Hydrochloric Acid → (3-Benzyloxy-5-bromophenyl)-acetic acid ethyl ester

Malonic acid tert-butyl ester ethyl ester (10.2 mL, 53.8 mmol) was added dropwise to a suspension of NaH (2.2 g of a 60% suspension in mineral oil, 53.8 mmol) in dioxane (200 mL) at room temperature and the mixture was stirred at this temperature for 1 hour before CuBr (7.7 g, 53.8 mmol) and 1-benzyloxy-3,5-dibromobenzene (9.2 g, 26.9 mmol) were added. The reaction mixture was heated to reflux for 5 h. HCl solution (1M aq, 100 mL) was carefully added and the mixture was extracted with iso-hexane (×3). The combined organic extracts were washed with HCl solution (1 M aq), water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give, in order of elution, recovered 1-benzyloxy-3,5-dibromobenzene (3.2 g, 9.4 mmol) in 35% yield and 2-(3-benzyloxy-5-bromo-phenyl)-malonic acid tert-butyl ester ethyl ester (7.2 g, contains 1.4 equivalent malonic acid tert-butyl ester ethyl ester, 10 mmol) as a colourless liquid in 37% yield. 2-(3-Benzyloxy-5-bromophenyl)malonic acid tert-butyl ester ethyl ester (7.2 g, contains 1.4 equivalent malonic acid tert-butyl ester ethyl ester, 10 mmol) was dissolved in glacial AcOH (50 mL) and heated to reflux for 12 hours. The AcOH was removed under reduced pressure. The residue was poured into Na2CO3 solution (sat. aq.) and the mixture was extracted with EtOAc (×3). The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure to give (3-benzyloxy-5-bromo-phenyl-)acetic acid ethyl ester (6.8 g, 9.7 mmol) as a yellow liquid in 97% yield. 1H NMR (CDCl3) δ 7.44-7.30 (m, 5H), 7.07-7.03 (m, 2H), 6.87-6.84 (m, 1H), 5.03 (s, 2H), 4.15 (q, 2H), 3.54 (s, 2H), 1.26 (t, 3H).

1. additionwere added
2. temperatureThe reaction mixture was heated
3. temperatureto reflux for 5 h
4. extractionthe mixture was extracted with iso-hexane (×3)
5. washThe combined organic extracts were washed with HCl solution (1 M aq), water, brine
6. dry with materialdried (MgSO4)
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. customThe residue was purified by flash column chromatography (EtOAc:petroleum ether)
10. customto give, in order of elution
11. temperatureheated
12. temperatureto reflux for 12 hours
13. customThe AcOH was removed under reduced pressure
14. additionThe residue was poured into Na2CO3 solution (sat. aq.)
15. extractionthe mixture was extracted with EtOAc (×3)
16. washThe combined organic extracts were washed with water, brine
17. dry with materialdried (MgSO4)
18. filtrationfiltered
19. concentrationconcentrated under reduced pressure

ORD record

ord-9b1bcdfbf9fe419082b448e2626d084f

Source dataset

uspto-grants-2009_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07557244B2