Potassium ethyl malonate → (S)-6-[2-(4-Acetylaminophenyl)ethyl]-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one

Temperature

15 °C

Potassium ethyl malonate (12.9 g) and magnesium chloride (7.6 g) are added to a flask followed by acetonitrile (70 mL) and tetrahydrofuran (45 mL) and the resulting mixture stirred at 15° C. for 3 hours under an inert atmosphere. To a second flask is added (S)-3-[2-(N-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid (23a) (9.6 g, 31 mmol correcting for 4.9% water content) and tetrahydrofuran (296 mL) followed by carbonyl diimidazole (8.0 g) and the resulting solution stirred at ambient temperature for 3 hours. The latter solution is then added over a 2 hour period to the potassium ethyl malonate-magnesium chloride complex in the first flask and the resulting mixture stirred overnight at 20° C. The mixture was concentrated under vacuum to remove solvent while maintaining the temperature below 40° C. Cold ethyl acetate (116 mL) and water (60 mL) are added to the residue followed by 37% hydrochloric acid (7 g) with agitation while maintaining the temperature below 10° C. The layers are allowed to settle and the aqueous layer separated. The organic layer is extracted twice with a solution of 37% hydrochloric acid (2.5 g) in water (22 mL) followed by a solution of sodium bicarbonate (2 g) in water (20 mL). The remaining organic layer is concentrated under vacuum to remove solvent. The residue is dissolved in methanol (10 mL) and a solution of sodium hydroxide pellets (3.0 g) dissolved in methanol (25 mL) is added and the resulting solution stirred at ambient temperature for 3 days. The solution was concentrated under vacuum to remove solvent. Water (60 mL) was added to the residue and then removed by concentrating under vacuum while maintaining the temperature below 45° C. The remaining oil is dissolved in water (60 mL) and the resulting solution added over 45 minutes to a solution of 3.9 g acetic acid in methanol (10 mL) and water (10 mL). The mixture is stirred overnight at ambient temperature and then cooled to 5° C. and filtered and the solid washed with water (100 mL) and vacuum dried at 60° C. to give 8.0 g (23 mmol; 74% correcting for HPLC purity and water content) of (S)-6-[2-(4-acetylamino-phenyl)ethyl]-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one (24a): HPLC: 95.1 %; Water (KF): 4.4%.

1. stirringthe resulting solution stirred at ambient temperature for 3 hours
2. additionThe latter solution is then added over a 2 hour period to the potassium ethyl malonate-magnesium chloride complex in the first flask
3. stirringthe resulting mixture stirred overnight at 20° C
4. concentrationThe mixture was concentrated under vacuum
5. customto remove solvent
6. temperaturewhile maintaining the temperature below 40° C
7. additionCold ethyl acetate (116 mL) and water (60 mL) are added to the residue
8. temperaturewhile maintaining the temperature below 10° C
9. customthe aqueous layer separated
10. extractionThe organic layer is extracted twice with a solution of 37% hydrochloric acid (2.5 g) in water (22 mL)
11. concentrationThe remaining organic layer is concentrated under vacuum
12. customto remove solvent
13. dissolutionThe residue is dissolved in methanol (10 mL)
14. dissolutiona solution of sodium hydroxide pellets (3.0 g) dissolved in methanol (25 mL)
15. additionis added
16. stirringthe resulting solution stirred at ambient temperature for 3 days
17. concentrationThe solution was concentrated under vacuum
18. customto remove solvent
19. additionWater (60 mL) was added to the residue
20. customremoved
21. concentrationby concentrating under vacuum
22. temperaturewhile maintaining the temperature below 45° C
23. dissolutionThe remaining oil is dissolved in water (60 mL)
24. additionthe resulting solution added over 45 minutes to a solution of 3.9 g acetic acid in methanol (10 mL) and water (10 mL)
25. stirringThe mixture is stirred overnight at ambient temperature
26. temperaturecooled to 5° C.
27. filtrationfiltered
28. washthe solid washed with water (100 mL) and vacuum
29. customdried at 60° C.

ORD record

ord-5e93badd0cb74fd78f3f6f41348ae2ff

Source dataset

uspto-grants-2002_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06380400B1