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Last Updated: March 29, 2024

Details for Patent: 6,121,465


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Title: Process for production drospirenone and intermediate products of the process
Abstract:Process for the production of drospirenone (6.beta., 7.beta.; 15.beta., 16.beta.-dimethylene-3-oxo-17.alpha.-pregn-4-ene-21, 17-carbolactone, DRSP) (1) and 7.alpha.-(3-hydroxy-1-propyl)-6.beta., 7.beta.; 15.beta., 16.beta.-dimethylene-5.beta.-androstane-3.beta., 5, 17.beta.-triol (ZK 92836) and 6.beta., 7.beta.; 15.beta., 16.beta.-dimethylene-5.beta.-hydroxy-3-oxo-17.alpha.-androstane-21, 17-carbolactone (ZK 90965) as intermediate products of the process. ##STR1##
Inventor(s): Mohr; Jorg-Thorsten (Berlin, DE), Nickisch; Klaus (Berlin, DE)
Assignee: Schering Aktiengesellschaft (Berlin, DE)
Filing Date:Feb 11, 1999
Application Number:09/242,334
Claims:1. A process for the production of 6.beta., 7.beta.; 15.beta., 16.beta.-dimethylene-3-oxo- 17.alpha.-pregn-4-ene-21, 17-carbolactone, ##STR9## comprising, catalytically hydrogenating 17.alpha.-(3-hydroxy-1-propynyl)-6.beta., 7.beta.; 15.beta., 16.beta.-dimethylene-5-androstane-3.beta., 5, 17.beta.-triol of Formula I ##STR10## into 7.alpha.-(3-hydroxy-1-propyl)-6.beta., 7.beta.; 15.beta., 16.beta.-dimethylene-5.beta.-androstane-3.beta., 5, 17.beta.-triol of Formula II ##STR11## oxidizing the compound of Formula II in the presence of ruthenium salt to form 6.beta., 7.beta.; 15.beta., 16.beta.-dimethylene-5.alpha.-hydroxy-3-oxo-17.alpha.-androstane-21, 17-carbolactone of Formula III ##STR12## and dehydrating the latter.

2. 6.beta., 7.beta.; 15.beta., 16.beta.-dimethylene-5.beta.-hydroxy-3-oxo-17.alpha.-androstane-21, 17-carbolactone ##STR13##

3. A process for the production of 6.beta., 7.beta.; 15.beta., 16.beta.-dimethylene-3-oxo-17.alpha.-pregn-4-ene-21, 17-carbolactone, comprising dehydrating a compound of Formula III, ##STR14## which was made by oxidizing in the presence of a ruthenium salt a compound of Formula II, ##STR15## which was made by catalytically hydrogenating a compound of Formula I ##STR16##

4. A process for the production of the compound of claim 2, comprising oxidizing in the presence of a ruthenium salt a compound of Formula II

5. A process for the production of the compound of claim 2, comprising oxidizing in the presence of a ruthenium salt a compound of Formula II, which was made by catalytically hydrogenating a compound of Formula I: ##STR17##

6. The process of claim 1, wherein said catalytic hydrogenating is performed in tetrahydrofuran with hydrogen on palladium-carbon.

7. The process of claim 1, wherein said compound of Formula II is reacted without isolation and intermediate working-up to prepare drospirenone.

8. The process of claim 1, wherein said oxidizing is performed in dimethylformamide at about 40.degree. C. with an excess of 3.7 equivalents of pyridinium dichromate.

9. The process of claim 1, wherein said dehydrating is performed by adding semi-concentrated hydrochloric acid.

10. The process of claim 1, wherein said ruthenium salt is RuCl.sub.3, RuO.sub.2, KRuO.sub.4 or K.sub.2 RuO.sub.4.

11. The process of claim 1, wherein said oxidizing is performed in the presence of a catalytic amount of RuCl.sub.3 and an oxidizing agent.

12. The process of claim 1, wherein said oxidizing is performed in the presence of, as oxidizing agent, butyl hydroperoxide, N-methyl-morpholine-N-oxide, M.sub.2 S.sub.2 O.sub.8, wherein M is Na or K, or MXO.sub.y, wherein M is Li, Na or K, X is B, Cl, Br, or I, and y is 1-4.

13. The process of claim 12, wherein said oxidizing agent is 1-3 equivalents of NaBrO.sub.3.

14. The process of claim 1, wherein said oxidizing is performed in the solvent acetonitrile, chloroform, methylene chloride, carbon tetrachloride, water, tetrahydrofuran, ter-butanol, ethyl acetate or a combination thereof.

15. The process of claim 14, wherein said solvent is an about 1:1 mixture of acetonitrile and water.

16. The process of claim 1, wherein said oxidizing is performed with a catalytic amount of RuCl.sub.3 and about 3 equivalents of NaBrO.sub.3 at 40-60.degree. C.

17. The process of claim 5, further comprising dehydrating the composition of claim 2 thereby preparing drospirenone.

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