Boron trifluoride etherate → HCID 66611976, compound

Participants

Reaction Conditions

Reaction Steps

To a dark brown slurry of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinonitrile (0.210 g, 0.354 mmol) in 7 mL THF was added titanium (IV) isopropoxide (0.125 mL, 0.425 mmol), and the reaction was cooled to −78° C. Ethylmagnesium bromide 1.0 M solution in THF (2.268 mL, 2.268 mmol) was added slowly dropwise and the reaction allowed to stir 1 h at −78° C. The reaction was allowed to warm to ambient temperature. After 2 h, boron trifluoride diethyl etherate (0.108 mL, 0.850 mmol) was added. After 1 h, boron trifluoride diethyl etherate (0.108 mL, 0.850 mmol) was again added. After 1 h, the reaction was quenched by addition of 1 N NaOH, and treated with EtOAc. The aq. layer was extracted 3× EtOAc, and 1×DCM. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting impure mixture was combined with additional impure material for the next reaction. 0.334 g of an impure mixture containing 4-(5-(1-aminocyclopropyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine was dissolved in 2 mL TFA and treated with triflic acid (0.238 mL, 2.68 mmol), and the reaction was sealed and heated to 80° C. for 0.5 h. The reaction was cooled, poured onto ice, treated with 10N NaOH until basic. The aqueous was extracted 3×DCM, 1×10% iPrOH/DCM, dried over sodium sulfate, filtered, and concentrated in vacuo. This material was dissolved in DMSO/TFA and purified by reverse phase HPLC, 10-60% ACN/H2O (+0.1% TFA); product-containing fractions were concentrated in vacuo to give 4-(5-(1-aminocyclopropyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine 2,2,2-trifluoroacetate (0.010 g, 0.020 mmol, 3.76% yield) as an orange solid. m/z (ESI, +ve ion) 383 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.03 (s, 1H), 8.94 (d, J=2.5 Hz, 1H), 8.53 (br. s., 3H), 8.38-8.49 (m, 2H), 8.30 (dd, J=12.7, 2.2 Hz, 1H), 7.96 (br. s., 1H), 7.84 (br. s., 1H), 3.94 (s, 3H), 2.46 (s, 3H),1.26-1.35 (m, 2H), 1.14-1.23 (m, 2H).

Provenance & Evidence