Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Patent
1992-06-15
1994-07-26
Rizzo, Nicholas S.
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
568364, 568369, C07J 6300, C07J 700
Patent
active
053328477
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a process for the preparation of 21-bromo-4-pregnene-3,20-dione derivatives of general Formula I ##STR2## wherein R.sub.1 is a hydrogen atom, a hydroxy group or an alkanoyl group of up to 6 carbon atoms, ##STR3## wherein R.sub.1, R.sub.2, R.sub.3, X, Y and V have the meanings given above and characterized by reacting to the reaction mixture, prior to bromination, per mole of steroid 0.01 to 1 mole of methanesulfonic acid and 1 to 2 moles of an ortho ester of general Formula III atoms, and
The 21-bromo-4-pregnene-3,20-dione derivatives of general Formula I are, as is known, valuable intermediate products usable, for example, for the preparation of 21-acyloxy-4-pregnene-3,20-dione derivatives of general Formula IV ##STR4## wherein R.sub.1, R.sub.2, R.sub.3, V, X and Y have the meanings given above and
It is known that these 21-bromo-4-pregnene-3,20-dione derivatives can be produced by the bromination of enamines of general Formula II, the latter compounds being synthetized, in turn, from 4-pregnene-3,20-dione derivatives of general Formula V ##STR5## wherein R.sub.1, R.sub.2, R.sub.3, V, X, and Y have the meanings given above.
Since the enamines of general Formula II as well as the 21-bromo-4-pregnene-3,20-dione derivatives of general Formula I produced therefrom show low stability and accordingly do not have a shelf life, the synthesis is performed under practical conditions in almost all cases by reacting these compounds further immediately after they have been formed.
Thus, Example 1 of DE-B 1,801,410 describes the conversion of 17.alpha.-hydroxy-4-pregnene-3,20-dione into 21-acetoxy-17.alpha.-hydroxy-4-pregnene-3,20-dione in a four-stage process. According to the patent, this process affords a yield of 66% of theory. However, it has been found under practical conditions that the attainable yield is, after all, substantially lower and hardly exceeds 55% of theory. Furthermore, the purity of the thus-obtained product of the process is barely 90% and accordingly unsatisfactory.
A somewhat improved process was developed by B. Gadsby et al. (John Friend and John A. Edwards, "Organic Reactions in Steroid Chemistry" vol. 2, van Nostrand Reinhold Comp., New York etc., 1972, p. 223). According to this method, as has been discovered under practical conditions, 17.alpha.-hydroxy-4-pregnene-3,20-dione is converted into 21-acetoxy-4-pregnene-3,20-dione in a yield of 62%. The purity of the resultant product is 94%. An essential deficiency of this process resides in that the bromination proper is conducted at -60.degree. C. whereby the reaction becomes very expensive.
Additionally worth mentioning is a method described in Japanese Patent Application 81.22797 (ref. Chem. Abstr. 95 : 43465j, 1981) according to which 17.alpha.-hydroxy-4-pregnene-3,20-dione can be converted into the 21-acetoxy-17.alpha.-hydroxy-4-pregnene-3,20-dione (purity 95%) with a yield of 67% of theory, as was found under practical conditions. The disadvantage of this process resides in that the bromination is performed in the presence of perchloric acid whereby the reaction mixture becomes a great explosion hazard. Additional drawbacks of this method are that the bromination is performed in a very high dilution and takes a relatively long period of time (7-8 hours).
It is possible with the aid of the process according to this invention, as will be described in greater detail in the examples, to convert the starting compounds of general Formula V with a yield of more than 90% of theory into products of general Formula IV (purity above 93%). Additional advantages of the process of the invention can be seen in that the bromination can be performed in a relatively concentrated solution approximately at room temperature within a relatively brief period of time without the need for using materials which represent an explosion hazard.
It has been mentioned above that the enamines of general Formula II, serving as the starting compounds for the process of the present invention are, in turn, produced from the 4-pregnene-3,20-dione de
REFERENCES:
patent: 3557158 (1971-01-01), Lincoln et al.
Joint Center for Chemistry, Sofia Chemical Abs., vol. 95, 1981 Abs. 43465j.
Ryakhovskaya, et al. Chem. Abs. vol. 114, 1991 Abstract 164613a.
Gadsby et al. J. Chem. Soc. C, 1968, pp. 2647-2656.
Rizzo Nicholas S.
Schering Aktiengesellschaft
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