Process for the preparation of 17.beta.-hydroxy-3-oxo-17.alpha.-pregn-4-ene-21-carboxylic acid .gamma.-lactone

A process for the preparation of 17.beta.-hydroxy-3-oxo-17.alpha.-pregn-4-ene-21-carboxylic acid .gamma.-lactone which comprises:

• a. mineral acid hydrolysis of sarsasaponin to afford sarsasapogenin;
• b. acetylation of sarsasapogenin followed by oxidation using a mixture of chromic acid in water and acetic acid to afford 3.beta.-acetoxy-5.beta.-pregn-16-en-20-one;
• c. conversion of the resulting 3.beta.-acetoxy-5.beta.-pregn-16-en-20-one to the corresponding oxime using hydroxylamine hydrochloride;
• d. rearrangement of that oxime using phosphoryl chloride and triethylamine to aford 3.beta.-acetoxy-5.beta.-androstan-17-one;
• e. alkaline hydrolysis of 3.beta.-acetoxy-5.beta.-androstan-17-one to afford the corresponding 3.beta.-hydroxy compound;
• f. reacting the 3-hydroxy compound with a lower alkyl vinyl ether in the presence of an acid catalyst to give a 3.beta.-(1-lower alkoxyethoxy)-5.beta.-androstan-17-one;
• g. ethynylating the ketone by means of an ethynylating agent selected from the group consisting of potassium hydroxide and acetylene, ethynylmagnesium chloride, lithium acetylide, or sodium acetylide to give the corresponding 17.alpha.-ethynyl-17.beta.-hydroxy compound;
• h. treating this 17.beta.-hydroxy compound with a lower alkyl vinyl ether in the presence of an acid catalyst to give the corresponding 3.beta.,17.beta.-bis[1-(lower alkoxy)ethoxy]-17.alpha.-ethynyl-5.beta.-pregnane;
• i. treating the resultant compound with a reagent selected from the group consisting of a Grignard reagent and lithium alkyl followed by carbonation to give 3.beta.,17.beta.-bis[1-(lower alkoxy)ethoxy]-5.beta.-pregn-20-yne-21-carboxylic acid;
• j. hydrolyzing the compound under mineral acid conditions to give 3.beta.,17.beta.-dihydroxy-5.beta.-pregn-20-yne-21-carboxylic acid;
• k. catalytic hydrogenation of this 20-yne as the triethylamine salt followed by treatment with a mineral acid to effect lactonization and give the desired 3.beta.,17.beta.-dihydroxy-5.beta.,17.alpha.-pregnane-21-carboxylic acid .gamma.-lactone;
• l. oxidation of the .gamma.-lactone to give 17.beta.-hydroxy-3-oxo-5.beta.,17.alpha.-pregnane-21-carboxylic acid .gamma.-lactone;
• m. treatment of the 3-oxo compound with bromine in an inert solvent to afford the corresponding 4-bromo-17.beta.-hydroxy-3-oxo-5.beta.,17.alpha.-pregnane-21-carboxylic acid .gamma.-lactone;
• n. dehydrobromination of the 4-bromo compound to afford 17.beta.-hydroxy-3-oxo-17.alpha.-pregn-4-ene-21-carboxylic acid .gamma.-lactone.