Sulfuric Acid → (5S)-5-(3-methyl-1,2-oxazol-5-yl)pyrrolidin-2-one

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Acetone oxime (2.924 kg, 40 mol) was dissolved in 17.5 L of THF stirred under N2, and the solution was cooled to -40° C. Addition of 8 L of n-butyllithium (10M in hexane, 6.09 kg) was carefully accomplished at a rate such that the temperature of the reaction did not rise above 5° C. To this solution was added 2.719 kg of the compound from step 4a above dissolved in 7 L of THF, also at a rate such that the temperature of the reaction did not rise above 5° C. After addition of the reactants, the mixture was stirred for 12 hr at room temperature. The mixture was cooled to 0° C., and 8.891 kg of H2SO4 and 4.8 L of water was added at a rate such that the temperature of the reaction did not rise above 35° C. The reaction was subsequently heated, and refluxing began at 60 ° C. The reaction was stirred for 1 hr, cooled to 20° C., and 9.32 kg of Na2CO3 was added slowly. The mixture was filtered, then the filter cake was reintroduced into the reactor and stirred with 15 L of ethyl acetate for 1 hr. The solution was filtered, and the residue was washed with 2.5 L of ethyl acetate. The solutions were combined and evaporated to dryness. The residual dark oil was stripped with xylene to remove excess acetone oxime. The residue was dissolved in t-butylmethylether (TBME), and water was added. A tarry residue, which contained polar side-products, separated. The TBME solution was evaporated, and the residue was allowed to stand for 2 hr. A colorless oil containing apolar impurities rose to the top and was removed. The remaining residue was mixed with twice the volume of TBME and seeded, with subsequent crystallization occurring at room temperature. m.p=90°-91° C.

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