AT210575B - Process for the preparation of 11β-oxy-16-oxo-steroids - Google Patents

Description

  

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 EMI1.1
 
 EMI1.2
 wherein R represents a free or esterified oxy group or a protected oxo group, R2 represents a free or esterified B-position oxy group, in the 2-position with a compound of the formula
Halogen-CHz-Y disubstituted, in which Y represents a free or functionally modified carboxyl or acetyl group together with -CH- or an allyl, methallyl or propargyl radical, in the compounds obtained with the following partial formula of ring C
 EMI1.3
   In any order, if necessary, the substituents -CH-Y in the 2-position are converted into acetic acid, acetaldehyde or acetonyl radicals, the 8-position substituent in the 2-position reacts with the oxy group in the 4-position,

   if necessary converts the a-position substituent in the 2-position into an acetonyl radical and condenses this with the keto group in the 1-position to form a 5-membered ring.



   The starting materials are accessible in a totally synthetic way. Process for the production of llss-oxy-16-oxo-steroids

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 EMI2.1
 
 EMI2.2
 
2-position where the halogen atom can also be represented by a so-called pseudohalogen, namely one with aliphatic or aromatic sulfonic acids, e.g. B. methanesulfonic acid or p-toluenesulfonic acid esterified oxy group. The group Y is a free or functionally modified carboxyl or acetyl group or together with —CH2— an allyl, methallyl or propargyl radical.



   . The substitution in the 2-position can also take place in stages by z. B. first converts the above-mentioned starting material into the corresponding β-keto acid ester, introduces the acetic acid or acetonyl radical or in particular the allyl, methallyl or propargyl radical into this and then, after hydrolysis and decarboxylation in the monosubstituted ketone thus obtained, the second substituent in 2- Introduces position. Another possibility for the gradual substitution consists in first converting the starting ketone into the corresponding enamine and then substituting this with or without the addition of condensing agents. The monosubstitution product obtained in this way can then be further substituted as indicated above.



   The substitution in the 2-position is carried out under the conditions customary for the substitution of ketones or β-dicarbonyl compounds, ie. H. in the presence of alkaline condensing agents, such as alkali metal alcoholates, amides or hydrides, or in the presence of quaternary ammonium bases, such as the product available under the brand name Triton B, carried out.



   In the compounds obtained with the following partial formula of ring C
 EMI2.3
 the optionally allyl, methallyl or propargyl radicals representing substituents -CHzY in the 2-position are then converted into acetic acid or acetonyl radicals. In the case of the allyl and methallyl radicals, this is done by oxidative cleavage of the double bond, e.g. B. by direct hydroxylation with osmium tetroxide or by epoxylation with peracids and hydrolysis and subsequent glycol cleavage with lead tetraacetate or periodic acid, by ozonation and cleavage of the ozonides and optionally oxidation of an aldehyde obtained to the acid, or by oxidation with potassium permanganate. This leads to compounds in which Y is a carboxyl, formyl or acetyl group.

   A propargyl radical in the 2-position can be converted into an acetonyl radical by hydration, in particular in the presence of formic acid or by addition of hypohalous acid and dehalogenation.



   The subsequent process stage consists in the reaction of the ss-position substituent in the 2-position with the free or functionally modified hydroxyl group in the 4-position. Compounds with a free or esterified acetic acid residue in the ss position are obtained by lactonization or transesterification with the substituent R 6-lactone. On the other hand, the carbonyl function of an acetonyl or acetaldehyde radical in the 2-position reacts with Rz to form a hemiketal or hemiacetal, from which water can be split off with the aid of an acid, if this does not happen spontaneously.

   The lactonization, transesterification, hemiketalization and hemiacetalization take place under the conditions customary for these reactions, often spontaneously, by heating or by mild acid catalysis.



   Surprisingly, in the compounds with the following sub-formula of ring C
 EMI2.4
 the 8-position allyl group also selectively, d. H. without the group being attacked, decompose by oxidation. For this purpose, various oxidizing agents such. B. potassium permanganate, compounds

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 of hexavalent chromium, such as chromium trioxide, but particularly suitable for ozone. After the reductive cleavage of the ozonide, an aldehyde is obtained which forms a hemiacetal with the free oxy group in position 4. By oxidation e.g. B. with dichromate you get the corresponding lactone directly.

   If oxidizing agents are used to break down the 8-position allyl group, which also attack free oxy groups, a free oxy group in the 4-position must be temporarily protected by esterification. The conversion of the a-position allyl radical in the allyl lactone obtained into the acetonyl radical is carried out by methods known per se, e.g. B. by addition of hypohalous acid, oxidation to the α-halo ketone and reductive removal of the halogen atom. Optionally, a less reactive halogen atom, e.g. B. chlorine or bromine, be exchanged for iodine before the reduction.



