Boron trifluoride etherate → HCID 66611976, compound

Temperature

-78 °C

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 10 N 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).

1. temperatureto warm to ambient temperature
2. waitAfter 2 h
3. waitAfter 1 h
4. waitAfter 1 h
5. customthe reaction was quenched by addition of 1 N NaOH
6. additiontreated with EtOAc
7. extractionThe aq. layer was extracted 3× EtOAc, and 1×DCM
8. dry with materialThe combined organics were dried over sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. customThe resulting impure mixture was combined with additional impure material for the next reaction
12. customthe reaction was sealed
13. temperatureheated to 80° C. for 0.5 h
14. temperatureThe reaction was cooled
15. additionpoured onto ice
16. extractionThe aqueous was extracted 3×DCM, 1×10% iPrOH/DCM
17. dry with materialdried over sodium sulfate
18. filtrationfiltered
19. concentrationconcentrated in vacuo
20. dissolutionThis material was dissolved in DMSO/TFA
21. custompurified by reverse phase HPLC, 10-60% ACN/H2O (+0.1% TFA)
22. concentrationproduct-containing fractions were concentrated in vacuo

ORD record

ord-81862c3e3dce41e1917f3c4a0a35869d

Source dataset

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08362241B2