BE535805A - - Google Patents

Description

       

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   The present invention relates to a process making it possible to prepare derivatives of pregnane, saturated or unsaturated, with an interesting physiological effect. The term "derivatives of pregnane" is also understood to mean compounds of the homo- and noregnan series, for example those which are derived from 19-nor and / or D-homo-prégnane, the side chain of the latter being fixed in particular in position 17a. These are pregnant compounds, saturated or unsaturated, 3, 18, 20-trioxygenated and their functional derivatives of any steric configuration, preferably having the configuration of natural active substances, that is to say. that is to say of compounds containing at least in positions 3, 18 and 20, hydroxy groups, oxo and / or acid groups,

   free or functionally modified, for example esters, lactones, ethers, thioesters, thioethers, thiol- and thion- esters, acetals, ketal mercaptals, enolic derivatives such as enol esters , enolic ethers or enamines, hydrazones, semi-carbazones and the like. In addition, these compounds may have other substituents, in particular in position 11 and / or 21, and on the other hand, in position 17, a free or functionally modified hydroxy or oxo group. Double bonds can, for example, be present in position 4 and 5 and / or 9 and 11.



   The process of the present invention consists in introducing a substituent in position 2 either of compounds of formula:
 EMI1.1
 in which R1 and R represent free or functional hydroxy or oxo groups
 EMI1.2
 if: i: .o: modified element, R3 can also be a hydrogen atom, R 2 represents a hydrogen atom or a methyl group, R4 a hydrogen atom or a free or functionally aldehyde group modified or a residue convertible into such a group, such as a free or functionally modified carboxylic or oxalyl group, as well as an ON group, either of corresponding compounds unsaturated in the ring,

   by reaction with an aliphatic compound whose carbon atom [alpha] carries a halogen or pseudo-halogen atom or an activated multiple bond between carbon atom starting from this carbon atom [alpha], and which possess in position the residue R, in particular a free or functionally modified oxygenated methyl group, in so far as, in the compounds obtained, R4 represents hydrogen, to be introduced in position 2 a substituent convertible into a group free or functionally modified aldehyde, to be added in position 1, in the compounds obtained, of partial formula of the C ring:

   
 EMI1.3
 or in the corresponding compounds unsaturated in [alpha], ss, a residue condensable with the carbon atone carrying R to give a six-membered ring, or a

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 substituent convertible into such a residue, to remove a hydroxy group in the compounds obtained which have a hydroxy group in position 1, to convert, if necessary, the residue in position 1 into a condensable residue, to be hydrogenated at any stage a double bond between carbon atoms in position [alpha], ss, and / or to transform the residue R in a manner suitable for the reaction to be carried out and finally to transform it into a free or functionally modified aldehydic or carboxylic group ,

   in cyclizing the compounds obtained, in transforming the remainder R5 into a methyl group or into an oxygenated, free or functionally modified methyl group, in splitting the polyhydrochrysene derivatives formed between carbon atoms 16 and 17, if appropriate after formation of a double bond in position 16, 17, and to cyclize the compounds obtained into cyclopentano-polyhydrophenanthrenic derivatives, to transform if necessary, at any reaction stage the substituent R and to hydrogenate the double bonds present in the D ring, and the if necessary to form an oxo group in ring A, and / or to introduce a double bond, to protect the hydroxy or oxo groups present, at any reaction stage, and / or to release the groups functionally modified oxo or hydroxy,

   and / or introducing at position 17 a free or functionally modified hydroxy group.



   Particularly suitable starting substances are compounds accessible by total synthesis, corresponding to the formula:
 EMI2.1
 wherein R represents a free or functionally modified aldehyde group or a substituent convertible into such a group, for example a carbalkoxy group, such as a carbomethoxy group or a carbethoxy group, or an alkoxyoxalyl group, for example a methoxy group. or ethoxy-ox-alkyl, or a free or functionally modified hydroxymethyl group, compounds which are readily accessible, for example by condensing the unsubstituted compounds in the 2-position, using esters of formic acid, of esters of carbonic acid, oxalic esters or with formaldehyde,

   in the presence of basic condensing agents. The condensation products formed can, by intramolecular esterification or etherification of a hydroxy group in position 4 with the substituent in position 2, form lactones or lactols (hemiacetals and hemiketals). The R4 substituent may also be of such a nature that it can be converted, at a subsequent reaction stage, to one of the groups indicated above, in particular to an aldehyde group. This is how it is achieved, for example, by condensing a compound not bearing a substituent in position 2 with an acetaldehyde, for example with dimethylacetaldehyde (isobutyric aldehyde) by passing through aldol, to the ethylidene compound in which the double bond is displaced upon addition of a substituent at position 2.

   This double bond can be subsequently split, either directly, for example by ozonization and reductive cleavage of ozonides using zinc, or indirectly by hydroxylation and splitting of the glycol, for example using lead tetracetate or d periodic acid with formation of an aldehyde.



   For the introduction of a substituent in position 2, it is envisaged,

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 according to the invention, aliphatic compounds having on the carbon atom has a halogen or pseudo-halogen atom, that is to say an aryl- or alkylsulfonyloxy group, or also ethylenic or acetyl compounds - activated nics. They have in position a free or functionally modified oxygenated methyl group, that is to say a free or functionally modified hydroxymethyl, formyl or carboxylic group. As the activating group at the position of the ethylenes or acetylenes indicated, only an aldehyde group or a free or functionally modified carboxylic group is taken into account.

   It is therefore possible in particular to use acrolein, or also esters of acrylic acid, acrylic nitrile or esters of propiolic acid, [alpha] -halogeno- [gamma] -hydroxy-propanes. , [alpha] -halogeno- [gamma] -oxo-propanes, ss-halo-propionic acids or their functional derivatives, etc.



   The introduction of the substituent by means of halogen- or pseu-do-halogeno-propanols is advantageously carried out under basic conditions, with alcoholates of amides or alkali metal hydrides or with quaternary ammonium bases such as Triton B ( trimethylbenzylammonium hydroxide). The addition takes place in a particularly easy manner in the case of compounds in which R represents a functionally modified carboxyl group, for example a carbalkoxy group.
The introduction of the substituent in position 2 by addition of unsaturated aliphatic compounds takes place under the conditions usually employed for the condensation according to the method of Michael,

     that is to say in the presence of basic or acidic condensing agents such as hydroxides or alcoholates of alkali metals, amines or quaternary ammonium bases such as triethylamine or Triton B, or also with using boron trifluoride or aluminum chloride. The reaction with halogeno- or pseudo-halo-propionic aldehydes or derivatives of aldehydes or halogeno- or pseudo-halo-propionic acids, such as esters, amides or nitriles, can take place using the same catalysts or the same condensing agents, because these halogeno- or pseudo-halogeno-derivatives easily convert into unsaturated compounds.

   The addition is carried out in an anhydrous or aqueous solvent such as tertiary butyl alcohol, ethyl acetate, benzene or ether, and in particular in tetrahydrofuran or in dioxane.



   If one introduces a substituent in position 2, for example by condensation according to the method of Michael, under strongly alkaline conditions, and one starts from compounds of the formula above in which R4 represents an oxygenated methyl group, free or functionally modified, this substituent is then split. Products are also obtained in which R denotes a hydrogen atom by subjecting both substitution products in which R 4 is an oxygenated methyl group, free or functionally modified, to an alkaline treatment, in particular in aqueous solution.

   In the products obtained in which R denotes a hydrogen atom, before carrying out the reaction with the ketone group in position 1, it introduces in position 2 an oxygenated methyl group, in particular a hydroxymethyl group. This advantageously takes place by condensation with formaldehyde in the presence of an alkaline condensing agent, for example potassium carbonate.
To the compounds obtained after the introduction of a substituent in position 2, another substituent is then added in position 1 which can be condensed to the carbon atom carrying the substituent R, -, giving rise to the formation of 'a six-link ring.

   The addition to the carbonyl group in position 1 takes place advantageously with the aid of organometallic compounds, such as Grignard compounds, al- metal acetylides.

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 cuddling or using the Reformatsky or Darzens method, so for example with compounds of lithium, acetylene or ethoxyacety- lene or using esters of halo-acetic acids, in the presence of metals such as zinc. In carrying out this reaction, for example in the reaction with metal acetylides, esterified hydroxy groups may be present.

   The residue to be added to the carbon atom 1 must, for the condensation with the carbon atom carrying the residue R5, present, for example, a terminal aldehyde group or a functionally modified, for example esterified, carbon-xyl group, or else a group convertible into such a group, so that cyclization can take place in the direction of aldol condensation or ester condensation The adducts obtained by using advantageously the lithium compound of an alkoxyacetylene can then be further transformed, for example according to the diagram:

    @
 EMI4.1
 
The product obtained after the addition can be converted either directly or after partial catalytic reduction of the acetylenic bond, for example with a palladium catalyst in the presence of pyridine by the action of a dilute mineral acid, into a ss -hydroxyester (III) or in an ester (V) unsaturated in [alpha], ss or in an aldehyde (IX) unsaturated in [alpha], ss. These compounds can be used for cyclization, either directly or in the case of the ss-hydroxy-ester (III) after cleavage of water, for example using thionyl chloride or phosphorus oxychloride in pyridine. and after saturation of the newly formed double bond.

   In an analogous manner, the addition of acetylene to the carbonyl group in position 1 results in an acetylene carbinol which, after partial catalytic reduction, and subsequent allylic transposition, provides an allyl halide or an allyl alcohol having an atom d. primary halogen or a primary hydroxyl group, and which, after oxidation to aldehyde (IX), or to the acid corresponding to ester (V), can, as described above, be used for cyclization. During the condensation carried out according to Reformatzky with esters of halogeno-acetic acids, an ester (III) of ss-hydroxycarboxylic acid is obtained which gives, after splitting water, an ester of type V, unsaturated in [alpha ], ss. The esters obtained can be converted into aldehydes in the same way by various routes.

   Thus, for example, with the aid of oxalyl chloride, it is possible to transform the acids obtained from the esters into acid chlorides, and to reduce the latter either directly to aldehydes or to transform them using diazomethane into diazoketone, then using glacial acetic acid into keto acetates

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 lithium aluminum hydride or sodium boron hydride to glycols, and then splitting the latter into aldehydes using lead tetracetate or periodic acid. It is also possible to reduce the esterified carboxylic group (VI) to carbinol (VII) and oxidize the latter to aldehyde (VIII).

   Another possibility for forming the aldehyde is to react the 1-ketone with an allule halide which is unsubstituted or substituted in the # position, for example with an allylmagnesium halide or with an ester of. bromocrotonic acid in the presence of zinc, and then splitting the double bond into aldehyde directly by ozonization or splitting it into aldehyde via glycols, then cleaving the hydroxy group attached to the carbon atom I.



   Before the addition to the ketone group in position 1, the free oxo groups which may be present are protected, in the substituents R4 and R, or in the ring A. This takes place advantageously by transformation into ketals or enol ethers, for example at using ethylene glycol, methyl alcohol or ethyl alcohol, or using esters of ortho-formic acid, in the presence of acid catalysts. An aldehyde group, for example R4 or R5, can be temporarily converted to a free or functionally modified carboxylic or carboxylic group.

   If, in the compounds obtained after the addition to the carbon atom 2, R3 is a hydroxy group and R and R are aldehyde groups, then it is formed, under the action of esterifying agents or etherification, compounds of partial formulas:
 EMI5.1
 With acetic anhydride and pyridine, for example, a compound of type X is obtained in which R 'then represents an acetoxy group.

   With hydrochloric acid in methanolic solution, it is possible, depending on the reaction conditions, to obtain compounds of type X in which R 'then represents a methoxy group, or compounds of type XI, in which R "and R' '' represent methoxy groups or in which R "represents a hydroxyl group, but R" on the other hand a methoxy group. In the latter case, the free hydroxy group can, if desired, be esterified, for example acetyl or benzoyl.



   Removal of the hydroxy group formed during the addition to the ketone group at position 1 can take place by cleavage of water, simultaneously with the further transformation of the added substituent. The elimination can, however, also be carried out using halogenating agents, where appropriate via the corresponding halides, and by reducing the halogen atom to be reduced.



    Prior to cyclization, the R substituent should, if necessary, be transformed such that the ss carbon atom in the substituent at position 2 is bonded to an aldehyde group or to a functionally modified carboxylic group. Acetalized aldehyde groups are for example set free by treatment with aqueous acid. A protected hydro-xymethyl group, for example esterified, is transformed into free hydroxymethyl group and then oxidized to an aldehyde or carboxylic group, then the latter is esterified.

