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

HRID 20767

반응식

HRID 20767 반응식
[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]

참가 물질

9

반응물 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

생성물 1

HCID 86634365{[2,3-Difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-benzyl]-methoxy-carbamoyl}acetic acid methyl ester수율 22.9%

시약·촉매·용매 3

HCID 6344Dichloromethane용매HCID 8028Tetrahydrofuran용매HCID 8857Ethyl Acetate용매

실험 절차

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.

후처리

  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))

출처 및 근거

ORD 기록
ord-a7e4a797c0e4461696133d7fadeb4aff
출처 데이터셋
uspto-grants-2010_06
특허 번호
US07745663B2

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