1,4-Dioxane → N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide

HRID 42403Notes

Reaction equation

HRID 42403 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[N:40][CH:41]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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].C(Cl)Cl.O>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:36]2[CH:41]=[N:40][C:39]([N:42]3[CH2:43][CH2:44][NH:45][CH2:46][CH2:47]3)=[CH:38][CH:37]=2)[CH:3]=1)=[O:16]

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 162179462-(Piperazin-1-yl)pyridine-5-boronic acid, pinacol esterHCID 674673876-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1 H-indole-4-carboxamide

Product 1

HCID 67468181N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolvent

Procedure

6-Bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxamide (1.9 g, 4.42 mmol), 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (1.277 g, 4.42 mmol) and potassium phosphate (tribasic) (2.81 g, 13.25 mmol) were placed in a 150 mL pressure vessel followed by addition of 1,4-dioxane (40 mL) and water (10.00 mL). The suspension was stirred and degassed under N2 for 15 min. (emulsion). Next added in PdCl2(dppf)-CH2Cl2 adduct (0.361 g, 0.442 mmol) and degassed for 2 min. The reaction flask was sealed and the contents heated at reflux for 2 h. The suspension was filtered, and dioxane was removed in vacuo. The resultant oil was partitioned between 300 mL of ethyl acetate and 100 mL of water, and the layers were separated. Decolorizing carbon was added, and after 10 min, the organic layer was filtered through short pad of silica. 300 mL of 1 M HCl was added and neutralized with NaOH (to pH ˜9). The contents were extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The product was suspended in diethyl ether and filtered. The title compound was isolated as a yellow solid (950 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.49 (br. s., 1H), 8.52 (d, J=2.27 Hz, 1H), 8.15 (t, J=5.05 Hz, 1H), 7.95 (dd, J=2.53, 8.84 Hz, 1H), 7.73 (d, J=1.26 Hz, 1H), 7.29 (s, 1H), 7.19 (d, J=1.52 Hz, 1H), 6.93 (d, J=9.09 Hz, 1H), 5.87 (s, 1H), 4.85 (quin, J=6.63 Hz, 1H), 4.35 (d, J=5.05 Hz, 2H), 3.49-3.63 (m, 4H), 2.81-3.02 (m, 4H), 2.24 (s, 3H), 2.16 (s, 3H), 2.11 (s, 3H), 1.43 (d, J=6.57 Hz, 6H); LCMS=513.3 (MH+).

Workup

  1. customdegassed under N2 for 15 min. (emulsion)
  2. customdegassed for 2 min
  3. customThe reaction flask was sealed
  4. temperaturethe contents heated
  5. temperatureat reflux for 2 h
  6. filtrationThe suspension was filtered
  7. customdioxane was removed in vacuo
  8. customThe resultant oil was partitioned between 300 mL of ethyl acetate and 100 mL of water
  9. customthe layers were separated
  10. additionDecolorizing carbon was added
  11. filtrationthe organic layer was filtered through short pad of silica
  12. addition300 mL of 1 M HCl was added
  13. extractionThe contents were extracted with ethyl acetate
  14. customThe organic layer was separated
  15. washwashed with brine
  16. dry with materialdried over MgSO4
  17. filtrationfiltered
  18. concentrationconcentrated in vacuo
  19. filtrationfiltered

Sources & evidence

ORD record
ord-67dabd936547454aa31765c789a04c08
Source dataset
uspto-grants-2013_09
Patent number
US08536179B2

Reaction notes

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