ES2726599A1 - USE OF METAL-ORGANIC COMPOUNDS FOR SELECTIVE REDUCTION OF KETOSTEROIDS (Machine-translation by Google Translate, not legally binding) - Google Patents

Abstract

Use of metal-organic compounds for the selective reduction of ketosteroids. The use of Metal-Organic hybrid compounds (MOFs), as heterogeneous catalysts for the reduction (chemo-, regio- and stereoselective) of ketosteroid-type compounds, is described. The use of these materials as catalysts makes it possible, in particular, to prepare derivatives of high added value that are difficult to obtain with other catalysts (homogeneous, heterogeneous or biocatalysts), or through alternative organic synthesis routes. Thus, for example, the use of the metal-organic compounds described in this patent makes it possible to selectively transform estrone into estradiol, or trans-androsterone into androstandiol with high diastereoselectivity to the corresponding isomer l7α -OH; as well as the regional and diastereoselective reduction of androstenedione to epitestosterone. (Machine-translation by Google Translate, not legally binding)

Description

D E S C R I P C I Ó N

USE OF METAL-ORGANIC COMPOUNDS FOR SELECTIVE REDUCTION OF

KETOSTEROIDS

Technical Field

Use of metal-organic hybrid materials as heterogeneous catalysts for the selective reduction of ketostereoids.

Background

Steroids form an extensive group of chemicals that have a common skeleton of 17 carbon atoms consisting of four fused rings (3 rings of 6 and a ring of 5 members). To facilitate the discussion from now on, the following scheme shows the numbering of the C atoms conventionally used, as well as the 4 fused rings (according to Moss, Pure. Appl.Chem., 1989, 61, 1783-1822):

Different steroids vary depending on the substituent groups attached to this skeleton, their position and the configuration of the nucleus. Small modifications in the structure of steroids can result in significant differences in their biological activity. Therefore, it is of great interest to develop routes to selectively modify existing steroid compounds to increase their activity and to prepare new steroid compounds with potential pharmacological activity. The most important area of research within this field is the stereoselective regional and stereoselective transformation using (bio) highly selective catalysts.

Steroid hormones are essential for the proper functioning of most organs in vertebrates and affect virtually every single organ and tissue in humans, playing a key role in their development, differentiation and homeostasis. Steroid hormones mediate a variety of physiological functions, including their function as anti-inflammatory agents or regulating events during pregnancy.

In the world hundreds of tons of steroid-based drugs are produced annually, most of them from androstenedione ketosteroid which, in turn, can be obtained on a large scale from affordable sterols, such as sitosterol, through transformations using microorganisms (see for example Malaviya and Gomes, J. Ind. Microbio !. Biotechnol., 2008, 35, 1235-1239; Herrington et al., WO2003064674)

Ketosteroids (also called oxosteroids) are steroids in which at least one hydrogen atom of the steroid nucleus has been replaced by a ketone group (C = O). Many of the endogenous steroid hormones, as well as their synthetic analogs used in medicine, are ketosteroids, such as glucocorticoids and corticosteroids in general (used, for example, in the treatment of asthma, rheumatoid arthritris, inflammatory bowel disease, lymphoproliferative disorders associated with leukemia or Hodgkin's disease, among others; Buttgereit et al. Lancet, 2005, 365, 801-803), or sex steroid hormones (estrogens, such as estrone and synthetic or paraben estrogens, used as contraceptives or in the treatment of osteoporosis and symptoms associated with menopause; progestins such as progesterone and synthetic analogues, such as etisterone, norethisterone or medroxyprogesterone, involved in the maintenance of pregnancy; and androgens such as testosterone, dihydrotestosterone or androstenedione, which stimulate the development of male sex organs and secondary sexual characteristics).

