BE562659A - - Google Patents

Description

       

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   The present invention relates to a process for the preparation of steroids substituted in 3,11,17, corresponding to the formula:
 EMI1.1
 

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 wherein R represents hydrogen or a methyl group, R 'a hydroxyl or an esterified hydroxyl or
 EMI2.1
 etherli'ié, Rif aubetituant21 - 0 or 0 * the latter also in esterified or etherified form, and RI "the substituents' * 0 <(orµev, the hydroxyl groups can also be present in esterified or etherified form, and RIV representing a hydrocarbon residue contain at most two carbon atoms.

   These are therefore compounds of the ¯5-3-hydroxy-androstene or ¯5-3-hydroxy-19nor-androstene series, their stereoisomers and their racemates bearing substituents at 3, II and 17 In positions 3, 11 and 17, there may be an esterified or etherified hydroxyl or hydroxyl, or else in position 11 an oxo group and in position 17 an oxo group, or together with a free, esterified or etherified tertiary hydroxyl group. , a methyl, ethyl, vinyl or ethinyl group. The orientation in space of the indicated monovalent substituents is any, i.e., they are α or β oriented.

   The ester residues indicated are, for example, those of saturated or unsaturated aliphatic carboxylic acids or of cycloaliphatic acids, of aromatic or heterocyclic carboxylic acids, for example of formic, acetic, propionic acids, butyric acids, valeric acids. such as n-valeric acid or trimethylacetic acid, caproic acids such as

 <Desc / Clms Page number 3>

 
 EMI3.1
 0-trimethylpropionic acid enanthic, caprylic, plargonic;

   caprlquG, unddcyllque acids, for example undecylenic acid, lauric, myristic, palmitic, stearic, oleic acid, cyclo-
 EMI3.2
 pentyl-, oyoloheXY1- or phenyl-aoetics or -propionics, benzoic acids, furan-2-carboxylic acids nicotinic acids, as well as dicarboxylic acids such as oxalic, suokinic or glutaric acids, carboxyl acids-
 EMI3.3
 substituted ic acids, such as O-keto-carboxylic acids, for example acetylaoetic, proplonylacetic, butyrylaoetic or caprinoylacetic acids, amino acids, etc.

   Instead of dicarboxylic acid residues there can also be
 EMI3.4
 have residues of sulfonic acids as well as residues of phosphoric, sulfuric or hydracids
 EMI3.5
 halogen. the ether residues are in particular those of monovalent or polyvalent aliphatic or cycloaliphatic alcohols, such as methanol, ltethanol, ethylene-glycol or propylene-glyool, eyalo-heatanol, tetrahydropyranol, benzyl alcohol or those of phenols.



   Surprisingly, such compounds exhibit a very high sodium elimination effect and are therefore of great therapeutic interest.



   The preparation of these compounds according to the present invention takes place: a) by transforming, into compounds of formula:

 <Desc / Clms Page number 4>

 
 EMI4.1
 in which R, R "as well as R" 'have the meaning given above, the ¯4-3-ketone group, in a manner known per se, into a free, esterified ¯5-3-hydroxy group or etherified or, b) by hydroxylating, according to microbiological methods known per se, in position 118 or in position 11a, compounds of formula:
 EMI4.2
 in which R, R 'as well as R "' have the meaning given above, or c) by degrading in a manner known per se to 17-hydroxyl group or 17-oxo group, the side chain located at 17 in compounds of formula;

   
 EMI4.3
 

 <Desc / Clms Page number 5>

 in which R, R 'as well as R "have the meaning given above and RV represents a methyl group or an oxygenated methyl group, and which optionally have an additional double bond at position 16, or d) by degrading in a manner known in itself as the 17-oxo group, the side chain located at 17 in
 EMI5.1
 these compounds of formula: .yR "Cit n V R R, in which R, R 'as well as R" have the given meaning
 EMI5.2
 above, Ru represents a methyl group or an oxygenated methyl group, and RAVI represents - - substituting them - 0 or / OR fi where appropriate by protecting the double bond in the 5 position, or e) by degrading in a manner known in itself as the 17-oxo group, the side chain located at 17 in compounds of formula:

   
 EMI5.3
 in which R, R 'as well as R "have the given meaning

 <Desc / Clms Page number 6>

 above and RVII represents a hydrocarbon residue, where appropriate while protecting the double bond in position 5.



   The variant a) of the process of the present invention consists of starting, for example, from derivatives of ¯4-3-oxo-androstene or from derivatives of ¯4-3-oxo-19-nor-androstene which contain in position 11 and 17 an oxo group or a free secondary hydroxyl group, esterified or etherified in a or p orientation, or which in position 17 contain a free, esterified or etherified tertiary hydroxyl group and at the same time a methyl, ethyl, vinyl or ethinyl group.



  These starting substances are known or can be prepared for example from compounds of 17-oxo-androstane or 17-oxo-19-nor-androstane saturated in ring A and ring B, oxygenated in position 3 and bearing corresponding substituents in position 11, by reaction with alkyl- or alkinyl-metal compounds, where appropriate by reducing the aloinyl residue, by forming the 3-oxo group and by introducing the double bond in position 4. The transformation according to The invention of the ¯4-3-ketone group in the ¯5-3a- or ¯5-3ss-free hydroxyl group, esterified or etherified, takes place according to methods known per se, as they have been used, for example,

   to convert cholestenone into cholesterin. Thus one can, according to Reich and Lardon, "Helv. Chim. Acta" 29, 671 (1946),

 <Desc / Clms Page number 7>

   brominated in position 6 the enol acetate of 4 -3-ketone
 EMI7.1
 with Nbromo-actamide, converting the bromooetone obtained into androgtane-, 6..diaxo-drivt using hydrochloric acid in methanol, then hydrogenating this derivative to compound 3.6-dlhydroxyld.

