Water → HCID 17747723, compound

To a stirred suspension of sodium borohydride (1.264 g, 33.41 mmol) in tetrahydrofuran (100 mL), N-acetyl-L-aspartic anhydride (5.0 g, 31.82 mmol, prepared as described in example A) was added in five portions at 0° C. over 1 h. The white suspension was warmed to room temperature, stirred for 3 h and cooled again to 0° C. Cold water (˜50 mL) was slowly added to the stirred mixture while the temperature was allowed to reach 15° C. After stirring overnight at room temperature, tetrahydrofuran was evaporated in vacuo. The residual aqueous solution was diluted with water to a volume of 100 mL and passed through a Dowex 50X8 ion exchange column (100 g). The ion exchange column was rinsed with water (3×100 mL). The resulting aqueous solution was concentrated in vacuo and the residue was taken up in a mixture of toluene (30 mL) and methanol (70 mL). The solvent was evaporated in vacuo. This procedure was repeated, i.e. the residue was taken up in toluene-methanol and concentrated again another three times. The remaining colorless oil (5.4 g) which consisted of a mixture of hydroxy-acid and lactone was dissolved in acetic acid (54 mL). Toluene (54 mL) was added and the solution was stirred at 110° C. for 2.5 h. After this time, all hydroxy-acid was cyclized to the desired lactone according to GC analysis of a reaction sample which had been concentrated and silylated. The reaction mixture was concentrated in vacuo. Three times the residue was taken up in toluene and concentrated again to give the crude product (4.2 g) as a white solid. For purification, the crude product was dissolved in acetonitrile (30 mL). Toluene (60 mL) was added to the solution and acetonitrile was partly removed from the mixture in vacuo, until the product started to crystallize. The product was collected by filtration, washed with toluene and tert-butyl methyl ether and dried in vacuo to afford (S)-N-(5-oxo-tetrahydro-furan-3-yl)-acetamide (3.8 g, 83% based on N-acetyl-L-aspartic anhydride) as white crystals. The structure of the compound was confirmed by 1H-NMR, MS, IR. and elemental analysis.

1. additionwas added in five portions at 0° C. over 1 h
2. temperaturecooled again to 0° C
3. customto reach 15° C
4. stirringAfter stirring overnight at room temperature
5. customtetrahydrofuran was evaporated in vacuo
6. additionThe residual aqueous solution was diluted with water to a volume of 100 mL
7. washThe ion exchange column was rinsed with water (3×100 mL)
8. concentrationThe resulting aqueous solution was concentrated in vacuo
9. additionthe residue was taken up in a mixture of toluene (30 mL) and methanol (70 mL)
10. customThe solvent was evaporated in vacuo
11. concentrationconcentrated again another three times
12. additionThe remaining colorless oil (5.4 g) which consisted of a mixture of hydroxy-acid and lactone
13. dissolutionwas dissolved in acetic acid (54 mL)
14. additionToluene (54 mL) was added
15. stirringthe solution was stirred at 110° C. for 2.5 h
16. concentrationhad been concentrated
17. concentrationThe reaction mixture was concentrated in vacuo
18. concentrationconcentrated again
19. customto give the crude product (4.2 g) as a white solid
20. customFor purification
21. dissolutionthe crude product was dissolved in acetonitrile (30 mL)
22. additionToluene (60 mL) was added to the solution and acetonitrile
23. customwas partly removed from the mixture in vacuo, until the product
24. customto crystallize
25. filtrationThe product was collected by filtration
26. washwashed with toluene and tert-butyl methyl ether
27. customdried in vacuo

ORD record

ord-936f34656a43460485fad5a90885f2de

Source dataset

uspto-grants-2009_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07485731B2