were added. After heating at 100° C. for another 24 hours, the reaction went to completion with no SM left. The crude product mixture was filtered through celite, concentrated in vacuo to provide 2-fluoro-5-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)benzonitrile which was used as is in the next reaction. LC/MS, m/e 450 (M+1). HPLC Rt, 3.60 min. Waters Sunfire C18 column (4.6×50 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 4 min, hold at 100% B 1 min, flow rate 4 mL/min.

Workup

  1. additionwere added
  2. temperatureAfter heating at 100° C. for another 24 hours
  3. waitleft
  4. filtrationThe crude product mixture was filtered through celite
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-8bd28ac5d8074fabacd1ae7abf9eb468
Source dataset
uspto-grants-2010_05
Patent number
US07723336B2

Reaction notes

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