HCID 67350538, compound → (R)-4-((3R,5R,8S,9S,10R,13R,14S,17R,Z)-6-ethylidene-3-hydroxy-10,13-dimethyl-7-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid

Compound 4 (258.37 g, 600 mmol, calculated as dried substance) was charged into an inert reactor. At a temperature of NMT 50° C., residual amounts of solvent were distilled off under vacuum. The residue was dissolved in methanol (360 mL) and water (54 mL) and caustic soda 50% wt. (54 mL) were added. The reaction mixture was heated up to 49° C. to 53° C. and stirred at this temperature for at least 2 hours. The pH of the reaction mixture is checked and verified to be >12. If the pH is <12, additional NaOH is added and the 2 hour reaction time is repeated. The solution was diluted with water (1000 mL) and the temperature was adjusted to 25° C. to 35° C. For the workup, reaction mixture was allowed to rest for at least 30 minutes. The phases were separated and the lower aqueous layer was transferred into a separate reactor and the organic layer was discarded. Ethyl acetate (1400 mL) and aqueous citric acid (244 g in 480 mL) were added with intensive stirring to the aqueous layer. The reaction mixture was stirred at 25° C. to 35° C. for 10 minutes. The phases were separated and the lower aqueous layer was discarded. Ethyl acetate was distilled off from the organic layer and replaced with ethyl acetate (800 mL). This operation was repeated until the water content of the distillate was NMT 1% or until a constant boiling point was reached. The suspension was cooled to 20° C. to 25° C., stirred for 30 minutes, and then the product was isolated and washed with ethyl acetate (100 mL, 3 to 4 times). Drying was done in a tumble dryer under vacuum at approximately 60° C. The yield is 118.71 g (47.5% from KLCA) of crude compound 5. Compound 4A, a mixture of E/Z isomers also can be used as starting material to produce compound 5A, a mixture of E/Z isomers.

1. distillationAt a temperature of NMT 50° C., residual amounts of solvent were distilled off under vacuum
2. dissolutionThe residue was dissolved in methanol (360 mL)
3. additionwater (54 mL) and caustic soda 50% wt. (54 mL) were added
4. temperatureThe reaction mixture was heated up to 49° C. to 53° C.
5. additionIf the pH is <12, additional NaOH is added
6. customthe 2 hour reaction time
7. customwas adjusted to 25° C. to 35° C
8. customFor the workup, reaction mixture
9. waitto rest for at least 30 minutes
10. customThe phases were separated
11. customthe lower aqueous layer was transferred into a separate reactor
12. additionEthyl acetate (1400 mL) and aqueous citric acid (244 g in 480 mL) were added
13. stirringwith intensive stirring to the aqueous layer
14. stirringThe reaction mixture was stirred at 25° C. to 35° C. for 10 minutes
15. customThe phases were separated
16. distillationEthyl acetate was distilled off from the organic layer
17. temperatureThe suspension was cooled to 20° C. to 25° C.
18. stirringstirred for 30 minutes
19. customthe product was isolated
20. washwashed with ethyl acetate (100 mL, 3 to 4 times)
21. customDrying
22. customwas done in a tumble dryer under vacuum at approximately 60° C
23. additionCompound 4A, a mixture of E/Z isomers also

ORD record

ord-38497161d01642db8abe55a178d985ba

Source dataset

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09238673B2