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Process For The Preparation Of Drospirenone

a technology of drospirenone and process, which is applied in the field of industrial scale preparation of drospirenone, can solve the problems of large quantity and practically unusability of highly toxic solvents, and achieve the effect of high final purity and high degree of purity

Inactive Publication Date: 2008-08-28
IND CHEM SRL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is a process for obtaining high purity drospirenone, which is suitable for use in pharmaceutical compositions. This process avoids the use of toxic and carcinogenic reagents and the need for chromatographic purifications of crude drospirenone to obtain a high final purity. The process involves oxidizing a specific compound with a suitable oxidizing agent in an organic solvent in the presence of a catalytic amount of a specific substance. This is followed by the addition of a protic acid directly into the reactor where the oxidation took place. The resulting drospirenone is highly pure and can be used as an active principle in pharmaceutical compositions.

Problems solved by technology

The use of this highly toxic solvent in relatively large quantities is one of the unfavourable aspects of this process.
This step constitutes a further disadvantage of the known process: chromic anhydride, as all Cr (VI) compounds, is actually a known carcinogen whose use is subject to legislative restrictions such that the precautions required during the use and disposal of these products render them practically unusable.

Method used

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  • Process For The Preparation Of Drospirenone
  • Process For The Preparation Of Drospirenone
  • Process For The Preparation Of Drospirenone

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 7α-bromo-5,6β-epoxy-15β,16β-methylene-3β-pivaloyloxy-5β-androstan-17-one

Step a)

[0036]67.5 g of 5,6β-epoxy-7β-hydroxy-15β,16β-methylene-3β-pivaloyloxy-5β-androstan-17-one are dissolved in 205 ml of pyridine in a 2 litre flask, under nitrogen.

[0037]17.5 ml of mesyl chloride are added from a dropping funnel, maintaining a temperature of 20 / 25° C.

[0038]The mixture is stirred for 1 hour at 20° C. to obtain a thick orange suspension.

[0039]The progress of the reaction is checked by TLC. Once the reaction is completed, 83.2 g of lithium bromide dissolved in 54 ml of water are added and the temperature is brought to 70 / 75° C. After 3 hours another 8 g of lithium bromide dissolved in water and 50 ml of pyridine are added.

[0040]At the end of the reaction (checked by TLC) the temperature is brought to 60° C. and 700 ml of water are added; it is left to cool to 15 / 20° C., maintaining under stirring for 1 hour at this temperature.

[0041]The solid is filtered off and washed with 500 ...

example 2

Preparation of 5-hydroxy-15β,16β-methylene-3β-pivaloyloxy-5β-androst-6-en-17-one

Step b)

[0046]27 g of powdered zinc suspended in 91 ml of THF (tetrahydrofuran) are fed into a 1 litre flask, under nitrogen.

[0047]A solution of 67.5 g of 7α-bromo-5,6β-epoxy-15β,16β-methylene-3β-pivaloyloxy-5β-androstan-17-one, prepared as described in Example 1, in 277 ml of THF is then added; 19.9 ml of glacial acetic acid are slowly added dropwise, maintaining the temperature below 60° C. during the addition. The reaction mixture is maintained under stirring for 3 hours at 59 / 60° C.

[0048]At the end of the reaction (checked by TLC) and after cooling to 50° C., the zinc is filtered off over dicalite and the filter washed with 200 ml of THF.

[0049]The filtered solution is brought to pH 9 with 60 ml of triethylamine.

[0050]The solution is concentrated under reduced pressure at 50° C. to obtain about 180 g of a semi-solid product which is dissolved in 500 ml of a 5% acetic acid-water solution (pH=4 with a pr...

example 3

Preparation of 3β,5-dihydroxy-15β-16β-methylene-5β-androst-6-en-17-one

Step c)

[0056]43 g of 5-hydroxy-15β,16β-methylene-3β-pivaloyloxy-5β-androst-6-en-17-one prepared as described above in Example 2, 430 ml of THF, 215 ml of methanol and 12.9 g of potassium hydroxide are fed into a 2 litre flask, under nitrogen at 20° C. The suspension is stirred at 20° C. for 3 hours.

[0057]At the end of the reaction (checked by TLC), the reaction mixture is poured into 2 litres of water, brought to pH 7 with 20% sulphuric acid (about 25 ml) then the suspension is stirred for 1 hour at 0 / 5° C. The solid is filtered off, washed with water and dried for 12 hours under reduced pressure at 50° C. to obtain 30.6 g of the title compound.

[0058]The analytical data obtained for a sample purified by chromatography correspond to those given in EP 0 075 189.

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Abstract

A process is described for the preparation of drospirenone, a synthetic steroid with progestogenic, antimineralocorticoid and antiandrogenic activity, useful for preparing pharmaceutical compositions with contraceptive action; comprising the oxidation of 17α-(3-hydroxypropyl)-6β,7β,15β,16β-dimethylene-5β-androstane-3β,5,17β-triol.

Description

FIELD OF THE INVENTION[0001]The present invention relates to the field of processes for synthesising steroids, and in particular to a process for the industrial scale preparation of drospirenone.STATE OF THE ART[0002]The compound of formula (I) given hereinafter, whose chemical name is 6β,7β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone, is commonly known as drospirenone:[0003]It is a synthetic steroid with progestogenic, antimineralocorticoid and antiandrogenic activity; by virtue of these characteristics drospirenone has long been used for preparing pharmaceutical compositions with contraceptive action for oral administration.[0004]Many processes are known in the literature for preparing drospirenone, for example the process described in European Patent No. 0 075 189, starting from 3β,7α,15α-trihydroxy-5-androsten-17-one passing via the intermediate 5,6β-epoxy-7β-hydroxy-15β,16β-methylene-3β-pivaloyloxy-5β-androstan-17-one.[0005]As described in EP 0 075 189, this in...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/585C07J53/00
CPCC07J53/008A61P15/00A61P15/18
Inventor COSTANTINO, FRANCESCALENNA, ROBERTOPIURI, SILVIA
Owner IND CHEM SRL
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