9-Triol, acetate

The final example of 1,2-additions of organoaluminums to masked ketone substrates is outlined in equation (15). The addition of a large excess (10 equiv.) of trimethylaluminum to a variety of triol acetals and ketals proceeds in relatively high overall yield. Although ketal substrates where R did not equal were not attempted, a number of acetals were prepared and upon exposure to MesAl they afforded the corresponding diastereomeric ethers with poor diastereoselectivity (33-17% de). 

A soln. of 300 mg. 17y ,17ay -dimethyl-D-homoandrostane-3y ,17a,17aa-triol acetate and iodine in glacial acetic acid refluxed 0.5 hr. under Ng, then the iodine reduced with a few drops of satd. aq. Na-bisulfite soln. 185 mg. 3 -acetoxy-17,17-dimethyl-D-homoandrostan-17a-one. M. Uskokovic et al., Am. Soc. 82, 4965 (1960). 

MeO)2CH2, LiBr, TsOH, CH2CI2, 23°, 83% yield. In this case a 1,3-methylene acetal is formed in preference to a 1,2-methylene acetal from a 1,2,3-triol. These conditions, also protect simple alcohols as their MOM derivatives. 

A benzylidene acetal is a commonly used protective group for 1,2- and 1,3-diols. In the case of a 1,2,3-triol the 1,3-acetal is the preferred product. It has the advantage that it can be removed under neutral conditions by hydrogenolysis or by acid hydrolysis. Benzyl groups and isolated olefins have been hydrogenated in the presence of 1,3-benzylidene acetals. Benzylidene acetals of 1,2-diols are more susceptible to hydrogenolysis than are those of 1,3-diols. In fact, the former can be removed in the presence of the latter. A polymer-bound benzylidene acetal has also been prepared." ... 

The presence of an a-bromo substituent may cause anomalies. With NaBH4, 2a-bromo-5a-cholestan-3-one gives a mixture of epimers, in which the 3p-o predominates. 4 -Bromo-17)5-hydroxy-5)5-androstan-3-one acetate gives 25% of the 315,4 -bromohydrin and 34% of the 3a,4)5-compound. Reduction of 7a-bromo-3)5,5a-diacetoxycholestan-6-one gives exclusively 7a-bromocholestane-3)5,5a,6a-triol 3,5-diacetate,whereas reduc-... 

Selective protection of 1,2- and m-l,3-diols can be achieved by formation of acetonides, acetals or orthoesters. Further selectivity is possible in special cases (e.g., acetonide formation). With 17a,20,21-triols, the 20,21-acetonide is obtained exclusively. 16a,17a,21-Trihydroxy-20-lcetopregnanes (20) react selectively with acetone to give 16,17-acetonides (21). 

Preferential formation of a 5-membered cyclic acetal is not a general rule in the steroid series e.g., the 1,3-dioxolane (23) is obtained directly from the parent triol (22) and acetone. 17,21-Acetals are obtained only by acetal exchange. ... 

A total of 50 ml (0.15 moles) of a 3 ethereal solution of methylmagnesium bromide is added slowly to a vigorously stirred solution of 5.8 g (12.5 mmoles) or 3,3 20,20-bisethylenedioxy-5a,6a-epoxy-5a-pregnane-ll/l,17a,21-triol in 400 ml of tetrahydrofuran. The solution is heated under reflux for 24 hr, cooled and treated with 32 ml of saturated ammonium chloride solution. The supernatant is decanted and the residue is washed with several portions of tetrahydrofuran. The combined supernatants are evaporated and extracted with ethyl acetate, washed with saturated salt solution, dried and concentrated to give 4,55 g (75%) of 3,3 20,20-bisethylenedioxy-6 -methyl-5a-pregnane-5a,ll, 17a,21-tetrol mp 170-172° after crystallisation from acetone-petroleum ether. The analytical sample is crystallized from acetone-petroleum ether mp 175-177° [aJo —11° (CHCI3). 

Upon cooling and filtering, there is obtained 2 g of 5jff-androstane-3a,6a,17 -triol-3,6-dinitrate 17-acetate mp 130-131°. Chromatography of the mother liquor residue over alumina yields an additional 0.4 g mp 134-135°. Total yield 68%. 

