Hydrochloric Acid → 4-(4-(1h-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-n-(2,4-difluorophenyl)nicotinamide, hydrochloride salt

HRID 1986063Notes

Reaction equation

HRID 1986063 reaction equation
[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[F:18])=[C:4]2[CH:3]=[CH:2]1.[Cl:19][C:20]1[C:25]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[O:27])=[CH:24][N:23]=[CH:22][CH:21]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>CN1C(=O)CCC1>[ClH:19].[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:20]4[C:25]([C:26]([NH:28][C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=5[F:36])=[O:27])=[CH:24][N:23]=[CH:22][CH:21]=4)=[CH:13][C:12]=3[F:18])=[C:4]2[CH:3]=[CH:2]1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 521998p-Toluenesulfonic acid monohydrateHCID 587732Pyridine-3-carboxamide, 4-chloro-N-(2,4-difluorophenyl)-HCID 160379654-((1H-Pyrrolo[2,3-B]pyridin-4-YL)oxy)-3-fluoroaniline

Product 1

HCID 162230054-(4-(1h-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-n-(2,4-difluorophenyl)nicotinamide, hydrochloride saltYield 18.3%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
160 °C

Procedure

A homogeneous mixture of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.039 g, 0.16 mmol), 4-chloro-N-(2,4-difluorophenyl)nicotinamide (0.043 g, 0.16 mmol) and p-toluenesulfonic acid monohydrate (Aldrich, 0.024 g, 0.13 mmol), in anhydrous NMP (1 mL), was microwaved in a CEM Explorer PLS microwave system (300 W). The temperature was measured with an IR temperature sensor and maintained at 160° C. After one hour, the reaction mixture was partitioned between chloroform and brine. The aqueous layer was extracted twice with chloroform, and the combined organic layers were 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 (1 mL), cooled to 0° C. and treated with HCl (4 N in dioxane, 1.0 mL, 4.0 mmol). The reaction mixture was stirred for ten minutes, before being lyophilized to afford the title compound (0.015 g, 18%) as an off-white solid.

Workup

  1. customthe reaction mixture was partitioned between chloroform and brine
  2. extractionThe aqueous layer was extracted twice with chloroform
  3. concentrationthe combined organic layers were concentrated in vacuo
  4. 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)
  5. dissolutionthat was dissolved in anhydrous THF (1 mL)
  6. temperaturecooled to 0° C.

Sources & evidence

ORD record
ord-1a5e511f99c144848e617b5287a3e992
Source dataset
uspto-grants-2009_06
Patent number
US07547782B2

Reaction notes

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