Hydroxysteroids in general (and among them 17-hydroxysteroids, such as testosterone / epitestosterone, dihydrotestosterone / dihydroepitestosterone, androstandiol or estradiol) are compounds of pharmaceutical relevance. A possible method of direct synthesis of these compounds consists in stereoselective reduction of the corresponding ketosteroids, as shown in the following scheme for several compounds:

It is known that the reduction of 17-ketosteroid compounds to the corresponding 17-hydroxy derivatives (ie, the OH group available without respect to the methyl group in position 18) can be carried out by a large variety of microorganisms (see for example the review article de Donova et al., Prncess Biochem., 2005, 40, 2253-2262). In contrast, the use of microorganisms for the reduction to 17a-hydroxy derivative isomers has only been described for some particular substrates, such as 16,16-difluoro-17-ketosteroids (see Charney and Herzog L. Microbial transformations of steroids. New York , London: Academic Press; 1967. p. 728). In addition, in many cases the reduction of ketosteroids by microorganisms is accompanied by other side reactions, which decrease the final yield obtained from hydroxy derivatives and complicate their purification and subsequent isolation. For example, during the biotransformation of the androst-1,4-dien-3,17-dione by Mucor racemosus , the reduction of the carbonyl group in position 17 occurs together with the hydroxylation at positions C-6p, C-14a and C -15a, giving rise to two monohydroxylated and three dihydroxylated by-products together with the desired product, 17p-hydroxyandrost-1,4-dien-3-one (Faramarzi et al., J. Mol. Catal. B: Enzym., 2009, 84, 1021-1025). The use of Mycobacterium sp. NRRL B-3683 instead, gives place to double reduction of the carbonyl group in position 17 and of the double bond 1,2-C = C (Liu et al., J. Ind. Micriobiol. Biot., 1994, 13, 167-171). On the other hand, the reduction of androstenedione to testosterone by Bacillus sp. It can be accompanied by monohydroxylation products in C-6, C-7, C-11 and C-14 (Schaaf and Dettner, J. Steroid. Biochem. Mol. Biol., 1998, 67, 451-65). Similarly, the reduction of 17-ketosteroids by Phycomyces blakesleeanus or Absidia coerulea can simultaneously produce hydroxylation in position 14a, while the use of Botryosphaerica obtuse can lead to monohydroxylation in position C-6 and dihydroxylation of the C6-C7 bond.

With these complications, it is clear that in many cases it can be difficult to obtain stereoselective 17-hydroxysteroid by reducing the corresponding 17-ketosteroid compounds by biocatalytic pathways using microorganisms. In addition, the use of microorganisms for steroid transformation has additional limitations associated with the low solubility in aqueous media of steroids in general or with the efficient regeneration of used cofactors (NADH or NADPH).

Beyond the use of biocatalytic methods, there is also the possibility in many cases of reducing 17-ketosteroid compounds by reducing chemical agents, such as NaBH4 or LiAlH4, although the 17p-OH isomer is usually the majority compound (Wheeler and Wheeler, Reductions of Steroidal Ketones, ch. 2 in Organic Reactions in Steroid Chemistry, Vol. I, Fried and Edwards (eds), Van Nostrand Reinhold, New York, 1972, pp. 61-110). Therefore, when the compound of interest is the 17a-OH isomer, most of the efforts have focused on the inversion of the corresponding 17p-hydroxysteroids by Mitsunobu reactions (Balssa, et al., Steroids, 2014, 86, 1 -4; Dodge and Lugar, Bioorg. Med. Chem. Lett., 1996, 6, 1-2) or displacement of the sulfonyl ester (Gua and Ding, Tetrahedron Lett. 2015, 56, 4096-4100; Shi et al ., Tetrahedron Asymmetry, 2010, 21, 277-284; Nambara et al., Chem. Pharm. Bull., 1969, 17, 1725-1729). However, both methods involve a high number of steps, including protection / deprotection reactions that employ expensive or non-commercial reagents. In many cases in addition, the final yields obtained from the desired 17a -OH steroid can be very low. Another limitation of reduction methods using chemical agents is regioselectivity. For example, it is known that 3-ketosteroids are more reactive than 17- or 20-ketosteroids (Góndós and Orr, J. Chem. Soc., Chem. Commun., 1982, 1239-1240). Therefore, if the desired compound is the corresponding 17-hydroxysteroid, its obtaining can be complicated if the molecule also has ketone groups in other positions. (in particular, in position 3), and in many cases a mixture of various mono and multi-hydroxy compounds can be obtained.

In summary, the methods currently available for the reduction of ketosteroid compounds to hydroxysteroids, both chemical and biocatalytic, may in many cases present some of the following main limitations, which makes their general application difficult.

