Ammonium Chloride → 6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-trifluoromethyl-pyrazin-2-ylamino)-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one

Temperature

100 °C

A solution of 6-chloro-2-methyl-4-(5-(trifluoromethyl)pyrazin-2-ylamino)pyridazin-3(2H)-one (109 mg, 0.36 mmol), 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 (264 mg, 0.54 mmol), potassium phosphate (189 mg, 0.89 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (17.0 mg, 0.04 mmol) in n-butanol (4 ml) and water (1 ml) was bubbled argon gas for 10 min. To this solution was added bis(dibenzylideneacetone)dipalladium(0) (10.3 mg, 0.02 mmol) was added and the resulting mixture heated to 100° C. for 2 hr. The mixture was cooled and then poured into a saturated ammonium chloride solution. The resulting mixture was extracted with methylene chloride (2×100 ml). The organic phases were combined and dried over MgSO4. The mixture was filtered and evaporated and the residue dissolved in dioxane (10 mL). To this solution was slowly added a 2 M lithium hydroxide solution (0.5 mL) and the resulting mixture stirred at room temperature overnight. The resulting mixture was poured into a saturated ammonium chloride solution. The mixture was extracted with methylene chloride (2×150 ml). The organic phases were combined and dried over MgSO4. The mixture was filtered and evaporated and the residue purified via automated flash chromatography (Analogix, SF15-24 g column, 1%-10% methanol/dichloromethane gradient) to give a light yellow solid which was recrystallized from methanol/dichloromethane to give 6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-trifluoromethyl-pyrazin-2-ylamino)-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one (65 mg, 31%) as a white solid: Mp 250-254° C.; LC/MS m/e calculated for C29H25F4N7O3 [M+H]+ 596.20, observed 596.3; 1H NMR (DMSO-d6) δ: 10.38 (s, 1H), 8.71-9.08 (m, 2H), 8.43-8.66 (m, 2H), 7.68-8.02 (m, 2H), 7.38-7.65 (m, 3H), 4.54-4.76 (m, 1H), 4.40 (br. s., 2H), 3.82 (s, 3H), 1.38 (s, 9H).

1. additionwas added
2. temperatureThe mixture was cooled
3. extractionThe resulting mixture was extracted with methylene chloride (2×100 ml)
4. dry with materialdried over MgSO4
5. filtrationThe mixture was filtered
6. customevaporated
7. dissolutionthe residue dissolved in dioxane (10 mL)
8. additionTo this solution was slowly added a 2 M lithium hydroxide solution (0.5 mL)
9. additionThe resulting mixture was poured into a saturated ammonium chloride solution
10. extractionThe mixture was extracted with methylene chloride (2×150 ml)
11. dry with materialdried over MgSO4
12. filtrationThe mixture was filtered
13. customevaporated
14. customthe residue purified
15. customto give a light yellow solid which
16. customwas recrystallized from methanol/dichloromethane

ORD record

ord-7145aa02b7424bf9a79dc2c6d60aea12

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08481540B2