Cesium carbonate → 5-Fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-amine

HRID 524875Notes

Reaction equation

HRID 524875 reaction equation
Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:18])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:17][O:16][CH2:15]2)[CH2:10][CH2:9]1.C(=O)(OC(C)(C)C)[NH2:20].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:18][C:6]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)=[C:2]([NH2:20])[CH:3]=[N:4][CH:5]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 77922tert-Butyl carbamateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 867209311-(3-Chloro-5-fluoro-4-pyridyl)-4-(oxetan-3-yl)piperazine

Product 1

HCID 867209325-Fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-amine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
115 °C

Procedure

In a pressure tube containing 1-(3-chloro-5-fluoro-4-pyridyl)-4-(oxetan-3-yl)piperazine (800 mg, 2.944 mmol) was added dioxane (6 mL). To this solution was added tert-butyl carbamate (517.3 mg, 4.416 mmol), Cs2CO3 (1.918 g, 5.888 mmol), xantphos (85.17 mg, 0.1472 mmol) followed by Pd2(dba)3 (134.8 mg, 0.1472 mmol). The tube was sealed and heated thermally for 60 h at 115° C. The reaction mixture was cooled to RT and filtered on a pad of celite. The cake was washed with EtOAc and the combined filtrate was concentrated in vacuo to a black oil. The residue was taken up in DCM (2 ml) and TFA (3 ml) was added. The resulting dark brown clear solution was stirred at RT for 2 h and then concentrated in vacuo. The residue was loaded onto a SCX-2 (10 g) cartridge. Flushed with MeOH (×3, CV) before eluting the desired product with 2M NH3 in MeOH (×3 CV). The basic eluent was concentrated in vacuo to afford a dark brown oil that was purified by chromatography on silica eluting with DCM-DCM:MeOH:NH3(90:10:1) a gradient of 100-0 to 30:70. Fractions containing product were collected and concentrated in vacuo to afford 5-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-amine as a light brown solid. 295 mg: MS (ES+) 253.2.

Workup

  1. customThe tube was sealed
  2. temperatureThe reaction mixture was cooled to RT
  3. filtrationfiltered on a pad of celite
  4. washThe cake was washed with EtOAc
  5. concentrationthe combined filtrate was concentrated in vacuo to a black oil
  6. additionTFA (3 ml) was added
  7. concentrationconcentrated in vacuo
  8. customFlushed with MeOH (×3, CV)
  9. washbefore eluting the desired product with 2M NH3 in MeOH (×3 CV)
  10. concentrationThe basic eluent was concentrated in vacuo
  11. customto afford a dark brown oil that
  12. customwas purified by chromatography on silica eluting with DCM-DCM
  13. additionFractions containing product
  14. customwere collected
  15. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-1cff97b3ca7e4759903b9dc0c623f3de
Source dataset
uspto-grants-2016_05
Patent number
US09340546B2

Reaction notes

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