Potassium Hydroxide → Levetiracetam

Temperature

0 °C

This example illustrates a varient of the process of Example 3, in which the intermediate 4-chlorobutanamide obtained in situ is not isolated. 84 g of anhydrous sodium sulfate are added to a suspension of 69.25 g (0.5 mole) of (S)-2-amino-butanamide hydrochloride in 600 ml of dichloromethane at ambient temperature. The mixture is cooled to 0° C. and 115 g of ground potassium hydroxide are added, followed by 8.1 g (0.025 mole) of tetrabutylammonium bromide dissolved in 100 ml of dichloromethane. A solution of 77.5 g of 4-chlorobutyryl chloride in 100 ml of dichloromethane is added dropwise at 0° C., with vigorous stirring. After 5 hours' reaction, a further 29 g of ground potassium hydroxide are added. Two hours later, the reaction mixture is filtered over Hyflo-cel and the filtrate evaporated under reduced pressure. The residue (93.5 g) is dispersed in 130 ml of hot toluene for 45 minutes. The resultant mixture is filtered and the filtrate evaporated under reduced pressure. The residue (71.3 g) is dissolved hot in 380 ml of ethyl acetate to which 23 g of 0.4 nm molecular sieve in powder form are added. This mixture is heated to reflux temperature and filtered hot. After cooling the filtrate, the desired product crystallizes to give 63 g of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.

1. customis not isolated
2. customAfter 5 hours' reaction
3. filtrationTwo hours later, the reaction mixture is filtered over Hyflo-cel
4. customthe filtrate evaporated under reduced pressure
5. additionThe residue (93.5 g) is dispersed in 130 ml of hot toluene for 45 minutes
6. filtrationThe resultant mixture is filtered
7. customthe filtrate evaporated under reduced pressure
8. dissolutionThe residue (71.3 g) is dissolved hot in 380 ml of ethyl acetate to which 23 g of 0.4 nm molecular sieve in powder form
9. additionare added
10. temperatureThis mixture is heated
11. temperatureto reflux temperature
12. filtrationfiltered hot
13. temperatureAfter cooling the filtrate
14. customthe desired product crystallizes

ORD record

ord-840ebd2394ad488bbd5e3cb5704f0d7a

Source dataset

uspto-grants-1987_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US04696943