1. The reduction reaction may be accompanied by side reactions, which significantly decreases the final yield of the desired product and complicates and increases its isolation and purification.

2. In many cases, the regioselectivity of the process is not the desired one, so the ketosteroid compound is reduced in a different position of the molecule or mixtures of mono- and multi-hydroxy products are produced.

3. Stereoselectivity to certain compounds is very difficult to achieve (eg, formation of 17a -OH steroid compounds, since obtaining the corresponding 17p-OH isomers is usually favored).

4. In many cases, it is necessary to use additional reactions to increase the final yield of the desired compounds (eg, Mitsunobu inversion for the preparation of 17a-OH compounds from the corresponding 17p-OH steroids). This implies the use of additional reagents (protective groups, oxidants, reducing agents, solvents, etc.), in many cases expensive and / or toxic (NaBH4 or LiAlH4), which generate waste management problems and increase the cost of the process.

For all the above, it is of great interest to develop new catalytic methods for obtaining hydroxysteroids by reducing the corresponding ketosteroids, which are effective, selective, rapid and low cost. If possible, they should involve reactions in one step, with non-toxic and inexpensive reagents, and easily scalable to obtain the desired products on a large scale. In addition, the conversion of ketosteroids into hydroexteroids should be stereoselective (including obtaining the 17a-OH isomer), regioselective (only the carbonyl group should be reduced in the desired position, even if the molecule contains carbonyl groups or other additional reducible groups in other positions of the molecule) and only the desired hydroxysteroid compound should be formed as the sole product of the reaction (without side reactions of hydroxylation, dihydroxylation, dehydration, etc., as described above). In addition, it is highly desirable that the catalyst used be solid (to facilitate its separation from the products), and that it is stable and reusable under the reaction conditions without significant loss of activity and / or selectivity.

Description of the Invention

The present invention describes the use of metal-organic materials as catalysts to selectively transform the ketone groups of ketosteroid compounds into the corresponding hydroxy derivatives. In particular, 17-ketosteroid compounds, which have a ketone group at position 17, and their selective conversion to the corresponding 17-hydroxysteroid are subject to the present invention. Some examples of 17-ketosteroid compounds include: androstendione, androstandione, androsterone, or estrone. However, the use of these same metal-organic compounds described in this patent can foreseeably extend to other ketosteroid compounds, with ketone groups in positions other than 17.

The present invention describes the use of metal-organic compounds as heterogeneous catalysts for the preparation of hydroxysteroid from the corresponding ketosteroids by means of a hydrogen transfer reaction of the Meerwein-Ponndorf-Verley type hydrogen (hereinafter MPV). It is described that this reaction can be carried out using as reducing agents secondary alcohols as a source of hydride, although there are also examples that describe the use of amines, sulfides and even hydrocarbons.

As will be seen through the examples included in this document, the ketosteroid reduction process is highly chemoregio- and stereoselective, it takes place in a single reaction stage and using low cost reagents and low toxicity ( viz., Alcohol secondary, such as isopropanol or 2-butanol), and the compounds used as catalysts can be reused for a long time without significant loss of activity and / or selectivity. Therefore, the use of the catalysts described in this invention represents an improvement with respect to alternative methods of chemical reduction with hydrides or by the use of mycoorganisms. Its use is particularly interesting in (although not limited to) obtaining products that are difficult to access through other alternative routes, such as the following:

1- Chemo and stereoselective reduction of 17-ketosteroids to 17a-hydroxysteroids. For example, reduction of estrone (10) to 17a -estradiol (12), or trans-androsterone (7) to androstan-3p, 17a -diol (9).

2- Regioselective reduction of 3,17-diones to 3-oxo-17a -OH derivatives. For example, reduction of androstenedione (1) to epitestosterone (3).