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The cyclization to polyhydroohrysenic derivatives takes place in the presence of catalysts or condensing agents, in an appropriate solvent.

   If the substituent at the carbon atom 1 contains, for example, a terminal carbalcoxy group, then one works by using strongly alkaline condensing agents, for example alkali metal alcoholates, amides or hydrides such as 1. Sodium ethoxide, sodium amide or sodium hydride. Compounds are then obtained which have a ketone group in the D ring. The condensation with the participation of an aldehyde group is already successful by simple heating, even in aqueous solution, advantageously under pressure, or in the presence of catalysts such as piperidine acetate or piperidine benzoate, in an inert solvent, for example. in dioxane or benzene.



   After cyclization to a polyhydrochrysene derivative, the substituent at position 17 can be converted into a methyl group, an oxygenated, free or functionally modified methyl group, for example an esterified or etherified hydroxymethyl group, an aldehyde group or a free carboxylic group or esterified.



   The cleavage of the polyhydrochrysene derivatives between carbon atoms 16 and 17 advantageously takes place from a compound unsaturated at 16, 17. 16-keto-compounds formed by cyclization of compounds having a terminal carbalkoxy group in the substituent at 1 'carbon atom 1, are for example reduced to 16-hydroxy-compounds using a complex metal hydride, for example using boron hydride and sodium, and the hydroxy group is cleaved to give a double bond at 16, 17.

   The oxidative cleavage of the double bond is advantageously carried out after reduction of the substituent in position 17 to an arbinolic group and protection of the hydroxy group formed, for example by externalification or etherification, and this by ozonization and reducing cleavage of ozonides, for example with zinc, or by hydroxylation, for example with osmium tetroxide or peracides, optionally via 16, 17-epoxides, and by hydrolysis and subsequent cleavage of glycols using lead or acid tetracetate periodic. If the carbon atom in position. 17 is bonded to a carbonyl group, the 16,17-epoxide can also be advantageously prepared by allowing hydrogen peroxide in alkaline solution to act.



   If the 16,17-glycols obtained before the cleavage have in position 17 a free hydroxymethyl, aldehyde or carboxylic group, during the cleavage of the glycols, in particular when periodic acid is used, it forms. dialdehydes with loss of a carbon atom.



   If the cyclization to the chrysene derivative has been carried out with a substituent which is unsaturated at the carbon atom 1c, for example with an ester of type (V), unsaturated at [alpha], ss, or with a. aldehyde of type (IX), unsaturated in [alpha], ss, polyhydroohrysene derivatives unsaturated in 14,15 are formed.



  These derivatives can also be split between carbon atoms 16 and 17. It is possible, for example, by the action of hydrogen peroxide in alcoholic solution, to convert an unsaturated 17-aldehyde ± 14.15116.17 into 16,17-epoxide. Passing through the 16, 17-glycol and then splitting the glycol, one obtains an unsaturated [alpha], ss aldehyde, in which the conjugated double bond [alpha], ss can be reduced chemically or via the catalytic, before the cyclopentanopolyhydrophenanthrene cyclopentanopolyhydrophenanthrene.



   If the substituent at position 17 has been converted to a methyl group after cyclization to polyhydrochrysene, the 16-oxo-17-methyl-polyhydrochrysene derivatives can be made to act on nitrosating agents, for example alkyl nitrites such as iso-amyl nitrite. In this case, the D ring is directly split, between the carbon atoms 16 and 17, with the formation of a free or esterified carboxylic group and a.

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 oximinogenic group
The cyclization into cyclopentanopolyhydrophenanthrene derivatives can be carried out according to the process described in the patent application filed in France on January 14, 1955 by Mr. Reichstein Tadéus and entitled: “Process for the preparation of oxygenated steroids”.

   The operation can be carried out in a suitable solvent, in the presence of catalysts or condensing agents. If the substituent attached to the carbon atom 1 contains, for example, a carbalkoxy group, then advantageously used, as in the case of the cyclization to polyhydrochrysene compounds, strongly alkaline condensing agents such as alcoholates, amides or hydrides alkali metals, such as sodium ethoxide, sodium amide or sodium hydride. In this case, compounds having a ketone group in the D ring are obtained.

   If an aldehyde group is present in the substituent at position 1, cyclization is already successful by simple heating, even in aqueous solution, advantageously under pressure or in the presence of catalysts such as piperidine acetate or piperidine benzoate in an inert solvent. like dioxane or benzene.



   Following cyclization to cyclopentanopolyhydrophenanthrenic derivatives, a substituent convertible into such a group can be converted into the acetyl group, the free or functionally modified hydroxy- or oxo-acetyl group; can also introduce at position 17 a free or functionally modified hydroxy group. Methods known in steroid chemistry are used in this case. For the formation of a hydroxyacetyl group, it is for example suitable to treat the methylketone with lead tetracetate, which leads directly to the acetoxyacetyl residue.

   By avoiding acidic reaction conditions, the acetyl group can also be converted by condensing it with an oxalic ester by reacting an alkali salt of the condensation product with iodine and then cleaving with an alooolate or hydroxide of a. alkali metal and exchanging the halogen atom for the acetoxy residue.



    The transformation of the substituent R4, for example of an oxygen-containing residue or of an unsaturated residue, into a free or functionally modified aldehyde group can take place at any stage. In the case where R is a carbalkoxy group or a lactonized carboxylic group with a hydroxy group attached to the carbon atom 4, it can, if desired after the addition of the substituent to the carbon atom 1, be reduced, with lithium aluminum hydride, hydroxyaldehyde or carbinol depending on the amount used. For the other reactions, the aldehyde group is advantageously protected by acetalization, etherification or esterification.

   If R4 is hydroxymethyl, then it can be oxidized to the aldehyde using mild oxidizing agents, for example with a complex of pyridine and chromic acid. If, on the other hand, one starts from a compound in which R4 represents an alkoxyoxalyl residue, for example an ethoxyoxalyl residue, the latter is then advantageously reduced using lithium aluminum hydride or with using boron hydride and sodium, then the glycolic or [alpha] -hydro-xy-carboxylic group formed is protected by acetonation. The groups released again can be degraded into aldehyde by the action of lead tetracetate or periodic acid.

   Cleavage with lead tetracetate can also take place simultaneously with the transformation of the substituent at the 17 position from an acetyl group to give an acetoxyacetyl group. If, however, compounds in which R4 represents an aldehyde group are used as starting substances, this is then advantageously protected, before the cyclization to a polyhydrochrysene derivative. In the case of 4ss-hydroxy compounds, this is done, curiously enough, very simply, since the aldehyde readily forms lactols with the hydroxyl group at

  <Desc / Clms Page number 8>

 position 4.

   These lactols can be converted into acetals, using active halides, for example benzyl halides, or using dihydropyran. It is also possible to acylate the lactol formed; it is therefore possible, for example, to obtain the acetates or the benzoates of lactol by operating in mild applications with acetic anhydride and pyridine or with benzoyl chloride. On the other hand, the acetals can be split with an aqueous acid. In the case of lactol benzyl ether, the cleavage is also successful by treatment with hydrogen in the presence of a catalyst such as palladium on animal black.

   For the hydrolysis of lactolic esters, dilute acids or alkalis, for example potassium bicarbonate in aqueous alcoholic solution, can be employed.



   The hydrogenation of double bonds can take place chemically or biochemically. For the chemical reduction, both catalytically activated hydrogen and nascent hydrogen are considered. In particular, it is possible to easily hydrogenate by the catalytic route, in alcoholic solution, for example in the presence of a palladium catalyst, a 16,17 double bond formed during the cyclization in
 EMI8.1
 cyclopentanopolyhydrophenanthrene This reduction can also be carried out with the aid of alkali metals, in particular lithium, in liquid ammonia. In an analogous manner, a 14,15 double bond can be reduced. which is conjugated with a carbonyl group,
If an oxo group is to be formed in the ring A, then we can, for example,

   transforming an esterified hydroxy group into a free oxo group, by saponifying it with the aid of bicarbonates, carbonates or alkali metal hydroxides and then carrying out an oxidation, or it is also possible to transform an oxo group into a free oxo group ketalised, by cleavage with aqueous acids. If desired, then a double bond can be introduced in a manner known per se, by halogenation and cleavage of the halogenated hydracid.



   In case it hasn't already happened. in other reactions the protected hydroxy or oxo groups are finally released. For example, ketals and acetals, both open-chain and cyclic, for example ethylene ketals, can be split by treatment with mineral acids or sulfonic acids at room temperature, preferably in the presence of a ketone. such as acetone, or in the presence of pyruvic acid, or also by moderate heating with dilute acetic acid. Under the same acidic conditions, the enolic ethers or the tetrahydropyran ethers are also split.

   In addition, benzyl ethers can easily be cleaved with the aid of hydrogen. presence of a catalyst, for example in the presence of palladium on support substances such as animal black or alkaline earth carbonates,
The method forming the object of the present invention also embraces the embodiments in which the measurements of the method are only partially executed and / or executed in another; in which order and / or in which one starts with compounds obtainable at any stage of the process and carries out some or all of the still remaining stages of said process.

   The present invention relates in particular to the stage of the process in which, between the carbon atoms 16 and 17, saturated or unsaturated polyhydrochrysene compounds of the formula are cleaved:

  <Desc / Clms Page number 9>

 
 EMI9.1
 in which R1 and R3 represent free or functionally modified hydroxy or oxo groups, and R3 may also be a hydrogen atom, R2 represents a hydrogen atom or a methyl group, R4 a free or functionally modified aldehydic group or a remains convertible into such a group, and R a methyl group or an oxygenated methyl group, free or functionally modified, said compounds also having in position 16, 17 a double bond or in position 16 a free or enolized bxo group.



   According to the present process, racemates or optically active compounds are obtained. At any stage of the process, the racemates can be split into their antipodes, according to methods known per se.



   The compounds obtained according to the present process are steroid-17-aldehydes and derivatives of pregnane, saturated or unsaturated, 3-oxygenated, in particular steroids-17-aldehydes 3,11-dioxygenated, first of all compounds 3,11 , 20-trioxygenates of 21-hydroxy-pregnane and their functional derivatives, the residue of which in position 13 represents a free or functionally modified aldehyde group or a residue convertible into such a group, as well as intermediate products for the preparation of these compounds .

   Among these products, the following should be particularly noted: the saturated and unsaturated compounds of polyhydrochrysene, of formula
 EMI9.2
   in which R to R5 have the meaning indicated above, and which have in position 16, 17 a double bond or a position 16 an oxo group, as well as their functional derivatives, in particular the compounds of
 EMI9.3
 

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 EMI10.1
 and their functional derivatives; saturated and unsaturated compounds; of formula:

   
 EMI10.2
   in which R1 and R3 represent free or functionally modified hydroxy or oxo groups, R3 can also be a hydrogen atom, R2 represents a methyl group or a hydrogen atom, R4 a free or functionally modified aldehyde group or a substituent convertible into such a group, R is hydrogen or a free or functionally modified hydroxy group, a methyl group or a hydroxymethyl group, free or functionally modified, and finally R6 an oxygenated methyl group, free or functionally modified, in particularly compounds of
 EMI10.3
 and their * functional derivatives.

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   By the expression oxygenated compounds and their functional derivatives, one understands the compounds which contain groups, hydroxy oxo and / or acids, free or functionally modified, such as esters, lactones, ethers, thio-esters, thio-ethers, thiol- and thion-esters, acetals, mercaptalas, celais, enol derivatives such as enol esters, epolic ethers or enamines, hydrazones, semi-carbazones and analogous derivatives.



   As is also apparent from the following patent applications filed in France: July 19, 1954 by Mr. Reichstein Tadéus, for: "New active substance and process for its isolation from adrenal glands" August 20, 1954 by Mr. Reichstein Tadéus, for: "Process for the preparation of functional derivatives of a new active substance in adrenal capsules", January 14, 1955 by Mr. Reiohstein Tadéus, for: "Process for the preparation of oxygenated steroids and new compounds thus obtained", January 14 1955 by Mr. Reichstein Tadéus, for: "Process for the preparation of oxygenated steroids", it turned out that one can attribute to aldosterone the following formulas which are in equilibrium with one another:

   
 EMI11.1
 
It follows that it is possible, according to the present invention, to prepare aldosterone, its functional derivatives and intermediates for their preparation. Therefore the products of the process can be used as medicaments or as intermediates for their preparation, for example for the preparation of aldosterone and its functional derivatives according to the process of the present invention and according to the process. described in each of the last two applications listed above.



