DD205170A1 - METHOD FOR THE PRODUCTION OF STEROIDS WITH A 4,9-DIENSYSTEM - Google Patents

Abstract

The production of steroids with a 3-keto-4,9-diene system is described. Such compounds have, because of their hormonal u.anthihormonellen effects phz.Interesse u.koennen zB used for fertility control werden.Bei the new method d.4,9-diene system starting from the corresponding 3-keto-5 (10) -en -steroids by bromination with polyvinylpyridinium bromide perbromide and subsequent dehydrobromination produced by means of polyvinylpyridine. The use of polymeric reagents offers advantages over the prior art.

Description

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Title of the invention

Process for the preparation of steroids with a 4 system

Field of application of the invention

The invention relates to a process for the preparation of steroids having a 4,9-diene system A _he general formula I

in which R 1 represents a methyl or ethyl radical, R _{2 represents} a hydroxyl group and R 0 represents either a hydrogen atom, a methyl group or a methyl group substituted by a hetero radical or in which R ₂ and R 1 together represent a carbonyl function hormonal and anti-hormonal effects, in particular because of their sometimes strong progestagenic activities, and can be used in suitable pharmaceutical preparations for the treatment of endocrinopathies and for the reproduction control in humans and in livestock.

Characteristic of the known technical solutions

The compounds sina 'obtainable by the present process ^; * bekanjcit · For their presentation one starts from 3-keto-5 (10) -en-steroids of the general formula II

2AO19 5 0

II

in which R,., IU and IU have the abovementioned meanings · Piese are converted by treatment with a brominating agent, usually with elemental bromine or pyridinium bromide perbromide in the 5,10-Jibribride and from it by means of pyridine 2 mol of hydrobromic acid to the compounds of In general, the procedure is such that the steroid of the general formula II in Pyrioder a mixture of a chlorinated hydrocarbon

and dissolves pyridine and at a temperature between O ⁰ O and -20 ⁰ O, the elemental bromine added dissolved or dissolved in a halogenated hydrocarbon, or the Pyridiniumbromidperbromid preferably added in portions · After completion of the addition of the hydrogen bromide to temperatures between 20 and 60 ^° C. and then the product of the general formula I is isolated by pouring the reaction mixture into dilute hydrochloric acid and repeated extraction with a halogenated hydrocarbon (Lit.:D.P.S.P.S.Pat., 132, 497; Perelman et al., J. Amer. 82 (1960) a402) i

The process has some significant technological and economical drawbacks. This includes the need to carefully control the addition of the brominating agent so that the concentration of virgin brominating agent in the reaction solution is kept as low as possible. By an increased temporal or local concentration of bromine in addition to the addition to a considerable extent substitution reactions and the resulting brominated by-products are difficult to separate from the final product later · Another disadvantage relates to the work-up of the reaction mixtures, in which an aqueous 2

-3- 2AO 1 9 5 0

Phase system is worked and must be very intense and repeatedly treated with dilute hydrochloric acid to remove the pyridine from the organic phase. From an economic point of view, the fact that the costly pyridine used on a large scale is present in a dilute hydrochloric acid solution at the end of the process from which it can practically not be recovered on the one hand, but on the other hand represents a wastewater load in this form, is to be regarded as a disadvantage and must be eliminated «

Object of the invention

The aim of the invention is the preparation of steroid derivatives with a 4 _J 9-diene system.

Explanation of the essence of the invention

The invention has for its object to provide a method for the bromination and dehydrobromination of 3-keto-.5 (10) -en-steroids, which makes it possible to produce 4,9-J) ien ** steroids, with significant disadvantages of the known Procedure can be avoided

According to the invention the object is achieved in that 3-keto-5 (10) - "steroids of the general formula II in which R ^, Ro and Ro have the abovementioned meaning in an organic solvent, in particular a halohydrocarbon such , After bromination and dehydrobromination, the polymer base and the spent, polymeric bromination agent are filtered off and these compounds of general formula I are obtained by evaporating off the solvent. ....

The process according to the invention is advantageously carried out as follows: The 3-eto-5 (10) -en-steroids of general formula II are dissolved in methylene chloride or chloroform and in the solution polyvinylpyridine in a ratio of 2 to 6 parts by weight of polymeric base Weight portion steroid suspended »

mm 4 ¹ m

2Λ019 5 O

Thereafter, the polyvinylpyridinium bromide perbromide is added in slight excess (molar ratio 1.5 to 1) at once with stirring;

The polymeric brominating agent is prepared as follows: 5 g of polyvinylpyridine are suspended in 70 ml of water and admixed with 10 ml of 4% hydrobromic acid. The mixture is stirred at room temperature for 1 hour, filtered off with suction, washed with water and ether. 9.0 g) is suspended in 50 ml glacial acetic acid and 60 to 70 * ⁰ O was added dropwise at ca 5.0 ml of bromine with stirring "It is stirred for one hour at this temperature and allowed to cool overnight ·