The present invention improves the hydrogen transfer or MPV reaction step through the use as a heterogeneous catalyst of metal-organic compounds preferably of Zr or Hf, as any of the compounds described in US20170008915, or similar materials. Preferably, the material used is crystalline and porous, such as Zr (or Hf) trimesates and derivatives known as MOF-808 (hereinafter, Zr-MOF-808 or Hf-MOF-808), such as those described in Furukawa et al., J. Am. Chem. Soc., 2014, 136, 4369-4381. Obtaining these materials can be carried out by a hydrothermal crystallization process, in which a solution containing a metal source (Zr or Hf), an organic ligand (such as trimesic acid or similar compounds) and a solvent is prepared or mixture of appropriate solvents. This solution is introduced into an autoclave or glass container, and hydrothermal synthesis is carried out at temperatures between 80 ° C and 150 ° C for a period of between 12 and 72 h. Alternatively, the catalysts used in this invention can be prepared by alternative synthesis routes, such as recently developed continuous syntheses (such as that described in Reinsch et al., EurJIC, 2016, 4490-4498).

The chemical process consists in contacting the ketosteroid that you want to reduce with the catalyst used in the reaction conditions described below. The amount of catalyst to be used can be adjusted to have between 2% and 30% molar metal with respect to the ketosteroid.

Specifically, the present invention describes the process of obtaining hydroxysteroid compounds from ketosteroids comprising, at least, the selective reduction of the keto group of the ketosteroid compound by means of a Meerwein-Ponndorf-Verley type reaction which is carried out in presence of at least one reducing agent and a catalyst based on a metal-organic compound of zirconium or hafnium. Preferably, said catalyst is selected from a catalyst of the type MOF-808 or its derivatives, preferably MOF-808-IP, MOF-808-Pydc, MOF-808-NH2, MOF-808-OH, MOF-808-Br and combinations thereof.

According to a particular embodiment, the amount of Zr or Hf used may be between 2% and 30% molar with respect to the ketosteroid.

The reaction conditions according to the present invention involve a temperature between 40 ° C and 150 ° C, preferably between 60 ° C and 120 ° C, and a contact time between 1 and 72 h, preferably between 4 and 72 h.

The reduction process of the ketosteroid compound is carried out in the presence of a reducing agent, preferably an alcohol, and more preferably a secondary alcohol, which acts as a solvent and as a source of hydrogen to reduce the ketone group. Preferably said secondary alcohol may be selected from isopropanol (IPA), 2-butanol (secBA), and combinations thereof and more preferably the alcohol is 2-butanol.

The alcohol can be used as a solvent for the reaction medium, in an alcohol: ketosteroid molar ratio that is preferably between 1 and 200 and more preferably between 5 and 40.

The catalytic process takes place at atmospheric pressure (or slightly above), so the use of highly specialized reactors is not required. The process can be carried out in a single reactor, which can be selected between a continuous reactor (for example selected between a continuous reactor of fixed or fluidized bed) or a discontinuous reactor (for example of stirred tank type), in which You can find the catalyst.

When operated in discontinuous mode, the catalyst, ketosteroid and alcohol are mixed in a suitable reactor, preferably by stirring the mixture at the reaction temperature. In the continuous method, the catalyst can be used in reactors selected from fixed bed, boiling bed, moving bed or in any other known configuration.

Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be partially detached. of the description and in part of the practice of the invention The following examples are provided by way of illustration, and are not intended to be limiting of the present invention.

Examples

The following examples are provided by way of illustration, and are not intended to be limiting of the present invention.

Example 1: Preparation of Zirconium Trimesate, Zr-MOF-808

In a particular embodiment of the present invention, the zirconium trimesate material, known as Zr-MOF-808, is prepared with molecular formula Zr6O5 (OH) 3 (BTC) 2 (HCOO) 5 (H2O) 2 (BTC = 1.3 , 5-benzenetricarboxylate, or trimesate), following an adaptation of the solvothermal synthesis described by Furukawa et al. in J. Am. Chem. Soc., 2014, 136, 4369-4381. For this, a solution containing 242.5 mg of ZrOCl28 H2O (0.75 mmol) and 105 mg of trimesic acid (0.5 mmol) in 22.5 mL of a 1: 1 DMF / HCOOH mixture (v / v). The solution is transferred to an autoclave with a Teflon jacket and heated inside a stove at 30 ° C for 48 h. After cooling to room temperature, the solid material is recovered by centrifugation and washed for 3 days by immersion in DMF (5 mL, changing the solvent twice a day for fresh solvent) and another 3 days in ethanol (5 mL, changing the solvent 2 times per day). After removing the solvent by centrifugation, the solid is air dried.

