Welcome to LookChem.com Sign In | Join Free
Home > Chemical Encyclopedia > Chemical Technology > Organic Chemical Technology >
 Double Hydroxylation Reaction: 16α-Methylcortexolone
  • Double Hydroxylation Reaction: 16α-Methylcortexolone
  • 16α-Methylcortexolone (CAS no.: 122405-63-4), which is also called as Pregn-4-ene-3,20-dione, 17,21-dihydroxy-16-methyl-, (16α)-(±)-, could be produced through the following synthetic routes.

    A. (Z)-16α-Methyl-20-trimethylsiloxy-4,17(20)-pregnadien-3-one. (All transfers are conducted under dry nitrogen; reagents are introduced into reaction vessels through rubber septa using a syringe.) An oven-dried, 300-mL, two-necked, round-bottomed flask equipped with a magnetic stirring bar, nitrogen-vacuum inlet, and rubber septum is charged with 6.25 g (20 mmol) of 16-dehydroprogesterone and 0.20 g (1.0 mmol) of cuprous bromide-dimethyl sulfide complex. After the apparatus is flushed with nitrogen, 100 mL of tetrahydrofuran (THF) and 7.7 mL (44 mmol) of hexamethylphosphoramide are added. The resulting clear solution, upon cooling to -78°C, becomes a white slurry to which 5.1 mL (40 mmol) of chlorotrimethylsilane is added dropwise. To the resulting yellow solution is added 23.7 mL (22 mmol) of a 0.93 M solution of methylmagnesium bromide in THF over a 30-min period. The resulting yellow slurry is then stirred at  -55 to -60°C for 12 hr followed by addition of 5.6 mL (40 mmol) of triethylamine dropwise. The reaction mixture is then poured into a vigorously stirred mixture of 50 mL of saturated aqueous sodium bicarbonate, 50 g of ice, and 200 mL of hexane. After stirring for 15 min, the mixture is transferred to a 1-L separatory funnel, and the organic phase is separated. The remaining aqueous phase is extracted three times with 50-mL portions of hexane. The combined organic phases are washed successively with 50 mL of water and 50 mL of brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 6.84–8.67 g of crude (Z)-16α-methyl-20-trimethylsiloxy-4,17(20)-pregnadien-3-one as an amorphous white solid. Analysis of crude (Z)-16α-Methyl-20-trimethylsiloxy-4,17(20)-pregnadien-3-one by 1H NMR indicates a chemical purity of 90–95% and a geometrical ratio of >95% (Z).

    B. 16α-Methylcortexolone. An oven-dried, 1-L, three-necked, round-bottomed flask, equipped with a magnetic stirring bar, nitrogen-vacuum inlet, 200-mL addition funnel topped with a nitrogen inlet, and a rubber septum, is charged with 7.20 g of the crude (Z)-16α-methyl-20-trimethylsiloxy-4,17(20)-pregnadien-3-one. The apparatus is flushed with nitrogen and 200 mL of methylene chloride (CH2Cl2) is added. Quickly under nitrogen flow, the rubber septum is removed from the flask and 12.8 g (128 mmol) of finely powdered, dry potassium bicarbonate is added to the solution, and the flask is resealed with the rubber septum. The flask is then immersed in an ice bath. With vigorous stirring of the mixture, 100 mL of a 0.5 M solution (50 mmol) of m-chloroperoxybenzoic acid (MCPBA) in CH2Cl2 is added dropwise via the addition funnel over a 2.5-hr period followed by a few mL of CH2Cl2to rinse the addition funnel. TLC is used to monitor the progress of the reaction. After stirring the reaction mixture for an additional 10 min after the addition is complete, the addition funnel, nitrogen-vacuum inlet, and rubber septum are removed and 100 mL of aqueous 0.5 M sodium thiosulfate solution is added, vigorous stirring is maintained at room temperature for 30 min. The mixture is then transferred to a 1-L separatory funnel, and the organic phase is separated. The aqueous phase is extracted three times with 50 mL of CH2Cl2. The combined organic extracts are concentrated on a rotary evaporator. The residue is dissolved in 100 mL of THF, and the solution is acidified to  pH 1 by addition of 10 mL of 1 N hydrochloric acid (HCl) to effect desilylation of the 21-trimethylsilyl ether of 16α-methylcortexolone. The homogeneous solution is allowed to stand at room temperature for 30 min and then most of the solvent is removed by rotary evaporation under reduced pressure. The residue is dissolved in 300 mL of CH2Cl2, transferred into a 1-L separatory funnel, and the solution washed with 50 mL of saturated aqueous sodium bicarbonate solution. After separation of the organic phase, the aqueous phase is extracted three times with 50-mL portions of CH2Cl2. The combined organic extracts are washed with 50 mL of brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 6.0 g of a white solid. Chromatographic purification on silica gel (300 g) with 3040% ethyl acetate/chloroform eluent gives 2.92 g (40.5%, 2 steps) of 16α-methylcortexolone.


    Prev:No record
    Next:No record
  • Back】【Close 】【Print】【Add to favorite
Periodic Table
    Hot Products