反应详情

温度

100 °C

To a stirred suspension of 4-amino-2-fluoro benzoic acid (3.0 g, 19.30 mmol) and the mixture of conc. HCl/water (2.7 mL/16.5 mL) was added cyanamide (1.86 g, 44.4 mmol) at room temperature. The reaction mixture was heated at 100° C. for 7 hours and then allowed to stand at room temperature (without stirring) for 16 hours. The precipitated solid was filtered off, washed with water and dried under vacuum to afford Int-1 (3.0 g, 78%) as a salt. Mass (m/z): 198 [M++1]. 1H NMR (200 MHz, dmso-d6): δ 7.99 (brs, 5H), 7.70 (t, J=8.4 Hz, 1H), 6.91-6.85 (m, 2H). To a stirred suspension of Int-1 (3.0 g, 15.2 mmol) in methanol (15 mL) was added acetyl chloride (16.2 mL, 22.8 mmol) drop wise at 0° C. over a period of 20 minutes. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized using NaHCO3 at 0° C. The precipitated solid was filtered off and the filtrate was concentrated under vacuum to get crude compound. The crude compound was washed with EtOAc (100 mL) to afford Int-2 (2.8 g, 87%) as white solid. Mass (m/z): 212 [M++1]. 1H NMR (200 MHz, dmso-d6): δ 8.16 (brs, 5H), 7.89 (t, J=8.6 Hz, 1H), 7.23-7.12 (m, 2H), 3.8 (s, 3H). To a stirred solution of Int-3 (1.0 g, 4.30 mmol), guanidine ester-2 (2.0 g, 9.6 mmol) in DMF (7.0 mL) was added K2CO3 (1.5 g, 10.9 mmol) at room temperature. The reaction mixture was heated at 130° C. for 16 hours. After the reaction completion, the reaction mixture was allowed to room temperature, poured into ice cold water (40 mL) and stirred for 30 minutes. The precipitated solid was filtered off, washed with water (3×5 mL) and dried under vacuum to get crude product. The crude material was purified by silica gel column chromatography eluting with 1% MeOH/DCM to afford Int-4 (0.7 g, 42%) as solid. Mass (m/z): 378 [M++1]. 1H NMR (200 MHz, dmso-d6): δ 10.31 (brs, 1H), 9.73 (d, J=6 Hz, 1H), 8.63 (d, J=5.6 Hz, 1H), 7.93-7.84 (m, 3H), 7.63-7.83 (m, 3H), 7.24 (d, J=5.4 Hz, 1H), 7.18-7.01 (m, 1H). To a stirred solution of Int-4 (0.7 g, 1.85 mmol) in methanol (5.0 mL), THF (5.0 mL) and water (3.0 mL) was added lithium hydroxide monohydrate (0.23 g, 5.57 mmol) at room temperature and then stirred for 16 hours. The volatiles were concentrated under vacuum. The residue was diluted with water (30 mL) and acidified to about pH 5 using 1 N HCl at 0° C. and stirred further for 30 minutes. The precipitated solid was filtered off, washed with water (2×30 mL) and dried under vacuum to afford Int-5 (0.559 g, 82%) as solid. Mass (m/z): 363 [M++1]. 1H NMR (200 MHz, dmso-d6): δ 10.47 (brs, 1H), 9.79 (d, J=6.8 Hz, 1H), 8.76 (d, J=5.6 Hz, 1H), 7.96-7.78 (m, 4H), 7.55 (d, J=8.4 Hz, 1H), 7.46 (t, J=5.4 Hz, 1H), 7.33 (d, J=5.6 Hz, 1H). To a stirred suspension of Int-5 (0.6 g, 1.65 mmol) in DMF (8 mL) was added EDCI (0.697 g, 3.60 mmol), HOBt (0.222 g, 1.65 mmol) and N-ethyldiisopropylamine (0.74 mL, 4.1 mmol) at 0° C. under inert atmosphere. After being stirred for 15 minutes at the same temperature, NH2OTHP (0.386 g, 3.3 mmol) was added to the reaction mixture at 0° C. The reaction mixture was allowed to warm to room temperature and stirred further for 16 hours. Reaction mixture was diluted with water (50 mL) and stirred for 30 minutes. The aqueous layer was extracted with DCM (3×50 mL) and the combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified over silica gel column chromatography eluting with 2.5% MeOH/DCM to afford Int-6 (0.395 g, 51%) as off-white solid.

1. customto stand at room temperature
2. filtrationThe precipitated solid was filtered off
3. washwashed with water
4. customdried under vacuum
5. customto afford Int-1 (3.0 g, 78%) as a salt
6. stirringThe reaction mixture was stirred at room temperature for 16 hours
7. customat 0° C
8. filtrationThe precipitated solid was filtered off
9. concentrationthe filtrate was concentrated under vacuum
10. customto get crude compound
11. washThe crude compound was washed with EtOAc (100 mL)
12. customto afford Int-2 (2.8 g, 87%) as white solid
13. temperatureThe reaction mixture was heated at 130° C. for 16 hours
14. customwas allowed to room temperature
15. stirringstirred for 30 minutes
16. filtrationThe precipitated solid was filtered off
17. washwashed with water (3×5 mL)
18. customdried under vacuum
19. customto get crude product
20. customThe crude material was purified by silica gel column chromatography
21. washeluting with 1% MeOH/DCM
22. customto afford Int-4 (0.7 g, 42%) as solid
23. stirringstirred for 16 hours
24. concentrationThe volatiles were concentrated under vacuum
25. additionThe residue was diluted with water (30 mL)
26. customat 0° C.
27. stirringstirred further for 30 minutes
28. filtrationThe precipitated solid was filtered off
29. washwashed with water (2×30 mL)
30. customdried under vacuum
31. customto afford Int-5 (0.559 g, 82%) as solid
32. additionwas added to the reaction mixture at 0° C
33. temperatureto warm to room temperature
34. stirringstirred further for 16 hours
35. customReaction mixture
36. stirringstirred for 30 minutes
37. extractionThe aqueous layer was extracted with DCM (3×50 mL)
38. dry with materialthe combined organic layer was dried over Na2SO4
39. concentrationconcentrated under reduced pressure
40. customThe crude material was purified over silica gel column chromatography
41. washeluting with 2.5% MeOH/DCM
42. customto afford Int-6 (0.395 g, 51%) as off-white solid