BE534867A - - Google Patents

Description

       

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   To the Belgian patent application filed by the applicant on July 23, 1954, for: "New active substance and method for its isolation from adrenal glands", is described the isolation and purification of a new compound, called aldosterone, biologically very active, from adrenal glands. Another Belgian patent application also filed by the applicant, September 10, 1954, for: "Process for the preparation of functional derivatives of a new active substance of adrenal capsules", describes functional derivatives of aldosterone; it appears that this has two hydroxyl groups, one of which is more easily esterified than the other.



   Based on the reactions described in the present patent, the constitution of aldosteione could be elucidated. The most important results are summarized in the following formula scheme:

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 EMI2.1
 Aldosterone Monoacetate daldosteroTie (the most easily esterified NAJO hydro = yl group 4 esterified 2 "ble Cro3 Or03, 0 CH 1 2 c) Ar, 0 CH 00 0 CO 00 H3C H3C 0.

   .H H29 Pt KHC03 0 CH20H n 0 ### CH Co 0-00 00 H3C ### H3C HO l Wolfi'-KisJuier l Nada 4 HO CE- COOH 0 CO COOH ¯0 - CO COOH H3C! T ")] f) ## l.CE HO l.CE 1.CH J2 i.CH ê2 2oCr03 loCR2N2 3 "Cr03 0 CE COOCH3 1 oCH2IF 0.-.- GO COOCH3 H 3 C 2oCr03 EY ## 0-
 EMI2.2
 3911 methyl diketo-allo-etia-nate

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For these reactions instead of starting from aldosterone, it is also possible to start from its functional derivatives in which the two hydroxyl groups are free or one of the hydroxyl groups is functionally modified, preferably esters, ethers, enolic esters, enolic ethers, acetals or their corresponding thio-derivatives, such as thio-ethers and thio-acetalsa
Based on the degradation reactions indicated above,

   the constitution of aldosterone responds to the following formulas, probably in equilibrium with each other:
 EMI3.1
 
As it emerges, aldosterone and its functional derivatives are 3,18-dioxygenated compounds of pregnane or corresponding functional derivatives.



   The present invention relates to a process for the synthetic preparation of degradation and transformation products of aldosterone and analogous compounds. They can also be converted into compounds which can be used in therapy, for example, into aldosterone, according to the process described in the application filed by the applicant, that same day, for “Process for the preparation of oxygenated steroids and new compounds thus obtained”.

   The constitution of this hormone is thus proven without ambiguity.
The process according to the present invention consists in that saturated or unsaturated compounds of formula:
 EMI3.2
 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, R5 of 1 hydrogen or a free or functional hydroxy group

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 patterned lament, a methyl group or a free or functionally modified hydroxymethyl group, and finally R6 an oxygenated, free or functionally modified methyl or ethyl group,

   are condensed intramolularly with reaction of the substituent R6 with the methylenic group attached to the carbon atom 20
The condensation according to the present process is carried out. preferably, with the aid of condensing agents, the choice of the agent also depending on the nature of the substituents R5 and R6.



    If R6 is an esterified hydroxymethylenic group capable of reacting in particular a halogenomethylenic group or a hydroxymethylenic group esterified with a sulfonic acid, for example with p-toluenesulphonic acid or methanesulphonic acid, the condensation is advantageously carried out in the presence of strong alkalis, such as alcoholates or alkali metal amides, provided that R5 represents hydrogen, a methyl group or a free or functionally modified hydroxymethyl group;

   if R5, on the other hand, is a functionally modified hydroxyl group, very strong alkalis, for example triphenylmethylsodium or phenyl-lithiumo, must be used.As condensation products, steroid compounds are then formed which exhibit, in position 17, a aldehyde, esterified carboxy, acetyl, or a free or functionally modified hydroxy-aoetyl group.



   But if R6 represents an aldehyde group, the condensation according to the present process already occurs under considerably milder conditions, in particular when R5 denotes hydrogen, a methyl group or a free or functionally modified hydroxymethyl group.
In this case, condensation can already occur by simple heating, even in aqueous solution. Besides the strong alkalis mentioned above, it is also possible to envisage other condensing agents, for example amines such as triethylamine or piperidine, or quaternary ammonium bases such as "Triton B" (trimethyl-benzyla- monium hydroxide), optionally also in the presence of organic acids,

   for example in the state of acetates or benzoateso The products formed during the cyclization are steroids unsaturated in position 16,17, having in position 17, for example an aldehyde group, acetyl, or a hydroxy group -acetyl free or functionally modified. The 16-17 double bond, conjugated with a carbonyl group, can be easily saturated with hydrogen, for example in the presence of a palladium catalyst, in alcohol solution.



   If compounds in which R6 denotes an esterified carboxyl group are used as starting materials in the condensation according to the present process, the process is carried out in an anhydrous medium and strong alkalis, for example alcoholates, are used. , alkali metal amides or hydrides. Steroid compounds are then obtained having an oxo group in position 16. These can easily be converted into enolic esters, for example enoltosylates or enol-mesylates (ester of methanesulfonic acid and of enol) which , on treatment with a hydrogenation catalyst, in particular with a nickel or palladium catalyst, provide sterols unsubstituted at the 16 position, saturated at the 16-17 position.



   In the final products obtained, a substituent which can be transformed by hydrolysis into an oxo or hydroxy group, for example at position 3,11 and / or 18, can be transformed into such a group. Thus, ketals and ac-

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 Open-chain or cyclic chain tals, for example ethylenecetals, can be cleaved by treatment with mineral acids or sulphonic acids, at room temperature, advantageously in the presence of a ketone such as acetone or pyruvic acid , or also by moderate heating with dilute acetic acid. Under the same acidic conditions, the enolic ethers or the tetrahydropyran ethers can also be cleaved.

   Benzyl ethers can furthermore be easily cleaved with hydrogen, in the presence of a catalyst, for example palladium on carrier materials, such as animal charcoal or alkaline earth carbonates.



   Hydroxy groups can be converted into oxo groups, for example by means of oxidants such as chromic acid in crystallizable acetic acid or by means of dehydrogenation ages, for example by heating. with copper powder, or by the action of metal alcoholates or phenolates, in the presence of ketones such as acetone or cyclohexanone.



   It is also possible to functionally modify the hydroxy or oxo groups as described, for example, in the aforementioned French patent application filed by the applicant on September 10, 1954, for "Process for the preparation of functional derivatives of a new active substance of adrenal capsules ".



   In the saturated 3-keto-compounds in the A ring, a double bond can be introduced at the 4,5-position in the usual manner, for example by halogenation and then cleavage of hydrogen halide.



   The racemates obtained can be split into their antipodes, at any stage of the process, by methods known per se.



   If, in position 13 of the steroid compounds obtained, there is a residue which can be converted into a free or functionally modified aldehyde group, for example a free or functionally modified carboxylic group, in particular a lactone or arbinol group, suitable agents can be used. required to its nature, for example reducing or oxidizing agents. Thus, for example, 18,11-lactones are converted by means of hydrides of alkali metals and aluminum, such as lithium aluminum hydride, into 11-hydroxyaldehydes or their cyclo-semi-acetals. or their 11,18-diols, depending on the reaction conditions.



   If compounds in which R denotes an aldehyde group are used as starting materials, this is advantageously protected before the condensation according to the present process. This is done in a surprisingly simple way, since the aldehyde extremely easily forms lactols (hemi-acetals) with the hydroxy group in position 4. These can be reacted with reactable halides, for example. benzyl halides, or with dihydropyran, to give acetals. The lactol formed is also acylated. Lactol acetates can thus be obtained, for example under mild conditions, with acetic anhydride and pyridine. Acetals can in turn be cleaved by aqueous acids.

   In the case of lactol benzyl ether, the cleavage can also be carried out by treatment with hydrogen, in the presence of a catalyst, such as palladium on animal black.



   The compounds which can be obtained by the present process are steroid-17-carboxylic acids, steroid-17-aldehydes or derivatives of pregnane saturated or unsaturated, oxygenated in position 3 or in particular in position 3 and 11, the remainder of which at position 13 is a free or functionally modified aldehyde group, or a residue convertible into such a group.

   By oxygenates and their functional derivatives, it is necessary to understand those which contain hydroxy, oxo and / or free acid groups

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 or fundamentally modified, for example estors, lactones, ethers, thio-esters, thio-ethers, thiol and thiomic esters, acetals, mercaptals, ketals, 13s enol derivatives such as enol esters, enolic ethers, enamines, hydrazones, semi-carbazones and the like
The polyhydrophenanthrenic compounds used as starting materials are of any steric configuration They can have a double bond, for example at 8, 8a or 8a,

   9 and / or in the side chain starting from the carbon atom 1. The substituents R3 and R4 can also be directly linked to each other, a carboxyl or aldehyde group in position 2 which can be lactonized or acetalized with a group. pe hydroxyl-in position 4.



   The starting materials of the present invention are new.



  They are prepared for example from compounds of formula:
 EMI6.1
 wherein R1 and R3 represent free or functionally modified hydroxy or oxo groups, and R3 also a hydrogen atom, R2 a hydrogen atom or a methyl group, and R4 is hydrogen or a free or transformed aldehyde group functionally or a substituent convertible into such a group, for example a carboxy or hydroxymethyl group, or also a CN group or from the corresponding compounds unsaturated in the ring by introducing a substituent in position 2 by means of compounds of the formula
X - CH2 - Y, in which X denotes an esterified hydroxy group capable of reacting and Y denotes the acetyl group or an oxygenated acetyl group or substituents convertible into such a group and when, in the compounds obtained,

   R4 denotes hydrogen, by introducing in position 2 a substituent trinsformable in a free or functionally modified aldehyde group, by fixing in position 1, in the compounds obtained having the partial formula of 1 '
 EMI6.2
 following ring: R4 ring sn> vame:

   CH 2 y =: 0 a residue condensable with the CH2 group attached to the carbon atom in position 2 in a 5- or 6-membered ring or a substituent convertible into such a residue, removing the hydroxy group, in compounds obtained which exhibit a group of this kind in position 1 and, in the compounds which exhibit in position 1, a residue which can be transformed into a residual residue

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 densable with the CH2 group at the 2 carbon atom, by transforming this residue into such a residue, and when the CH2 group attached to the 2 carbon atom is not bonded to a carbonyl group, by transforming the stay Y in order to have a group of this kind
Compounds of formula:
 EMI7.1
 which are fully synthetically accessible are particularly suitable starting materials;

   in this formula, R4 represents hydrogen or an esterified aldehyde or carboxy residue, for example carbo-methoxy or carbethoxy or a CN group. These compounds are easily accessible by condensation of compounds unsubstituted in position 2 with esters of formic acid or carbonic acid, in the presence of alkaline condensing agents. Cyan compounds are formed by the action of alkalis on isoxazols prepared from 2-formyl compounds by treatment with hydroxylamine.

   The condensation products formed can give lactones or lactols (hemi-acetals or hemi-ketals) by intramolecular esterification or etherification of an OH group in position 4 with the substituent in position 20
In order to effect the substitution at the 2-position, compounds of the formula X-CH2-Y are used, in which X represents an esterified, reactable hydroxy group suitable for the substitution, thus, in particular, an atom. halogen, such as bromine or iodine, or a hydroxy group esterified with an aliphatic or aromatic sulfonic acid, for example methanesulfonic or p-toluenesulfonic acid o The group Y is an acetyl or acetyl residue oxygen,

   for example an esterified or etherified hydroxacetyl residue, or else a group which can be transformed into such a residue Among these groups, particularly suitable are esterified carboxy groups which can be transformed into an acetyl or substituted acetyl group, for example by passing with an acid chloride and reaction with diazomethane in a manner known per se, or also with nitrile groups or free or acetalized aldehyde groups, which provide acetyl groups, optionally after cleavage of the acetal, by reaction with metal compounds of methane, for example methyl-magnesium iodide or methyl-lithium, directly or after oxidation It is also possible to convert a nitrile or aldehyde group,

   by saponification or oxidation, into a carboxyl group and then converting it as described above into an acetyl group. It is also possible to saponify a nitrile group or oxidize an aldehyde group to form a carboxyl group and convert the carboxylic group into an acetyl group. acetyl group as indicated above o Another possibility of forming the acetyl group consists in carrying out the substitution in position 2 with esterified allyl alcohols which can react, in particular with allyl or methallyl halides or with propargyl halides. The residue Y in this case represents, for example, an ethylenic or propylenic group, this residue possibly also being substituted for the CH 3 group by an etherified or esterified free hydroxy group.

   By oxidative scission of the double bond

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 EMI8.1
 -;:. "- Q-.z: 6IT :: 2 '? By hydroxylation with osmium tetroxide, e splitting of the glycol with 3rd lead tetracetate or periodic 1-' acid, or by 030Lisptio and cleavage of l Ozonide, compounds are obtained in which Y is either an aldehyde group or an acetyl group.

   In the first case, the fermentation of the acetyl residue can be carried out as described above. The transformation of the ethylenic group into an oxygenated acetyl residue can also be carried out by the attachment of hypohalogenous acids with the formation of hydrogen halogen, oxidation into halogenated ketone and exchange of halogen for an oxygenated function, If the residue Y represents an ethinyl group, it can be converted directly into an acetyl group, by hydration.



   If, in the compounds obtained after the reaction with a compound
 EMI8.2
 of formula X-CH2-Y 'R 4 rep: .a: â * e a hydrogen atom, the latter is replaced, according to the present process, in particular by a hydroxymethyl group. This replacement is advantageously carried out by condensation with formaldehyde in the presence of an alkaline condensing agent, for example potassium carbonate.



   In the compounds substituted in position 2 by an esterified carboxy group, or by an aldehyde or CN group, the substitution in position 2 is carried out under the usual conditions for the substitution of compounds.
 EMI8.3
 posed i-di Y xonylated, that is to say in the presence of condensing agents al- .ïnsé 00L alcoholates, amides, hydrides, or carbonates of metals. ".1 .s¯s' or a.as # 1 in the presence of quaternary ammonium bases such as "Tri- ton B" o It is also possible to react the 3-dioarbonyl compounds before the substitution at the carbon atom 2, with secondary amides such as diethylamine or pyrrolidine in a in obtaining the corresponding enamines, then introducing a substituent in the presence or without condensing agents
If an allyl halide is used as a substituting agent,

   it is also possible to form first of all, in a customary manner, an enolallyl ether, then to transpose the latter by heat treatment into a C-allyliqueo derivative
To the compounds obtained after the substitution in position 2, another substituent is attached in position 1 which can be condensed with the CH2 group attached to carbon atom 2, with the formation of a 5- or 6-membered ring. nons Before attaching the substituent in position 1, it is possible, if desired, to modify the other substituents, in particular those which are in position 2 and 4. Thus, for example, a group can be reduced to a carbinonic group. ester and / or carbonyl in a substituent in position 2.



  When lithium aluminum hydride is used for this reaction, at the same time an esterified hydroxy group is released in position 4 and the ketone group is reduced in position 1. Before the substitution. in position 1, this hydroxy group must therefore be oxidized again in position 1 The hydroxy groups in position 4 and in the substituent in position 2 can be protected against this oxidation by esterification or ether-
 EMI8.4
 fïcatîon.

   But if one uses, for example, a 1, .dihydrogy-2-hydroxymethyl compound, it occurs, depending on the steric position of the substituents and the oxidizing agent used, for example 1,4-diketo-2- acids. carboxylic acids, lactones of 1,4-hyàrozy-2-canbozylic acids, hemi-acetals of 1-keto-4-hydroxy-2-formyl compounds or 1-hrdra3r-2-formyl-4-ketone compounds
The addition to the carbonyl group in position 1 takes place, advantageously using organometallic compounds, such as Grignard compounds, alkali metal acetylides, or by the Darzens or Reformatzki method, therefore, by example, with halogenoacid diacid esters

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 ticks, in the presence of metals such as zinc,

   or tertiary butyl acetate in the presence of lithium amide The residue to be attached to carbon atom 1 must contain, for condensation with the CH2 group at carbon atom 2, a terminal esterified carbinol group capable of reacting, for example a halogen atom or a sulfonyloxymethyl group such as a mesyloxy- or tosyloxy-methyl group or an aldehyde group or functionally modified carboxy groups, for example esterified carboxy groups, or a residue convertible into these groups, in order that the closure of the ring according to the present process can take place as an alkylation, aldol condensation or ester condensation.

   For example, the Grignard compound prepared from alkoxyacethylenes is used with advantage, the compounds formed which can be further processed according to the scheme:
 EMI9.1
      
The product obtained after the addition to the carbon bonyl group can be converted into an α, ss-unsaturated ester (V) or an aldehyde (IV), either directly or after partial catalytic reduction of the acetylenic bond, for example with an palladium catalyst in the presence of pyridine, by the action of dilute mineral acid. These compounds can be used directly or after saturation of the new double bond produced, for the closure of the ring. But they can also be reduced for example with complex hydrides of light metals,

   such as lithium aluminum hydride, to the corresponding carbinols and then, after esterification with an aliphatic or aromatic sulfonic acid, be subjected to the closing of the ring. In an analogous manner, the addition of acetylene to the carbonyl group in position 1 results in an acetylene carbinol which, after catalytic reduction then allylic transposition provides an allyl halide or an allyl alcohol with an alcohol group. primer which, after oxidation to aldehyde (IV) or to acid (V) as described above, can be used for closing the ring.

   By condensation with esters of halo-aoetic acids, according to Reformatzki, an ester of ss-hydroxycarboxylic acid is obtained, which, after cleavage of water, gives an ester α, ss -unsaturated, of the type Vo The esters obtained can also be converted into aldehyde in different ways.

     For example, the acids obtained from the esters can be reacted with chlo-

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   @ axalyl so as to obtain diacid chlorides and reduce them either directly to aldehyde, or to react them with azomethane so as to obtain diazo-ketones which are trancformed with acetic acid crystallizable into ketol acetate, then these are reduced with lithium aluminum hydride or bare sodium hydride to glycols and split the latter with lead tetracetate or periodic acid. - that in aldehydes.

   Another possibility for the formation of the aldehyde is to react the 1-ketone with an allyl halide which is unsubstituted or substituted in the # position; for example with an allyl-magnesium halide or an ester of bromo-crotonic acid, in the presence of zinc, to split the double bond directly by ozonization or by passing through the glycols so as to obtain the aldehyde, then to split the hydroxy group at carbon atom 1.



   To introduce a chain of three carbon atoms, one can use Grignard compounds of 1-halogenated propanes such as 1-chlo-ro-3-acy1-hydroxy-propanes, which are easily accessible from trimethylene chlorobromide. , or 3-halo-propionic aldehyde, in particular in the form of its acetals.



   Before addition to the ketone group in position 1, the oxo groups optionally present in the substituents Y and R4 or in the ring A are protected. This is advantageously achieved by transformation into ketals or erolic ethers, for example by means of ethylene glycol or orthoformic esters in the presence of acid catalysts Removal of the hydroxy group produced upon addition to the ketone group at position 1 preferably takes place by splitting water together with 'we transform the attached substituent.

   This elimination can, however, also be carried out by means of halogenating agents with formation of the corresponding halides and elimination of the halogen atom by reduction, or by heating in the presence of agents which make it possible to split the halogen. water of these compounds, such as oxalic acid or boric acid
Before the cyclization according to the present process, the substituent Y must be transformed so that at the CH2 group attached to the carbon atom 2 a free carbonyl group is formed. The acetalized carbonyl groups are set free, for example by treatment with aqueous acid. The transformation of the various substituents has already been described above. It is not necessary for the following phases of the process to transform the substituent Y into an acetyl or oxygenated acetyl group, before the cyclization.

   Closure of 1 ring can take place when the Y substituent is for example a carbalkoxy, aldehyde or acetyl group.



   The present invention also relates, as new industrial products, to the products in accordance with those obtained by the process defined above.



   The following examples illustrate the invention without however limiting it. Between each part by weight and each part by volume, there is the same ratio as between the gram and the cubic centimeter. Temperatures are indicated in degrees centigradeo
Example 1
A 5.62 parts by weight of 4bss-methyl-lss- (2'-tosyl-oxyethyl) -2a-acetonyl-2ss-hydroxymethyl-7-ethylenedioxy-1,2,3,4,4aa, 4b, 5,6 , 7,8,10,10ass-dodecahydrophenanthrene-4b-ol, in 40 parts by volume of methanol is added with stirring 5.4 parts by volume of 2n methanolic solution of sodium methylate while passing a stream of ' nitrogen After 24 hours, water is added and extracted with chloroform.

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   Stirred for 2 hours at room temperature, in a stream of nitrogen, 4 parts by weight of the residue of the chloroform solutions dried then evaporated in vacuo, 125 parts by volume of benzene, 50 parts by volume of methanol and 75. parts by volume of a 2n methanol solution of sodium methoxide. After having diluted with water and extracted with chloroform, the residue of the chloroform solution washed, dried and then evaporated in vacuo is chromatographed on alumina.
 EMI11.1
 



  This gives d, l A -3-ethylene to Dioxy-11fi, 18-alpha-hydroxy-20-oxo-pregnene.