   The condensation of the acetonyl radical in the a position in the 2-position with the 1-keto group to form a 5-membered ring takes place in the presence of catalysts or condensing agents in a suitable solvent, e.g. B. in the presence of strongly alkaline condensing agents such as alkali metal hydroxides, alcoholates, amides or hydrides, eg. B. potassium hydroxide, sodium ethylate, sodium amide or potassium tert-butoxide, or in the presence of catalysts such as piperidine acetate or piperidine benzoate in an inert solvent such as. B. dioxane or benzene. The conversion of an acetic acid residue in the 2-position into an acetonyl residue, which must be carried out before the condensation, if necessary, can be carried out in a manner known per se.

   This conversion is achieved, for example, by reacting the corresponding acid chloride with a methyl metal compound, such as. B. methylmagnesium iodide or dimethylcadmium, or with diazomethane via the diazoketone, also with malonic ester and subsequent hydrolysis and decarboxylation. It is also possible to convert an a-position acetaldehyde radical in the 2-position into an acetonyl radical, in particular by reaction with a methyl metal compound and subsequent oxidation of the carbinol formed, or by oxidation to the acetic acid radical and further structure as described above. A free oxo group present in ring A is protected before the mentioned conversion reactions. This is advantageously done by conversion into ketals or enol ethers, e.g.

   B. with the help of ethylene glycol or o-formic acid ester in the presence of acidic catalysts.



   The condensation of the acetonyl radical in the a-position in the 2-position with the keto group in the 1-position usually gives the dehydration products of the following partial formula directly
 EMI3.1
 However, it is also possible that the corresponding 14-oxy compound is formed during the condensation under mild conditions. This oxy group is removed by splitting off water or with the aid of halogenating agents via the corresponding halides and reductive removal of the halogen atom.



   According to the process, the 16-oxosteroids obtained, which are unsaturated in the 14, 15-position, have a bridge of 2 carbon atoms between carbon atom 13 and the 11ss-oxy group according to the following partial formula
 EMI3.2
 The radical forming said bridge can contain a free or functionally modified oxo or hydroxyl and / or methyl group in the 18a position and / or have a double bond in the 18-18 position. The new 16-oxo-steroids obtained have z. B.

   Structures as shown by the following

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 Partial formulas are illustrated:
 EMI4.1
 
The products of the process are extremely suitable intermediates for the production of 11, 18-dioxigenated, in particular 3, 11, 18, 20-tetraoxygenated steroids, i.e. H. z. B. the highly effective adrenal cortex hormone aldosterone (18-oxocorticosterone, A4-3, 18, 20-trioxo-11 B, 21-dihydroxy-pregnen) and related compounds.

   In the new 16-oxo-steroids of the present invention which are saturated or unsaturated in the 14, 15-position, on the one hand an oxyacetyl radical can be introduced in the 17-position, and on the other hand, the process products with a bridge from carbon atom 13 to the 11B-hydroxyl group can be free or functionally modified 18-oxo-llss-oxy compounds are broken down.



   The introduction of the oxyacetyl radical in the 17-position of the process products after the 14, 15 double bond has been saturated by catalytic hydrogenation can be carried out via a 17-carboxy, i.e. H. an ethic acid, or 1'7-acetyl compound, d. H. a 20-oxo-pregnane. The ethic acid derivatives are obtained by condensation of the 16-ketone with carbonic acid esters, such as diethyl or dimethyl carbonate, or with oxalic esters, and subsequent decarbonylation. 20-Oxo-pregnanes are formed when the 16-ketone is converted with acetic acid derivatives. For the construction of the Ätianäuren and 20-Oxo-pregnane to compounds with an oxyacetyl radical in the 17-position one uses the known methods, eg.

   B. the diazoketone synthesis in ethic acids and the lead tetraacetate method in 20-oxo-pregnanes. The latter can also be converted into the 21-oxy derivatives while avoiding acidic reaction conditions by condensing them with oxalate, reacting an alkali metal salt of the condensation product with iodine and then carrying out acid cleavage with an alkali metal alcoholate or hydroxide and replacing the halogen atom with an acyloxy radical or a hydroxyl group . Another method consists in converting the 20-oxo-pregnanes via their 20,21-enol derivatives by treatment with bromine or iodosuccinimide and replacing the 21-halogen atom as described above.



   The 16-oxo group can be eliminated at any reaction stage. However, this oxo group can advantageously be eliminated directly after the introduction of the substituent in the 17-position, whereby various known methods can be used, such as the WolffKishner reduction and its variants, the Clemmensen reduction, especially the route via 16-enol sulfonic acid esters, e.g. 16-enol methanesulfonic acid ester and enol-p-toluenesulfonic acid ester. The reductive removal of the enolsulfonic acid residue is easy in the presence of a Raney nickel or palladium catalyst.



   The substituent in the 13B position can also be converted into a formyl group at any reaction stage. Various methods can be used for this purpose. The lactones, obtained according to the above information by lactonization of the 13B-acetic acid residue with the hydroxyl group in the 11ss position, can be z. B. by the action of organometallic compounds, e.g. B. Grignard compounds, especially aryl magnesium halides, split, the acetic acid residue being converted into a substituted oxyethyl residue. In this, the hydroxyl group can be eliminated with the formation of a double bond by the methods customary for this reaction. The elimination of water takes place particularly easily when the substituent in the 13B position is a diaryloxyethyl radical.

