Ammonia → 6-[(Aminocarbonyl)(2,6-difluorophenyl)amino]-2-(2,4-difluorophenyl)-3-pyridinecarboxamide

HRID 2390950Notes

Reaction equation

HRID 2390950 reaction equation
ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[N:29]=[C:28]([NH:30][C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].C([N:42](C(C)C)CC)(C)C.[NH3:48]>C1COCC1>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[N:29]=[C:28]([N:30]([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])[C:5]([NH2:42])=[O:11])[CH:27]=[CH:26][C:22]=1[C:23]([NH2:48])=[O:24]

Participants

6

Reactant 4

HCID 222AmmoniaHCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 21939656HCID 21939656, compound

Product 1

HCID 103411546-[(Aminocarbonyl)(2,6-difluorophenyl)amino]-2-(2,4-difluorophenyl)-3-pyridinecarboxamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-30 °C

Procedure

Triphosgene (38.87 g, 0.1276 mol, 0.9 eq) and Compound 9 (51.14 g, 0.1412 mo, 1 eq.) were charged to a reactor. Anhydrous THF (486 mL, 9.5 vol) was then added and the clear solution was cooled to −30±5° C. Diisopropylethylamine (73.79 mL, 0.424 mol, 3.0 eq) in THF (103 mL, 2.5 vol) was charged to the reactor keeping the temperature below −20° C. After addition, the reaction mixture was warmed to 20±3° C. The mixture was stirred for 2 hours and was then filtered through Celite®, and the cake was rinsed with THF (767 mL, 15 vol). The filtrate was cooled to −30° C. and anhydrous NH3 (3 equiv.) added. The resulting white slurry was purged with N2 and warmed up to 20±3° C. for 1 hour. The reaction mixture was then cooled to 0±5° C. for 30 minutes. The mixture was again filtered and the reactor was rinsed with THF (255 mL, 5 vol). The cake was rinsed with H2O (255 mL, 5.0 vol) followed by 1N H2SO4 (10 vol). The solid was then transferred to a vacuum oven and dried at 35±3° C. to give the title Compound, 10, as a white solid. (1H NMR, 500 MHz; DMSO-d6) δ 7.97 (d, 1H), 7.85 (s, 1H), 7.56 (quin, 1H), 7.45 (q, 1H), 7.40 (s, 2H), 7.28 (t, 3H), 7.15 (td, 1H), 7.06 (d, 1H).

Workup

  1. customthe temperature below −20° C
  2. additionAfter addition
  3. temperaturethe reaction mixture was warmed to 20±3° C
  4. filtrationwas then filtered through Celite®
  5. washthe cake was rinsed with THF (767 mL, 15 vol)
  6. temperatureThe filtrate was cooled to −30° C.
  7. customThe resulting white slurry was purged with N2
  8. temperaturewarmed up to 20±3° C. for 1 hour
  9. temperatureThe reaction mixture was then cooled to 0±5° C. for 30 minutes
  10. filtrationThe mixture was again filtered
  11. washthe reactor was rinsed with THF (255 mL, 5 vol)
  12. washThe cake was rinsed with H2O (255 mL, 5.0 vol)
  13. customdried at 35±3° C.

Sources & evidence

ORD record
ord-2cae77c54db4457b8b197fb94e0fa414
Source dataset
uspto-grants-2012_09
Patent number
US08273896B2

Reaction notes

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