Ammonium Chloride → acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzyl ester

Temperatur

100 °C

A solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (153 mg, 0.31 mmol), 6-chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one (61 mg, 0.21 mmol), potassium phosphate (110 mg, 0.52 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (9.87 mg, 0.02 mmol) in butanol (4 ml) and water (1 mL) was flushed with argon before (bis[dibenzylideneacetone]dipalladium) (5.95 mg, 0.01 mmol) was added and the resulting solution heated at 100° C. in for 2 h. The resulting mixture was cooled, poured into a saturated solution of ammonium chloride and extracted with methylene chloride (2×100 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was dissolved in dioxane (10 mL) and treated with a lithium hydroxide solution (0.5 mL, 2.0 M), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was poured into a saturated ammonium chloride solution and extracted with methylene chloride (2×150 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 1% to 10% methanol in dichloromethane) to give acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzyl ester (56 mg, 46%) as a light yellow solid: mp. 188-193° C.; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.37 (s, 9H) 2.34 (s, 3H) 2.77 (t, J=5.29 Hz, 2H) 3.50 (s, 2H) 3.63-4.06 (m, 5H) 4.17-4.67 (m, 3H) 5.98 (s, 1H) 7.33-8.05 (m, 6H) 8.50 (d, J=2.64 Hz, 1H) 9.24 (s, 1H).

1. additionwas added
2. temperatureThe resulting mixture was cooled
3. extractionextracted with methylene chloride (2×100 mL)
4. customThe layers were separated
5. dry with materialthe organic phase dried over magnesium sulfate
6. filtrationThe mixture was filtered
7. concentrationconcentrated in vacuo
8. dissolutionThe residue was dissolved in dioxane (10 mL)
9. additiontreated with a lithium hydroxide solution (0.5 mL, 2.0 M)
10. additionThe resulting mixture was poured into a saturated ammonium chloride solution
11. extractionextracted with methylene chloride (2×150 mL)
12. customThe layers were separated
13. dry with materialthe organic phase dried over magnesium sulfate
14. filtrationThe mixture was filtered
15. concentrationconcentrated in vacuo
16. customThe residue was purified by flash chromatography (silica gel, 24 g, 1% to 10% methanol in dichloromethane)

ORD-Eintrag

ord-316b7fba2c25454d8768a78182a8450a

Quelldatensatz

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08481540B2