   The double bond thus formed is then used for the oxidation of the double bond of the allyl and methallyl radicals

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 The methods described above are cleaved by oxidation and the 13B-formyl compounds are obtained.



  This conversion process is illustrated in the following partial formula:
 EMI5.1
 
 EMI5.2
 

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 EMI6.1
    B. hydrophenanthren-l-on-4ss-ol are dissolved in 500 cm3 of acetone, mixed with 25 cm3 of concentrated hydrochloric acid and refluxed for 20 minutes at a bath temperature of 800. Then 25 g of crystallized sodium acetate and 250 cm3 of water are added and the acetone is distilled off in vacuo at a bath temperature of 60 °.



  A yellow, partially crystallized oil separates out. The precipitated substance is dissolved by adding 1000 cm3 of methylene chloride and the organic solution is washed with water, 2N sodium hydroxide solution and water, dried with sodium sulfate and evaporated. 8, 42 g of crystallized 2,2-diallyl-4bi3-methyl-1, 2, 3, 4, 4aci, 4b, 5, 6, 7, 9, 10, 10ass-dodecahydrophenanthren-1, 7-dione-4ss are obtained -ol, which melts at 152-153 after recrystallization from methanol or methylene chloride-ether.



   The cleavage of the ketal can also be carried out in the following way: 5, 8 g of crude 2,2-diallyl-4bss-methyl-7-ethylenedioxy-1, 2, 3, 4, 4aot, 4b, 5, 6, 7, 8 , 10, 10a8-dodeca- hydrophenanthren-l-on-4ss-ol are dissolved in 50 cm3 of glacial acetic acid with heating, mixed with 50 cm3 of water and the mixture is heated to 90-950 for one hour. It is then evaporated to dryness in vacuo, the reaction product already beginning to separate out in crystalline form during the evaporation.

   The residue is recrystallized from methanol and gives 5.3 g of pure 2, 2 -diallyl- 4bss-methyl- - 1, 2, 3, 4, 4aa, 4b, 5, 6, 7, 9, 10, 10ass-dodecahydrophenanthren- 1,7-dione-4ss-ol in front of F. = 152-153.



   Acetylation of 3.0 g of this compound with 25 cm3 of acetic anhydride in 25 cm3 of pyridine at 800 for 12 hours gives 2,2-dially-4ss-acetoxy-4bss-methyl-1,2,3,4,4aα, 4b, 5,6,7,9,10,10ass-dodecahydrophenanthren-1,7-dione as a pale yellow oil, easily soluble in ether and methanol, which completely crystallizes after a few days.

   The pure compound recrystallized from ether-hexane melts at 97-99, has a strong maximum in the ultraviolet spectrum at 238 mu (# = 15450) and shows the following characteristic bands in the infrared spectrum: at
 EMI6.2
 4ss-Acetoxy-4bss-methyl-7-ethylenedioxy-1,2,3,4,4aα, 5,6,7,8,10,10ass obtained from this compound with pyridine and acetic anhydride at room temperature for 48 hours in quantitative yield -do- decahydrophenanthren-1-one from F. = 105-1070 as described above with allyl iodide.



  After the ketal cleavage, the above 2,2-diallyl-4ss-acetoxy-4bss-methyl-
 EMI6.3
    1, 2, 3, 4, 4aa, 4b, 5, 6, 7, 9, 10, 10ass-dodecahydrophenanthren-1, 7-dion.phenanthren-l, 7-dion-4B-ol are dissolved in 550 cm3 of ethyl acetate and cooled to -30. A stream of dry, ozone-containing oxygen is then allowed to flow through the solution until about 2.2 molar equivalents of ozone are consumed. The solution is then mixed with 30 cms of glacial acetic acid in the cold and 50 g of zinc dust are added in portions with stirring. After one hour, the cold solution is filtered off with suction through Supercel and washed with saturated sodium hydrogen carbonate solution and water. The ethyl acetate solution is then dried with magnesium sulfate and evaporated.

   The crude dialdehyde obtained is dissolved in a mixture of 80 cm3 of benzene and 30 cm3 of glacial acetic acid. At a temperature of 0 to 50, a solution of 4.0 g of crystallized sodium dichromate in 50 cm3 of glacial acetic acid is added dropwise with stirring over the course of 30 minutes, and the mixture is stirred for a further 30 minutes at room temperature. Then it is diluted with 220 cm3 of benzene and 100 cm3 of water and shaken out. The separated benzene solution is washed again with 100 cm3 of water and then extracted with 1N sodium hydroxide solution. After drying and evaporation of the benzene solution, an oily neutral product is obtained, which partly consists of unchanged diallyl compound. The alkaline extracts are made Congo acidic with 5N sulfuric acid while cooling and extracted with chloroform. The chloroform extracts are combined, dried and evaporated in vacuo.

