Sodium Methoxide → 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-{[(2-hydroxy-acetyl)-methoxy-amino]-methyl}-N-(2-hydroxy-ethoxy)-benzamide

HRID 20768Notes

Reaction equation

HRID 20768 reaction equation
COC(=O)C[C:5](=[O:34])[N:6]([CH2:9][C:10]1[CH:15]=[C:14]([C:16](=[O:22])[NH:17][O:18][CH2:19][CH2:20][OH:21])[C:13]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:12]([F:32])[C:11]=1[F:33])[O:7][CH3:8].[CH3:36][O-:37].[Na+]>CO.[Cl-].[NH4+]>[F:32][C:12]1[C:13]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:14]([CH:15]=[C:10]([CH2:9][N:6]([C:5](=[O:34])[CH2:36][OH:37])[O:7][CH3:8])[C:11]=1[F:33])[C:16]([NH:17][O:18][CH2:19][CH2:20][OH:21])=[O:22]

Participants

5

Reactant 2

HCID 10942334Sodium MethoxideHCID 86634365{[2,3-Difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-benzyl]-methoxy-carbamoyl}acetic acid methyl ester

Product 1

HCID 117068243,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-{[(2-hydroxy-acetyl)-methoxy-amino]-methyl}-N-(2-hydroxy-ethoxy)-benzamideYield 44.5%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 25517Ammonium ChlorideSolvent

Procedure

To a solution of acetoxyacetic acid (13.9 mg, 0.12 mmol) in methylene chloride (1 ml) were added 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (18.9 mg, 0.12 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.5 mg, 0.12 mmol), and the mixture was stirred for 3 hours. This solution was added dropwise to a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-benzamide (50.0 mg, 0.10 mmol) obtained in Example 15 in THF (2 ml), and triethylamine (40.9 μl, 0.29 mmol) was added thereto. The mixture was stirred for 24 hours. The reaction mixture was diluted with ethyl acetate (45 ml), and washed with saturated aqueous ammonium chloride (20 ml), and then with saturated brine (2×20 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was roughly purified by preparative TLC (CH2Cl2/MeOH (10:1)) to give {[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-benzyl]-methoxy-carbamoyl}acetic acid methyl ester (14.0 mg, containing impurities) as a colorless oil. To a solution of the resultant {[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-benzyl]-methoxy-carbamoyl}acetic acid methyl ester (14.0 mg, containing impurities) in methanol (1 ml) was added sodium methoxide (3.0 mg, 0.06 mmol), and the mixture was stirred for 2 hours. The reaction mixture was diluted with saturated ammonium chloride, and extracted with methylene chloride (30 ml and 15 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was purified by preparative TLC (CH2Cl2/MeOH (10:1)) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-{[(2-hydroxy-acetyl)-methoxy-amino]-methyl}-N-(2-hydroxy-ethoxy)-benzamide (F-5, 5.8 mg, 12% for 2 steps) as a colorless oil.

Workup

  1. extractionextracted with methylene chloride (30 ml and 15 ml)
  2. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  3. concentrationconcentrated under reduced pressure
  4. customThe resultant residue was purified by preparative TLC (CH2Cl2/MeOH (10:1))

Sources & evidence

ORD record
ord-02d22259b28e47aea2683f7cb664679e
Source dataset
uspto-grants-2010_06
Patent number
US07745663B2

Reaction notes

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