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

HRID 1398339Notes

Reaction equation

HRID 1398339 reaction equation
Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=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+].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.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:15][C:10]1[N:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8](=[O:16])[N:7]([CH3:17])[C:6]1[CH:18]=[C:2]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH:3]=[CH:4][C:5]2=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 867103378-Chloro-4,6-dimethyl-5H,6H-benzo[c]2,7-naphthyridin-5-one

Product 1

HCID 86710338(S)-tert-butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamateYield 53.9%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 8-chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (60 mg, 0.232 mmol), (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (101 mg, 0.464 mmol), Cs2CO3 (113 mg, 0.348 mmol), Pd(OAc)2 (15.6 mg, 0.070 mmol) and 2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (5.91 mg, 0.014 mmol) in toluene (5 mL) was purged with nitrogen for 5 min and heated at 100° C. overnight (14 h). After cooling, the reaction mixture was filtered through diatomaceous earth (Celite®), concentrated under reduced pressure and dissolved in ethyl acetate (5 mL). The organic layer was washed with brine (2×10 mL) and water (20 mL); dried over Na2SO4 and concentrated under reduced pressure to afford (S)-tert-butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (55 mg crude) as a gummy solid. The crude product was used in the next step without further purification. LC/MS, (ESI) m/z 440.4 [(M+H)+, calcd for C25H34N3O4, 440.2]; LC/MS retention time (method D): tR=0.89 min.

Workup

  1. customwas purged with nitrogen for 5 min
  2. temperatureAfter cooling
  3. filtrationthe reaction mixture was filtered through diatomaceous earth (Celite®)
  4. concentrationconcentrated under reduced pressure
  5. dissolutiondissolved in ethyl acetate (5 mL)
  6. washThe organic layer was washed with brine (2×10 mL) and water (20 mL)
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-d4bba6e08e5d4a59ad1ff176aaa34323
Source dataset
uspto-grants-2014_12
Patent number
US08901305B2

Reaction notes

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