   The acetic acid is distilled off from the oil obtained in a high vacuum at a bath temperature of 800. The residue, which from the crude monolactone des 2, 2-bi-carboxymethyl- -4bss-methyl-1, 2, 3, 4, 4aa, 4b, 5, 6, 7, 9, 10, 10a8-dodecahydrophenanthrene-1, 7-dione-48-ol is purified by chromatography on magnesium silicate. The compound melts from methanol-chloroform recrystallized at 286.



   Example 3: 3.2 g of the monolactone des 2,2, -di-carboxymethyl-4bss-methyl-1,2,3,4,4aα, 4b 5,6,7,9,10,10ass-dodecahydrophenanthren-1 , 7-dione-4ss-ol are dissolved in 150 cm3 of ethylene dichloride, mixed with 4.0 cm3 of ethylene glycol and 60 mg of p-toluenesulphonic acid, and so strong for 8 hours

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 heated so that slowly about 200 cm3 of solvent distill off, the volume of the reaction solution being kept constant by slow, steady addition of dry ethylene dichloride. It is then allowed to cool, washed with a solution of 200 mg sodium acetate in 30 cm3 water, then twice with water, dried and the ethylene chloride solution evaporated in vacuo.

   You win from the residue
 EMI7.1
   2-Di-carboxymethyl-4bss-methyl-7-ethylenedioxy-1, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10aB-dodecahydrophenanthren-1-one-4 B -ols.



     1.6 g of the above monolactone are dissolved in 30 cm3 of absolute benzene, 0.4 cm3 of oxalyl chloride are added and the mixture is left to stand at 250 for 45 minutes. The mixture is then evaporated in vacuo at a bath temperature of 300 and the residue is freed from volatile constituents by taking up several times in benzene and evaporating in vacuo. The crude acid chloride obtained is dissolved in 25 cm3 of absolute benzene.



  At the same time, a solution of dimethylcadmium is prepared as follows: 0.65 g of magnesium shavings are covered with 50 cm3 of absolute ether and reacted with 4.5 g of methyl iodide. After the reaction has ended, the mixture is cooled in ice and 2.5 g of anhydrous cadmium chloride are added and the mixture is stirred for one hour at 15-200 with exclusion of moisture. Then it is diluted with 25.0 cm3 of absolute benzene and the solution of the crude acid chloride is stirred within 10 minutes added dropwise. After one hour, the mixture is heated to about 400 and stirred at this temperature for a further 3 hours. Then 50 cm of ice-cold 0.5N ammonium chloride solution is added and the mixture is shaken well.

   Undissolved salts are filtered off, washed with a 1: 1 ether-benzene mixture and the organic layer is washed again with water, dried with magnesium sulfate and evaporated. to dry up. The residue consists of the crude lactone of 2a-acetonyl-2B-carboxyrnethyl- 4bB-meÙyl-7-äthylendioxy- -1, 2, 3, 4, 4aci, 4b. 5, 6, 7, 8, 10, 10ass-dodecahydrophenanthren-l-one-48-ols. For purification, the crude product is chromatographed on aluminum oxide (activity II). The pure compound of F. = 228-23 is obtained from the fractions eluted with benzene by crystallization from an acetone-ether mixture.



   Example 4: 10 g of 2, 2-diallyl-4bB-methyl-l, 2, 3, 4, 4aa, 4b, 5, 6, 7, 9, 10, 10aB-dodecahydro- phenanthrene-l, 7-dione-4ss -ol are dissolved in 400 cm3 of ethyl acetate and 150 cm3 of methanol and treated with vigorous stirring at -65 to -750 for 90 minutes with a stream of oxygen which introduces about 0.8 millimoles of ozone per minute. Then nitrogen is blown through for a few minutes and then a mixture of 200 cm3 of methanol and 100 ems of water is added, immediately followed by about 100 g of zinc dust activated with dilute acetic acid and made into a paste in alcohol and 40 cm of glacial acetic acid.



  The external cooling is removed and 10 minutes later another 40 cm3 of glacial acetic acid are added.



  As soon as the temperature has risen to -10, the unused zinc is decanted off, washed with ethyl acetate and the organic solution is diluted with 500 cm3 of benzene. The acidic components are then removed by shaking out with 200 cm3 of saturated soda solution each time. After the solvents have been distilled off, an almost colorless, viscous oil is obtained, from which the dialdehyde of the formula, which is present as a di-hemiacetal, is obtained when stirred with ether
 EMI7.2
 is obtained in colorless crystals which, after redissolving from a chloroform / methanol mixture, melt at 178 with evolution of gas and which in the infrared spectrum, in addition to very strong hydroxyl bands, are at 2.82/2, 92J. 1 show only one keto band at 5, 96 u.
 EMI7.3
 oxidized for about 14 hours at room temperature.