   The hydroxyl in position 6 can be partially removed from the latter with hydrochloric acid in alcohol, better however after acylating only the hydroxyl in position 3, directly with phosphorus oxychloride. , or it can be eliminated in the form of a mesylate in pyridine. Dimesylation of 3,6-diol and treatment with metal acetates, or
 EMI7.2
 well the 3-mona-togy.a, tion of ,, 6-d101 and the action of phosphorus oxychloride in pyridine also lead to the goal.

   According to other methods, the acetate is treated
 EMI7.3
 enol of A4., - odtone with potassium amide in liquid ammonia (Biroh, "J. Ohem.Soo." 1950, 225), with lithium aluminum hydride (Dauben
 EMI7.4
 and Eastham, "J. Am. Chem, Boa." 11, '2305 [1950]) or with boron sodium hydride in an aqueous alcoholic solution (Belleau and Gallasher, bid. 73. 4458 L .951 Dauben f and Eastham, ibis. 3., 4463 [19511 ).



  In the case of variant b), one starts, for example, from derivatives of o5 - hydroxy- or o5-3a-hydro.i androstene or -19-nor-androstene, the hydroxyl of which in position 3 is presented under free form, in esterified form (for example with a carboxylic acid or with a halogenated hydracid) or in etherified form,

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 which are unsubstituted in position 11, but contain in position 17 an oxo group, a free secondary hydroxyl group, etherified or esterified in orientation a or ss, or a free tertiary hydroxyl group, esterified or etherified and, in addition, a group methyl, ethyl, vinyl or ethinyl.



   In accordance with this variant of the present process, these compounds are hydroxylated at position 118 or 11a according to microbiological methods known per se, by incubating the starting substances, for example aerobically, together with living microorganisms capable of introducing oxygen in position 11.

   However, it is also possible to more or less separate the enzymes from the culture filtrate or from the microorganisms and then not work in the presence of living microorganisms. Microorganisms; for example those of the groups Mucorales., Penicillium, Actinomycetes, such as Streptomycetes, Aspergillus,
Cunninghamella, Curvularia or fungi imperfecti are cultivated in a manner known per se, for example in fixed cultures or in cultures immersed with agitation, which advantageously contain assimilable carbon, in particular carbohydrates.

   The simplest process in practice is described in what follows without the invention being limited by the indications which are given: the organisms are cultured in apparatus and under conditions similar to those used in

 <Desc / Clms Page number 9>

 manufacture of antibiotics under the name of submerged culture process. After development of the cultures, the starting substances indicated are added, in the form of fine dispersions or solutions, for example in methanol, acetone or ethylene glycol, followed by incubation.



  Finally, the liquid is separated from the mycelium, the filtrate and / or the mass of mycelium are extracted, then the reaction products are isolated from the extract in a manner known per se, for example by partitioning between solvents in mixtures of non-solvent solvents. miscible with each other, by adsorption, chromatography, crystallization, transformation into functional derivatives such as Girard compounds and the like.

   A few mioroorganisms which are considered for the process are indicated below: Position 11a: Rhizopus nigricans, Rh. Arrizus
Aspergillus niger, Asp.ochraceus
Penicillium notatum, P. adametzi, P. jan- thinellum
Mucor mucedo Lenzites sepiaria
Tilletia tritici
Neurospora sitophila, N. crassa.



  Position 11ss: Curvularia lunata, C. pallescens, C. fallax,
0. braohyspora
Cunninghamalla Blakesleena
Streptomyces fradiae
Stigmina platani.

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   According to variant c) of the present process, the side chain can be degraded, for example compounds
 EMI10.1
 following: derivatives of α5-20-oxo-pregnene and of 1.20-cxo-19-nor-pregnene which contain in position 3 a free hydroxyl, esterified or etherified, in orientation α or, and which also present in position 11a or 118 a free, esterified or etherified hydroxyl group or an 11-oxo group, at the 21 carbon atom exclusively hydrogen or a free, esterified or etherified hydroxyl group or an oxo group and which, where appropriate, have in position 16 , 17 a double bond.



   According to this variant, the starting substances are, for example, first of all converted to oximes at position 20 and the 24-oximes obtained are subjected to Beckmann transposition, for example by treatment with acids or acid halides. , such as sulphonic acids or their halides, preferably in the presence of bases, in particular tertiary amines. If the starting material contains a double bond at 1617, then acylated 17-enamines are obtained which can, by hydrolysis, be easily converted into 17-ketimines and finally into 17-ketones.

   If the starting substance is saturated in the D-ring, then the reaction products which form after the Beckmann transposition are acylated 17-amines which can be transformed into compound

 <Desc / Clms Page number 11>

 17-hydroxylated by hydrolysis and by nitrogenous acid, These two possibilities are illustrated by the diagram of formula below
 EMI11.1
 
The 20 ... crossed out ketones in the D ring; used as starting substances can furthermore be degraded in an operational phase in 17ss-acetoxy-compounds, for example by making act organic peracids like perbenzoic acid and monoperphthalic acid.

   In this case, it is necessary for the double bond located at 5,6 to be intermediately protected, for example by adding a halogen or a halogenated hydracid.



   Finally, the 20-ketones are also degraded into 17-ketones according to the scheme of partial formulas below:
 EMI11.2
 This process therefore consists in transforming the 20-ketones

 <Desc / Clms Page number 12>

 in 21-arylidene compounds, for example in.

   benzylidene derivatives, subsequently reducing the ketone group, for example by means of light metal hydrides such as lithium aluminum hydride, lithium boron hydride or boron hydride and sodium, in subjecting the 20 ols obtained to water removal, for example by treatment with a suitable dehydrating agent, such as organic or inorganic acids or their anhydrides.

   This elimination takes place easily, for example, by boiling treatment with lower organic fatty acids, in the simplest case with formic, acetic, propionic or butyric acid. To degrade the diene compound in the side chain obtained by oxidation, hexavalent chromium compounds, such as chromic acid, potassium permanganate, will be used, or ozonization, or degradation by oxidation in passing through 17,20-glycols, by means of periodic acid or lead tetracetate. During oxidation, it is advantageous to protect the double bond located at position 5,6 as described above.



