Potassium Phosphate, Tribasic → acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{8-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-imidazo[1,2-b]pyridazin-6-yl}-benzyl ester

関与物質

反応条件

反応手順

In a 50 mL test tube, 6-chloro-N-(5((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (170 mg, 475 μmol, Eq: 1.00) and potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (225 mg, 475 μmol, Eq: 1.00) were combined with BuOH (10 ml) to give an orange solution. Water (2.5 ml) was added. X-PHOS (22.6 mg, 47.5 μmol, Eq: 0.1) and potassium phosphate tribasic (202 mg, 950 μmol, eq: 2) were added. Bis(dibenzylideneacetone)palladium (13.7 mg, 23.8 μmol, Eq: 0.05) was added. The tube was purged with argon and sealed. The solution was warmed in an oil bath at 100° C. for 1.5 hours. The solution was cooled to room temperature. The reaction mixture was poured into 75 mL H2O and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 50% to 100% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient) to give a residue. The residue was triturated with Et2O. LC/MS analysis showed that the crude material was a mix of products: 12% 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{8-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-imidazo[1,2-b]pyridazin-6-yl}-phenyl)-2H-phthalazin-1-one and 88% acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{8-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-imidazo[1,2-b]pyridazin-6-yl}-benzyl ester by UV. (157 mg, 48%). The mixture was taken into the next reaction “as is.” LC/MS-ESI observed [M+H]+ 648 and 690.

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