Methylhydrazine → 3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-[2-(2,2,2-trifluoro-ethylamino)-ethoxy]-benzamide

HRID 2218483Notes

Reaction equation

HRID 2218483 reaction equation
[F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][CH2:5][CH2:6][O:7][N:8]1C(=O)C2C(=CC=CC=2)C1=O.CNN.FC1C(O[C:32](=[O:50])[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[C:34]=2[NH:41][C:42]2[CH:47]=[CH:46][C:45]([I:48])=[CH:44][C:43]=2[CH3:49])=C(F)C(F)=C(F)C=1F.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CCOCC.ClCCl>[F:40][C:35]1[C:34]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([I:48])=[CH:44][C:43]=2[CH3:49])=[C:33]([CH:38]=[CH:37][C:36]=1[F:39])[C:32]([NH:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][C:2]([F:20])([F:19])[F:1])=[O:50]

Participants

8

Reactant 4

HCID 6061MethylhydrazineHCID 81531DiisopropylethylamineHCID 222861382-[2-(2,2,2-Trifluoro-ethylamino)-ethoxy]-isoindole-1,3-dioneHCID 233984843,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid pentafluorophenyl ester

Product 1

HCID 101444603,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-[2-(2,2,2-trifluoro-ethylamino)-ethoxy]-benzamideYield 87.6%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

Dichloromethane (5 mL) was added to 2-[2-(2,2,2-trifluoro-ethylamino)-ethoxy]-isoindole-1,3-dione (0.46 g, 1.6 mmol) and the resultant solution was cooled to 0° C. Methylhydrazine (0.086 mL, 1.62 mmol) was added and the resultant solution was stirred at ambient temperature for 1 h. Ether (20 mL) was added and the precipitate was filtered and the filtrate was concentrated in vacuo. Dimethylformamide (5 mL) was added and the resultant solution was treated sequentially with 3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid pentafluorophenyl ester (0.847 g, 1.51 mmol) and diisopropylethylamine (0.60 mL, 3.4 mmol). The resultant reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water (4×) and saturated brine, dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (hexanes-ethyl acetate, 1:1) afforded 3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-[2-(2,2,2-trifluoro-ethylamino)-ethoxy]-benzamide (0.70 g, 83% yield) as a waxy foam: 1H NMR (400 MHz, Acetone-d6) δ 10.98 (br s, 1H), 8.69 (br s, 1H), 7.52 (br s, 2H), 7.39 (dd, J=8.6 Hz, 2.0 Hz, 1H), 7.00 (m, 1H), 6.55 (dd, J=8.6 Hz, 6.4 Hz, 1H), 3.27 (q, J=10.0 Hz, 2H), 2.90 (br t, J=4.9 Hz, 2H), 2.82 (br s, 2H), 2.30 (s, 3H); 19F NMR (376 MHz, Acetone-d6) δ −73.1 (t, J=10.0 Hz, 3F), −133.8 (s, 1F), −143.2 (s, 1F); MS (APCI+)=530.0.

Workup

  1. filtrationthe precipitate was filtered
  2. concentrationthe filtrate was concentrated in vacuo
  3. additionDimethylformamide (5 mL) was added
  4. customThe resultant reaction mixture
  5. washwashed with water (4×) and saturated brine
  6. dry with materialdried over magnesium sulfate
  7. concentrationconcentrated in vacuo
  8. customPurification by silica gel chromatography (hexanes-ethyl acetate, 1:1)

Sources & evidence

ORD record
ord-9592439be5f44f9db1dd4ca077f5168c
Source dataset
uspto-grants-2008_08
Patent number
US07411001B2

Reaction notes

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