   According to the procedure d), the side chain located at 17 is degraded to a 17-oxo group, for example of ¯5-17-hydroxy-20-oxo- or ¯5-17,20-dihydroxy-pregnene derivatives or -19-nor-pregnene which contain in position 3 a free hydroxyl, esterified or etherified ,. in ostentation

 <Desc / Clms Page number 13>

 
 EMI13.1
 a or p> elii; x5 that in p081tion lIa or 115 a free hydroxyl es.t11f'1 or Yï '.' 3. or a group ..: 54d5 rei. ': 7-C.' carbon 2i excluded from hydrogen or also a free, esterified or th6rifivated hydroxyl or an oxo group. NotaEB'aent <3es ag @ t dtoxyat1on, for example aeiëc Pf! "'J.ot1ique or sodium bielî1tri, was used for this purpose.

   In these methods of oxidation @ p & cfique8 and relatively gentle, we can dispense with protecting the double bond located at 5,6.



  .In the value 0) 0 we start for example from derivatives of α5 androstene and é-wl9-no; -andro # tene which contain in position 3 a free hydroatmie, estdiï ± 16 or eth () r: 1fiê in orientation a or PO ate more in position IIa or a Â, 'oa.e: ",' a" esterified or etherified or a group .5 ... wVdntY and in position I? a remainder JS11J d..sYV4.ti ICi'VaA.Y saturated one or more times unsaturated. Compounds of this kind are, for example, lia- or l1t3-hyroY.y- or 11-oxou-aholesté ,. rinê, -3a-choleatr1nê, -s1toaterin -stigmaaterin.

   In this ace, 11 was advantage: ùe protections? .t: .. egt as indicated above the double bond at 596p because for this side chain degradation vigorous oxidation methods are required, for example oxidation using chromic acid in solution. acid or vigorous oxidation at 3v? 's3.1'k'2. e potassium.



  In the compounds of A5-3-hydro-adrostene and of A5¯3-liliclroxy-ig-iior-ardrostè7ae or <3ana leuxa stereoiso-

 <Desc / Clms Page number 14>

 mothers which are obtained according to the above variant, it is possible to transform hydroxyls and oxo groups located in position II and / or 17 into one another.

   For the reduction of oxo groups, the usual methods are suitable, in particular the use of light metal hydrides such as lithium aluminum hydride, lithium boron hydride or lithium. boron sodium hydride. To dehydrogenate hydroxyls to oxo groups, a series of known methods are also used, with or without protection of the 5,6 double bond (such as its saturation with a halogen or a halogenated hydracid or its transformation into iso-steroids), for example oxidation using chromium trioxide in glacial acetic acid, or a complex of chromium trioxide and pyridine,

   or the oxidation according to Oppenauer in its various known embodiments.



   .



   The products of the process comprising free hydroxyls and / or oxo groups can, in a manner known per se, be converted into their functional derivatives such as esters, ethers, enol esters, enol ethers, acetals. , in their corresponding thiol derivatives, for example in thio-ethers, in thio-acetals and in esters of thio-acids, as well as in hydrazones and in oximes.



   In esters and enolic esters, the acids are those of the acids indicated at the beginning.

 <Desc / Clms Page number 15>

 
 EMI15.1
 



  In ethers, enolic ethers, acetals or in thio-dërlvdg iorxùexioontillntx, the residues may be of the allcyclic aliphatic, araliphatic aromatic or Mterocyclic sdrie. Such residues are, by xGmpl $ 9 gycup @ s aleeyies or alkylenes, such as methyl groups or such groups as benzylo-se groups gyoupisa di- or triphenylmthyleej groups or carbohydrate residues such as those of glucose , galactose
 EMI15.2
 or maltose.
 EMI15.3
 



  For thrification and acetalization, for example, peaetive esters of corresponding alcohols are used, in particular halogenated hydracids, organic single tallow acids or orthoroic acid3 as well as ilbre alcohols, tdtra-alkylellielum and 3l181oguêS. Depending on the agents used, one works in the presence of acidic or basic condensing agents and catalyst, for example sulphonic acids, mineral acids such as halogenated hydracids or sultur1qus acids, or organic bases, especially amines. -
 EMI15.4
 smells.
 EMI15.5
 



  The production of thio-acetalo and the noble thio-ethera is effected, for example, by treatment with mercaptanic compounds. The enolic thlo-6-horsers and thio-acetals are prepared in advance, by making

 <Desc / Clms Page number 16>

 reacting the acyclic thioacetals obtained with heavy metal derivatives forming mercaptides. As mercaptanic compounds, use is made in particular of alkylmercaptans ,, for example methyl-, ethyl-, benzylmercaptan, or ethylene-dimercaptan and the like, in the presence of acid catalysts such as hydrochloric acid, sulfuric acid, toluenesulfonic acid, zinc chloride or pyridine hydrochloride.

   Derivatives of heavy metals forming mercaptides are, in particular, oxides or inorganic or organic salts, for example chlorides, nitrates, carbonates, acetates, propionates, benzoates of mercury, cadmium, silver , copper, lead, bismuth, cobalt or nickel. The reaction is advantageously carried out in the absence of water and, where appropriate, in the presence of organic or inorganic agents capable of binding acids, for example in the presence of pyridine, collidine or carbonates such as carbonates of alkali metals, alkaline earth metals or carbonates of heavy metals.

   Cleavage of meroaptan from acyclic thioacetals can also be achieved by heating.



   By appropriate selection of the reaction conditions and the amount of the agents employed, it is possible to functionally completely or only partially modify the hydroxyls or oxo groups present, for example to esterify or etherify them.