The material obtained in Example 1 has an X-ray diffraction diagram totally analogous to that published in J. Am. Chem. Soc., 2014, 136, 4369-4381.

Example 2: Preparation of hafnium trimesate, Hf-MOF-808

For the synthesis of the Hf-MOF-808 material, proceed as follows. A first solution containing HfCl4 (241 mg, 0.75 mmols) was prepared in a DMF: HCO2H mixture (2.5: 4.2 ml). A second solution containing the trimesic acid ligand (53 mg, 0.25 mmols) in 5 mL of DMF was prepared. The two solutions were mixed at room temperature and the mixture was placed in a 25 mL glass flask and left in an oven at 135 ° C for 24 h. After cooling to room temperature, the solid material is recovered by filtration and washed first with DMF (3x5 mL) and finally with ethanol (3x5 mL) and finally the solid is air dried.

The material obtained in Example 2 has an X-ray diffraction diagram totally analogous to that of the material of Example 1.

Example 3: Preparation of compounds derived from MOF-808 zirconium trimesate with two ligands: MOF-808-IP, MOF-808-Pydc, MOF- 808 -NH 2 , MOF-808-OH and MOF-808-Br

Materials with MOF-808 type structure were prepared containing as an organic component a mixture of trimesate and various dicarboxylic ligands in a 9 to 1 ratio. For this, the same synthetic procedure described in Example 1 was followed but replacing 10 mol% of the trimesic acid used in the synthesis for an equimolar amount of the following dicarboxylate ligands: a) isophthalic acid (8.3 mg, 0.05 mmol) for the MOF-808-IP sample; b) 3,5-pyridinedicarboxylic acid (8.4 mg, 0.05 mmol) for sample MOF-808-Pydc; c) 5-hydroxyisophthalic acid (9.1 mg, 0.05 mmol) for sample MOF-808-OH; and d) 5-aminoisophthalic acid (9.1 mg, 0.05 mmol) for the sample MOF-808-NH2. The remaining steps of the synthesis were identical to those used in Example 1.

Similarly, an additional MOF-808 type material, called MOF-808-Br, was prepared in which 10% of the trimesic acid used in the synthesis described in Example 1 was replaced by an equimolar amount of 2-bromo-1 acid , 3,5-benzenetricarboxylic acid (14.4 mg, 0.05 mmol), and following the other synthesis steps identical to those described in Example 1.

All the materials described (MOF-808-IP, MOF-808-Pydc, MOF-808-OH, MOF-808-NH2 and MOF-808-Br), have high crystallinity and X-ray diffractograms very similar to that obtained for MOF-808 material, which shows that all these materials are isostructural.

The materials described in this Example 3 are provided by way of illustration, and are not intended to be limiting of the present invention. These examples demonstrate that it is possible to obtain MOF-808 type materials with two ligands simultaneously in the same structure, which may lead to significant differences in reactivity in ketosteroid reduction.

Example 4. Stereoselective reduction of estrone to 17a-estradiol

A) Using Zr-MOF-808 prepared in example 1 as catalyst and 2-propanol as reducer

The reaction was carried out as follows: In a glass reactor, 5mg of the Zr-MOF-808 catalyst prepared according to example 1, was added to a solution of 20 mg (0.08 mmol) of estrone (Aldrich> 99%) in 1 mL of isopropanol (ca. 16 eq). The reactor was heated at 80 ° C for 48 hours, determining the conversion of estrone and the yield to the reaction products of three or four aliquots taken during this interval. The total yield to estradiols (17-17p) obtained after 24 hours of reaction was 87%, with no other reaction byproducts detected. The mass reaction balance was greater than 98%.

The products were analyzed by gas chromatography using an HP-5 capillary column 30m long, 0.32mm internal diameter and 0.25 pm phase thickness. The products were identified by mass spectrometry and by comparison with commercial pure products. The diastereoselectivity of the estradiols was 63% to the 17a isomer. This value was determined from the 1 H NMR spectra of the reaction filtrate.

B) Using Zr-MOF-808 prepared in example 1 as catalyst and 2-butanol as reducer

The procedure was similar to that described in example 4A, but replacing isopropanol with 2-butanol. The reaction temperature used in this case was 120 ° C. The total yield to estradiols (17-17p) obtained after 8 hours of reaction was 91%, with no other reaction byproducts detected. The mass reaction balance was greater than 98%. The diastereoselectivity was 87% to the 17a isomer.

