Hydrochloric Acid → HCID 59176796, compound

Temperature

110 °C

To a stirred solution of 3-methoxypyridin-2-amine (4.0 g, 32.2 mmol) in ethanol (40 mL) was added 3-chloro-2,4-pentanedione (5.5 mL, 48.0 mmol) at room temperature. The reaction mixture was heated to reflux and then stirred for 18 hours. The volatiles were concentrated under reduced pressure. The crude material was purified by column chromatography eluting with 15% EtOAc/hexane to afford Int-1 (2.5 g, 38%). Mass (m/z): 205 [M++1]. 1HNMR 200 MHz (CDCl3): δ 9.23 (d, J=6.2 Hz, 1H), 6.78 (t, J=7.4 Hz, 1H), 6.61 (d, J=7.8 Hz, 1H), 4.01 (s, 3H), 2.77 (s, 3H), 2.67 (s, 3H). A solution of Int-1 (02.5 g, 12.2 mmol) in DMF-DMA (15 mL) was stirred at reflux temperature for 48 hours. The volatile was concentrated under reduced pressure. The residue was diluted with diethyl ether and stirred for 20 minutes. The precipitated solid was filtered off, washed with hexane-ether and dried under vacuum to afford Int-2 (2.5 g, 81%) as brown color solid. Mass (m/z): 260 [M++1]. 1H NMR 200 MHz (CDCl3): δ 9.23 (d, J=6.2 Hz, 1H), 7.78 (t, J=12.6 Hz, 1H), 6.78 (t, J=7.4 Hz, 1H), 6.61 (d, J=7.8 Hz, 1H), 5.57 (d, J=12.4 Hz, 1H), 4.01 (s, 3H), 3.04 (brs, 6H), 2.77 (s, 3H). To a solution of Int-2 (2.5 g, 9.6 mmol) in DMF (12 mL) was added Int-3 (4.6 g, 24.0 mmol), followed by K2CO3 (3.9 g, 28.8 mmol) at room temperature. The reaction mixture was heated to 110° C. and then stirred for 16 hours. The reaction mixture was allowed to room temperature, diluted with ice cold water 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 (2.8 g, 75%) as brown solid. Mass (m/z): 390 [M++1]. 1HNMR 200 MHz (dmso-d6): δ 10.12 (s, 1H), 9.31 (d, J==6.2 Hz, 1H), 8.60 (d, J=5.6 Hz, 1H), 7.92-7.86 (m, 4H), 7.19 (d, J=5.4 Hz, 1H), 6.95-6.85 (m, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 2.63 (s, 3H). A mixture of Int-4 (2.8 g, 7.17 mmol) and 4 N HCl (50 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 (2.3 g, 88%) as solid. Mass (m/z): 376 [M++1]. 1HNMR 200 MHz (dmso-d6): δ 10.12 (s, 1H), 9.31 (d, J=6.2 Hz, 1H), 8.60 (d, J=5.6 Hz, 1H), 7.92-7.86 (m, 4H), 7.19 (d, J=5.4 Hz, 1H), 6.95-6.85 (m, 2H), 3.81 (s, 3H), 2.63 (s, 3H). To a stirred suspension of Int-5 (1.0 g, 2.6 mmol) in DMF (8 mL) were added HOBt (0.35 g, 2.6 mmol), EDCI (1.1 g, 5.8 mmol), N-ethyldiisopropylamine (1.1 mL, 6.64 mmol) and o-phenylenediamine (0.28 g, 2.6 mmol) at 0° C. After the completion of addition, the reaction mixture was allowed to room temperature and the stirring was continued for 16 hours. The reaction mixture was diluted with ice cold water (80 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 2% MeOH/DCM to afford the title compound (0.24 g, 20%) as solid. Mass (m/z): 466 [M++1]. 1H NMR (200 MHz, dmso-d6): δ 10.0 (s, 1H), 9.53 (s, 1H), 9.33 (d, J=5.8 Hz, 1H), 8.59 (d, J=5.6 Hz, 1H), 7.93 (brs, 4H), 7.16-7.21 (m, 2H), 7.0-6.85 (m, 3H), 6.77 (d, J=7.2 Hz, 1H), 6.61 (d, J=7.0 Hz, 1H), 4.87 (bs, 2H), 3.95 (s, 3H), 2.63 (s, 3H). 13C NMR (125 MHz, dmso-d6): δ 164.7, 159.2, 158.0, 156.8, 147.7, 145.6, 143.3, 143.0, 139.6, 128.4, 127.0, 126.5, 126.2, 123.6, 120.6, 118.5, 117.8, 116.2, 116.1, 112.7, 110.0, 103.9, 55.8, 16.5.

1. temperatureThe reaction mixture was heated
2. temperatureto reflux
3. concentrationThe volatiles were concentrated under reduced pressure
4. customThe crude material was purified by column chromatography
5. washeluting with 15% EtOAc/hexane
6. customto afford Int-1 (2.5 g, 38%)
7. temperatureat reflux temperature for 48 hours
8. concentrationThe volatile was concentrated under reduced pressure
9. additionThe residue was diluted with diethyl ether
10. stirringstirred for 20 minutes
11. filtrationThe precipitated solid was filtered off
12. washwashed with hexane-ether
13. customdried under vacuum
14. customto afford Int-2 (2.5 g, 81%) as brown color solid
15. stirringstirred for 16 hours
16. customwas allowed to room temperature
17. additiondiluted with ice cold water
18. stirringstirred further for 20 minutes
19. filtrationThe precipitated solid was filtered off
20. washwashed with water (2×10 mL)
21. customdried under vacuum
22. customto afford Int-4 (2.8 g, 75%) as brown solid
23. stirringwas stirred
24. temperatureat reflux temperature for 3 hours
25. temperatureThe reaction mixture was cooled to 0° C.
26. stirringstirred for 20 minutes
27. filtrationThe precipitated solid was filtered off
28. washwashed with water (2×10 mL)
29. customdried under vacuum
30. customto afford Int-5 (2.3 g, 88%) as solid
31. additionAfter the completion of addition
32. customwas allowed to room temperature
33. waitthe stirring was continued for 16 hours
34. stirringstirred for 20 minutes
35. filtrationThe precipitated solid was filtered off
36. washwashed with water (2×10 mL)
37. customdried under vacuum
38. customThe crude material was purified over silica gel column chromatography
39. washeluting with 2% MeOH/DCM

ORD record

ord-bee4604f13484f69aff82add545391d6

Source dataset

uspto-grants-2012_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08124764B2