1,4-Dioxane hydrochloride → ethyl 4-(2-fluorophenyl)-7-(morpholine-4-carbonyl)-9H-pyrido[3,4-b]indole-1-carboxylate

HRID 2361244Notes

Reaction equation

HRID 2361244 reaction equation
[NH2:1][CH2:2][CH:3]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10].O=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C1(C)C=CC=CC=1.Cl.O1CCOCC1>O1CCOCC1.C1(C)C=CC=CC=1.[Pd]>[F:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]1[C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:1][CH:2]=1

Participants

7

Reactant 3

HCID 204431481,4-Dioxane hydrochlorideHCID 67994639(3-(2-Amino-1-(2-fluorophenyl)ethyl)-1H-indol-6-yl)(morpholino)methanoneHCID 86599969Ethyl glyoxylate toluene

Product 1

HCID 67994855ethyl 4-(2-fluorophenyl)-7-(morpholine-4-carbonyl)-9H-pyrido[3,4-b]indole-1-carboxylateYield 19.8%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 1140TolueneSolventHCID 312751,4-DioxaneSolvent

Procedure

To a yellow, homogeneous solution of (3-(2-amino-1-(2-fluorophenyl)ethyl)-1H-indol-6-yl)(morpholino)methanone (0.270 g, 0.736 mmol) and 50% ethyl 2-oxoacetate/toluene (0.321 mL, 1.619 mmol) in 1,4-dioxane (30 mL) was added 4 N HCl/dioxane (0.368 mL, 1.472 mmol) under nitrogen, and the reaction was stirred overnight. The reaction was concentrated in vacuo, diluted with water and basified to pH ˜10 (by litmus paper) with NaHCO3. This was extracted with EtOAc (3×), and the organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give crude product which was used in the subsequent step. This was combined with 10% Pd/C (0.710 g, 0.668 mmol) in toluene (10 mL), and the solution was refluxed. After 45 min, the reaction was cooled to room temperature and filtered through a pad of CELITE®, rinsing with EtOAc. The filtrate was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 24 g column eluting with 0-100% EtOAc/hexanes. Appropriate fractions were collected and concentrated in vacuo to give the desired product (0.0592 g, 0.132 mmol, 19.8% yield) as an off-white solid.

Workup

  1. concentrationThe reaction was concentrated in vacuo
  2. additiondiluted with water and basified to pH ˜10 (by litmus paper) with NaHCO3
  3. extractionThis was extracted with EtOAc (3×)
  4. washwashed with brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto give crude product which
  9. temperaturethe solution was refluxed
  10. waitAfter 45 min
  11. filtrationfiltered through a pad of CELITE®
  12. washrinsing with EtOAc
  13. washThe filtrate was washed with brine
  14. dry with materialdried over MgSO4
  15. filtrationfiltered
  16. concentrationconcentrated in vacuo
  17. customto give a residue which
  18. customwas purified by flash chromatography
  19. washeluting with 0-100% EtOAc/hexanes
  20. customAppropriate fractions were collected
  21. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-ac3cf881ac5141389ec6b4088af18100
Source dataset
uspto-grants-2014_04
Patent number
US08685969B2

Reaction notes

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