   To 1 part by weight of this compound is added a solution of 0.2 part by weight of p-toluenesulfonic acid in 60 parts by volume of acetone and the mixture is stirred overnight. After addition of a saturated solution of sodium chloride, followed by extraction with chloroform, the residue produces chloroform solutions which are dried and then evacuated.
 EMI11.2
 rees, α, l-llp, 18-dihydroxy ..- progesterone The 3-monocetal, described above, of this compound can be converted into d, 1-18-hydroxy-corticosteroneo The infrared spectrum of this compound is identical to that of 1 $ -hydrox, γ-corticosterone, described in Example 38, prepared from aldosterone.



   Example 2.



   A solution in 500 parts by volume of benzene, 21%, is subjected to slow distillation for 4 hours in a nitrogen atmosphere.
 EMI11.3
 parts by weight of (2 # 43) -lactone from Ip-formylmet1-2a.-acetonyl- 2 (3-carboxy.-4b (3-methyl-7-ethylenioxy-1, 2, 3, 4y 4aa, 4b 5 , 6, 7 '8 10 10 al-do-decahydrophênanthréne-q. (Crude 3-ol, described in Example 13, and 1.67 parts by weight of Triton B (trimethylbenzyl-ammonium hydroxide), in 4.5 parts by volume of tertiary butanol It is cooled, diluted with ether, the solution shaken successively with a 2 times molar solution of monosodium phosphate, water, a normal solution of sodium carbonate and water, dried over sodium sulfate then evaporated in vacuo.



   The residue is dissolved in benzene in order to purify it, and then chromatographed on neutral alumina by the pass method. As the eluting agent, benzene, mixtures of benzene and ether (9: 1) and (1: 1), ether and a mixture of ether and acetic ester (9: 1) are used. 1) The eluates are examined chromatographically by touches on paper, under a quartz lamp and the strongly absorbent fractions are combined. By recrystallization using acetone-ether and isopropyl ether-ether.
 EMI11.4
 that, pure (11) -lactone is isolated from α, 1-516 - etbylene-dioxy-llp-hydroxy-20-oxo-pregnadiene-18-otque.



  This compound can be converted as follows into the (18 -.) 11 (3) - lactone of del- A 4-3,20-ioxo-11 @ -hyàroxy-pregnene-18-oigueo In a hydrogen atmosphere, the mixture is stirred at at room temperature a solution of 19.23 parts by weight of del- e 5elC 3-ethylenedioxy-llp-hydroxy-20-oxo-pregnadiene-18-oic (lez lli) -lactone in 500 parts by volume of ethanol, in the presence of 10.0 parts by weight of a 2% palladium-strontium carbonate catalyst. After absorption of gas of 1.05 equivalent, the hydrogenation practically stops o The catalyst is filtered off and the solvent is distilled off in vacuo, For purification, a benzene solution of the residue is filtered through a layer of activated carbon, then the filtrate is evaporated in vacuo.

   From the residue, it is extracted by recrystallization from ether, using methylene chloride as a favorable agent.
 EMI11.5
 risking dissolution, (18 11 @) - laatone del- to 5-3-ethylenedioxy- 11i-hydroxy 20-oxo pregnene-18-oqueo
A solution of 19.33 parts by weight of (18 # 11 (3) -lactone of d, 1- # 5-3-ethylenedio- is stirred for 48 hours at room temperature.

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 EMI12.1
 :: y-llli7osy '* 20-oxo-prengen-l8-olque and 4;

   3 parts by weight of p-toluenesulphonic acid, in 500 parts by volume of aât0a Os dilute alo2 with water, and remove the acetone by vacuum distillation. The reaction product is taken up in a mixture of ether and ethylene chloride (3: 1), the extract is washed with normal sodium bicarbonate solution and with water, dried over sulphate. sodium, then evaporates in
 EMI12.2
 the void.

   By crystallization from 1: ether, the (18 #. 113) -lactone of d, 1- 4-3,2-dioxo-llP-hydroxy-pregnene-18-oiqu60 is obtained. The 3-ethylenedioxy derivative, described above, of this compound, is converted into the (18 11 @) - lactone α, 1- / y ° -3,20dloo-lli hydroxy-21-acetoxyprregnene-18-oic, according to the process of the patent filed in same name today and having the title "Process for the preparation of new steroids and compounds thus obtained." 5 The infrared spectrum of a solution of this product is identical to that of the optically active compound described in Example 29.
 EMI12.3
 



  If one uses for the cyclization the (2-y 4µ) -lactone of lp-for- mlmethyl-2ot-c .acetoxyacetonyl m2 (3carboxy ° 'hmethyl7-et: aylènedioy-l,, 3, °, 4aas4b, 56t7 $, lslla-dodeaahydrophenanthrene = í-ol, as a starting material, after hydrogenation of the 16,17 double bond and cleavage of the ketal as described above, the (18 # llp) -lactone of d, 1- # is obtained. 4
 EMI12.4
 -, 2dī -lii-hydrox, y-21, acetoxy-pregnene-18-oic which also provides: .- 1 2c: x: .ti :::> n, an infrared spectrum identical to that of the optically active compound described in example 29.



   Example 3.



   In 30 parts by volume of benzene, 0.250 part is dissolved in
 EMI12.5
 weight of the lactone described in Example 22, of lfi, 2a, di- (formylmethyl) -2fi- carboxy- ° b (3-methyl -'- ethyl èâe-di oxyml, 2, 3, °, áct, 4b a 5 r 6 s? A $ 1 s la (3-dodë ca-hydrophenanthrene-4 (3-o1, adds 0.06 part by volume of crystallizable acetic acid and 0.04 part by volume of piperidine, then boiled in a nitrogen atmosphere for 1 hour, using a water separator.



  After cooling, the solution is diluted with ether, then washed with water, sodium bicarbonate solution and water, dried and evaporated in vacuo. The product is chromatographed. crude on 10 parts by weight of alumina. From the fractions eluted with
 EMI12.6
 benzene-ether mixtures, the (18 - pllfi) -laatone is extracted from d, l- Ô5'16- 3-ethylene-dioxy Ili hydro 17forrayl-androstadiene-1 $ -oiqueo
This compound can be transformed as follows
By hydrogenation with a catalyst of palladium and calcium carbonate in alcoholic solution, according to the indications of Example 2, the corresponding compound is obtained in a good yield, saturated in position 16, 17.



   If we boil this lactone, first for about 30 minutes with a little concentrated hydrochloric acid, in acetone, we obtain
 EMI12.7
 after the usual treatment, the (18 11 (3lactone of cl5l-A 4-3-oxo-llI3, - hydroxY-17 -formyl-androstene-18-oique.



   0.037 part by weight of this substance is dissolved in 8 parts by volume of crystallizable acetic diacid, and then a solution of 0.04 part by weight of sodium dichromate in a mixture of 0.1 part by volume of water is added and 5 parts by volume of crystallizable acetic acid, and left to stand for 12 hours at room temperature. Water is then added, diluted with a mixture of chloroform and ether and separated in the usual way, by stirring with a solution of sodium carbonate, as an acid fraction and as a neutral fraction. The sodium extracts are acidified and the extracts with chloroform. The chloroform extracts are washed with

  <Desc / Clms Page number 13>

   1: do saturated sodium chloride solution and dried, then evaporated.

   The residue is esterified in a mixture of ether and methanol with excess diazomethane, then the solvent is evaporated in vacuo. The gross product
 EMI13.1
 provides, after chromatography on alumina, the (18 llj3) -laotone of at, 1-2 to 4-3-oxo-11 @ -hyàroxy-18-oique-etienate of methyl, whose infrared spectrum is identical to that of ester prepared from aldosterone, described in Example 29.



     Example 4.



   In 30 parts by volume of benzene, 5 parts by volume are dissolved
 EMI13.2
 weight of 1 (3-2c-di- (carbometho $ ymethyl) -2i-car'bethoxy.- ° b (3-methyl-7-ethylene-dioXY-l, 2,3,4,4aa, 4b, 5 , 6,7,: 10a-dodecahydrophenanthrene-4-one, add sodium ethoxide (prepared by dissolving 0.44 part of sodium in methanol and evaporating the methanol in a vacuum), then boiling It is refluxed for 8 hours in a nitrogen atmosphere, with stirring After cooling, the mixture is poured into ice-water, ether added and extracted three times with ether. By acidification of the alkaline part aqueous with ice-cold dilute phosphoric acid, at pH 4-5, it precipitates
 EMI13.3
 d, 1- A 8-11, 16-dioxo-3-ethylene-ethylene-dioxy-18-oate-methyl etienate, which gives a positive reaction to ferric chloride.



   This compound can be transformed as follows: In a solution
 EMI13.4
 of 3.2 parts by weight of to, 1-Ô 5-11,16-toioxo-3-ethylene to ethyl-methyl etienate-18-oate, in 40 parts by volume of pyridine, 4 parts by weight are added p-toluenesulfonic acid chloride and leave the mixture to stand for 24 hours at room temperature, in a nitrogen atmosphere.

   A saturated sodium bicarbonate solution is then added to the reaction mixture to neutralize the pyridine hydrochloride formed and the excess of p-toluene sulfonic acid chloride, followed by stirring thoroughly, eluting with ice-water. , it precipitates the d, 1-
 EMI13.5
 A 5,16¯II-oxo-3-ethylenedioxy-16-p-toluenesUlfonYloxy-18-oate-ethyl-methyl etiadienate colored brownish which can be decolorized by filtering its benzene solution through Norit ( bleaching charcoal).



   Stirred in a hydrogen atmosphere, at room temperature, under a pressure of about 10 atmospheres, 1 part by weight of d.
 EMI13.6
 A '-11-oxo-3-ethylene to dioxy-16-p-toluene-sulfonyloxy-i8-oate-ethyl etiadienate, dissolved in 50 parts by volume of benzene, after addition of 2 parts by weight of a catalyst palladium and calcium carbonate. When the hydrogen is no longer absorbed, the catalyst is removed by filtration, and the solution is evaporated in the video.This gives d, 1- # 5-11-oxo-3-ethylenedioxy-18 Ethyl oate-methyl etienate.
 EMI13.7
 



  To a solution of 1 part by weight of d, 1- A 5-11-oxo-3-ethylene-dioxy-18-oate ethyl-methyl etienate in 100 parts by volume of ethanol is added in portions of excess sodium boron hydride After the evolution of hydrogen has ceased, the reaction mixture is boiled for a further 1 hour at reflux, 30 parts by volume of water added, then most of the ethanol is distilled off shaking. The brownish melt thus obtained is allowed to cool, introduced into ice water and extracted with benzene for the separation of neutral substances.



  By acidifying the alkaline solution to pH 4-5 with dilute, ice-cold phosphoric acid, the (18 # 11 @) - lactone of d, l- acid is obtained.
 EMI13.8
 Etienic O 5-11p-hydroxy-3-ethylenedioxy-18-oic By cleavage of the ketal group, as described in Example 2, the (18-11) -actone of d-acid is obtained. 1- to 4-3-oxo-11 @ -hy-

  <Desc / Clms Page number 14>

 
 EMI14.1
 '-w -1 $ 3oqueéti niqte,. dant the infrared spectrum is identical to that of the optically active compound described in Example 29, obtained by degradation of aldosterone,
 EMI14.2
 The starting materials for the cY01Ísatir.s in the process can be prepared according to Example 50
Example 5.



   4.4 parts by weight of
 EMI14.3
 4b (3 methl-2-car'béthoçy-q. (Ethoy - carboxy '-éthlenedïox3rml 2 3, 4, 4aa, 4b, 5.6,7,8,10,10ap-dodecahydrophenanthrene-1-one in 20 parts in volume of absolute dioxane, in a stirred vessel lined with glass beads, in a nitrogen atmosphere, with part by weight of sodium hydride, add 3 parts by volume of metallyl bromide dropwise and stir during 6 hours at 55-65. After cooling the reaction mixture, first 5 parts by volume of ethanol are added and then, after diluting the feed with plenty of benzene, 20 parts by weight of ice, after which the mixture is stirred. all for a few minutes while cooling.

   The aqueous phase is separated from the organic phase and the latter is extracted once more with ice-water. After drying the solution in the organic solvent and then removing the solvent in vacuo, the mixture is obtained.
 EMI14.4
 4bfi-methj = 1 -? - methallyl-2-carbethoxy-4fl-ethoxycarboxy- J-ethylene-dioxy-1,2, 3, 4, 4aa, 4b, 5, s, 8 s 1a3-dodecahyd-ophénanthr enealore under the shape of a reddish .null.

   The separation into the two isomeric compounds at the 2 carbon atom is described in 1 example which follows
 EMI14.5
 4b (3-methyl-2-carbé-hox-q.; Ethoxoarboy-ethylenedioxy-I, 2? 3, 4, 4aa, 4b, 5, 6,, 8,1f11.0a (3-dodéce, hydrophér.anthrëneione , used as a starting material is obtained as follows:
Stir for 12 hours at 55-65.4 parts by weight of 4bss-
 EMI14.6
 methyl-7-ethylenedioxy-1 2 3 9 4;

   . acc, 5 6, Î, 8, l, 10a3mdo de cahvd.rophenanthr ene-4ss-ol-1-one in 12 parts by volume of diethyl ester of carbonic acid and 20 parts by volume of absolute dioxane with 2 parts by weight of sodium hydride, in a nitrogen atmosphere in a stirred vessel lined with glass beads. After cooling, 10 parts by volume of ethanol are added to the reaction mixture, diluted with benzene, and extracted. twice with a little ice water.

   The benzene solution, dried over potassium carbonate, gives, after removal of the solvent in vacuum
 EMI14.7
 d, b (3-methrl2-car bethoyQ.i-ethocarboxr-'ethylenedioy-1, 2, 3, 4, 4acr, -4b 5,6,7,8,10,10afi-àoàéaahydrophenanthrene-1-one, that we obtain, from its solution in petroleum ether, in colorless crystals, melting at 115
Example 6
Strongly stirred for 40 hours at room temperature in a nitrogen atmosphere, a mixture of 10.673 parts by weight of 2-carbetho-
 EMI14.8
 xy-4 (3-etb.oycarboy-q.b3-methl = 7-ethylenedzor-1 s 2, 3 4 4aa, 4b, 5, 6, 8,1, 10a3-dodecahydrophenanthrene-1-one 8,342 parts by weight of carbonate anhydrous potassium, finely powdered, 183 parts by volume of anhydrous acetone and 69.4 parts by volume of methallyleo iodide Then evaporated in vacuo to 25 at most,

   takes up the residue in ice water and in a mixture of ether and benzene (2: l), shakes the organic phase to 0 with normal potassium hydroxide and water, then evaporate in vacuum the solution in the mixture of ether and benzene, dried over sodium sulfate. By recrystallization with isopropyl ether and ether
 EMI14.9
 from petroleum, we obtain 2a-methallyl-2p-carbethoxy-4P '=' ethoxycarboxy-4bp-methl-7-etçyl, enedioxiy I, 2a3,4,4aa, 4b, 5 ,,, 8,10,10ai = dodecahydraphenanthre - pure ne-1-one, melting at 99.5-101.



   The residue from the evaporation of the mother liquor is dissolved in a medium.

  <Desc / Clms Page number 15>

 
 EMI15.1
 1a, nge hPxa.ne-benzene (9: 1) and chromatographed on 240 parts by weight of alumina. As eluting agents, mixtures of hexane-benzene (9: 1), and (1: 7) and benzene are successively used. The first hexane-benzene eluate (1: 1) is extracted by crystallization from isopropyl ether -
 EMI15.2
 petroleum ether, a further quantity of 2a, -methallyl-2-carb - 'thoxy-4P-ethoxycarboçy-4bi-methyl-7-ethyl-enedïoxy-1 2 3. .aCt, 4b, 5, 6, 7, 8 to 10, 10ai - dodecahydrophenanthrene-1-one pure, mp 99.5-101.

   The following eluates, obtained with hexane-benzene (1: 1) and benzene give, crystal-
 EMI15.3
 read in ethanol at 95, the pure epimer 2i-methallyl-2cc-carbethoxy-4i-etho-xycarboxy-4bfi-methyl-7-ethylene toioxy-1,2,3,4,4aa, 4b, 5,6, 7,8,10,10afi-àoàé-cahydrophenanthrene-1-one, melting at 94.5-95.5 0 2-carbethoxy-4 (3w.thoxycarboxy-4b3-methyl - ethylenedioxy-1,2, 344aa, 4b, 5,67,8,10a (3-dodecahydrophenanthrene-1-one, used as starting material is prepared as follows:

   
Has a suspension of 5.848 parts by weight of 4bp-methyl-7-ethyl-
 EMI15.4
 1enedioxy-1, 2, 3, 4, 4aCC, 4b, 5 6 7 8,10,10ai-dodé cahydrophênanthrêne - 1 - one-4 (3-ol in 48.50 parts by volume of diethyl ester carbonic acid, 1.77 parts by weight of sodium hydride are added in a nitrogen atmosphere and the mixture is stirred, first for hours at room temperature, then 12 hours at a temperature of 55-60 bath is then added at 0, cautiously, to the reaction mixture, to destroy the sodium hydride @n excess, 40 parts by volume, of an anhydrous mixture of ethanol and ether (1:

  10), then, after dilution with 98 parts by volume of ether, it is extracted successively with ice water, with a normal solution of ice-cold potassium hydroxide, then again with ice-water. The ethereal solution is evaporated, dried over sodium sulfate, the diethyl ester of the carbonic acid is removed in a high vacuum and the residue recrystallized.
 EMI15.5
 in little ether. In this way, 2-carbethoxy-4p-ethoxy-car'ocxy-4'b (3-methyl-7-ethylenedioxy1 2, 3 4 4a 4b, 5 6, 8,10, 10ai-dodeaahy-drophenanthrene- 1-one, fondant to them-l16 e
Example 7.



   To a solution of ethyl-magnesium bromide prepared from 2.20 parts by weight of magnesium and 6.87 parts of ethyl bromide in 50 parts by volume of anhydrous ether is added over 25 minutes, 7 88 parts by weight of freshly distilled ethoxyacetylene in 46.5 parts by volume of ether. After the evolution of ethane has ceased, the mixture is first stirred for a further 40 minutes at room temperature, then the mixture is added dropwise.
 EMI15.6
 a solution of 1.226 parts by weight of 2a-methallyl-2fi-carbethoxy-4fi-etho-xycarboxy-4bp-methyl-7-ethylenedioxy-1,2,3,4,4aa, 4b, 5,6,7,8, 10,10ap-dodecahydrophenanthrene-1-one, melting at 99.5-101, in 32.5 parts by volume of benzene.

   Stir the mixture for 18 hours at room temperature then add ice and a saturated solution of ammonium chloride, then separate the organic layer. The ether-benzene extract is washed with water, dried over sodium sulfate, filtered and evaporated in vacuo.



  The residue is dissolved in a hexane-benzene mixture (3: 1) and chromatographed on a column, prepared with hexane, of 132 parts by weight of alumina.



  With hexane-benzene mixtures (3: 1) and (1: 1) and with benzene, only traces of the substance are dissolved. The eluates obtained with the benzene-ether mixture (19: 1), with the ether and with the ether-acetic ester mixture (9: 1) are examined chromatographically on paper using a phenyl-cellosolve-heptane system. , using an antimony trichloride solution as an indicator.



   In the portions eluted with the benzene-ether mixture (19: 1) is mainly the starting material unchanged o The fractions dissolved with ether and the first fraction of the ether-acetic ester mixture

  <Desc / Clms Page number 16>

 
 EMI16.1
 .9: 1) consist above all of a substance more strongly polar than the starting material, exhibiting with antimony trichloride, under the quartz lamp, a red-cinnabar color. These eluates are combined and separated from strongly polar impurities on cellulose by partitioning using the 80% heptane methanol system.

   We thus obtain the 1- (é-
 EMI16.2
 thaxyethinyl -2tc-méthallyl-2-ca, rbêthox, y- ° -éthe: - =: arbogy- ° b (3-methyl-7- V thyl enedioy-1, 2, 3, °, 4acc? 4b, 5, 6,, 8,10,10a3-dodé cahydrophéanthr en-1-ol, pure, in the form of a colorless amorphous product.



   Similarly, the reaction of the 2p-methallyl- epimer
 EMI16.3
 2a-carbetho] rY-4P-ethoxycarboxy - 4bp-methyl-7-ethylenediozy-1.2,3,4,4aà, 4 "o, j, 6, 'j, 8 10,10a3-dodecahydrophenanthrene-1-one melting at 94.5-95.5, gives 1- (ethogy-ethinyl) -2 (3-me < <.. s.lyl-2ct-carbethoxy 4 (3-ethoxycarboxy-4b (3-:

  nthyl-2-ethylenedioxy-1,2,3, ° -áoc, ° b, 5,6,7,8? 10,10a3dodecahydrophenanthrene-1-olo 0.124 part by weight of 1- (ethoxy-ethinyl- 2E-methal- lyl-2 (3-car'bêthoy-43-ethoxycarboy- ° b (3-methyl-'ethyl èr¯edioxy-1 j 2, 3, °, 4aa ,, ° b, 5,6,7 , 8,10,10ai-dodecahydrophenanthrene-1-ol in 4.75 parts by volume of tetrahydrofuran, with 0.25 part by volume of 2.5 times normal sulfuric acid, then the solution is left to stand for 4 hours at ambient temperature is then added 5 parts by volume of a 0.2 molar solution of sodium bicarbonate, then evaporated in a vacuum, at 25 at most, to a velocity of about 1 part. The crude product is taken up in ether, wash the solution with water, dry over sodium sulfate, filter and evaporate.

