Lithium Hydroxide → 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid

HRID 1767816Notes

Reaction equation

HRID 1767816 reaction equation
C[O:2][C:3]([C:5]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:19]([F:30])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:7]=2[CH:6]=1)=[O:4].O1CCCC1.O.[Li+].[OH-]>O.Cl.C(OCC)(=O)C.O1CCCC1>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:20]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]3[N:11]([CH2:12][CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][O:14]4)[CH:10]=[N:9][C:8]=3[C:19]=2[F:30])=[C:23]([Cl:29])[CH:24]=1

Participants

7

Reactant 3

HCID 3939Lithium HydroxideHCID 21881883Oxolane--water (1/1)HCID 688190776-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid methyl ester

Product 1

HCID 211141606-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acidYield 100%

Reagents, catalysts & solvents 3

HCID 313Hydrochloric AcidSolventHCID 962WaterSolvent2×HCID 21939870Tetrahydrofuran ethyl acetateSolvent

Procedure

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid methyl ester 11q is suspended in 4:1 tetrahydrofuran/water (2.5 mL) and aqueous 1 M LiOH is added (2.5 mL). After stirring at room temperature for 16 hours, the reaction mixture is homogeneous and the reaction is complete. The reaction mixture is cooled to 0° C., diluted with water and aqueous 2 M HCl is added dropwise until the pH of the solution is 1-2, at which time it turns to a suspension. The reaction mixture is poured into a separatory funnel and diluted with ethyl acetate/tetrahydrofuran and water and the layers separated. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated under reduced pressure to yield 0.11 g (100%) of the pure desired product as a white solid. MS ESI (+) m/z 482, 484 (M+, Br pattern) detected.

Workup

  1. additionis added (2.5 mL)
  2. temperatureThe reaction mixture is cooled to 0° C.
  3. additionis added dropwise until the pH of the solution
  4. additionThe reaction mixture is poured into a separatory funnel
  5. customthe layers separated
  6. extractionThe aqueous layer is extracted with ethyl acetate
  7. washThe combined organic layers are washed with brine
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-c8fb80d76d3840969a1186741dcf529f
Source dataset
uspto-grants-2007_06
Patent number
US07235537B2

Reaction notes

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