4-Isobutyl-2-pyrrolidinone

Pale Yellow Oil

Pregabalin intermediate

Pregabalin (P704800)

Impurity in commercial preparation of Pregabalin.

To 600 mL of methanol, 50.00 g of nitro compound (01), 18.04 g of NiCl2-6H2O was added; the solution was cooled down to 0C-5C and 18.2 g of sodium borohydride was added. After addition, the temperature was raised to 40C-45C and stirred for 12 hours. Then the mixture was cooled down to room temperature, drops of aqueous hydrochloric acid solution, adjust the pH = 2-3. The reaction solution was concentrated under reduced pressure until the system was free of obvious methanol (gas chromatography detection), ethyl acetate was added for extraction, washed with water, and the organic layer was dried and concentrated to obtain the lactam compound (02) Isobutyl-2-pyrrolidinone, a light yellow oily substance of 31.20 g, yield 96.0%, purity 99.10%.

4-Isobutyl-2-pyrrolidinone was formed during Hofmann reaction of (R)-(-)-3-carbamoylmethyl-5-methylhexanoic acid in the presence of bromine and sodium hydroxide^[1].

[1] Sripathi, S., Somesetti, N. R., Veeramalla, R., Challa, N. R., Peddi, S., Karnati, V. R. (2010). Synthesis and characterization of impurities of an anticonvulsant drug, Pregabalin. Arkivoc, 2010 1. https://doi.org/10.3998/ARK.5550190.0011.A22