   The separation of the transposition product, on cellulose, by distribution
 EMI16.4
 tition with the 80% methanol -heptane system gives 1: 1- (carbethoxy-methyl ene) -2a-methallyl-2p-oarbethoxy-4P-ethoxycarboxy-4bp-methyl-7-ethylene dior-1 2, 3 r 4 s 4aas 4b 5 7 8,10 '10af3-do de eahydz ophenanthrene, having an absorption maximum in the ultra-violet at 225 mu. In the chromatogram on paper, this compound shows under the quartz lamp an intense yellow color with antimony trichloride and a dark green color with phosphoric acid.



   Example 80
1.18 part by weight of magnesium shavings are covered with 20 parts by volume of absolute ether, and added dropwise at room temperature, protected from moisture, with stirring, a mixture of 6 parts by weight of ethyl bromide and 50 parts by volume of absolute ether.

   When the reaction which begins with a low boiling point is completed, a solution of 3.74 parts by weight of freshly prepared ethoxyacetylene in 20 parts by volume of absolute ether is added in small portions, then the mixture is stirred until 'so that no more ethaneo emerges
Into the reaction mixture formed is introduced at 20-25, with vigorous stirring, a solution of 8.6 parts by weight of 4bp-methyl-.
 EMI16.5
 2OE-methallyl-2fi-aanbethoxy-4fi-ethoxy-aarboxy-7-ethyleneàioxy-1,2,3,4,4aOE, 4b- 5,6,7,8, la, ioafi-àocécahyàrophenanthrene-1-one in 75 parts by volume of absolute benzene The mixture is further stirred for 2 1/2 hours at 20-25, then poured into 200 parts by weight of a water-ice mixture,

     and add a saturated solution of ammonium chloride until good separation of the layers After separation of the solution in benzene-ether, the aqueous layer is extracted once more with 300 parts by volume of ether, washed. organic solutions with water, they are combined, dried, then the solvent is evaporated in vacuo, at a bath temperature of 50. The re-
 EMI16.6
 sidu obtained is 4bfi-methyl-20E-methallyl-1-ethoxyethinyl-2fi-aarbethoxy-4i-ethoycarbo, y - âthylênedioy-l, 2, 3, ° áas4'b, 5, 6, 7, 8,1f? ' 10ai-dodecahy- arophenanthien-1-olo

  <Desc / Clms Page number 17>

 
100 parts by volume of dioxane are added to 15.3 parts by weight of this compound, then after addition of 6.5 parts by volume of 10% aqueous sulfuric acid, the mixture is stirred for 4 hours at 25.

   Then add 15 parts by volume of saturated sodium bicarbonate solution, and concentrate the reaction mixture in vacuo to about 40 parts by volume, dilute with 200 parts by volume of ether, and wash the ethereal solution. once, with 80 parts by volume of water. After drying over magnesium sulfate, the solution is evaporated, then the last residues of dioxane are removed in a vacuum. The oily residue obtained is chromatographed on alumina, by the pass method.

   From the eluates of petroleum ether ether, then ether, we first obtain a compound which, according to its infrared spectrum, does not contain
 EMI17.1
 more hydroxy group and qni has the structure of a 4bp-methyl-2ct-methallyl-1,1-carbethoxy-methyl ene-2i - carbethox; y-43-ethoxycarbor-7-ethyl enedioxy-, 1 2,3 , 4,4aa, 4b, 5,6,7,8,10,10ap-dodecahydrophenanthrene then a compound containing hydroxyl, which is probably 4bfi-methyl-2a-methallyl-1-carbethoxymethyl-2i-carbethoxy -Q.3-Ethoycarboy-7-ethyl enedior-1 2, 3, 4 4aa, 4b-5,6y7,8,10,10,10ap-dodecabydrophenanthrene-1-ol.



   By treating the hydroxyl-free compound 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 for 5 hours at reflux, followed by removal of the methanol in vacuum, the salt of
 EMI17.2
 potassium of 4bfi-methyl-20E-me% hallyl-1,1-carboxy-methylene-2p-aarbethoxy-7-ethylenedioxr-1,2,3,4s4aas4b569781ds10ai-dodecahydrophenanthrene-43-0l as an oily precipitate.



   By addition of water and moderate heating, this salt is redissolved, extracted with 150 parts by volume of ether, the aqueous solution weakly acidified with a phosphate buffer (pH approximately 6), then the free acid extracted, as quickly as possible, with three portions each of 100 parts by volume of chloroform.

   After drying over sodium sulfate, the combined chloroform extracts are filtered and then evaporated in vacuo.
 EMI17.3
 at a bath temperature of 35 o The residue consists of 4bi-methyl-2a-m-% h & llyl-1,1-oarboxy-methylene-2fi-canbethoxy-7-ethylene toioxy-1,2,3,4,4aOE-4b , 5, 6, 7, 8, 1a, loap-aoaecahydrophenan% hrene-4 @ -ol, substantially pure
To a suspension of 1 part by weight of this crude acid in 5 parts by volume of tetrahydrofurano is added while cooling with dry ice, 100 parts by volume of liquid ammonia, then the reaction solution is stirred well. Then added, in small portions, 6.5 parts by weight of freshly cut metallic potassium under toluene and then, when everything is added, the mixture is stirred for a further 2 hours at about -40.

   Anhydrous isopropyl alcohol is then introduced slowly, dropwise by means of a tap funnel, until the dark coloration of the dissolved metallic potassium disappears. The excess ammonia is then allowed to evaporate at the temperature room, add 200 parts by volume of benzene then, carefully, 100 parts by volume of water, and mix the layers well o The benzene solution is discarded o The aqueous alkaline solution is acidified with a phosphate buffer to pH 5- 6, then one extracts immediately several times with chloroform.

   The chloroform extracts are washed with saturated sodium chloride solution, combined, dried, filtered and evaporated in the video.The residue obtained is dissolved in dioxane and left to stand overnight with excess diazoethane in ether, at room temperature o By evaporation in vacuum
 EMI17.4
 we obtain 4bfi-me% hyl-20E-me% hallyl-1fi-carbé% hoxymethyl-2fi-canbethozy-7-ethylenedioxy-1, 2, 3, q., q.aoc, 4b, 5, &, 7 , 8,10,10ai-dodecahdrophenanthrene-Q. (3-ol crude, which can be purified by chromatography on alumina.



   Example 9
 EMI17.5
 Add 7.36 parts by weight of 4bfi-methyl-2a-methallyl-1fi-car-

  <Desc / Clms Page number 18>

 
 EMI18.1
 'ethc metb.y123-carbethoy <7ethylenedioxy-1, 2, 3, ° 9 ác, Lr, 5, 6, 7, 8,10, 10aj3-dodeeahydrophenanthrene- ° mol described in Example 8 and 800 parts by volume of tetrahydrofuran absolute to 2 parts by weight of lithium aluminum hydride and 50 parts by volume of tetrahydrofuran, with stirring in a stream of nitrogen. After 24 hours of stirring at room temperature, the excess reducing agent is destroyed by cooling, carefully adding 10 parts by volume of water, followed by further stirring for 2 hours.

   It is then filtered through celite and washed well with tetrahydrofuran. The filtrate concentrated in vacuo in a stream of nitrogen.
 EMI18.2
 te, we obtain 4tP-methyl-lp- (2'-hydroxyethyl) -2a-metallyl-2p-hydroxymé% hyl-7-ethylenedioxy-1,2,3,4,4aa, 4b, 5, 6, 7 , 8,10,10afi-daaecahydrophenanthrene -4ss-ol, which shows, in the infrared, the characteristic absorption of hydroxy groups at 2.75 #.



   To a solution of 5 parts by weight of the triol obtained in 100 parts by volume of anhydrous pyridine is added little by little, with stirring, in a stream of nitrogen, 2.6 parts by weight of 1 p acid chloride. toluenesulphonic and then left to stand overnight at room temperature. The mixture is then poured onto a mixture of ice and a saturated solution of sodium bicarbonate, then extracted several times with ether. From the residue of the organic solution, dried and then concentrated in vacuo, one obtains
 EMI18.3
 4bfi-methyl-1fi- (2'-tosyloxyethyl) -20E-methallyl-2fi-hydroxymethyl-7-ethyl- -redioxy-1 2, 3, 4, 4acx, 4b, 5 y s, 8; 1a, 10a3-dode cahydrophenanthrene- ° (3-oI.



   To 4 parts by weight of the tosylate obtained, 50 parts by volume of benzene and 10 parts by volume of tetrahydrofuran are added, then 2.3 parts by weight of osmium tetroxide. The reaction solution is left to stand for 25 minutes at room temperature o 50 parts by volume of alcohol and a solution of 5.1 parts by weight of sodium sulphite in 30 parts by volume of water are then added successively, then stirred for 30 minutes The upper organic layer is separated, filtered, then the lower layer is treated with alcohol and also filtered.After high concentration of the organic solutions in vacuum, water is added, then extracted with chloroform until 'to exhaustion
Has 3 parts by weight of the residue of the chloroform solutions dried then evaporated in vacuo,

   40 parts by volume of methanol and 11 parts by volume of pyridine, 2.1 parts by weight of periodic acid in 5 parts by volume of water are added, with stirring, and stirred for 30 minutes After addition of water it is extracted several times with chloroform. From the residue of chloroform solutions dried then evaporated in a vacuum,
 EMI18.4
 we get 4bfi-methyl-lfi- (2-tosyloxyethyl) -2a-aaetonyl-2fi-hyàroxymethyl- '-ethyl enedioy 1, 2, 3, °, áa, 4b, 5, 6, 7, 8,10 s IOai-dodec, hydrophenanthrene-í-ol. The cyclization of this compound to d, l # A 5-3-ethylenedioxy-ll (3-l8-dihydro-xy-20-oxo-pregnene is described in Example la
Example 10.



   Stirred for 16 hours at room temperature, a solution
 EMI18.5
 tion of 0.981 parts by weight of 2a-methallyl-2p-carbethoxy-4p-ethoxycarboxy- ° bi-met.pl¯7-ethylenedioxy¯1,2a3,4,4aaq4b? 5? 6? 8,10,10a- dodecahydro-phenanthrene-1-ane, melting at 99.5 101, and 0.840 part by weight of sodium hydride and boron in 25 parts by volume of anhydrous ethanol It is then introduced dropwise into a ice-cold mixture of 11 parts by volume of a 4 molar solution of disodium phosphate and 19.5 parts by volume of water, rinse the reaction vessel with 10 parts by volume of water and 5 parts by volume of ethanol and concentrate in vacuum at room temperature to 12-15 parts by volume The suspension obtained is extracted with methylene chloride, the extracts washed with water,

   dry them over sodium sulfate, filter then evaporate For purification

  <Desc / Clms Page number 19>

 the residue is dissolved in a hexane-benzene mixture (9: 1) and chromatographed on 49 parts by weight of floridin by the pass method. With hexane-benzene mixtures (9: 1) and (1: 1) only large quantities of substance are obtained. The fractions eluted with benzene, benzene-ether mixtures (9: 1) and (1: 1) give, on crystallization from e-
 EMI19.1
 petroleum ther, 20e-methallyl-2fi-carbethoxy-4fi-ethoxycarboxy-4bfi-methyl-7-ethylenedioxy-1,2,3,4,4aOE, 4b, 5, 6,7, 8,10,10afi-docecahydrophenanthcene -1-ol, pure, mp 92-94.5.



   The same compound is obtained when we proceed as follows:
To a solution prepared in a dry nitrogen atmosphere, of 12.260 per-
 EMI19.2
 ties by weight of 2a-methallyl-2p-oarbethoxy-4p-ethoxyoarboxy-4bp-methyl-7-ethylened3oaçy-1 2,3,4,4aa, 4b, 5,6, i, 8,10,10a (3-dodecahydrophenanthrene -1-one described in Example 5, in 312.5 parts by volume of anhydrous ethanol are added to 20-25, 10.5 parts by weight of sodium boron hydride. The mixture is stirred for 40 hours at room temperature. The mixture is then poured into a mixture of 157.5 parts by volume of a 4 molar solution of monosodium phosphate and 315 parts by weight of ice, and rinsed with 150 parts by volume of ice-cold water.

   The reduction product was extracted with ether, then the ethereal extract was washed with 2 molar monosodium phosphate solution and with water, dried over sodium sulfate and evaporated. By crystallization of the residue from isopropyl ether-pen-
 EMI19.3
 ta-ie, we obtain 2oc-methallyl-2i-carbethoy-q. (3-etho, yearbay-4b (3-methyl-7-ethylenedioxy-1,2,3,4,4aOE-4b, 5,6, 7,8,10,10afi-dodecahyàrophenanthcene-1-ol, which exists in two modifications, the stable modification melting at 99-101 and the unstable modification melting from 94 with transposition.
 EMI19.4
 



  Has a solution of 1.646 parts by weight of 2a-methallyl-2j3-oarbethoxy-q. (3-ethoxycar'boy-qb (3 methyl-7-ethylenedioxy-1,2,3, 4 4aa 4b 5 s 6 8,10-10afl-dodecahyàrophenanthrene-1-ol in 46.07 parts by volume of anhydrous ethanol, a solution of 14.72 parts by weight of potassium hydroxide in 11.51 parts by volume of water is added. The mixture is heated for 1 hour with stirring, in a nitrogen atmosphere, in a 90-95 bath, then cooled in ice-water o 128.7 parts by volume of water are added and carbon dioxide is passed through until a touch on thymolphalein paper is no longer positive and extraction is carried out with methylene chloride to remove small amounts of neutral substances.

   The remaining alkaline sodium carbonate solution is carefully acidified with 5 molar phosphoric acid, to pH 5, extracted with methylene chloride, the extracts are washed with water, dried over sodium sulfate.
 EMI19.5
 and evaporated; this gives 2, -methallyZ-2 (3-carboxy-4bi-methyl-7-ethyl-7, enedioy-1, 2, 3, 4, Q.aa, ° b, 5, 6, 7, 8, 1,10a3-dode cahydrophenanthrene-1, qi-diol which already partially lactonizes during its separation The crude crystalline product is dissolved in 130 parts by volume of boiling benzene, the solution is boiled for 30 minutes to complete the lactonisa- tion, then remove the benzene by vacuum distillation.



   The residue is recrystallized from ether, using methylene chloride to promote dissolution.This gives (2 # 4ss) -lac-
 EMI19.6
 tone of 2a-methallyl-2 @ -carboxy-4b @ -methyl-7-ethylene to dioxy-1,2,3,4,4aa, 4b-5,6,7,8,10,10ap-dodecahydrophenanthrene-l, q. (3-diol, pure, melting at 246-249.



   To a suspension of the chromium trioxide-pyridine complex, prepared in a dry nitrogen atmosphere, from 25.15 parts by weight of chromium trioxide and 750 parts by volume of anhydrous pyridine, is added one shot a solution of 9.363 parts by weight of (2 # 4bss) -lactone
 EMI19.7
 20E-methallyl-2 @ -carboxy-4bfl-me% hyl-7-ethylene to dioxy-1,2,3,4, 4aOE-4b, 5, 6, 7,

  <Desc / Clms Page number 20>

 
 EMI20.1
  <'¯', r 1,091-Gap-ùûàéûa-hydrophenanthrene-194P-diol in 250 parts by volume of anhydrous pyridine, and heat to 60-65 for 14 hours, with stirring.

   After cooling, the pyridine is removed by vacuum distillation to a small remainder, with as much care as possible, added to the wet residue 500 parts by weight of ice and vigorously shaken after watering 625. parts by volume of ice water, with a mixture of 3750 parts by volume of ether and 1250 parts by volume of methylene chloride. Vacuum filtered through diatomaceous earth on the emulsion produced, to get rid of solid fractions, the upper phase of the filtrate is washed with a 4 molar solution of monosodium phosphate and with water, dried over sodium sulphate. , then evaporated.



   The crude crystalline product of the dehydrogenation is dissolved in benzene, the solution is filtered through a layer of activated charcoal to decolorize it, and then the filtrate is evaporated in vacuo. On recrystallization of the residue from ether, using methylene chloride to facilitate dissolution, the (2 # 4ss) -lactone of 2a-methane is obtained.
 EMI20.2
 thallyl-2 (3-carbogy-4bi-methyl-T-ethyl edior 1, 2, 3, 4, 4aü 4b, 5, 6,?, 8, lf, 10a3 clodecahydrophenanthrene-1-one-49-01, melting at 188-190
Example 11
Has a solution of ethylmagnesium bromide;

     prepared from 2.432 parts by weight of magnesium and 9.820 parts by weight of ethyl bromide in 110 parts by weight of anhydrous ether, added over 30 minutes at an internal temperature of 12-15, 7.88 parts by weight of freshly distilled ethoxyacethylene in 51.5 parts by volume of anhydrous ether.

   Counted from the cessation of the evolution of ethane, stirred for a further 15 minutes while cooling with ice water, then homogenize the two-phase system by adding 110 parts of benzene will then add dropwise a solution of 7,115 parts by weight of
 EMI20.3
 2 rkethallyl-2carbogym4bi-methyl? -ethylene-dioxy-l, 2, 3, Q (2 # 43) -Iactone, 4atx 4b, 5, 6,?, 8, 10,10a3-do3écahydrophênanthr en-í -ol-1-one described in Example 10. The mixture is stirred for 3 hours at 0-3, ice is added and a saturated solution of ammonium chloride, the ether-benzene layer is washed with the chloride solution. ammonium and with water, dried over sodium sulfate, filtered and then evaporated under reduced pressure.

   The residue is dissolved in ether and filtered through a layer of activated carbon to decolorize it. By concentrating, we obtain the (2 # 4ss) -lacto-
 EMI20.4
 ne of I-ethoxyethinyl-2a mQth.ally123earboxy4b (3-methyl? -ethylenedioxy-1, 2, 3,4,4aOEL4b, 5,6, 7, 8, lQ, 10afi-aodécahyàrophenanthrene-1,4fi-aiol, melting at 138-140 o A second crystalline modification of the same substance melts at 142-143.



   Shake a solution of 221.3 parts by weight of (2 # 4ss) -
 EMI20.5
 1-ethoxyethinyl-20E-methallyl-2 @ -earboxy-4b @ -methyl-7-ethylenedioxy-le213i4e4aa-4bi5,6i7e8ylO, 10ap-dodecahyd.rophenanthrene-le4P-diol in 6500 parts by volume in the presence of anhydrous pyridine lactone of 100 parts by weight of a 10% palladium-calcium carbonate catalyst at room temperature in a hydrogen atmosphere.

   After gas absorption
 EMI20.6
 of 1 molecular equivalent, the hydrogenation is practically stopped, the catalyst is separated by filtration through a layer of Super Cel, rinsed with pyridine, then the filtrate is completely evaporated in vacuo. The crystalline residue is dissolved. in ether, filter the solution through a layer of activated carbon to purify it, then concentrate the filtrate to a small volume, and carefully add petroleum ether.

   he
 EMI20.7
 crystallizes from (2 ----> 49) -lactone from 1-ethayvznyl-2ec! ethallyl-2 (3-car-boxy-4bp-methyl-7-ethylene toioxy-1,2,3,4,4aOE, 4b -5,6,7,8,10, loafi-àoàécahydro-phenanthrene-1,4p-diol having two melting points, one at 108.5-110 and the other 136-137.5 o A second modification of the same substance melts at

  <Desc / Clms Page number 21>

 138-139.



   In a solution prepared in a dry nitrogen atmosphere, 4.45
 EMI21.1
 parts by weight of (2. 4 (3) -lactone of 1-ethoxyvinyl2a, -methallyl-2-carboy-4bi-methyl-7-ethylene-dioxy-1,2,3,4,4e.a-4b, 5 , 6,78,10,10a (3-dodecahydrophenanthrene-1,4-diol, in 200 parts by volume of anhydrous pyridine, is introduced dropwise, over 5 minutes, at 0-3, 55 parts by volume of a 2 molar solution of very pure thionyl chloride in anhydrous pyridine.

   The mixture is stirred at 0-3 for a further 15 minutes poured onto a mixture of 1000 parts by volume of a 1 molar solution of mono-ammonium carbonate with 1000 parts by weight of ice, then rinsed with 1250 parts by volume of ethero After shaking carefully, the ethereal solution is washed with a 1 molar, ice-cold solution of mono-ammonium carbonate and ice-water, dried over sodium sulfate, filtered off the drying agent, then evaporated. the ethereal solution in the video By recrystallization of the residue in ether, we obtain
 EMI21.2
 holds (2fi -> 4) -lactone of lel-formylmethylene-2a-methallyl-2p-oarboxy- .b3-methyl-7-ethylenedioxy-1 s 2, 3, 4, 4acx., 4b, 5, 6, 7, 8,10,10ai-dodecahydrophenanthrene-4 (3-0l, melting at 188-190 o Example 12 A solution of 8,

  85 parts by weight of (2 # 4ss) -lactone
 EMI21.3
 1-ethoxy -, - thinyl-2a-methallyl-2p-carboXY-4bp-methyl-7-ethylenedioxy-1, 2,3,4,4aa-4b56,7,8,10,10a3-dodecahydrophenanthrene-l'43 -diol, described in Example 11, in 190 parts by volume of tetrahydrofuran, 10 parts by volume of 2.5n sulfuric acid are added with gentle stirring. After standing for 6 hours at room temperature, the mixture is poured into 200 parts by volume of 0.2 molar sodium bicarbonate solution, then the tetrahydrofuran is removed by vacuum distillation. The residue diluted with water is extracted with ether; the ethereal extracts are washed with water, dried over sodium sulfate and strongly concentrated.



