Hydrochloric Acid → 2-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)-4-methoxynicotinamide

HRID 1986090Notes

Reaction equation

HRID 1986090 reaction equation
Cl.[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[C:38]1[N:54]=[CH:53][CH:52]=[C:51]([O:55][CH3:56])[C:39]=1[C:40]([NH:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[F:50])=[O:41].Cl>CN1C(=O)CCC1>[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:54]=[CH:53][CH:52]=[C:51]([O:55][CH3:56])[C:39]=4[C:40]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=4[F:50])=[O:41])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]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:54]=[CH:53][CH:52]=[C:51]([OH:55])[C:39]=4[C:40]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=4[F:50])=[O:41])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 162230054-(4-(1h-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-n-(2,4-difluorophenyl)nicotinamide, hydrochloride salt2×HCID 577213242-Chloro-N-(2,4-difluorophenyl)-4-methoxynicotinamide

Product 2

HCID 162233072-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)-4-methoxynicotinamideHCID 178522147HCID 178522147, compound

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
140 °C

Procedure

To a homogeneous mixture of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.037 g, 0.15 mmol, Compound C of Example 1) and 2-chloro-N-(2,4-difluorophenyl)-4-methoxynicotinamide (0.045 g, 0.15 mmol), in anhydrous NMP (0.50 mL), was added HCl (4N in 1,4-dioxane, 0.15 mL, 0.60 mmol). The mixture was microwaved in a CEM Explorer PLS microwave system (300 W), with the temperature measured with an IR temperature sensor and maintained at 140° C. for six hours. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were concentrated in vacuo. The resultant residue was purified by preparative (RP) HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 50% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and concentrated in vacuo to afford 2-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)-4-methoxynicotinamide (Example 15) (0.006 g) as an off-white solid and 2-(4-(1H-pyrrolo[2,3-b]pyridine-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)-4-hydroxynicotinamide (Example 16) (0.042 g) as a white solid.

Workup

  1. customThe mixture was microwaved in a CEM Explorer PLS microwave system (300 W), with the temperature
  2. customThe reaction mixture was partitioned between water and EtOAc
  3. extractionThe aqueous layer was extracted twice with EtOAc
  4. concentrationthe combined organic layers were concentrated in vacuo
  5. customThe resultant residue was purified by preparative (RP) HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 50% to 90% aqueous methanol with 0.1% TFA)
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-e86db9282d6c40cb8d01201075342432
Source dataset
uspto-grants-2009_06
Patent number
US07547782B2

Reaction notes

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