   The excess chromate is then destroyed with methanol and the oxidation mixture is taken up in a benzene / ethyl acetate mixture. After shaking out the chromium salts through dilute sodium chloride solution, the newly formed acids are extracted by shaking with semi-saturated soda solution, the combined soda solution is acidified using 5N sulfuric acid and the sulfuric acid solution is extracted using chloroform. After drying and evaporation of the

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   Chloroform extracts are obtained by crystallizing the residue from a methanol / chloroform mixture, a lactonecarboxylic acid in colorless crystals, which on the basis of analysis and infrared spectrum gives the formulas
 EMI8.1
 can be assigned and which melts at 2860 with decomposition.

   It shows a strong absorption maximum (E = 15900) in the ultraviolet spectrum at 237 ml. This lactonic acid is identical to the compound described in Example 2.



   The methyl ester of the formula is obtained by stirring the acid in the methanol / ether mixture and adding diazomethane solution
 EMI8.2
 which is precipitated from methanol in colorless crystals containing crystal methanol, which melt at 1320.
 EMI8.3
 250 cm3 of benzene and 190 cm3 of methyl-ethyl-dioxolane are distilled off through a column of 70 cm3 of solvent. Then it is allowed to cool slightly, 500 mg of p-toluenesulfonic acid and 20 cm3 of benzene are added and the mixture is heated to the boil again. 285 cm3 of solvent are then distilled off over the course of 4 1/2 hours, whereupon the contents of the flask are cooled, diluted with benzene and poured onto 100 cm3 of saturated sodium bicarbonate solution. After the aqueous phase has been shaken out again with benzene, the organic solutions are washed with water, dried and evaporated in vacuo.

   The crude ketal is purified by chromatography on 200 g of aluminum oxide (activity II) and the pure methyl ester of the monolactone of 2,2-di-carboxymethyl-4bss-methyl-7-ethylene-dioxy-1,2,3 is obtained from the benzene fractions. 4,4aα, 4b, 5,6,7,8,10,10ass-dodecahydrophenanthren-1-one-4ss-ols of m.p. = 220, 5-223.



   A solution of 1.4 g of potassium carbonate in 10 ems of water is added to 500 mg of the ketal obtained and 10 cm 3 of methanol, and the mixture is refluxed for 3 hours in a stream of nitrogen. Most of the methanol is then evaporated off in vacuo and the residue with 20 cm, a 4m sodium
 EMI8.4
 Introduces about 0.7 millimoles of ozone per minute. Then nitrogen is blown through for 3 - 5 minutes and then a solution of 200 cm3 of methanol and 100 cm3 of water is added, immediately followed by about 50 g of zinc dust activated with dilute acetic acid and made into a paste in alcohol and 40 ems of glacial acetic acid. The external cooling is removed and about 10 minutes after the first addition of glacial acetic acid, a further 40 cm3 of glacial acetic acid is added.

   About 15-20 minutes after adding the zinc, the temperature should still be about -100

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 be. Unused zinc is then decanted off, washed with ethyl acetate and, after dilution with 500 cm3 of benzene, freed from acidic components by shaking it out several times with 200 cm3 of saturated soda solution each time. After drying with sodium sulphate and distilling off the solvent, an almost colorless, viscous oil is obtained from which unchanged starting material is recovered by repeated stirring with ether.



   15 g of the neutral ozonation product remaining after the starting material has been separated off are dissolved in 100 cm of glacial acetic acid. The solution is diluted with 250 cm3 of thiophene-free benzene and 150 cm3 of an 8% solution of sodium dichromate in glacial acetic acid are added at 5-100 cm. After stirring for about twelve hours at room temperature, the excess chromate is destroyed by adding 100 cm3 of methanol. For work-up, the oxidation mixture is poured into 2 l of benzene, washed twice with 600 cm3 of 5% sodium chloride solution each time and then with saturated soda solution until the acidic components are removed, the aqueous extracts being extracted twice more with a mixture of benzene and ethyl acetate.

   After drying the combined organic solutions over sodium sulfate, an oily neutral product is obtained by distilling off the solvent, from which through
 EMI9.1
 
 EMI9.2
 is obtained in colorless crystals, which melts at 2080 after redissolving from methanol and shows the 6-lactone band at 5, 75 u and two ketone bands at 5, 82 and 5, 96 in the infrared spectrum.



     3.0 g of the mother liquor obtained after separating off the lactone described above are evaporated to dryness, dissolved in a mixture of equal parts by volume of benzene and hexane and chromatographed on 90 g of aluminum oxide (activity II). From the fractions (650 mg) eluted with benzene-ether 1: 1, the compound of the formula is obtained by crystallization from ether or methanol
 EMI9.3
 which melts at 140-141.5 and shows an absorption maximum at 237 mg (e = 18500). In the infrared spectrum, the band at 2.76 JL typical for the OH group is missing, however, the following bands emerge: 5, 83j (6-ring ketone), 5, 95 and 6.15 (α, ß-unsaturated ketone) and another gang at 6, 08 but.



   From the fractions eluted with benzene and with a benzene-ether mixture 1: 1, a further amount of the above-described allyl lactone with a melting point of 2080 is obtained.



