Trifluoroacetic acid → 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

Temperature

80 °C

A glass microwave reaction vessel (80 mL) was charged with tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (3.000 g, 4.66 mmol) and trifluoroacetic acid (5.39 mL, 69.9 mmol) in 1,2-dichloroethane (20 mL). The reaction mixture was stirred and heated in a CEM Voyager Model (Large-Scale Unit) Microwave at 80° C. for 5 min (100 watts, Powermax feature on). The mixture was concentrated in vacuo to remove as much residual TFA as possible. The crude mixture (3.4 g) was dissolved in THF (30 mL), cooled to −20° C., then sodium carbonate (4.94 g, 46.6 mmol) was added to the mixture. After 10 min, methanesulfonyl chloride (3.63 mL, 46.6 mmol) was added dropwise. Following addition, the mixture was allowed to slowly warm to ambient temperature overnight. The mixture was diluted with DCM and water (30 ml). The reaction mixture was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4. The solution was filtered and concentrated in vacuo to give crude product as a tan oil. This was purified by chromatography through a SiliCycle SiliaSep pre-packed silica gel column (120 gram) eluting with a gradient of 10% to 100% EtOAc in hexane over 30 min, followed by a gradient of 1% to 15% MeOH in DCM over 20 minutes to give 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.702 g, 2.74 mmol, 58.7% yield) as light-yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.46 (dd, J=9.00, 2.15 Hz, 1H); 8.24 (d, J=1.37 Hz, 1H); 7.23 (dd, J=8.51, 6.94 Hz, 4H); 6.86 (t, J=8.71 Hz, 4H); 4.81 (d, J=1.96 Hz, 4H); 3.81 (d, J=6.26 Hz, 6H); 3.60 (s, 2H); 3.23 (s, 4H); 2.74-2.80 (m, 3H); 2.56-2.61 (m, 4H); 2.55 (s, 3H). m/z (ESI, +ve ion) 622.1 (M+H)+.

1. customA glass microwave reaction vessel (80 mL)
2. concentrationThe mixture was concentrated in vacuo
3. customto remove as much residual TFA as possible
4. dissolutionThe crude mixture (3.4 g) was dissolved in THF (30 mL)
5. temperaturecooled to −20° C.
6. additionaddition
7. temperatureto slowly warm to ambient temperature overnight
8. extractionThe reaction mixture was extracted with CH2Cl2 (3×20 mL)
9. dry with materialThe combined organic extracts were dried over Na2SO4
10. filtrationThe solution was filtered
11. concentrationconcentrated in vacuo
12. customto give crude product as a tan oil
13. customThis was purified by chromatography through a SiliCycle SiliaSep pre-packed silica gel column (120 gram)
14. washeluting with a gradient of 10% to 100% EtOAc in hexane over 30 min
15. waitfollowed by a gradient of 1% to 15% MeOH in DCM over 20 minutes

ORD record

ord-121a78efdf9245d5a8440e56c91dc596

Source dataset

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08772480B2