Hydrochloric Acid → HCID 10541874, compound

Temperature

85 °C

A solution of potassium tert-butoxide (20.0 g, 0.78 mol) at 55° C. in t-BuOH (249 mL) was treated with a premixed solution of diethyl succinate (40.4 mL, 0.243 mol) and 3-bromobenzaldehyde (18.9 mL, 0.162 mol) dropwise. Upon completion of the addition, the reaction mixture was warmed to 85° C. and stirred for 2 h. After 2 h, the reaction mixture was cooled to 25° C. The reaction mixture was acidified to pH<4 with 2 N aqueous HCl and concentrated. The aqueous suspension was then extracted with ethyl acetate (3×). The organic layers were combined and washed with saturated aqueous NaHCO3 (5×). The basic aqueous washes were combined and reacidified with 2 N aqueous HCl to pH 1. Finally, the aqueous phase was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure, which afforded the desired half ester (39.1 g, 77%) as an orange oil. The half ester (39.1 g, 0.124 mol) was dissolved in acetic anhydride (178 mL) and NaOAc (18.7 g, 0.137 mol) was added. The reaction mixture was warmed to 140° C. and stirred for 6 h. Upon completion, the reaction mixture was cooled to 25° C. and poured into H2O. The aqueous layer was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in anhydrous ethanol (620 mL). K2CO3 (104 g, 0.624 mol) was added, and the reaction mixture was warmed at 80° C. for 1 h. The reaction mixture was cooled and acidified to pH 1 with 2 N aqueous HCl. The ethanol was removed under reduced pressure and the aqueous suspension was extracted with ethyl acetate (3×). The organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography (SiO2, 16×30 cm, 0-15% EtOAc/hexanes gradient elution) provided 7 (5.4 g, 15% over 3 steps) as a yellow solid and its 7-bromo isomer (12.4 g, 34% over 3 steps). 1H NMR (CDCl3, 500 MHz) δ 8.16 (s, 1H), 8.07 (s, 1H), 7.89 (d, J=6.5 Hz, 1H), 7.73 (d, J=6.5 Hz, 1H), 7.63 (s, 1H), 7.29 (t, J=10 Hz, 1H), 4.43 (q, J=6.0 Hz, 2H) 1.44 (t, J=6.0 Hz, 3H). 13C NMR (CDCl3, 125 MHz) δ 165.9, 152.7, 136.3, 133.6, 130.6, 129.2, 126.7, 123.6, 122.7, 115.2, 112.3, 61.3, 14.3. IR (film) νmax3367, 2979, 1690, 1227 cm−1. ESI-TOF HRMS m/z 294.9959 (M+H+, C13H11BrO3 requires 294.9964).

1. additionUpon completion of the addition
2. waitAfter 2 h
3. temperaturethe reaction mixture was cooled to 25° C
4. concentrationconcentrated
5. extractionThe aqueous suspension was then extracted with ethyl acetate (3×)
6. washwashed with saturated aqueous NaHCO3 (5×)
7. extractionFinally, the aqueous phase was extracted with ethyl acetate (3×)
8. dry with materialdried over Na2SO4
9. concentrationconcentrated under reduced pressure, which
10. customafforded the
11. temperatureThe reaction mixture was warmed to 140° C.
12. stirringstirred for 6 h
13. temperatureUpon completion, the reaction mixture was cooled to 25° C.
14. extractionThe aqueous layer was extracted with ethyl acetate (3×)
15. dry with materialdried over Na2SO4
16. concentrationconcentrated under reduced pressure
17. dissolutionThe residue was dissolved in anhydrous ethanol (620 mL)
18. temperaturethe reaction mixture was warmed at 80° C. for 1 h
19. temperatureThe reaction mixture was cooled
20. customThe ethanol was removed under reduced pressure
21. extractionthe aqueous suspension was extracted with ethyl acetate (3×)
22. dry with materialdried over Na2SO4
23. concentrationconcentrated under reduced pressure
24. washFlash chromatography (SiO2, 16×30 cm, 0-15% EtOAc/hexanes gradient elution)
25. customprovided 7 (5.4 g, 15% over 3 steps) as a yellow solid and its 7-bromo isomer (12.4 g, 34% over 3 steps)

ORD record

ord-9466291e9c494c2395a17f79409ba87d

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09139596B2