Process for production drospirenone and intermediate products of

Details Process for production drospirenone and intermediate products of Process for production drospirenone and intermediate products of

1999-02-11

2000-09-19

Trinh, Ba K.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D30794

Patent

active

061214655

DESCRIPTION:

BRIEF SUMMARY
The invention relates to a 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) 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.
Drospirenone (6.beta., 7.beta.; 15.beta., 16.beta.-dimethylene-3-oxo-17.alpha.-pregn-4-ene-21, 17-carbolactone, DRSP, INN) has been known for some time as a steroidal active ingredient (DE 26 52 761 C2 and DE 30 22 337 A1), and the production of the last 4 steps is carried out in a single-pot reaction; in which after dimethylene propinol ZK 34506 is hydrogenated, none of the intermediate stages dimethylene propanol and 5-.beta.--OH-DRSP that are passed through are isolated (see diagram below). ##STR2##
The dimethylene propinol ZK 34506 is hydrogenated in tetrahydrofuran with hydrogen on palladium-carbon into dimethylene propanol ZK 92836. The hydrogenating solution that is thus obtained, which contains propanol ZK 92836 as the main product and varying proportions of lactol, is reacted without isolation and intermediate working-up to drospirenone ZK 30595 (DRSP).
For this purpose, a change of solvent from tetrahydrofuran to dimethylformamide first takes place and then the propanol is oxidized at 40.degree. C. with an excess of 3.7 equivalents of pyridinium dichromate (PDC) to a mixture of DRSP and 5--.beta.--OH--DRSP. The 5--.beta.--OH group in the oxidation product is labile compared to acids, Lewis acids and basic conditions at elevated temperatures, since in all cases, a more thermodynamically stable product is obtained with the formation of the .DELTA.-4, 5-unsaturated ketone in the drospirenone. The elimination of the .beta.-OH group in the 5--.beta.--OH--DRSP results in more thermodynamically stable drospirenone, and it was not possible to suppress it.
The mixture generally contains differing proportions of the two components, whereby 5--.beta.--OH--DRSP is generally present as a main component at a ratio of 2-3:1. In the last stage of the single-pot sequence, the two-component mixture is converted by adding semi-concentrated hydrochloric acid into the DRSP, crude.
In the table below, the last four operating preparations are summarized.


______________________________________ Purity (100% Preparation Yield, crude (%) Method) ______________________________________ 537201 57.2 98.9 202 63.7 99.09 203 46.5 99.18 204 58.3 98.81 Total Mean Yield: 56.4 Mean Purity: 98.9 ______________________________________
By the means of all operational preparations, starting from dimethylene propinol, a theoretical yield of 56% DRSP, crude at an HPLC purity of 98.9%, is achieved.
The object of the invention is the provision of a new production process for drospirenone, which is more selective and simpler in execution than that from the prior art and, in addition, is ecological (savings of a chromium trioxide oxidation).
This object is achieved according to the teaching of the claims.
The invention contains a process for the production of drosporenone (6.beta., 7.beta.; 15.beta., 16.beta.-dimethylene-3-oxo-17.alpha.-pregn-4-ene-21, 17-carbolactone, DRSP) ##STR3## by catalytic hydrogenation of 17.alpha.-(3-hydroxy-1-propynyl)-6.beta., 7.beta.; 15.beta., 16.beta.-dimethylene-5-androstane-3.beta., 5, 17.beta.-triol (ZK 34506) ##STR4## 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 (ZK 92836) ##STR5## then oxidation with use of commercially available ruthenium salts, such as RuCl.sub.3, RuO.sub.2, KRuO.sub.4, K.sub.2 RuO.sub.4, but preferably in the presence of catalytic amounts of RuCl.sub.3 (1 mol %) and conventional, simple oxidizing agents such as butyl hydroperoxide, N-methyl-morpholine-N-oxide, M.sub.2 S.sub.2 O.sub.8 (M=Na, K), MXOy (M

REFERENCES:
patent: 4416985 (1983-11-01), Petzoldt et al.
patent: 4435327 (1984-03-01), Petzoldt et al.
patent: 5106995 (1992-04-01), Plotkin
Bittler et al., "Synthesis of Spirorenone-A Novel Highly Active Aldosterone Antagonist," Angewandte Chemie. International Edition, vol. 21, Issue 9, pp. 696-697 (1982).

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