  The crystallizate obtained is recrystallized from alcohol. We thus obtain
 EMI21.4
 if the (2-4fi) -lactone of 1-carbethoxymethyl-2a-methallyl-2fi-carboxy-4bfi-methyl-7-ethylene to dioxy-1,2,3,4, 4aa-4b, 5,6,7,8, 10,10afi-dodecahyàrophenanthrene-1, q.3-diol, m.p. 167-169.



  Has a solution, cooled to 10, of 5.754 parts by weight of (2 4fi) -lactone of 1-carbethoxymethyl-2cc-methallyl-23-carboxy-4b (3-methyl-7-ethylenedioxy-1, 2, 3, 4, 4aGC-4b, 5, 6, 7, 8,10, 3Oa (3-dode aahydrophenanthrene-1, tj. (3-diol in 112.5 parts by volume of anhydrous pyridine, added over 1 minute) te, 37.5 parts by volume of a 2 molar solution, prepared separately, of very pure thionyl chloride in anhydrous pyridine, and the mixture is stirred for a further 9 minutes at a bath temperature of 20.

   The mixture is then poured by diluting it with 1250 parts by volume of ether onto 750 parts by volume of a 1 molar solution of sodium bicarbonate and 500 parts by weight of ice; the ethereal layer is washed with a 0.5 molar solution of sodium bicarbonate and water, it is dried over sodium sulfate, evaporated, and the pyridine is removed in vacuo
Two substances can be isolated from the residue by fractional crystallization in ether. The first fraction gives, after re-
 EMI21.5
 crystallization from ether of pure (2 -..., q.3) -Iactone of a 1,1-carbethoxymethylene-20.-methallyl-2i-ca.rbo-4: (3-methyl -7-ethyl eneaiaxy-1,2,3,4,4aa, 4b, 5,6,7, $, 10,10ai-dode cahydrophenanthrene-4 (3-ol-melting at 200-201.

   A second fraction consists of an isomeric substance, melting lower, which is purified by dissolving it in ether and filtering through a layer of activated carbon. Highly concentrated filtrate crystallizes the pure (2 # 4P) -lactone of 1,1-carbethoxymethylene-2a-methallyl-.
 EMI21.6
 23-carboçy-d, b3-methyl-7-ethylenedioy-1, 2, 3, 4, 4aa 4b 'S, 6, 7, 8,10, 10ai-dod-

  <Desc / Clms Page number 22>

 
 EMI22.1
 vaûß dr oprenanthrene-4 (3mo1 isomer, melting at 100th "Î-10l15o
By alkaline saponification, followed by reduction of this compound with potassium in liquid ammonia, a crude product is obtained from which, after esterification with diazomethane, then reduction with lithium hydride. and aluminum,

   we can isolate the
 EMI22.2
 4bp-methyl-1 P- (2 '-hydroxyethyl) -2a "methallyl-2p-hydroxymethyl-7-ethylene-dioy-1, 2, 3, 4, 4a0t, -4b, 5, 6, 7, 8, lf , 10a3-dodeeahydrophenanthrene-43-0l Example 13 A solution of 39.85 parts by weight of (2 # 4ss) - is stirred
 EMI22.3
 i, i-Formylmetbylene-20E-methallyl-2fi-carboxy-4b @ -methyl-7-ethylene-dioxy-1,2,3,4,4aa, 4b, 5,6,7,8,10, loa lactone @ -àodécahyàrophenanthrene-4fl-ol described in Example 11, in 1000 parts by volume of anhydrous ethanol, in the presence of 10-parts by weight of catalyst containing 2.5% palladium-strontium carbonate, at room temperature, in a hydrogen atmosphere. After absorption of gas of 0.95 mol equivalent gas, the catalyst is filtered off and the filtrate is evaporated in vacuo.

   The mixture obtained is fractionated by distribution chromatography on cellulose, using an 80% methanol system, heptane. From the weakly polar fractions, which greatly reduce the solution of argento-diammine, there is obtained by recrystallization from ether and from a mixture of ether and petroleum ether.
 EMI22.4
 (2 # 4fi) -pure 1fl-formylmethyl-20E-methally-1-2p-carboxy-4bfi-methy 1 -? - ethylenei.oxy-I, 2, 3, 4, 4aGC, 4b, 5, 6, 7, 8,10, lf3a3-doc.ecahydrophenanthrene -4ss-ol.
 EMI22.5
 



  Has 4.005 parts by weight of (2 4fi) -lactone of 1-formylmethyl -2cc-methallyl-2 (3-carboy-q.bimethyl-7-ethylenedioxyi, 2, 3,., 4aa-4b, 5, 6 , 7, 8,10,10ap-dodeoahydrophenanthrene-4p-ol, in 50 parts by volume of benzene, 2.670 parts by weight of osmium tetroxide are added and the mixture is stirred for 3 hours in a nitrogen atmosphere. 350 parts by volume of methanol and a solution of 6.30 parts by weight of sodium sulphite in 100 parts by volume of water, shaken the mixture for 20 minutes, in a nitrogen atmosphere and frees from the solid reduction products, in thread - trant through a layer of Super Gel, The filtrate is freed from organic solvents, in a vacuum,

   and the aqueous suspension is extracted with methylene chloride. The extract, washed with ice-cold normal sodium carbonate solution and water and dried over sodium sulfate, leaves, on evaporation, a residue of practically completely crystalline.



   The crude hydroxylation product thus obtained is dissolved in 89.0 parts by volume of methanol and 1.0 part by volume of pyridine, and a solution of 3,400 parts by weight of paraperiodic acid in 10.0 parts by weight is added. volume of water. After stirring for 1 hour at room temperature and nitrogen atmosphere, dilute with water and then extract with a mixture of ether and methylene chloride (3: 1).

   The extract washed with water and dried over sodium sulphate leaves, on evaporating
 EMI22.6
 tion in vacuum, the (2. 4 (3) crude mlaetone of lfl-formylmethyl-2a-acetonyl-23-carbog, pq.b (3methyl = 7-ethylenedioxy-l, 2, 3, 4 4aQ 4b, 5, 6, 7, 8,10, ltag-dodécahydrophenanthrene-4i-olo It is advantageously subjected, without prior purification, to the cyclization described in Example 20
Example 14
To 0.5 part by weight of lithium amide and 10 parts by volume of ammonia is added while cooling with an acetone-carbon dioxide bath, in a stream of nitrogen, with stirring, 2.32 parts by weight of tert-butyl acetate and 4 parts by volume of dry ether.

   At the above
 EMI22.7
 gray-brown pension, then 0.6 part by weight of 2a-methallyl-2fi-

  <Desc / Clms Page number 23>

 
 EMI23.1
 carbethoxy-4p-ethox.yearboxY-4bp-methyl-7-ethylenedioxy-1,23,4,4aae4b, 5e6j 7,8,10,10afi-dodecahydrophenanthiene-1-one in 1 part by volume of dioxane, and the the mixture is rinsed with 4 parts by volume of ethero. The cooling is then removed, the ammonia is allowed to evaporate and the mixture is stirred overnight in a stream of nitrogen. The ether also gradually volatilizes causing it to form a viscous mass. The latter is diluted with ether and poured into a solution of 10 parts by weight of ammonium chloride in water.

   The aqueous phase is extracted once more with ether and the ethereal solutions are washed with water, after which the residue obtained after drying the solution and evaporating the ether is chromatographed on 32 parts by weight. alumina (activity II). Minimal amounts of offset material are first eluted with an equal part mixture of benzene and petroleum ether.

   From the benzene fractions, a crystalline mixture of the two epimers in position 1, 1- (carbo-tertio-butyl-
 EMI23.2
 oxy-methyl) -2oc methallyl-2 (3-carbethogy-43-ethoxycarboxy-4'b (3-methyl-7-ethylene-dioxy-1,2,3,4,4aoe, 4b, 5, 6,7, 8, la, loa @ -doàécahyàrophénan% hrene-1-ols, melting at 156-157, while benzene-ether fractions, we obtain the (2 ## 4P) -lactone of 1- (carbo-% er% io -bu% yloxymethyl-2a-methallyl-2 @ -carbo- xy-4bi - methyl-7-ethylenedioxr-1 2 s 3 4 4aa 4b 5 6 7, 8, la, IOai-dodé cahydro-phenan% hrene- 1,4fi-diol, melting at 188-1900.



  0.065 part by weight of the (2 --74P) -laotone of 1-carbo-tertio-butoxy-methl-2a-methallyl-2 (3-car-boxy-4bp-methyl-7-ethylene-toioxy-) is carefully ground in a mortar. 1,2,3,4,4aa-4b, 5,6,7,8,10,10ap-àodécahy- cLrophenanthrene-1,4 (3-diol, and 0.20 part by weight of boric acid, then one maintained in a sublimation apparatus, under a vacuum of 0.04 mm, for 10 minutes, in a metal bath heated to 300. The sublimate is then dissolved in benzene and the benzene solution washed with water.



  After recrystallization of the residue of the benzene solution which has been dried and then evaporated from a mixture of benzene, ether and petroleum ether, one obtains
 EMI23.3
 (2 4P) -lactone of 1,1- (carbo-tertio-butoxymethylene-20E-methallyl-2fi-carboxy-4bfi-methyl-7-ethylene toioxy-1,2, 3,4,4aOE, 4b, 5, 6,7,8,10,10afi-àoàéca-hydrophenanthrene-4p-ol, in fine needles, melting at 180.5-182.



   If this compound is treated in an alcoholic solution, in a nitrogen atmosphere, for 2 hours, with a half-normal solution of potassium hydroxide, then acidified with phosphoric acid to a pH of 5, a mixture of crude acids is obtained by extraction with a mixture of chloroform and alcohol in the volumetric proportion of 2: these acids are dissolved in a mixture of benzene and chloroform, briefly heated to the boiling point, then esterified with diazoethaneo The solution obtained is evaporated to dryness.

   From the residue an ester is obtained which is identical
 EMI23.4
 (2- * 4fi) -lactone tick of 1,1-earbethoxy-methylene-20E-methallyl-2fi- oarbo-4b (3-methyl-7-ethylene-divxy-12,3,44aa, 4b, 5s678, 14,1dai-dodecahydrophenanthrene-4p-ol, described in example 12a
Example 15
Acetylene is introduced into a solution of 0.75 part by weight of sodium in 60 parts by volume of ammonia until discoloration, while cooling with a bath of acetone and carbon dioxide snow.

   To the suspension obtained of sodium acetylenide in ammonia, is added
 EMI23.5
 then, with stirring, 1) 5 part by weight of 2a, -methallyl-2 (3-car'bethoxy-43-ethorce, rbor-4'b (3-methyl-7-ethylenedioxy-1 2, 3 4 , 4a-4b 5, 6 7 8 1Q, Iaa3-¯ dodecahydrophenanthrene-1-one, described in Example 6, in 90 parts by volume of absolute ether, then rinsed with 90 parts by volume of ether.



  The cooling bath is then removed and stirred overnight in a weak stream of nitrogen. The next day, while cooling with ice water, 165 parts by volume of a 20% solution of ammonium chloride are added.

  <Desc / Clms Page number 24>

 



    After separation of the aqueous layer, it is extracted again with ether, after which the organic solutions are washed twice with water, combined, dried over sodium sulfate, filtered and then evaporated.



  After recrystallization of the residue from ether, 1.25 part is obtained.
 EMI24.1
 by weight of 1-ethinyl-2a methallyl2i-car bethoy-Q- (3-thoxycarboxy-4bi-methyl-7-ethYlenedioxy-1,2,3,4e4acLe4b9596y7.e8,10, LOap-doclecahydrophenanthrene-l-ol , which melts at 165-168.
 EMI24.2
 3 parts by weight of 1 ethiny3car'binol described above (melting point 165-168), dissolved in 80 parts by volume of absolute pyridine, are hydrogenated using a 2% palladium-calcium carbonate catalyst. After absorption of When the amount of hydrogen is three times that calculated to convert the triple bond to a double bond, the uptake of hydrogen ceases. After removal of the catalyst by filtration and washing with benzene, the filtrate is evaporated in vacuo and the residue is taken up in petroleum ether.

   It crystallizes, 2.82 parts by weight of 1-vinyl-2a-
 EMI24.3
 methallyl-2p-oarbethoxy-4P-ethoxycarboxy-4bp-methyl-7-ethylenedioxy-1,2,3) 4,4aa, 4b, 5,6,7,8,10,10ap-dodecahydrophenanthrene-1-ol ,, which bottom at 133-135.50
To split the ketal, a solution of 0.2 part by weight of the vinylcarbinol obtained in 20 parts by volume of crystallizable acetic acid is left to stand with a mixture of 0.02 part by volume of acetyl chloride and 2 parts by volume of crystallizable acetic acid, pen-
 EMI24.4
 for 1 1/2 hour; at room temperature. 1 vinyl2cz-methallyl-2i- oarbethoxy-4p-ethoxycarboxy-4'bP -methyl-1,2,3,4,4aa, 4b, 5,6,7,8,10,10afi-dodecahydrophenanthrene-1- ol-7-one produced, melts at 139-140.5, after recris-
 EMI24.5
 tallization in 1 petroleum ether; x max = 240 mu (= 16800).



   To 0.35 part by weight of phosphorus tribromide in 3 parts by volume of hexane and 2 parts by volume of benzene, a solution is added
 EMI24.6
 0.48 part by weight of 1 vinylm2E methallyl-2-earbethoxy-q.-ethoxycar- 'boy4b3-methyl-j-ethylenedoycl, 2, 3, 4.4aGC, 4b, 5, 6, 7, 8,10, 10a3-dQdecahydro-phenanthrene-1-ol in 2 parts by volume of benzene, 1 part by volume of hexane and 2 -drops of pyridineo After addition of two other parts by volume of hexane, the mixture is left to stand overnight in a current nitrogen, at -10, -15 o The following day, poured into a dilute sodium bicarbonate solution, and extracted twice with ether, after which the ethereal solutions were washed successively with water, dilute hydrochloric acid, water, dilute sodium bicarbonate solution, then water, dry,

   The residue is then evaporated off for 48 hours in a closed container with 1 part by weight of anhydrous potassium acetate and 50 parts by volume of dry acetone. The potassium bromide formed is then separated by filtration, and excess potassium acetate, and washed with acetone. The residue of the evaporated filtrate is then chromatographed on 15 parts by weight of alumina (activity II). With a mixture of equal parts benzene and petroleum ether, a first crystallization is eluted which
 EMI24.7
 consists of 1-vinyl-2cc-methallyl-23carbethoxy-Q. (3-ethoxycar'boxr-4b3-methyl-12,3,4, Q.atti4br5,6,, 8,10,10a (3dodecahydrophenanthrene1oI-7-one, and which is identical to the product described above of the ketal cleavage, melting at 139-140.5.

   By elution with pure benzene, a second product of the crude formula C27H38O7, melting at 191-192.5 and max 240 mu
 EMI24.8
 (E = 17000) to which can be attributed the structure of a 1,1- (21-hydro-xyethyliàene) -20E-methallyl-2fi-carbethoxy-4fi-ethoxycarboxy-4bfi-methyl-1,2, 3,4 , 4aa, 4b, 5,6,7,8, la, loafi-àodécahyàrophenanthrene-7-oneo
By saponification of crude fractions of the chromatogram, melting at 139-140.5, obtained after removal of the cleavage products of the ketal, with potassium carbonate in aqueous methanol, then briefly heating in benzene, a lactone is obtained which is transforms, by

  <Desc / Clms Page number 25>

 treatment with ethylene glycol in benzene, in the presence of a weak
 EMI25.1
 amount of p-toluenesulfonic acid, in the (2 ---> 49) -lactone of 1,

  1- (2'- Hydxoxyethylidene j2Ct-methallyl-23-carboy4b (3-methyl -? - ethylenedioxy-1, 2, 3, 4, 4s.a, 4b, 5, 6, 7 s 8,10, IOa3- dodeoahydrophenanthrene-q.3-ol If this compound is treated with freshly precipitated manganese dioxide and the resulting crude product is chromatographed on alumina, we obtain (2 # 4ss) -
 EMI25.2
 1 1-formylmethyl ene2oc-methallyl-2i-car'bo lactone, yq.b (3-methyl-7-ethyl enedioxy-le2,3,4,4aa, 4b-5,6i7,8el0el0ap-dodécah, ydrophenanthrene -4-01 described in Example 11.



   Example 16
In a solution of 1.045 parts by weight of lithium aluminum hydride in 25 parts by volume of tetrahydrofuran prepared in a dry nitrogen atmosphere, is poured dropwise, with stirring at 30
 EMI25.3
 minutes, a solution of 0.491 part by weight of 2a methallyl-2i-carbethoy-qi-ethoxycarboxy-4bi-methyl-7-ethyl enediogy-1, 2, 3, 4.4e.c., 4b, 5, 6, 7, 8, 10,10afi-dodecahydrophenanthrene-1-one, described in Example 6, melting at 99.5-101, in 20 parts by volume of anhydrous tetrahydrofuran. After a reaction time of 2 hours, the mixture is cooled to 0 and the excess hydride is destroyed, by carefully adding a mixture of 4 parts by volume of water and 5 parts by volume of tetrahydrofuran dropwise. .



    The inorganic salts are removed by filtration using Super Cel, and the filtrate is evaporated in the video.Recrystallization of the residue from acetone and from mixtures of acetone and ether, gives 2a -methal-
 EMI25.4
 lyI-2 (3- (hydroxymethylj-4b-methyl-7-ethylene diogy-1,2,3,4,4aa, 4b, 5,6,7,8, 10,10a3-dodecahC7.rophenanthrene-143-diol pure, melting at 146-148.



  The reduction, carried out in an analogous manner, of 0.491 part by weight of the 2p-methallyl-2a-carbethoxy-4fi-ethoxycarboxy-4bfi-methyl-7-ethylenediogy-1,23,4,4aa, 4b, 5 ,, epimer 7, $, 10'10a (3-dodecahydrophenanthrene - 1-one, melting at 94.5-95.5 gives an almost completely crystalline crude product, which is obtained by recrystallization from mixtures of
 EMI25.5
 tetrahydrofuran and ether, and methanol, 2 (3 methallyl-2, - (hydroxy-methyl j-4b3-methyl-7-ethylenedioxr-1, 2, 3, 4, 4acx, 4b, 5, 6 s 7 10, 10a (pure 3-dodé cahydophéx.anthrene-1,4i-diol, melting at 208-210 o A mixture of 3,200 parts by weight of 2a-methallyl is heated at 60 for 18 hours with stirring. -2p- (hydroxymethyl) -4bp-methyl-7-ethyl enedi ogy-1, 2, 3, 4, q.acx, qb, 5,, 7, 8, I0, 10a (3mdodê cahydrophénanthr en-l, 4i- diol,

   mp 146-148, 3,200 parts by weight of succinic anhydride and 15 parts by volume of pyridine. The mixture is cooled to 0, the pyridine removed by washing with normal hydrochloric acid, ice cold, then extracted several times with an ice-cold 2.5% solution of sodium bicarbonate. The semi-ester thus separated is immediately put back into freedom by acidification of the alkaline extracts, taken up in ether and methylated with an excess of an ethereal solution of diazo-methane. After evaporation in vacuo, the residue is recrystallized from ether, using methylene chloride to promote dissolution, and the mixed mono-methosuccinate ester is thus obtained,

     esterified with the hydroxymethyl group of 2a-methal-
 EMI25.6
 lyl-2 (3- (b.ydro $ ymethyl j-4b (3-methyl-7-ethyl en.edioy-1 2 3, 4, 4e.a, 4b, 5, 6, 7, 8, 1010a3-dodecahydxophenanthrene -1í-diol, 115.5-11700
To a mixture of 0.5 part by weight of chromic acid and 10 parts by volume of pyridine is added with stirring a solution of 0.5
 EMI25.7
 part by weight of 2tx metha, llyl-2 (3- (hydroxymethylj-4b-methyl-7-et.ylenedioy-123,4,4aa, 4b5a, 7: 8,10? 10ai-dodecahydrophenanthrene- mono-methosuccinate) 1,4i-diol, mp 115.5-1170.

   After stirring overnight, evaporate in the vacuum of a water pump at a bath temperature of about 40, and the residue is boiled five times with 25 parts by volume.

  <Desc / Clms Page number 26>

 
 EMI26.1
 The ethereal extracts are washed successively with water, ice-cold 0.5n hydrochloric acid, and ice-cold 5% sodium bicarbonate solution, dried and then evaporated.

