Morpholine → 2-(5-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-2-morpholinopropanenitrile

Participants

Reaction Steps

A solution of 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (Example 271, 0.564 g, 0.925 mmol) and morpholine (0.201 mL, 2.313 mmol) in DCM (4.5 mL) was treated with tetraisopropoxytitanium (0.678 mL, 2.313 mmol). The reaction was sealed and stirred rapidly overnight. Cyanodiethylaluminum (1.0 M in toluene; 2.313 mL, 2.313 mmol) was added and the reaction was resealed and stirred overnight. EtOAc was added followed by sat'd NaHCO3 (cautiously). An exotherm and effervescence was observed, so the reaction was poured onto ice and treated with EtOAc and sat'd aq. NaHCO3. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 2-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-2-morpholinopropanenitrile (0.650 g, 0.921 mmol, 100% yield) as a yellow solid. m/z (ESI, +ve ion) 706 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.99 (br. s., 1H); 9.00 (d, J=2.5 Hz, 1H); 8.50 (d, J=2.5 Hz, 1H); 8.03 (dd, J=12.1, 2.2 Hz, 1H); 7.97 (d, J=2.2 Hz, 1H); 7.17-7.26 (m, 4H); 6.82-6.93 (m, 4H); 4.73-5.01 (m, 4H); 4.03 (s, 3H); 3.82 (s, 3H); 3.79 (s, 3H); 3.61-3.71 (m, 4H); 2.64-2.76 (m, 2H); 2.60 (s, 3H); 2.44-2.54 (m, 2H); 1.75 (s, 3H).

Provenance & Evidence