   The invention also relates, as new industrial products, to the compounds obtained by carrying out the process defined above.
The invention is described in more detail in the non-limiting examples which follow. In these examples, there is between each part by weight and each part by volume the same ratio as that existing between the gram and the cubic centimeter. Temperatures are given in degrees centigrade.



  Example 1.



   While cooling on ice, add to a solution of 5 per-

  <Desc / Clms Page number 12>

 
 EMI12.1
 parts by weight of 4b methyl-2-hydroxymethylene-7-ethyl'snedioxy-Is2,3, á ° $ 4b, 5,6,7? 8,10,10ap-dodecahydrophenanthrene-4p-ol-1-one in 40 parts in dry tertiary butyl alcohol by volume, a solution of 0.88 parts by weight of freshly distilled acrolein in 10 parts by volume of dry tertiary butyl alcohol. While cooling in ice, a solution of 0.05 part by weight of potassium in 1 part by volume of tertiary butyl alcohol is added to this solution, under a nitrogen atmosphere, with stirring.



  After stirring for 6 hours (while cooling with ice and under a nitrogen atmosphere), the reaction mixture is diluted with plenty of benzene and 200 parts by volume of ice-water are added. The aqueous phase is separated from the organic phase and the latter is shaken again with ice water. After drying and removing the solvent by vacuum distillation, the residue obtained is dissolved in 20 parts by volume of dry pyridine and added, at 0, in the absence of moisture, 15 parts of acetic anhydride. then let stand 24 hours at 20 - 25. The reaction mass is then dissolved in pure ether, washed several times with cold dilute hydrochloric acid, with water, with sodium bicarbonate solution and again with dry water over sodium sulfate. sodium and evaporated to dryness in vacuo.

   The residue is dissolved in 100 parts by volume of absolute alcohol, added to 0 5 parts by volume of absolute alcohol containing a trace of hydrochloric gas, and the reaction mixture is left to stand for 10 hours at room temperature, protected from sunlight. humidity. At the end of this time, the solution is neutralized with sodium acetate and evaporated in vacuo. The residue is taken up in ether, shaken with 1% water, the ethereal solution dried over sodium sulfate and evaporated in vacuo. The residue obtained is the crude acetate of
 EMI12.2
 ° b-methyl2-formyl-2a- (3'93mdiethogypropyl) -7-ethylenedex3r 12'3g4'4a4b, 5-6, T'8s10910a-dodecyhydrophenanthrene- ° - ol-1-one cyclosemiacetal.



  Example 2.
 EMI12.3
 



  Has a suspension of 100 parts by weight of ° b-methyl-2-hydro $ y-methylene-7-ethylenedioxy-l'2,34,4a4b956Ta8a10'10a-dodecahydrophenanthrene-43-ol-1-one in 300 parts by volume of dioxane, 75 parts by volume of freshly distilled acrolein to which 0.125 part by weight of hydroquinone has been added is added at room temperature. The reaction mixture is stirred for 7 hours at room temperature; everything goes into solution, and it is left to stand for another 16 hours. While ice-cooling and stirring, a 1% anhydrous methanolic solution of 1% hydrochloric acid is then added dropwise, carefully, until the pH of the reaction mixture is 7.0.

   750 parts by volume of methanol are then added, stirred while cooling for 2 hours, the crystalline precipitate formed is separated by filtration and washed on the filter with cold methanol. In this way 35 parts by weight of 4bp-me are obtained.
 EMI12.4
 thyl2-fornyl-2 (3 oxopropyl mT-ethylenedioxr 19 2, 3, 4 4aa ° b? 5 6 Ï9 $ 10,10a-dodecahydrophenanthrene-4-ol-1-one melting at 175-177, which can be purified by recrystallization from benzene, in the pure state it melts at 181.
 EMI12.5
 



  Has a solution of 1.5 parts by weight of 4hp-methyl-26-formyl-2 <X- (3'-ogo-prapylTmethylénediogy-123,4gáa '° b56? T987.OIOa-dodecahydrophenanthrene- ° -ol-1-one in 23 parts by volume of dry pyridine, added at 0, 1.3 parts by volume of acetic anhydride and leave the reaction mixture to stand for 16 hours at room temperature, protected from moisture. At this point, cool to 0, carefully add 10 parts by volume of methanol, evaporated to dryness under vacuum at a bath temperature not exceeding 45 and the residue dissolved in 35 parts by volume of boiling methanol.

   On cooling, it crystallizes the acetate of 4bp-me-
 EMI12.6
 thyl-2p-formyl-2tx = (33 oxo-propyl) -7-ethylenedioxy-l, 2,3,4,4aa, 4b, 5,6,7,8,10,

  <Desc / Clms Page number 13>

 
 EMI13.1
 10α-dodecahdrophenanthrene- ° -ol-1-one, m.p. 195-202. According to elemental analysis and following the infrared spectrum which, between 2.7 and 2.9, does not show an absorption band of a free hydroxy group, the acetate is assigned the formula : not
 EMI13.2
 According to this formula, the substance can be in four stereoisomeric forms: By repeated recrystallization from methanol, one of the stereoisomers is obtained in pure form:

   melting point 235-236 0
Away from humidity, heat gently, in a water bath, a
 EMI13.3
 suspension of 20.5 parts by weight of 4bp-methyl-2p-formyl-2 <x- (3'-oxopropyl) -7-ethylenedioxy-1,2,3'4'4ai4b959697'8'1010a-dodecahydrophenanthrene-q.-ol-1-one in 355 parts. by volume of absolute methanol, everything goes into solution o The solution is cooled to 0 and added, while stirring, 16.3 parts by volume of a solution of hydrochloric gas in absolute methanol, which contains per part by volume 0.001 part by weight of hydrochloric acid. The reaction mixture is stirred for half an hour at 0 to + 3; a crystalline precipitate slowly forms. It is neutralized with a dilute solution of sodium methanolate in absolute methanol, the mixture is sucked up through a suction funnel and the crystals are washed with cold methanol.

   By recrystallization from methanol or from a mixture of benzene and methanol, 4bss-methyl-
 EMI13.4
 2-formyl-2fx- (3 ', 3' l.imé thoxypropyl) -7-ethylene di o $ yl, 2, 3 4 4aa, ° t 5 6 7 8 10,10a-dodecahydrophenanthrene- ° -ol-1- one pure, which melts in 1880.



  In 5000 parts by volume of freshly distilled acetone on
 EMI13.5
 calcium chloride, 100 parts by weight of 4bfi-methyl-2fi-formyl-2t (3 ', 3'-dimethoxypropyl) -7ethylenedioxr 1, 2, 3, °, 4.a.rr ° h, 5, are dissolved 6, 7, 8r 10,10ap-doclecahydrophenan-threne-4-ol-1-o, not melting at 188, then, after adding 33 parts by volume of 36% hydrochloric acid, the mixture is stirred at temperature room temperature for exactly 3 minutes. At the end of this time, 600 parts by volume of a once molar aqueous solution of sodium bicarbonate are added all at once and the reaction mixture is stirred for a further 5 minutes. It is evaporated in vacuo to drying, the residue stirred with 2000 parts by volume of benzene and the benzene solution is filtered off from undissolved inorganic constituents.

   By évapora-
 EMI13.6
 tion of the filtrate, it crystallizes 4bp-methyl-2-formyl-205 - (31-ozo-propyl) -7-ethylene-dioxy-1,2,3 °, 4acxa ° b, 5'6,7i8,10 , 10α-dodecahydrophenanthrene-4-ol-1-one described above in this example and melting at 1810.



  Example 3.



  Has a suspension of 75 parts by weight of 4bi - methyl-2-hydroxy-methylene-'j-ethylene dioy-1,2,3, °, 4aa, 5'6,7,8,10,10a-dodecahydrophenanthrene - 4ss-ol-1-one in 225 parts by volume of dioxane, 46 parts by volume of freshly distilled acrolein are added at room temperature, to which 0.012 part by weight of hydroquinone has been added. The reaction mixture is stirred for 7 hours at room temperature; everything goes into solution; let stand another 16 hours. At this moment, we evaporate

  <Desc / Clms Page number 14>

 the reaction mixture under vacuum until drying, at a bath temperature at most equal to 40. The residue is taken up in 735 parts by volume of absolute methanol; a precipitate is formed.

   While stirring, and protected from moisture, the suspension is cooled to 0 and 30 parts by volume of a solution of hydrochloric gas in absolute methanol, which contains per part by volume 0.014. part by weight of hydrochloric acid. After stirring for a few minutes, keeping the temperature between 0 and +3, everything goes into solution and a short time later a precipitate begins to form.

   After 30 minutes, the reaction mixture is neutralized with a dilute solution of sodium methoxide in absolute methanol, the precipitate is separated by filtration and washed with methanol, then with ether By recrystallization from a mixture of benzene and of methanol, we obtain
 EMI14.1
 ° b-methyl-2-formyl2t (3 '3 -dimethoxypropyl) 7ethyleneclio 1r2934 áa' ° b516? '8q10'i0a-dodecahydrophenanthrene ° -ol1-one described in Example 2, mp 188.



   From the mother liquor, it is possible, by fractional crystallization or by chromatography on aluminum oxide according to the method by
 EMI14.2
 passage, isolate the ° bmethyl2t (3, 3qdimethoypropyl) -7-ethylenedior l 23, ° áa, ° b56s7810i10a-dodeoahydrophenanthrene ° -ol-1-one melting at 102-103. The preparation of this compound is also described in Example 5.



   In 15 parts by volume of dry pyridine, 1 part is dissolved in
 EMI14.3
 weight of ° b-methyl2forml 2r (3 3 mdimethor propyl) - ethylenedioxy-1 2.3, °, 4aa ° b56? 8,10,10adodscahydrophënanthréneí-olml-one and add to the solution at room temperature, 10 parts by volume acetic anhydride. The reaction mixture is allowed to stand for 16 hours at room temperature, under cover. from humidity, evaporated in vacuo until desiccation at a bath temperature of 50 and frees the residue of the last residues of pyridine and acetic anhydride by taking it up several times, each time in 10 parts by volume of benzene, and then evaporating in vacuo.

   By crystallizing the residue in methanol, one obtains
 EMI14.4
 holds cyclosemiacetal acetate from ° b = methyl-2-formylm2t, (3 3 - diméhoxypropyl) -7-étl.ylènediogr 12? 3'4'4a94b5a6a? a8i1010a-dadécahy> àrophénanthnène-4fi-ol-1-one , with a melting point of 1910.



  A solution of 5 parts by weight of 4b6-methy 1-2 (3-formyl-2 (X- (3 ', 3'-dimethoxypropyl) -7-ethylene-dioxy-1,2,3,4) is cooled to 0. , 4aa, 4b, 5,6,7,8,10, 10ap-dodecahydrophenanthrene = -4P * -ol-1-one in 22 parts by volume of dry pyridine, and add dropwise, with stirring and to the In the absence of humidity 3.5 parts by volume of freshly distilled benzoyl chloride, During the addition of the benzoyl chloride, the temperature of the reaction mixture is maintained at +5 while cooling externally. to 5 and then allow the temperature to rise slowly to room temperature.

   After stirring for 16 hours, the reaction mixture is poured onto an ice-cooled solution of 10 parts by weight of sodium bicarbonate in 300 parts by volume of ice-water; the reaction product precipitates in the form of a solidified oil. The aqueous suspension of this product is extracted three times with 75 parts by volume of ether each time, the ethereal solution washed with a dilute solution of bi-. Sodium carbonate cooled with ice, then with water, with an aqueous solution of 1% hydrochloric acid cooled with ice and finally with water again, until neutral reaction with sunflower. The ethereal solution is dried over sodium sulfate, filtered and evaporated to dryness.

   The residue gives, in a mixture of ether and petroleum ether, colorless crystals.
 EMI14.5
 of cyclosemiacetal benzoate of b-metlsyl-2formyl-2 (3 q3 -dimeth gypropyl 'e-thylene-diogy 1, 2 3 s ° á' ° h 5r 9 7 t 8 10y IOadodeca.hydrophenanthrene = 4-01- 1-one, melting point 143e This product shows a ma-

  <Desc / Clms Page number 15>

 
 EMI15.1
 absorption ximum at 231 mu, log t = °, I2, Example 4e A a suspension of 5 parts by weight of 4bp-methyl-2p-formyl- 2a- (3o, 3-dimtho $ propl) - -ethylenediox- 1,2,34 # aa, 4b56'Ï'810,10ā dodécahydrophênanthrène-4p-ol-l-one described in Example 2, in 250 parts by volume of absolute methanol, 2.5 parts by volume of a solution of hydrochloric acid in absolute methanol which contains, part by volume, 0.23 part by weight of hydrochloric acid.

