Cesium carbonate → tert-butyl((2S)-1-((5-cyclopropyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate

HRID 870906Notes

Reaction equation

HRID 870906 reaction equation
Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH:16]3[CH2:18][CH2:17]3)[O:8][C:6]=2[CH:7]=1.[OH:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:29]([O:28][C:27](=[O:33])[NH:26][C@@H:21]([CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:20][O:19][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH:16]3[CH2:18][CH2:17]3)[O:8][C:6]=2[CH:7]=1)([CH3:32])([CH3:31])[CH3:30]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 7018766Boc-L-leucinolHCID 866958998-chloro-5-cyclopropyl-5H-chromeno[3,4-c]pyridine

Product 1

HCID 86724427tert-butyl((2S)-1-((5-cyclopropyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamateYield 53.4%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred solution of 8-chloro-5-cyclopropyl-5H-chromeno[3,4-c]pyridine (275 mg, 1.067 mmol) in toluene (3 mL) was added (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (696 mg, 3.20 mmol), cesium carbonate (427 mg, 1.310 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1′,1′-biphenyl]-2-yl)phosphine (272 mg, 0.640 mmol) and palladium (II) acetate (71.9 mg, 0.320 mmol). Nitrogen was bubbled through the reaction mixture for 10 min then the mixture was heated at 80° C. for 12 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (1×15 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified via silica gel chromatography (ethyl acetate/pet ether) to give tert-butyl-(2S)-1-(5-cyclopropyl-5H-chromeno[3,4-c]pyridin-8-yloxy)-4-methylpentan-2-ylcarbamate (250 mg, 0.57 mmol, 50% yield). LCMS (ESI) m/e 439.2 [(M+H)+, calcd for C26H35N2O4 439.3]; LC/MS retention time (Method C): tR=2.16 min.

Workup

  1. customNitrogen was bubbled through the reaction mixture for 10 min
  2. temperatureThe reaction mixture was cooled to room temperature
  3. filtrationfiltered through celite
  4. additionThe filtrate was diluted with water (10 mL)
  5. extractionextracted with ethyl acetate (3×15 mL)
  6. washThe combined organic extracts were washed with brine (1×15 mL)
  7. dry with materialdried over sodium sulfate
  8. concentrationconcentrated under reduced pressure
  9. customThe crude product was purified via silica gel chromatography (ethyl acetate/pet ether)

Sources & evidence

ORD record
ord-45decf8e05e84430a2cf073aeaea083f
Source dataset
uspto-grants-2015_03
Patent number
US08969564B2

Reaction notes

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