The polyvinylpyridinium bromide perbromide is filtered off with suction, washed with water and then with benzene. After drying over KOH, 13.0 g of polymeric perbromide are obtained. The course of the bromination-dehydrobromination reaction is monitored by thin-layer chromatography. After the reaction has ended, the polymeric reagents are filtered off and can be regenerated. Evaporation of the filtrate under reduced pressure gives the 4,9-4) iene derivative corresponding to the general formula I embedded image The invention is based on the surprising finding that polyvinylpyridinium bromide perbromide, in contrast to the known polymeric Bromierungsmittein (lit; * Synthesis 1979 "64) hardly substitution reaction reactions, but dats with his help, the bromine practically exclusively can be added to the double bond *

As a result of the use of the process according to the invention, there are the following advantages: Since virtually no bromine substitution products are formed with polyvinylpyridinium bromide perbromide, the brominating agent does not need to be metered in excessively. The use of "excessively in one go" is used completely avoided by pyridine, so that no wastewater problems arise or «eliminates the need for destruction of the waste liquors« The polymer reagents used are removed by simple filtration and can be repeatedly regenerated

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become"

The following examples are intended to explain the process according to the invention.

Embodiment ·

· 17-olydomethyl-17-yl-hydroxy-ortho-4-tert-9-dien-3-one

0.313 g (1 mmol) of 17öd-cyanomef- chyl-17β-hydroxy-est; r-5 (10) -en-3-one are dissolved at room temperature in 50 ml of methylene chloride and therein 2.0 g of polyvinylpyridine (PVP J.M., J. Chem Frechet J, org Chem 43 (1978) 2618). With vigorous stirring, 0.4-5 g of polyvinylpyridinium bromide perbromide (PVP * HBr ^ Br ₂ ) are added all at once. The mixture is stirred at room temperature for 20 hours, the polymeric reagents are filtered off with suction and washed several times with methylene chloride. The combined filtrates are added concentration i _# V 0.26 g (83% of theory..) 17 <^ - i * Oyanomethyl-17-iiydroxy "-estr - 4 _t 9- <lien-3-one, m.p., 210 to 212 ⁰ After recrystallization from methanol or ethyl acetate

· 17ß ^ hydroxy-ö s tra-A, ° wüen-3-one

0.27 g (1 mmol) of i7β-hydroxy-oestr-5 (10) -en-3-one are dissolved in 50 ml of chloroform at tree temperature and 2 g of polyvinylpyridine (PVP) are added to the solution. 0.45 g of polyvinylpyridinium bromide perbromide (PVP · HBr · Br ₂ ) are added all at once »Stirred for 20 hours at room temperature, then the polymeric reagents are filtered off with suction and washed several times with chloroform. The combined filtrates are concentrated i.v. and give 0.23 6 (84% d. · 07h) i7ß- ydroxy £ «^ stra-4,9 ~ dien-3-one, m.p. · 180-182 ⁰ C after recrystallization from methanol ·

· Azidomethyl-17β-hydroxy-estra-4,9-diene-3-one

0.33 g (i mmol) of i7c-azidomethyl-i7β-hydroxy-ostr-5 (10) -en-3-one are dissolved in 50 ml of methylene chloride at room temperature and 2 g of polyvinylpyridine (PVP) are added to the solution. 0.45 g of polyvinylpyridinium bromide perbromide (PVP.HBr * Br.sub.1) are added in one portion and the mixture is stirred

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Suspension for a further 20 hours at room temperature. Thereafter, the polymeric reagent is filtered off, washed thoroughly with methylene chloride and the combined filtrates are concentrated by evaporation. 0.28 g (86% dTh *) of VjaC- azidomethyl-

Bp · 202 to 205 ° 0 naoh

Recrystallization from methanol «

Claims (1)

24019 5 0 invention claim Process for the preparation of steroids with a 4,9-diene system of general formula I. at the R ,. a methyl or ethyl radical, Rg is a hydroxyl group and R "is either a hydrogen atom, a methyl group or a methyl group substituted by a hetero radical or in which R" and R ~ together represent a carbonyl function, characterized in that 3-keto-5 (10) -en-steroids of general formula II II where R,., Rp ^{} ma} · ^R 3 have ^{the abovementioned} meaning in an organic solvent, preferably a halohydrocarbon in the presence of polyvinylpyridine with polyvinylpyridinium bromide perbromide added, after the reaction, the polymeric reagents filtered off and the compounds by evaporation of the filtrate pure receives "