   The above-described compound of F. = 140-141.5 is converted into the methyl ketone of the formula according to the information in Example 11 via the iodohydrin and iodine ketone
 EMI9.4
 

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   convicted. When heated in a benzene solution with potassium tertiary butoxide in absolute benzene, this compound produces the dl-A'-3, 16-dioxo-11ss, 18a-oxido-18-homo-androstatriene of the formula analogously to the information in Example 14
 EMI10.1
 
 EMI10.2
    : A solution of 580 mg 2a-allyl-4bB-methyl-28-carboxymethyl-1,2, 3, 4, 4aa, 4b, 30 ems benzene and 0.6 cm3 ethylene glycol is boiled for 6 hours using a water separator. It is then poured into dilute sodium bicarbonate solution and extracted three times with ether.

   The organic solutions are washed with water, dried and evaporated. The residue is obtained by chromatography on 18 g of aluminum oxide (activity II) with a mixture
 EMI10.3
 
 EMI10.4
 
 EMI10.5
 
 EMI10.6
 

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 The bromohydrin can also advantageously be isolated by pouring the reaction solution into four times the amount of water and suctioning off the precipitated, white, powdery reaction product and washing it thoroughly with water.



     44 g of the bromohydrin described are mixed with 150 cm3 of glacial acetic acid. A solution of 3.50 g of chromium trioxide in 3 cm3 of water and 150 cm3 of glacial acetic acid is added to the suspension obtained and shaken at 20-250 until a clear solution is obtained. It is left to stand for 18 hours and the excess oxidizing agent is destroyed by adding 15 cm3 of methanol. After one hour, the mixture is evaporated to about 50 cm3 in vacuo at a bath temperature of 600, diluted with water and extracted several times with chloroform. The chloroform extracts are washed with water and sodium bicarbonate solution until a weakly alkaline reaction, then washed again with water, dried and evaporated in vacuo.



  3.716 g of a solid, yellowish, crystallized neutral product are obtained. The pure bromoketone of the formula is obtained by crystallization from a mixture of methylene chloride and methanol
 EMI11.1
 in well-developed crystals from F. = 197-198 (in vacuo, with decomposition). In the ultraviolet spectrum, the compound shows a strong absorption maximum at 238 μm (= 15,300). In the infrared spectrum one observes the band of 6-lactone at 5.74 bu, that of the two unconjugated ketones at 5.83.11 and that of the ci, ss-unsaturated keto group at 5, 96 and 6, 16 bu.



   2.20 g of crude bromine ketone are dissolved in 300 cm3 of acetone and refluxed with 3.0 g of sodium iodide for 2 hours at a bath temperature of 800 mm with a calcium chloride seal. Then it is evaporated to dryness in vacuo at a bath temperature of 40-500, the residue is dissolved in methylene chloride and the solution is washed with water, dilute sodium thiosulphate solution and water. On evaporation of the dried methylene chloride solution, 2.24 g of crude, crystallized iodine ketone with a melting point of 134-1360 (in vacuo, with decomposition) of the formula are obtained
 EMI11.2
 which, after recrystallization from a mixture of methylene chloride and methanol, melts at 146-1580 with decomposition.



     2.0 g of the crude iodine ketone are dissolved in 150 cm3 of hot glacial acetic acid and stirred with about 10 g of activated zinc dust for 20 minutes at 70-800 with exclusion of moisture. The zinc dust was activated by treatment with ice-cold 2N sulfuric acid for 5 minutes, washed well with water and acetone and stored under acetone. The hot reaction solution is diluted with 100 cm3 of benzene and filtered off with suction. The zinc residue is washed thoroughly with 100 cm3 of benzene and the filtrate is evaporated in vacuo to about 10 cm3 and diluted with 150 cm3 of methylene chloride. The solution is then washed with water, 0.5N sodium bicarbonate solution and water and re-extracted with methylene chloride. The combined methylene chloride solutions are dried and evaporated.

   L, 47 g of an oily neutral product are obtained, from which, by crystallization from acetone and benzene, a total of 1.06 g of crude, crystallized methyl ketone (lactone of 2a-acetonyl-2B-carboxymethyl-4bB-methyl-

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   -1, 2, 3, 4, 4aa, 4b, 5, 6, 7, 9, 10, 10ass-dodecahydrophenanthren-1, 7-dione-4ss-ols) of the formula
 EMI12.1
 can be isolated. Recrystallization from acetone or methanol gives the pure compound, crystallized in fine needles, of F. = 220-223.

   In the ultraviolet spectrum it has an absorption maximum at 237 mg (e = 15,750), while in the infrared spectrum, in addition to the 6-lactone band at 5.75, that of the unconjugated ketones at 5.82 and those of the cx.8-unsaturated keto group can be observed at 5.95 / l and 6.16 bol



   The same compound can also be obtained by direct debromination of the above-described bromine ketone from F. = 197-1980 with activated zinc in glacial acetic acid in the manner described above.



  In this way, 61 mg of crystallized crude product is obtained from 100 mg of bromoketone, from which the pure methyl ketone is isolated by recrystallization from acetone or methanol.



