Cesium carbonate → (S)-tert-butyl (1-((6-isopropyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate

HRID 1398304Notes

Reaction equation

HRID 1398304 reaction equation
Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH:16]([CH3:18])[CH3:17])[C:6]=2[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:26]([NH:33][C@H:34]([CH2:39][OH:40])[CH2:35][CH:36]([CH3:38])[CH3:37])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:16]([N:7]1[C:6]2[CH:19]=[C:2]([O:40][CH2:39][C@@H:34]([NH:33][C:26](=[O:27])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH:3]=[CH:4][C:5]=2[C:14]2[C:9](=[CH:10][N:11]=[CH:12][CH:13]=2)[C:8]1=[O:15])([CH3:18])[CH3:17]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 7018766Boc-L-leucinolHCID 867103128-chloro-6-isopropylbenzo[c][2,7]naphthyridin-5(6H)-one

Product 1

HCID 86710313(S)-tert-butyl (1-((6-isopropyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamateYield 21.6%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

To a solution 8-chloro-6-isopropylbenzo[c][2,7]naphthyridin-5(6H)-one (250 mg, 0.917 mmol) in toluene (2 mL) at room temperature was added cesium carbonate (448 mg, 1.375 mmol) and di-tert-butyl(2′,4′,6′-triisopropyl-[1′,1′-biphenyl]-2-yl)phosphine (234 mg, 0.550 mmol) and the mixture was degassed for 5 min. The mixture was then treated with N-Boc-L-leucinol (591 mg, 2.75 mmol) followed by palladium(II)acetate (61.7 mg, 0.275 mmol) and degassed for another 10 min. The reaction mixture was sealed and heated at 80° C. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth (Celite®). The bed was washed with ethyl acetate and the combined filtrate was concentrated under reduced pressure to afford crude product which was purified by combi flash (gradient of ethyl acetate and petroleum ether) afford (S)-tert-butyl (1-((6-isopropyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (160 mg, 0.198 mmol, 21% yield) as an off-white solid. LC/MS (ESI) m/e 454.2 [(M+H)+, calcd for C26H36N3O4 454.3]; LC/MS retention time (method C): tR=2.17 min.

Workup

  1. customthe mixture was degassed for 5 min
  2. customdegassed for another 10 min
  3. customThe reaction mixture was sealed
  4. temperatureThe reaction mixture was then cooled to room temperature
  5. filtrationfiltered through diatomaceous earth (Celite®)
  6. washThe bed was washed with ethyl acetate
  7. concentrationthe combined filtrate was concentrated under reduced pressure
  8. customto afford crude product which
  9. customwas purified by combi flash (gradient of ethyl acetate and petroleum ether)

Sources & evidence

ORD record
ord-9aa460fe5c6e4bd1b9250b14bc315318
Source dataset
uspto-grants-2014_12
Patent number
US08901305B2

Reaction notes

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