   The reaction mixture is stirred for 45 minutes at 30; after half an hour everything has gone into solution. Neutralized with 4 parts by volume of a normal aqueous solution of sodium bicarbonate and evaporated to dryness in vacuo. The oily residue is dissolved in benzene (10 parts by volume) and chatographic, according to the pass-through method, on a column containing 150 parts by weight of aluminum oxide (activity II). From the eluates obtained with ether, 4 parts by weight of a compound are isolated which melts at 167 after recrystallization from methanol. This compound presents
 EMI15.2
 an absorption maximum at 238 µl = 4.17, and in the infrared spectrum, between 2.75 and 2.9, does not show a characteristic band for the hydroxy group.

   This compound is attributed the constitution of a mono- ether.
 EMI15.3
 methyl of ° b-mthl-2foraylm2e- (3Aoxo-propyl) -1,2s34? 4aa ° b, 5,, 7,9,10,10a-dodecahydrophenanthren ° -ol-7.-1,> acetalized dione, of formula :
 EMI15.4
 
 EMI15.5
 ± W; LeMJ2.L, e Je While heating gently, is dissolved in 200 parts by volume of methanol, 5 'parts by weight of 4b-methyl-2-ormyl-2Cr- (3r, 3'-dimethoxy- propyl-7-thylenedioy-1s2,3sQ, 4aas4bs5s6ss8s1Qs1aa-doclca, y drophnan threne-4p-ol-1-one described in Example 2. 5 parts by volume of a normal aqueous solution of sodium hydroxide are added and Boil the reaction mixture for 5 minutes in reflux condenser.

   After cooling to room temperature, the solution is neutralized with the addition of 5 parts by volume of a normal aqueous hydrochloric acid solution, then evaporated in vacuo until dissolving. The residue is dissolved in water and ether, the ethereal layer is washed with water, dried over sodium sulphate, filtered and evaporated to dryness. From the residue, by crystallization from a mixture of ether and hexane, 4bss- is obtained.
 EMI15.6
 meth.-2a- (3 '3 -dim th o, ypropyl) -s thrl ênedi oxy-1 s 2 s 3 s q. s q.aa, Q.b s 5 s 6 s Ï s 8 10,10afi-dodecahydrophenanthrene-4fi-oi-1-one, which melts at 102-1030.

   This compound is identical to that already described in Example 3o A a solution of 10 parts by weight of q.bmethyl-2 (3QS3 -dimtho-xy-propyl -? - ethylenediox, p 1,2y3,4s4aas4bs5sss8, lOs10a -doâécahydrophna, n-threne-4p-ol-l-one in 150 parts by volume of dioxane, a solution of 80 parts by weight of potassium carbonate in 80 parts by volume of water and 60 parts by volume of a 30% aqueous solution of formaldehyde After having left to stand for 20 to 20 hours, the mixture is diluted

  <Desc / Clms Page number 16>

 reaction with 5000 parts by volume of ether and washing the ethereal layer with water - After evaporating to dryness, the product is, in the form of an oil
 EMI16.1
 yellow, a mixture of ° bi-tethyl = 2hydromethylm2- (3Q3'-dimethox, r propyl)

   -7-ethylenediox3r r2q3944aa4b'Sb'8910a10a3-dodcahydrophenanthrene-4fi-ol-1-ones epimers at carbon atom 2, This mixture is dissolved in 50 parts by volume of pyridine and the whole is added to a suspension of a complex of chromium trioxide and pyridine prepared from 9 parts by weight of chromium trioxide and 350 parts by volume of dry pyridine The mixture is stirred for 19 hours at room temperature, then diluted with 3000 parts by volume d ether, extracted with an ice-cold tetra-molar solution of disodium phosphate, and separates the insoluble inorganic fractions by filtration through a layer of Super Gel.

   The ethereal solution is then washed with 1 water, dried over sodium sulfate, filtered and evaporated in vacuo. From the residue, the first fraction is obtained by fractional crystallization in a mixture of
 EMI16.2
 ether and petroleum ether and in methanol, the ° bi-methyl-2-formyl-2t ', - (3,3'-dimethogypropyl) jethylenedioxy 1,2,3,4., 4a4bi5,6,7, 8,10,10a dodecahydrophenanthrene-4! 3-01-1-one described above, which melts at 187, and which, in solution, is at least partly in the form of cyclosemiacetal Example 6.



   1.77 parts by weight of magnesium shavings are covered with 30 parts by volume of absolute ether and, while stirring, a mixture of the mixture is added dropwise at room temperature and protected from humidity. 15 parts by volume of ethyl bromide and 75 parts by volume of ether. When the reaction which occurs with a weak boiling is completed, one adds
 EMI16.3
 in small portions a solution of 61 parts by weight of freshly prepared ethozyacetylene in 30 parts by volume of absolute ether and stir the mixture until no more ethane is evolved.



   While stirring at 20-25, there is introduced into this reaction mixture a solution of 12.1 parts by weight of the acetate of the cyclosemiacetal of the
 EMI16.4
 ° bme-hyl-2-formyl-2o (3 ', 3Qmdiethoprapylethrlénediogy-1,2,3? °, 4aa, 4'b, 5,6,? 8,10,10adodecahydrophenanthrene ° mol-1-one in 115 parts by volume of absolute benzene The reaction mixture is further stirred for 3 hours at 20-25 and then poured onto 300 parts by weight of a mixture of ice and water, followed by addition of a saturated solution of ammonium chloride until good separation of the layers occurs.

   After separation of the solution of benzene and ether, the aqueous layer is again extracted with 450 parts by volume of ether, the organic solutions are washed with water, combined, dried and the solvent removed in vacuo, at a bath temperature of 40. The residue obtained is acetate
 EMI16.5
 crude ayalosemiaaetal of ° b.methyl2formyllethoyethinyl-2 (3 ', 38- diethoxypropyl me-hylenedioa l, 2, 3, 49 aa, ° b 5 6,, 8s 10,10a (3-dadéahydro- phenanthrene1, ° diolo
To 15.3 parts by weight of this compound, 100 parts by volume of dioxane are added and after adding 6.5 parts by volume of a 10% aqueous solution of sulfuric acid, the mixture is stirred for 4 hours at 20 minutes. .

   Then 15 parts by volume of a saturated sodium bicarbonate solution are added and the reaction mixture is concentrated under vacuum to about 40 parts by volume diluted with 200 parts by volume of ether and the ethereal solution washed once with 80 parts by volume of water. After having dried over magnesium sulfate, the solution is evaporated and the last residues of dioxane are removed in vacuo. The oily residue obtained is chromatographed on aluminum oxide, according to the pass method.

   From the eluates obtained with a mixture of petroleum ether and ether and with ether, we first obtain a compound which, according to its infra-red spectrum, does not -

  <Desc / Clms Page number 17>

 closes no free hydroxyl group and is assigned the structure of
 EMI17.1
 a cyclosemiacetal acetate of Q.bmethl - forml-1,1-carbethoxymethylen-2t- (3 '3'-diethaxypropyl) -7 ethlene-dior 1, 2, 3 Q. 4aa, 4b, 5, 6, 7, 8 10ap-dodecahydrophenanthrene-4P-ol.



   By treating at reflux for 5 hours 1.3 part by weight of the compound indicated above with a solution of 3 parts by weight of potassium carbonate in a mixture of 35 parts by volume of water and 35 parts by volume of methanol , and by removing the methanol under vacuum, the
 EMI17.2
 potassium salt of qb-methyl-23-formyl-l, l, -carbonethlene-2c- (3 ', 3 -d.iê-thoxypropgl) -7-ethhrlenedio-1 y 2, 3, 4, 4aa, 4b 5, 6 '7, $, 10,10a - dodscahydrophenanthrene-4-ol as an oily separation. This salt is dissolved again by adding water and heating moderately, extracted with 150 parts by volume of ether, the aqueous solution weakly acidified with a phosphate buffer (pH 6 approximately) and the free acid extracted on it. as quickly as possible using 3 portions of 100 parts by volume of chloroform each.

   After drying over sodium sulfate, the combined chloroform extracts are filtered and evaporated in vacuo at a bath temperature of 35. The residue is dissolved in 15 parts by volume of dry pyridine and added at 0, protected from humidity, 0.65 part by volume of benzoyl chloride in little chloroform. After leaving for 16 hours at 25 hours, the reaction mixture is dissolved in pure ether, washed several times with cold dilute hydrochloric acid, with water with sodium bicarbonate solution and again with water. water, dry over sodium sulfate, filter and evaporate in vacuo. We get 'the
 EMI17.3
 4bfi-methyl-2fi-formyl-1,1-oarboxymethylene-20E - (3 ', 3'-diethoxypropyl) -1-ethylenedioxy-1,2,3,4,4aa, 4b, 5, 6, cyclosemiacetal benzoate 1,8,10,10ao-decahydrophenanthrene-4-ol.



   To a suspension of 1 part by weight of this crude acid in 5 parts by volume of tetrahydrofuran is added, while cooling with dry ice, 100 parts by volume of liquid ammonia and the reaction solution is mixed well. Then added in small portions 6.5 parts by weight of freshly cut metallic potassium under toluene and, when everything is added, stirred for a further two hours at about -40.

   With stirring, enough anhydrous isopropyl alcohol is then added slowly, dropwise, using a funnel, so that the dark tint due to the dissolution of metallic potassium disappears. Then the excess ammonia is allowed to evaporate at room temperature, 200 parts by volume of benzene are added and carefully 100 parts by volume of water are added, then the layers are mixed well. Throw away the benzene solution.



  With phosphate buffer, the aqueous alkaline solution is acidified to a pH of 5 to 6 and immediately extracted several times with chloroform. The chloroform extracts are washed with a saturated solution of sodium chloride, combined, dried, filtered and evaporated in vacuo. The residue obtained is dissolved in dioxane and left to stand overnight at room temperature with an excess of diazoethane in ether.

   By evaporating in vacuo, the crude benzoate of cyclo-
 EMI17.4
 4b3-methyl-2-formyl1-carbethoxymthyl-2a- (3'a3P-diethopropyl) semiacetal =? - ethylenediogy 1,2,3,4,4,4b, 5,6s?, $ '10,10a- dodeeahydrophenartthrene-4ss-ol, which can be purified by chromatography on aluminum oxide Example 7-
5.55 parts by weight of lithium wire is covered with 500 parts by volume of absolute ether and, while stirring, is added dropwise at room temperature, under a nitrogen atmosphere and protected from humidity. , a mixture of 42 parts by volume of freshly distilled bromobenzene and 50 parts by volume of absolute ether.

   When the reaction that occurs

  <Desc / Clms Page number 18>

 after a gentle boiling is complete, a solution of 28 parts by weight of freshly prepared ethoxy-acetylene in 200 parts by volume of benzene is added; a white precipitate of the compound of ethoxyacetylene and lithium is formed.



   Into this reaction mixture is introduced at 0, with stirring, a solution in 1000 parts by volume of benzene of 20 parts by weight of 1 acetate, described in Example 3, of the 4bss-methyl-cyclosemiacetal. 2ss-for-
 EMI18.1
 myl-2tx (3, 3 -dimethoxyproprl) - ethylenedioxr 1, 2, 3, °, áa, t..b, 5 6, 7, 8, 7.0, 10a-dodecahydrophenanthrene-4-ol1-one and stir for one hour three quarters at room temperature At the end of this time, the reaction mixture is poured onto 5000 parts by weight of ice-cold water containing 19.2 parts by weight of glacial acetic acid. After separation from the benzene solution, the layer is extracted aqueous several times with 500 parts by volume of benzene and a mixture of benzene and ether (1: 1) each time.

   The organic solutions are combined, washed with water, dried over sodium sulfate and evaporated in vacuo until drying. From the residue
 EMI18.2
 by crystallization from ether, 4bfi-methyl-1-ethoxyethinyl-2-formylm2 (3 Q, 3 dimét..ogypropyl) methylenedioxy-1, 2, 3, °, áa, 4b s 5, 6, ?, 8,10,10a <dodecahydrophenanthrènemls ° diol which can be further purified by crystallization from ether or from a mixture of acetone and ether.



