Dichloromethane → N-(2-Fluoro-5-(2-(4-methylpiperazin-1-yl)benzylcarbamoyl)phenyl)-7-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-carboxamide

HRID 335271Notes

Reaction equation

HRID 335271 reaction equation
Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:36])[NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)[CH:17]=[CH:16][C:15]=3[F:37])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40](B(O)O)[CH:39]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl.O1CCCOB1C1C=NC=CC=1>CN(C=O)C.CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:37][C:15]1[CH:16]=[CH:17][C:18]([C:20](=[O:36])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[CH:19][C:14]=1[NH:13][C:11]([C:8]1[N:5]2[CH:6]=[CH:7][C:2]([C:40]3[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=3)=[CH:3][C:4]2=[N:10][CH:9]=1)=[O:12]

Participants

11

Reactant 6

HCID 6344Dichloromethane3×HCID 8471TriethylamineHCID 10796Cesium carbonate3×HCID 27343783-Pyridinylboronic acidHCID 41980053-(1,3,2-Dioxaborinan-2-yl)pyridine2×HCID 712830957-Bromo-N-(2-fluoro-5-(2-(4-methylpiperazin-1-yl)benzylcarbamoyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide

Product 1

HCID 71283325N-(2-Fluoro-5-(2-(4-methylpiperazin-1-yl)benzylcarbamoyl)phenyl)-7-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-carboxamide

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst3×HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

Under nitrogen, 7-bromo-N-(2-fluoro-5-(2-(4-methylpiperazin-1-yl)benzylcarbamoyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (Ex 1.1, step 1) (120 mg, 0.212 mmol), pyridine-3-ylboronic acid (33.8 mg, 0.212 mmol), triethylamine (0.030 ml, 0.212 mmol), cesium carbonate (69.1 mg, 0.212 mmol) and PdCl2(dppf).CH2Cl2 adduct (17.33 mg, 0.021 mmol) in DMF (3 ml) were heated at 85° C. overnight. A further portion of cesium carbonate (24.34 mg, 0.075 mmol) and PdCl2(dppf).CH2Cl2 adduct (6.10 mg, 7.47 μmol) were added along with 3-(1,3,2-dioxaborinan-2-yl)pyridine (34.6 mg, 0.212 mmol) and heated continued at 85° C. for 26 hrs. A further portion of cesium carbonate (24.34 mg, 0.075 mmol) and PdCl2(dppf).CH2Cl2 adduct (6.10 mg, 7.47 μmol) and 3-(1,3,2-dioxaborinan-2-yl)pyridine (34.6 mg, 0.212 mmol) were added. The reaction was heated at 100° C. for 2 hrs. The reaction mixture was diluted with EtOAc and water and the resulting product which precipitated out was collected by filtration. Further product was contained in the organic phase, which was washed with sat. NaHCO3, brine, dried (MgSO4) and concentrated in vacuo. The crude residue was combined with the precipitated product and purified by chromatography on silica eluting with 0-20% MeOH/DCM. The resulting solid was purified by preparative LC-MS eluting with 0.1% diethylamine 30-70% acetonitrile/water. The product fractions were partitioned between EtOAc and NaHCO3. The organic portion was separated, dried (MgSO4) and concentrated in vacuo to afford the title compound;

Workup

  1. temperatureheated
  2. customthe resulting product which precipitated out
  3. filtrationwas collected by filtration
  4. washwas washed with sat. NaHCO3, brine
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. custompurified by chromatography on silica eluting with 0-20% MeOH/DCM
  8. customThe resulting solid was purified by preparative LC-MS
  9. washeluting with 0.1% diethylamine 30-70% acetonitrile/water
  10. customThe product fractions were partitioned between EtOAc and NaHCO3
  11. customThe organic portion was separated
  12. dry with materialdried (MgSO4)
  13. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-9575426c854f483cb02bd8db10d2c8b1
Source dataset
uspto-grants-2014_11
Patent number
US08883819B2

Reaction notes

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