Sodium Iodide → HCID 5329407, compound

HRID 1275550Notes

Reaction equation

HRID 1275550 reaction equation
[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=4)=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>CN(C=O)C>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][N:19]([CH2:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]5)[C:18](=[O:22])[CH:17]=4)=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1

Participants

6

Reactant 4

HCID 5238Sodium IodideHCID 10796Cesium carbonate2×HCID 79624N-(3-chloropropyl)piperidine hydrochloride2×HCID 18414211HCID 18414211, compound

Product 1

HCID 5329407HCID 5329407, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

4-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one (14) ##STR24## (4.57 g, 15.9 mmol) was dissolved in 30 mL anhydrous DMF under Ar. Sodium iodide (2.86 g, 19.1 mmol), cesium carbonate (11.9 g, 36.6 mmol) and N-chloropropylpiperidine HCl salt (3.78 g, 19.1 mmol) were added and the reaction was warmed to 40° C. After 3 days additional portions of N-chloropropylpiperidine HCl salt (1.9 g, 9.6 mmol) and cesium carbonate (6.0 g, 18 mmol) were added. After an addtional 16 h the bulk of the DMF was removed in vacuo. The residue was diluted with water and extracted 3x with 5% n-BuOH in CH2Cl2. The combined organic phases was dried over Na2SO4, filtered and concentrated. The residue was purified in several batches by preperative reverse phase HPLC, dissolving sample in MeOH, eluting with 5:95 acetonitrile/water (0.1% H3PO4) to 50:50. Fractions containing pure product were concentrated to remove the bulk of the acetonitrile, basified to pH 8 w/Na2CO3 (s), and extraced 3x with 5% BuOH in CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and concentrated to afford 3.70 g of pure 4-(1-phenyl-1H-benzoimidazol-5-yl)-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one (15). 1H NMR (CDCl3) δ8.17 (s, 1H), 8.10 (s, 1H), 7.63-7.50 (m, 7H), 7.45 (d, J=7.1Hz, 11H), 6.85 (d, J=1.6 Hz, 1H), 6.52 (dd, J=1.8, 7.1Hz, 1H), 4.05 (t, J=6.8 Hz, 2H), 2.38-2.34 (m, 4H), 2.00 (t, J=6.8 Hz, 2H), 1.65-1.58 (m, 6H), 1.45 (M, 2H). Elemental analysis: Calc'd C, 75.70, H, 6.84, N, 13.58; Found C, 75.32, H. 6.87, N. 13.37. ##STR25## 5-Bromo-l-phenyl-1H-benzoimidazole (11) (9.71 g, 35.6 mmol), diboron pinacol ester (9.93 g, 39.1 mmol), potassium acetate (10.5 g, 107 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.78 g, 1.1 mmol) were stirred in 40 mL anhydrous DMF under Ar. The solution was degassed three times by alternating vacuum and argon atmosphere. The reaction was heated to 80° C. for 1 8 h. After cooling the reaction was diluted with water and extracted 3x with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated to afford 11.8 g 1-phenyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazole (16) which was used without purification. ##STR26## Sodium hydride (0.073 g, 3.0 mmol) was stirred in 4 mL anhydrous DMF under Ar. The solution was cooled to 0° C. and 3-iodo-5-hydroxypyridine (0.305 g, 1.38 mmol) was added gradually. After bubbling had subsided N-chloropropylpiperidine hydrochloride (0.330 g, 1.67 mmol) was added slowly. The reaction was then allowed to warm to ambient temperature. After 40 h the reaction was diluted with water and extracted 3x with EtOAc. The combined organic phases were washed was washed with saturated NaCl (aq), dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (2×16 cm silica, 9:1 CH2Cl2/MeOH) afforded 192 mg 5-iodo-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one (18) (40% yield). 1H NMR (CDCl3) δ7.72 (d, J=2.6 Hz, 1H), 7.40 (dd, J=2.6, 9.5 Hz, 1H), 6.37 (d, J=9.5 Hz, 1H), 3.96 (t, J=6.6 Hz, 2H), 2.35 (bs, 4H), 2.26 (t, J=6.6 Hz, 2H), 1.92 (t, 6.6 Hz, 2H), 1.60 (m, 4H), 1.46 (m, 2H). ##STR27##

Workup

  1. customAfter an addtional 16 h the bulk of the DMF was removed in vacuo
  2. additionThe residue was diluted with water
  3. extractionextracted 3x with 5% n-BuOH in CH2Cl2
  4. dry with materialThe combined organic phases was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified in several batches by preperative reverse phase HPLC
  8. dissolutiondissolving sample in MeOH
  9. washeluting with 5:95 acetonitrile/water (0.1% H3PO4) to 50:50
  10. additionFractions containing pure product
  11. concentrationwere concentrated
  12. customto remove the bulk of the acetonitrile
  13. dry with materialThe combined organic phases were dried over Na2SO4
  14. filtrationfiltered
  15. concentrationconcentrated

Sources & evidence

ORD record
ord-71c2ab674691400c9751b4c15bc6ed5a
Source dataset
uspto-grants-2000_12
Patent number
US06162804

Reaction notes

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