  In the pure state, this compound melts at 157. The same product is obtained, melting at 157, using as starting substance the benzoate, described in example.
 EMI18.3
 ple 3, cyclosemiacetal of 4b-methyl-2formyl-2a- (3 ', 3'-dimethoxy-propyl) -ethylenediogy1,, 3 ° 4a9 ° b5,6a, 8a.0? 10a-dodecahydrophêna threne-4ss-ol -1-one.



   The mother liquor of the above product, prepared from acetate, is evaporated to dryness and chromatography in a benzene solution on a column of 100 parts by weight of aluminum oxide (activity II), using the pass-through method. From the eluates obtained with benzene, there is obtained by crystallization from a mixture of ether and hexane, a compound melting at 102 and which, according to the melting point of the mixture and the rate of migration in the mixture. chromatogram on paper (propylene glycol-cyclohexane system)
 EMI18.4
 toluene) is identical to ° b-methyl 2r (3 939mdimethoxypropyl) 7-ethylene-dior-l'2,3,4, áo, ° b, 596,98910,10adodécahydrophenanthrenem ° -ol-1-one described in the examples 3 and 50 Another compound, isolated from the eluates obtained with benzene, melts at 1690;

    'is 4bss-methyl-2ss- (3', 3 '
 EMI18.5
 dimethoxypropyl) - ethylenedior-1,2,3,44a4-bs5s6T98s10910a-dodecahydro-phenanthrene-4fi-ol-1-oneo From the eluates obtained with ether, a further small amount of ° bmetiylml ethogyethir.yl is obtained. -2-formyl- 2 (3 8 J 3'-dimethogypropyl) ethylene diogy 1, 2, 3, °, ác, ° b, 5, 6 '?, 8,10910ai-doclecahydrophenanthrene-1,4P-diol.



  The ° b3-méthyi.-2 (3, 3 e.-d3mêthogypropyl) é tla.yiênediox l, 2, 3, °, 4i4b56iy $ s10'10adodecahydrophenanthrenem ° -ol = Ione which is obtained here as by-product, and which melts at 169, can be transformed into the epimeric compound at carbon 2 as follows:
In 100 parts by volume of methanol, 5.5 parts are dissolved in
 EMI18.6
 weight of ° bmethyl 2 (3, 38dimethoxypropyl) - ethylenediop 1,293,44aa, 4bs5.6? , 8, 10, lOadod.écahydrophânanthrène4-ol-lmone, add 100 parts by volume of a methanolic solution of tetranormal sodium hydroxide, then boil the whole for 15 minutes at reflux. Evaporated to dryness in vacuo, the residue dissolved in water and ether, the ethereal solution washed with water, dried over sodium sulfate, filtered and evaporated to dryness.

   By crystallization from petroleum ether, we obtain 4bss-methyl-2 [alpha] -
 EMI18.7
 (3 ', 3 -din? Ethoxypropyl) = ethylenediox 1, 2, 3, °, áoG, ° b, 5, 6,', 8,10910a-do-decahyd: '\ .. phenanthrene-4-01-I -one, melting at 102-103, already described in Examples 3 and 50

  <Desc / Clms Page number 19>

 Example 8,
With 400 parts by volume of a 0.1 molar solution of sulfuric acid, a solution in 2000 parts by volume of free benzene is shaken vigorously for 3 and a half hours at room temperature.
 EMI19.1
 thiophene, 11 parts by weight of 4bfi-methyl-1-ethoxyethinyl-2fi-formyl-2a- (3 ', 3'-imethoxypropyl) -7-ethylene toioxy-1, 2,3,4, 4aOE, 4b , 5, 6, 7, 8,10, lOadodécahydrophenanthrene-l, 4diol described in example 7,

   melting at 157 The benzene solution was then separated, washed with 2% aqueous sodium bicarbonate solution followed by water, dried over sodium sulfate, filtered and evaporated to dryness. The partly crystalline residue is dissolved in a mixture of petroleum ether and ether (20: 1) and is chromatographed, according to the passage method, on a column of 330 parts by weight of aluminum oxide. (activity II). The fractions eluted with a mixture of petroleum ether and ether (9:

  1), crystalline, give, on recrystallization from a mixture of ether and petroleum ether, 4bp-m-
 EMI19.2
 thyl-I-carbethoxymethyl-2-formyl-2cG- (3 '3 -dimethogypropyl) -7-ethylene-dioxy-1,2,3,4,4aa, 4b, 5., 6,7,8,10,10af -dodecahydrophenanthrene-1,4f3-diol, melting point 138.



   To a solution, cooled to 10, of 5.5 parts by weight of 4bp-me-
 EMI19.3
 thyl-1-earbéthaxymethyl-2 (3-formyl-2tz- (3, 3 diméthogypropyl) -'- éthylênedior- 1,2,3'4,4aa, 4b, 56,7,8,10, I0a-dodecahydrophenanthrene-1 4-diol in 110 parts by volume of dry pyridine, 35 parts by volume of a 2 times molar solution of very pure thionyl chloride in dry pyridine are poured in. The mixture is stirred for 10 minutes at a temperature. from 10 to 20, dilute with 1100 parts by volume of ether and pour over 1200 parts by volume of an ice-cooled molar aqueous solution of sodium bicarbonate.

   The ethereal layer is washed with 0.5 molar solution of sodium bicarbonate and with water, dried over sodium sulphate, filtered and evaporated to dryness and the residue removed under vacuum from the last residues of pyridine. , The oily product obtained shows in the ultra-violet spectrum a strong absorption at 236 m which is characteristic for the unsalted ester.
 EMI19.4
 tured in, fie qb-methyl-1oarbethoxymethylene-23-formyl = 2x- (3 ', 3'-dimetho $ ypropyl) -7-ethylene-dioxy'1,2,3, °, á, ° b'S, 6,7,810I0a-dodecahydrophenanthrene-4p-ol thus obtained provided by saponification, subsequent benzoylation and reduction with potassium in liquid ammonia, as described in Example 6, the benzoate of 4bp-methyl cyclosemiacetal -2p-for-
 EMI19.5
 myl-I - carboymethyl = 2- (3, 3 -dimethoxypropyl) -7-ethylen,

  ediogy-1,2? 34 4aa, 4b, 5,6,7'B, IO, 10a3-dodeeahydrophenanthrene-4o1. By treatment with hydrochloric acid in acetone according to the procedure described in Example 2, the 2a- (3 ', 3'-imethoxypropyl) group is converted to the 20e- (3'-oxo group. -propyl) o By treatment with hydrochloric acid in absolute alcohol, the free aldehyde group is acetalized again and the benzoate, described in Example 6, of the cyclosemiacetal of 4bss- is obtained.
 EMI19.6
 methyl-2-formyl-li-aarbéthagymethyl-2cx- (3? 3'-diethogypropyl) -7-ethylene-dioxy-1,2,34,4aa, 4b, 5s67a8,10,10a-dodecahydrophenanthrene-4-o1Q Example 9 .



   In 2 parts by volume of dry pyridine, 3.5 parts are dissolved
 EMI19.7
 by weight of 4b.methyl-2-formyl-2 - (3 '3 -dimethox, ypropyl) -7-ethylene.e-dioy-1, 2, 3, Q., 4acx, 4b, 5, 6, 7 , 8, It3,10a-dodecahydrophenanthren -.- 01-1-one described in Example 2, with a melting point of 188, and add at room temperature, with stirring, the chromium trioxide complex and pyridine prepared from 3.5 parts by weight of chromium trioxide and 10 parts by volume of dry pyridine * The suspension is stirred for 16 hours at room temperature, diluted with 50 parts by volume of benzene , repeatedly wash the benzene solution with water and

  <Desc / Clms Page number 20>

 finally dried over sodium sulphate and evaporated to dryness in vacuo. The residue is recrystallized from methanol.

   The lactone is obtained from
 EMI20.1
 4b-methyl-2:; arbog 2tGa (3 "'3emdimethogypropyl) - ethylene-dioy-1 2, 3,4, 4a, 4b, 5,6,7 $ s1010a-dodecahydrophenatathrene-4-ol = 1-one under the form of colorless crystals, melting at 182, and showing in the infrared spectrum, at 5.59 #, the characteristic absorption band for a '(-lactone.
 EMI20.2
 



  The treatment of the above lactone of 4b-methyl-2-carboxy-2rx (3 '' 3 e-dimethoxypropyl) -'- ethylenedioy 1, 2, 3, 4, Q.acG, 4b, 5, 6, 7, 8,1,10a- aoàécahyàrophenanthrene-4fi-ol-1-one with hydrochloric acid in acetone, as shown in Example 2 for the acetal cleavage, provides the 4bfi-methyl-2fi-aarboxy-2a- (3 "-oxopropyl) -7-ethylene-diogy l, 2, 3, 4, 4aaa ° ¯ba 5a 6 s 7 g lactone:

  10a 10a3-dodecahydrophênanthréne-4i-ol-1-one, melting at 150, and which can, by acetalization with hydrochloric acid in absolute methanol, be converted back to the lactone of 4bss-
 EMI20.3
 methyl-2i-carboxy 2 (3, 3 -dimethoxypropyl) -7-ethylenedioxy-1,2,34,4aa, 4b 5, 6, ', $, 10, IOadodecahydrophenanthrenQ.-ol-1-one
To 3.47 parts by weight of a pickled lithium wire covered with 200 parts by volume of ether, is added slowly, dropwise, with stirring under a dry nitrogen atmosphere, 26.25 parts by volume of fresh bromobenzene. - highly distilled. The reaction takes place with a low boil.



  When all of the bromobenzene has been added, the reaction mixture is boiled weakly at reflux for 1.5 hours, the lithium being completely consumed. Cooled to 0 and slowly added a solution of 19.25 parts by weight of freshly prepared ethoxyacetylene in 60 parts by volume of absolute benzene free of thiophene. The compound of lithium and ethoxyacetylene then separates out in the form of a white precipitate.

   The reaction mixture is slowly warmed to room temperature and a solution of 10.5 parts by weight of the lactone of the mixture is added.
 EMI20.4
 4b-methyl-2-carbogy 2o (3e, 3'mdimethoxypropyl) -7-ethylenedior 1,23s4, Q.acx, qb, 5, 6, 7, 8, ï0310a-dodêcahydrophênaathrène-Q.ol-I¯-one, melting at 182 in 100 parts by volume of dry benzene free of thiophene. The reaction mixture is stirred under a nitrogen atmosphere for 2 hours at room temperature, then poured into 1000 parts by weight of ice-cold water, shaken thoroughly and the aqueous phase extracted three times with 750 times each. parts by volume of a mixture of benzene and ether (1: 1).



  After having combined them, the organic phases are washed with water until having a neutral or sunflower reaction, dried over sodium sulfate, filtered and evaporated in vacuo until desiccation o The oily residue is dissolved in 45 parts by volume ether After allowing to stand for a while at room temperature, crystals begin to separate. After 16 hours at 6, crystallization is complete. The crystalline precipitate is filtered off with suction and washed on the filter with a mixture of petroleum ether and ether (1: 1).

   After recrystallization from ether, one obtains in the state
 EMI20.5
 pure lactone of ° b (: i-methylm2carbog 1-ethaxyethinyl = 2 (3 '? 3'-dimetho- ypropyl) 7-ethylenediay 1,2,3Q., 4a, 4b, 5,, 7,8,10, 10a-dodecahydraphenan threne-1,4fi-diol, melting point 1 ° 0 o From the mother liquor, chromatography on aluminum oxide, a further quantity of the same can be obtained. compound Example 10.



   To a solution cooled to 0, 1.7 parts by weight of 4bp-me-
 EMI20.6
 thylm2i-formyl-2û (33 mdimétl.oypropyl) -7éthylènediog 1,2,3, Q., 4aet ° b, 5,6,7,8,10,10afi-doàéaahydnophénanthnene-4fi-ol-1-one described in l Example 2, melting at 188, in 70 parts by volume of absolute methanol distilled over magnesium.-ethylate, a solution of 1.7 parts by weight is added

  <Desc / Clms Page number 21>

 hydrogen chloride gas in 12 parts by volume of absolute methanol, then stirred for 1 hour at 0 to +2, a crystalline precipitate separating out.

   It is filtered, washed on the filter with 10 parts by volume of cold absolute methanol, then successively with 10 parts by volume of 75% methanol, with 5 parts by volume of 50% methanol, with 10 parts by volume of a 0.1 molar aqueous solution of sodium bicarbonate and finally with water, until the filtrate has a neutral or sunflower reaction.

