Hydrochloric Acid → 2-(4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)nicotinic acid

HRID 1986087Notes

Reaction equation

HRID 1986087 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.F[C:38]1[N:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40]([OH:42])=[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:46]=[CH:45][CH:44]=[CH:43][C:39]=4[C:40]([OH:42])=[O:41])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 960892-Fluoronicotinic acidHCID 162230054-(4-(1h-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-n-(2,4-difluorophenyl)nicotinamide, hydrochloride salt2×

Product 1

HCID 577213212-(4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)nicotinic acidYield 85%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
120 °C

Procedure

To a homogeneous mixture of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.10 g, 0.42 mmol, Compound C of Example 1) and 2-fluoronicotinic acid (Aldrich, 0.084 g, 0.59 mmol), in anhydrous NMP (0.50 mL), was added HCl (4N in 1,4-dioxane, 0.42 mL, 1.7 mmol). The mixture was microwaved in a CEM Explorer PLS microwave system (300 W). The temperature was measured with an IR temperature sensor and maintained at 120° C. for two hours followed by 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 the desired compound (0.13 g, 82%) as an off-white solid. 1H NMR (DMSO-d6) δ 13.75 (br s, 1H), 12.11 (s, 1H), 10.60 (s, 1H), 8.40 (dd, 1H, J=4.7, 1.9 Hz), 8.24 (dd, 1H, J=7.7, 1.9 Hz), 8.10-8.20 (m, 2H), 7.30-7.49 (m, 3H), 6.90 (dd, 1H, J=7.7, 4.8 Hz), 6.48 (d, 1H, J=5.8 Hz), 6.31-6.40 (m, 1H); HRMS(ESI+), 365.1050 (M+H)+ calc, 365.1038 (M+H)+ found.

Workup

  1. customThe mixture was microwaved in a CEM Explorer PLS microwave system (300 W)
  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-43e71515500b4413903654e56d744c72
Source dataset
uspto-grants-2009_06
Patent number
US07547782B2

Reaction notes

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