Water → Buparlisib

참여 물질

반응 조건

반응 단계

The reactor was charged at 20° C. with 111.7 g 4,4′-(6-chloropyrimidine-2,4-diyl)dimorpholine 3, 108.5 g K2CO3 and 4.54 g Tetrakis(Triphenylphosphin)Palladium (0). 125 ml water and 500 ml 1,2-Dimethoxyethan were added. The white suspension was warmed within 30 min to 90° C. A solution of 100 g 6-acetamido-4-(trifluoromethyl)pyridin-3-ylboronic acid B3 in 450 ml 1,2-Dimethoxyethan was constantly added within a period of 4½ h. The funnel was washed with 50 ml 1,2-Dimethoxyethan. The reaction mixture was cooled to 70° C. within 30 min. 1000 ml water were added. 1000 ml solvent was removed by distillation (70° C., 400 mbar to 260 mbar). 1000 ml water was added. 1000 ml solvent was removed by distillation (70° C., 400 mbar to 260 mbar). The reaction mixture was cooled to 20° C. within 30 min. The precipitate was collected by filtration and washed with 300 ml water. The reactor was charged with the precipitate and 1900 g 1N HCl were added. The reaction mixture was warmed to 75° C. within 30 min. The reaction mixture was stirred for 3 h at 75° C. The reaction mixture cooled to 20° C. within 1 h and stirred over night at 20° C. The precipitate was removed by filtration and washed with 200 ml water. The reactor was charged with the filtrate and everything was rinsed with 100 ml water. pH was adjusted to pH11.9. 1800 ml Isopropylacetate were added and the mixture was stirred. The phases were separated and the organic layer was collected. Solvent was removed (70° C., 280 mbar) until the volume was reduced to 725 ml. 1800 ml Isopropylacetate were added and the mixture was stirred. The phases were separated and the organic layer was collected. Solvent was removed (70° C., 280 mbar) until the volume was reduced to 725 ml. The reaction mixture was cooled to 20° C. within 30 min and stored over the week end. The reaction mixture was filtered over a bed of HYO and washed with 225 ml Isopropylacetate. The reactor was charged with the filtrate and 735.5 g of solution 1 (61.2 g N-Acetyl-cystein and 600 g water, pH adjusted to pH 7 with 4 N NaOH) were added. The reaction mixture was warmed to 64° C. within 15 min. The reaction mixture was stirred at 64° C. for 2 h. The reaction mixture was cooled to 20° C. within 45 min. The phases were separated and the aqueous layer was removed. 1926.5 ml 1N HCl were added and the mixture was stirred for 15 min. The phases were separated and the aqueous layer was collected. 947 ml 1N HCl were added and the mixture was stirred for 15 min. The phases were separated and the aqueous layer was collected. The organic layer was removed from the reactor. The reactor was charged with the combined aqueous layers. pH was adjusted to pH 2.3. 39 g Silabond were added. The reaction mixture was warmed to 64° C. within 20 min. The reaction mixture was stirred for 2 h at 64° C. The reaction mixture was coiled to 20° C. within 30 min. The precipitate was removed by filtration. The residue was washed with 500 g water. The reactor was charged with the combined filtrates. pH was adjusted to pH 5.0 with 4 N NaOH The reaction mixture was cooled to 0° C. The reaction mixture was stirred for 60 min. The product was collected by filtration and washed with 500 g cold (˜10° C.) water. The product was dried until constant weight was obtained to yield 136.8 g (84.9%) 5-(2,6-Di-4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine 5.

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