   The precipitate thus washed is dried under vacuum over phosphorus pentoxide after recrystallization from methanol, a 4bss-monomethyl ether is obtained.
 EMI21.1
 thyl-2-f ormyl-2- (3 a-oxo-propyl) - j, 7 dimethoxy 1 2 3 4 4acx, 4b, 5, 6, 7,5,10,10ai-dodecahydrophenanthrene-q.-olI-one with a melting point of 196% which probably corresponds to the formula:
 EMI21.2
 In 2,500 parts by volume of acetone, 50 per-
 EMI21.3
 parts by weight of this methyl ether of 4'bp -iRethyl-2p-formyl-2cï- (3'-oxopropyl) -7y7-dimethoxy-1,2 * 3a4,4a, 4b, 5,6,7, 9,10,10a-dodecahydrophenanthren-4ss-ol-1-one with a melting point of 196 and while stirring adds to the suspension at room temperature 17 parts by volume of hydrochloric acid at 36%.

   After one minute, everything has gone into solution and after three minutes the reaction mixture is neutralized by adding 30 parts by volume of a molar solution of sodium bicarbonate. Evaporated under reduced pressure until drying, the residue taken up in benzene, the benzene solution filtered to separate the insoluble inorganic constituents and evaporated to dryness. In a mixture of ether and petroleum ether, it crystallizes the methyl ether, described in Example 4,
 EMI21.4
 qb-methl-2-forml-2a .- (3'-oo-propyl) -1,23,4,4a, 4b, 5,6, T, 9,10 10ap-dodeoahydrophenanthrene-4P-ol-1 , 7-dione, melting at 167.



   To 0.96 part by weight of a lithium wire covered with 25 parts by volume of absolute ether, is added slowly, dropwise, with stirring under a nitrogen atmosphere, 7.27 parts by volume of freshly distilled bromobenzene. . The reaction begins immediately and the reaction mixture warms to boiling. When the addition of the bromobenzene is finished, the mixture is boiled weakly for an hour at reflux, all the lithium disappearing. The mixture is cooled to 0 and slowly added, with stirring, under a nitrogen atmosphere, a solution of 5.8 parts by weight of ethoxyacety- lene in 20 parts by volume of dry benzene free of thiophene; a white precipitate of the lithium compound of ethoxyacetylene forms.

   Stir for another ten minutes and add, at +5, a solution of 2.7 parts in
 EMI21.5
 volume of methyl ether, mp 196, of 4bp-methyl-2 (3-formyl-2tx- (3'-oxoP-proprl)> '-dimethor-1? 2 3, q. 4atx, 4b 5 6 "9.10 10a.-dodecahydrophenanthrene-q.-ol-1-one in 100 parts by volume of dry benzene.



  The temperature of the reaction mixture is allowed to rise to 20, and stirred for a further two hours. The mixture is then poured into 300 parts by volume of ice-water, the aqueous layer extracted several times with ether, the extracts combined with the layer of ether and benzene, and washed with water until 'Neutral After having dried over sodium sulfate and filtered, the solvent is evaporated off under reduced pressure. The crystalline residue is reoristallized from ether.

   A monomethyl ether is obtained, melting

  <Desc / Clms Page number 22>

 
 EMI22.1
 at 178-180, Qb-re-hyl-2-formy7.1-é-tho $, yé-hïnyl-2c (3-oxo-proprl-T -dimehoxy-123i44af4b5671010a-dodeeahydrophenanthrene-1Q.- diol, which corresponds probably to the formula:
 EMI22.2
 An isomeric compound melting at 195 is isolated from the mother liquor.



  Example 11.



   In the presence of 0.25 part by weight of a palladium and calcium carbonate catalyst containing 10% palladium, a solution of 5 parts by weight is shaken at room temperature, under a hydrogen atmosphere.
 EMI22.3
 lactone, described in Example 9, ° bmmethyl-2-earbogyl-1-ethoxy-thinyl-2 (3 ', 3 -dimethoaypropyl) m7methylenedioxy 1,2,3,4s4aUCs ° bs5s6s7s8s 10,10a-dodecahydrophenanthrene1, ° diolg in 250 parts by volume of alcohol and 0.5 part by volume of pure pyridine. When a molecular equivalent of hydrogen has been introduced, the reaction stops. The catalyst is separated by filtering through a thin layer of Super-Cel, washed with alcohol and the filtrate evaporated to dryness under reduced pressure.

   The crystalline residue is recrystallized from a mixture of ethyl acetate and ether.
 EMI22.4
 of oil. The lactone thus obtained, 4bp-methyl-2p-oarboxy-1-ethoxy; .- vinyl-2Ex (3 t, 3 B-dlmethoxy propyl) 7métb.ylënedioxy-i, 2 3s ° s ° s 4bs 5s 6 s's 8s 10a-dodecahydrophenanthrene-1,4-diol melts in a solution of 3.3 parts by weight of the lactone of 4bi-methyl-2-carboxy-I-ethaxyvinyl-2 (3, 3 mdimethogypropyl) -7-ethylenedioy -1,2,3s4,4aas ° b, 5,6,7,8,10,10a-dodecahydrophenanthrene-lsí-dial in 135 parts by volume of anhydrous pyridine, added at 0, under a nitrogen atmosphere in 2 minutes, 38 parts by volume of a 2 times molar solution of very pure thionyl chloride in anhydrous pyridine.

   After stirring for 15 minutes at 0, the reaction mixture is poured into 700 parts by volume of a cold 0.5 molar solution of sodium bicarbonate and then rinsed with 1000 parts by volume of methylene chloride. The organic layer is shaken thoroughly and the organic layer is washed with a 0.5 molar solution of sodium bicarbonate cooled with ice, then with cold water, dried over sodium sulfate, and after filtration the solution evaporates to dry under reduced pressure. By crystallizing the residue in ether, the lactone is obtained
 EMI22.5
 melting at 159, Qb-methyl2-car'boxy-1formylmethylene-2cx- (3's3'-dimethopropyl) -7-ethylenedioay 1s2s3,4 4aas4bs5sês7s8slOslOa-dodecahydraphenanth-4fi-giolet whose spectrum shows an ultralight spectrum maximum absorption at 236 m (log # = 3.85).



   3.75 parts by weight of this lactone are dissolved in 100 parts by volume of alcohol and the whole is shaken at room temperature, under a nitrogen atmosphere, in the presence of 1.1 part by weight of a catalyst. palladium and 5% palladium barium sulphate. After absorption of 0.97 molecular equivalent of hydrogen, the reaction is stopped. The catalyst is separated by filtration and the filtrate is evaporated in vacuo.

   From the residue, crystallization from a mixture of ether and ether is obtained
 EMI22.6
 petroleum, 4bfi-methyl-2fi-carboxy-lfi-formylmethyl-2a- (3 ', 3'-dimethcxypropyl) -7-ethylenedioxy-l = 1s2s3,4sá, as4hs5s6s7s8s10,10a-dodecahy to 4fi-olophenanthrene

  <Desc / Clms Page number 23>

 In 250 parts by volume of dry acetone, 5 parts are dissolved in
 EMI23.1
 weight of the lactone of ° b-methyl -? - carbor-1-'ormylmé $ hyl-2t- (3'3'-di-methoxypropyl) - ethylene di ox 1? a 3 4, 4ac, 4b, 5r 6, Î, 8,10,10a-dodecahydro-phenanthrene-4ss-ol and, after adding 1.65 part by volume of 36% hydrochloric acid, stirred for three minutes at room temperature.

   Neutralize by adding 30 parts by volume of a molar aqueous solution of sodium bicarbonate, diluted with 2500 parts by volume of water and thoroughly extracted with a mixture of methylene chloride and ether (1: 3). The organic layer is washed with water, dried over sodium sulfate, filtered and evaporated in vacuo to dryness. The oily residue which is constituted by the crude lactone of 4bss-met- is dissolved in 450 parts by volume of benzene.
 EMI23.2
 thyl-2-carboxy-li-f ormylméthy2-2cc- (3'-oxo-propyl) -7-ethyl enedior-1 2 3, °, 4aa4b56'Îy8al0al0a-dodecahydrophenanthren- ° -ol-adds 12 parts by volume of glacial acetic acid and 9 parts by volume of piperidine, then boil the whole under a nitrogen atmosphere for one and a half hours in an apparatus provided with a water separator.

   After cooling, the solution is washed with water, with sodium bicarbonate and again with water, dried over sodium sulfate and evaporated under reduced pressure The residue is dissolved in benzene and chromatographed on 150 parts by weight of aluminum oxide. The combined benzene eluates provide
 EMI23.3
 (18 11) lactone of d, 51611-hydrogy-3-ethylenediogy-17-orrayl-77-homoandrostadiene-18-oique which is recrystallized from a mixture of ether and petroleum ether.



    Example 12.



   While stirring in a stream of nitrogen, to 0.1 part by weight of lithium aluminum hydride in 50 parts by volume of tetrahydrofuran is added 6.25 parts by weight of the benzoate, described in example 6, from oy-
 EMI23.4
 closemiacetal of ° b-methyl-I-carbethoxymethyl-2-formyl-2C1 (3 ', 3 -dié-thoxypropyi) -7-ethylenedioxy-1,2,3,4,4a, 4b, 5,6,7,8 10,10afi-αoeahydrophenanthrene-4P-ol in 800 parts by volume of absolute tetrahydrofuran.



  After stirring for 24 hours at room temperature while cooling, any excess reducing agent present is destroyed by carefully adding 2 parts by volume of acetone, then continued stirring for a further two hours. It is then filtered through Celite and washed well with tetrahydrofuran.

   From the filtrate conoentré under vacuum, in a stream of nitrogen, one obtains the benzoate of the cyclosemiacetal of
 EMI23.5
 ° b-methyl-1- (2e-hydroxy-ethyl) -2-ormyl-2e- (38,3'-dieth, oxypropyl) - ethylenedioxyl'2 3, ° '4a, 4b, 5,6, 2'8'10'10a-dodecahydrophenanthrene- ° 3-.01 which, in the infra-red spectrum, shows the characteristic absorption at 2.75 for the hydroxyl group ,,
To a solution of 4 parts by weight of this compound in 40 parts by volume of pyridine is added, with vigorous stirring, a mixture of 4 parts by weight of chromic acid anhydrous in 40 parts by volume of pyridine. The reaction mixture is allowed to stand overnight at 20-25.



  It is then poured into 400 parts by volume of water and extracted with four portions of 300 parts by volume each of chloroform. The chloroform extracts are washed with water, dried over sodium sulfate and evaporated in vacuo. The crude benzoate of cyclosemiacetal of 4bp-methyl-
 EMI23.6
 1.-formylmethyl-2-formyl-2c (3 ', 3 -diethopropyl) -7-ethylene-dioxy-l 2 3' qi qa, aa q.'by 5 '6 Z 8 10 10a-dodéca, 3hydrophenanthrene- ° 3--0l,
3 parts by weight of this compound are dissolved in 45 parts by volume of glacial acetic acid and 2.25 parts by volume of water, then heated for 5 minutes at 30-35 The reaction mixture is poured into 450 parts by volume. - water lume, and quickly extracted with 4 portions of each 100 parts by volume of a mixture of chloroform and ether (1: 3).

   We wash twice

  <Desc / Clms Page number 24>

 its the chloroform and ether extracts with each time 100 parts by volume of water, dried over magnesium sulphate, evaporated in vacuo in a stream of nitrogen, then the residue is taken up in 60 parts by volume of benzene dry. 4 parts by volume of glacial acetic acid and 3 parts by volume of piperidine are added, then the reaction mixture is heated to 60, under a nitrogen atmosphere, in an apparatus which makes it possible to separate the water formed by azeotropic distillation. After one hour, the reaction is terminated; Cool, dilute the benzene solution with ether and wash the benzene and ether solution successively with cold dilute hydrochloric acid, with water, with sodium bicarbonate solution and. again to the water.

   After drying over magnesium sulfate, the solution of benzene and ether is evaporated off in vacuo. We obtain
 EMI24.1
 (IIp ----> 18) -cyolosemiacetal 18-benzoate of al- A 5,16- llhydroxy-3-ethylenediogy 1formyl 18-oo-Dah.omoandrastadiene.



  Example 13.