   From the residue, the ester is obtained
 EMI26.2
 mixed monomethosucciniate to the hydroxymethyl group of 2CC methallyl-2, - (hydroxymethyl) 4bfi-methyl-7-ethyrlenedioxy-1,2,3,4,4aOE-4b, 5,6,7,8,10,10ap- dodecahydrophenanthrene- l-ol-4-one, melting at 140-141 o
By more vigorous oxidation, such as that which is described in the following example, this compound can be converted into 1,4-diketoneo
Example 17
To a solution of the pyridine-chromic acid complex prepared from 2.660 parts by weight of chromic acid and 75 parts by volume of pyridine is added dropwise, with stirring, a solution of 0.985 part by weight. weight of mixed ester monomethosuccinate, esterified to the group
 EMI26.3
 2oc-methallyl-2 (3- (hydroxymethyl) -q.bi-methyl-7-ethyl'snedioxy-1,2,3,4,4ac, 4b, 567,8, I,

  10a3-dodecahydrophenanthrene-1, ° -3-diol, mp 115.5-117. The mixture is stirred for 12 hours at 60, evaporated in vacuo and the residue boiled five times with 50 parts by volume of ether. The combined ether extracts are washed successively with water and hydrochloric acid. Ice-cold 0.5n and an ice-cold 2.5% sodium bicarbonate solution, then dried and evaporated. The residue is a clear, thick oil which cannot be crystallized. In the infrared spectrum of this product, the characteristic OH band is missing at 2.78 µ for the hydroxyl compounds of this series.

   We are in the presence of the mixed ester monomethosuccina-
 EMI26.4
 te, esterified at the hydroxymethyl group of 20E-methallyl-2fi- (hydroxymethyl) -4b-methyl-1-ethylenedioxy-1,2,3,4,4aa, 4b, 5,6,7,8,10,1Oa- dodecahydrophenanthrene-1,4-dione.



   2.95 parts by weight of magnesium shavings are covered with 75 parts by volume of absolute ether, then a solution of 10 is added dropwise with stirring at room temperature in a nitrogen atmosphere. , 4 parts by volume of ethyl bromide in 75 parts by volume of ether. When the reaction is completed, a solution of 10.6 parts by weight of freshly prepared ethoxy-acetethylene in 100 parts by volume of absolute ether is introduced dropwise, with stirring and cooling with water. , and stirred until evolution of ethane has ceased.



  To the reaction solution is first added to 3-5, with stirring, 60 parts by volume of absolute benzene and then, over 30 minutes, a solution of 7.42 parts by weight of the esterified monomethosuccinate mixed ester. to the group
 EMI26.5
 2a-methallyl-2fi- (hydroxymethyl) -4bfi-methyl-7-ethylene- toioxy-1,2,3,4,4aOE, 4b, 5, 6, 7,8,10,10afi-àoàécahyàrophenanthrene-1 hydroxymethyl , 4-aione, in 25 parts by volume of benzene. Stirred 6 hours while cooling with ice-water, 6 hours at room temperature, pour into 500 parts by weight of ice-water and add a solution of 20 parts by weight of ammonium chloride in 30 parts by volume. of water. As soon as the emulsions are broken, the two layers are separated.

   The aqueous layer is extracted three more times with 100 parts by volume of ether. The combined organic solutions are washed with water, dried, filtered in a column through 5 parts by weight of activated carbon and 2 parts by weight of magnesium silicate, then evaporated. From the residue dissolved in 15 parts by volume of ether, it crystallizes after the slow addition of 5 parts by volume of pen-
 EMI26.6
 tane, 2oc-methallyl-4b (3-methyl-1-ethoxyethinyl-2i- (hydroymethyl) -7-ethylene toioxy-1,2,3,4 q.aGC, 4b, 5,6,7,8, 10,10α-dodecahydrophenanthrene-1-ol-4 one, mp 141-142.



   If this compound is reduced to 0 in a mixture of absolute ether and tetrahydrofuran, with lithium aluminum hydride, and the crude product of the reduction, dissolved in tetrahydrofuran, is treated,

  <Desc / Clms Page number 27>

 as indicated in Example 12, for 6 hours, with dilute aqueous sulfuric acid, then isolates the reaction compound according to the indications of Example 12, a mixture is obtained from which it is possible to isolate at pure state
 EMI27.1
 1,1-carbethoxymethylene-20E-methallyl-2fi- (hy <iroxmethyl) -7-ethylenedioxy-1,2,3,4,4aa, 4b, 5,6,7,8,10,10ap-dodecahydrophenanthrene-4p-ol.

   In this compound, the bond located in position a, p with respect to the carbethoxy group, is allowed to saturate with nascent or catalytically activated hydrogen. By a further reduction with lithium aluminum hydride, we obtain -
 EMI27.2
 holds 4bp-methyl-1- (2'-hydroxyethyl) -2a-methallyl-? fi-hydroxymethyl-7-ethyl enedioxy-1, 2, 3, q., q.act-qb, 5, 6, 7, $, 10, 10ai-dodecahydrophenanthrene-4 (3-0l already described in Example 120
Example 18
To a suspension of the chromium trioxide-pyridine complex prepared from 4.01 parts by weight of chromium trioxide and 200 parts by volume of anhydrous pyridine, there is added a solution of 3.785 parts in
 EMI27.3
 weight of 20E-methallyl-2fi- (hydroxymethyl) -4bfi-methyl-7-ethylenedioxy-1,2,3,44aa ,, 4b-5,6,7,8,10,10ai-dodecahydrophenanthrene-1,4j3- diol,

   melting at 146-148, described in Example 16, in 50 parts by volume of pyridine and stir the mixture for 40 hours at room temperature. Then diluted with 1500 parts by volume of ether and 500 parts by volume of ethylene chloride, the solution is extracted with a 4 molar solution of phosphate
 EMI27.4
 r1 ("1o <.) dique, then insoluble inorganic compounds are separated by filtration through a layer of Super Cel. The sther-methylene chloride solution was further washed with water, with normal sodium carbonate solution and with water, dried over sodium sulfate and evaporated. From the mixture of the dehydrogenation products thus obtained, a first component of methylene chloride can be separated.

   The first fraction provides, upon recrystallization from acetone, 2-methal-
 EMI27.5
 lyl.-2 (3-f ormyl-4bi-methyl-7-ethyl enedi.oxy1, 2, 3, 4, 4aa., 4b, S b 9 Î 8,10,10a3-dodecahydrophenanthrene-1-ol-4- one pure, melting at 233-235 o The residue of the evaporation of the mother liquor, in practice entirely crystalline, is separated in its components by distribution on cellulose by means of the methanol-water system (4: 1), ligroine- benzene- (2:

  1) o By elution of the most polar zone, detectable with the zinc chloride indicator, showing a blue fluorescent under the quartz lamp, using a mixture of ether and 95% ethanol (4sl ) then recrystallization from ether, one obtains the
 EMI27.6
 2a-methallyl-2i-hydroxymethyl-4b (3-methyl-7-ethylenedio, y-1, 2, 3, q., Q.ao, ° b, 5, 6,7,8, io, loafi-dodecahydrophenanthrene -i-oi-4-one pure, melting at 1755-178 An analogous elution of the more weakly polar bordering zones, fluorescent in light green under the quartz lamp with the zinc chloride indicator, provides, on l evaporation, a crystalline residue which is dissolved in methylene chloride and filtered through a layer of Super Cel to purify it.

   From the highly concentrated filtrate it crisps
 EMI27.7
 tallises by addition of ether pure la (2 --- j 4fi) -lactone of 2a-methallyi-2p-carboxy-4bfi-methyl-7-ethylenedioxy-1,2,3,4,4aOE, 4b, 5, 6,7,8,10, loafi-dodecahydrophenanthrene-l, q. (3-diol, melting point 246-249, which is identical to the substance described in Example 10 as an intermediate.



   0.5 part by weight of the mixed ester monomethosuccinate esterified with the hydroxymethyl group of 2a-methallyl-4bp-methyl-2p- (hydro-
 EMI27.8
 xymethyl) -7-ethylenediox, y-1, 2, 3, q., q.aGC, 4b, 5, 6, 7, 8,10, IOa3-dodé cahydrophênanthrene-l, q. (3-diol, in 2 parts by volume of pyridine and 0.5 part by volume of acetic anhydride The solution is left to stand for 24 hours at room temperature and diluted with 50 parts by volume of ether.

   The ethereal solution is washed twice, each time with 20 parts by volume of water, twice each time with 20 parts by volume of normal ice-cold hydrochloric acid, twice with each time 20 parts by volume of cold water solution.

  <Desc / Clms Page number 28>

 2.5% sodium carbonate, and again with 20 parts by volume of water. The residue is dried over sodium sulphate and then evaporated. The residue is recrystallized from a mixture of equal volumes of ether and pentane. It crystallizes the monoacetate of the mixed ester monomethosuccinate, esterified.
 EMI28.1
 to the hydroxymethyl group, 20E-mµthallyl-4bfi-methyl-2fi- (hydroxymethyl) -7- ethylenedioxy-1,2,3,4,4aC, 4b, 5,6 ,, $, 10,10aidodecahydrophenanthrene-l, Qi- diol, melting at 138-140.



   Has a solution of 2 parts by weight of (2 # 4ss) -lactone from
 EMI28.2
 2a methallyl-2 (3-carboxy-4b (3-methyl-ethylenedioxy-1,23, q., 4at, 4b, 5,6,7, 8,10,10afi-àodécahyàrophenanthrene-1,4fi-aiol, in 70 parts by volume of tetrahydrofuran, a solution of 0.23 part of lithium aluminum hydride in 20 parts by volume of tetrahydrofuran is added dropwise at room temperature After stirring for 4 hours, slowly introduce a mixture of 1 part by volume of water and 5 parts by volume of tetrahydrofuran, stir for a further 10 minutes, add 2 parts by weight of diatomaceous earth, stir again for 10 minutes and drain.

   The clear filtrate is then evaporated off under reduced pressure. From the residue, fractional crystallization from acetone is obtained by hemiacetal of 2a-me-
 EMI28.3
 thallyl-2i-formyl-q.bi-methyl-râthylenedioxy-1, 2, 3, q., 4aG, qb, 5, 6,, 8, IQ, lta (3iodéoahydrophenanthrene-l, 4p-diol, melting at 192- 194 o Example 19
 EMI28.4
 Has a suspension of 1.311 parts by weight of 2-carbethoxy-4P-ethoxycarbaxr-4bimethyl-7-ethylenedioy-1, 2, 3;

   4, 4aa, 4b, 5, 6, 7, 8,1 #, LOa3- dodecahydrophenanthrene-1-one, in 22.5 parts by volume of anhydrous acetone, 1.038 part by weight of fresh potassium carbonate is added calcined and 7.5 parts by volume of freshly distilled allyl iodide and stirred for 48 hours under a nitrogen atmosphere, at 25-28 o It is then concentrated in vacuo at a bath temperature of 30, to 5 parts by volume , diluted with a benzene-ether mixture (1: 1) and washed with ice-water, with cold normal sodium hydroxide solution and with water. The benzene-ether solution dried over magnesium sulfate gives, after evaporation, 1.548 parts by weight of a yellow oil. For purification, this crude product is chromatographed on 50 parts by weight of alumina (activity II).



  With the hexane-benzene mixture (9: 1), only traces of impurities are dissolved, while with the hexane-benzene mixture (1: 1) one elutes, in total,
 EMI28.5
 1,265 parts by weight of the two -2-allyl-2-carbethoxy-4P - = 'ethoxycarboxy-4bj3-methyl-7-ethylene to dioxy-1,2,3,4,4aa, 4b, 5,6,7,8,10 , 10afi-tooaecahydrophenanthnene-1-epimeric at carbon atom 2, in the form of a colorless oil, which does not give any coloration with ferric chloride. The fractions eluted with benzene and a benzene-ether mixture still contain some starting material and give a dark red color with ferric chloride.



   Instead of allyl iodide, allyl chloride can also be used for alkylation.
 EMI28.6
 



  Has a solution of 5 parts by weight of 2-carbetho $ y-4 (3-ethogycarbox Q.bi-methyl-7-ethylenedioy-1, 2, 3, Q., 4aoc, 4b, 5, 6, T , 8,1, lQai-dodeca-hydrophénantbnene-1-one in 100 parts by volume of acetone (anhydrous), one adds 4.5 parts by weight of freshly calcined potassium carbonate, 35 parts by volume of allyl chloride and 3 parts by weight of dried potassium iodide. The mixture is stirred for 3 days under a hydrogen atmosphere. The mixture is then concentrated in vacuo to 30 to about 10 parts by volume, taken up in a chloroform-ether mixture, washed. with ice water, twice with normal solution of ice-cold sodium hydroxide, then with water and dry over sodium sulfate.

   The evaporated solution gives 5.38 parts by weight of crude product, which is chromatographed on 150 parts.

  <Desc / Clms Page number 29>

 by weight of alumina.



   The fractions eluted with mixtures of petroleum benzene-ether, pure benzene and benzene containing 5% ether give 3.4 parts by weight, are amorphous and consist of a mixture of the two 2-allyl-2-carb-
 EMI29.1
 thpxy-q.3-ethoxycarboxy-7-ethyl èedioxy.-1, 2, 3, °, áa, qb, 5, 6, 7, 8,10,10a3-dodecUiydophenanthrene-1-ones, epimers carbon atom 2.



   The fractions eluted with ether-benzene mixtures, with ether alone, chloroform and chloroform containing 5% methanol, give in an ether-petroleum ether mixture 1.060 parts by weight of crystallized starting material.



   Example 20
In 10 parts by volume of absolute ether, 0.685 parts by weight of the mixture described in Example 19 of the two 2-allyl-2-carbedes are dissolved.
 EMI29.2
 thoxy-4fi-ethoxycarboxy-4bfi-methyl-7-ethylenedioxy-1,2,3,4,4aa, 4b, 5, 6,7, 8, la, 10afi-dodecahydrophénanthnene-1-ones. A boiling solution of 0.70 part by weight of lithium aluminum hydride in 30 parts by volume of absolute ether is added and boiled for 10 minutes. Then poured into 12 parts by volume of a saturated solution of Seignette salt, then extracted with chloroform. The extracts are washed with water, hydrochloric acid, sodium carbonate solution and with water.

   By evaporating the chloroform solutions, 0.504 part by weight of crude product is obtained, from which it can be isolated by crystallization in the mixture.
 EMI29.3
 aoetone-ethor 0.14 part by weight of 2a-hydroxymethyl-2fi-allyl-4bfi-methyl-7-ethylenedioxy-1,2,3, °, ácx, 4b5,6,7,8,10,10a3-dodecahydrophênanthrene- 1,4 (- diol, melting point 182-184. The mother liquor is chromatographed on 15 parts by weight of alumina.



   From the fractions eluted with the ether-benzene mixture (l; l) a further 0.055 part by weight of the above compound is obtained, while with the ether and the chloroform-ether mixtures it is not possible to elute a substance. unitary. The fractions eluted with chloroform (0.072 part by weight) give, crystallized from acetone-ether, 0.060 part.
 EMI29.4
 by weight of 2a-allyl-2p-hydroxymethyl-4bp-methyl-7-ethylenedioxy-1,2,3,4, áü-qb, 5, 6 '7, $, 10, 10a (3 ... dodecahydropb.ênaxthrëne -1, í-diol, as colorless needles, melting at 156-159.



   By acetylating 0.019 part by weight of this compound in 0.2 part by volume of pyridine and 0.1 part by volume of acetic anhydride for 16 hours to about 20 hours and separating the reaction product in the usual manner, 0.011 part by volume is obtained by weight of an acetate, melting at 112-115, after recrystallization from ether-petroleum ether.
 EMI29.5
 



  0.370 part by weight of 2a-allyl-2j3-hydroxymethyl- ° b3-methyl-7-ethylenedio 1, 2, 3, 4, áa ,, ° b, 5, 6, 7, 8 10 'l0ai-dodé is dissolved. cahydrophenanthrene-le4p-diol described above in 2 parts by volume of crystallizable acetic acid and add 12 parts by volume of a mixture of 2% chromic acid in crystallizable acetic acid. After 3/4 of an hour, we can still detect µ'chromic acid. The reaction product is isolated in the usual manner and 0.231 part by weight of a neutral substance is obtained which is chromatographed on 8 parts by weight of alumina.

   The first fractions eluted with benzene are obtained by crystallization in
 EMI29.6
 petroleum ether-ether, a small amount of 2-allyi-4bfi-methyi-7-ethylenedioxy-1,2,3,4,4aa, 4b, 5,6,7,8,10,10,10afi-dodecahydrophenanthiene-1 , 4- dione, melting at 130-132. Another benzene fraction gives, by crystallization from petroleum ether-ether, a small quantity of (2 # 4ss) -
 EMI29.7
 2a-allyl-2fi-carboxy-4bfi-methyl-7-ethylenedioxy-1,2,3,4,4aa, 4b.516,7,8elO, 10ap-dodecahydrophenanthrene-4p-ol-1-onee lactone, melting at 185-189.

  <Desc / Clms Page number 30>

 



     Of the. first fraction eluted with a benzene-ether mixture (95: 5), a small quantity of a compound melting at 150-155 is obtained, while the other fractions eluted with mixtures of benzene and ether containing 5 10% ether gives on crystallization from a mixture of acetone and ether 0.012 part by weight of a crystalline compound with a melting point of 210-212.



   From the fractions (0.026 part by weight) eluted with mixtures of benzene and ether containing 10 to 12% of ether, 0.018 part is obtained by crystallization from a mixture of acetone and ether. in weight
 EMI30.1
 (2 Q.3) -lactone of 2a-allyl-2fi-aarboxy-4b @ -methyl-7-ethylene toioxyi, 2,3,4,4aOE, 4b, 5, 6, 7, 8,10, loafi- doaahydrophenanthnene 1,4β3-diol which crystallizes in fine needles, melting at 233-237 a
Example 21
 EMI30.2
 Has 3.15 parts by weight of 4bfi-methyl-7-ethylene-dioxy-1,2,3,4, 4aCC, 4b, 5,6,7,8,1Os10a3-dodecahydrop.enanthrene-1-one-4 -ol, melting at 205-212, in 60 parts by volume of absolute benzene and 20 parts by volume of tertiary butanol, a hot solution of 0.6 part by weight of potassium in 30 parts by volume of tertiary butanol is added,

   then 15 parts by volume of allyl chloride in 15 parts by volume of benzene. The solution is boiled for a quarter of an hour, diluted with water, concentrated in vacuo and extracted with a mixture of chloroform and ether.



  The extracts washed with water and then dried over sodium sulfate give, when evaporated, 3.44 parts by weight of crude product. By crystallization from a mixture of chloroform and ether, 1.34 part by weight of the starting substance can be recovered, melting at 200-212 ° C. The mother liquor is evaporated off and the product is chromatographed on 60 parts by weight. aluminum oxide.

   The fractions eluted with mixtures of benzene and ether containing up to 50% ether afford a total of 202 parts by weight of crude product from which or removed by crystallization from a.
 EMI30.3
 mixture of ether and petroleum ether, 1.2 parts by weight of 2-allyl-4bp-methyl-7-ethylenedior-12,3,4,4att 4b, 5,6,7s $, 10 , 10a (3-dodecahydrophënanhrene-1-one-Q.3-ol, as thick needles, melting at 112-114 o
The other fractions eluted with mixtures of benzene and ether and ether alone still provide 0.07 part by weight of starting material.



   1.2 part by weight of the above compound, melting at 112-114, is dissolved in 20 parts by volume of dioxane, 6 parts by volume of a 40% aqueous solution of formaldehyde are added, then 0.6 part by weight of potassium carbonate in 17 parts by volume of water, and let stand 16 to about 20 hours. It is then extracted with a mixture of chloroform and ether and the extracts washed with water. The washed and dried extracts are evaporated off. From the residue (1.44 parts by weight), crystallization is obtained from ether or a mixture of chloroform and ether, 2a-hy-
 EMI30.4
 draymethyl-23-allyl-Qb (3-methyl-7-ethylenedioy-1, 2, 3 s4, 4aa? 4b, 5, 6, 7, 8 10, 10ap-dodeoahydrophenanthrene-1-one-4p-ol in colorless flakes , melting at 199-202.



   The mother liquor (1.19 parts by weight) is chromatographed on 40 parts by weight of alumina. The fractions eluted with mixtures of benzene and chloroform containing up to 50% chloroform give 0.278 part by weight of a compound melting at 98-100, after crystallization from a mixture of ether and ether of oil.

   From the other fractions eluted with mixtures of benzene and chloroform, a further 0.315 part is obtained.
 EMI30.5
 by weight of the 2a-hydroxy-methyl-2p-allyl compound which has just been described, melting at 198-202, while the latter fractions eluted with the mixture

  <Desc / Clms Page number 31>

 gede benzene and chloroform, as well as with pure chloroform (0.32 part by weight), is obtained by fractional crystallization in a medium.
 EMI31.1
 mixture of ether and petroleum ether, 0.22 part by weight of 2a-allyl-2 (3-hydroxymetbyl-4bp-methyl-7-ethylenedioxy-1,2,3,4? 4aa, 4 ' b, 5? 6,7,8,10,10ap-do-decahydrophenanthxene-1-one-4 (3-0l, melting point 126-132 and 0.075 parts by weight of 2oC hydroxymethyl-2i-allyl-4b (3- methyl-7-ethylene-dioxy-1, 2, 3, 4, 4a, 4b, 5,6,7,8e10,

  10ap-dodecahydrophenanthrene-le4p-diol, triol identical to that described in Example 20, melting point 182-184.



