Hydrochloric Acid → Pregabalin

A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with acetone (200 ml), (3S)-5-methyl-3-(2-oxo-2{[(1S)-1-phenylethyl]amino}ethyl) hexanoic acid compound (50 g, 0.172 mole), and with triethylamine (21.7 g, 0.215 mole), and cooled to −10° to −20° C. followed by addition of solution of methyl chloroformate (18.67 g, 0.196 mole in 50 ml acetone). The mixture was stirred for 1 hour at a temperature of −10° to −20° C., followed by addition of solution of sodium azide (27.92 g, 0.429 mole in water). The resulted slurry was maintained for 1 hour at −10° to −20° C., quenched over ice water followed by extracting the mass with sufficient amount of toluene. The toluene layer was slowly added over a refluxing mixture of toluene and methyl alcohol, followed by stirring for 2 to 4 hours followed by stripping of solvents results into an oily mass. 4N hydrochloric acid (600 ml), phenol (2.42 g, 0.0257 mole), sodium chloride (40.2 g, 0.687 mole) was added to the oily mass and was heated to 105°-110° C. for 15-24 hours, and then cooled to room temperature, i.e., about 20° to about 25° C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 150 ml of iso-butanol, the organic layer was separated, and Bu3N was added in an amount sufficient to provide a pH of 4-4.5. The (S)-Pregabalin was precipitated, filtered, and washed with 25 ml of iso-butanol which on crystallization from isobutanol water mixture resulted in (S)-Pregabalin as white crystals in a 67% yield. Purity: 99.9% area by HPLC.

1. customA three-necked flask equipped with an addition funnel
2. customthermometer pocket, drying tube and a mechanical stirrer
3. temperatureThe resulted slurry was maintained for 1 hour at −10° to −20° C.
4. customquenched over ice water
5. extractionby extracting the mass with sufficient amount of toluene
6. additionThe toluene layer was slowly added over a refluxing mixture of toluene and methyl alcohol
7. stirringby stirring for 2 to 4 hours
8. customresults into an oily mass
9. temperaturewas heated to 105°-110° C. for 15-24 hours
10. customi.e., about 20° to about 25° C
11. customto provide a pH of 1
12. extractionThe solution was then extracted with 150 ml of iso-butanol
13. customthe organic layer was separated
14. additionBu3N was added in an amount sufficient
15. customto provide a pH of 4-4.5
16. customThe (S)-Pregabalin was precipitated
17. filtrationfiltered
18. washwashed with 25 ml of iso-butanol which on crystallization from isobutanol water mixture
19. customresulted in (S)-Pregabalin as white crystals in a 67% yield

ORD record

ord-70145446b91747e384b7d02cc00cbb7d

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08097754B2