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

HRID 524958Notes

Reaction equation

HRID 524958 reaction equation
Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:18])[C:7]=1[C:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:17][O:16][CH2:15]2)[CH2:12][CH:13]=1.[C:19](=[O:26])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH2:20].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:18][C:6]1[C:7]([C:8]2[CH2:9][CH2:10][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:12][CH:13]=2)=[C:2]([NH:20][C:19](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=[N:4][CH:5]=1

Participants

6

Reactant 4

HCID 77922tert-Butyl carbamateHCID 23676156Sodium t-butoxideHCID 25112535BrettphosHCID 867210133-chloro-5-fluoro-4-[1-(oxetan-3-yl)-3,6-dihydro-2H-pyridin-4-yl]pyridine

Product 1

HCID 86721014tert-butyl N-[5-fluoro-4-[1-(oxetan-3-yl)-3,6-dihydro-2H-pyridin-4-yl]-3-pyridyl]carbamateYield 24.2%

Reagents, catalysts & solvents 1

HCID 25112535BrettphosCatalyst

Procedure

3-chloro-5-fluoro-4-[1-(oxetan-3-yl)-3,6-dihydro-2H-pyridin-4-yl]pyridine (572 mg, 2.129 mmol), tert-butyl carbamate (1.246 g, 10.64 mmol), sodium tert-butoxide (1.044 g, 10.86 mmol), BrettPhos pre-catalyst (84.78 mg, 0.1064 mmol) and BrettPhos (57.11 mg, 0.1064 mmol) were placed in a sealable tube and 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. 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 dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column, eluting with 0 to 100% EtOAc/Petroleum Ether, loaded in DCM) to give tert-butyl (5-fluoro-1′-(oxetan-3-yl)-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridin]-3-yl)carbamate as a pale yellow solid (180 mg, 24% Yield). Also isolate 197 mg of a mixture of SM and product. MS (ES+) 350.2.

Workup

  1. customdegassed by vacuum/nitrogen cycles (×5)
  2. additionDry dioxane (10 mL) was added
  3. customwas placed into a pre-heated block at 100° C.
  4. customquenched with saturated NH4Cl
  5. washThe cartridge was washed with EtOAc/saturated NH4Cl
  6. customthe layers of the filtrate separated
  7. extractionThe aqueous layer was extracted with EtOAc (×3)
  8. dry with materialthe combined organic extracts were dried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe residue was purified by column chromatography (ISCO Companion, 80 g column, eluting with 0 to 100% EtOAc/Petroleum Ether, loaded in DCM)

Sources & evidence

ORD record
ord-d616dc2c66f44a7c98e3fe224622a813
Source dataset
uspto-grants-2016_05
Patent number
US09340546B2

Reaction notes

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