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With potassium carbonate In acetonitrile at 100℃; for 6 h;
To a solution of 5-bromo-2-chloropyrimidine (4 g, 20.68 mmol) in acetonitrile (40 mL) was added 2-methoxyethanamine (5.5 mL, 63 mmol) and potassium carbonate (14 g, 100 mmol) . The mixture was heated at 100 and stirred for 6 h. The reaction mixture was concentrated to remove solvent. The residue was diluted with water (30 mL) . The resulting mixture was extracted with DCM (50 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 9/1 to give a colorless oily product (4.43 g, 92.3) .[1798]MS (ESI, pos. ion) m/z: 233.2 [M+1]+.
Synthesis of 4-(4-{2-[(2-methoxyethyl)amino]pyrimidin-5-yl}phenyl)-N- [5-(2-methyl-l,3-thiazol-4-yl)pyridin-2-yl]tetrahydro-2H-pyran-4-carboxamide (example 207)To a solution of 1-105 (75 mg, 0.16 mmol), KOAc (157 mg, 1.6 mmol),PdCi2(dppf).CH2Ci2 (33 mg, 0.04 mmol) in dioxane (2.0 mL) at room temperature is added R-8 (115 mg, 0.46 mmol). The reaction mixture is heated at 100 C in a sealed tube for 16 hours. The reaction mixture is allowed to cool to room temperature, followed by the addition R-31 (88 mg, 0.38 mmol) in THF (2.0 mL), 20% Na2C03 solution (2.0 mL), and Pd(PPh3)4 (23 mg, 0.20 mmol). The reaction mixture is heated in the microwave at 120 C for 60 minutes, allowed to cool to room temperature, and partitioned between EtOAc and H20. The combined organics are washed with H20, dried with Na2S04, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si02, 0-10% MeOH in EtOAc) to give the title compound 207 (36 mg).
With potassium carbonate; In acetonitrile; at 100℃; for 6h;
To a solution of 5-bromo-2-chloropyrimidine (4 g, 20.68 mmol) in acetonitrile (40 mL) was added 2-methoxyethanamine (5.5 mL, 63 mmol) and potassium carbonate (14 g, 100 mmol) . The mixture was heated at 100 and stirred for 6 h. The reaction mixture was concentrated to remove solvent. The residue was diluted with water (30 mL) . The resulting mixture was extracted with DCM (50 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 9/1 to give a colorless oily product (4.43 g, 92.3) .[1798]MS (ESI, pos. ion) m/z: 233.2 [M+1]+.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃;Inert atmosphere;
A mixture of 5-bromo-N- (2-methoxyethyl) pyrimidin-2-amine (2.55 g, 11.0 mmol) , bis (pinacolato) diboron (5 g, 19.69 mmol) , potassium acetate (3.2 g, 33 mmol) and Pd (dppf) Cl2(0.8 g, 1 mmol) in 1, 4-dioxane (40 mL) was stirred at 90 under N2overnight. The reaction mixture was cooled to rt and diluted with water (20 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 7/3 to give a yellow oily product (9.0 g, 82) .[1801]MS (ESI, pos. ion) m/z: 280.1 [M+1]+
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 3h;
A mixture of 0.5 g (2.48 mmol) 5-bromo-N,N-dimethyl-pyrimidin-2-amine, 0.8 g (3.24 mmol) bis(pinacolato)diborone, 0.6 g (6.38 mmol) KOAc, 0.2 g (0.25 mmol) (0358) Pd(dppf)CI2 * DCM and dioxane is heated to 100C for 4.5 h. After cooling to RT, the reaction mixture is filtered through a pad of Celite and evorated, water is added and the mixture is extracted with EtOAc. The organic phases are pooled, dried and evaporated The crude product is purified by FC. (0359) Yield: 0.6 g (96%), ESI-MS: m/z = 250 (M+H)+, Rt(HPLC): 0.22 min (HPLC-A)
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