Cesium carbonate → N-(5-(3-cyano-8-((5-methoxypyridin-2-yl)(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazin-6-ylamino)-2-methylphenyl)acetamide

HRID 889456Notes

Reaction equation

HRID 889456 reaction equation
Cl[C:2]1[CH:3]=[C:4]([N:13]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][N: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.[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([NH:38][C:39](=[O:41])[CH3:40])[CH:37]=1.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.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=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].[Cu]I>[C:11]([C:8]1[N:6]2[N:7]=[C:2]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([NH:38][C:39](=[O:41])[CH3:40])[CH:37]=3)[CH:3]=[C:4]([N:13]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][N:24]=3)[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:5]2=[N:10][CH:9]=1)#[N:12]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 794922-Acetylamino-4-aminotolueneHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866413806-Chloro-8-((5-methoxypyridin-2-yl)(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carbonitrile

Product 1

HCID 68592466N-(5-(3-cyano-8-((5-methoxypyridin-2-yl)(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazin-6-ylamino)-2-methylphenyl)acetamideYield 61.8%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 31374DimethylacetamideSolvent

Conditions

Temperature
125 °C

Procedure

A mixture of 5B (60 mg, 0.14 mmol), N-(5-amino-2-methylphenyl)acetamide (46.8 mg, 0.29 mmol), Pd2(dba)3 (13.1 mg, 0.014 mmol), Xantphos (18.2 mg, 0.031 mmol), copper(I) iodide (13.6 mg, 0.071 mmol) and Cs2CO3 (186 mg, 0.57 mmol) in DMA (1 mL) was purged with nitrogen and heated at 125° C. After 1.5 hours, the reaction mixture was diluted with ethyl acetate, washed with 15% NH4OH, dried over Na2SO4, and concentrated to dryness under reduced pressure. The resulting oil was purified by silica column chromatography (gradient=0%-100% hexanes to ethyl acetate in 12 min.) to isolate 5C (47.5 mg, 60.7% yield). HPLC: Rt=3.805 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=549.2 [M+H]+.

Workup

  1. customwas purged with nitrogen
  2. additionthe reaction mixture was diluted with ethyl acetate
  3. washwashed with 15% NH4OH
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated to dryness under reduced pressure
  6. customThe resulting oil was purified by silica column chromatography (gradient=0%-100% hexanes to ethyl acetate in 12 min.)

Sources & evidence

ORD record
ord-cada5c103fff495abdd35d894e151976
Source dataset
uspto-grants-2012_08
Patent number
US08252795B2

Reaction notes

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