DD232605A3 - PROCESS FOR REDUCING ESTRON-3-METHYL ETHER DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the reduction of estrone-3-methyl ether derivatives to the corresponding estradiol-3-methyl ether derivatives by means of sodium borohydride as a reducing agent. The aim of the invention is the production of intermediates of Steroidtotalsynthese on economically particularly auspicious and technically simple manner. The reduction of Estron-3-methyl ether derivatives is carried out by the action of 0.45 to 0.6 moles of sodium borohydride in a benzene-methanol mixture at room temperature on estrone-3-methyl ether derivatives of the general formula I, in which u represents an unsaturated or gesaettigte bond , The corresponding estradiol-3-methyl ether derivatives are obtained by concentration in crystalline form. Formula I

Description

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lost. The implementation of the reduction in heterogeneous phase also requires a considerable excess of sodium borohydride due to the extended reaction time. The use of large quantities of sodium borohydride leads to a strongly alkaline reaction of the reducing medium and thus to the modification of alkali-sensitive steroid ketones, such as, for example, 8,14-bis-dehydroestrone-3-methyl ether. The reduction products of such compounds are obtained in highly contaminated, oily form and can be purified only by extreme methods such as high vacuum distillation, column chromatography and fractional crystallization with very large yield losses. Reduction of 17-keto-I4cx-H steroids, using the usual polar solvents such as ethanol, methanol, tetrahydrofuran-water, yields, in addition to the 17β-hydroxy steroids, appreciable amounts of the 17 (X isomers prior to further processing of the reduction products must be removed by recrystallization.

Object of the invention

The present process aims at the reduction of saturated and unsaturated estrone-3-methyl ether derivatives in an economical and technically simple manner and serves to prepare estradiol-3-methyl ether derivatives which are important intermediates in the synthesis of highly effective steroid hormones.

the essence of the invention

The invention has for its object to obtain at maximum conversion per reaction volume, minimum Natriumborhydridmengen and simple isolation reduction products whose quality allows further processing without prior purification.

It has been found that the reduction of estrone-3-methyl ether derivatives in benzene-methanol mixtures of suitable composition, preferably 1: 1, at high steroid concentration and room temperature within 20 to 30 minutes is completed. This high reaction rate is all the more surprising, since reductions with sodium borohydride in benzene are not expired and have not previously been described.

According to the invention, when using a Benzo1-Methano! -Mixture 0.45 to "0.6 moles of sodium borohydride for complete reduction of one mole of estrone-3-methyl ether derivatives, which at a stoichiometric consumption of 0.25 moles of sodium borohydride per mole of steroid ketone Due to the high rate of decomposition of sodium borohydride by alcohols was not expected.

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The increase in stereospecificity in the reduction process which occurs with the use of the reaction conditions according to the invention, which leads to a marked reduction in the 170C-hydroxysteroids in comparison with the previously used polar solvents, was likewise unforeseeable.

Finally, even in the case of alkalisensitive steroids, such as 8,14-bis-dehydroestrone-3-methyl ether, the uniform course of the reaction and the gentle reduction conditions give in a simple manner isolatable, readily crystalline crude products in very good yields and in a quality which permits further processing without prior purification ,

The new is essentially that a benzene-methanol mixture of suitable composition, preferably 1: 1, wherein the inventive implementation is not limited only to the mixing ratio 1: 1, used as a reaction medium, the maximum at a maximum steroid concentration Sodium borohydride and high steroid specificity in a short time under gentle conditions, a complete reduction of estrone-3-methyl ether derivatives allowed and thus provides good quality reaction products in high yields. The method outlined differs from the prior art shown by the high steroid concentration not previously described for such compounds, which constitutes an essential prerequisite for the economical design of a technical implementation.

The reuse of the benzene-methanol mixtures distilled off from the reaction mixture under reduced pressure and the saving of considerable amounts of sodium borohydride are further favorable economic factors of the present process. In addition, the simple isolation of estradiol-3-alkyl ether derivatives by concentration of the reaction solution and suction of the crystalline crude product of high quality and a yield of 95 to 98% is a significant technical advantage.

The invention will be explained in more detail below on some embodiments.

embodiments example 1

d, 1-8-dehydroestradiol-3-ethyl ether

300 g of d, l-8-dehydroestrone-3 ^ ethyl ether are dissolved in 1.8 1 of benzene and treated with 1.8 1 of methanol. To this reaction mixture at room temperature 18 g of sodium borohydride are added. After 30 to 45 minutes, the reduction is complete. The reaction solution is reduced to one quarter of the original volume in vacuo

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concentrated. 30 ml of glacial acetic acid in 300 ml of water are added with stirring to the resulting crystal pulp and the remaining benzene is distilled off in vacuo. Water is added to the crystalline distillation residue and, after standing for a short time, filtered off with suction at room temperature, washed neutral with water and dried.

