Sodium Hydroxide → 6-tert-Butyl-2-{3-[5-(5-cyclobutylaminomethyl-pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one

온도

110 °C

In a 15 mL microwave reaction vial was added 6-chloro-4-(5-cyclobutylaminomethyl-pyrazin-2-ylamino)-2-methyl-2H-pyridazin-3-one (71 mg, 221 μmol, Eq: 1.00) in 7 mL n-butanol and 1.4 mL water. Argon was bubbled through the reaction mixture. To the reaction was added acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (218 mg, 309 μmol, Eq: 1.39), potassium phosphate tribasic (103 mg, 487 μmol then X-PHOS (15.8 mg, 33.2 μmol, Eq: 0.15). The mixture was purged with argon and (dibenzylideneacetone)palladium (9.55 mg, 16.6 μmol, Eq: 0.075) was added. The tube was sealed and heated at 110° C. (bath temp) for 3 hrs. The reaction mixture was allowed to cool to room temperature, a solution of NaOH (189 mg) in water (1.5 mL) was added and the mixture was stirred in an oil bath at 37° C. for 3 hrs. The crude reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The organic phase was concentrated and chromatographed on silica gel eluting with 5-10% (10% in NH4OH in MeOH) in (1/1) EtOAc/n-heptane to give a pure fraction (pale yellow) and mixed fractions (yellow). The pure fraction was concentrated and dissolved in DCM. Methanol was added to make a 10% solvent mixture of MeOH in DCM. Heptane was added which resulted in immediate precipitation of solid. The suspension was allowed to sit at room temperature overnight and the resultant solid was filtered, washed with n-heptane and dried to afford 35 mg (25%) of the title compound as an off-white solid. mp: 163-167° C.

1. customIn a 15 mL microwave reaction
2. customArgon was bubbled through the reaction mixture
3. additionwas added
4. customThe tube was sealed
5. temperatureto cool to room temperature
6. customThe crude reaction mixture
7. extractionextracted with dichloromethane (3×10 mL)
8. concentrationThe organic phase was concentrated
9. customchromatographed on silica gel eluting with 5-10% (10% in NH4OH in MeOH) in (1/1) EtOAc/n-heptane
10. customto give a pure fraction (pale yellow)
11. additionmixed fractions (yellow)
12. concentrationThe pure fraction was concentrated
13. dissolutiondissolved in DCM
14. additionMethanol was added
15. additiona 10% solvent mixture of MeOH in DCM
16. additionHeptane was added which
17. customresulted in immediate precipitation of solid
18. waitto sit at room temperature overnight
19. filtrationthe resultant solid was filtered
20. washwashed with n-heptane
21. customdried

ORD 기록

ord-926ccfb1e2cb485d907431faf2a28284

출처 데이터셋

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08481540B2