   Example 9: 8.5 g of the 2α-allyl-4bss-methyl-2ss-carboxymethyl--1,2,3,4,4aα, 4b, 5,6,7,9,10,10ass described in Example 6 -dodecahydrophenanthren-1,7-dione-4ss-ol-lactons are dissolved in 170 cm3 of glacial acetic acid and treated with 1.7 cm3 of water and 4.65 g of silver acetate. Then, while stirring vigorously, 6.7 g of powdered iodine are added in portions over the course of an hour and the mixture is then stirred for a further 2 hours at room temperature. The precipitate, which consists of silver iodide and the very sparingly soluble reaction product, is then filtered off with suction and washed with 34 cm3 of water. The moist residue is extracted at 600 for 45 minutes by stirring with 600 cms of a mixture of equal parts of chloroform and alcohol.

   It is filtered off and the extraction is repeated in the same way with 300 cm3 of a chloroform-alcohol mixture. The combined extracts are evaporated to almost dryness in vacuo, with copious amounts of crystals being deposited during the evaporation.



  The residue is mixed with 100 cm3 of ether and filtered off with suction. The iodohydrin obtained (9.35 g) of the formula
 EMI12.2
 melts at 157-161 with severe decomposition. It can be recrystallized from a mixture of chloroform and methanol. In alcoholic solution it shows a strong absorption maximum at 238 mg (E = 17250). In the infrared spectrum of the compound in Nujol, as with the corresponding bromohydrin described in Example 8, the following bands are observed: at 2.88 li (hydroxyl), 5.76 (S-lactone), 6.04 and 6.18 11 (ci, 8-unsaturated ketone).



   The glacial acetic acid filtrate is also evaporated to dryness in vacuo and the residue is extracted with an alcohol-chloroform mixture. A further 0.74 g of the above-described iodohydrin are thus obtained.



     Be is pie I 10: To a solution of 2.0 g of the 2a-allyl-4b6-methyl-25-carboxymethyl-1,2,3,4,4aα, 4b, 5,6,7 described in Example 6 , 9,10,10ass-dodecahydrophenanthren-1,7-dione-4ss-lactons in 20 cms of dimethylformamide are added 2.06 g of iodosuccinimide and 1.0 cm3 of glacial acetic acid and 1.0 cm3 of water are added while stirring. After 5 minutes a clear solution is formed and, on further stirring, the reaction product begins to separate out as a white precipitate after about 20 minutes. After a reaction time of 4 hours, the mixture is poured into 200 cm3 of water, the precipitate is filtered off with suction and washed thoroughly with water.

   The residue, dried over phosphorus pentoxide, yields after recrystallization

 <Desc / Clms Page number 13>

 from a mixture of alcohol and chloroform 2.61 g of the iodohydrin of the formula described in the previous example
 EMI13.1
 
 EMI13.2
 
 EMI13.3
 
 EMI13.4
 
 EMI13.5
 which is obtained from acetone in colorless leaflets with a F. = 2280 in a yield of 11 to 13 g and is identical to the methyl ketone described in Example 8 with a F. = 220-2230.

 <Desc / Clms Page number 14>

 



   Example 12: A solution of 280 mg of the lactone of 2α-acetonyl-2ss-carboxymethyl--4bss-methyl-1,2,3,4,4aα, 4b, 5,6,7,9,10,10ass- Dodecahydrophenanthren-1,7-dione-4ss-ol and 25 mg of p-toluenesulfonic acid in 25 cm3 of benzene and 0.5 cm3 of ethylene glycol are boiled for 5 1/2 hours using a water separator, the receiver of which is filled with calcium chloride. It is then poured into dilute sodium bicarbonate solution and shaken out several times with ether. After washing the ethereal solutions with water, drying and evaporation, the solution of the residue in 2 cm3 benzene is chromatographed on 10 g aluminum oxide (activity II).

   In the first benzene fractions there is a compound of F. = 178-182 of the probable formula
 EMI14.1
 The infrared spectrum only shows the 6-lactone band at 5, 78 u.



   Unchanged starting material is recovered from the later benzene and ether fractions.



   Example 13: From a solution of 500 mg of the lactone of 2a-acetonyl-2B-carboxymethyl--4bss-methyl-1,2,3,4,4aα, 4b, 5,6,7,9,10,10ass- dodecahydrophenanthren-1,7-dione-4ss-ol in 35 cm3 benzene and 18 cm3 methyl-ethyl-dioxolane are distilled off 6 cm3 solvent; it is then cooled, 50 mg of p-toluenesulfonic acid are added and 70 cm3 of liquid is distilled off through a column over the course of 3 1/2 hours, the volume of the reaction mixture being kept constant by adding benzene.



  The cooled reaction solution, diluted with benzene, is washed successively with dilute sodium bicarbonate solution and water, dried and evaporated in vacuo. When the residue is chromatographed on 16 g of aluminum oxide (activity II), small amounts of a compound of F. = 202-2040 and later the desired lactone are obtained from the first benzene fractions
 EMI14.2
 Connection is identical. The infrared spectrum no longer shows the band characteristic of c (, ss-unsaturated ketones at about 5.95 u, but only one band at 5.82 u (6 -lactone + methyl ketone).



