Hydrochloric Acid → Valproic Acid

Temperatur

50 °C

A 2-L flask is charged with 21.6 g (200 mmol) of lithium valerate, 9.5 g (100 mmol) of anhydrous magnesium chloride and 250 mL anhydrous tetrahydrofuran (freshly distilled from sodium, benzophenone). The stirred mixture is warmed to 50° C. allowing the metathetical exchange to occur and a homogeneous solution is produced within 5-15 minutes. The slightly hazy solution is cooled and 5.1 g (200/4 mmol) of diisopropylamine is added. Some precipitate forms and continued stirring fails to effect solution. Finally, 120 mL of a standard solution (1.67M; 200 mmol) of n-butyllithium in heptane is added in four portions at 15-minute intervals at 25°-30° C. After addition of the first portion, a homogeneous solution is produced but addition of the remaining portions yields a turbid mixture. After addition of the final portion, the mixture is permitted to stir for 2 hours at ambient temperature. Then the heterogeneous mixture is cooled to 0° C. and 24.6 g (200 mmol) of 1-bromopropane is added over 10 minutes. Finally, the mixture is warmed to 50° C. for 12 hours overnight. At the conclusion of the reaction period, the mixture is cooled and 200 mL of 6N hydrochloric acid solution is added at a temperature <15° C. followed by 100 mL of water. The phases are separated and the aqueous layer is back-extracted with 100 mL of diethyl ether. The organic layers are combined and the solution is washed with brine, dried (magnesium sulfate), evaporated and the residue is distilled through a 6" heated helices packed column to afford 6.5 g of 2 -propylpentanoic acid; bp 89°-92° C./2 mm.

1. distillationfreshly distilled from sodium, benzophenone)
2. customa homogeneous solution is produced within 5-15 minutes
3. temperatureThe slightly hazy solution is cooled
4. additionAfter addition of the first portion
5. customa homogeneous solution is produced
6. additionaddition of the remaining portions
7. customyields a turbid mixture
8. additionAfter addition of the final portion
9. stirringto stir for 2 hours at ambient temperature
10. temperatureThen the heterogeneous mixture is cooled to 0° C.
11. temperatureFinally, the mixture is warmed to 50° C. for 12 hours overnight
12. customAt the conclusion of the reaction period
13. temperaturethe mixture is cooled
14. customThe phases are separated
15. extractionthe aqueous layer is back-extracted with 100 mL of diethyl ether
16. washthe solution is washed with brine
17. dry with materialdried (magnesium sulfate)
18. customevaporated
19. distillationthe residue is distilled through a 6"
20. temperatureheated helices

ORD-Eintrag

ord-a9d0b860244340ce8cd0939d8347cb0a

Quelldatensatz

uspto-grants-1991_08

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US05041640