   The last fractions eluted with chloroform, as well as with chloroform containing 5% methanol, give, crystallized from ether, another compound melting at 128-132.
 EMI31.2
 



  0.028 part by weight of 2a-allyl-2p-hydroxymethyl-4bfi-me% hyl-7-ethylenedioxy-1,2,3,4,4aa, 4b, 5,6,7, 8, 10,10afi-dodecahydrophenan is dissolved - threne-1-one-43-0l in 0.3 part by volume of crystallizable acetic acid and oxidized in one and a half hours with 0.7 part by volume of a 2% solution of chromic acid in crystallizable acetic acid. The mixture is then concentrated in a vacuum, taken up in a mixture of chloroform and ether and the extracts washed with water, sodium carbonate solution and water.

   The evaporated organic solution gives 0.205 part by weight of a crude product which is chromatographed on 1 part by weight of aluminum oxide. The fractions eluted with a mixture of benzene and petroleum ether give 0.0055 part by weight of crude product which, on crystallization from a mixture of acetone and petroleum ether, gives 0.0025 part by weight. 2a-allyl-2p-carbo- (2 # 4ss) lactone
 EMI31.3
 xy-4bfi-methyl-7-ethyleneàioxy-1,2,3,4,4àa, 4b, 5,6,7,8,10,10afi-dodecahydro-phenenanthrene-1-one-4i-ol, melting point 185- 189, already described in Example 20.



   To a boiling solution of 0.08 part by weight of lithium aluminum hydride in 6 parts by volume of absolute ether is added a solution of 0.05 part by weight of 2a-allyl-2p-hydroxymethyl- 4bp-m-
 EMI31.4
 thyl-7-ethylenedioxy-1,2,3,4,4aa, 4b, 5,6,7,8,10,10ap-dodecahydrophenanthrene-1-one-4ss-ol, described above, in 1 part by volume of dioxane, and boil for 10 minutes. The mixture is then poured into 2 parts by volume of a saturated solution of Seignette salt, and then extracted with a mixture of chloroform and ether. The extract washed with water, hydrochloric acid, sodium carbonate solution and water leaves a residue of 0.076 part by weight which is chromatographed on 2 parts by weight of sodium oxide. aluminum.

   The first chloroform fractions give, crystallized from a mixture of acetone and ether, two by-products melting at 230-232 and 175-180, respectively, while the last chloroform fractions are obtained by crystallization in a mixture of acetone and ether, 0.019 part by weight of colorless needles, melting at 156-159, which
 EMI31.5
 are identical to 2a-allyl-2p-hydroxymethyl-4bp-methyl-7-ethylenedioxy-1,2,3,4,4aa, 4b, 5,67810,10a3-dodecahydrophëna, threne-lq. (3-diol, described in example 20.



   Example 22
3.2 parts by weight of the mixture of epimers are dissolved at the atom
 EMI31.6
 carbonate 2, 2-allyl-2-carbethoxy-4 # -ethoxy-carboxy-4b @ -methyl-7-ethylenedioxy-1,2,34,4aa4b56,7,8,10,10a (3-dodecahydrophenanthrene -1-one in 100 parts by volume of absolute alcohol, add 2.5 parts by weight of sodium boron hydride and leave to stand for 3 days at about 20, then weakly acidic with l dilute acetic acid, the alcohol is evaporated off in vacuo, the residue is taken up in a mixture of chloroform and ether (1: 3), washed with water, with a solution of sodium carbonate and with water , then dried over sodium sulfate.

   The evaporated solution gives 3.13 parts by weight of crude product, which is isolated, by crystallization.

  <Desc / Clms Page number 32>

 in a mixture of ether and petroleum ether, 0.630 part by weight of 2a-
 EMI32.1
 hydroymethyl-2 (3-allyl-4bi rxethyl-4i-ethoxycarboy-7séthy 1 enediogy-I, 2, 3, -, 4aa, 4b, 5,6,7,8, I0,10a (3-dodecahydrophenanthrene-1 = ol , in fine needles melting at 180-182.



   The mother liquor (2.45 parts by weight) is boiled for 2 hours with 5 parts by weight of potassium hydroxide in 150 parts by volume of alcohol, then mixed with 50 parts by volume of water. The alcohol is removed in vacuo and the aqueous mixture is extracted with a mixture of chloroform and ether. The extracts washed with water and dried over sodium sulphate give 0.268 part by weight of residue (neutral part), which is isolated by crystallization from a mixture of ether and petroleum ether.
 EMI32.2
 0.168 part by weight of 2a hy droxymethyl-2 (3-allyl-4b (3-methyl-7-ethylene-dioçY-1,2s3,4,4a., 4b, 5t6J7,8,10910a (3-dodecahydrophenanthrene-1, 4 (3-diol already described in Example 21, melting point 182-184 (conversion at 165).

   Hydrochloric acid is added to the aqueous alkaline extracts until acidic reaction in Congo, then extracted with chloroform. These extracts provide 1.39 parts by weight of residue (acid + lactone). By crystallization from a mixture of acetone and ether, 0.73 part by weight is obtained.
 EMI32.3
 (2.-4 (3) -laetone 2a-allyl-2j3-oarboxy-4bp-methyl-7-ethylenedioxy-1,2 3,4,4aa, 4b, 567? 8,10,10ai-dodecahydrophenanthrene- 1.43diol, melting point 233-237, already deprived in Example 20. The mother liquor is dissolved in a mixture of chloroform and ether (3: 1) and separated by stirring with a solution of sodium carbonate. acidic fraction and a neutral fraction.



  0.43 part by weight of neutral fraction and 0.22 part by weight of acid fraction are obtained o From the neutral fraction, another 0.225 part by weight of the above lactone is obtained o The acid fractions provide
 EMI32.4
 by crystallization from ether, 20E-aarboxy-2fi-aiiyl-4bfi-methyl-7-ethylenedioxy-1,2,3,4,4aa, 4b, 5,6,7,8,10,10afi-dodecahydrophenanthrene -1.4diol, mp 216-220.



   1.2 part by weight of chromium trioxide is added in portions to 12 parts by volume of pyridine, then 0.55 part by weight of the lactone described above, melting at 233-237, in 6 parts is added. by volume of pyridine. The mixture is heated for 6 hours at 60-65 under a nitrogen atmosphere, then diluted with chloroform, filtered and the residue washed with chloroform. The filtrate is evaporated in vacuo, almost until drying, the residue is taken up: in a mixture of chloroform and ether, then washed with water, hydrochloric acid, sodium carbonate solution and again with water. After having dried over sodium sulphate, the solution is evaporated and the residue crystallizes from a mixture of acetone and ether.

   0.36 part by weight of the (249) -lactone from
 EMI32.5
 2a-allyl-2fi-aarboxy-4bfi-methyl-7-ethyleneàioxy-1,2,3,4,4aa, 4b, 5,6, 7, 8,10,10ai-dodecahydrophenanthrene-1-one4i-ol, melting at 185-189, which is identical to the compound described in Examples 20 and 210
Is added slowly, protected from moisture, 0.306 part by weight of ethyl bromide in 10 parts by volume of absolute ether (distilled over phosphorus pentoxide), to 0.068 part by weight of shavings of magnesium activated. When the reaction is complete, add dropwise
 EMI32.6
 te in 10 minutes and with stirring, 1 part by weight of ethyl acetylene in 20 parts by volume of benzene, then shaking for a further hour.

   A solution of 0.5 part by weight of the lactone described above, melting at 185-189, in 20 parts by volume of benzene is then added, then left to stand for 4 hours at approximately 20. Then poured onto ice and extracted with ether. The emulsions are destroyed with a saturated solution of ammonium chloride. The ethereal solution is washed with water, dried over sodium sulfate and evaporated. The crude product obtained (0.65 part by weight) is chromatographed on 16 parts by weight of aluminum oxide.

  <Desc / Clms Page number 33>

 



  Fractions eluted with benzene provide 0.14 part by weight of the starting material. From the fractions dissolved with mixtures of benzene and ether containing up to 50% ether, crystallization is obtained from a mixture of ether and petroleum ether, 0.265 part.
 EMI33.1
 by weight of 1-ethoxyethinyl-2a-allyl-2fi-carboxy-4bp-methyl-7-ethylenedioxy-1,2,3 (2 4P) -lactone: 4,4aa, 4b, 5,6,7? S, 10.10a (3-dodeoahydrophenanthrene-1,4p-diol, in thick platelets, melting at 149-1520.



   The other fractions eluted with mixtures of benzene and ether and with pure ether (0.057 part by weight) yield in the ether in the form of colorless prisms melting at 180-182, the carbon epimeric compound 1.



   0.099 part by weight of the ethoxyethinyl compound, described above, melting at 149-152, is stirred in a hydrogen atmosphere in 2 parts by volume of absolute alcohol and 0.5 part by volume of very pure pyridine, with 0.060 part by weight of catalyst containing 2% palladium and calcium carbonate. After 5 minutes the reaction begins to occur and it is complete after 12 minutes 8 parts by volume of hydrogen are absorbed. The reaction mixture is filtered, diluted with ether and washed with water.

   The solution dried over sodium sulphate and evaporated gives 0.099 part by weight of the residue from which is isolated, by crystallization, from a mixture of ether and petroleum ether, 0.075 part by weight.
 EMI33.2
 1- (2'-ethoxyvinyl) -2a-allyl-2p-carboxy-4bp-metlyl-7-ethylenedioxy-1s234a4aa, 4b, 5670810,1a (3-dodecahydrophénanthxè- ne-1) ut 4P) -lactone , 4ss-diol, in colorless prisms, melting at 120-122.



   0.094 part by weight of this compound is dissolved in 6 parts by volume of dioxane, 1 part by volume of water and 0.8 part by volume of 0.2 normal sulfuric acid are added, then left to stand for 16 to 20 hours approximately.



  It is then diluted with ether, washed with water, with a solution of potassium bicarbonate and again with water. The ethereal solution is dried and evaporated. The residue (0.092 part by weight) gives, by crystallization from a mixture of ether and petroleum ether, 0.073 part by weight of starting material which is again left to stand for 3 to 20 days with sulfuric acid. diluted in aqueous dioxane. By isolating the reaction product, 0.069 part by weight of crude product is obtained, from which 0.021 part by weight of starting material is recovered again.



   The mother liquors for the two loads are chromatographed on 3 parts by weight of alkali-free aluminum oxide. From the fractions eluted with mixtures of benzene and petroleum ether, another 0.03 part is obtained. by weight of starting material, and from the fractions eluted with benzene and with mixtures of ether and benzene containing up to 50% ether, crystallization from a mixture of acetone and petroleum ether, 0.014 part by weight of (2 # 4P) -lactone
 EMI33.3
 1,1-formyl-methylene-2a-allyl-2b-aarboxy-4bfi-methyl-7-ethylene-dioxy-1, 2,3,4aa-4b, 5,6,7,8,10, ioap-àoàecahydrophenanthrene -4 # -ol, in flat needles, melting at 162-164.

   The infrared spectrum of this compound compressed in
 EMI33.4
 The potassium bromide shows the bands of β-lactone (S, 66AU), of the unsaturated α-aldehyde (3 (6, 0) and of the ketal group (9,1 4Ao).



   From the fractions eluted with chloroform, a small amount of a compound crystallizing in petroleum ether can be isolated in colorless needles, melting at 188-192.



   A solution of 0.40 part by weight of the formylmethylenic compound described above, melting at 162-164, in 10 parts by volume of ethanol is stirred in the presence of 1 part by weight of palladium catalyst. (10%), calcium carbonate, under a hydrogen atmosphere. After absorption of 1.1 molecular equivalents, the hydrogenation is stopped. The

  <Desc / Clms Page number 34>

 The solution freed from the catalyst by filtration is evaporated in vacuo to drying and the product is chromatographed on aluminum oxide.

   From the fractions strongly reducing a solution of argon-to-diammine, one obtains, by crystallization in a mixture of ether and
 EMI34.1
 petroleum ether, (2 - .. ° (3) -lactone of 1p-formylmethyl-2a-allyl-2p-carbor- ° b (3-methyl-'j-ethylenedioxy-1,2,3,. , .a0 (,, -b, 5, 6, 7, 8,1Q, lQai-dodecahyrophenanthrene-4i-olo
0.502 part by weight of this compound is dissolved in 20 parts by volume of ethyl acetate free of acetic acid, then, with vigorous stirring, treated at -60 with a stream of oxygen containing about 3% ozone. .



   When approximately 1.5 mol of ozone has been consumed, the ozone supply is interrupted and nitrogen is passed through. The mixture is allowed to warm up slowly to -10, 5 parts by volume of glacial acetic acid are added and then, in portions, 5.0 parts by weight of zinc powder, then stirred for a further 15 minutes at -10 to 0 ° C. the mixture of unconsumed zinc, by vacuum filtration and the filtrate is poured into 100 parts by volume of an ice-cold bicarbonate solution. The solution is carefully extracted and then washed again in acetate. ethyl with a solution of bicarbonate and water, dried, then evaporated in vacuo with care, at a bath temperature of 25. An amorphous residue is obtained which is purified by chromatography on neutral aluminum oxide.

   From the crystallized fractions, greatly reducing an al- solution
 EMI34.2
 caline dtargento-diammine, we obtain the (2 ---> 49) -lactone of 1i, 2ct di- (formylmethyl) -2i-earboy- ° b (3methyl7-ethylenedioxyl, 2,3,4? 4aü, 4b, 5 , 6, 7,8,10,10afi-dodecahydrophenanthrene-4fi-olo
If in the above formylethyl compound the free aldehyde group is protected by acetalization, in particular by reaction with ethylene glycol, then, after addition of hypobromous acid (by reaction with brominated acetamide to nitrogen in aqueous tertiary butanol in the presence of acetic acid and sodium acetate) and subsequent oxidation with ohromic acid, to a bromoketone in which the bromine atom can be replaced by an acetoxy group,

   by treatment with potassium acetate in anhydrous acetone It is possible to use for the cyclization, in a manner analogous to that of Example 2,
 EMI34.3
 1 (3foryl-methyl-2ct (aetoxr acetonyl) (2-- 4 (3) -lactone) -23-carbo-xy-4bfi-methyl-7-ethylenedioxy-1,2,3,4,4aa, 4b, 5,6,7,8, 1a, loaµ-dodecahydro-phenanthrene-4 {3-01 obtained.



   Example 23
In 200 parts by volume of benzene, 12.8 parts are dissolved in
 EMI34.4
 weight of 4bfi-methyl-2-carbethoxy-7-ethylenedioxy-1,2,3,4,4aOE, 4b, 5,6,7,8, 10,10aµ-doàécahyàrophenanthrene-1,4-dione, m.p. 121- 123 (obtained by reacting the diketone unsubstituted in position 2 with the diethyl ester of carbonic acid in the presence of sodium hydride) then successively added a solution of 1.56 parts by weight of potassium in 200 parts by volume of tertiary butanol and 8 parts by volume of methyl bromacetate. The mixture is boiled for 8 hours, with stirring under a nitrogen atmosphere. The mixture is then stirred for a further 8 hours at room temperature, cooled with ice, added ice-water and extracted with ether.

   The ethereal solution is washed with an ice-cold normal solution of potassium hydroxide, from which is obtained, acidifying with dilute phosphoric acid to a pH of 4 to 5.1, 1 part by weight of the substance starting point Washed with water until neutral, then dried, the ethereal solution gives up, after evaporation of the ether, 11.7
 EMI34.5
 parts by weight of ° b-methyl-2-carbethoy-2-carbomethoymethyl-7-ethyl-

  <Desc / Clms Page number 35>

 
 EMI35.1
 rcdio - 1,, 3, 4 4aa, 4b 5, 7, 8,10,10a3 - dodecahydrophenanthrene-1, q.-dione colored in light yellow, which, after recrystallization from methanol, melts at 106-108.



   To a solution of ethylmagnesium bromide prepared from 1.2 part by weight of magnesium and 4.62 parts by volume of ethyl bromide in 100 parts by volume of ether is added, at about 50, a solution of 7.5 parts by volume of ethoxyethylene in 25 parts by volume of ether. After the end of the ethane scission, which lasts about 15 minutes, 50 parts by volume of benzene are added. In the thus prepared solution of ethoxyacetylene-magnesium bromide, a solution of 10.9 parts by weight of
 EMI35.2
 4bµ-methyl-2-aarbethoxy-2-aa, rbomethoxymethyl-7-ethyleneàioxy-1,2,3,4,4aOE, 4b, 5,6, 7, 8,10,10afi-doàeaahydrophenanthrene-1,4-dione in 125 parts by volume of benzene.

   The reaction product then separates out as a white precipitate. After stirring for 4 hours, pour into a mixture of water and ice, add an ice-cold saturated ammonium chloride solution to separate the layers, then wash the solution three times. ether and benzene, with saturated sodium chloride solution. After evaporation of the solvent, 12.1 parts by weight of a light brown colored crystallizate is obtained, which melts at 126-134 on decomposition.

   By recrystallization from a mixture of methyl chloride
 EMI35.3
 lene and ether, 10.3 parts by weight of 4bp-methyl-1-ethoxyethinyi-2-carbetho.y-2-carbomethoxymethyl-7-ethylenedioxy-12,3,44aü, 4b, 5,6,7 , 8,10,10ap-dodecahydrophenanthrene-4-one-1-ol which melts at 149-150 on decomposition.
 EMI35.4
 



  By -chromatography of the above ethozy-ethinyl-carbinol, on aluminum oxide, the carbomethoxy group of the carbomethoxymethyl residue saponifies, and the carboxylic group lactonizes with the hydroxy group at 1; obtains the corresponding lactone which, after crystallization from a mixture of methylene chloride and ether, melts at 170-172, decomposing.



   10 parts by weight of the ethoxy-ethinyl-carbinol described above are dissolved in 76 parts by volume of tetrahydrofuran, cooled with a mixture of ice and water, 4.7 parts by volume of acid are added. sulfuric 2n, and let stand 14 hours at room temperature. 46 parts by volume of a 0.5-n solution of sodium bicarbonate are then added and the tetrahydrofuran is evaporated off in vacuo at room temperature. The residue is taken up in ether and, after stirring the ethereal solution 3 times with saturated sodium chloride solution, then drying, evaporated.

   By crystallization of the residue (10.5 parts
 EMI35.5
 in weight),. q., 6 parts by weight of 4bµ-methyl-1-carbethoxy-methyl-2-carbethoxy-2-carbomethoxymethyl-7-ethylenedioxy-1,2,3,4,4aOE, 4b, 5, 6,7 are obtained ) 8,10,10àj3-dodeoahydrophenanthrene-4-one-1-ol which, after recrystallization, melts at 144-146, without decomposition. The mother liquor contains 4bµ-methyl-1,1-carbethoxymethylene-2-carbethoxy-2-carbomethoxymethyl-7-ethyl enediox, y-1, 2,,., 4aa, 4b, 5, 6, 7, 8 lE , 10aj3-dode cahydrophenanthrene-Q.-oxy.



   0.64 parts by weight of the above-described hydroxy ester, melting at 144-146, is dissolved in 37 parts by volume of pyridine and a mixture of 0 to about 7 is added. 32 parts by volume of thionyl chloride in 3.7 parts by volume of pyridine. The reaction mixture is allowed to stand for 10 to about 10 minutes, poured into 50 parts by volume of ice water which contains 5 parts by weight of sodium bicarbonate, and extracted with a mixture of ether and d. petroleum ether.



  After washing with water, drying and evaporation, 0.6 part by weight is obtained.
 EMI35.6
 4bfi-methyl-1,1-carbethoxymethylene-2-carbethoxy-2-carbomethoxymethyl-7- ethyl enedioy-1 2, 3, 4, 4acx, 4b, 5, 6 i 7 8,10 '10a (3-dodé cahrdrophênanthr ene-Q.-one

  <Desc / Clms Page number 36>

 which is boiled, without purification, for 3 hours, in a mixture of 12.5 parts by volume of methanol, 12.5 parts by volume of water and 1.75 parts by weight of potassium carbonate, whereby the esterified carboxylic groups of the residues in position 1 and 2 are saponified. Concentrate the reaction mixture to approximately half in vacuo and extract with ether (virtually no neutral fractions).

   After acidifying the aqueous alkaline solution, with phosphoric acid
 EMI36.1
 diluted to a pH of 4 to 5, we obtain 4bfi-methyl-1,1-cabboxy-methylene-2-carbethoxy-2-carboxymethyl-7-ethylenedioxy-1,2,3,4,4aa, 4b , 5,6, 7,8,10,10afi-dodecahydrophenanthrene-4-one which, after recrystallization from a mixture of ethyl acetate and petroleum ether, melts at 200.5-208 while decomposing.