The excess of N-chlorosuccinimide is destroyed by the addition of about 15 drops of allyl alcohol and 180 ml of water is then added with stirring. This mixture is held at 0°C for about one hour. The precipitated 16/3-methyl-1,4-pregnadiene-9o-chloro-11/3,17o,21-triol-3,20-dione-21-acetate is recovered by filtration. A solution of 250 mg of the chlorohydrin in 5 ml of 0.25N perchloric acid in methanol is stirred for about 18 hours at room temperature to produce 16/3-methyl-9o-chloro-11/3,17o,21-trihydroxy-1,4-pregnadiene-3,20-dione which is recovered by adding water to the reaction mixture and allowing the product to crystallize. Propionic anhydride is then used to convert this material to the dipropionate. 

A mixture of 5 g of the 21-acetate of SCt-chlorohydrocortisone, 7 g of chloranii and 100 cc of n-amyl alcohol was refluxed for 16 hours, cooled and diluted with ether. The solution was successively washed with water, 5% sodium carbonate solution and water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Chromatographic purification of the residue yielded the 21-acetate of 6-chloro-A -pregnatriene-11 3,17a,21 -triol-3,20-dione. ... 

To 6a-fluoro-16a-hydroxy-hydrocortisone 21-acetate, described by Mills et al, J. Am. Chem. Soc., volume 81, pages 1264 to 1265, March 5, 1959, there was added acetic anhydride in dry pyridine. The reaction mixture was left at room temperature overnight and was then poured with stirring into ice water. The resulting precipitate was filtered, washed with water and crystallized from acetone-hexane to give 6a-fluoro-16a-hydroxy-hydrocortisone-16a,21-diacetate. This was reacted with methane-sulfonyl chloride in dimethyl formamide in the presence of pyridine at 80°C for 1 hour. The mixture was cooled, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the ethyl acetate was evaporated. By recrystallization of the residue from acetone-hexane there was obtained 6a-fluoro-A <" -pregnadiene-16o ,17a,21-triol-3,20-dione 16a,21 diacetate. 

The above crude bromohydrin was mixed with 2.5 grams of potassium acetate and 60 cc of acetone and refluxed for 6 hours, at the end of which the acetone was distilled, water was added to the residue and the product was extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. Recrystallization of the residue from methanol furnished 800 mg of the 16,21-diacetate of 6o-fluoro-9(3,11(3-oxido-A -pregnene-16o,l7a,2l-triol-3,20-dione with MP 120° to 124°C by chromatography of the mother liquors on silica gel there was obtained 180 milligrams more of the same compound with MP 117° to 119°C. The analytical sample was obtained by recrystallization from methanol it showed MP 125° to 127°C. 

To a solution of 0,85 gram of 1,4-pregnadiene-11(3,17o ,21-triol-3,20-dione (prednisolone) in 5 ml of pyridine are added 3 ml of acetic anhydride. The reaction mixture is allowed to stand at room temperature overnight and Is then diluted with ice water. The resulting precipitate is filtered from the mixture and recrystallized from acetone-hexane. There is recovered 0.45 gram of 1,4-pregnadiene-11(3,17o ,21-triol-3,20-dione 21-acetate, MP 235°-239°C. On recrystallization, the MP rose to 237°-239°C. 

Because the condensation between a diketene acetal and a diol proceeds without the evolution of volatile byproducts, this method allows the preparation of dense, crossUnked materials by using reagents having a functionality greater than 2 (15). Even though either or both the ketene acetal and alcohol could have functionalities greater than 2, only triols were investigated because the synthesis of trifunctional ketene acetals is extremely difficult. 

To prepare crosslinked material, 2 eq of the diketene acetal is reacted with 1 eq of the diol and the resulting prepolymer is then reacted with a triol or a mixture of diols and triols. 

Because the ketene acetal-terminated prepolymer is a viscous Liquid at room temperature, therapeutic agents and the triol can be mixed into the prepolymer at room temperature and the mixture crosslink id at temperatures as low as 40°C. This allows incorporation of heat-sensitive therapeutic agents into a solid polymer under very mild conditions of thermal stress. However, because the prepolymer con-tedns reactive ketene acetal groups, any hydroxyl groups present in the therapeutic agent will result in the covalent attachment of the therapeutic agent to the matrix via ortho ester bonds (16). 

It is clear then that more than one mechanism is operative for glycol fission. In the case of c -cyclopentanediols and camphanediols a cyclic ester is a necessary intermediate. For tra/js-decalin-9,10-diol a non-cyclic mechanism must operate which cannot function for cholestane-3/ ,6j8,7a-triol and is inefficient for /rans-camphanediols. It is pertinent that while the fission of glycols capable of forming cyclic esters proceeds several hundred times faster in benzene than in acetic acid, the reactions of trans-decalin-9,10-diol and tra/ij-hydrindane-l,6-diol are 4-5-fold slower in benzene . ... 

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