Acetic Acid → HCID 11727251, compound

9α-hydroxyandrost-4-ene-3,17-dione (100 g, 0.324 mol) was added to 450 mls tetrahydrofuran. To the resulting mixture, trimethyl orthoformate (105 ml, 0.97 mol) and (+/-) camphor sulfonic acid (3.5 g, 0.015 mol) was added. The mixture was then stirred at 20°-25° C. for 4 hours under nitrogen. Triethylamine (2.2 ml, 0.015 mol) was added to neutralize the camphor sulfonic acid. The reaction mixture was concentrated under vacuum (27-28 inches Hg.) at 5°-10° C. to 250 mls. and cooled to 0°-5° C. Sodium methoxide (26 g, 0.48 mol) was added over 20 minutes at 0°-5° C. Diethyl oxalate (53 ml, 0.39 mol) was added over 20 minutes at 0°-5° C. The mixture was agitated at 20°-25° C. over 16 hours under nitrogen. The mixture was then charged to a 1 liter glass autoclave and sodium iodide (24.3 g, 0.162 mol) added. The autoclave was purged with nitrogen three times and charged with methyl chloride (30-35 g, 0.62-0.71 mol). The contents of the autoclave were then heated to 60°-65° C. with agitation and maintained at this temperature for 16 hours. The mixture was cooled to 20°-25° C. and transferred to a 2 liter 3 neck flask. Tetrahydrofuran was displaced with 1.2 liters methanol under vacuum (27-28 in. Hg) at 10°-15° C. The resulting mixture was cooled to 0°-5° C. and sodium methoxide (52.5 g, 0.97 mol) was added over 30-40 minutes. The mixture was stirred at 0°-5° C. for about 16 hours under nitrogen. Methanol was displaced under vacuum (27-28 in Hg.) with 600 mls water at 0°-10° C. The mixture was cooled to 0°-5° C. and acidified to pH=8.0 with acetic acid (182 ml, 3.2 mol). The mixture was added to 10 liters 0°-5° C. water with stirring over 15 minutes. The precipitate was then filtered and washed with water (2×500 ml). Then the cake was dried in a vacuum oven at 35°-40° C. under a nitrogen bleed to constant weight to give 9α-hydroxy- 3-methoxy-16β-methylandrost-3,5-dien-17-one (87-88 g, 81%).

1. concentrationThe reaction mixture was concentrated under vacuum (27-28 inches Hg.) at 5°-10° C. to 250 mls
2. temperatureand cooled to 0°-5° C
3. stirringThe mixture was agitated at 20°-25° C. over 16 hours under nitrogen
4. additionadded
5. customThe autoclave was purged with nitrogen three times
6. temperatureThe contents of the autoclave were then heated to 60°-65° C. with agitation
7. temperaturemaintained at this temperature for 16 hours
8. temperatureThe mixture was cooled to 20°-25° C.
9. temperatureThe resulting mixture was cooled to 0°-5° C.
10. stirringThe mixture was stirred at 0°-5° C. for about 16 hours under nitrogen
11. temperatureThe mixture was cooled to 0°-5° C.
12. stirringwith stirring over 15 minutes
13. filtrationThe precipitate was then filtered
14. washwashed with water (2×500 ml)
15. customThen the cake was dried in a vacuum oven at 35°-40° C. under a nitrogen

ORD record

ord-8d603d2a068f4a68a71e12d73d515f69

Source dataset

uspto-grants-1996_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05502183