Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Patent
1991-01-17
1992-08-18
Mars, Howard T.
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
552540, 552543, 552544, 552552, 552553, 552554, 552555, 552557, 552599, 552603, 552605, 552608, 552610, 552611, 552650, 552651, C07J 700, C07J 900
Patent
active
051401061
DESCRIPTION:
BRIEF SUMMARY
SUMMARY OF THE INVENTION
The invention relates to a process for the production of 3-deoxy-4-ene steroids of the general formula I ##STR2## in which R.sub.1, R.sub.2 and R.sub.3 mean a hydrogen atom or a methyl group, esterified or etherified hydroxy group, --C.tbd.CR.sub.6 with R.sub.6 meaning a hydrogen atom, an alkyl group with a maximum of 4 carbon atoms or a halogen atom, group or a vinylidene group, chloromethylene group or a hydroxymethylene group and in which the bonds represent three single bonds or one double bond and two single bonds or a conjugated double bond, which is characterized in that a 3-oxo-4-ene steroid of the general formula II ##STR3## in which R.sub.1, R.sub.2, R.sub.3, X, Y, Z and U have the above-mentioned meaning and R'.sub.4 and R'.sub.5 mean the same as R.sub.4 and R.sub.5 or together represent an oxy group, is reduced with a reaction mixture of trifluoroacetic acid or trichloroacetic acid, optionally of another carboxylic acid and sodium borohydride. pharmacologically effective substances or valuable intermediate products for the production of pharmacologically effective compounds (DE-A 2 361 120; EP-B 17 094 and EP-B 34 114).
Thus, for example, 3-deoxy-4-ene steroids of the general formula Ia ##STR4## in which R'.sub.3 represents a hydrogen atom or a methyl group, carbon atoms, chloroethinyl group or a 1-propinyl group, are marked by a strong gestagen effectiveness. Examples of such gestagenally effective steroids are lynestrenol (17alpha-ethinyl-4-estren-17beta-ol) and desogestrel (17alpha-ethinyl-18-methyl-11-methylene-4-estren-17beta-ol).
According to the known prior art, the 3-deoxy-4-ene steroids of the general formula I are produced from the 3-oxy-4-ene steroids of the general formula I so that the latter, for example, are converted by ethanedithiol to 3-thioketals and in the latter the thioketal group is cleaved by sodium or lithium in liquid ammonia. This process is quite expensive because of the high energy costs spent and further has the drawback that it is very harmful to the environment because of the very offensive odor.
In contrast, the process according to the invention is a single-stage reaction, simple to perform, and with little harm to the environment, in which, just as in the previously known two-stage process, yields of about 60 to 85% of theory are achieved.
The process according to the invention is suitably performed so that primarily the sodium borohydride is reacted at a temperature of -10.degree. C. to +20.degree. C. in the trifluoroacetic acid or trichloroacetic acid and optionally another carboxylic acid. Since in this case, a great foam formation takes place as a result of generation of hydrogen, acetonitrile is suitably added to the trihaloacetic acids before the beginning of the reaction, by which the foam formation is largely suppressed. When trifluoroacetic acid is used it is necessary, with the use of trichloroacetic acid it is not always necessary to add additional carboxylic acids to the trihaloacetic acids. Such carboxylic acids can be monocarboxylic acids, dicarboxylic acids or tricarboxylic acids, such as, for example, propionic acid, butyric acid, pivalic acid, succinic acid, citric acid or especially the very reasonably priced acetic acid. In the following embodiments, an excess of reactant/solvent mixture is always used for the reaction of sodium borohydride with trihaloacetic acids, so that clear solutions are formed. The minimal amount each of reactant/solvent mixture necessary for an industrial performance and its optimal composition must be determined in individual cases by preliminary experiments, as they are familiar to one skilled in the art.
The steroid to be converted--dissolved in an inert solvent--can be put into the sodium borohydride/trihaloacetic acid reaction mixture thus prepared, which optionally contains another carboxylic acid. But purer process products are often obtained if this reaction mixture is put into a solution of the steroid. Normally, a reaction mixture produced from 2.5 mol to 20 mol of sodium borohydri
REFERENCES:
patent: 3099656 (1963-07-01), Zderic et al.
patent: 3471531 (1969-10-01), Hughes et al.
Gribble, Gordon, W., et al. "Reactions of Sodium Borohydride in Acidic Media; IV. Reduction of diarylmethanols and triaylmethanols in Trifluoroacetic acid." Synthesis. No. 3, pp. 172-176 (1977).
Gribble, Gordon W., et al. "Reactions of Sodium Borohydride in Acidic Media; VII Reduction of Diaryl Ketones in Trifluoroacetic Acid." Synthesis, No. 10, pp. 763-765 (1978).
Chemical Abstracts 100:94990n (Mar. 13, 1989).
Hofmeister Helmut
Laurent Henry
Tilstamm Ulf
Winterfeldt Ekkehard
Kestler Kimberly J.
Mars Howard T.
Schering Aktiengesellschaft
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