Hydrochloric Acid → Ethyl 3-(5-chloro-2-hydroxyphenyl)-3-oxo-propionate

Temperature

-10 °C

A solution of lithium hexamethyldisilazide (800 mL of 1.0 M solution in THF, 800.0 mmol) was chilled to −78° C. under a nitrogen atmosphere. A solution of 5-chloro-2-hydroxyacetophenone (45.493 g, 266.67 mmol) in THF (130 mL) was added dropwise to the stirred solution over 0.5 hour. The reaction was held at −78° C. for 1 hour, warmed to −10° C. for 2 hours, warmed to 0° C. for 1 hour, then cooled to −78° C. Diethyl carbonate (35.54 mL, 34.65 g, 29.34 mmol) was added via syringe in one portion. The temperature was maintained at −78° C. for 0.5 hour, warmed to room temperature over 0.5 hour, and stirred for 3 hours. The crude reaction mixture was carefully poured over a mixture of rapidly stirred ice (1200 mL)/conc HCl (222 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo yielding an oil that began to crystallize. Hexanes (150 mL) was added and crystallization proceeded. The crystalline product was collected by vacuum filtration to afford the title compound (29.04 g, 45%) as tan crystalline needles: mp 71.8-73.1° C. 1H NMR (CDCl3/300 MHz) 7.63 (d, 1H, J=2.4 Hz), 7.45 (dd, 1H, J=8.9, 2.6), 6.98 (d, 1H, J=8.9 Hz), 4.25 (q, 2H, J=7.3 Hz), 3.98 (s, 2H), 1.29 (t, 3H, 7.3 Hz). FABLRMS m/z 249 (M+Li). EIHRMS m/z 242.0346 (M+, Calc'd 242.0346). Anal. Calc'd for C11H11ClO4: C, 54.45; H, 4.57. Found: C, 54.48; H, 4.62.

1. temperaturewarmed to 0° C. for 1 hour
2. temperaturecooled to −78° C
3. temperatureThe temperature was maintained at −78° C. for 0.5 hour
4. temperaturewarmed to room temperature over 0.5 hour
5. customThe crude reaction mixture
6. customThe layers were separated
7. extractionthe aqueous phase was extracted with ethyl acetate
8. washThe combined organic phase was washed with brine
9. dry with materialdried over Na2SO4
10. filtrationfiltered
11. concentrationconcentrated in vacuo
12. customyielding an oil that
13. customto crystallize
14. additionHexanes (150 mL) was added
15. customcrystallization
16. filtrationThe crystalline product was collected by vacuum filtration

ORD record

ord-567f586de0d54be8bed6decf56b4003b

Source dataset

uspto-grants-2004_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06806288B1