4-Aminobutyric acid methyl ester hydrochloride → 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-pyrrolidin-1-ylmethyl)-benzamide

HRID 2038649Notes

Reaction equation

HRID 2038649 reaction equation
Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.C([BH3-])#N.[Na+].[F:14][C:15]1[C:16]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])=[C:17]([CH:25]=[C:26]([CH:29]=O)[C:27]=1[F:28])[C:18]([NH:20][O:21][CH2:22][CH2:23][OH:24])=[O:19]>CO>[F:14][C:15]1[C:16]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])=[C:17]([CH:25]=[C:26]([CH2:29][N:2]2[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[C:27]=1[F:28])[C:18]([NH:20][O:21][CH2:22][CH2:23][OH:24])=[O:19]

Participants

5

Reactant 3

HCID 27563834-Aminobutyric acid methyl ester hydrochlorideHCID 5003444Sodium cyanoborohydrideHCID 231323883,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide

Product 1

HCID 116281483,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-pyrrolidin-1-ylmethyl)-benzamideYield 47%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Methyl 4-amino-butyrate hydrochloride (commercially available, 48 mg, 0.312 mmol) and sodium cyanoborohydride (20 mg, 0.312 mmol) were added to a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (50 mg, 0.104 mmol) obtained in Step F of Example 1 in methanol (2.0 mL). The mixture was stirred at room temperature for 18 hours. Then, the reaction vessel was equipped with a reflux condenser, and the mixture was heated at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (Mega Bond Elut, Varian, 5% methanol/methylene chloride as an eluent) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-pyrrolidin-1-ylmethyl)-benzamide (Compound H-3, 26.8 mg, 47%) as a white solid.

Workup

  1. customThen, the reaction vessel was equipped with a reflux condenser
  2. temperaturethe mixture was heated at 80° C. for 2 hours
  3. customAfter completion of the reaction
  4. extractionthe reaction mixture was extracted with ethyl acetate
  5. washthe organic layer was washed sequentially with water and saturated brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationconcentrated under reduced pressure
  8. customThe resultant residue was purified by silica gel flash chromatography (Mega Bond Elut, Varian, 5% methanol/methylene chloride as an eluent)

Sources & evidence

ORD record
ord-24d85250b8524999978ad8131f3eb423
Source dataset
uspto-grants-2013_11
Patent number
US08575391B2

Reaction notes

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