Cesium carbonate → HCID 86710446, compound

HRID 1398475Notes

Reaction equation

HRID 1398475 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.[F:19][C:20]([F:34])=[CH:21][CH2:22][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24][OH:25].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[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:25][CH2:24][C@@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH:21]=[C:20]([F:34])[F:19])[CH:3]=[CH:4][C:5]2=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 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-oneHCID 86710445HCID 86710445, compound

Product 1

HCID 86710446HCID 86710446, compoundYield 46.3%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

A suspension of 8-chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (1.26 g, 4.88 mmol), prepared as in Example 16, Part G, (S)-tert-butyl (5,5-difluoro-1-hydroxypent-4-en-2-yl)carbamate (1.39 g, 5.86 mmol), 2-di-t-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.42 g, 0.98 mmol), Pd(OAc)2 (0.11 g, 0.49 mmol), Cs2CO3 (3.18 g, 9.76 mmol), and anhydrous toluene (15 mL) was purged with nitrogen for 10 minutes and heated to 90° C. overnight (15 h). After cooling, the reaction mixture was filtered through diatomaceous earth (Celite®), concentrated under reduced pressure and dissolved in ethyl acetate (50 mL). The organic layer was washed with brine (1×100 mL) and water (1×100 mL); dried over Na2SO4 and concentrated under reduced pressure to afford an amber oil. The crude material was purified over SiO2 (1-5% 2M ammonia in methanol/dichloromethane gradient elution) to afford (S)-tert-butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-5,5-difluoropent-4-en-2-yl)carbamate (1.04 g, 2.26 mmol, 46% yield) as a tan solid. LC/MS, (ESI) m/z 460.0 [(M+H)+, calcd for C24H28F2N3O4, 460.2]; 1H NMR (400 MHz, CDCl3) δ ppm 8.59 (d, J=5.5 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.73 (d, J=5.8 Hz, 1H), 6.83 (dd, J=8.8, 1.8 Hz, 1H), 6.79 (br. s., 1H), 5.13-4.89 (m, 1H), 4.39-4.21 (m, 1H), 4.20-3.96 (m, 3H), 3.66 (s, 3H), 3.12 (s, 3H), 2.61-2.31 (m, 2H), 1.48 (s, 9H).

Workup

  1. customwas purged with nitrogen for 10 minutes
  2. temperatureAfter cooling
  3. filtrationthe reaction mixture was filtered through diatomaceous earth (Celite®)
  4. concentrationconcentrated under reduced pressure
  5. dissolutiondissolved in ethyl acetate (50 mL)
  6. washThe organic layer was washed with brine (1×100 mL) and water (1×100 mL)
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated under reduced pressure
  9. customto afford an amber oil
  10. customThe crude material was purified over SiO2 (1-5% 2M ammonia in methanol/dichloromethane gradient elution)

Sources & evidence

ORD record
ord-6e02b0874dcc49fb804fa2a684d36dfe
Source dataset
uspto-grants-2014_12
Patent number
US08901305B2

Reaction notes

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