Diisopropylethylamine → HCID 46183761, compound

Temperature

100 °C

5-(1-(2-Methoxypyridin-4-yl)ethyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine. 1-(2-Methoxypyridin-4-yl)-1-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-c]pyridin-5-yl)ethanol (0.348 g, 0.810 mmol), methanesulfonic anhydride (0.353 g, 2.026 mmol), N,N-diisopropylethylamine (0.565 mL, 3.24 mmol), and N,N-dimethylformamide (9 mL) were combined in a sealable vessel with a stirbar. Nitrogen gas was blown in to blow out air. The resulting mixture was sealed, stirred vigorously, and heated at 100° C. for 24 h. A very large excess of both methanesulfonic anhydride and N,N-diisopropylethylamine were added in order to push the reaction to completion. The resulting mixture was sealed, stirred vigorously, and heated at 100° C. for another 1 h. The resulting mixture was diluted with ethyl acetate, saturated aqueous sodium bicarbonate, and water and shaken in a reparatory funnel. The layers were separated. The water layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was dissolved in ethyl acetate and purified using flash chromatography (Biotage) (20-80% ethyl acetate in hexane) to give an impure tan solid. MS (ESI) m/z 412.0 [M+1]+. The tan solids were dissolved in 1-methyl-2-pyrrolidinone (3 mL) with stirring at room temperature and then diluted with ethanol (3 mL). A combination vacuum/nitrogen/hydrogen manifold was attached. The atmosphere in the flask was removed and replaced with nitrogen three times. Palladium (10 wt. % on activated carbon) (0.122 g, 0.115 mmol) was added and the atmosphere in the flask was removed and replaced with hydrogen three times. The resulting mixture was stirred vigorously under a hydrogen balloon at room temperature for 2.5 h. The atmosphere in the flask was removed and replaced with hydrogen three times. The resulting mixture was stirred vigorously under a hydrogen balloon at 50° C. for 1.5 h. The atmosphere in the flask was removed and replaced with hydrogen three times. The resulting mixture was stirred vigorously under a hydrogen balloon at 60° C. for 27 h. The resulting black mixture was filtered through Celite and purified using reverse-phase preparatory HPLC (30-100% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 35 min). Fractions containing the desired product were loaded onto a Strata X—C ion exchange column from Phenomenex. The column was washed successively with water, acetonitrile, methanol, and then 5% ammonium hydroxide in methanol. The product came off with the 5% ammonium hydroxide in methanol eluent and was concentrated on a rotary evaporator and dried under high vacuum to give the desired product (0.172 g, 0.416 mmol, 51% yield over two steps) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.08 (s, 1H), 8.08 (d, J=4.69 Hz, 1H), 7.77 (d, J=8.59 Hz, 2H), 7.64-7.71 (m, J=7.42, 8.98 Hz, 1H), 7.54-7.64 (m, 3H), 7.16 (d, J=7.03 Hz, 1H), 6.92 (dd, J=1.37, 5.27 Hz, 1H), 6.80 (s, 1H), 4.84 (q, J=7.03 Hz, 1H), 3.80 (s, 3H), 1.72 (d, 3H); 19F NMR (376 MHz, DMSO-d6) δ (ppm)-60.10 (s, 3F); MS (ESI) m/z 414.4 [M+1]+.

1. customThe resulting mixture was sealed
2. customthe reaction to completion
3. customThe resulting mixture was sealed
4. stirringstirred vigorously
5. temperatureheated at 100° C. for another 1 h
6. stirringshaken in a reparatory funnel
7. customThe layers were separated
8. extractionThe water layer was extracted with ethyl acetate
9. washThe combined organics were washed with brine
10. dry with materialdried over magnesium sulfate
11. filtrationfiltered
12. concentrationconcentrated on a rotary evaporator
13. dissolutionThe residue was dissolved in ethyl acetate
14. custompurified
15. customto give an impure tan solid
16. stirringwith stirring at room temperature
17. customThe atmosphere in the flask was removed
18. customthe atmosphere in the flask was removed
19. stirringThe resulting mixture was stirred vigorously under a hydrogen balloon at room temperature for 2.5 h
20. customThe atmosphere in the flask was removed
21. stirringThe resulting mixture was stirred vigorously under a hydrogen balloon at 50° C. for 1.5 h
22. customThe atmosphere in the flask was removed
23. stirringThe resulting mixture was stirred vigorously under a hydrogen balloon at 60° C. for 27 h
24. filtrationThe resulting black mixture was filtered through Celite
25. custompurified
26. customreverse-phase preparatory HPLC (30-100% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 35 min)
27. additionFractions containing the desired product
28. washThe column was washed successively with water, acetonitrile, methanol
29. concentrationwas concentrated on a rotary evaporator
30. customdried under high vacuum

ORD record

ord-955e48eab71d4e39ab254f7617bc093a

Source dataset

uspto-grants-2012_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08299056B2