 <Desc / Clms Page number 17>

 In the compounds obtained, hydroxyls or
 EMI17.1
 functionally modified oxo groups can be transformed into free groups.

   In this way we can also partially set free the functional groups
 EMI17.2
 nally odorless, sotaaNnent in polyubatituated drifts This takes place, for example, by chemical or enzymatic hydrolysis, for example using acidic or
 EMI17.3
 basic, by alcoholysis, by acetal1satlon coupled or especially in the case of residues of araliphatic acids or alcohols also, by hydrogenation.

   From the acetals containing sulfur, the cyclic semi-acetals are obtained, preferably using salts of heavy metals such as mercury chloride in the presence of basic agents, for example cadmium carbonate. From the derivatives obtained in this way or also directly and which are only partially modified, for example esterified or etherified, it is possible, by subsequent functional transformation, for example by esterification or etherification,
 EMI17.4
 preparing polyâtibstltuds derivatives, in particular also esters or mixed ethers or ester-ethers.

   By an appropriate choice of the reaction conditions, it is also possible, with the agents indicated above and from the partially or totally modified derivatives, to obtain the free compounds again.



   In the 17-edtones obtained, we can, if we

 <Desc / Clms Page number 18>

   le.désire, Introduce in position 17 a hydrocarbon residue comprising at most 2 carbon atoms, that is to say a methyl, ethyl, vinyl or ethinyl residue. To this end, 17-ketone is reacted with the corresponding Grignard compound or with the corresponding alkali metal compound, for example with chloride, bromide or iodide.
 EMI18.1
 methyl- or deethyl-magnesium, on 1.a.uurr-.nIa.eQ on lithium-ethyl, on Bod1umacetYlene, potassium-acetylene or lithium-acetylene.



   These hydrocarbon residues preferably enter position 17a; next to it we also get the 17ssdératifs. By an appropriate choice of the reduction conditions, an ethinyl residue can then be converted into a vinyl or ethyl residue. Likewise, the tertiary hydroxyl located in position 17, in the compounds obtained, can also be esterified according to known methods, easily in the case of the hydroxyls located at 17a, under vigorous conditions in the case of the hydroxyls located in 17ss, for example with anhydrides of oarboxylic acids in the presence of catalysts, such as perchloric acid
 EMI18.2
 or p-toluenesulfonic acid, or with carboxylic acid halides and tertiary bases.



   The present invention also embraces mixtures of substances intended for use in human or veterinary medicine, which contain the compounds indicated

 <Desc / Clms Page number 19>

 
 EMI19.1
 of the series of ù 5¯3 or A53hydroJ-19-nor-androstene and a solid or liquid excipient. These blends are prepared according to known methods, for example by using supporting materials.
 EMI19.2
 organic or inorganic pharmaceutical port, suitable for pareiiteral, enteral or topical application.

   Substances which do not react with the products of the process, for example water, vegetable oils,
 EMI19.3
 banzyl alcohol, polyethyleneglyoola, gelatin lactose, smiaonq mQ1eiUm stearate, tala, petrolatum, cholesterol or other oxygenates. Preparations for parenteral administration, preferably solutions, primarily oily or aqueous solutions, as well as suspensions, emulsions or implantates will be obtained in particular; for enteral application, also tablets or dragees are prepared and for topical application ointments or creams.



  If necessary, the preparations can be sterilized or added to them with auxiliary substances such as preservatives, stabilizers, wetting or emulsifying agents, salts serving to vary the osmotic pressure, or buffers.



   The invention is described in more detail in the non-limiting examples which follow, in which the temperatures are indicated in degrees centigrade.

 <Desc / Clms Page number 20>

 



   Example 1 ----------- To 5 g of oortisone 21-acetate, one adds
 EMI20.1
 5 cm3 of isopropenyl acetate and 40 mg of p-tolu @ ne <- sulfonic acid. The suspension is boiled for two hours under reflux in the absence of moisture, the cortisone acetate gradually passing into solution. Cooled. 100 mg of anhydrous sodium acetate are added and evaporated in vacuo.
 EMI20.2
 



  The 3-no3-arsa.e obtained as residue is used without further purification for the following reaction; this product is dissolved in 100 cm3 of methanol, the solution is cooled with ice, and slowly added, while stirring well, a solution of 4 g of boron sodium hydride in 100 cm3
 EMI20.3
 of methanol, as well as 10 cm3 of a decinormal solution of sodium hydroxide, then the reaction mixture is allowed to stand for 4 hours at 20, boiled for 3 hours at reflux and carefully added a mixture of 60 cm3 of hydrochloric acid concentrated and a little ice.



    Concentrated under vacuum, taken up in ethyl acetate, the ethyl acetate solution washed with water, dried and evaporated. The reaction product is dissolved in 250 cm3 of dioxane, a solution of 10 g of periodic acid in 60 cm3 of water is added to the solution, left to stand for 15 hours at 20, and then the solution is concentrated in vacuo.

   The suspension obtained is taken up in ethyl acetate, the ethyl acetate solution is washed with water, dried and evaporated.

 <Desc / Clms Page number 21>

 
 EMI21.1
 residue is a mixture of 5-3,11-dîllYdroXY-17-oxoresidu is a mixture of A'-311- <3ihydroxy-17-oxo-androstenes, the components of which can be separated by chromatography. Both isomers show in the infra-red spectrum the characteristic bands for ketones, free hydroxyl groups and isolated double bonds. By allowing the two isomers to stand for 15 hours, at 20 hours, in a mixture of pyridine and acetic anhydride, the corresponding 3-mono-acetates are obtained from the above two compounds.

   To isolate the latter, water is added to the solutions and concentrated in vacuo.



  The residue is then taken up each time in ethyl acetate. The ethyl acetate solutions are washed with hydrochloric acid and water, dried and evaporated. We obtain as residue on the one hand the 3Ó- and
 EMI21.2
 on the other hand the corresponding 3 - aeëtoxy.-6ërivës.



