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

HRID 20766

Reaction equation

HRID 20766 reaction equation
[CH3:1][O:2][CH2:3][C:4]([OH:6])=O.ON1C(=O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:31][C:32]1[C:33]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([I:57])=[CH:53][C:52]=2[F:58])=[C:34]([CH:42]=[C:43]([CH2:46][NH:47][O:48][CH3:49])[C:44]=1[F:45])[C:35]([NH:37][O:38][CH2:39][CH2:40][OH:41])=[O:36].C(N(CC)CC)C>C(Cl)Cl.C1COCC1.C(OCC)(=O)C>[F:31][C:32]1[C:33]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([I:57])=[CH:53][C:52]=2[F:58])=[C:34]([CH:42]=[C:43]([CH2:46][N:47]([O:48][CH3:49])[C:4](=[O:6])[CH2:3][O:2][CH3:1])[C:44]=1[F:45])[C:35]([NH:37][O:38][CH2:39][CH2:40][OH:41])=[O:36]

Participants

9

Reactant 5

HCID 8471TriethylamineHCID 12251Methoxyacetic AcidHCID 730263-hydroxy-1,2,3-benzotriazin-4(3H)-oneHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 115335813,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-benzamide

Product 1

HCID 115705873,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-{[methoxy-(2-methoxy-acetyl)-amino]-methyl}-benzamideYield 34%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of methoxyacetic acid (9.0 μl, 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 (3 ml), and triethylamine (40.9 μl, 0.29 mmol) was added thereto. The mixture was stirred for 15 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 purified by preparative TLC (CH2Cl2/MeOH (10:1)) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-{[methoxy-(2-methoxy-acetyl)-amino]-methyl}-benzamide (Compound F-6, 19.1 mg, 34%) as a colorless oil.

Workup

  1. additionwas added
  2. stirringThe mixture was stirred for 15 hours
  3. washwashed with saturated aqueous ammonium chloride (20 ml)
  4. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customThe resultant residue was purified by preparative TLC (CH2Cl2/MeOH (10:1))

Sources & evidence

ORD record
ord-5987972dc41345a4a5c7a0139d3a5d35
Source dataset
uspto-grants-2010_06
Patent number
US07745663B2

Linked notes

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