Potassium Hydroxide → (S)-7-Cyano-4-((3-hydroxypyridin-4-yl)methyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-ylcarbamic acid isopropyl ester

HRID 449845Notes

Reaction equation

HRID 449845 reaction equation
[CH:1]([O:4][C:5](=[O:29])[NH:6][C@@H:7]1[CH2:28][C:10]2[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3Br)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].[OH-:30].[K+]>O.O1CCOCC1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[CH:1]([O:4][C:5](=[O:29])[NH:6][C@@H:7]1[CH2:28][C:10]2[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[OH:30])[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]

Participants

8

Reactant 2

HCID 14797Potassium HydroxideHCID 66933638(S)-4-((3-Bromopyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydrocyclopenta[b]indol-2-ylcarbamic acid isopropyl ester

Product 1

HCID 66933295(S)-7-Cyano-4-((3-hydroxypyridin-4-yl)methyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-ylcarbamic acid isopropyl esterYield 101.7%

Reagents, catalysts & solvents 5

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 11953610Di-tert-butyl[3,4,5,6-tetramethyl-2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphaneCatalyst2×HCID 962WaterSolvent2×HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of (S)-4-((3-bromopyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydrocyclopenta[b]indol-2-ylcarbamic acid isopropyl ester (3.81 g, 7.05 mmol), potassium hydroxide (1.34 g, 23.9 mmol), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (230 mg, 479 μmol), tris(dibenzylideneacetone)dipalladium (110 mg, 120 μmol) in water (50 mL) and 1,4-dioxane (50 mL) is heated at 100° C. for one hour. Tris(dibenzylideneacetone)dipalladium (110 mg, 120 μmol) and 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (230 mg, 479 μmol) are added and the mixture is heated for 3 h. The reaction is diluted with water and dichloromethane. The layers are then separated and the aqueous layer is washed with dichloromethane twice. The aqueous portion is acidified to pH 1-2 with a few drops of 5 M HCl and then neutralized to pH 7 with potassium carbonate. Ethyl acetate is added and the bi-layer is filtered. The organic phase is separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a brown residue. The residue is triturated with ether twice and dried under vacuum. It is then purified by flash chromatography eluting with 1% to 6% methanol in chloroform to obtain impure product (˜2.8 g). It is purified by preparative super critical fluid chromatography (column: ethylpyridine 20×150 mm (Princeton Chromatography, Inc.); flow rate: 70 mL/min @ 35° C. and 100 psi; eluent: 5-50% MeOH with 0.1% isopropylamine:carbon dioxide) to obtain the title compound as a white solid (548 mg, 20%). LC-ES/MS m/z 391.2 [M+H]+, TR=2.63 min.

Workup

  1. temperaturethe mixture is heated for 3 h
  2. customThe layers are then separated
  3. washthe aqueous layer is washed with dichloromethane twice
  4. additionEthyl acetate is added
  5. filtrationthe bi-layer is filtered
  6. customThe organic phase is separated
  7. dry with materialdried over anhydrous sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customto obtain a brown residue
  11. customThe residue is triturated with ether twice
  12. customdried under vacuum
  13. customIt is then purified by flash chromatography
  14. washeluting with 1% to 6% methanol in chloroform

Sources & evidence

ORD record
ord-e9367d91ca214de989becd6c52a42c4a
Source dataset
uspto-grants-2013_07
Patent number
US08486943B2

Reaction notes

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