Citric Acid → HCID 18630138, compound

1.3M s-BuLi in cyclohexane (25.4 mL, 0.033 mol) was added dropwise to THF (50 mL), TMEDA (3.83 g, 0.033 mol), and the compound of Example c (4.10 g, 0.015 mol), cooled to -78° under nitrogen with stirring. After stirring for 20 min, MeI (2.45 g, 0.01725 mol) was added all at once. The mixture was stirred for 1 h, and 25% citric acid (50 mL) was added. The mixture was extracted three times with CH2Cl2. The combined extracts were washed twice with water, dried (MgSO4), and concentrated. To the resulting mixture were added 30 mL thionyl chloride and 5 drops of DMF. After stirring at RT overnight, the mixture was concentrated to dryness; 50 mL toluene were added; and again the mixture was concentrated. This process was repeated 3 times. The crude product, a brown oil, was dissolved in 30 mL toluene and added to a 100 mL solution of 70% ethyl amine in water which had been cooled to 5° in an ice bath. After stirring overnight, the mixture was washed with 10% HCl and three times with water, dried (MgSO4), concentrated, and purified by HPLC eluting with 1:3 ethyl acetate/hexanes. Two fractions were obtained. When each was concentrated, Compound 48 crystallized as a white solid in a 20% yield. m.p. 115-117° C. Compound 49 crystallized as a white solid in a 42% yield. m.p. 64-66° C.

1. stirringAfter stirring for 20 min
2. stirringThe mixture was stirred for 1 h
3. extractionThe mixture was extracted three times with CH2Cl2
4. washThe combined extracts were washed twice with water
5. dry with materialdried (MgSO4)
6. concentrationconcentrated
7. additionTo the resulting mixture were added 30 mL thionyl chloride and 5 drops of DMF
8. stirringAfter stirring at RT overnight
9. concentrationthe mixture was concentrated to dryness
10. addition50 mL toluene were added
11. concentrationand again the mixture was concentrated
12. dissolutionThe crude product, a brown oil, was dissolved in 30 mL toluene
13. additionadded to a 100 mL solution of 70% ethyl amine in water which
14. temperaturehad been cooled to 5° in an ice bath
15. stirringAfter stirring overnight
16. washthe mixture was washed with 10% HCl and three times with water
17. dry with materialdried (MgSO4)
18. concentrationconcentrated
19. custompurified by HPLC
20. washeluting with 1:3 ethyl acetate/hexanes
21. customTwo fractions were obtained
22. concentrationWhen each was concentrated
23. customCompound 48 crystallized as a white solid in a 20% yield
24. customCompound 49 crystallized as a white solid in a 42% yield

ORD record

ord-f086c1817bdc427bb8e5faae94818e6e

Source dataset

uspto-grants-2000_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06133252