Dimethyl oxalate → HCID 13314920, compound

3-Methoxyandrosta-3,5-dien-17-one (I, 50.0 g) was dissolved in THF containing TEA (1 ml). Dimethyloxalate (55.5 ml) was added and the mixture cooled to 2°. Sodium methoxide (25%) in methanol (45.7 ml) was added slowly over 10 minutes. The ice bath was removed and the reaction warmed to 24° over five minutes with stirring. The mixture was stirred at 20°-25° for 55 minutes, then cooled to 5° over 10 minutes. Acetic acid (2.4 ml) was added, immediately followed by TEA (17.4 ml), then paraformaldehyde (7.49 g), followed by methanol (63 ml). The ice bath was removed and the mixture warmed to 20°-25° over 5 minutes. The mixture was stirred at 28° for 5 hrs and stored in a freezer (-20°) overnight. The mixture was then warmed to 20°-25° and stirred at 25° for 4 hrs for a total time of approximately 9.0 hrs at 20°-28°. Water (300 ml) and ethyl acetate (300 ml) were added, the mixture stirred and the layers separated. The organic layer was washed with saline (2×100 ml). The aqueous portion is backextracted with ethyl acetate (2×100 ml, washing each with 50 ml of saline). The organic phases are combined, concentrated under reduced pressure to an oil, taken up in methylene chloride (450 ml) and ethyl acetate (200 ml). This mixture was dried over sodium sulfate, filtered and concentrated under reduced pressure to a solid. Trituration of the solid with boiling methanol (100 ml) containing 1% TEA gives the title compound in crystalline form.

1. temperaturethe mixture cooled to 2°
2. customThe ice bath was removed
3. temperaturethe reaction warmed to 24° over five minutes
4. stirringThe mixture was stirred at 20°-25° for 55 minutes
5. temperaturecooled to 5° over 10 minutes
6. additionAcetic acid (2.4 ml) was added
7. customThe ice bath was removed
8. temperaturethe mixture warmed to 20°-25° over 5 minutes
9. stirringThe mixture was stirred at 28° for 5 hrs
10. customstored in a freezer (-20°) overnight
11. temperatureThe mixture was then warmed to 20°-25°
12. stirringstirred at 25° for 4 hrs for a total time of approximately 9.0 hrs at 20°-28°
13. additionWater (300 ml) and ethyl acetate (300 ml) were added
14. stirringthe mixture stirred
15. customthe layers separated
16. washThe organic layer was washed with saline (2×100 ml)
17. washwashing each with 50 ml of saline)
18. concentrationconcentrated under reduced pressure to an oil
19. dry with materialThis mixture was dried over sodium sulfate
20. filtrationfiltered
21. concentrationconcentrated under reduced pressure to a solid
22. additionTrituration of the solid with boiling methanol (100 ml) containing 1% TEA

ORD record

ord-79e8473163804889a355821c9a1df2cc

Source dataset

uspto-grants-1984_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US04443377