5alpha-Dihydroprogesterone → Ganaxolone

Participants

Reaction Conditions

Reaction Steps

Titanium tetrachloride (350 uL, 3.2 mmol) is added in a dropwise fashion to a solution of titanium tetraethoxide (2.42 g, 10.6 mmol) in tetrahydrofuran (anhydrous, 30 mL) cooled to 0° C. After stirring for 20 min at 0° C., methyl magnesium chloride (3M, 4.3 mL 12.9 mmol) in tetrahydrofuran solution is added dropwise while maintaining the temperature below 5° C. After stirring for an additional 20 minutes at 5° C., 5α-pregnane-3,20-dione (2.53 g, 8 mmol) was added in one portion. The reaction is warmed to 40° C. and stirred for 4 hours. The reaction mixture is quenched with 20 mL of methanol and the solvent removed in vacuo. The reaction mixture is partitioned between 100 ml of 3N HCl and 100 mL of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and brine and the solvent removed in vacuo to afford crude ganaxolone as a white solid of 75.9% pure ganaxolone by HPLC (Table 1, entry 3).

Provenance & Evidence