Cesium carbonate → 7-[(2-chloro-5-fluoropyridin-4-yl)amino]-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-one

HRID 1045939Notes

Reaction equation

HRID 1045939 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:19]2[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]2)=[C:12]2[C:16]=1[C:15](=[O:17])[N:14]([CH3:18])[CH2:13]2.[Cl:28][C:29]1[CH:34]=[C:33](I)[C:32]([F:36])=[CH:31][N:30]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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>[Cl:28][C:29]1[CH:34]=[C:33]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([N:19]3[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]3)=[C:12]3[C:16]=2[C:15](=[O:17])[N:14]([CH3:18])[CH2:13]3)[C:32]([F:36])=[CH:31][N:30]=1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 248204952-Chloro-5-fluoro-4-iodopyridineHCID 598492047-amino-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-one

Product 1

HCID 866551437-[(2-chloro-5-fluoropyridin-4-yl)amino]-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-oneYield 70.3%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

Cesium carbonate (960 mg, 2.95 mmol) was added to 7-amino-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-one (425 mg, 1.47 mmol), 2-chloro-5-fluoro-4-iodopyridine (379 mg, 1.47 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (51.2 mg, 0.09 mmol) and palladium(II) acetate (13.23 mg, 0.06 mmol) in dioxane (15 mL) under an atmosphere of nitrogen. The resulting suspension was heated at 80° C. for 18 hours and then allowed to cool to room temperature. The mixture was filtered and then filtrate evaporated. The residue was dissolved in EtOAc (150 mL), and the solution washed sequentially with a saturated solution of NaHCO3 (75 mL), water (75 mL), and finally with a saturated solution of NaCl (75 mL). The organic layer was dried over MgSO4 and then evaporated. The residue was triturated with Et2O and dried to afford 7-[(2-chloro-5-fluoropyridin-4-yl)amino]-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-one (432 mg, 70% yield); 1H NMR spectrum (300.132 MHz, CDCl3): δ 1.11 (6H, d), 2.70 (4H, m), 2.76 (1H, m), 3.07 (4H, m), 3.18 (3H, s), 4.37 (2H, s), 7.14 (1H, d), 7.33-7.41 (2H, m), 8.06 (1H, d), 9.40 (1H, d); Mass spectrum: m/z (ESI+) (M+H)+ =418.31.

Workup

  1. temperatureto cool to room temperature
  2. filtrationThe mixture was filtered
  3. customfiltrate evaporated
  4. dissolutionThe residue was dissolved in EtOAc (150 mL)
  5. washthe solution washed sequentially with a saturated solution of NaHCO3 (75 mL), water (75 mL)
  6. dry with materialThe organic layer was dried over MgSO4
  7. customevaporated
  8. customThe residue was triturated with Et2O
  9. customdried

Sources & evidence

ORD record
ord-e31176853ba44f32a853c971a1de2e08
Source dataset
uspto-grants-2013_10
Patent number
US08569298B2

Reaction notes

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