Cesium carbonate → HCID 178477891, compound

HRID 1842519Notes

Reaction equation

HRID 1842519 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl.[NH:9]1[CH2:12][CH:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=3[N:14]=2)[CH2:10]1.F[C:24]1[CH:29]=[C:28]([CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[CH:26][N:25]=1.[Cl-].[NH4+]>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[NH:17][C:13]([CH:11]3[CH2:12][N:9]([C:26]4[CH:27]=[C:28]([CH:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[CH:29]=[CH:24][N:25]=4)[CH2:10]3)=[N:14][C:15]=2[CH:21]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 25517Ammonium ChlorideHCID 585484782-fluoro-4-(tetrahydro-2H-pyran-4-yl)pyridineHCID 178478572HCID 178478572, compound

Product 1

HCID 178477891HCID 178477891, compoundYield 51.8%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of cesium carbonate (1.08 g, 3.31 mmol), 2-(azetidin-3-yl)-5-chloro-1H-benzo[d]imidazole dihydrochloride (as described in Preparation 5) (0.23 g, 0.83 mmol), and 2-fluoro-4-(tetrahydro-2H-pyran-4-yl)pyridine (0.15 g, 0.83 mmol) in DMA (1 mL) under argon was heated to 110° C. for 18 h. The mixture was then cooled to RT, ethyl acetate and saturated aqueous ammonium chloride were added and the layers were separated. The organic layer was washed with water (2×), brine, and dried over anhydrous magnesium sulfate. The aqueous layer was then extracted with ethyl acetate (2×) and the combined extracts were washed with water (2×), brine, and added to the original organic layer. The combined organic extracts were filtered and concentrated in vacuo to give an oil that was purified by reversed phase HPLC to give an oil. This oil was partitioned between ethyl acetate and saturated aqueous sodium carbonate solution. The biphasic mixture was stirred vigorously for 30 mins, the layers were separated, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 5-chloro-2-(1-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole (0.16 g, 0.43 mmol, 51% yield) as a white solid. [M+1] 369. IC50 (uM) 1.169.

Workup

  1. temperatureThe mixture was then cooled to RT
  2. customthe layers were separated
  3. washThe organic layer was washed with water (2×), brine
  4. dry with materialdried over anhydrous magnesium sulfate
  5. extractionThe aqueous layer was then extracted with ethyl acetate (2×)
  6. washthe combined extracts were washed with water (2×), brine
  7. additionadded to the original organic layer
  8. filtrationThe combined organic extracts were filtered
  9. concentrationconcentrated in vacuo
  10. customto give an oil that
  11. customwas purified by reversed phase HPLC
  12. customto give an oil
  13. customThis oil was partitioned between ethyl acetate and saturated aqueous sodium carbonate solution
  14. customthe layers were separated
  15. dry with materialthe organic layer was dried over anhydrous magnesium sulfate
  16. filtrationfiltered
  17. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-532df64c37e848548ba17d56a6c908b5
Source dataset
uspto-grants-2015_02
Patent number
US08946230B2

Reaction notes

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