2,5-PyriMidinediaMine, N2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]- synthesis

Yield:910904-67-5 26%

Reaction Conditions:

with hydrogen;palladium 10% on activated carbon in methanol at 20; for 1 - 2 h;Product distribution / selectivity;

Steps:

34; 109

Example 34. iV-f4-(2-PvrroIidiii-l-vI-ethoxv)-phenvI1-pvrimidine-2.5-diamine (22); [0170] A methanolic solution of compound 21 described in Example 33 (1.5g, 6.48 mmol) was purged with argon for several minutes then treated with 10% Palladium on carbon (0.85 g). Reaction atmosphere was evacuated and replaced with hydrogen added via hydrogen-filled balloon. After 2 hours, hydrogen balloon removed and reaction solvents purged with argon. Celite was added to reaction solvent and resulting slurry was filtered through pad of celite. Solvents were then removed providing the desired amine as a yellow solid (0.36 g, 26%).; Example 92. iV²-(4-(2-(PyrroIidm-l-vnethoxy)phenvI)pyrimidine-2.,5-diamine (54); [0262] To a solution of the 2-amino-5-nitropyrimidine (0.54 g, 4 mmol) in anhydrous 1,4-dioxane (20 mL) was added l-[2-(4-bromophenoxy)ethyl]pyrrolidine (1.62 g, 6 mmol), Cs₂CO₃ (5.2 g, 16 mmol), Pd₂(dba)₃ (0.36 g, 0.4 mmol), and Xantphos (0.7 g, 1.2 mmol). The suspension was heated under reflux for 2 h under argon. The solid was filtered off and washed with EtOAc. The filtrate was washed with brine (1 x 100 mL) and the aqueous was extracted with EtOAc (3 x 50 mL). Combined organic solution was dried (Na₂SO₄) and concentrated until 10 mL remain solution before adding hexane (100 mL). The mixture was sonicated for 2 min. The solid was collected by filtration and EPO washed with hexane. The crude material was further purified by flash column (CH₂Cl₂ :MeOH:NH₃.H₂O = 100:10:1). The obtained yellow solid was dissolved in MeOH (200 mL) and bubbled with Ar for 2 min. before adding 10% Pd-C. The mixture was hydrogenated for Ih at room temperature. The catalyst was filtered off and washed with MeOH. The filtrate was concentrated in vacuo. The desired product was obtained as a yellow solid (0.48 g, 40%).

References:

WO2006/101977,2006,A2 Location in patent:Page/Page column 55; 88-89