Ethyl bromoacetate → (2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid ethyl ester

HRID 457972Notes

Reaction equation

HRID 457972 reaction equation
[Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8](=[O:18])[C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([F:16])=[CH:11][C:10]=2[OH:17])=[C:4]([F:21])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28]([O:30][C:31](=[O:34])[CH2:32]Br)[CH3:29]>CC(C)=O>[CH2:28]([O:30][C:31](=[O:34])[CH2:32][O:17][C:10]1[CH:11]=[C:12]([F:16])[C:13]([CH3:15])=[CH:14][C:9]=1[C:8](=[O:18])[NH:7][CH2:6][C:5]1[CH:19]=[CH:20][C:2]([Br:1])=[CH:3][C:4]=1[F:21])[CH3:29]

Participants

5

Reactant 3

HCID 7748Ethyl bromoacetateHCID 11430Potassium CarbonateHCID 18468169N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-hydroxy-5-methyl-benzamide

Product 1

HCID 22093479(2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid ethyl esterYield 93%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent2×

Conditions

Temperature
50 °C

Procedure

A stirring solution of N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-hydroxy-5-methyl-benzamide (1.69 g, 4.76 mmol) in acetone (24 mL, 0.2 M) was treated with an aq K2CO3 solution (3.6 mL, 2 M, 7.12 mmol) and ethylbromoacetate (0.63 mL, 5.69 mmol) in acetone (24 mL, 0.2 M) and heated to 50° C. for 2.5 h. After cooling to room temperature, the solution was concentrated, acidified to pH 1 with 2 N HCl, and diluted with ethyl acetate (100 mL) and washed with 50 mL of saturated aq NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated to provide [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid ethyl ester (1.95, 93%) as a white solid: mp 128–129° C.; Rf 0.42 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 8.79 (bd t, J=4.5 Hz, 1 H), 8.10 (d, J=9.0 Hz, 1 H), 7.34 (t, J=8.3 Hz, 1 H), 7.26–7.23 (m, 1 H), 7.21 (t, J=2.3 Hz, 1 H), 6.53 (d, J=10.5 Hz, 1 H), 4.66 (d, J=3.9 Hz, 1 H), 4.65 (s, 2 H), 4.28 (q, J=7.2 Hz, 2 H), 2.23 (bd d, J=1.5 Hz, 3 H), 1.30 (t, J=7.2 Hz, 3H); Anal. calcd for C19H18BrFNO4: C, 51.60; H, 4.10; N, 3.17. Found C, 51.65; H, 4.19; N, 3.10.

Workup

  1. temperatureAfter cooling to room temperature
  2. concentrationthe solution was concentrated
  3. additiondiluted with ethyl acetate (100 mL)
  4. washwashed with 50 mL of saturated aq NaCl
  5. dry with materialThe organic layer was dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-738833e73aea4edb8f51c006c3cd24f4
Source dataset
uspto-grants-2007_03
Patent number
US07189749B2

Reaction notes

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