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

HRID 457940

Reaction equation

HRID 457940 reaction equation
[Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[OH:16])=[C:4]([F:20])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CC(C)=O>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][O:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[C:8](=[O:17])[NH:7][CH2:6][C:5]1[CH:18]=[CH:19][C:2]([Br:1])=[CH:3][C:4]=1[F:20])[CH3:33]

Participants

5

Reactant 3

HCID 7748Ethyl bromoacetateHCID 11430Potassium CarbonateHCID 18468196N-(4-bromo-2-fluoro-benzyl)-4-chloro-2-hydroxy-benzamide

Product 1

HCID 22093478[2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-chloro-phenoxy]-acetic acid ethyl esterYield 94%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent

Conditions

Temperature
50 °C

Procedure

A solution of N-(4-bromo-2-fluoro-benzyl)-4-chloro-2-hydroxy-benzamide (3.25 g, 9.06 mmol) in acetone (45 mL, 0.2 M) was treated with aq K2CO3 (2 M, 6.8 mL, 14 mmol) and ethyl bromoacetate (1.2 mL, 11 mmol). After being heated to 50° C. for 8 h, the solution was cooled to room temperature and concentrated under reduced pressure until most of the acetone was removed. The solution was acidified to pH 1–2 with 2 N HCl, diluted with ethyl acetate and washed with saturated aq NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. Purification by MPLC (10–60% ethyl acetate in heptane, 23 mL/min, 70 min) gave [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-chloro-phenoxy]-acetic acid ethyl ester as a white crystalline solid (3.78 g, 94%): mp 126–127° C.; Rf 0.61 (50% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) δ 8.90 (t, J=6 Hz, 1 H), 7.82 (d, J=8.4 Hz, 1 H), 7.52–7.47 (m, 1 H), 7.39–7.31 (m, 2 H), 7.28 (d, J=1.8 Hz, 1 H), 7.14 (dd, J1=8.4 Hz, J2=1.8 Hz, 1 H), 5.00, (s, 2 H), 4.49 (d, J=6 Hz, 2 H), 4.16 (q, J=7.2 Hz, 2 H), 1.18 (t, J=6.6 Hz, 3 H). ESI-LC/MS m/z calcd for C18 H11BrClFNO4: 444.7; found 446.0 (M+1)+. Anal. calcd for C16H16BrClFNO4: C, 48.62; H, 3.63; N, 3.15; Cl, 15.95. Found C, 48.57; H, 3.63; N, 3.11; Cl, 16.00.

Workup

  1. temperaturethe solution was cooled to room temperature
  2. concentrationconcentrated under reduced pressure until most of the acetone
  3. customwas removed
  4. additiondiluted with ethyl acetate
  5. washwashed with saturated aq NaCl
  6. dry with materialThe organic layer was dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customPurification by MPLC (10–60% ethyl acetate in heptane, 23 mL/min, 70 min)

Sources & evidence

ORD record
ord-813937eeb9994e2f8cacf544791d2a97
Source dataset
uspto-grants-2007_03
Patent number
US07189749B2

Linked notes

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