Sulfuric Acid → 6-chloro-4-(2-methoxypyridin-3-yl)-N-methylpyridazin-3-amine

Temperature

100 °C

To a solution of 6-chloro-4-(2-methoxy-pyridin-3-yl)-pyridazin-3-ylamine (270 mg, 1.14 mmol) in triethyl orthoformate (6 mL) was added 1 drop of trifluoroacetic acid. The reaction mixture was stirred at 100° C. for 3 hours and then concentrated under vacuum (60° C./20 mbar). The residue was dissolved in 5 mL toluene and concentrated again. This was repeated for 3 times to completely remove all volatiles. The residue was dissolved in ethanol (6 mL) and sodium borohydride (86.3 mg, 2.28 mmol) was added in portions at 0° C. The reaction mixture was heated to 90° C. and stirred at this temperature for 2 hours. The reaction was cooled down to 0° C. and the pH was adjusted to 1 by addition of 0.25M aqueous sulfuric acid (5 mL). The yellow reaction mixture was stirred at room temperature for 3 hours, poured on 10% aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL) (pH ca. 8) and the layers were separated. The aqueous layer was extracted a second time with ethyl acetate (50 mL). The organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). Light yellow solid (100 mg, 35%). MS (ESI+): m/z=251.069 ([M+H]+).

1. concentrationconcentrated under vacuum (60° C./20 mbar)
2. dissolutionThe residue was dissolved in 5 mL toluene
3. concentrationconcentrated again
4. customto completely remove all volatiles
5. dissolutionThe residue was dissolved in ethanol (6 mL)
6. temperatureThe reaction mixture was heated to 90° C.
7. stirringstirred at this temperature for 2 hours
8. temperatureThe reaction was cooled down to 0° C.
9. stirringThe yellow reaction mixture was stirred at room temperature for 3 hours
10. customthe layers were separated
11. extractionThe aqueous layer was extracted a second time with ethyl acetate (50 mL)
12. washThe organic layers were washed with brine (50 mL)
13. dry with materialdried over magnesium sulfate
14. filtrationfiltered
15. concentrationconcentrated under vacuum
16. customThe compound was purified by silica gel chromatography on a 20 g column
17. washeluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100)

ORD record

ord-e0de8fa829a740d7b7fb645652a3a408

Source dataset

uspto-grants-2014_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08748434B2