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

HRID 1398321Notes

Reaction equation

HRID 1398321 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]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:6]=2[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:27]([NH:34][C@H:35]([CH2:40][OH:41])[CH2:36][CH:37]([CH3:39])[CH3:38])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:17]1([CH2:16][N:7]2[C:6]3[CH:20]=[C:2]([O:41][CH2:40][C@@H:35]([NH:34][C:27](=[O:28])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:36][CH:37]([CH3:39])[CH3:38])[CH:3]=[CH:4][C:5]=3[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8]2=[O:15])[CH2:19][CH2:18]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 7018766Boc-L-leucinolHCID 11618717Di-tert-butyl(2',4',6'-tris(propan-2-yl)-(1,1'-biphenyl)-2-yl)phosphaneHCID 867103258-chloro-6-(cyclopropylmethyl)benzo[c][2,7]naphthyridin-5(6H)-one

Product 1

HCID 86710326(S)-tert-butyl (1-((6-(cyclopropylmethyl)-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamateYield 49%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

To a solution 8-chloro-6-(cyclopropylmethyl)benzo[c][2,7]naphthyridin-5(6H)-one (100 mg, 0.351 mmol) in anhydrous toluene (5 mL) at room temperature was added cesium carbonate (172 mg, 0.527 mmol) and Boc-L-leucinol (229 mg, 1.054 mmol) and the mixture was degassed with nitrogen for 5 min. The mixture was then treated with di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (48.5 mg, 0.211 mmol) followed by palladium(II)acetate (23.65 mg, 0.105 mmol) and degassed for another 10 min. The reaction mixture was sealed and heated at 80° C. After overnight stirring the reaction mixture was cooled to room temperature and filtered through diatomaceous earth (Celite®). The bed was washed with ethyl acetate (15 mL) and the filtrate was concentrated under reduced pressure to afford crude compound which was purified by preparative HPLC (ethyl acetate in petroleum ether) to afford (S)-tert-butyl (1-((6-(cyclopropylmethyl)-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (80 mg, 0.172 mmol, 49% yield) as a brown gummy solid. LC/MS (ESI) m/e 466.3 [(M+H)+, calcd C27H36N3O4466.3]; LC/MS retention time (method A): tR=2.199 min.

Workup

  1. customthe mixture was degassed with nitrogen for 5 min
  2. customdegassed for another 10 min
  3. customThe reaction mixture was sealed
  4. temperaturewas cooled to room temperature
  5. filtrationfiltered through diatomaceous earth (Celite®)
  6. washThe bed was washed with ethyl acetate (15 mL)
  7. concentrationthe filtrate was concentrated under reduced pressure
  8. customto afford crude compound which
  9. customwas purified by preparative HPLC (ethyl acetate in petroleum ether)

Sources & evidence

ORD record
ord-a8ceec232cb94c4ca456017a29213a34
Source dataset
uspto-grants-2014_12
Patent number
US08901305B2

Reaction notes

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