   In 70 parts by volume of methanol, 4.6 parts are dissolved in
 EMI24.2
 weight of 18-benzoate, described in Example 12, of (1118) -cyclosemiacetal from to, 1- & to 5yl6-11P-hydroxy-3-ethylenedio3: -17-formvl-18-ozo-D-homo-androsta, diene, add 0.2 part by weight of boron sodium hydride in 50 parts by volume of methanol, and stir 3 hours at 20-25. The solvent is evaporated in vacuo as well as possible, added to the residue 100 parts by volume of ice-water and extracted with 3 portions each 75 parts by volume of a mixture of benzene and ether (1: 1). The benzene and ether solution is washed twice with 50 parts by volume of water each time, dried over sodium sulphate and evaporated in vacuo.

   The residue is dissolved in 50 parts by volume of dry pyridine and added to 0, protected from moisture, 3.1 parts by volume of benzoyl chloride in little chloroform. After having isolated the reaction product in the usual way
 EMI24.3
 the dibenzoate of (11-I8) cyclosemiacetal of d, l-516-Ili-hydroxy-17-hydroxy-methyl-18-oxo-3-ethylene to dioxy-I-homo-androstaàiene is obtained, which can be purified byahromatography.
5.7 parts by weight of this compound are dissolved in 170 parts by volume of benzene and cooled to 0.

   While stirring, an ice-cooled solution of 2.54 parts by weight of osmium tetroxide in 100 parts by volume of ether is added and the reaction mixture is allowed to stand for 8 days in the dark at. 20-25. The brown precipitate formed is separated by filtration, washed with ether, suspended in 50 parts by volume of alcohol and stirred vigorously for 45 minutes with a solution of 6.8 parts by weight of sodium sulphite. sodium in 35 parts by volume of water. The reaction mixture was strongly concentrated in vacuo at a bath temperature of the extract with 3 portions of chloroform of 100 parts by volume each, filtering off the water insoluble fractions and the chloroform.

   The chloroform extract is then washed with water and evaporated in vacuo after drying over sodium sulfate.



   To 3 parts by weight of the residue obtained after having dried and evaporated the chloroform solution under vacuum, 40 parts by volume of methanol and 11 parts by volume of pyridine are added with stirring 2.1 parts by weight of periodic acid in 5 parts by volume of water and continue to agitate for 30 minutes. After adding water, it is extracted several times with chloroform.

   From the residue obtained after having dried the chloroform solution and evaporated the chloroform under vacuum, in a stream of nitrogen is obtained the dibenzoate of cyclosemiacetal of 4bf3-methyl-.
 EMI24.4
 1-formy'lnsthyl 2mformyl-2t (3 -hydroxy-2'-ogo-propyl) - -ethylenedio 1, 2,34,4a, 4b, 5,6,, $, 10,10adodscahydraphenatthrene-4-oI as we dissolve

  <Desc / Clms Page number 25>

 in 60 parts by volume of benzene and which is oxidized, in a manner analogous to that described in Example 11, by addition of piperidine and acid
 EMI25.1
 glacial acetic, d, 1-5 6-11, 21dihydror-18, 20-dioxo-3-é'k, βlenedioxy-prégnad.iene 18,21-dibenzoate (III-18) -cyclosemyacetal.



   In 50 parts by volume of pure methanol, 1 part by weight of the compound obtained is dissolved, a solution of 0.01 part by weight of potassium hydroxide in 10 parts by volume of methanol and 1 part by weight of methanol is added. 2% palladium charcoal catalyst, and stirred in a hydrogen atmosphere until one molecular equivalent of hydrogen has been absorbed. The catalyst is filtered off, washed with methanol, neutralized the solution by adding 0.01 part by weight of glacial acetic acid and concentrated in vacuo. The residue is taken up in chloroform, washed with water, dried over sodium sulfate and evaporated to dryness under vacuum. From the residue, we obtain by crystal-
 EMI25.2
 lization of (11 18) -oyclosemiacetal 18,21-dibenzoate from d, 1- 5- 11i21-dihydrox 18,20-dioxom3 thylnedioxy-prêgnx.e.



  Example 14
In the presence of 0.25 part by weight of a catalyst containing palladium and calcium carbonate containing 10% palladium, a solution of 3.5 parts by weight is shaken at room temperature in a hydrogen atmosphere. of
 EMI25.3
 methyl ether, described in Example 10, 4bp-methyl-2p-formyl-1-ethoxy-ethinyl-2 - (3'-oxo-propyl) -7,7-imethoxy-1,2 3, 4 , q.aCG 4b 5 6i j, 9,10,10a-do-decahydrophenanthrene-1,4fi-diol of formula: '
 EMI25.4
 with a melting point of 180, in 200 parts by volume of alcohol and 0.35 part by volume of pure pyridine. After absorption of a molecular equivalent of hydrogen, the absorption of gas ceases.

   The catalyst is separated by filtration, the filtrate is evaporated to dryness under reduced pressure and the residue is obtained by crystallization from a mixture of ethyl acetate and ether.
 EMI25.5
 petroleum, methyl ether, melting at 195, 4'bp-ntethyl-2p-fors) yl-1-thoxyvinyl-2a- (39-oxo-propyl-7,7dimthor-1,2,3,4a4b, 5,6,7,, 10,10a -dodecahydrophenanthrene-1,4-diol of formula:
 EMI25.6
 
In 285 parts by volume of anhydrous pyridine, 7.1 parts by weight of this methyl ether are dissolved, the solution is cooled to 0 and added under a nitrogen atmosphere, 82 parts by volume of a 2 times molar solution.

  <Desc / Clms Page number 26>

 re of very pure thionyl chloride in anhydrous pyridine.

   After stirring for 15 minutes at 0, the reaction mixture is poured into 1500 parts by volume of a 0.5 molar solution of ice-cold sodium bicarbonate. Extracted with methylene chloride and the methylene chloride solution washed with cold 0.5 molar sodium bicarbonate solution and with cold water until neutral, dried over sodium sulfate, filter and evaporate in vacuo until drying. By crystallization from a mixture of ether and petroleum ether, the residue
 EMI26.1
 provides 4bp-methyl-2p-forE! yl-1-formyl-methylene-2oc- (3t-ogo-propyl) methyl ether? 9 7 dimethoy 1, 2? 3 4, 4aa, Q.b, 5, 6 7 9,10 10 al-dodecahydrophenanthrene-4 # -ol which in the ultraviolet spectrum shows at 235-236 mu. Characteristic absorption.



   Catalytic hydrogenation of this compound in alcoholic solution in the presence of a 5% palladium barium sulfate catalyst, the reaction being terminated after absorption of one molecular equivalent of hydrogen, provides 4bp-methyl- methyl ether
 EMI26.2
 2-formrl-1 - formylmethl-2oc (3t-ozo-propyl) -7-â.imethogy I, 2,34, Q.atx, 4b 5,6? Z, 910,10a-dodecahydrophenanthren-4-ol de formula :
 EMI26.3
 To a solution of 2.25 parts by weight of this methyl ether in 110 parts by volume of a 95% aqueous acetone solution, 0.8 part by volume of 36% hydrochloric acid is added and the mixture is stirred. for 80 minutes at room temperature.

   Diluted with 1200 parts by volume of methylene chloride, washed successively with a cold molar solution of sodium bicarbonate and with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue is dissolved in 220 parts by volume of benzene. After adding 5.5 parts by volume of glacial acetic acid and 4 parts by volume of piperidine, the solution is boiled for one and a half hours under a nitrogen atmosphere, in an apparatus provided with a separator. water The benzene solution is cooled and washed with water, with sodium bicarbonate solution and again with water, dried with sodium sulphate and evaporated to dryness in vacuo.

   The residue
 EMI26.4
 contains d, 1- ° 16lli = hyâroxy the form3r103 I8-di ogo - homo-androstadien which is probably in the form of its (Il- 18-cclosemiaeétale It is dissolved in 55 parts by volume of anhydrous pyridine , add 3.2 parts by volume of acetic anhydride and leave to stand for 16 hours at room temperature.

   Poured onto 450 parts by weight of ice, then rinsed with 800 parts by volume of benzene, shaken thoroughly and the benzene layer washed with cold dilute hydrochloric acid, with water, with a cold molar solution of sodium bicarbonate. sodium and finally again with water, After drying over sodium sulfate, filtered and evaporated to dryness, the oily residue is dissolved in 20 parts by volume of benzene and chromatographed on aluminum oxide free of alkali From the eluates obtained with benzene, after recrystallization from a mixture of ether and petroleum ether or from aqueous methanol, the acetate is obtained.
 EMI26.5
 pure (llp ##. l8) -oyclosemiacetal from d, l- .6 4 l'll-hdroy 17 f ormyl-

  <Desc / Clms Page number 27>

 
 EMI27.1
 3.18 dioxo-D-homo-androstadiene, Example 15.



   After having added 0.8 part by weight of boron sodium hydride, a solution of 6.2 par- is stirred for 16 hours at room temperature.
 EMI27.2
 ties eg weight of (7. $ - 17.) - lactone, described in example 11, of d, l-, 65> 1 -11p-hydroxy-3-ethylene to dioxy-17-formyl-I-homa-anàroxtaàiene -18-oîque in 200 parts by volume of alcohol. By carefully adding 2 parts by volume of glacial acetic acid, the excess reagent is destroyed, the mixture is diluted with 2000 parts by volume of water and extracted three times with 250 parts by volume of methylene chloride each time. The methylene chloride solution is washed with water, dried over sodium sulfate, filtered and evaporated.

   The dry residue is dissolved in 24 parts by volume of anhydrous pyridine and slowly added to 5, with stirring and protected from humidity, 2.9 parts by volume of freshly distilled benzoyl chloride, taking care to that the temperature does not rise above +7. Stirred for another half hour at 5 and then allowed the temperature to rise slowly to room temperature. After 16 hours, the mixture is poured into 340 parts by volume of ice water and rinsed with 100 parts by volume of methylene chloride. Extraction is carried out twice more with 150 parts by volume of methylene chloride each time, the extracts washed with a cold molar solution of sodium bicarbonate, with water, with dilute hydrochloric acid and again with water. , dried over sodium sulfate and concentrated in vacuo.

   The residue is dissolved in 20 parts by volume of benzene and after briefly treating the solution with activated charcoal, it is filtered through a small column of aluminum oxide. From the filtrate, after having concentrated and added petroleum ether, one obtains
 EMI27.3
 d, 1-5) l6npbyoye (18 - llp) -lactone benzoate - {; iee dioxy-17-hydroxymethyl-D-homo-androstadiene-18-oic which is purified by crystallization from a mixture of 'acetone and water.



  Example 16.



   Has a solution of 4.9 parts by weight of the benzoate, described in Example
 EMI27.4
 ple 15, (18 --- llp) -lactone, dl-516-lI-hydrox-3-ethyleneedâox l7-hydroxymethyl-I-homo-androstadiene-18-oic acid in 27 parts by volume of tetrahydrofuran, is added dropwise dropwise at -15 with stirring a solution of 0.21 part by weight of lithium aluminum hydride in tetrahydrofuran. During the addition, the temperature is maintained below -10.

   When the reagent has been added (lasting about 30 minutes), the reaction mixture is allowed to warm slowly to room temperature, again cooled to 0 and carefully added 10 parts by volume of acetone. Approximately two thirds of the solvent is then evaporated off under reduced pressure, the residue is poured onto 200 parts by weight of ice and the cold mixture is acidified with 6 parts by volume of crystallizable acetic acid. The mixture is extracted rapidly three times with 100 parts by volume of methylene chloride each time, the extracts are washed with water until they have a neutral reaction with sunflower, dried over sodium sulphate and concentrated in vacuo. .

   The dry residue is dissolved in 13 parts by volume of anhydrous pyridine and added to 5, with stirring and protected from moisture, 1.3 parts by volume of freshly distilled venzoyl chloride.



  The reaction product is isolated as described in Example 15. Purification of the crude product by chromatography on aluminum oxide (activity II) gives, from the eluates obtained with benzene, the dibenzoate.
 EMI27.5
 described in Example 13, (11 18) -cclosemiacetal of d, l- 5'16-lI-- hyàroxy-17-hYdroxyméthy1-18-oxo-3-éthyléne àioxy-D-homo-androstadiéneo 2.4 parts by weight of this benzoate in 235 parts in

  <Desc / Clms Page number 28>

 volume of ethyl acetate, cooled to -30 and passed a dry stream of ozone-containing oxygen through this solution until about 1.05 molecular equivalents of ozone had been consumed. 14 parts by volume of glacial acetic acid were added and while stirring added portionwise to the solution 20 g of zinc powder.

   After one hour, the zinc and zinc salts are filtered off, then the ethyl acetate solution is washed with 5% sodium bicarbonate and water.



