Trifluoroacetic acid → 5-(Tert-butoxycarbonylamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid

HRID 2038651Notes

Reaction equation

HRID 2038651 reaction equation
[C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[F:23][C:24]1[C:25]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:38]=2[F:44])=[C:26]([CH:30]=[C:31]([CH:34]=O)[C:32]=1[F:33])[C:27]([OH:29])=[O:28]>C(#N)C>[C:4]([O:3][C:1]([NH:2][CH2:34][C:31]1[C:32]([F:33])=[C:24]([F:23])[C:25]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:38]=2[F:44])=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28])=[O:8])([CH3:7])([CH3:6])[CH3:5]

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 12052TriethylsilaneHCID 77922tert-Butyl carbamateHCID 231323253,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-5-formyl-benzoic acid

Product 1

HCID 866343665-(Tert-butoxycarbonylamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

tert-Butyl carbamate (commercially available, 187 mg, 1.602 mmol), trifluoroacetic acid (123 μL, 1.602 mmol), and triethylsilane (255 μL, 1.602 mmol) were added sequentially to a suspension of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-benzoic acid (225 mg, 0.534 mmol) obtained in Step A of Example 5 in acetonitrile (anhydrous, 20 mL). The mixture was stirred at room temperature for 5 days. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, and the resultant residue was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resultant crude product was purified by silica gel flash chromatography (Mega Bond Elut, Varian, 5% methanol/methylene chloride as an eluent) to give 5-(tert-butoxycarbonylamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid. [LC/MS m/z 523 (M+1)]. Then, trifluoroacetic acid (0.5 mL) was added to a solution of the resultant product in methylene chloride (20 mL), and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, and the resultant residue was recrystallized from a mixed solvent of diethyl ether:hexane (1:1) to give 5-aminomethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid trifluoroacetate (285 mg, 99% in 2 steps) as white crystals.

Workup

  1. customAfter completion of the reaction
  2. customthe reaction mixture was evaporated under reduced pressure
  3. extractionthe resultant residue was extracted with ethyl acetate
  4. washThe organic layer was washed sequentially with water and saturated brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. customevaporated under reduced pressure
  7. customThe resultant crude product was purified by silica gel flash chromatography (Mega Bond Elut, Varian, 5% methanol/methylene chloride as an eluent)

Sources & evidence

ORD record
ord-0932d7c315fb4a2cb2c9318da694bcb9
Source dataset
uspto-grants-2013_11
Patent number
US08575391B2

Reaction notes

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