Triethylamine → (R)-(-)-1-CBZ-3-pyrrolidinol

Temperature

7.5 °C

A 22-L, 3-neck, round bottom flask equipped with mechanical stirrer, thermocouple, addition funnel and nitrogen bubbler was charged with 425 g (4.88 mol) of (3R)-3-hydroxypyrrolidine, 8 L of dichloromethane, and 1 L (7.17 mol) of triethylamine. The solution was cooled to 5-10° C. with an ice bath and then 1000 g (5.86 mol) of benzyl chloroformate was added dropwise over a period of about 1.5 h keeping the reaction temperature below 20° C. The reaction mixture was stirred for an additional h in the ice bath, then the bath was removed and the reaction mixture was allowed to warm to ambient temperature overnight. The mixture was poured into a large extractor containing about 15 L of saturated aqueous sodium bicarbonate solution. The aqueous phase was back-extracted with two 2-L portions of dichloromethane. The combined organics were dried over magnesium sulfate and concentrated to give an orange oil. The crude material was taken up in dichloromethane, applied to a 5-kg column of silica gel prepacked in 50% ethyl acetate/hexane, and eluted sequentially with 8 L of 50%, 16 L of 75%, then 100% ethyl acetate/hexane to provide the title compound as a yellow oil which crystallized upon standing.

1. additionthermocouple, addition funnel
2. customthe reaction temperature below 20° C
3. customthe bath was removed
4. temperatureto warm to ambient temperature overnight
5. additionThe mixture was poured into a large extractor
6. additioncontaining about 15 L of saturated aqueous sodium bicarbonate solution
7. extractionThe aqueous phase was back-extracted with two 2-L portions of dichloromethane
8. dry with materialThe combined organics were dried over magnesium sulfate
9. concentrationconcentrated
10. customto give an orange oil
11. washeluted sequentially with 8 L of 50%, 16 L of 75%

ORD record

ord-eb9ae6be574347fa865b25ea02274692

Source dataset

uspto-grants-2010_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07671073B2