Piperidine → 2-[2-(5-Chloro-1H-indol-2-YL)-ethyl]-isoindole-1,3-dione

HRID 730941Notes

Reaction equation

HRID 730941 reaction equation
C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15]C(=O)C(F)(F)F)=[C:11](I)[CH:10]=1.[CH2:23]([N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])[CH2:24][C:25]#[CH:26].N1CCCCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O.O1CCCC1>[Cl:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[NH:15][C:25]([CH2:24][CH2:23][N:27]1[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]1=[O:37])=[CH:26]2

Participants

9

Reactant 4

HCID 8082PiperidineHCID 8471TriethylamineHCID 11171619N-(3-Butynyl)phthalimideHCID 12129715N-(4-Chloro-2-iodophenyl)-2,2,2-trifluoroacetamide

Product 1

HCID 534240202-[2-(5-Chloro-1H-indol-2-YL)-ethyl]-isoindole-1,3-dione

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
30 °C

Procedure

Dichlorobis(triphenylphosphine)palladium (II) (43 g, 0.061 mol), copper (I) iodide (20.2 g, 0.106 mol), and triethylamine (782 g, 7.74 mol) is added to a stirred mixture of N-(4-Chloro-2-iodophenyl)-2,2,2-trifluoroacetamide (1800 g, 5.15 mol) and tetrahydrofuran (1.80 L). A solution of 2-(but-3-ynyl)-1H-isoindole-1,3(2H)-dione (1098 g, 5.51 mol) and tetrahydrofuran (11 L) is added to the reaction mixture slowly over 6 hours, maintaining a reaction temperature of 30° C. The reaction mixture is allowed to stir at room temperature overnight. The reaction mixture is filtered under reduced pressure and the triethylammonium iodide cake is washed with tetrahydrofuran (2×550 mL). The filtrate is concentrated under reduced pressure to a volume of less than 6 L, and N,N-dimethylformamide (8 L) is added to the residue. The mixture is concentrated until tetrahydrofuran is removed. Piperidine (535 g, 6.29 mol) is added to the mixture. The mixture is stirred and warmed to 100° C. The mixture is maintained at 100° C. until the product/starting material ratio is >97/3. The mixture is cooled to 32° C. Water (4.2 L) is added to the stirred mixture over >100 min, allowing the temperature of the mixture to rise to 45° C. The mixture is cooled (0-5° C.). The product is collected by filtration and dried to give 2-[2-(5-Chloro-1H-indol-2-yl)-ethyl]-isoindole-1,3-dione (1173 g, 73%, 98.1% purity, largest single impurity 1.2%. 1H NMR (DMSO-d6): δ11.35 (s, 1H), 7.83 (m, 4H), 7.41 (d, 1H, J=2.0 Hz), 7.29 (d, 1H, J=8.6 Hz), 6.99 (dd, 1H, J=2.0, 8.6 Hz), 3.94 (t, 2H, J=7.1 Hz), 3.08 (t, 2H, J=7.1 Hz).

Workup

  1. filtrationThe reaction mixture is filtered under reduced pressure
  2. washthe triethylammonium iodide cake is washed with tetrahydrofuran (2×550 mL)
  3. concentrationThe filtrate is concentrated under reduced pressure to a volume of less than 6 L, and N,N-dimethylformamide (8 L)
  4. additionis added to the residue
  5. concentrationThe mixture is concentrated until tetrahydrofuran
  6. customis removed
  7. stirringThe mixture is stirred
  8. temperaturewarmed to 100° C
  9. temperatureThe mixture is maintained at 100° C. until the product/starting material ratio
  10. temperatureThe mixture is cooled to 32° C
  11. customto rise to 45° C
  12. temperatureThe mixture is cooled (0-5° C.)
  13. filtrationThe product is collected by filtration
  14. customdried

Sources & evidence

ORD record
ord-33373845068f4d24b355fd82456e02a9
Source dataset
uspto-grants-2009_09
Patent number
US07582771B2

Reaction notes

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