Piperidine → 2-(4-fluorophenyl)-5-[4-(methylthio)phenyl]4-piperidino-3(2H)-pyridazinone

Temperature

-78 °C

To a slightly heterogeneous solution of piperidine (99.7 mg, 1.17 mmol) and toluene (8 mL) cooled to −78° C. was slowly added dropwise an n-BuLi solution (0.235 mL, 0.59 mmol, 2.5 M in hexanes). After stirring at −78° C. for 10 minutes, the cooling bath was removed and the mixture stirred an additional 1 hour at 23° C. The 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (400 mg, 1.17 mmol) was dissolved in portions in toluene (3×6-7 mil aliquots) with a heat gun and cooled to 0° C. prior to transfer via syringe to the lithium amide solution (cooled to −78° C.). The addition was made slowly along the interior wall of the reaction vessel. This reaction mixture was stirred overnight, slowly warming to 23° C. as the cooling bath evaporated. The reaction was quenched with water and diluted with a large excess of ethyl acetate. The layers were separated, and the ethyl acetate layer washed with additional water and brine and dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes 1:2) to provide 440 mg (95%) of 2-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-4-piperidino-3(2H)-pyridazinone.

1. customthe cooling bath was removed
2. stirringthe mixture stirred an additional 1 hour at 23° C
3. temperaturecooled to 0° C.
4. additionThe addition
5. stirringThis reaction mixture was stirred overnight
6. temperatureslowly warming to 23° C. as the cooling bath
7. customevaporated
8. customThe reaction was quenched with water
9. additiondiluted with a large excess of ethyl acetate
10. customThe layers were separated
11. washthe ethyl acetate layer washed with additional water and brine
12. dry with materialdried over MgSO4
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. customThe residue was chromatographed (flash silica gel, ethyl acetate/hexanes 1:2)

ORD record

ord-a2b400032b61471a85d77856abf705ab

Source dataset

uspto-grants-2006_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07001895B2