Dimethylformamide → 5-iodo-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one

Temperature

0 °C

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##

1. customwas used without purification
2. customAfter bubbling
3. additionwas added slowly
4. temperatureto warm to ambient temperature
5. extractionextracted 3x with EtOAc
6. washThe combined organic phases were washed
7. washwas washed with saturated NaCl (aq)
8. dry with materialdried over Na2SO4
9. filtrationfiltered
10. concentrationconcentrated
11. customPurification by flash column chromatography (2×16 cm silica, 9:1 CH2Cl2/MeOH)

ORD record

ord-1345211e4ae840e6bac83b629c60edc2

Source dataset

uspto-grants-2000_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06162804