Hydrochloric Acid → 2-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-n-(2,4-difluorophenyl)nicotinamide, hydrochloride salt

HRID 1986068Notes

Reaction equation

HRID 1986068 reaction equation
FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O.C([C:25]1[CH:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]3[N:55]=[CH:54][CH:53]=[CH:52][C:40]=3[C:41]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][C:45]=3[F:51])=[O:42])=[CH:34][C:33]=2[F:56])[CH:28]=[CH:27][N:26]=1)(=O)N.O.[N:58]1C=CC=CC=1.[ClH:64]>CN(C=O)C>[ClH:64].[NH2:58][C:25]1[CH:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]3[N:55]=[CH:54][CH:53]=[CH:52][C:40]=3[C:41]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][C:45]=3[F:51])=[O:42])=[CH:34][C:33]=2[F:56])[CH:28]=[CH:27][N:26]=1

Participants

7

Reactant 5

HCID 313Hydrochloric Acid2×HCID 962WaterHCID 1049PyridineHCID 12041285BistrifluoroacetoxyiodobenzeneHCID 577213642-(4-(2-Carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)nicotinamide

Product 1

HCID 162231052-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-n-(2,4-difluorophenyl)nicotinamide, hydrochloride saltYield 35%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

Bis(trifluoroacetoxy)iodobenzene (0.10 g, 0.23 mmol) was added to a solution of 2-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)nicotinamide (0.080 g, 0.17 mmol), water (0.006 g, 0.33 mmol) and pyridine (0.27 mL, 3.33 mmol) in anhydrous DMF (5 mL) at room temperature. The reaction mixture was stirred for 69 hours before 6N aq HCl (2 mL) was added and the reaction stirred for an additional fifteen minutes. The mixture was extracted twice with Et2O and the combined organic layers discarded. The aqueous layer was neutralized with 1M NaHCO3(aq) then extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The resultant residue was purified by preparative HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 34% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and lyophilized to an off-white solid that was dissolved in anhydrous THF (2 mL), cooled to 0° C. and treated with HCl (4N in dioxane, 1.0 mL, 4.0 mmol). The reaction mixture was stirred for ten minutes, before being lyophilized to afford the title compound (0.029 g, 35%) as an off-white solid. 1H NMR (DMSO-d6) δ 10.72 (s, 1H), 10.49 (s, 1H), 8.32-8.40 (m, 2H), 8.13 (dd, 1H, J=13.7, 2.4 Hz), 7.82-7.92 (m, 3H), 7.29-7.53 (m, 4H), 7.05-7.15 (m, 1H), 6.97-7.01 (m, 1H), 6.64-6.66 (m, 1H), 6.12 (d, 1H, J=2.4 Hz); HRMS(ESI+), 452.1334 (M+H)+ calc, 452.1341 (M+H)+ found.

Workup

  1. additionwas added
  2. extractionThe mixture was extracted twice with Et2O
  3. extractionthen extracted with EtOAc
  4. dry with materialThe combined organic layers were dried over anhydrous MgSO4
  5. concentrationconcentrated in vacuo
  6. customThe resultant residue was purified by preparative HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 34% to 90% aqueous methanol with 0.1% TFA)
  7. dissolutionthat was dissolved in anhydrous THF (2 mL)
  8. stirringThe reaction mixture was stirred for ten minutes

Sources & evidence

ORD record
ord-2822422df8ec4956add3b17681e2c0d0
Source dataset
uspto-grants-2009_06
Patent number
US07547782B2

Reaction notes

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