Sodium Carbonate → (rac.)-(1R*,5S*)-3-(6-Bromo-pyridin-3-yl)-8-aza-bicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic Acid 8-tert-butyl Ester 2-methyl Ester

HRID 2428175Notes

Reaction equation

HRID 2428175 reaction equation
[Br:1][C:2]1[N:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:36][O:37][C:38]([C:40]1[C@@H:41]2[N:55]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C@H:44]([CH2:45][C:46]=1OS(C(F)(F)F)(=O)=O)[CH2:43][CH2:42]2)=[O:39]>CCO.O.C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:36][O:37][C:38]([C:40]1[C@@H:41]2[N:55]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C@H:44]([CH2:45][C:46]=1[C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:43][CH2:42]2)=[O:39]

Participants

9

Reactant 4

HCID 10340Sodium Carbonate2×HCID 11776Triphenylphosphine2×HCID 27627062-Bromopyridine-5-boronic acid2×HCID 131728966(rac.)-(1R*,5S*)-3-Trifluoromethanesulfonyloxy-8-aza-bicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic Acid 8-tert-butyl Ester 2-methyl Ester

Product 1

HCID 131728971(rac.)-(1R*,5S*)-3-(6-Bromo-pyridin-3-yl)-8-aza-bicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic Acid 8-tert-butyl Ester 2-methyl EsterYield 40.4%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalyst2×HCID 702EthanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

6-Bromopyridine-3-boronic acid (5.00 g, 24.8 mmol), Pd(OAc)2 (278 mg, 1.24 mmol) and PPh3 (650 mg, 2.48 mmol) were suspended in EtOH (67 mL). A sol. of Na2CO3 (3.15 g, 29.7 mmol) in water (25.3 mL) was added. A sol. of compound A1 (10.3 g, 24.8 mmol) in THF (25 mL) was added, and the mixture was heated to reflux for 4 h. 6-Bromopyridine-3-boronic acid (5.00 g, 24.8 mmol) was added again, and 1 h later Pd(OAc)2 (278 mg, 1.24 mmol) and PPh3 (650 mg, 2.48 mmol) and Na2CO3 (3.15 g, 29.7 mmol) were added. The mixture was stirred at reflux for 1 h, and was allowed to cool to rt. The solvents were removed under reduced pressure. EtOAc was added, and the mixture was washed with aq. sat. NaHCO3 (2×), with aq. sat. NH4Cl, and with brine. The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 20:80) yielded the title compound (4.24 g, 40%). LC-MS: tR=1.01 min, ES+: 423.19.

Workup

  1. temperaturethe mixture was heated
  2. temperatureto reflux for 4 h
  3. temperatureat reflux for 1 h
  4. customThe solvents were removed under reduced pressure
  5. additionEtOAc was added
  6. washthe mixture was washed with aq. sat. NaHCO3 (2×), with aq. sat. NH4Cl
  7. dry with materiallayer was dried over Na2SO4
  8. filtrationfiltered
  9. customthe solvents were removed under reduced pressure
  10. customPurification of the crude by FC (EtOAc/heptane 20:80)

Sources & evidence

ORD record
ord-2e10f37acbf54fa1a50a68fa6a610957
Source dataset
uspto-grants-2011_06
Patent number
US07968720B2

Reaction notes

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