L-Pyroglutamic Acid → (S)-4-((5-Oxo-2-pyrrolidinyl)carbonyl)morpholine

Temperature

45 °C

The reaction vessel is charged with 30 g L-pyroglutamic acid and 4.71 g 1-hydroxybenzotriazole hydrate. The solids are then suspended in 190 ml anhydrous acetonitrile and the mixture is then heated to 45° C. Subsequently, 20.24 ml morpholine is added via a dropping funnel within 20 min, and the dropping funnel is then washed with 5 ml anhydrous acetonitrile. The resulting mixture is then heated to 65° C. and 29.32 g N—N′-diisopropylcarbodiimide added within 1 h via a dropping funnel. After complete addition, the dropping funnel is washed with 5 ml anhydrous acetonitrile and the reaction mixture is stirred at 65° C. for an additional 30 min. The resulting suspension is then cooled to ambient temperature, filtered and the filter cake washed with 3×30 ml acetonitrile. The filtrate is concentrated under heating and reduced pressure to approx. ½ of its original volume and the residue is then seeded with 16 mg (S)-5-(morpholine-4-carbonyl)pyrrolidine-2-one. Concentration under reduced pressure is continued until approx ⅓ of the original volume of the filtrate is reached. While further concentrating the filtrate under reduced pressure and removing approx. 95 ml of distillate, simultaneously 210 ml 2-methyltetrahydrofuran is added. The suspension is then cooled to 0° C. and the solids are isolated by filtration. The filter cake is washed with 3×20 ml icooled 2-methyltetrahydrofuran and dried at 55° C. under vacuum to give 42.54 g of (S)-5-(morpholine-4-carbonyl)pyrrolidine-2-one as fine white crystals (98.0% purity by HPLC, ee (HPLC)>99.6% [4-a, R1=H; R4=morpholine]).

1. washthe dropping funnel is then washed with 5 ml anhydrous acetonitrile
2. temperatureThe resulting mixture is then heated to 65° C.
3. addition29.32 g N—N′-diisopropylcarbodiimide added within 1 h via a dropping funnel
4. additionAfter complete addition
5. washthe dropping funnel is washed with 5 ml anhydrous acetonitrile
6. temperatureThe resulting suspension is then cooled to ambient temperature
7. filtrationfiltered
8. washthe filter cake washed with 3×30 ml acetonitrile
9. concentrationThe filtrate is concentrated
10. temperatureunder heating
11. concentrationConcentration under reduced pressure
12. concentrationWhile further concentrating the filtrate under reduced pressure
13. customremoving approx. 95 ml of distillate, simultaneously 210 ml 2-methyltetrahydrofuran
14. additionis added
15. temperatureThe suspension is then cooled to 0° C.
16. customthe solids are isolated by filtration
17. washThe filter cake is washed with 3×20 ml
18. customdried at 55° C. under vacuum

ORD record

ord-3b13d0a989e745459f13ff57df71ed88

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09206116B2