  In 20 cm3 of chloroform, 1 g of the A5-3-acetoXY-ll-hYdrOXY-17-oxo-anarostene thus obtained is dissolved and added to the solution 0.2 cm- of bromine. After a short time, the solution is discolored, it is then evaporated carefully in vacuo. The residue is dissolved, the 3ss-
 EMI21.3
 aceto. ,,, ry-Ilp-hydroxy-17-oxo-5 $ 6-dîbromoandrostane, in 20 cm 3 of 90% acetic acid and 2 cm 3 of dldth7lene chloride.



  The solution is cooled to 0 and added to it a solution of 0.23 g of chromium trioxide in 10 cm3 of 90% acetic acid, left to stand for 20 hours at 20, add a little

 <Desc / Clms Page number 22>

 of sodium bisulphite, concentrated in vacuo after adding water thereto and the residue was taken up in ethyl acetate. The ethyl acetate solution is washed with dilute hydrochloric acid and water, dried and evaporated in vacuo. The residue is dissolved in 20 or-3 of glacial acetic acid, the 20-fold solution is shaken with 5 g of zinc powder added in small portions, then the solution is evaporated in vacuo after filtering it.

   The residue is dissolved in ethyl acetate, the ethyl acetate solution washed with dilute hydrochloric acid and water, dried and evaporated. In 50 cm3 of methanol,
 EMI22.1
 the -.3etxy-1.,. 7d.exD.a.ndroCne obtained as residue is dissolved, 0.5 g of sodium carbonate and a little water are added to the solution, then the solution is boiled for one hour at reflux . The reaction solution is then concentrated under vacuum, the residue is taken up in acetate.
 EMI22.2
 ethyl, washed with water the solution in acetate <3'ëthy le, dried and evaporated.

   The -.3-droxy-x9, -âioxo-androstene obtained as residue exhibits in the infrared spectrum the characteristic bands of hydroxyl, of 5 and 6-membered ketones and of the isolated double bond.



   In a similar way we transform the ¯5-
 EMI22.3
 3a, Ile-dihydroxy-17-oxo-androstene to α-3a-hydrox..i, 7!? Dioxo-androstene. Degradation to 17-ketone. ' chain

 <Desc / Clms Page number 23>

 
 EMI23.1
 side of 3ellel7o2Or2l-Pentol obtained by reduction by means of boron hydride and Ëe Ëe Ëe, instead of being efaeoctuee with acid can also be carried out at! 'aio of 40 g of bisN; sodium utlaabe in 400 cm 3 of 50% acetic acid, stirring for 2 hours at a0 1, thus obtaining the & '- 3pll-ëih? Droxy' * 17-os: o-an <3rogtene.



  80i, ioe isolate this product ;, the reaction mixture is filtered, the bissmth salts washed with lS6thnol and the CGU2 Ci solution evaporated. chlorhyà acid: neither diluted ct of Iloau, dries it and 1 "evaporates. The 65¯3bllÓihroJr11-oxo-mnroat @ ne is obtained.



  EJtel1ple 2 A 1 g of dadr4nostrcnel ori adds 10 -cù13 of acetate G "-l ', OPrOP6nYlo- and 50 1% 9 of p-'loluene-sulfuric acid The suspension is boiled for 20 hours at reflux in the shelter. de 'hhiiidità-' the adrclnosterona paaaant little by little in solution. The solution is cooled;, 100 mg G 'RC ± anhydrous sodium téite is added to it and evaporated in vacuo. By reerlotallizing the residue in methanol, one obtains adrenostdrone 3-enol-acetate, melting point 125-1380. This compound is dissolved for 1 day in 100 cm3 of methanol, the solution is cooled to 0% while stirring well, slowly added to it. 1 g of hydride

 <Desc / Clms Page number 24>

 boron and sodium in 25 cm3 of methanol and 10 cm3 of a decinormal solution of sodium hydroxide.

   The reaction mixture is left to stand for 24 hours at 20, boiled for a short time at reflux, concentrated in vacuo and carefully added to it a mixture of 15 cm3 of concentrated hydrochloric acid and a little ice. The suspension is taken up in ethyl acetate, the solution in ethyl acetate is washed with water, dried and evaporated under
 EMI24.1
 empty. A mixture of o5-3, ..,, 7-tr.hydroxy-androstènes is obtained as residue. The mixture obtained is dissolved in 5 cm 3 of pyridine and 10 cm 3 of acetic anhydride, then allowed to stand for 15 hours at 20.

   Water is then added cautiously, the suspension evaporated in vacuo and the residue taken up in ether. The ethereal solution is washed with dilute hydrochloric acid and water, dried and evaporated. From the residue obtained, it is possible, by recrystallization from a mixture of ether and pentane, to obtain the
 EMI24.2
 A5-3,17-d.actoxy-1.-hydroxy-androstene with a melting point of 200-2030j ta] 21 = -680 (o - 1.009 in dioxane). In the infra-red spectrum, it shows characteristic bands, among others at 2.77, (OR) .. 5.79 (ester),
 EMI24.3
 as well as at 7.30u and 9.71u in the domain of F1ngerprint.



   80 mg of the diacetate obtained are dissolved in 10 cm3 of methanol. Add 2 cm3 of water and 80 mg of potassium carbonate to the solution, boil it for one hour

 <Desc / Clms Page number 25>

 at reflux and concentrated in vacuo. The resulting suspension is extracted with ethyl acetate. The ethyl acetate solution is washed with water, dried and evaporated. The residue is recrystallized from a mixture of acetone and
 EMI25.1
 pentane, to give A5. ,, 11,17.trihydroxy-androstene which melts at 227-2300.



   In 10 em3 of pyridine, 1 g of
 EMI25.2
 5-3.3? -D.a'axy-2'i-hytroxy - andrcane described above, melting point 200-203. A solution of 500 mg of chromium trioxide in 30 cm3 of pyridine is added to this solution, at 0, and left to stand for 20 hours at 20.

