Ammonium Chloride → 4-(2-((5-Fluoro-6-methoxy-3-pyridinyl)amino)-5-((1r)-1-((2s)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-n,n-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

Participants

Reaction Conditions

Reaction Steps

Lithium bis(trimethylsilyl)amide (1.0 M solution in THF, Aldrich; 9.23 mL, 9.23 mmol) was added dropwise over 5 min to a mixture of 4-(2-fluoro-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.000 g, 3.08 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, Inc., 0.656 g, 4.62 mmol) in THF (30.8 mL) at 0° C., and the resulting reddish-brown solution was stirred at 0° C. for 1 h. Saturated NH4Cl (aq., 50 mL) was added and the reaction mixture was partitioned between EtOAc (100 mL) and half-saturated NH4Cl (aq., 50 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was adsorbed onto silica gel and purified by column chromatography (80 g of silica gel, 0% to 100% EtOAc/hexanes) gave 4-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.90 g, 2.461 mmol, 80% yield) as a yellow solid. m/z (ESI, +ve) 771.8 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.89 (s, 1H); 8.69-8.73 (m, 1H); 8.20-8.24 (m, 1H); 8.08 (dt, J=12.37, 1.05 Hz, 1H); 7.95-7.98 (m, 1H); 7.18-7.24 (m, 4H); 6.82-6.90 (m, 4H); 4.78-4.88 (m, 4H); 4.01 (s, 3H); 3.97-4.01 (m, 1H); 3.81 (s, 3H); 3.78 (s, 3H); 3.18-3.20 (m, 1H); 3.08-3.15 (m, 2H); 2.75-2.87 (m, 2H); 2.67 (s, 3H); 2.56-2.63 (m, 1H); 2.59 (s, 3H); 2.43-2.51 (m, 1H); 1.40 (d, J=6.85 Hz, 3H); 1.07 (d, J=6.26 Hz, 3H).

Provenance & Evidence