Cesium carbonate → 6-chloro-N-(pyridin-4-yl)-8-(pyrimidin-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide

HRID 1943500Notes

Reaction equation

HRID 1943500 reaction equation
[N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3][CH:2]=1.[Cl:8][C:9]1[CH:10]=[C:11](Cl)[C:12]2[N:13]([C:15]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[O:19])=[CH:16][N:17]=2)[N:14]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CO.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]>[Cl:8][C:9]1[CH:10]=[C:11]([NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)[C:12]2[N:13]([C:15]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[O:19])=[CH:16][N:17]=2)[N:14]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 689584-AminopyrimidineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 596246716,8-Dichloro-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Product 1

HCID 596244986-chloro-N-(pyridin-4-yl)-8-(pyrimidin-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamideYield 10.1%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A solution of pyrimidin-4-amine (37.0 mg, 0.389 mmol) in degassed dioxane (4 mL) was treated with 6,8-dichloro-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (100 mg, 0.325 mmol), Pd2(dba)3 (14.86 mg, 0.016 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (9.39 mg, 0.016 mmol), and Cs2CO3 (211 mg, 0.649 mmol). The reaction was purged with argon and heated to 100° C. for 4 hours. The reaction was then cooled to room temperature and concentrated. The crude reaction product was dissolved in a small amount of MeOH, filtered and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm). The product (retention time=22.555 minutes) was isolated and lyophilized to dryness to afford 6-chloro-N-(pyridin-4-yl)-8-(pyrimidin-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (12 mg, 10.08%). HPLC Rt=2.463 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=367.0.

Workup

  1. customThe reaction was purged with argon
  2. temperatureThe reaction was then cooled to room temperature
  3. concentrationconcentrated
  4. customThe crude reaction product
  5. filtrationfiltered
  6. custompurified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm)
  7. customThe product (retention time=22.555 minutes) was isolated

Sources & evidence

ORD record
ord-9438814579e8437997301dd246759bdc
Source dataset
uspto-grants-2013_03
Patent number
US08389527B2

Reaction notes

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