反应详情

温度

70 °C

A solution of (S)-4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (9.6775 g, 12.77 mmol) in TFA (65 mL) was treated dropwise with trifluoromethanesulfonic acid (5.67 mL, 63.8 mmol) and the mixture was stirred for 1 h at 70° C. The volatile material was removed in vacuo, and the residual sticky oil was cooled to 0° C. (external ice bath). About 100 g ice was added, and the mixture was carefully quenched with 1 N NaOH(aq) until slightly basic. The mixture was stirred overnight, and the resulting yellow precipitate was collected by filtration and washed with isopropanol (100 mL). The collected yellow solid was purified by column chromatography (silica gel, 0% to 5% (2.0M ammonia in MeOH)/DCM, followed by repurification on silica gel, DCM to 40% EtOAc/DCM to EtOAc) to provide a yellow solid. This solid was washed with hot toluene several times to give (S)-4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (3.808 g, 58%) as a yellow solid. m/z (ESI, +ve ion) 518 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 11.95 (s, 1H), 8.67-8.75 (m, 1H), 8.41 (s, 1H), 8.38 (d, J=12.91 Hz, 1H), 8.27 (s, 1H), 7.90 (br s, 1H), 7.76 (br s, 1H), 3.93 (s, 3H), 3.91 (br s, 1H), 3.12-3.30 (m, 3H), 2.90 (d, J=14.28 Hz, 1H), 2.85 (s, 3H), 2.65-2.78 (m, 2H), 2.55-2.64 (m, 1H), 2.44 (s, 3H), 2.13-2.28 (m, 1H), 1.16 (d, J=6.06 Hz, 3H).

1. customThe volatile material was removed in vacuo
2. temperaturethe residual sticky oil was cooled to 0° C. (external ice bath)
3. additionAbout 100 g ice was added
4. customthe mixture was carefully quenched with 1 N NaOH(aq) until slightly basic
5. stirringThe mixture was stirred overnight
6. filtrationthe resulting yellow precipitate was collected by filtration
7. washwashed with isopropanol (100 mL)
8. customThe collected yellow solid was purified by column chromatography (silica gel, 0% to 5% (2.0M ammonia in MeOH)/DCM, followed by repurification on silica gel, DCM to 40% EtOAc/DCM to EtOAc)
9. customto provide a yellow solid
10. washThis solid was washed with hot toluene several times