Methane → CJ 023423

HRID 2422415Notes

Reaction equation

HRID 2422415 reaction equation
[CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH3:12])[C:6]=2[N:13]=1)[CH3:2].[S:23]([N:33]=[C:34]=[O:35])([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C>C(Cl)Cl>[CH2:1]([C:3]1[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:34]([NH:33][S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[O:35])=[CH:18][CH:19]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH3:12])[C:6]=2[N:13]=1)[CH3:2]

Participants

5

Reactant 3

HCID 297MethaneHCID 77703p-Toluenesulfonyl isocyanateHCID 21875878HCID 21875878, compound

Product 1

HCID 11677589CJ 023423Yield 41.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a clean and dry 12 L 3-neck round-bottom flask were charged 2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanamine (422 g, 1.43 moles) and CH2Cl2 (3.37 L). Tosyl isocyanate (217 mL, 1.43 moles) dissolved in CH2Cl2 (851 mL) was added to the reaction keeping the temperature below 21° C. and was stirred for at least 90 minutes. The reaction was deemed complete by HPLC and activated charcoal (DARCO KB-B, 4.2 g) was added. The resulting slurry was filtered through a 0.5-micron filter into a speck free 5 L 3-neck round-bottom flask and the filter washed with CH2Cl2 (421 mL). The reaction was atmospherically concentrated to a minimum stirable volume and displacement continued with speck freed acetone until an internal temperature of 58° C. to 62° C. was achieved and final volume was ˜1.3 L. The reaction was cooled to at least 30° C. and seed of N-[({2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide Polymorph Form A was added. The reaction was allowed to granulate between 20° C. and 25° C. for at least 10 hours. After cooling reaction to 0° C. to 5° C. and granulating for at least 2 hours, the reaction was filtered on a speck free filter. The solids were washed two times with speck free acetone (1.68 L) cooled to 0° C. to 5° C. The wet-cake was returned to a speck free 12 L 3-neck round-bottom flask and speck free ethyl acetate (4.4 L) was added. The slurry was heated to at least 75° C. and held for at least 2 hours. The reaction was cooled to at least 30° C. and the solids were filtered on a speck free filter. The solids were washed with speck free ethyl acetate (1.6 L). The wet-cake was returned to the same speck free 12 L 3-neck round-bottom flask and speck free ethyl acetate (4.4 L) was added. The slurry was heated to at least 75° C. and held for at least 2 hours. The reaction was cooled to at least 30° C. and the solids were filtered on a speck free filter. The solids were washed with speck free ethyl acetate (1.6 L). The product was dried at 45° C. to 50° C. for at least 24 hours to yield 289 g the title product, Polymorph Form A (41.4% yield, 98.68% purity by HPLC).

Workup

  1. customTo a clean and dry 12 L 3-neck round-bottom flask
  2. additionwas added to the reaction
  3. customthe temperature below 21° C.
  4. additionwas added
  5. filtrationThe resulting slurry was filtered through a 0.5-micron
  6. filtrationfilter into a speck free 5 L
  7. washround-bottom flask and the filter washed with CH2Cl2 (421 mL)
  8. concentrationThe reaction was atmospherically concentrated to a minimum stirable volume and displacement
  9. customuntil an internal temperature of 58° C. to 62° C.
  10. temperatureThe reaction was cooled to at least 30° C.
  11. additionseed of N-[({2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide Polymorph Form A was added
  12. waitto granulate between 20° C. and 25° C. for at least 10 hours
  13. temperatureAfter cooling
  14. customreaction to 0° C. to 5° C.
  15. waitgranulating for at least 2 hours
  16. filtrationthe reaction was filtered on a speck free filter
  17. washThe solids were washed two times with speck free acetone (1.68 L)
  18. temperaturecooled to 0° C. to 5° C
  19. customround-bottom flask and speck free
  20. additionethyl acetate (4.4 L) was added
  21. temperatureThe slurry was heated to at least 75° C.
  22. waitheld for at least 2 hours
  23. temperatureThe reaction was cooled to at least 30° C.
  24. filtrationthe solids were filtered on a speck free filter
  25. washThe solids were washed
  26. customround-bottom flask and speck free
  27. additionethyl acetate (4.4 L) was added
  28. temperatureThe slurry was heated to at least 75° C.
  29. waitheld for at least 2 hours
  30. temperatureThe reaction was cooled to at least 30° C.
  31. filtrationthe solids were filtered on a speck free filter
  32. washThe solids were washed
  33. customThe product was dried at 45° C. to 50° C. for at least 24 hours

Sources & evidence

ORD record
ord-a1f49e7d34ca4f78bec8b56f5303f965
Source dataset
uspto-grants-2011_06
Patent number
US07960407B2

Reaction notes

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