Water → 107797-60-4

Temperature

0 °C

A 2-L three-necked, round-bottomed flask was equipped with a mechanical stirrer, heating mantel, 250-mL graduated additional funnel, and an 8-in., air-cooled vigreux column topped with a water-cooled distillation head and a 1-L receiving flask. The assembly was flushed with nitrogen and charged with trans-4-hydroxy-L-proline (100 g, 0.76 mol) and tetrahydrofuran (THF, 1.2 L), and boron trifluoride etherate (123.9 g, 0.88 mol). The mixture was heated at a rate sufficient to cause the THF to reflux gently and borane-methyl sulfide complex (360 mL, 3.6 mol) was added dropwise over 2 hrs. The solution was then refluxed for 24 hrs. The methyl sulfide, collected at stillhead was discarded, and the reaction mixture was cooled to 0° C. and quenched by the slow addition of methanol (300 mL). The reaction mixture was concentrated by distillation at reduced pressure and the residue was dissolved in 6N sodium hydroxide (1 L) and refluxed for 6 hrs. After cooling to room temperature, the insoluble material was removed by filtration and the filtrate was concentrared at reduced pressure. In order to remove the insoluble materials, the residue was dissolved in 2-propanol (1 L), filtered and concentrated. The operation was repeated three times, affording an oil, which was dissolved in 35% formaldehyde solution (200 mL) and formic acid (600 mL). The reaction mixture was refluxed for 24 hrs and concentrated at reduced pressure. The residue was dissolved in methanol (800 mL) and treated with potassium carbonate (100 g) and refluxed for 6 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated and dissolved in methylene chloride (600 mL) and filtered again. The filtrate was concentrated and Kugelrohr distilled (200°-220° C./1 mmHg) to give (2S, 4R)-4-hydroxy-1-methyl-2-pyrrolidinemethanol (54.48 g, 54.5%) as a viscous oil.

1. customA 2-L three-necked, round-bottomed flask was equipped with a mechanical stirrer
2. temperatureheating mantel, 250-mL
3. temperature, air-cooled vigreux column
4. temperaturecooled
5. distillationdistillation head and a 1-L receiving flask
6. customThe assembly was flushed with nitrogen
7. temperatureThe mixture was heated at a rate sufficient
8. temperatureto reflux gently
9. additionborane-methyl sulfide complex (360 mL, 3.6 mol) was added dropwise over 2 hrs
10. temperatureThe solution was then refluxed for 24 hrs
11. customThe methyl sulfide, collected at stillhead
12. customquenched by the slow addition of methanol (300 mL)
13. concentrationThe reaction mixture was concentrated by distillation at reduced pressure
14. dissolutionthe residue was dissolved in 6N sodium hydroxide (1 L)
15. temperaturerefluxed for 6 hrs
16. temperatureAfter cooling to room temperature
17. customthe insoluble material was removed by filtration
18. customIn order to remove the insoluble materials
19. dissolutionthe residue was dissolved in 2-propanol (1 L)
20. filtrationfiltered
21. concentrationconcentrated
22. customaffording an oil, which
23. temperatureThe reaction mixture was refluxed for 24 hrs
24. concentrationconcentrated at reduced pressure
25. dissolutionThe residue was dissolved in methanol (800 mL)
26. additiontreated with potassium carbonate (100 g)
27. temperaturerefluxed for 6 h
28. temperatureThe mixture was cooled to room temperature
29. filtrationfiltered
30. concentrationThe filtrate was concentrated
31. dissolutiondissolved in methylene chloride (600 mL)
32. filtrationfiltered again
33. concentrationThe filtrate was concentrated
34. distillationKugelrohr distilled (200°-220° C./1 mmHg)

ORD record

ord-7fae779db95d465b8263e4e4785e3a6f

Source dataset

uspto-grants-1996_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05571909