   The ester unsaturated in a, ss can be transformed as follows into the corresponding saturated ester:
To 0.1 part by weight of palladium catalyst, previously hydrogenated, in 30 parts by volume of ethanol, 0.5 part is added in
 EMI36.2
 weight of 4b (3-methyl-l, l-carbethoxy-methylene-2-car'bethoy-2-carbetho $ y-2-car'bomethoymëthyl - ethyl enedioxy-., 2, 3, 4, 4aoc, 4b, 5, 6r 7, 8,1Q, lQa3-dodecahy drophenanthrene-4-one and stirred in a hydrogen atmosphere at room temperature.After 12 hours, 25 parts by volume of hydrogen had been absorbed and the hydrogenation was obtained. 'stopped.

   By filtration and evaporation of
 EMI36.3
 solvent, one obtains 4bi-methyl-1-carbethoxymethyl-2-carbethoxy-2-carbo-methoxymethyl-7-ethylenedioxy-1,2,3,4,4aOE, 4b, 5,6,7,8,10,10aµ -dodeaahydrophenanthrene-4-one which no longer shows any absorption in the ultra-violet.



   Example 24
 EMI36.4
 2.2 parts by weight of. 2-formyl-4bfi-methyl-7-ethylene-dioy-1, 2, 3, 4, 4att, 4b, 5, 6,, 8, .0, laa (3-dode cahydrophenanthrene-1-one-4i-ol in a mixture of 20 parts by volume of absolute alcohol and 2 parts by volume of pyridine, and boiled for 10 minutes with 1.32 parts by weight of powdered hydroxylamine hydrochloride, in a bath at 1000 under protection of calcium chloride, the mixture is then evaporated in a vacuum to approximately 3 parts by volume, 60 parts by volume of ice-cold water are added, then filtered off to give 1.325 parts by weight of the isoxazo derivative.
 EMI36.5
 lic (d, l- A 5,6J13,14; 16,17-3-ethylenedioxy-11µ-hydno> gy-15-oxa-16-aza- androstatriene), in the form of a white powder, melting at 218 -220.



  The filtrate is brought to approximately pH 5 with 2n sulfuric acid, then extracted with methylene chloride. The solution in methylene chloride, washed and then dried, leaves, on evaporation, 0.38 part by weight of a residue, from which it is possible to isolate, by crystallization from acetone, another quantity of the compound. described above. The compound recrystallized from acetone, melts at 232-233.5, and shows, in the ultra-violet spectrum, a maximum at 226 m # (# = 5350).



   On treatment with one molecular equivalent of potassium (tertiary) butoxide in tertiary butanol, the compound is converted to
 EMI36.6
 me in 2-cyano-4b (3-methyl-7-ethylene-dioy-1,2,3,4,4aa, 4b, 5,6,7,8,1C? 10a3dodecahydrophenanthrene-1-one-4 # - ol, which can be used in a manner analogous to that indicated in Example 7.



   Example 25
0.4597 part by weight of aldosterone hydrate is dissolved in 70 parts by volume of very pure methanol and mixed with 90 parts by volume of a solution of sodium periodate. (This solution is prepared as follows: 1.25 parts by weight of Na2H3106 are suspended in about 70 parts by volume of water, and sulfuric acid is added.

  <Desc / Clms Page number 37>

 2n with stirring, until clear acid reaction with sunflower, then make up to 100 parts by volume with water). After an hour long needles formed. After standing for two hours, the methanol is evaporated off in vacuo, the residue entered with 100 parts by volume of chloroform and 700 parts by volume of chloroform-ether (1: 3), then two more times, with each times 600 parts by volume of chloroform-ether (1: 3).

   The organic solvents are then washed at approximately 0, twice with 60 parts by volume of a sodium carbonate solution and twice with 60 parts by volume of water, dried over sodium sulphate and then evaporated in the mixture. empty. The neutral, crystalline fraction thus obtained is 0.317 part by weight, it is (20 # 18) - 18,11-cyclo-hemi- acetal lactone / 4-3,18-dioxo-11ss -hydroxyetienic, of formula:
 EMI37.1
 
After recrystallization from acetone, ether, it is obtained in the form of pointed prisms or colorless flakes, melting at 307-313 (by coloring brown); (a) D25 = 121.2 # 2 (c = 0.9154 in chloroform).

   By concentration of the mother liquor, a further amount of the above lactin can be obtained, which after sublimation under 0.03 mm at 192-210 melts at 307-313.



   To isolate the acid formed during the oxidation, the aqueous solutions obtained above are mixed with 0 using sodium carbonate solutions, with 140 parts by volume of 2n sulfuric acid, until hardly acidic reaction in congo, then exhausted three times with each time 700 parts by volume of chloroform-ether (1: 3). It is then washed three times with 50 parts by volume of water each time, dried over sodium sulphate and the solvent is then evaporated off.

   The crystalline residue, 0.045 part by weight, is crude # 4-3,18-dioxo -11ss-hydroxy-ethenic acid, of formula
 EMI37.2
 
On recrystallization from acetone-ether this compound gives short, colorless prisms which, when heated under the microscope, turn about 220-240 to transparent flakes, melting at about 295-303, taking a brown coloring.



  * Demonstration of the formaldehyde formed during the above reaction: The aqueous sulfuric solutions obtained above are brought to a pH of about 5-6 with 20 parts by volume of 2n sodium carbonate solution, then evaporated completely dry, under 80 mm, at 60. The distillate is mixed with 0.5 part by weight of dimedon and 50 parts by volume of crystallizable acetic acid, heated for one hour at 100 and left.

  <Desc / Clms Page number 38>

 rest sixteen hours to about six. After having filtered off, washed with water and dried, 0.066 part by weight of a crystalline product, melting at 192-195, formaldehyde derivative of dimedon is obtained.

   A further quantity of the aqueous acetic solution can be isolated by extraction with ether.
Example 26
Sublime at 210-230 at 0.03 mm, 0.04 part by weight of the acid.
 EMI38.1
 4-3,18-dioxo-llp-hydroxy-ethiene described in Example 25. The sublimate is dissolved in 250 parts by volume of chloroform and 750 parts by volume of ether, and washed with 50 parts by volume 2n sodium carbonate solution, 50 parts by volume of water, 30 parts by volume of 2n sodium carbonate solution, and three more times with 30 parts by volume of water each time. These solutions are further treated each time in a second separating funnel with 400 parts by volume of chloroform-ether.

   The chloroform-ether solutions are combined, dried over sodium sulphate, after evaporation, 0.03 part by weight of re is obtained.
 EMI38.2
 neutral sidu, which is the / -3,18-dioxo-11µ-hydroxy-etienic acid 18,11-hemi-acetal (20 18) -lactone described in Example 25.



    Example 27 j 0.969 part by weight of (20 # 18) - lactone from
 EMI38.3
 18,11-cyclohemiacetal of 4-3,18-dioxo-llp-hydroxy-etienic acid, described in Examples 25 and 26, in solution in crystallizable acetic acid, in the presence of 0.5 part by weight of prehydrogenated platinum oxide.



  After seven minutes, 123.5 parts by volume (calculated 132 parts by volume) of hydrogen had been absorbed, and the hydrogenation ceased. The isolated hydrogenation product (1.02 parts by weight) consists primarily of colorless flakes, melting at 222-265 (on decomposition); it is a mixture of isomers at position 5 of (20 # 18) -lactone of 18,
 EMI38.4
 3,113dihydroy-18-oxo-etianic acid 11-cyclohemiacetal, of the form:
 EMI38.5
 By treating this compound with acetic anhydride-pyridine, one obtains
 EMI38.6
 3-acetoxy-II-hydroxy-18-oxo-etianic acid (20 - 18) -lactone of 18,11-cyclohemiacetal, which crystallizes in methanol in flat needles, melting at 218-225;

     ([alpha]) D25 = 0 (c = 0.5246 in chloroform) -
The non-acetylated mixture can be converted to the known 3,11-diketo-alloetianic acid methyl ester as follows:
1.02 parts by weight of the above hydrogenation product is heated for thirteen and a half hours at 148, in a sealed tube evacuated, in a mixture of 3 parts by volume of. hydrazine hydrate with a solution of 3.55 parts by weight of sodium ethoxide in 50 parts by volume of ethanol. By isolating the reaction product, 0.3 part by weight of neutral fraction and 0.78 part by weight of acid fraction are obtained.

   The latter provides, after crystallization from acetone-ether, 0.36 part by weight of (18 # llp) -lactone of 3ss- acid.
 EMI38.7
 llp-dihydroxy-alloetianic-18-olque, of formula

  <Desc / Clms Page number 39>

 
 EMI39.1
 which melts at 270-275 (decomposition). Another 0.11 part by weight, melting at 252-268 (decomposition), is obtained from the mother liquor of the acid.



  The remainder of the acidic fraction (0.32 part by weight) is amorphous.



   The amorphous acid (0.32 part by weight) is esterified with diazomethane, and the methyl ester thus obtained, in solution in crystallizable acetic acid, is oxidized with 0.2 part by weight of trioxide. of chrome. After two hours, the oxidation is stopped, the reaction product is isolated and the crude product is chromatographed on 30 parts by weight of aluminum.

   From the crystallized fractions, after recrystallization from ether-pentane, crystals melting at 205-212, which are identical to the known methyl ester of 3,11-dioxo-alloetianic acid, are obtained.
From the neutral fraction, the (20 # 18) -lac- toue of 3ss, 11ss-18-trihydroxy-alloetianic acid can be isolated with the formula:
 EMI39.2
 
Example 28
The (18 # 11ss) -lactone of 3ss, 11ss-dihydroxy-alloetianic-18-oic acid obtained in Example 27 (0.47 part by weight) is esterified with diazo-methane. recrystallizes the crude product from a mixture of acetone and ether.

   The methyl (18 # 11ss) -lactone of 3ss, 11ss-dihydroxy-18-oic -alloetianate thus obtained, of formula
 EMI39.3
 bottom at 232-236; (a) D25 = + 81.5 6 (c = 0.362 in chloroform).



   0.35 part by weight of the above estermethyl lactone is dissolved in 40 parts by volume of very pure crystallizable acetic acid.

  <Desc / Clms Page number 40>

 
 EMI40.1
 7 parts by volume of a 2% solution of chromium trioxide in crystallizable acetic acid are added 3 After two hours (a little chromium trioxide can still be detected in the reaction solution), the oxidation is stopped by addition of methanol, water is added, and the oxidation product is isolated by extraction with chloroform-ether.

   This
 EMI40.2
 product crystallizes from aceton-ether-pentaria in hexagonal flakes (0.28 part by weight) and melts at 209-211; [aJn5 = + 1Ql z '8 (c = 0.2523 in chloroform); it is the (18 ---? ll \ 3) -lactone of the 3-oxo-11µ-hydroxy-18-oic-allo-6tianate of methyl, of formyl:
 EMI40.3
 
 EMI40.4
 The above 3p-hydroxy methyl ester, γ - lactone provides, on acetylation with acetic anhydride-pyridine, the (18 µp) -lactone of 3p-acetoxy-3lµ-hydroxy-18-oiane-alloetanate. methylo It crystallizes in m- -lh ?, nol-acetone, in the form of rhombohedral flakes that melt at 194-195 (a) D26 = + 64.1 (c = 0.4836 in chloroform);

   
Example 29
0.1267 part by weight of aldosterone monoacetate, melting at 190-192, is dissolved in 12 parts by volume of crystallizable diacetic acid, and 1 part by volume of 2% solution of chromium trioxide is added.
 EMI40.5
 in acetic acid crystallisaôleo After fifteen minutes, the chromium trioxide is consumed, and 1 part by volume of the same solution is added once again:

   After three and a half hours, a little methanol is added to the reaction solution, left to stand for a further hour, then evaporated at 30; In vacuo, the residue is taken up in chloroform-ether (1: 3), washed twice at 0, each time with 15 parts by volume of normal sodium carbonate solution, and twice with 10 parts each time. - parts by volume of water; the chloroform-ether solution is dried and then evaporated in vacuo. The neutral fraction is recrystallized twice from acetone-ether, then washed with ether and pentaneo La (18 # 11ss)
 EMI40.6
 -lactone of 4-3,20-dioxo-11µ-hydroxy-21-acetoxyprégnene-18-oîgue thus obtained crystallizes in colorless flakes partially also in druses)
 EMI40.7
 it melts in 187-190.

   After recrystallization from chloroform-ether,
 EMI40.8
 this compound melts at 198-199 (flat needles); ia-1 26 = + 12 (c = 0.6186 in chloroform). 8-. o
To saponify the acetate group, 0.63 part by weight of the above compound is dissolved in 100 parts by volume of methanol, add a

  <Desc / Clms Page number 41>

 solution of 0.7 part by weight of potassium bicarbonate in 24 parts by volume of water, and left to stand for forty-eight hours at 18, After acidification with dilute hydrochloric acid, extraction is carried out with chloroform - ther ( 1: 3), wash the extract with water, sodium bicarbonate solution, and again with water, then, after drying, the solvent is evaporated in vacuo.

   The neutral fraction thus obtained amounts to 0.35
 EMI41.1
 part by weight is the (18,111) -laotone of A4-3,20-dioxo-11p-21-dihydroxypregnene-18-olque acid. After recrystallization from acetone-ether, it forms small grains melting at 203-218.,
For the oxidative cleavage of the ketol group, 0.58 part by weight of this compound, melting at 203-218, is dissolved in 60 parts by volume of methanol, 120 parts by volume of a solution of sodium periodate are added. , prepared as indicated in Example 25 and left to stand for a quarter to 20 hours. The reaction mixture is then made weakly acidic in congo and extracted with chloroform-ether (1: 3).

   After washing with a dilute solution of sodium carbonate, and with water, drying and then evaporating the solvent, 0.3 part by weight of a neutral fraction is obtained. To obtain the acid formed during the oxidation, the solutions obtained are acidified with sodium carbonate solutions and extracted with chloroform-ether (1: 3). The chloroform-ether solution washed with water gives , after drying and then evaporation, 0.28 part by weight of the
 EMI41.2
 4l 4-3-oxo-11 (3-hydroxy-etienic-18-.occus (# 113) -lactone, the lormule:
 EMI41.3
 which, after crystallization from acetone-ether, is obtained in the form of fine grains, melting at 310-320.

   By methylation with diazomethane and recrystallization from aoetone-ether, the corresponding methyl ester is obtained, melting at 219-225 (prisms).



   The above acid, melting at 310-320, can be hydrogenated according to the indications of Example 27, thus obtaining (18 # 11ss) -
 EMI41.4
 3µ-Liµ-dihyàroxy-alloétianigue-18-oic acid lactone, melting at 270-275 (decomposition) described in Example 270
0.17 part by weight of the (18 = 11μ) -lactone of the
 EMI41.5
 A 4-3-oxo-ll (methyl-18-olque 3-hydroxy-etianate, described above, melting at 219-225, in 150 parts by volume of crystallizable acetic acid and it is hydrogenated in the presence of 0.15 part by weight of platinum oxide at 22. After stopping the hydrogenation, the catalyst is removed by filtration, the filtrate is evaporated in vacuo and the residue is taken up in chloroform-ether (1 : 3).

   The chloroform-ether solution is then washed twice with water, dried and then evaporated in vacuo. The crude residue is 0.17 part, by weight and melts at 210-230, after recrystallization in 1. acetone-ether. By further recrystallization the melting point rises to 232-236 o This compound is identical to (18 # 11ss) -
 EMI41.6
 Lactone of 3 (3,11 (3-dihydrog, methyl-18-methyl-γ-alloetianate, described in Example 28.



   Example 30
0.7 part by weight of aldosterone hydrate is dissolved in 70 parts by volume of methanol, and 128 parts by volume of sodium periodate solution (prepared as indicated in Example 25) are added.

  <Desc / Clms Page number 42>

 



  The repair of crystalline needles already begins after a few minutes. After two hours, the methanol is removed in a vacuum at 20. 2n sulfuric acid is then added to 0, until the reaction is just discernible in congo, then extracted three times, each time with 1000 parts by volume of chloroform-ether (1: 3) (for the treatment of aqueous phase see below). The three extracts are washed separately, each time with the following quantities: 100 parts by volume of water, 100 parts by volume of solution, 0.2n of sodium carbonate, 50 parts by volume of water 100 parts by volume of sodium carbonate solution and twice, each time with 50 parts by volume of water. Solutions dried over sodium sulfate give on evaporation 0.67 part by weight of neutral fraction.

   The aqueous and sodium extracts are acidulated with sulfuric acid, then extracted with chloroform-ether (1: 3), (see treatment of the acidic aqueous phase below). The extracts washed with a little water and then dried over sodium sulphate, give by evaporation, 0.04
 EMI42.1
 part by weight 4-3,18-aioxo-11fi-hydroxy-etienic aid (see example 24).



   The neutral fractions (0.67 part by weight) give, in ac-
 EMI42.2
 tone-ether, 0.45 part by weight of the (20.,18j3) -lactone of the 18,11-cyclohemiacetal of 4-3,18-ioxo-llfi-hydroxy-etienic acid described in the example 25, melting at 309-315 (decomposition). The mother liquors still give some of the same compound after distillation in a flask for molecular distillation, or after chromatography on alumina.



   Demonstration of the formaldehyde formed during the oxidation: the two acidic aqueous phases extracted with chloroform-ether are combined, they are brought to pE 5 with sodium carbonate, and they are distilled to dryness under 80 mm, at 60 temperature de baino The distillate is mixed with 0.5 part by weight of dimedon and 30 parts by volume of crystallizable acetic acid, heated for one hour at 100, then left to stand for 12 hours at 0.

   It crystallizes 0.066 part by weight of needles melting at 192-194. The mother liquor is exhausted with ether, the solution is evaporated, washed with a little water and dried over sodium sulfate, and The residue is chromatographed on 20 parts by weight of magnesium silicate Kieselgur (Celite # 545) (2: 1). The fractions eluted with benzene (0.08 part by weight) give, in ether-pentane, a little more of the formaldehyde-dimedon compound (melting point about 180). The fractions eluting with benzene-ether and the pure ester give free dimedon (melting point 130-135).



   The combined crystals of the formaldehyde compound are sublimated in a flask for molecular sublimation at 105-115, under 0.02 mm.



  The sublimate in ether-pentane gives crystals melting at 192-194. Formaldehyde-dimedon and a mixed sample melt at the same temperature. The infrared spectra are also the same.



   Example 31
6.9 parts by weight of crude aldosterone hydrate are dissolved in 600 parts by volume of methanol and left to stand for one and a half hours with 1200 parts by volume of sodium periodate solution.



  After having isolated the reaction product as indicated in the examples
 EMI42.3
 Ples 25 and 30, 2.1 parts by weight of A 4-3,18-dioxo-ll-hydroxy-etienic acid and 3.78 parts by weight of neutral fraction are obtained. The latter gives, in acetone-ether, 0.47 part by weight of (20 # 18) -
 EMI42.4
 A 4--3,18-diogo-11 (3-etene) 18,11-cclohemiacetal lactone, m.p. 285-305 (decomposition).



   We obtain in a similar way, from 19.5 parts in

  <Desc / Clms Page number 43>

 weight of crude aldosterone hydrate, 9.6 parts by weight of ± 4-3,18-dioxo-11p-hydroxy-etienic acid described in Example 25 and 7.6 parts by weight of neutral fraction. The latter provides in acetone-ether,
1.5 parts by weight of the lactone described above, melting at 303-312 (decomposition).



   The lactone mother liquors from these two tests are distilled in a molecular distillation flask at 0.02 mm. The fractions pass at a bath temperature of 195 are discarded. The distillate obtained from 195-230 still gives, in acetone-ether, about 0.07 part by weight of crystallized lactone, melting at 275-295. - Ohromatography of the remaining mother liquors on alumina (free of alkali) still provides traces of crystalline lactone from the eluitable fractions with petroleum ether-benzene, as well as with pure benzene.



   The not quite pure fractions of the crystallized lactone are sublimated in a flask for molecular sublimation, at 0.02 mm and
210-230 bath temperature The sublimate immediately gives pure crystals in acetone-ether. Melting point 307-311 (decomposition).



   Example 32
0.19 part by weight of aldosterone hydrate is dissolved in 5 parts by volume of pure crystallizable acetic acid, and mixed with 1.65 part by volume of a 2% solution of chromium trioxide in. crystallizable acetic acid (= 0.033 part by weight of chromium trioxide).



  A yellow-brown precipitate (chromium trioxide complex) is immediately produced which only gradually dissolves. The chromium trioxide is consumed after about two minutes, then 4 more equal portions of chromium trioxide solution are added (therefore in total 0.165 part by weight of chromium trioxide: 5.0 equivalents).



   The first is consumed after five minutes, the second after ten minutes and the third after forty-five minutes, while the fourth is no longer consumed after another hour and a half. It is then evaporated in a vacuum at 30, mixed with water and 10 parts by volume of 2n sulfuric acid, then exhausted with chloroform-ether (1: 3). The separation is analogous to what is indicated in Examples 25 and 30. It gives a trace of acid fraction and 0.18 part by weight of neutral fraction, which gives, in acetone-ether, 0.09. part by weight of colorless kernels, melting at 298-3100. This compound is also allowed to sublimate under 0.01 mm, at 200-230, without decomposing. From the melting point of a mixture and from the chromatogram on paper, it is identical to the lactone described in Examples 25, 30 and 31.