Yield: 300 g crude product of d, l-8-dehydroestradiol-3-methyl ether with a melting point of 130 to 138 ^° C.

Example 2

d, 1-8.14-Bisdehydroestradiol-3 ^ nethylether

100 gd, l-8,14-bis-dehydroestrone-3-niethyl ether are treated as described in Example 1 with 7 g of sodium borohydride for 40 minutes. The reaction mixture is concentrated in vacuo and neutralized with acetic acid. By suction filtration of the resulting crystals 100 gd, l-8,14-Bisdehydroestradiol-3 ^ ethyl ether as a crude product of mp. 98 to 105 ⁰ C and λ 310 nm: = 21 500.

Max

Example 3

d, 1-9 (11) -dehydro-3-methyl-3-methyl-ether

20 g of d, l-9 (11) -dehydroestrone-3-methyl ether results in Example 1 19 g of d, 1-9 (11) -Dehydroestradiol-3 ^ ethyl ether as a crude product having a mp. 129-137 ° C and

λ 264 nm: = 17 500

 Max

Example 4 d-Estradiol-3 ^ 3iethylether

10 g of d-estrone-3-fliethyl ether are dissolved in 100 ml of benzene and 100 ml of methanol and treated with stirring at room temperature with 0.8 g of sodium borohydride. The workup of the reaction mixture of Example 1 gives after intensive drying 9.5 g of d-estradiol-3-methyl ether as a crude product of mp. 116 to 121 ⁰ C and / O _- T ₀ = + 76 ° (in chloroform c = 1)

Example 5

d, l-8-Dehydroestradiol 3-methyl ether

1 g of d, l-8-dehydroestrone-3-ethyl ether is dissolved in 7.2 ml of benzene and treated with 3.6 ml of methanol. To the reaction mixture is added 60 mg of sodium borohydride. After 10 minutes, the reduction is complete and the workup is as described in Example 1

Yield: 0.98 g d, l-8-Dehydroestradiol-3 ^ nethylether, mp 127-135 ⁰ C..

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Example 6

d, 1-8-Dehydroestradiol 3-methyl ether

0.5 g of d, l-8-dehydroestrone-3-methyl ether are dissolved in 3.5 ml of benzene, treated with 7 ml of methanol and reduced by addition of 0.35 g of sodium borohydride at room temperature. After 20 minutes, the reaction mixture is worked up as described in Example 1

Yield: 470 mg of d, 1-8-dehydroestradiol-3-methyl ether of melting point 128 to 133 ^° C.

Claims (1)

123,334 Invention claim: Process for the reduction of estrone-3-methyl ether derivatives to the corresponding estradiol-3-methyl ether derivatives using sodium borohydride, characterized in that the estrone derivatives of general formula I in which u can be an unsaturated or saturated bond are dissolved in a benzoic acid derivative Methanol mixture, preferably 1: 1, reduced at room temperature with less than 0.6 moles of sodium borohydride per mole of Estronderivat to the corresponding Estradiolderivaten and isolated the reduction products by concentration of the reaction solution in crystalline form. For this 1 page formulas Field of application of the invention The present invention relates to a process for the reduction of estrone-3-methyl ether derivatives to the corresponding estradiol-3-methyl ether derivatives using sodium borohydride as the reducing agent. Characteristic of the known technical solutions Sodium borohydride is known as a reducing agent for carbonyl groups and has proven itself as such in the steroid field. It is characterized by a good stereospecificity, which leads in the case of 17-keto-14 (X-Η-steroids predominantly to 17ß-hydroxysteroids.As reaction media are polar solvents such as methanol, ethanol, isopropanol, tetrahydrofuran-water, dimethylformamide proposed the same water, pyridine and mixtures thereof. a substantial excess of sodium borohydride is used for the reduction. the reaction times range from 20 minutes at the methanol-water mixtures, and 24 hours with the use of isopropanol as the reaction medium. the reaction temperatures are values of -30 ⁰ C. To the boiling points of the solvent mixtures, less polar steroid ketones, such as, for example, 8-dehydro-estrone-3-ethyl ether, due to their low solubility in the customary polar reaction media, permit only relatively low steroid concentrations and therefore require considerable reduction in the industrial performance of the reaction Reaction volumes Conditions of this type allow only a low mass conversion per reaction vessel and are economically unprofitable. Low steroid concentrations and large amounts of the usual polar solvents, in particular alkanols and solvent-water mixture, require a considerable excess of sodium borohydride, which is known to be decomposed very rapidly by these solvents even at room temperature, and thus to the reductant.