C) Using Hf-MOF-808 prepared in example 2 as catalyst and 2-butanol as reducer

The procedure used was completely analogous to that used in Example 4B, but replacing the catalyst Zr-MOF-808 with the same amount of matter1 Hf-MOF-808 obtained in Example 2. The total yield to estradiols (17 to 17p) obtained after 48 hours of reaction was 99%, without other reaction by-products being detected. The mass reaction balance was greater than 98%. The diastereoselectivity was 77% at the 17th isomer.

D) Using MOF-808-Pydc prepared in example 3 as catalyst and 2-propanol as reducer

The procedure was completely analogous to that described in example 4A, but replacing the catalyst Zr-MOF-808 with the same amount of material MOF-808-Pydc obtained in example 3. The total yield to estradiols (17a 17p) obtained after 24 hours of reaction it was 91%, without other reaction byproducts being detected. The mass reaction balance was greater than 98%. The diastereoselectivity was 62% at isomer 17a.

E) Using NaBH4 as a reducer

The procedure used in this example was as follows. First, estrone (40 mg, 0.15 mmol) was dissolved in 5 mL of ethanol. Separately, a solution of NaBH40.5 M in ethanol (18.9 mg NaBH4 in 1 mL of ethanol) is prepared, which is added to the first solution under stirring and at 80 ° C. Stirring is maintained for 15 min and is increased at reflux temperature. Immediately after the mixture begins to boil, the heating is stopped and the mixture is allowed to stand for another 5 min. To stop the reaction and precipitate the product, 10 mL of H2O are added and cooled in an ice water bath for 15 min. Finally, the product is recovered by filtration and washed with cold H2O. The reaction products are analyzed analogously to that described in the previous examples by 1 H NMR. Under these conditions, a final estrone conversion of> 99% was obtained, with a 97% diastereoselectivity to the 17 p isomer.

F) Effect of temperature on conversion and stereoselectivity

The effect of the reaction temperature on the final conversion and stereoselectivity was determined, both for IPA and secBA, and using the catalyst Zr-MOF-808 prepared in Example 1 as a catalyst. For this, it was operated analogously to that described in Examples 4A and 4C, with the reaction temperature varying between 80 ° C and 130 ° C.

In all cases, only the formation of estradiols was detected as a single reaction product, and the mass balances were greater than 98%. The results obtained are shown in the following Table.

G) Reusability of the Zr-MOF-808 catalyst

To study the stability and reusability of the Zr-MOF-808 catalyst for the stereoselective reduction of estrone to 17a-estradiol, we proceeded as follows. First, the reaction was carried out under conditions analogous to those described in example 4B. After 8 h of reaction, the solid catalyst was recovered from the reaction medium by filtration, washed with fresh 2-butanol (3x5 mL) and dried at room temperature and in air for 12 hours. After checking that the material maintained a high crystallinity, comparable to that of the starting material, it was reintroduced into the reactor together with fresh solvent and estrone and a second catalytic cycle was carried out in exactly the same conditions. In this way, a total of 6 times was carried out, and it was found that the material continued to maintain its crystallinity intact, while the conversion of estrone after 8 hours of reaction and the stereoselectivity to the 17th -estradiol isomer were practically the same as those obtained for the fresh material, as summarized in the following Table.

Example 5. Stereoselective reduction of trans-androsterone to androstan-3p, 17a-diol using the Zr-MOF-808 catalyst prepared in Example 1

The procedure used was as follows: In a glass reactor, 10 mg of the Zr-MOF-808 catalyst prepared according to example 1, was added to a solution of 10 mg of transandrosterone (0.034 mmol) in 1 mL of 2-butanol ( ca. 30 eq). The reactor was heated at 120 ° C for 48 hours, determining the conversion of trans-androsterone and the yield to the reaction products of three or four aliquots taken during this interval. Only the formation of the corresponding diols was observed as the only reaction product. The final conversion of trans-androsterone after 24 h was 94%, with a stereoselectivity of 84% to the androstan-3p, 17a-diol isomer. The mass reaction balance was greater than 98%.

