反应详情

温度

5 °C

To a 5-Liter 4 neck round bottom flask equipped with a mechanical stirrer, temperature probe, addition funnel, and nitrogen inlet adapter was added 100.0 grams (333.3 mmol) of retinoic acid and 1.0 liter of ethyl acetate (EtOAc). The slurry was cooled to an internal temperature of 5° C. Triethylamine (50.7 milliliters, 366 mmol) was added all at once via graduated cylinder. To the thin slurry was then added trimethylacetyl chloride (45.1 milliliters, 366 mmol) via addition funnel over 23 minutes at an internal temperature of less than 5° C. After 3.5 hours, the reaction was judged to be complete by HPLC analysis. To the bright yellow slurry of the mixed anhydride was added a thin suspension of 4-aminophenol (76.3 grams, 700 mmol) in 500 milliliters of pyridine over 30 minutes at an internal temperature of 3-5° C. After 2 hours, the reaction was judged to be complete by HPLC analysis. To the slurry was added 500 milliliters of water over 10 minutes at an internal temperature of 4-8° C. After stirring for 30 minutes the layers were separated and the aqueous layer was extracted with 500 milliliters of EtOAc. The combined organic layers were washed with 3M HCl (3×700 milliliters). The pH of the last wash was 1-2 as determined by pH paper. The organic layer was then washed with 30% aqueous K2CO3 (3×600 milliliters) and brine (2×600 milliliters). The organic layer was held overnight at 0-10° C. The next morning the solution was dried with 50 grams of Na2SO4. After filtration of the drying salts, the amber solution was concentrated to a final volume of about 250 milliliters via rotary evaporation at an external temperature of 45-50° C. The thick slurry was allowed to cool to ambient temperature and 700 milliliters of heptane was added via addition funnel over about 45 minutes. The slurry was cooled to an internal temperature of 0-5° C. and held at this temperature for about 2 hours. The slurry was filtered and washed with a 0-10° C. 5/1 (v/v) mixture of heptane/EtOAc (1×200 milliliters, 1×150 milliliters) to give 161 grams of crude fenretinide wet cake (LOD=25%, 93% yield based on LOD, 98% pure by area percent).

1. customTo a 5-Liter 4 neck round bottom flask equipped with a mechanical stirrer
2. additiontemperature probe, addition funnel, and nitrogen inlet adapter
3. waitAfter 2 hours
4. customwere separated
5. extractionthe aqueous layer was extracted with 500 milliliters of EtOAc
6. washThe combined organic layers were washed with 3M HCl (3×700 milliliters)
7. washThe pH of the last wash
8. washThe organic layer was then washed with 30% aqueous K2CO3 (3×600 milliliters) and brine (2×600 milliliters)
9. waitThe organic layer was held overnight at 0-10° C
10. dry with materialThe next morning the solution was dried with 50 grams of Na2SO4
11. filtrationAfter filtration of the drying salts
12. concentrationthe amber solution was concentrated to a final volume of about 250 milliliters
13. customvia rotary evaporation at an external temperature of 45-50° C
14. temperatureto cool to ambient temperature
15. addition700 milliliters of heptane was added via addition funnel over about 45 minutes
16. temperatureThe slurry was cooled to an internal temperature of 0-5° C.
17. waitheld at this temperature for about 2 hours
18. filtrationThe slurry was filtered
19. washwashed with a 0-10° C
20. addition5/1 (v/v) mixture of heptane/EtOAc (1×200 milliliters, 1×150 milliliters)