  After having dried the solution in ethyl acetate over sodium sulphate, having filtered it and having evaporated it to dryness under reduced pressure, the crude reaction product is subjected to the cyclization reaction by operating as described above. described in Examples 11 and 13. After purification chromatogra-
 EMI28.1
 phic, 5 ï60 obtains the 18,21-dibenzoate of (11,418) -cyclosemiacetal from d, 1- - -11Q-21--hydroxy-18,2o-ioxo-3-ethyleneàioxy-pregnanien, identical to the compound described in Example 130 Example 17
A solution of 7.3 parts by weight of 18-aceto is cooled to 0.
 EMI28.2
 tatte described in Example 14, of (11 18) -cyclosemiacetal of d, l-, Í6 -11Q-hydroxy-17-fonmyl-18-oxo-I-homo-anarostaàiene-3-one in 165 parts by volume of methanol and, while stirring, add dropwise a solution of 1,

  02 part by weight of boron sodium hydride in 25 parts by volume of methanol. The reaction mixture is stirred for 8 hours at 0, carefully added 0.45 part by volume of glacial acetic acid, most of the solvent is evaporated off in vacuo, the residue is repeatedly extracted with 150 parts by volume each time. of methylene chloride, wash the methylene chloride solution with sodium bicarbonate and water, dry it over sodium sulfate and concentrate in vacuo.

   The residue is acetylated by treating it with acetic anhydride dissolved in pyridine; by isolating the reaction product in the usual manner and by purifying it by chromatography, the diacetate is obtained
 EMI28.3
 pure (II-I8) -cyclosemiacetal from d, l- / J 4,16¯ll! 3-hydroxy-17-hydroxymethyl-3 ,, 18-toioxo-I-homo-androstadieneo
5.5 parts by weight of this diacetate are dissolved in 250 parts by volume of ethylene dichloride, 8 parts by volume of ethylene-glycol and 0.65 part by weight of p-toluene-sulfonic acid are added, and heating so as to remove by distillation, over 8 hours, about 350 parts by volume of solvent. The volume of the reaction solution is kept constant by adding ethylene dichloride dropwise.

   The mixture is left to cool, washed with a molar solution of sodium bicarbonate and with dry water and the solvent is evaporated off under reduced pressure. The residue provides the
 EMI28.4
 (11 18) -cyelosemiacetal diacetate of d, 1-5) 16-np-.bydroxy-17-hydroxymethyl-3-ethylenedioxy-18-oxo-D-homo-androstadiene The corresponding dibenzoate is described in Example 13. The other transformations described therein can also be carried out, in a completely analogous manner, with the diacetate.



  Example 18.



   To one part by weight of the dibenzoate-ketal described in Example 13, a solution of 0.2 part by weight of p-toluenesulphonic acid in 60 parts by volume of acetone is added and stirred overnight. After adding a saturated solution of sodium chloride and extracting with chloroform, from the residue, chloroform solutions are obtained.
 EMI28.5
 ched and evaporated, the l, 21-dibenzoate of (11-18) -ayc.osemiacetal from la to, 1-18-oxo-corticosténoneo A 1.2 part by weight of the dibenzoate, 190 parts by volume are added

  <Desc / Clms Page number 29>

 methanol, after which, while stirring in a stream of nitrogen, a solution of 1.9 parts by weight of potassium bicarbonate in 45 parts by volume of water is added. The reaction solution is allowed to stand in a closed cup under reduced pressure for 3 days at 20.

   The mixture is strongly concentrated in vacuo, in a stream of nitrogen, at a bath temperature of 40, and the aqueous residue is extracted with 4 portions each 40 parts by volume of a mixture of chloroform and ether (1: 3). . We wash the solution
 EMI29.1
 organic with water, dries and evaporates. The del-18-ozo-corticosterone which is thus obtained is purified by crystallization from a mixture of acetone and ether.



  Example 190
In 180 parts by volume of methanol, 1 part by weight of the dibenzoate, described in Examples 13 and 16, of (11ss # 18) -cyclose- is dissolved.
 EMI29.2
 miacetal of del- A 5'1 & -lli, 21-dihydroxy-18,20-dioxv-3-ethylenedioxy-pregnadiene and adds a solution of 0.2 part by weight of potassium carbonate in 2 parts by volume of water, as well as 5 parts by volume of a 30% hydrogen peroxide solution. The reaction mixture is allowed to stand for 48 hours at 0, 2 parts by weight of solid monopotassium phosphate are added and evaporated at a bath temperature of 25 to about 20 parts by volume. 100 parts by volume of water are then added and extracted with a total of 200 parts by volume of methylene chloride, divided into 3 portions. The extracts are washed well with water, dried and evaporated.



   The crude product obtained, partially saponified, is subsequently benzoylated with pyridine and benzoyl chloride using
 EMI29.3
 chloroform as a diluent. The dibenzoate of (11 -. 18) -cyclosemiacetal of d, 1- 5-11,21-dihydroxy-16,17-cx-oxado-1 $, 20-dioxo-3-ethylenedior-pregnene which is obtained after this treatment is dissolved in 50 parts by volume of cold crystallizable acetic acid, then 0.5 part by volume of a 32% solution of hydrobromic acid in glacial acetic acid is added.

   The mixture is maintained for 30 minutes at 15 and then poured into 500 parts by volume of ice water containing 5 parts by weight of potassium hydroxide. The cloudy solution is extracted with a total of 500 parts by volume of Methylene chloride divided into 3 portions and washed the extracts with a solution of sodium bicarbonate and with water, dried and evaporated in vacuo under a nitrogen atmosphere. The residue is taken up in 35 parts by volume of 95% ethanol and while stirring the heating for 5 hours at 50 with 10 parts by weight of a Raney nickel catalyst. The catalyst is filtered off and the filtrate evaporated to dryness.

   By chromatographic purification on aluminum oxide
 EMI29.4
 nium, the 18,21-dibenzoate of (11-18) -cyclosemia- ketal of d, 1-, (4,111? cx, 2i-trihydroxy-3,18,20-trioxo- Pregnene By hydrolyzing this benzoate in a manner analogous to that described in Example 18, del- A 4-11P, 17OE, 21-trihydrox-3el8,2O-triozo-pregnene or its (lly- 18) -cyclosemia.cetal
CLAIMS.

** ATTENTION ** end of DESC field can contain start of CLMS **.


    

Claims (1)

1) A process for the synthesis of steroids characterized in that it consists in introducing a substituent in position 2, ie compounds of the formula: <Desc / Clms Page number 30> EMI30.1 in which RI and R3 represent free or functionally modified hydroxy or oxo groups, R3 can also be a hydrogen atom, R2 represents a hydrogen atom or a methyl group, R4 a hydrogen atom - or a free aldehyde group or functionally modified or a residue convertible into such a group, such as a carboxylic or oxalyl group. EMI30.2 bre or formally modified, thus, -also a CN group,: .S.Qi: 1? of corresponding compounds unsaturated in the nucleus, by reaction with a - EMI30.3 aliphatic compound of which the carbon atom carries a .atome .. 'ti'.ha.log.àne or pseudohalogen or an activated multiple bond, entered carbon atoms, EMI30.4 starting from this carbon atom, - and having in position fi the re-st 1t "in particular an oxygenated methyl group, free or? onotionnel1em.ent aodifie- .. as long as, in gomp9nés., o% tu us; jR TepoExR% * ¯àe "1" hydno 'p-to introduce in position 2 a subst: ir1i1iant.' "t: r: ansfo.blte n a group.> J3.1) free or functional iéilty- dic1Ilen.t modifies , aition 'en. PQsi: i? .1 {{<. L -in the compounds obtained, êd # - ,; f {) rmuJ. \ 'T; 1.jii14e .jL' â.nn, 13 ivatç a3 EMI30.5 or in the corresponding compounds unsaturated in [alpha], ss, a residue condensable with the carbon atom carrying R, to give a six-membered ring or a substituent convertible into such a residue, to remove a group hy- droxy in the compounds obtained which have a hydroxy group in position 1, in converting the remainder in position 1 into a condensable residue, if necessary, in hydrogenating at any stage a double bond between carbon atoms in position [alpha], ss and / or transforming the residue R5 in a manner suitable for the reaction to be carried out, and finally transforming it into a free or functionally modified aldehyde or carboxylic group, in cyclizing the compounds obtained, in converting the residue R into a methyl group or into an oxygenated methyl group, free or functionally modified, in cleaving the polyhydrochrysene derivatives formed, between carbon atoms 16 and 17, where appropriate after formation of a double bond in position 16, 17, and in cyclizing the compounds obtained into cyclopentano-polyhydrophenanthrene derivatives, in converting the substituent R, where appropriate at any reaction stage, and in hydrogenating the double bonds present in the ring D, and where appropriate to form an oxo group in ring A and / or to introduce a double bond, to protect the hydroxy or oxo groups present, at any reaction stage and / or to release functionally modified oxo or hydroxy groups, and / or to introduce in position 17 a free or functionally modified hydroxy group. The present invention can also be characterized by the points <Desc / Clms Page number 31> following: 1) As starting substances, saturated or unsaturated compounds, in the nucleus, of the formula: EMI31.1 2) A compound of formula is used as starting substances: EMI31.2 its cyclosemiacetal or its enol. 3) A substituent is introduced in position 2 by reaction with acrolein. 4) The operations of the process are carried out only in part and / or they are carried out in a different order and / or one starts from an intermediate product obtained at any stage of the process and one carries out partially or in part. all of the still remaining stages of said process. 5) The saturated or unsaturated compounds of polyhydrochrysene, of formula, are split between carbon atoms 16 and 17: EMI31.3 in which R1, R2, R3 and R4 have the meaning given under 1), R5 represents a methyl group or a functionally modified oxygenated methyl group, said compounds having in addition in position 16, 17 a double bond, or in position 16 an enolized, free or functionally modified oxo group. 6) The unsaturated polyhydrochrysenes in 16, 17 are split using ozone 7) The unsaturated polyhydrochrysenes at 16, 17, indicated under 5) are converted into 16,17-dihydroxy compounds and the latter cleaved. EMI31.4 8) The 16-0 $ 0-17-.methyl-polyhydrochrséniq.es derivatives of the formula defined under 5) are cleaved, by causing nitrosating agents to act. <Desc / Clms Page number 32> II) As new industrial products: 9) The pomposés obtained by carrying out the process defined under 1) and 1) to 8). 10) Saturated and unsaturated compounds of formula: EMI32.1 in which R1 and R3 represent free or functionally modified hydroxy or oxo groups, and R3 may also be a hydrogen atom, R2 represents a hydrogen atom or a methyl group, R4 a free or functionally modified aldehyde group or a residue convertible into such a group, and R5 a methyl group or a free or functionally modified oxygenated methyl group, said compounds further exhibiting in position 16,17 a double bond or in position 16 a free or functionally modified hydroxy or oxo group and in position 17 an atom. hydrogen or a free or functionally modified hydroxy group. II) Compounds of formula: EMI32.2 in which R, R4 and R have the meaning given under 10) and which additionally exhibit in position 16,17 a double bond, or in position 16 a free or functionally modified hydroxy or oxo group, and in position 17 an atom of hydrogen or a free or functionally modified hydroxy group, as well as their functional derivatives. 12) The compound of formula: EMI32.3 and its functional derivatives, 13) The compound of formula: <Desc / Clms Page number 33> EMI33.1 and its functional derivatives. 14) Saturated and unsaturated compounds of formula: EMI33.2 wherein R1 and R3 represent free or functionally modified hydroxy or oxo groups, and R3 can also be a hydrogen atom, R2 represents a methyl group or a hydrogen atom, R4 a free or functionally modified aldehydic group or a substituent convertible into such a group, R5 is hydrogen or a free or functionally modified hydroxy group, a methyl group or a free or functionally modified hydroxymethyl group, and finally R6 is a free or functionally modified oxygenated methyl group. 15) Compounds of formula: EMI33.3 in which R3, R4, R5 and R6 have the meaning indicated under 14), and their functional derivatives. 16) Compounds of formula: <Desc / Clms Page number 34> EMI34.1 in which R-, R and R5 have the meaning indicated under 14), and their functional derivatives. 17) The compound of formula: EMI34.2 and its functional derivatives. 18) The compound of formula: EMI34.3 and its functional derivatives. EMI34.4 19) Le at 4-1117a, 21-trihydroxy-3,18,20-trioxopregnene or its cyclosemiacetal, and its functional derivatives.