tert-Butyl carbamate → tert-butyl N-[5-fluoro-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl]carbamate

HRID 524952Notes

Reaction equation

HRID 524952 reaction equation
Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:15])[C:7]=1[C:8]1[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH:13]=1.[C:16](=[O:23])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[NH2:17].CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C>[F:15][C:6]1[C:7]([C:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH:13]=2)=[C:2]([NH:17][C:16](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:3]=[N:4][CH:5]=1

Participants

6

Reactant 4

HCID 77922tert-Butyl carbamateHCID 23676156Sodium t-butoxideHCID 25112535Brettphos2×HCID 867210073-chloro-5-fluoro-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)pyridine

Product 1

HCID 86721008tert-butyl N-[5-fluoro-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl]carbamate

Reagents, catalysts & solvents 1

HCID 25112535BrettphosCatalyst2×

Conditions

Temperature
100 °C

Procedure

3-chloro-5-fluoro-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)pyridine (377 mg, 1.663 mmol), tert-butyl carbamate (974.1 mg, 8.315 mmol), sodium tert-butoxide (815.1 mg, 8.481 mmol), BrettPhos pre-catalyst (66.25 mg, 0.08315 mmol) and BrettPhos (44.63 mg, 0.08315 mmol) were placed in a sealable tube an degassed by vacuum/nitrogen cycles (×5). Dry dioxane (10 mL) was added and the resulting mixture was placed into a pre-heated block at 100° C. and stirred at this temperature for 16 hours. Further portions of BrettPhos pre-catalyst (66.25 mg, 0.08315 mmol) and BrettPhos (44.63 mg, 0.08315 mmol) were added and the reaction heated at 100° C. for 8 hours. The reaction mixture was cooled to ambient temperature and quenched with saturated NH4Cl. The mixture was passed through a pre-wetted (EtOAc) celite cartridge (2.5 g). The cartridge was washed with EtOAc/saturated NH4Cl and the layers of the filtrate separated. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts were washed with brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 10% MeOH/DCM, loaded in DCM) to give tert-butyl (5-fluoro-1′-methyl-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridin]-3-yl)carbamate. MS (ES+) 308.2.

Workup

  1. customan degassed by vacuum/nitrogen cycles (×5)
  2. additionDry dioxane (10 mL) was added
  3. customwas placed into a pre-heated block at 100° C.
  4. temperatureThe reaction mixture was cooled to ambient temperature
  5. customquenched with saturated NH4Cl
  6. washThe cartridge was washed with EtOAc/saturated NH4Cl
  7. customthe layers of the filtrate separated
  8. extractionThe aqueous layer was extracted with EtOAc (×3)
  9. washthe combined organic extracts were washed with brine (×1)
  10. dry with materialdried (MgSO4)
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customThe residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 10% MeOH/DCM, loaded in DCM)

Sources & evidence

ORD record
ord-1b3b3856e0f34c7c827c143d472514a6
Source dataset
uspto-grants-2016_05
Patent number
US09340546B2

Reaction notes

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