   The reaction mixture is then poured onto a mixture of concentrated hydrochloric acid and ice, then a little of a sodium bisulfite solution is added. stirred for 5 minutes, the suspension is extracted with ethyl acetate. The resulting solution is washed with dilute hydrochloric acid, with water with dilute sodium carbonate solution and again with water, dried and evaporated. By recrystallization of the residue from a mixture of ether and pentane, the ¯5-3,17- is obtained.
 EMI25.3
 11-diacetoxy-oxo-anaiostene with a melting point of 173-175.



  In the infra-red spectrum, it shows characteristic bands, among others at 5.78 5 * 86 7e3 (Dgs 7.36; i, 9j589 and 9.75.



   Hydrolyzed with potassium carbonate

 <Desc / Clms Page number 26>

 80 mg of 11-keto-diacetate as described above
 EMI26.1
 by the â ..- h3'drox; .. d.acfcae. After similar treatment, the Q′-3,, 3.7d3.hydroxy-x-eo-andros: rae obtained in a mixture of acetone and pentane or in a mixture of ether and pentane is recrystallized. The pure compound melts at 230-2320 and shows bands in the infra-red spectrum
 EMI26.2
 features, among others at 2; 779, 5e879s 8 $ 86g and 9.46.



   Example 3
In 10 cm3 of pyridine, 1 g of
 EMI26.3
 5-3,,. ,, 7-rih, ydroxy-artdraetne obtained according to Example 5 melting at 227-2Oo, then added 2 g of suekinic anhydride. The solution is left to stand for two hours at 40-50, then a little water is added and concentrated in vacuo.



  The residue is dissolved in ethyl acetate, the solution obtained is washed with dilute hydrochloric acid and water, dried and evaporated. We obtain as residue the
 EMI26.4
 0-3-succiny.oxy-il, .'- d3hydroy-.andras; ne. The latter is dissolved in 20 cm3 of chloroform and added to the solution 0.15 cm3 of bromine in a little chloroform.

   After a short time, the solution is evaporated under vacuum, the
 EMI26.5
 5-suacinyloxy-11,17-àihydroxy-5,6-dibromo-anàrostane formed in 50 om of 90% acetic acid and 5 cm3 of ethylene chloride, add to the solution, at o, a solution of 0, 6 g of chromium trioxide in 20 cm3 of acetic acid at

 <Desc / Clms Page number 27>

 90%, then let the solution stand for 24 hours at 20. A little sodium bisulfite solution is then added to the oxidation mixture, evaporated in vacuo after adding water, then the residue is taken up in ethyl acetate. The ethyl acetate solution is washed with dilute hydrochloric acid and water, dried.
 EMI27.1
 and evaporated.

   The 3-sucolnyloxy-11,11-dioxo-5.6dibromo-andro2tane thus obtained is dissolved in 20 em3 of glacial acetic acid and the solution is shaken; at 200 # with 5 g of zinc added in small portions, then evaporate the solution under vacuum after having filtered it. The residue is taken up in ethyl acetate, the solution obtained is washed with dilute hydrochloric acid and water, dried and evaporated.
 EMI27.2
 under vacuum. The α5-5-sucoinyiaxy-11,17-dioxo-androstene thus obtained is dissolved in 50 cm3 of methanol, 1 g of sodium carbonate and a little water are added to the solution, then it is boiled under reflux. during one hour. It is then concentrated in vacuo, the residue is taken up in ethyl acetate, the solution in ethyl acetate is washed with water, dried and the solvent is removed in vacuo.

   We obtain as residue
 EMI27.3
 45-3-hyclroxy-11,17-dioxo-androstene. For acetylation at position 3, this compound is allowed to stand for 15 hours at 20 hours with a mixture of 5 cm3 of pyridine and 10 cm3 of acetic anhydride, after which the reaction mixture is concentrated in vacuo, after adding thereto. the water. We

 <Desc / Clms Page number 28>

 takes up the residue in ethyl acetate, washing the solution in ethyl acetate with dilute hydrochloric acid and water, drying it and evaporating it.

   We get as
 EMI28.1
 residue A5-3-aaetoxy-11,17-dioxo-anarostene which, in the infra-red spectrum, shows the characteristic bands of 5- and 6-membered ketones of the aoetate group and of the 5,6 double bond; the hydroxyl bands are missing.



   Example -----------
In 100 cm3 of methanol, 5 g of
 EMI28.2
 5'1-3-aceto-11,20-dioxo-prdgnad3ine and add 10 am3 of pyridine and 2 g of hydroxylamine hydrochloride. The solution is boiled for 30 minutes at reflux, concentrated in vacuo and the residue taken up in ethyl acetate. The ethyl acetate solution is washed with dilute hydrochloric acid and water, dried and evaporated. The crude oxime obtained is dissolved in 20 cm3 of pyridine, added to the solution, below 5.5 g of p-toluene-sulfonic acid chloride, stirred for 2 hours at 10 and for 2 hours at 20 , then pour into a mixture of 50 cm3 of concentrated sulfuric acid and ice.

   The suspension is left to stand for 20 hours at o, then extracted with ethyl acetate, the solution in ethyl acetate washed with water, with dilute sodium carbonate solution and again at the water,

 <Desc / Clms Page number 29>

 it is dried and evaporated in vacuo. For acetylation, the residue obtained is dissolved in 10 cm3 of pyridine and 20 cm3 of acetic anhydride, a little water is added after 20 hours and concentrated in vacuo. The suspension obtained is extracted with ethyl acetate, the ethyl acetate solution washed with dilute hydrochloric acid and water, dried and evaporated in vacuo. We get as
 EMI29.1
 residue 1a5 - aa'coxy-i., â7dc.oxo-tnârosbne.

   The infra-red spectrum clearly shows an ester group band, an isolated double bond, a 6-membered ketone and a 5-membered ketone.



