Etoposide

Etoposide is a chemotherapy medication used for the treatments of a number of types of cancer. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA.

A solution of 3 β (20 g, 26.01 mm01) in THF (150 ml) was added to a mixture of wet 5percent-Pd/C (2.5 g, 50percent water wet) in THF (50 ml) in a Buchi apparatus under nitrogen atmosphere. It was purged three times with nitrogen and hydrogen, and hydrogenated at 50 psi at room temperature. After 4 h, it was carefully depressurized and transferred out from the hydrogenation setup, which was washed with warm THF (55 °C, 2 x 200 ml). The rich reaction mixture was filtered on a Buchner funnel containing a 0.45 μm nylon membrane filter and celite-521. The celite cake was washed with the THF which had been used to clean the reactor. The filtrate was evaporated to .similar.50 ml of a light yellow solution. Water (300 ml) and 10percent NaHSO3 (3 ml) were added and stirred at room temperature for 30 min and at 3 °C for 30 min. The resulting colorless slurry was filtered, washed with cold water (2 x 25 ml) and dried to give etoposide (4, 14.83 g) in 96.8percent weight yield with purity of 100.0percent.A slurry of 3β (25 g, 32.5 mmol) in acetone (250 ml) and 5percent Pd/C (50percent water wet) was charged to a 1L hydrogenating vessel. Additional amount (250 ml) acetone was used to wash in the 3β and the catalyst. The resulting slurry was purged six times with nitrogen followed by hydrogen, and hydrogenated at 3 bar pressure and room temperature for an hour. On completion of the reaction, MeOH (250 ml) was added to solubilize the product, and the catalyst was removed by filtration. The reactor was rinsed with MeOH (250 ml), which was subsequently used in washing the spent catalyst. The combined filtrates were treated with NaHSO3 solution (1N, 7.5 ml) to remove any color and the solvent exchanged for MeOH by distillative exchange. The resultant MeOH slurry (325 ml) was heated to 65 °C, at which point water (500 m l) was added. The crystalline slurry was heated at 85 °C to form a clear solution, seeded with etoposide and cooled slowly to room temperature and then to 0 °C where it was held for an hour. The product was isolated by filtration and dried in vacuo to give etoposide (4, 17.6-17.99 g) in an average of 93.3percent weight yield with HPLC area percent greater than 99percent based on three runs.THF:CH3OH (1:1, 30 ml) was added to a mixture of 3β (2 g) and 4percent wet Pd/C catalyst in a Parr-shaker bottle. It was purged three times with hydrogen and hydrogenated at 50 psi. After 3.5 h at room temperature, the slurry was filtered through celite and was washed with warm methanol (56°C, 3 x 15 ml). The combined filtrates were evaporated to a solid to which water (25 ml) was added and evaporated to remove .similar.5 ml. The resulting aqueous slurry (.similar.25 ml) was stirred at room temperature for 15 min and at 20°C for 15 min, and filtered. The solid etoposide was washed with water (2 x 5 ml) and dried at 40°C to constant weight (1.42 g, 92.5percent yield). According to HPLC, it contained 99.7percent of 4.

anticonvulsant