Phosphoric Acid → MEK-162

HRID 591120Notes

Reaction equation

HRID 591120 reaction equation
C([O:5][CH2:6][CH2:7][O:8][NH:9][C:10]([C:12]1[C:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=2[F:30])=[C:20]([F:31])[C:15]2[N:16]=[CH:17][N:18]([CH3:19])[C:14]=2[CH:13]=1)=[O:11])(C)(C)C.C(#N)C.P(=O)(O)(O)O>C(O)C.O>[OH:5][CH2:6][CH2:7][O:8][NH:9][C:10]([C:12]1[C:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=2[F:30])=[C:20]([F:31])[C:15]2[N:16]=[CH:17][N:18]([CH3:19])[C:14]=2[CH:13]=1)=[O:11]

Participants

5

Reactant 3

HCID 1004Phosphoric AcidHCID 6342AcetonitrileHCID 737757875-[(4-Bromo-2-fluorophenyl)amino]-N-[2-(1,1-dimethylethoxy)ethoxy]-4-fluoro-1-methyl-1H-benzimidazole-6-carboxamide2×

Product 1

HCID 10288191MEK-162

Reagents, catalysts & solvents 1

HCID 19096565Water ethanolSolvent

Conditions

Temperature
51.5 °C

Procedure

6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid-(2-tert-butoxyethoxy)-amide (Compound 5) monohydrate is added in 3 portions to a premixed solution of Acetonitrile and excess Phosphoric acid (85% aqueous solution) at internal temperature 20-25° C. After stirring for about 15 minutes, the suspension is heated to internal temperature 50-53° C. The suspension is maintained at this temperature for 6 hours, cooled to internal temperature 20-25° C. The mixture is then heated to internal temperature 35-37° C. and diluted with Ethanol-Water (3:1 v/v). EKNS and CEFOK are added, the reaction mixture is stirred approximately 15 minutes and filtered over a funnel coated with CEFOK. The filtrate is cooled to approximately 30° C. 3 N aqueous potassium hydroxide (KOH) is added to the cooled filtrate over a period of 90 minutes until a pH-value of about 8.1 is reached. The suspension is heated to internal temperature 60-63° C., stirred at this temperature for a period of about 2 hours, cooled to 20-23° C. over a period of about 45 minutes, filtered over a funnel, and dried at 50° C. pressure<100 mbar over a period of about 17 hours, providing 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide (Compound A) as a white powder.

Workup

  1. temperatureThe suspension is maintained at this temperature for 6 hours
  2. temperaturecooled to internal temperature 20-25° C
  3. temperatureThe mixture is then heated to internal temperature 35-37° C.
  4. additionEKNS and CEFOK are added
  5. stirringthe reaction mixture is stirred approximately 15 minutes
  6. filtrationfiltered over a funnel
  7. temperatureThe filtrate is cooled to approximately 30° C
  8. addition3 N aqueous potassium hydroxide (KOH) is added to the cooled filtrate over a period of 90 minutes until a pH-value of about 8.1
  9. temperatureThe suspension is heated to internal temperature 60-63° C.
  10. stirringstirred at this temperature for a period of about 2 hours
  11. temperaturecooled to 20-23° C. over a period of about 45 minutes
  12. filtrationfiltered over a funnel
  13. customdried at 50° C. pressure<100 mbar over a period of about 17 hours

Sources & evidence

ORD record
ord-29dfff6394a84daca15a1d614a073396
Source dataset
uspto-grants-2016_01
Patent number
US09238627B2

Reaction notes

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