   The starting material used can be obtained, for example, as follows;
In 100 cm3 of glacial acetic acid one
 EMI29.2
 Dissolve 5 g of 3,3.1-c3.oxo-a, 5a-spirostane and add little hydrobromic acid in glacial acetic acid. While stirring, a solution of 3.8 g of bromine in 50 cm3 of glacial acetic acid is then added slowly, dropwise. The solution is allowed to stand for 24 to 20 hours, then diluted with water and the mixture extracted with ether. The ethereal solution is washed with water, dried and evaporated in vacuo. The residue is dissolved in 100 cm3 of acetone, 10 g of sodium iodide is added to the solution, boiled for two hours at reflux and con- tained.
 EMI29.3
 vacuum center.

   The A -2-iodo-3-ketone thus obtained provides,

 <Desc / Clms Page number 30>

 when the iodine atom in position
 EMI30.1
 2, t1-3, Il-dioxo.-22a-sp3.rostne.



   To move the double bond located in
 EMI30.2
 position 4, 8 cl 3 of isopropenyl acetate and 50 mg of p-toluene-sulfonic acid are added to the above 4-ap1rostene, then the solution is boiled for 2 hours at reflux away from the humidity.



   After treating as instructed to
 EMI30.3
 Example 1 gives the 3-enoi-acetate of â 4 - ', 11-dioxo- - 22a-epirostene which, also according to example 1, is reduced to m5-3,11.-dihydrox.Y- 22a-spi.rotne with the aid of boron and sodium hydride.



   After acetylation and separation of isomers
 EMI30.4
 from the mixture, ti5-3-acetoxy-31-hydroxy-22a-spi rostene is obtained which is oxidized to 45-3e-aedtoxy-11-oxo-'22a-spirostene.



   For the degradation of the side chain, that is to say the isomerization to a furostenic derivative, the oxidation of the latter and the cleavage of the acyl residue in position 16, known methods are used and obtained from this
 EMI30.5
 so at 05 '' - 3 ° ..actox-1x, 20-d3oxo-prgnadiene. Example 5
 EMI30.6
 ... ----- .....-......



   In 200 cm3 of methanol and with 0.5 g of a 5% palladium catalyst on calcium carbonate,
 EMI30.7
 hydrogen, at 200.5 g of 5'-3-acetoxy-11,20-diox--

 <Desc / Clms Page number 31>

   pregnadiene. After having filtered the solution, it is evaporated
 EMI31.1
 soue empty and obtains as residue 6-3-acetoxy-11,26dioxo-pregnene. The latter is dissolved in 50 em3 of chloroform and treated to 0 with 2.6 g of bromine. The decolorized solution is evaporated under vacuum, treated with o the di-bromide obtained with a solution of 4 g of perbenzoic acid in 30 cm3 of chloroform. then with 3 cm3 of 10% sulfuric acid in glacial acetic acid, leave to stand for two days at o and then for 8 days at 20 in the dark.



  Water and ether are then added to the editorial solution, the ethereal solution is washed with dilute sodium bicarbonate solution and with water, dried and evaporated.



  The residue is dissolved in 100 cm3 of glacial acetic acid and added in portions, at 20, while stirring, a total of 25 g of zinc powder. After having filtered the solution, it is then concentrated in vacuo and the residue extracted with ethyl acetate. The ethyl acetate solution is washed with dilute hydrochloric acid and water, dried and
 EMI31.2
 evaporated. The 3,1? -Diaatoa-12-oxo-endrostne obtained as residue exhibits in the infrared spectrum a clear band of ester group, as well as the bands of an isolated double bond and of a 5-membered ketone.



   Example 6
In 200 cm3 of anhydrous isopropanol, dissolve
 EMI31.3
 5 g of 0-hydroxy-Il, 2n-diaxv-21-benzylidne-prgnéne

 <Desc / Clms Page number 32>

 
 EMI32.1
 (obtained by reacting 65-3-hydroxy-: LI, 20-dioxopregnene with benzalelehyde and 116- * sodium rhvate in ethanolic solution) and 15 g of IsoproPYlato rPalumin1um.



  The mixture is heated for 12 hours at boiling point and then slowly distilled off a little solvent.



  To isolate the reaction product, 800 cm3 of a Seignette salt solution are added to the mixture, the suspension is extracted with ethyl acetate, the ethyl acetate solution is washed with water and dried. and evaporates it.



  To remove the hydroxyl in position 20 ,, the
 EMI32.2
 21-benzylldnîque compound of A5¯3,11p20-tr1hydroxy-pregnene which is obtained as residue in 100 cm3 of glacial acetic acid, the solution is boiled for 6 hours at reflux, then the acetic acid is evaporated off in vacuo, taken up again the residue in ethyl acetate, the ethyl acetate solution washed with dilute sodium bicarbonate solution and water, dried and evaporated. We dissolve
 EMI32.3
 in 50 OM3 of chloroform the compound 21- <benzylideniQue of 65,17 (20) -3-acetoXY-ll-hydroxy-pr4gna1ene which is thus obtained, added to the solution a solution of 2.10 g of bromine in 20 cm3 of chloroform,

   evaporated under vacuum
 EMI32.4
 after decoloration and dissolve the 5.6-dibromide in 200 am of ethyl acetate. The ethyl acetate solution is cooled to -40 and ozone is introduced until ozone consumption decreases markedly. To isolate the

 <Desc / Clms Page number 33>

 The reaction product is concentrated somewhat in vacuo, 100 cc of glacial acetic acid is added thereto and again concentrated in vacuo. The solution in glacial acetic acid obtained is shaken, at 20, with a total of 25 g of zinc powder which is added in portions.

   After having filtered the solution, it is concentrated in vacuo, the residue is taken up in ethyl acetate, the ethyl acetate solution is washed with dilute hydrochloric acid and water, dried and evaporates it; we get ¯5-3-acetoxy-
 EMI33.1
 l1p-hydroxy-11-oxo-anenostene.


