Chloroacetaldehyde → 7-Chloroimidazo(1,2-b)pyridazine

Temperature

90 °C

A mixture of 3,5-dichloropyridazine (1.49 g, 10.0 mmol, Maybridge, MO08501), benzophenone imine (2.01 g, 11.1 mmol, Aldrich, Cat. No. 293733), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (208 mg, 0.360 mmol), tris(dibenzylideneacetone)dipalladium(0) (165 mg, 0.180 mmol) and 1,4-dioxane (30 mL) was degassed and recharged with nitrogen for three times, and was heated and stirred at 90° C. overnight. After cooling, the mixture was filtered through a pad of silica gel, and washed with THF. [LCMS (M+H)+: m/z=294.1/296.0 corresponds to 5-chloro-N-(diphenylmethylene)pyridazin-3-amine]. The filtrate was treated with 3 N HCl aq. (6 ml) at RT and stirred for 30 min. The mixture was adjusted with NaOH (2 N) to pH=7. The resulting mixture was concentrated under reduced pressure to about the volume of 30 mL. [LCMS (M+H)+: m/z=130.1/132.0 corresponds to 5-chloropyridazin-3-amine]. Isopropanol (50 mL) and chloroacetaldehyde (10.0 mL, 78.7 mmol) was added to the solution. The mixture was heated and stirred at 90° C. for 5 h. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and extracted with water. The combined aqueous layers were adjusted to about pH=9 with 1 N NaOH aq. Solution. The resulting solution was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (0.988 g, 64.3%) which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=153.9/155.9.

1. temperaturewas heated
2. temperatureAfter cooling
3. filtrationthe mixture was filtered through a pad of silica gel
4. washwashed with THF
5. additionThe filtrate was treated with 3 N HCl aq. (6 ml) at RT
6. stirringstirred for 30 min
7. concentrationThe resulting mixture was concentrated under reduced pressure to about the volume of 30 mL
8. temperatureThe mixture was heated
9. stirringstirred at 90° C. for 5 h
10. temperatureAfter cooling
11. concentrationthe mixture was concentrated under reduced pressure
12. additionThe residue was diluted with ethyl acetate
13. extractionextracted with water
14. extractionThe resulting solution was extracted with ethyl acetate (3×30 mL)
15. washThe combined organic layers were washed with brine
16. dry with materialdried over MgSO4
17. filtrationfiltered
18. concentrationconcentrated under reduced pressure

ORD record

ord-e68c17490a784a65af0f2f5cb5b21a24

Source dataset

uspto-grants-2014_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08754114B2