Triethylamine → {[2,3-Difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-benzyl]-methoxy-carbamoyl}acetic acid methyl ester

HRID 2038643Notes

Reaction equation

HRID 2038643 reaction equation
[C:1]([O:4][CH2:5]C(O)=O)(=[O:3])[CH3:2].ON1[C:15](=[O:16])C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:33][C:34]1[C:35]([NH:52][C:53]2[CH:58]=[CH:57][C:56]([I:59])=[CH:55][C:54]=2[F:60])=[C:36]([CH:44]=[C:45]([CH2:48][NH:49][O:50][CH3:51])[C:46]=1[F:47])[C:37]([NH:39][O:40][CH2:41][CH2:42][OH:43])=[O:38].C(N(CC)CC)C>C(Cl)Cl.C1COCC1.C(OCC)(=O)C>[CH3:5][O:4][C:1](=[O:3])[CH2:2][C:15](=[O:16])[N:49]([CH2:48][C:45]1[CH:44]=[C:36]([C:37](=[O:38])[NH:39][O:40][CH2:41][CH2:42][OH:43])[C:35]([NH:52][C:53]2[CH:58]=[CH:57][C:56]([I:59])=[CH:55][C:54]=2[F:60])=[C:34]([F:33])[C:46]=1[F:47])[O:50][CH3:51]

Participants

9

Reactant 5

HCID 8471TriethylamineHCID 730263-hydroxy-1,2,3-benzotriazin-4(3H)-oneHCID 83766Acetoxyacetic acidHCID 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 86634365{[2,3-Difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-benzyl]-methoxy-carbamoyl}acetic acid methyl esterYield 22.9%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

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. additionwas added
  2. stirringThe mixture was stirred for 24 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 roughly purified by preparative TLC (CH2Cl2/MeOH (10:1))

Sources & evidence

ORD record
ord-50a19a297f6942ec9d1abcb1d64e8809
Source dataset
uspto-grants-2013_11
Patent number
US08575391B2

Reaction notes

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