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Allyl bromide → 1-Allyl-2-(4-(tert-butoxycarbonyl)pyridin-3-yl)-3-cyclohexyl-1h-indole-6-carboxylic acid

HRID 860735
Notes
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Reaction equation

HRID 860735 reaction equation
[H-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]1[NH:17][C:18]2[C:23]([C:24]=1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[CH:22][CH:21]=[C:20]([C:31]([O:33]C)=[O:32])[CH:19]=2)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:35](Br)[CH:36]=[CH2:37]>CN(C=O)C.C1COCC1.CO.[OH-].[Na+]>[CH2:37]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([C:31]([OH:33])=[O:32])[CH:19]=2)[C:24]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[C:16]1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH:36]=[CH2:35]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 3

HCID 7841Allyl bromideHCID 24758Sodium hydrideHCID 69207220Methyl 2-(4-(tert-butoxycarbonyl)pyridin-3-yl)-3-cyclohexyl-1H-indole-6-carboxylate

Product 1

HCID 692078291-Allyl-2-(4-(tert-butoxycarbonyl)pyridin-3-yl)-3-cyclohexyl-1h-indole-6-carboxylic acid

Reagents, catalysts & solvents 3

HCID 6228Dimethylformamide
Solvent
HCID 14798Sodium HydroxideSolvent
HCID 21899815MeOH tetrahydrofuranSolvent

Procedure

To a suspension of NaH (19.5 mg of 60% dispersion in mineral oil, 0.488 mmol) in DMF (2 mL), methyl 2-(4-(tert-butoxycarbonyl)pyridin-3-yl)-3-cyclohexyl-1H-indole-6-carboxylate (100 mg, 0.222 mmol) was added and the reaction mixture was stirred at rt for 10 min. Allyl bromide (0.040 mL, 0.466 mmol) was then added, and the reaction mixture was stirred at rt for 3 hr. It was then quenched by the addition of water and acidified using 1N HCl solution. A yellowish precipitate formed which was collected by filtration to give the crude ester product in sufficient purity to proceed to the next step. This material was then dissolved in a THF/Methanol mixture (3 mL/3 mL) and 2N NaOH solution (2 mL) was added. The reaction mixture was heated at 100° C. under microwave conditions for 15 min. It was then concentrated and the pH was adjusted to 4–5 using 1N HCl solution. This mixture was then extracted using ethyl acetate and the organic layer was dried with MgSO4, filtered and evaporated and the resultant residue was purified using Prep. reverse phase HPLC to afford the title compound as a yellow solid, (50 mg, 44% yield two steps). MS m/z 516(MH+); 1H NMR (500 MHz, CD3OD) □ ppm 1.22–1.48 (m, 13 H) 1.70–2.02 (m, 5 H) 2.15 (m, 1 H) 2.37 (m, 1 H) 3.88 (dd, J=16.63, 5.04 Hz, 1 H) 4.13 (m, 1 H) 4.51 (m, 1 H) 4.76 (m, 1 H) 4.87 (m, 1 H) 5.04–5.21 (m, 3 H) 5.79 (m, 1 H) 5.97 (m, 1 H) 7.58 (d, J=5.80 Hz, 1 H) 7.78 (m, 1 H) 7.90 (d, J=8.24 Hz, 1 H) 8.13 (s, 1 H) 8.50 (s, 1 H) 8.67 (d, J=5.80 Hz, 1 H).

Workup

  1. additionwas added
  2. stirringthe reaction mixture was stirred at rt for 3 hr
  3. customIt was then quenched by the addition of water
  4. customA yellowish precipitate formed which
  5. filtrationwas collected by filtration
  6. customto give the crude ester product in sufficient purity
  7. additionwas added
  8. temperatureThe reaction mixture was heated at 100° C. under microwave conditions for 15 min
  9. concentrationIt was then concentrated
  10. extractionThis mixture was then extracted
  11. dry with materialthe organic layer was dried with MgSO4
  12. filtrationfiltered
  13. customevaporated
  14. customthe resultant residue was purified

Sources & evidence

ORD record
ord-677faba54a904dca9150ef33f59d4afa
Source dataset
uspto-grants-2006_12
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07153848B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes