4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine → 4-(2-((5-Fluoro-6-methoxypyridin-3-yl)amino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine

Participants

Reaction Conditions

Reaction Steps

4-(2-(5-Fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (456.7 mg, 0.6026 mmol) was dissolved in trifluoroacetic acid (9.5 mL) and the reaction flask was fitted with a reflux condenser and put in a preheated oil bath (75-77° C.) and stirred for 16 h. The reaction was cooled to room temperature and concentrated. The reaction was diluted with DCM (40 mL) and treated with saturated sodium bicarbonate and 5N NaOH to raise the pH of the aqueous phase to about 8. Then, the layers were separated and the aqueous phase was extracted with DCM and 10:1 DCM/MeOH. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, treated with MeOH, and filtered. The solid was washed with MeOH. The solid was not >95% pure by HPLC, so the filtrate and solid were combined, concentrated, and purified on a silica gel column according to the procedure described by Still et al. (Journal of Organic Chemistry, 1978, 43, 2923-2925) using this eluent system: 30:1 DCM/2N ammonia in MeOH to 20:1 DCM/2N ammonia in MeOH to 15:1 DCM/2N ammonia in MeOH to 5:1 DCM/2N ammonia in MeOH. The fractions with product were collected, concentrated, treated with MeOH, and filtered. The solid was washed with MeOH, collected, and dried under high vacuum to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (194.7 mg, 62% yield) as a yellow powder. 1H NMR (CDCl3, 400 MHz) δ 11.93 (s, 1H), 8.71 (d, J=2.54 Hz, 1H), 8.31 (t, J=2.25 Hz, 1H), 8.27 (d, J=2.35 Hz, 1H), 8.05 (d, J=2.15 Hz, 1H), 5.42 (br s, 2H), 4.04 (s, 3H), 3.56 (quartet, J=6.65 Hz, 1H), 3.24 (t, J=4.69 Hz, 4H), 2.78 (s, 3H), 2.68-2.54 (m, 7H), 1.44 (t, J=6.85 Hz, 3H). m/z (ESI, pos. ion) 518 (M+H)+.

Provenance & Evidence