Dichloroacetic Acid → Ro-4987655

HRID 20758Notes

Reaction equation

HRID 20758 reaction equation
[F:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][CH2:20][CH2:21][C:22](=[O:25])NC)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].ClC(Cl)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:4]([CH:12]=[C:13]([CH2:16][N:17]2[C:22](=[O:25])[CH2:21][CH2:20][CH2:19][O:18]2)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]

Participants

4

Reactant 2

HCID 6597Dichloroacetic AcidHCID 231323693,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(E)-[4-(methylamino)-4-oxobutoxy]iminomethyl]benzamide

Product 1

HCID 11548630Ro-4987655Yield 91%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(E)-3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl-propoxyimino)-methyl]-benzamide (8.0 g, 13.5 mmol) obtained in Step C of Example 28 was suspended in methylene chloride (240 ml), and borane-pyridine complex (5.45 ml, 53.8 mmol) and dichloroacetic acid (6.65 ml, 80.8 mmol) were added thereto at room temperature. The reaction mixture was stirred at room temperature for 15 hours, and dichloromethane was removed under reduced pressure with a rotary evaporator. The residue was diluted with 1,2-dichloroethane (240 ml), and the mixture was stirred at 60° C. for 8 hours, and filtered. The residue obtained by concentrating the filtrate was diluted with ethyl acetate (800 ml), and washed sequentially with water (400 ml), saturated aqueous sodium bicarbonate (400 ml), and saturated brine (400 ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH (25:1)) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-[1,2]oxazinan-2-ylmethyl)-benzamide (Compound G-1, 6.93 g, 91% yield).

Workup

  1. customat room temperature
  2. customdichloromethane was removed under reduced pressure with a rotary evaporator
  3. additionThe residue was diluted with 1,2-dichloroethane (240 ml)
  4. stirringthe mixture was stirred at 60° C. for 8 hours
  5. filtrationfiltered
  6. customThe residue obtained
  7. concentrationby concentrating the filtrate
  8. additionwas diluted with ethyl acetate (800 ml)
  9. washwashed sequentially with water (400 ml), saturated aqueous sodium bicarbonate (400 ml), and saturated brine (400 ml)
  10. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  11. concentrationconcentrated under reduced pressure
  12. customThe residue was purified by silica gel column chromatography (CH2Cl2/MeOH (25:1))

Sources & evidence

ORD record
ord-319e69871efa4a0ebc0f68175d777ccb
Source dataset
uspto-grants-2010_06
Patent number
US07745663B2

Reaction notes

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