Pregnan-2,17-dione

A solution of 0.25 g sodium borohydride in 140 ml of ethanol is added to a stirred solution of 0.56 g of calcium chloride in 60 ml of ethanol at —25°. The vigorously stirred mixture is treated dropwise at —25° over 5 min with 4.87 g of 1 la-hydroxy-5/S-pregnane-3,20-dione in 100 ml of ethanol. After a further 3 hr at —20°, 10 ml of 40% aqueous acetic acid is added and the mixture is evaporated to dryness under vacuum. The residue is dissolved in 150 ml of ether and the ethereal solution is washed with 30 ml of 2 A hydrochloric acid and twice with 30 ml of water and dried over Na2S04. Removal of the solvent gives 4.6 g of crystals, which are recrystallized from 20 ml of ether to yield 2.9 g (60%) of the dihydroxy ketone, mp 182-184° [aj 110° (ethanol). 

Deuteration at C-3 by Lithium Aluminum Deuteride Reduction of 5a.-Pregnane-3,20-dione 3-Tosylhydrazone 20-Ethylene keta ... 

A solution of 16jS-methyl-l la,17a,21-trihydroxy-5j5-pregnane-3,20-dione 21-acetate (52), 45 g, in dioxane (297 ml) is cooled to 15° and treated over a 5 min period with a solution of bromine (34.2 g) in dioxane (594 ml) precooled to 18°. After 2 min a solution of sodium acetate (60 g) in water (600 ml) is added and the mixture poured into ice water (8 liters). The precipitate is filtered off, washed to neutrality with water, and dried to give the crude dibromide (53), 55.7 g mp 125-126° (dec.) [aJu 58°. A mixture of dibromide (53), 55.5 g, lithium bromide (27.8 g), lithium carbonate (27.8 g) and DMF (1.11 liters) is refluxed under rapid stirring for 6 hr. The mixture is concentrated under vacuum to about 250 ml, poured into ice water (8 liters) containing hydrochloric acid (250 ml), and extracted with methylene dichloride. The extracts are washed to neutrality with water and evaporated to dryness. The residue is dissolved in acetone, evaporated to dryness under reduced pressure, redissolved in acetone and crystallized by the additon of hexane. This gives the dienone (54) 24.4 g, mp 236-239°. 

Cyano-3 -hydroxy-5a-pregnan-20-one A suspension of 5a-pregnane-3, 20-dione (2 g) in ethanol (90 ml) is treated with acetone cyanohydrin (4 ml) and three drops of triethylamine and stirred at room temperature until complete dissolution. After 3 hr, the solution is diluted with 200 ml of water, acidified with acetic acid and the crystalline precipitate is thoroughly washed with water and dried under vacuum to give 2.1 g (97%) of product mp 172-178° (dec). A sample recrystallized from ethyl acetate melts at 176-179° (dec) [a]p 86° (ethyl acetate). 

Deuteration at C-3 by lithium aluminum deuteride reduction of 5a-pregnane-3, 20-dione 3-tosylhydrazone 20-ethylene ketal, 177... 

Several routes to 2,3-diketones have been reported. The most practical and general method is that of Ruzicka, Plattner and Furrer as adapted by Nace and Nelander for synthesis of the diosphenol corresponding to 5a-pregnane-2,3,20-trione (44) starting from 5a-pregnane-3,20-dione (40). The overall yield of diosphenol (44) by this route is 62% based on... 

The crystalline material was removed by filtration and was recrystallized from methylene chloride-acetone to yield a total of 8 g of 5a,6a-oxido-17a-hydroxyallopregnane-3,20-dione 3,20-bis-(ethylene ketal) of MP 211° to 215°C. For analytical purposes, another recrystallization from methylene chloride-acetone gave pure 5a,6a-oxido-17a-hydroxyallo-pregnane-3,20-dione 3,20-bis-(ethylene ketal) of MP 216° to 218.5°C. 

A single crystallisation is unlikely to lead to the isolation of pure crystals. In practice the product recovered in this process contains about 90% 11 a-hydroxyprogeterone with low levels of other products (especially 5 a-pregnane-3,20-dione and 60, lla-dihydroxyprogesterone). An example of a manufacturer who uses microbial 11a hydroxylation is Upjohn progesterone is used as substrate. 

According to an alignment ofthree human CAR ligands (clotrimazole, androstanol and 5 3-pregnane-3,20-dione) leading to a pharmacophore model, three H features... 

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