Example 6. Regional and stereoselective reduction of androstenedione to epitestosterone using the Zr-MOF-808 catalyst prepared in example 1

The procedure used was as follows: In a glass reactor, 10 mg of the Zr-MOF-808 catalyst prepared according to Example 1, were added to a solution of 10 mg androstenedione (0.035 mmol) in 1 mL of 2-butanol (ca .30 eq). The reactor was heated at the desired temperature for 48 hours, determining the conversion of androstenedione (AD) and the yield to the reaction products of three or four aliquots taken during this interval. The reaction products observed consisted of mixtures of mono-reduction products of the ketone group in position 17 (epitestosterone, ET, and testosterone, T), as well as double reduction of the ketone groups in position 3 and 17 (mixture of several isomers 3 , 17-dioxosteroids, Dioles). In no case was the formation of 3-hydroxy-17-oxo products observed (ie reduction of the keto group in position 3). The proportion observed between mono- and double reduction products depended on time and reaction temperature. The amount of testosterone formed was always very low (less than 5% compared to the amount of epitestosterone observed). The results obtained are summarized in the following Table.

a The distribution of products was determined from the 1 H and 13 C NMR spectra. The amount of testosterone formed was always very low (less than 5% compared to the amount of epitestosterone observed), very close to the detection limits of the technique used. Given its low concentration, the amounts of testosterone listed in the Table are only approximate, and the actual value is probably below. No additional products were observed, and the mass balance at the end of the reaction (isolated yield of the products) was greater than 98% in all cases.

According to these results, working at a reaction temperature of 60 ° C it is possible to achieve conversions of up to 70-80% of AD, maintaining a selectivity to monoreduction products above 80%, and a steroselectivity of> 95% at epitestosterone

Claims (15)

1. - Process for obtaining hydroxysteroid compounds from ketosteroids comprising the selective reduction of the keto group of the ketosteroid compound by means of a Meerwein-Ponndorf-Verley type reaction which is carried out in the presence of at least one reducing agent and a catalyst based on a metal-organic compound of zirconium or hafnium. 2. - Process for obtaining hydroxysteroid compounds according to claim 1, characterized in that the catalyst is of the MOF-808 type or derivatives. 3. - Process for obtaining hydroxysteroid compounds according to claim 2, characterized in that the derivative is selected from MOF-808-IP, MOF-808-Pydc, MOF-808-NH2, MOF-808-OH, MOF-808-Br and combinations thereof. 4. - Process for obtaining hydroxysteroid compounds according to any one of claims 1 to 3, characterized in that the amount of Zr or Hf used is between 2% and 30% molar with respect to the ketosteroid. 5. - Process for obtaining hydroxysteroid compounds according to any one of claims 1 to 4, characterized in that it is carried out at a temperature between 40 ° C and 150 ° C, and a contact time between 4 and 72 hours. 6. - Process for obtaining hydroxysteroid compounds according to any one of claims 1 to 5, characterized in that the reducing agent is an alcohol. 7. - Process for obtaining hydroxysteroid compounds according to claim 6, characterized in that the alcohol is a secondary alcohol. 8. - Process for obtaining hydroxysteroid compounds according to claim 7, characterized in that the alcohol is selected from isopropanol, 2-butanol and combinations thereof. 9. - Process for obtaining hydroxysteroid compounds according to claim 8, characterized in that the alcohol is 2-butanol. 10. Process for obtaining hydroxysteroid compounds according to claims 7 to 9, characterized in that the molar ratio between alcohol and ketosteroid compounds is between 1 and 200. 11. Process for obtaining hydroxysteroid compounds according to claim 10, characterized in that the molar ratio between alcohol and ketosteroid compounds is between 5 and 40. 12. - Process for obtaining hydroxysteroid compounds according to any one of claims 1 to 11, characterized in that it is carried out in a single reactor. 13. - Process for obtaining hydroxysteroid compounds according to claim 12, characterized in that it is carried out in a continuous reactor or a discontinuous reactor. 14. Process for obtaining hydroxysteroid compounds according to claim 13, characterized in that it is carried out in a continuous reactor selected from fixed milk, boiling bed or mobile bed. 15. Process for obtaining hydroxysteroid compounds according to claim 13, characterized in that it is carried out in a batch reactor.