6. (a)
Ketopantoyl lactone is readily prepared by the oxidation of
d,l-pantoyl lactone (Note
8) with
bromine as follows.
4 Into a 500-mL, round-bottomed flask fitted with a
mechanical stirrer,
dropping funnel,
condenser, and
thermometer is charged
13.0 g (0.1 mol) of d,l-pantoyl lactone (Note
7) and
150 mL of carbon tetrachloride. The mixture is stirred and heated to reflux.
Bromine (16.5 g, 0.103 mol) in 100 mL of carbon tetrachloride is slowly added from the dropping funnel over 3 hr. After 8 hr, generation of
hydrogen bromide subsides and the red color of
bromine almost disappears, indicating completion of the reaction. Dry air is bubbled through the solution to remove the remaining
hydrogen bromide and the small quantity of
bromine. The solvent is removed with a rotary evaporator and further evacuated with a
vacuum pump to afford
12.8 g (
100%) (Note
9) of almost pure
ketopantoyl lactone. One recrystallization from
150 mL of carbon tetrachloride (heat to reflux and then cool to −10°C) affords
11.6–12.2 g (
90–95%) of pure
ketopantoyl lactone, mp
66–67.5°C. (b) An alternative procedure preferred by the checkers to prepare highly pure
ketopantoyl lactone follows. A
5-L, round-bottomed flask equipped with a mechanical stirrer, condenser, thermometer, and dropping funnel is charged with
700 g of Ca(OCl)2 (analyzed as 20% active chlorine) and 1.5 L of acetonitrile dried overnight over Linde 4A molecular sieves.
d,l-Pantoyl lactone (165 g) (Note
7) is dissolved in
500 mL of dried acetonitrile. The
Ca(OCl)2 slurry is stirred while

1/7 of the
pantoyl lactone solution is added. The temperature of the exothermic reaction is controlled with an
ice bath to below 35°C. The remainder of the
pantoyl lactone solution is added in

75-mL aliquots over 25–30 min while taking care to control the temperature. The ice bath is removed and stirring is continued. After 3.5 hr, GLC analysis indicates 94% product. The reaction mixture is filtered and the solids are rinsed with
acetonitrile. The crude product is dried on a rotary evaporator and further evacuated overnight to yield
105.6 g. The material is dissolved in
methylene chloride, dried over
Na2SO4, filtered through Celite, and concentrated under reduced pressure. The crude product (
94.1 g) is then purified by refluxing and stirring overnight with
500 mL of ethyl ether. The slurry is allowed to stand at 5°C. The solids are filtered, washed with cold
ether, and dried in a vacuum oven at room temperature for 6 hr to afford
80.8 g (86% recovery) of pure ketopantoyl lactone.
Ketopantoyl lactone has also been reported to be easily prepared by the oxidation of
d,l-pantoyl lactone with alkaline metal hypochlorite
5 or by reaction of
sodium dimethylpyruvate with
formaldehyde in the presence of
potassium carbonate.
6