反应详情

900 g of N-Benzyl-N-trimethylsilylmethyl-amine (4654 mmol) were dissolved in 5.6 l THF at 20-25° C. 450 ml of 36% aqueous formaldehyde (5880 mmol, 1.26 equiv.) were added over 15 min, keeping the temperature between 20-25° C. After 15 min, a mixture of 760 ml diethyl fumarate (1 equiv.), 2.25 l THF and 11.2 ml trifluoroacetic acid (0.03 equiv.) was added over 15 min. The reaction mixture was stirred overnight keeping the temperature between 20-30° C. (in process control by GC). 3.5 l of 1N HCl were added, followed by 2.3 l heptane. The aqueous phase was separated and washed with 3.4 l heptane. The heptane phases were washed sequentially with 3.5 l 1N HCl. 4.5 l MTBE were added to the combined aqueous phases. 720 ml of 32% NaOHaq were added (pH 13) under vigorous stirring. The aqueous phase was separated and re-extracted with 4.5 l MTBE. The MTBE phases were washed sequentially with 2.2 l water, combined and concentrated to dryness at 45° C. to give 1.295 kg of crude (rac)-trans-N-benzyl-pyrrolidine-3,4-dicarboxylic acid diethyl ester. If required, the crude cycloadduct can be distilled.

1. custombetween 20-25° C
2. additionwas added over 15 min
3. custombetween 20-30° C.
4. customThe aqueous phase was separated
5. washwashed with 3.4 l heptane
6. washThe heptane phases were washed sequentially with 3.5 l 1N HCl
7. addition4.5 l MTBE were added to the combined aqueous phases
8. addition720 ml of 32% NaOHaq were added (pH 13) under vigorous stirring
9. customThe aqueous phase was separated
10. extractionre-extracted with 4.5 l MTBE
11. washThe MTBE phases were washed sequentially with 2.2 l water
12. concentrationconcentrated to dryness at 45° C.