Cesium carbonate → (S)-methyl 4-(4-((2-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)-2-fluorophenyl)nicotinate

HRID 1398283Notes

Reaction equation

HRID 1398283 reaction equation
Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:25]([NH:32][C@H:33]([CH2:38][OH:39])[CH2:34][CH:35]([CH3:37])[CH3:36])([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].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>[C:28]([O:27][C:25]([NH:32][C@@H:33]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:38][O:39][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]

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 86695906Methyl 4-(4-chloro-2-fluorophenyl)nicotinate

Product 1

HCID 86710300(S)-methyl 4-(4-((2-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)-2-fluorophenyl)nicotinateYield 60%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

Methyl 4-(4-chloro-2-fluorophenyl)nicotinate (50 mg, 0.188 mmol) in toluene (1 mL) was treated with cesium carbonate (92 mg, 0.282 mmol) and N-Boc-L-Leucinol (121 mg, 0.565 mmol). The mixture was purged with nitrogen gas for 5 min and treated with di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (48.0 mg, 0.113 mmol). After purging the mixture with nitrogen for another 5 min, palladium(II)acetate (42.3 mg, 0.188 mmol) was added and nitrogen bubbled through for another 10 min. The mixture was sealed tightly and heated at 80° C. for 12 h. The mixture was filtered through a bed of diatomaceous earth (Celite®) and washed with ethyl acetate (2×3 mL). The washings were concentrated under reduced pressure. The residue was purified by combi flash (ethyl acetate and petroleum ether) to afford (S)-methyl 4-(4-((2-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)-2-fluorophenyl)nicotinate (50 mg, 0.112 mmol, 60% yield). LC/MS (ESI) m/e 447.2 [(M+H)+, calcd for C24H32FN2O5 447.2]; LC/MS retention time (method C): tR=2.17 min.

Workup

  1. customThe mixture was purged with nitrogen gas for 5 min
  2. customAfter purging the mixture with nitrogen for another 5 min
  3. customnitrogen bubbled through for another 10 min
  4. customThe mixture was sealed tightly
  5. filtrationThe mixture was filtered through a bed of diatomaceous earth (Celite®)
  6. washwashed with ethyl acetate (2×3 mL)
  7. concentrationThe washings were concentrated under reduced pressure
  8. customThe residue was purified by combi flash (ethyl acetate and petroleum ether)

Sources & evidence

ORD record
ord-be20929a0d844e579715627a27a25481
Source dataset
uspto-grants-2014_12
Patent number
US08901305B2

Reaction notes

Loading…