Reaction Steps
A mixture of 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (1.00 g, 3.03 mmol), 6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylsulfanyl]-2-methyl-pyridin-3-ylamine (0.85 g, 2.85 μmol), palladium acetate (0.0379 g, 0.169 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (0.120 mL, 0.338 mmol), and sodium 2-methylpropan-2-olate (0.437 g, 4.55 mmol) in 20 mL dioxane were heated at 80° C. for 14 h. Mixture was transferred into a separatory funnel and extracted with CH2Cl2 and brine. Organic phases were dried over MgSO4, filtered, and concentrated. To the residue, 4M HCl in dioxane (ca. 10 mL) was added and stirred at room temperature for 1 h. Mixture was purified by HPLC; fractions containing pure product were collected, ammonium hydroxide was added (ca 5 mL), and partly concentrated. Residue was extracted with 1M NaOH and CH2Cl2. Organic phases were dried over MgSO4, filtered, and concentrated to give 4-{6-[6-(2-hydroxy-ethylsulfanyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester as a yellowish solid (HCl salt, 219 mg, 15%). 1HNMR (CDCl3, 400 MHz) δ 1.25-1.27 (d, J=6.3 Hz, 6H), 1.76-1.83 (m, 2H), 1.99-2.05 (m, 2H), 2.50 (s, 3H), 3.27-3.29 (m, 2H), 3.37-3.44 (m, 2H), 3.76-3.82 (m, 2H), 3.95 (s, 3H), 3.95-4.01 (m, 2H), 4.91-4.97 (m, 1H), 5.33-5.38 (m, 1H), 5.66-5.68 (m, 1H), 6.82 (s, 1H), 5.33-5.38 (m, 1H), 5.66-5.68 (m, 1H), 6.82 (s, 1H), 7.21-7.23 (d, J=8.5 Hz, 1H), 8.08 (s, 1H), 8.17-8.19 (d, J=8.5 Hz, 1H). Exact mass calculated for C22H31N5O5S 477.2 found 478.4 (MH+).
