B.
(3S,4S)-3-Amino-1-(3,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone. An aqueous solution of crude
L-(S)-glyceraldehyde acetonide2 (estimated content, 190 mmol) is placed in a
1000-mL, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar (32 mm) and a
100-mL, pressure-equalizing dropping funnel that is connected to an
argon flow line.
Dichloromethane (200 mL, (Note 5)) is added to the aqueous solution and the
dropping funnel is charged with a solution of
3,4-dimethoxybenzylamine (31.1 g, 0.186 mol, (Note 8)) in
dichloromethane (50 mL). The flask is flushed with
argon and an
argon atmosphere is maintained throughout the entire reaction sequence until the final work up. The solution is vigorously stirred and cooled to 10°C with an
ice-water bath. The solution of
3,4-dimethoxybenzylamine is added dropwise over 5 min, the mixture is stirred for 20 min and then transferred into a
1000-mL separatory funnel. The organic phase is separated and the aqueous layer is extracted with
dichloromethane (2 × 100 mL). The combined organic layers are collected in a
1000-mL Erlenmeyer flask and dried over
magnesium sulfate under
argon. After the
magnesium sulfate is removed by filtration and thoroughly washed with three
100-mL portions of dichloromethane, the filtrate is placed in a
1000-mL, round-bottomed flask and concentrated to about 100 mL (Note
9). The solution is transferred to a
500-mL, two-necked, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar, a
thermometer, and a
250-mL, pressure-equalizing dropping funnel connected to an
argon flow line. The solution is cooled to 0°C (
ice-methanol bath) and treated with
triethylamine (33.5 mL, 0.24 mol, (Note 10)). The dropping funnel is filled with a solution of
phthalylglycyl chloride (41.5 g, 0.186 mol) in
dichloromethane (75 mL). This solution is added dropwise over 45 min. The reaction mixture is stirred for 1 hr at room temperature, then transferred to a
1000-mL separatory funnel before sequentially washing with water (2 × 200 mL), cold
2 N hydrochloric acid (100 mL), saturated, aqueous
sodium bicarbonate solution (100 mL), and
brine (100 mL). The organic phase is dried over a mixture of
magnesium sulfate and Fuller's earth (Fluka), filtered, and evaporated under reduced pressure. The resulting yellow syrup (
72 g, 0.154 mol,
82% from
3,4-dimethoxybenzylamine, (Note
11)) is dissolved in
1,2-dichloroethane (200 mL, (Note 5)), treated with
N-methylhydrazine (8.9 mL, 0.170 mol, (Note 12)) and refluxed for 60–80 min. The resulting suspension is cooled to room temperature and filtered by suction using a Büchner funnel. The crystals are thoroughly washed with two
100-mL portions of 1,2-dichloroethane and discarded. The combined organic solutions are evaporated to a heavy syrup under reduced pressure. The residue is dissolved in
ethyl acetate (400 mL) and sequentially washed with water (2 × 150 mL) and aqueous
10% sodium chloride solution. The organic layer is dried over
magnesium sulfate, filtered by suction using a Büchner funnel and evaporated. The resulting crystals are recrystallized from
ethyl acetate/
hexane (2:1). Approximately
30–32 g of
(3S,4S)-3-amino-1-(3,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone are obtained (
49–52% from
3,4-dimethoxybenzylamine;
54% from
5,6-O-isopropylidene-L-gulono-1,4-lactone2) as pale yellow crystals, mp.
101–103°C (Note
13).