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Ethyl oxoacetate → Ethyl 4-(2-fluorophenyl)-7-methyl-6-(pyrimidin-5-yloxy)-9H-pyrido[3,4-b]indole-1-carboxylate

HRID 2361253
Notes
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Reaction equation

HRID 2361253 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([CH3:27])=[C:17]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)[CH:18]=2)[NH:13][CH:12]=1)[CH2:9][NH2:10].O=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl.O1CCOCC1>O1CCOCC1.C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:11]2[C:19]3[C:14](=[CH:15][C:16]([CH3:27])=[C:17]([O:20][C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:18]=3)[NH:13][C:12]=2[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:10][CH:9]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 3

HCID 70211Ethyl oxoacetateHCID 204431481,4-Dioxane hydrochlorideHCID 679946462-(2-Fluorophenyl)-2-(6-methyl-5-(pyrimidin-5-yloxy)-1H-indol-3-yl)ethanamine

Product 1

HCID 67994650Ethyl 4-(2-fluorophenyl)-7-methyl-6-(pyrimidin-5-yloxy)-9H-pyrido[3,4-b]indole-1-carboxylateYield 22.4%

Reagents, catalysts & solvents 3

HCID 23938
Palladium
Catalyst
HCID 1140TolueneSolvent2×
HCID 312751,4-DioxaneSolvent

Procedure

To a solution of 2-(2-fluorophenyl)-2-(6-methyl-5-(pyrimidin-5-yloxy)-1H-indol-3-yl)ethanamine (0.262 g, 0.724 mmol) and 50% ethyl 2-oxoacetate in toluene (0.316 mL, 1.593 mmol) in 1,4-dioxane (18.10 mL) under nitrogen was added 4 N HCl/1,4-dioxane (0.543 mL, 2.172 mmol). After stirring overnight, the reaction was concentrated in vacuo and dissolved in water. Saturated aqueous NaHCO3 was added until pH ˜12 by litmus paper. The solution was extracted with EtOAc (2×). After separation of the layers, the organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give crude product which was used in subsequent step. This was added to 10% Pd/C (0.770 g, 0.724 mmol) in toluene (10.34 mL), and the reaction was refluxed for 45 min. After cooling to room temperature, the reaction was filtered through a pad of CELITE® and rinsed with EtOAc. The filtrate was concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 40 g column eluting with 0-2% MeOH/CH2Cl2. Appropriate fractions were collected and concentrated in vacuo to give the desired product (0.0716 g, 0.162 mmol, 22.4% yield) as a tan solid.

Workup

  1. concentrationthe reaction was concentrated in vacuo
  2. dissolutiondissolved in water
  3. additionSaturated aqueous NaHCO3 was added until pH ˜12 by litmus paper
  4. extractionThe solution was extracted with EtOAc (2×)
  5. customAfter separation of the layers
  6. dry with materialthe organic layer was dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto give crude product which
  10. temperaturethe reaction was refluxed for 45 min
  11. filtrationthe reaction was filtered through a pad of CELITE®
  12. washrinsed with EtOAc
  13. concentrationThe filtrate was concentrated in vacuo
  14. customto give a residue which
  15. customwas purified by flash chromatography
  16. washeluting with 0-2% MeOH/CH2Cl2
  17. customAppropriate fractions were collected
  18. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-413cd0ee19594f0cb6b2e394599d2cfe
Source dataset
uspto-grants-2014_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08685969B2

Reaction notes

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