   The polarity in Bush's B5 system is roughly equal to that of adrenosterone, or lower. Using the formamide-cyclohexane-benzene- (1: 1) system at 40, RF = 0.34 (adrenosterone RF = 0.59).



   Example 33 0.73 part by weight of 21-monoacetyl-aldosterone, melting at 198-199, is dissolved in 70 parts by volume of very pure crystallizable acetic acid, and 5.3 parts by volume of solution are added to 2% chromium trioxide (= 0.11 part by weight of chromium trioxide) which is consumed after twenty five minutes at 20. Once again 3 parts by volume of the same solution (= 0.06 part by weight of chromium trioxide) are added which are also consumed after another forty five minutes. A third addition of 3 parts by volume (= 0.06 part by weight) is not consumed after another one and a half hours. 3 parts by volume of methanol are added and left to stand for two more hours.

   By isolating the reaction product according to the indications of Example 30, no frac is obtained, -

  <Desc / Clms Page number 44>

 % acid ion, but 0.73 part by weight of crude, neutral product. In acetone ether, 0.64 part by weight of crystals melting at 196-199 and 0.01 part by weight melting at 194-197 are obtained. Recrystallization from acetone-ether gives long hexagonal flakes. melting at 198-200 a new reoristallization in methanol-ether gives 0.55 part by weight of hexagonal flakes (partially limited in rhombs), melted
 EMI44.1
 from 193-194;

   (a] 4 = + Il T 2 0 3 (c = 0.6186 in chloroform) Reduction test: positive; absorption in ultraviolet: positive; in the chromatogram on paper (propylene glycol-toluene), this compound
 EMI44.2
 migrates, as 11-dehyàro-21-aeétyl-cortieosteroneo This compound is the (18 llp) -lactone of 4l 4-3,20-dioxo-llfl-hyàroxy-21-acetoxy-pregnene-18-oic, described in Example 29.



   Example 34
2.01 parts by weight of the (2 -718) -lactone of the
 EMI44.3
 4 4-3,18-dioxo-11-hydroxyetienzic acid 18,11-cyclohemiacetal, melting at 304-310 (decomposition), in 200 parts by volume of crystallizable acetic acid, with 0.175 part by weight of prehydrogenated platinum dioxide. The absorption of hydrogen is complete after fifty minutes (consumption of 330 parts by volume of hydrogen at 22.4, under 731 mm, corresponding to 2.14 mol). The crude hydrogenation product is allowed to stand for sixteen hours at 20 in 20 parts by volume of acetic anhydride and 30 parts by volume of absolute pyridine.

   It is then evaporated in a vacuum at 40, taken up in chloroform-ether (1: 3), washed with each time 30 parts by volume of dilute hydrochloric acid, water, potassium bicarbonate solution and water ( 2 times), dry over sodium sulphate then evaporate. The residue (2 parts by weight) in a little acetone ether (about 1:10) gives 0.8 part by weight of fine needles, melting at 199-220.

   Purification is most successful by dissolving in acetone-ether (1: 1), adding methanol and high concentration; Almost pure methanol remains 0.42 part by weight of flat needles, turning into thin, long needles, around 219, melting point 222-226 a This compound is (20 # 18) -lactone of 18,11-cyclohemia-
 EMI44.4
 3i-Acetoxy-Ilihydroxr 18oxoetianic acid ketal, described in Example 27.



   Example 35
0.92 part by weight of (20 # 18) -lactone, described in Examples 27 and 34, of the invention is heated at 100 for an hour and a half.
 EMI44.5
 3p-acetoicy.-ilp-hydroicy-18-oxo-etianic acid 18,11-cyclohemiacetal, melting at 218-225, with 12 parts by volume of hydrazine hydrate in a small sealable tube, of first open. The solution of 3.25 parts by weight of sodium ethoxide in 50 parts by volume of ethanol is then added, sealed under 80 mm of pressure and heated for fourteen hours at 151.



  After cooling, the alcohol is removed in vacuo, the residue is mixed with a little water and exhausted three times, each time with 1000 parts by volume of chloroform-ether. The extracts, washed with water and then dried over sodium sulphate, leave 0.08 part by weight of residue by evaporation (neutral fraction).



   The aqueous phase and the washing waters are brought to pH 1 with hydrochloric acid, to 0, and then exhausted again 3 times with chloroform-ether (1: 3). These 3 extracts are washed against the current with. following each other with each time 30 parts by volume of the following solutions: water, 2n sodium carbonate solution, water, 2n sodium carbonate solution, water, water o It is dried over sodium sulfate, then evaporated ;

   we obtain 0.14 part by weight of the residue of (20 # 18) -
 EMI44.6
 lactone, 3p, 11fl-18-trihyàroxy-alloetianic acid, described in example

  <Desc / Clms Page number 45>

 ple 27, which partially crystalline
The sodium carbonate extracts and the washing water are combined, hydrochloric acid is added to 0 until an acid reaction in congo, then the mixture is exhausted again with chloroform-ether. The extracts washed with water and dried over sodium sulfate give no evaporation.
0.67 part by weight of residue (acid).

   Separation of acids: the mixture of acids (0.67 part by weight) gives in acetone-ether two fractions of a total of 0.45 part by weight of crystals melting at 251-268, and as a third fraction, 0 0.5 part by weight, mp 235-265 ° As purification is not easily successful here, the combined crystals (0.5 part by weight) are esterified as well as the product contained in the mother liquors ( 0.17 part by weight) with diazo methaneo
Crystallized acids (0.5 part by weight) give 0.51 part by weight of crude methyl ester. Recrystallization from acetone, ether provides a mixture of coarse prisms and fine needles. These can be separated using ether-pentane.

   By careful fractionation and further crystallization, 0.17 part by weight of coarse prisms, melting at 232-237, of (18 # 11ss) -lactone of 3ss-acid, 11ss-methyl-dihydroxy-alloetianate, is obtained. 18-olque described in Example 28 The remaining mother liquors (0.34 part by weight) are combined with the mixture of methyl esters (0.18 part by weight) of the 0.17 part by weight of the mother liquors crystallized acid This product (0.52 part by weight) is used for acetylation (see below).



   .



   The above methyl ester (0.17 part by weight), melting at 232-237, is left to stand, with 1.5 part by weight of absolute pyridine and 1 part by weight of acetic anhydride, for sixteen hours. to 20.



  By isolating the reaction product in the usual manner, 0.18 parts by weight of crude product are obtained. In a little acetone with ether, crystals melting at 185-194 are obtained; in a little methanol, hexagonal blades melting at 194-195 of (18 # 11ss) -lactone of methyl-18-oic-3ss-acetoxy-11ss-hydroxyalloetianate.



   Separation of the methyl ester mother liquors: The methyl ester mother liquors (0.52 part by weight) are acetylated as above and the acetate mixture is chromatographed (0.56 per- , tie by weight), on 50 parts by weight of alumina.



   Fractions 1 to 12 (eluted with petroleum ether-benzene up to 50% benzene content) give only little residue, and at most traces of crystals.



   Fraction 15 (eluted with pure benzene) gives in ether pentane a few flat, doubly pointed needles of a by-product melting at 198-201. The mother liquor is combined in fractions 13-14 and gives in a little ether with pentane, a little more square, thick plates, melting at 182-185.



   Fractions 16 to 18 (eluted with pure benzene as well as with benzene-ether (95: 5)) give, in ether-pentane, 0.018 part by weight of pure (18 # 11 (3) -lactone of Methyl-18-oic-3ssacetoxy-11ss-hydroxy-alloetianate, m.p. 190-195, and from the wastes a further bit of the same compound, m.p. 180-191.



   Fraction 19 gives a bit of a mixture of crystals, melting at 172-186.



   Fractions 20 to 26 (eluted with benzene-ether at 10-50% ether content) give, in ether-pentane, 0.097 part by weight of methyl 3ss-acetoxy-11ss-hydroxy-alloetianate, melting at 193 -202 and, at

  <Desc / Clms Page number 46>

 from the mother liquor, another 0.083 part by weight of the same compound melting at 188-200 0
Example 36
Was heated at 100 for two hours, 1.91 parts by weight of a
 EMI46.1
 mother liquor of 3µ-acetoxy-11J-hydnoxy-18-oxo-etanic acid (20 ---> 18'-laoton pure 18,11-cyclohemiacetal) with 30 per - parts by volume of hydrazine hydrate, add 7.4 parts by weight of sodium ethylate in 100 parts by volume of ethanol, then heat seventeen hours to 151, isolating the reaction product as described above. indicated in Example 35, we get 0,

  45 parts by weight of neutral fraction, 0.44 per-
 EMI46.2
 weight of the (20 --- 18) -lactone of 3P-11p) 18-trihydroxy-al-loetianic acid, described in Example 27, and 0.85 part by weight of acids. The 0.87 part by weight of acids (0.93 part by weight) and acetyl (1.02 part by weight) are methylated. This material is chromatographed on 100 parts by weight of alumina (40 fractions).



   From fractions 13 to 24, 0.27 part by weight of (18 # 11ss) is obtained
 EMI46.3
 -Aeide3 crude lactone (3-acetoxy 113 - ^> ydroxysalloé, methyl-18- ofque anate, milling 185-193.



   Fractions 25 to 27 sleep some (18 # llp) -lactone impu-
 EMI46.4
 re of methyl-18-oic 3p-acetoxy-llp-hydroxy-alloetianate melting at 182-192.,
 EMI46.5
 Fractions 28-38 give G. 16 parts by weight of pure methyl 3 (3-acetoy-11-h-vdroxy-allcâtianatr, mp 192-1990.



  Example 37 0.58 part by weight of the (20 ----> 18'-lactone of 3p, 11p, 18-trihydroxy-alloetianic acid, described in Examples 25, 35 and 36, is dehydrogenated with trioxide. chromium in crystallizable acetic acid, until no more 20 chromium trioxide is consumed.

   By isolating the reaction product in the usual manner, 0.44 part by weight of crude neutral product is obtained, which is chromatographed on 30 parts by weight of alumina. The fractions eluted with ether-methanol (8-50% methanol content) (0.04 part by weight) crystallize.
 EMI46.6
 lizations in acetone-ether yield fine, colorless needles, united in druses, melting at 275-290 (with transformation into coarse needles), of (20-- 18 µm. 3,11-dî.ozo- acid actone). l6-hydroxy-al-loetianic of the formula:

   
 EMI46.7
 Example 38
 EMI46.8
 0.112 part by weight of the 1R 11j3j-lacton described in Example 29, A -3.25-ioxo-11 @ -21-alihyàroxy-pregnene-18-oic acid, is dissolved in 100 parts by volume of ethylene dichloride. After addition of 0.05 part by weight of p-toluenesulfonic acid and 5 parts by volume of pure ethylene glycol, the ethylene dichloride is slowly removed by distillation.

   By continuous addition of new sol-

  <Desc / Clms Page number 47>

 Before, the volume of the reaction solution is kept constant. After four hours, the contents of the flask are treated, twice, with each fcis
 EMI47.1
 100 parts by volume of a 1% solution of ca = 1: sodium content and twice each time with 100 parts by volume of water, the organic solution is dried, then evaporated in vacuo, The residue is : la (18 # 11 (3) -lactone
 EMI47.2
 of 1 5-3, 20-diethylenedioYy-ll, 21-dïryfirogyprégnanel8-oic acid, which is dissolved, without purifying it, in 500 parts by volume of tetrahydrofuran.

   After cooling to -10 to -15, a tetrahydrofuran solution of lithium aluminum hydride, which is calculated for the reduction of the lactone group to a hemiacetal group, is added with stirring. The cooling bath is then removed and the cooling bath is left. temperature rise to around 20. The tetrahydrofuran sol'ion is diluted with 500 parts by volume of ether, then washed successively with 0.1 times normal sulfuric acid and water, dried, then evaporated in the video.
 EMI47.3
 purification of 5.-3,20-diethylenedioxy-113,21-dihydroy-18oo-pregnene
 EMI47.4
 crude, of formula: CH20H OH CH20H OH j 2 CEOE iiī CHO C / 1 0] 0- CR 1 Q - 0] HO- '0 4 - "CH" "0 HJ3') H3C e- v -¯e without purification, in 50% acetic acid, then let stand overnight at about 20.

   The reaction mixture is extracted twice with 500 parts by volume of chloroform-ether (1: 3) each time, the extracts are washed twice, each time with 100 parts by volume of water, dried over sodium sulfate. then evaporates in the video From the crude product thus obtained, we can extract 1 aldosterone, by chromatography.
If, in the above reduction, an excess of lithium aluminum hydride is used, after cleavage of the ketal there is obtained the
 EMI47.5
 A 4-3,20-dioxo-llfl, 18,21-tni-hydroxy-pnégnèn? (18-hydroxy-cortioosterone),
 EMI47.6
 of formula; CH2OH 1 CH OH Go HO H30

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


    

Claims (1)

CLAIMS. 1) A process for the preparation of oxygenated steroids, characterized in that one condenses intramolecularly, by reaction of the substituent R6 with the methylenic group attached to the carbon atom 2, saturated or unsaturated compounds of the formula: <Desc / Clms Page number 48> EMI48.1 .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 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 free or functionally modified hydroxymethyl group, and finally R6 an oxygenated methyl or ethyl group, free or functioning modified , The present invention can also be characterized by the following points: 1) In the compounds formed, the; substituent R4 in a free or functionally modified aldehyde group, provided that said substituent is convertible into such a group. 2) As starting materials, compounds of the formula given under I) in which R 6 represents an esterified hydroxymethyl group capable of reacting are used. 3) As starting materials, compounds of the formula given under I) in which R6 represents an aldehyde group are used. 4) As starting materials, compounds of the formula given under I) in which R6 represents an esterified carboxylic group are used. 5) In the steroid compounds formed, a double bond in position 16,17a is saturated with hydrogen. 6) In the steroid compounds formed, an oxo group in position 16 is replaced by hydrogen. 7) Starting substances of the formula given under I) in which R1 represents a ketalised oxo group, and which have a double bond in position 8a, 9 II) As new industrial products: 8) The compounds obtained by carrying out the process mentioned under I) 1-7. 9) Steroid-17-carboxylic acids oxygenated at 3 and their functional derivatives, the remainder of which in position 13 represents a free or functionally modified al-dehyde group, or else a residue convertible into such a group. <Desc / Clms Page number 49> EMI49.1 10) 16-oxo-steroid-17-carboxylic acids oxygenated at 3 and their functional derivatives, the residue of which at position 13 represents a free or functionally modified aldehyde group, or a residue which can be transformed into such a group. EMI49.2 II) Steroid-17-carboxylic acids dioxygenated in 3,11 and their functional derivatives of which the remainder in position 13 represents a free or functionally modified aldehyde group, or a residue convertible into such a group. 12) Saturated and unsaturated 18-oxo-etianic acids, 3,11-dioxygenated and their functional derivatives. EMI49.3 13) A 4-3-oxo-llP-hydroxy-etienic acids and their functional derivatives, the residue of which at position 13 represents a free or functionally modified aldehyde group, or a residue convertible into such a group. EMI49.4 14) α -3, 18-dioxo-ll (3-hydroxy-etienic acid and its functional derivatives. 15) Saturated and unsaturated etien-18-oic acids, dioxy. generated in 3.11, and their functional derivatives. 16) Saturated and unsaturated 16-oxo-etianic-18-oic acids, (14-oxygenated in 3.11, and their functional derivatives. 17) Saturated and unsaturated (18 # 11 (3) -lactones of llp-hydroxy-etianic-18- oic acids, oxygenated in 3, and their functional derivatives EMI49.5 18) (18 llj3) -laotone from A 4-30o $ o-11 (3-hydroy-etene-18-orca and its functional derivatives. 19) The (18 - r Ilp) -laotone of A 4-3,16-dioxo-llp-hydro-xy-etien-18-oic acid and its functional derivatives. 20) Steroids-17-aldehydes oxygenated in 3 and their functional derivatives of which the remainder in position 13 represents a free or functionally modified aldehyde group, or a residue convertible into such a group EMI49.6 21) The steroids-17-aldehydes unsaturated in 16,17 and oxygenated in 3, and their functional derivatives of which the residue in position 13 is a free or functionally modified aldehyde group, or a residue convertible into such a group. 22) Steroid-17-aldehydes dioxygenated in 3,11 and their functional derivatives of which the residue in position 13 is a free or functionally modified aldehyde group, or a residue transformable into such a group. EMI49.7 23) Ô-3-oxo-lip-hydroxy-androstene-17-aldehydes and their functional derivatives of which the residue in position 13 is a free or functionally modified aldehyde group, or a residue convertible into such a group. EMI49.8 24) (18-3 11 (3) -lactone duA 4¯3-oxo-llp-hydroxy-androstene-17-aldehyde-18-01 as. 25) Saturated and unsaturated compounds of pregnane, dioxygenated at 3.20 and unsubstituted at 21, and their functional derivatives of which the residue in position 13 is a free or functionally modified aldehyde group, or a residue convertible into such a group. 26) Saturated and unsaturated compounds of 16-oxo-pregnane, dioxygenated at 3.20, and their functional derivatives, the remainder of which is in position 13 <Desc / Clms Page number 50> is a free or functionally modified aldehyde group, or a substituent convertible into such a group. 27) Saturated and unsaturated compounds of pregnane, unsaturated at 16.17, and dioxygenated at 3.20, and their functional derivatives whose remainder in position 13 is a free or functionally modified aldehyde group or a transformable residue in such a group 28) Saturated and unsaturated compounds of pregnane, trioxygenated in 3,11,20 and on-substituted in 21, and their functional derivatives of which the residue in position 13 is a free or functionally modified aldehyde group, or a residue transformable into such a group 29) Ballast, saturated and unsaturated compounds of 18-oxo-pregnan, trioxygenated in 3,11,20 and unsubstituted in 21, and their functional derivatives. EMI50.1 30) The 6 4-3,20-dic> xo-llp-hyeo3rj-pregnenes unsubstituted in 21 and their functional derivatives of which the residue in position 13 is a free or functionally modified aldehyde group, or a residue convertible into such a group . EMI50.2 31) 6 4-3,18,20-trioxo-III-hydroxy-pregnene and its functional derivatives. 32) Saturated and unsaturated pregnan-10-oiques, trioxygenated in 3,11,20, and their functional derivatives. EMI50.3 33) Saturated and unsaturated (18 - g> 11 (3) -lactones of lli-hydroxy-prégriane-18-oiques, dioxygenated in 3.20, and their functional derivatives 34) La (18 -> llp ) -lactone of 4-3,20-diogo-lli-hydxoxy-pregnene 18-o3que and its functional derivatives o 35) La (18 # 11 (3) -1.actone of 4,16¯3 20-dioxo-llp- hydroxy, -pregnacliene-18-oic and its functional derivatives 36) .4 3,18r20-triogo-lli hydror-pregnene and its functional derivatives. 37) Saturated and unsaturated compounds of 18-hydroxy-pregnan, trioxygenated in 3,11,20, and their functional derivatives. EMI50.4 38) & 4-3.2Q-dioxo11.1 $ -dihydroxy-pregnene and its functional derivatives. 39) Saturated and unsaturated compounds of 16-ogo-21 hydroxy-pregnan, dioxygenated in 3.20, and their functional derivatives of which the remainder in position 13 is a free or functionally modified aldehyde group, or a transformable residue in such a group EMI50.5 40) 21-hydroxy-pregnan compounds unsaturated in position 16,17, dioxygenated in 3.20, and their functional derivatives of which the remainder in position 13 is a free or functionally modified aldehyde group, or a residue convertible into such a group 41) Saturated and unsaturated compounds of 21-hydroxy-pregnan dioxygenated in 3.20, and their functional derivatives of which the residue in position 13 is a residue convertible into a free or functionally modified aldehyde group. 42) Saturated and unsaturated compounds of 21-hydroxy-pregnane, trioxygenated in position 3,11,20 and their functional derivatives, the remainder of which in position 13 is a residue which can be transformed into a free or functionally modified aldehyde group. EMI50.6 43) The 6.4-3520-cliozo-llg521-dihydroxy-pregnenes, the remainder of which <Desc / Clms Page number 51> at position 13 is a residue convertible into a free or functionally modified aldehyde group. EMI51.1 44) Saturated and unsaturated 21-hydroxy-pregnane-18-oiquex, trioxygenated in 3,11,20, and their functional derivatives. 45) Saturated and unsaturated (18 --113) -lactones of saturated and unsaturated 11,21-dihydroxy-pregnan-18-oques, dioxygenated in 3.20, and their functional derivatives. EMI51.2 46) The (18 -? 11 (3) -lactone of α -3,20-dioxo-III-21-dihydxoxy pregnene-18-oic and its functional derivatives. 47) Saturated and unsaturated compounds of 18,21-dihydroxy-pregnan, trioxygenated in 3,11,20 and their functional derivatives. EMI51.3 48) 4 4-3 20-dixo-lli, 18, 21-trihydro, p-prêgnene and its functional derivatives.