Hydrochloric Acid → HCID 44611237, compound

Temperature

0 °C

To a stirred solution of 3-fluoro-pyridin-2-ylamine (1.0 g, 8.92 mmol) in ethanol (20 mL) was added 3-chloro-pentane-2,4-dione (2.5 mL, 22.3 mmol) at room temperature. The reaction mixture was heated to reflux and then stirred for 48 hours. After the reaction completion, the volatiles were concentrated under reduced pressure and the residue was purified over silica gel column chromatography eluting with 2% MeOH/DCM to afford Int-1 (0.75 g, 44%) as off-white solid. Mass (m/z): 193 [M++1]. 1HNMR 200 MHz (CDCl3): δ 9.54 (d, J=7 Hz, 1H), 7.18 (t, J=7 Hz, 1H), 6.99-6.89 (m, 1H), 2.83 (s, 3H). 2.65 (s, 3H). A solution of Int-1 (0.75 g, 3.9 mmol) in DMF-DMA (10 mL) was stirred at reflux temperature for 48 hours. The reaction mixture was allowed room temperature and diluted with hexane (25 mL) and stirred for 10 minutes. The precipitated solid was filtered off, dried under vacuum to afford Int-2 (0.75 g, 78%) as brown color solid. Mass (m/z): 248 [M++1]. 1HNMR 200 MHz (CDCl3): δ 9.43 (d, J=6.2 Hz, 1H), 7.81 (d, J=12.4 Hz, 1H), 7.05 (t, J=7.6 Hz, 1H), 6.84-6.77 (m, 1H), 5.56 (d, J=12.2 Hz, 1H), 2.96 (s, 3H), 2.88 (s, 3H), 2.78 (s, 3H). Synthesis of Int-4: To a solution of Int-2 (1.5 g, 6.07 mmol) in DMF (25 mL) was added Int-3 (3.5 g, 18.2 mmol), followed by K2CO3 (2.5 g, 18.2 mmol) at room temperature and the reaction mixture was stirred at 110° C. for 16 hours. The reaction mixture was allowed to room temperature, poured in to ice-cold water (70 mL) and stirred further for 20 minutes. The precipitated solid was filtered off, washed with water (2×10 mL) and dried under vacuum to afford Int-4 (1.5 g, 68%) as brown solid. Mass (m/z): 364 [M++1]. 1HNMR 200 MHz (dmso-d6): δ 10.29 (s, 1H), 9.63 (d, J=6.8 Hz, 1H), 8.69 (d, J=5.6 Hz, 1H), 7.88 (s, 3H), 7.70 (t, J=10.6 Hz, 1H), 7.29-7.23 (m, 2H), 4.83 (brs, 1H), 3.9 (s, 3H), 2.73 (s, 3H). A mixture of Int-4 (1.5 g, 3.97 mmol) and 4 N HCl (20 mL) was stirred at reflux temperature for 3 hours. The reaction mixture was cooled to 0° C. and stirred for 20 minutes. The precipitated solid was filtered off, washed with water (2×10 mL) and dried under vacuum to afford Int-5 (1.0 g, 71%) as pale yellow solid. Mass (m/z): 364 [M++1]. 1HNMR 200 MHz (dmso-d6): δ 10.29 (s, 1H), 9.63 (d, J=6.8 Hz, 1H), 8.69 (d, J=5.6 Hz, 1H), 7.88 (s, 3H), 7.70 (t, J=10.6 Hz, 1H), 7.29-7.23 (m, 2H), 4.83 (brs, 1H), 2.73 (s, 3H). To a stirred suspension of Int-5 (0.8 g, 2.20 mmol) in DMF (10 mL) were added HOBt (0.29 g, 2.20 mmol), EDCI (1.05 g, 5.5 mmol), N-ethyldiisopropylamine (1.0 mL, 5.5 mmol) and NH2OTHP (0.51 g, 4.40 mmol) at 0° C. The reaction mixture was warmed to room temperature and the stirring was continued for 16 hours. The reaction mixture was poured in to ice-cold water (50 mL) and stirred for 20 minutes. The precipitated solid was filtered off, washed with water (2×10 mL) and dried under vacuum. The crude material was purified over silica gel column chromatography eluting with 3% MeOH/DCM to afford Int-6 (0.45 g, 44%) as white solid. Mass (m/z): 463 [M++1].

1. temperatureThe reaction mixture was heated
2. temperatureto reflux
3. concentrationAfter the reaction completion, the volatiles were concentrated under reduced pressure
4. customthe residue was purified over silica gel column chromatography
5. washeluting with 2% MeOH/DCM
6. customto afford Int-1 (0.75 g, 44%) as off-white solid
7. temperatureat reflux temperature for 48 hours
8. customwas allowed room temperature
9. stirringstirred for 10 minutes
10. filtrationThe precipitated solid was filtered off
11. customdried under vacuum
12. customto afford Int-2 (0.75 g, 78%) as brown color solid
13. customSynthesis of Int-4
14. stirringthe reaction mixture was stirred at 110° C. for 16 hours
15. customwas allowed to room temperature
16. stirringstirred further for 20 minutes
17. filtrationThe precipitated solid was filtered off
18. washwashed with water (2×10 mL)
19. customdried under vacuum
20. customto afford Int-4 (1.5 g, 68%) as brown solid
21. stirringwas stirred
22. temperatureat reflux temperature for 3 hours
23. stirringstirred for 20 minutes
24. filtrationThe precipitated solid was filtered off
25. washwashed with water (2×10 mL)
26. customdried under vacuum
27. customto afford Int-5 (1.0 g, 71%) as pale yellow solid
28. temperatureThe reaction mixture was warmed to room temperature
29. waitthe stirring was continued for 16 hours
30. stirringstirred for 20 minutes
31. filtrationThe precipitated solid was filtered off
32. washwashed with water (2×10 mL)
33. customdried under vacuum
34. customThe crude material was purified over silica gel column chromatography
35. washeluting with 3% MeOH/DCM
36. customto afford Int-6 (0.45 g, 44%) as white solid

ORD record

ord-36070701995a4b118ee9539198bbe7d7

Source dataset

uspto-grants-2012_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08124764B2