Hydrochloric Acid → Sorafenib Impurity 43

HRID 658477Notes

Reaction equation

HRID 658477 reaction equation
CN[C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[OH-:19].[K+].Cl.[CH3:22][Si](Cl)(C)C>C(O)C.O>[CH3:22][O:19][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 6397ChlorotrimethylsilaneHCID 14797Potassium HydroxideHCID 166551294-(4-Aminophenoxy)-N-methylpicolinamide

Product 1

HCID 57833322Sorafenib Impurity 43Yield 42%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 4-(4-Aminophenoxy)pyridine-2-carboxylic acid methylamide (15.0 g, 61.7 mmol) and potassium hydroxide (34.6 g, 617 mmol) in ethanol (400 mL) and water (40 mL) was stirred at 90° C. for 48 h. After cooling to RT, 2.0 N hydrochloric acid was slowly added to the reaction mixture until pH=5. The solvent was removed completely and the residue redissolved in MeOH (400 mL). After slow addition of trimethylsilylchloride (178 mL, 140 mmol, 2.27 eq) at 0° C., the reaction mixture was stirred at reflux for 24 h and cooled to RT. The mixture was filtered, and the filtrate concentrated under reduced pressure and then partitioned between DCM and water. The organic layer was then washed with 1M aqueous sodium bicarbonate solution, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue was washed further with H2O and reextracted with EtOAc/Hex (1:2 v/v) to afford the desired ester (6.27 g, 42%) as a light brown solid. 1H-NMR (DMSO-d6) δ 8.51 (d, J=5.7 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H), 7.10 (dd, J=5.7, 2.7 Hz, 1H), 6.86 (dt, J=9.0, 2.4 Hz, 2H), 6.63 (dt, J=8.7, 2.4 Hz, 2H), 5.18 (br s, 2H), 3.86 (s, 3H); MS LC-MS [M+H]+=245, RT=1.04 min; TLC (75% EtOAc/hex), Rf=0.20.

Workup

  1. temperatureAfter cooling to RT
  2. customThe solvent was removed completely
  3. dissolutionthe residue redissolved in MeOH (400 mL)
  4. stirringthe reaction mixture was stirred
  5. temperatureat reflux for 24 h
  6. temperaturecooled to RT
  7. filtrationThe mixture was filtered
  8. concentrationthe filtrate concentrated under reduced pressure
  9. custompartitioned between DCM and water
  10. washThe organic layer was then washed with 1M aqueous sodium bicarbonate solution
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. customevaporated under reduced pressure
  14. washThe resulting residue was washed further with H2O

Sources & evidence

ORD record
ord-7fdb3186ff0a4fcc826a136845854382
Source dataset
uspto-grants-2011_12
Patent number
US08076488B2

Reaction notes

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