반응 #151
ord-834b5e1dd58a47728397e6966452dba7
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Tris(dibenzylideneacetone)dipalladium(0) (1.703 g, 1.86 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (2.58 g, 4.46 mmol) were dissolved in toluene (50 ml) in a 500 mL two-necked round-bottomed flask equipped with a condensor and activated at 50 °C for 40 min under argon. 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (12.84 g, 46.30 mmol), 4-(4-bromobenzyl)morpholine (13.64 g, 53.25 mmol), Sodium tert-pentoxide (8.16 g, 74.09 mmol) and extra toluene (250 mL) were added. The total volume of the reaction mixture was deoxygenized carefully by switching vacuum-argon 10-times and heated to 110 °C under argon. After 10 min the mixture turned into green. The reaction was monitored by HPLC, after 22 h only ca 65 %. The reactuion was stopped and the mixture was cooled to room temperature. Toluene was removed in vacuo. The residual was dissolved in dichloromethane ( 1.2 L) and extracted with water (2*1 L). The aqueous phase was extracted with EtOAc(600 mL). The combined orange organic phases were filtered through a celitepad and concetrated in vacuo. Dark orange brown sticky gum was obtained which solidified over 2 weeks. This solid was slurried in EtOAc (60 mL) at reflux point for 1 h, then it was cooled to rt slowly with vigorous stirring. Filtration afforded a light yellow solid and an orange filtrate. 0.5 g of the filtercake was purified by preparative HPLC, it afforded 303 mg light yellow solid which was submitted to PARD directly (EN01460-38-001). 1.8 g of the filtercake was purified by preparative HPLC, it afforded 1.02 g light yellow solid and 1.015 g was submitted to PARD directly in a standard bascoded bottle (EN01460-38-002) (barcode: 30152995). The residual material was used for recrystallization studies in the RSL group.