Acetic Acid → Efavirenz aminoalcohol

Temperature

58 °C

To a slurry of DDQ (9.42 g, 41.5 mmol) in t-butyl methyl ether (33 ml) at 10° C. was added a solution of (S)-5-chloro-α-(cyclopropylethynyl)-2-(4-methoxyphenyl)methyl]amino]-α-(trifluoromethyl)benzenemethanol (16.38 g, 40 mmol). After 5 minutes the resulting slurry was filtered at 30° C. and the resulting solids washed with 5 ml t-butyl methyl ether. The filtrate was washed with 5% aqueous sodium bicarbonate then partially concentrated by distilling 70 ml solvent. Methanol (25 ml) was added followed by distilling 25 ml of solvent. Methanol (25 ml) and 6N NaOH (4 ml) were added followed by distillation of 20 ml of solvent. 4N NaOH (26 ml) was added and the mixture heated briefly to 58° C. then cooled to 30° C. A solution of sodium borohydride (0.60 g, 15.9 mmol) in 0.5 N NaOH (6 mL) was added. After 15 minutes, water (45 ml) was added followed by acetone (1 ml). After 0.5 hours, acetic acid (12 ml, 210 mmol) was added to a pH of 7.5. The resulting slurry was cooled to about 0° C., filtered and the product was washed with water then dried in vacuo at 40° C. The crude product was reslurried at room temperature with methylcyclohexane, cooled to about 0° C. and filtered. This material was further purified by recrystallization from t-butyl methyl ether/hexanes to give 9.95 g (86%) as a white solid. The physical characteristics were identical with product prepared by the two step (p-chloranil/NaBH4) process. (Example 6, above)

1. filtrationAfter 5 minutes the resulting slurry was filtered at 30° C.
2. washthe resulting solids washed with 5 ml t-butyl methyl ether
3. washThe filtrate was washed with 5% aqueous sodium bicarbonate
4. concentrationthen partially concentrated
5. distillationby distilling 70 ml solvent
6. additionMethanol (25 ml) was added
7. distillationby distilling 25 ml of solvent
8. additionMethanol (25 ml) and 6N NaOH (4 ml) were added
9. distillationfollowed by distillation of 20 ml of solvent
10. addition4N NaOH (26 ml) was added
11. temperaturethen cooled to 30° C
12. waitAfter 0.5 hours
13. temperatureThe resulting slurry was cooled to about 0° C.
14. filtrationfiltered
15. washthe product was washed with water
16. customthen dried in vacuo at 40° C
17. customwas reslurried at room temperature with methylcyclohexane
18. temperaturecooled to about 0° C.
19. filtrationfiltered
20. customThis material was further purified by recrystallization from t-butyl methyl ether/hexanes
21. customto give 9.95 g (86%) as a white solid

ORD record

ord-b934d72af6bc42d4afb13ae1cf10b1b8

Source dataset

uspto-grants-2000_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06040480