Reaktion #536880

Reaktionsgleichung

4-(5-(1-acetylpiperidin-4-yl)pyridin-2-ylamino)-6-chloro-2-methylpyridazin-3(2H)-one

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

xPhos

potassium phosphate

→

desired compound

2-(3-(5-(5-(1-acetylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-6-tert-butyl-8-fluorophthalazin-1(2H)-one

2-(5-(5-(1-acetylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)benzyl acetate

Lösungsmittel

dioxane water

Reaktionsbedingungen

Aufarbeitung

1. 1
   Sonstigethose described above instep 7 of preparation of Example 6
2. 2
   SonstigeAfter work up, the product was purified by preparative HPLC on silica gel

Vorschrift

This reaction was carried out under similar conditions to those described above instep 7 of preparation of Example 6. A solution of 4-(5-(1-acetylpiperidin-4-yl)pyridin-2-ylamino)-6-chloro-2-methylpyridazin-3(2H)-one (66 mg, 182 μmol), 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 (90.2 mg, 182 μmol), xPhos (8.7 mg, 18.2 μmol) and potassium phosphate (96.8 mg, 456 μmol) in 10 ml of dioxane/water (9:1) was degassed with nitrogen for 10 minutes and bis(dibenzylideneacetone)palladium (0) (5.24 mg, 9.12 μmol) was added. The reaction mixture was heated to 100° C. for 2 hr. After work up, the product was purified by preparative HPLC on silica gel, using a gradient of 0% to 5% methanol/ethyl acetate. This provided 1:1 ratio of desired compound and 2-(5-(5-(1-acetylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)benzyl acetate. The resultant mixture was dissolved in methanol (4 ml) and to this was added 2 N NaOH (468 μl). The reaction was stirred at room temperature for 56 h. The methanol was removed by evaporation and the resultant solution was acidified with 1N HCl and extracted with EtOAc. The organic extract was washed with water, dried over NaSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 4 g, 0% to 50% of MeOH in 50% EtOAc/Hexane) to afford the desired product as a white solid (61 mg, 26.2%). (M+H)+=652.5, 653.7 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.57 (s, 1H), 8.41 (br. s., 1H), 8.28 (br. s., 1H), 8.19 (br. s., 1H), 7.40-7.71 (m, 6H), 6.99 (d, J=8.2 Hz, 1H), 4.80 (d, J=12.9 Hz, 1H), 4.41 (br. s., 2H), 4.11 (q, J=7.0 Hz, 2H), 3.85-3.99 (m, 3H), 3.18 (t, J=12.7 Hz, 1H), 2.52-2.83 (m, 2H), 2.13 (s, 3H), 1.89 (t, J=12.7 Hz, 2H), 1.60 (br. s., 2H), 1.38-1.46 (m, 9H).

Quelle