Ammonium formate → Pregabalin

Temperature

45 °C

(S)-5-Methyl-3-nitromethyl-hexanoic acid ethyl ester (VIII, R1=ethyl) (10.4 g) were dissolved in 160 mL of MeOH. 4 g of 10% Pd/C and 20 g of ammonium formate were added. After a few minutes an exothermic reaction was observed. After 30 minutes HPLC analysis indicated complete conversion. The catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to a volume of about 20 mL. Water (20 mL) was added, then the solution was again concentrated unter reduced pressure to about 20 mL. Then 50 mL of 6N aqueous HCl were added and the mixture was refluxed for 6 hours. After complete conversion, the reaction mixture was concentrated under reduced pressure to about 20 mL. Water (20 mL) and 2-propanol (40 mL) were added and the reaction mixture was heated to 45° C. KOH was added until a pH of 7 was reached. The product started to crystallize. Within about 60 minutes the reaction mixture was cooled down to 10° C. Stirring was continued for 1 hour, then the product was isolated by filtration. The filter cake was washed with 90 mL of a 1:1 mixture of cold H2O/2-propanol. After drying, 5.9 g of substantially pure pregabalin (purity 98.0%) were obtained (yield: 81%).

1. customAfter a few minutes an exothermic reaction
2. customThe catalyst was removed by filtration
3. concentrationThe filtrate was concentrated under reduced pressure to a volume of about 20 mL
4. additionWater (20 mL) was added
5. additionThen 50 mL of 6N aqueous HCl were added
6. temperaturethe mixture was refluxed for 6 hours
7. concentrationAfter complete conversion, the reaction mixture was concentrated under reduced pressure to about 20 mL
8. additionWater (20 mL) and 2-propanol (40 mL) were added
9. additionKOH was added until a pH of 7
10. customto crystallize
11. temperatureWithin about 60 minutes the reaction mixture was cooled down to 10° C
12. waitwas continued for 1 hour
13. customthe product was isolated by filtration
14. washThe filter cake was washed with 90 mL of a 1:1 mixture of cold H2O/2-propanol
15. customAfter drying

ORD record

ord-9f2445b77a97408085c538702f9c22c7

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08546112B2