    

Claims (1)

Claims. l. A process for the preparation of steroids substituted in 3,11,17, characterized in that a) in compounds of formula: EMI34.1 in which R represents hydrogen or an OH methyl group, R "the substituents -0, or H 'the latter also in esterified or etherified form and R"' the substituent OH OH -O, OH or RlV 'since the hydroxyl groups can also be present in esterified or etherified form, and RIV representing a hydrocarbon residue comprising at most two carbon atoms, the ¯4-3-ketone group is converted into a free ¯5-3-hydroxy group, esterified or etherified; in a manner known per se, or that, b) is hydroxylated in position 11ss or 11Ó, according to microbiological methods known per se, compounds of formula: EMI34.2 <Desc / Clms Page number 35> in which R and R "'have the meanings indicated above and R' represents a hydroxyl or an esterified or etherified hydroxyl group, or that, c) in compounds of the formula: EMI35.1 in which R, R 'as well as "have the meaning indicated above and RV represents a methyl group or an oxygenated methyl group, and which optionally have an additional double bond at position 16, the side chain located at 17 is degraded to a 17-hydroxyl or 17-oxo group, in a manner known per se, or that, d) in compounds of formula; EMI35.2 in which R, R 'as well as R "have the meaning in- EMI35.3 stated above, R represents a methyl group or an oxygenated methyl group and R VI the substituents -0 or / OR H the side chain located at 17 is degraded into a 17-oxo group in a manner known in itself, if applicable <Desc / Clms Page number 36> by protecting the double bond located in position 5, or that, e) in compounds of formula: EMI36.1 in which R. R 'as well as R "have the meaning indicated above, RVII represents a hydrocarbon residue, the side chain located at 17 is degraded to a 17-oxo group, in a manner known per se , if necessary by protecting the double bond located in position 5. The present process can be further characterized by the following points 1) The starting point is androstene or 19-nor-androstene derivatives which contain in position 17 a free, esterified or etherified tertiary hydroxyl group and in addition a methyl, ethyl, vinyl or ethinyl group. 2) we start with ¯5-20-oxo-pregnene and ¯5-20-oxo-19-nor-pregnene derivatives which contain a hydroxyl group in position 3, free, esterified or etherified in a or ss orientation, thus that in position 11O or 11Ó a free hydroxyl group, esterified or etherified, or an oxo group in position 11, and at the carbon atom 21 exclusively <Desc / Clms Page number 37> hydrogen or a free, esterified hydroxyl or oxo group. or etherified, and which optionally have a double bond in position 16,17. 3) We start from ¯5-17-hydroxy-20-oxo or ¯5-17,20-dihydroxy-pregnene or -19-nor-pregnene derivatives which contain in position 3 a free hydroxyl, esterified or etherified in orientation a or ss, additionally in position 11O or 11ss a free, esterified or etherified hydroxyl group, or an 11-oxo group, and at carbon 21 exclusively a hydrogen atom or alternatively a free hydroxyl or oxo group, esterified or etherified. 11. As a new industrial product: 4) The steroids substituted in 3,11,17 which correspond to the formula EMI37.1 in which R represents hydrogen or a group EMI37.2 methyl, R1 is a hydroxyl or an esterified or ethereal hydroxyl group, R "the subs3tuunbs = 0 or OH the latter also in esterified or 6th form, and RU 'the substituents = 0 .. <H or the groups hydroxyls which may also be provided in esterified or etherified form, and RIV representing a hydrocarbon residue comprising at most two carbon atoms. <Desc / Clms Page number 38> EMI38.1 5) The derivatives of α5.sndrostene and of A5-19-nor-androstene which have in positions 3, 11 and 17 a free, esterified or etherified hydroxyl group. EMI38.2 6) The derivatives of 5 ... aridrosbene and of A5 -19-nor- androstene, which have in positions 3, 11 and 17 a free hydroxyl group, esterified or etherified and, in addition, in position 17, a hydrocarbon residue having at most two carbon atoms. EMI38.3 7) Drifts of A5-androstene and of 45-19-nor-androstene which exhibit in position 11 an oxo group and in position 3 and 17 a free, esterified or etherified hydroxyl group. EMI38.4 8) Derivatives of A5.l1-oxo-androstene and 05.-..- o0 - .. 9nar-androtne which have in position 3 'and 17 a free hydroxyl group, esterified or etherified and, in addition .. in position 17, a hydrocarbon residue comprising at most two carbon atoms. 9) The derivatives of A5-androstene and of ¯5-19-nor-androstene which have in position 17 an oxo group and in position 3 and II a free hydroxyl group, esterified or etherified, their esters and their ethers. EMI38.5 10) Derivatives of d5-androatne and of A5-19-noT-androstene which have in position 11 and 17 an oxo group and in position 3 a free, esterified or etherified hydroxyl group. <Desc / Clms Page number 39> II) Mixtures of substances containing EMI39.1 0.001% to 10% of one of the compounds containing 0 in, 11,17 which are defined under 4) to 10), as well as an excipient. 12) Mixtures of substances containing 0.001% to 10% of one of the steroids substituted in 3,11,17 which are defined under 4) to 10), as well as a solid excipient. EMI39.2 13) Mixtures of substances containing from 0.001% to 10% of one of the steroids substituted in 3,11,17 which are defined under 4) to 10), as well as a liquid excipient. 14) Mixtures of substances containing per tablet from 0.02 mg to 100 mg of one of the substitute steroids in 3,11,17 which are defined under 4) to 10). 15) Mixtures of substances containing per oily ampoule from 0.02 mg to 100 mg of one of the steroids substituted in 3,11,17 which are defined under 4) to 10). 16) Mixtures of substances containing per crystalline ampoule from 0.02 mg to 100 mg of one of the steroids substituted in 3,11,17 which are defined under 4) to 10).