Hydrochloric Acid → HCID 131727490, compound

HRID 1986103Notes

Reaction equation

HRID 1986103 reaction equation
[ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1.[Cl:37][C:38]1[N:47]=[CH:46][CH:45]=[CH:44][C:39]=1[C:40]([NH:42][CH3:43])=[O:41].Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>O.C(O)(C)C.CN1C(=O)CCC1>[ClH:37].[ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:38]4[N:47]=[CH:46][C:45]([Cl:1])=[CH:44][C:39]=4[C:40]([NH:42][CH3:43])=[O:41])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 516892Sodium BicarbonateHCID 122869552-Chloro-N-methylnicotinamideHCID 162230054-(4-(1h-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-n-(2,4-difluorophenyl)nicotinamide, hydrochloride salt2×

Product 1

HCID 131727490HCID 131727490, compoundYield 99%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 68474125HCID 68474125, compoundSolvent

Conditions

Temperature
100 °C

Procedure

4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (70 mg, 0.29 mmol, Compound C of Example 1) and 2-chloro-N-methylnicotinamide (59 mg, 0.29 mmol) were suspended in 3:1 isopropanol-NMP (2.9 mL). 4N HCl in 1,4-dioxane (0.22 mL, 0.86 mmol) was added and the reaction was heated to 100° C. for 168 h. The reaction was diluted with 30 mL of H2O and then basified with sat. aq. NaHCO3 soln. (5 mL). The aqueous layer was extracted EtOAc (3×10 mL). The combined organic layers were washed with 10% LiCl (15 mL), dried (MgSO4) and concentrated. The crude product was purified by preparative (RP) HPLC chromatography (YMC S5 ODS, 30×75 mm, 10 minute gradient from 33% to 90% aqueous methanol with 0.1% TFA, 40 mL/min). The fractions containing the desired product were combined and concentrated. The product residue was dissolved in MeOH (2 mL) and acidified with 4N HCl in 1,4-dioxane (0.10 mL). Concentration afford the desired product as a brown solid (3.3 mg, >99% HPLC purity). 1H NMR (CD3OD) δ 8.33 (d, 1H, J=2.54 Hz), 8.31 (d, 1H, J=7.12 Hz), 8.17 (dd, 1H, J=13.48, 2.29 Hz), 8.09 (d, 1H, J=2.03 Hz), 7.56 (d, 1H, J=3.56 Hz), 7.33-7.43 (m, 2H), 6.91 (d, 1H, J=6.61 Hz), 6.68 (d, 1H, J=3.56 Hz), 2.93 (s, 3H); MS(ESI+) m/z 412.2 (M+H)+.

Workup

  1. extractionThe aqueous layer was extracted EtOAc (3×10 mL)
  2. washThe combined organic layers were washed with 10% LiCl (15 mL)
  3. dry with materialdried (MgSO4)
  4. concentrationconcentrated
  5. customThe crude product was purified by preparative (RP) HPLC chromatography (YMC S5 ODS, 30×75 mm, 10 minute gradient from 33% to 90% aqueous methanol with 0.1% TFA, 40 mL/min)
  6. additionThe fractions containing the desired product
  7. concentrationconcentrated
  8. dissolutionThe product residue was dissolved in MeOH (2 mL)
  9. concentrationConcentration

Sources & evidence

ORD record
ord-43dcb8ea0fa149bb94df7d6556cef67b
Source dataset
uspto-grants-2009_06
Patent number
US07547782B2

Reaction notes

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