   Example 14: 670 mg of the lactone des 2α-acetonyl-2ss-carboxymethyl-4bss-methyl--1,2,3,4,4aα, 4b, 5,6,7,9,10,10ass-dodecahydrophenanthrene-1 , 7-dione-4ss-ol with a F. = 220-2230 are dissolved in 100 cm3 of benzene and traces of moisture are removed by distilling off 5 cm3 of benzene. Add 50 cm3 of an anhydrous benzene solution of potassium tert prepared as follows. Butylate: 325 mg of potassium are dissolved in 15 cm3 of tert. Butyl alcohol and evaporated to dryness in vacuo. Then about 30 cm3 of benzene are added, the mixture is again completely evaporated and the residue is taken up in 100 cm3 of absolute benzene. Traces of moisture are removed by distilling off a few cubic centimeters of benzene.

   The reaction solution is boiled for 5 hours under reflux and with a calcium chloride seal at a bath temperature of 1100, acidified with 1.0 cm3 of glacial acetic acid, the color changing from dark purple to light yellow, and then boiled for a further 2 hours. After cooling, it is diluted with 15 cm3 of chloroform and the solution is washed with water, sodium bicarbonate solution and water. The aqueous solutions are extracted twice with chloroform. After drying and evaporation in vacuo, the combined organic solutions give 650 mg of an oily crude product which crystallizes on addition of acetone.

   Crystallization from an acetone-ether mixture gives 415 mg of the lactane of d1- # 4,14-3,16-dioxo-11ss-hydroxy-18-carboxy-androstadiene of the formula
 EMI14.3
 

 <Desc / Clms Page number 15>

 
 EMI15.1
 
 EMI15.2
 
 EMI15.3
 Chromatogram fractions are returned to starting material after treatment with acetone and p-toluenesulfonic acid.



   Example 18: 13 g of the lactone of dl-A'-llss-Oxy-3, 16-dioxo-18-carboxy-androstadiene are dissolved in 960 cms of benzene and 480 cms of methyl-ethyl-dioxolane distilled over lithium aluminum hydride. 250 cm3 of solvent are then distilled off in a stream of nitrogen using a Vigreux column. A solution of 1.43 g of p-toluene is then added to the still boiling solution

 <Desc / Clms Page number 16>

 sulfonic acid in 1.11 hot benzene, dried by distilling off benzene until the distillate is clear, the benzene distilled off being replaced again. 850 cms of solvent are then distilled off within one hour.

   In the following 4 hours, a total of 2400 cms of solvent are distilled off, the volume of the reaction solution being increased by slowly adding 600 cm3 of benzene, then a mixture of 280 cm3 of methyl-ethyl-dioxolane distilled over lithium aluminum hydride and 320 cm3 of benzene and finally 1200 cm3 of absolute Benzene keeps constant. The cooled reaction mixture is then poured onto 200 cm3 of semi-saturated sodium bicarbonate solution, whereupon the aqueous phase is shaken out once more with benzene. After washing the organic solutions with water, drying and evaporation, the residue is chromatographed on 400 g of aluminum oxide (activity II).

   The lactone of dl-A- -3-ethylenedioxy-11ss-oxy-16-oxo-18-carboxy-androstadiene described in Example 17 is obtained from the benzene fractions, while unchanged starting material can be recovered from the ethyl acetate fractions.



   In an analogous manner, the dl-A ″ - 3, 16-dioxo-llss-18a-oxido-18-homo-androstatriene of the formula described in Example 6 is obtained
 EMI16.1
 the corresponding monoketal with a ketalized 3-keto group, which has a strong absorption maximum (E = 16300) at 230mp.



    Example 19: 7.14 g of 4bss-methyl-7-ethylenedioxy-1,2,3,4,4aα, 4b, 5,6,7,8,10,10ass-dodeca-hydrophenanthren-1-one-4ss-ol become suspended in 75 cm3 of dioxane and with stirring in a nitrogen atmosphere with half of a mixture of 2.1 g of potassium with 62 cm3 of tert. Butyl alcohol prepared butylate solution is added. Then 5.0 g of powdered potassium iodide are added and 3.6 cm3 of propargyl bromide are allowed to flow in. After stirring for 30 minutes, the remainder of the potassium butoxide solution is added and another 3.6 cm3 of propargyl bromide is allowed to flow in. The mixture is left to stir for a further 2 hours at room temperature, diluted with 200 cm of benzene, filtered off with suction and the salts remaining on the suction filter are washed with benzene. The filtrate is washed twice with water, dried and evaporated in vacuo.

   The residue represents the crude 2,2-dipropargyl-4bss-methyl-7-ethylenedioxy-1, 2,3,4,4aα, 4b5,6,7,8,10,10ass- - dodecahydrophenanthren-1-one-4ss -ol. It is dissolved in 200 cm3 of hot acetone and, after adding 10 cm of conc. Hydrochloric acid refluxed for 25 minutes. A solution of 12.0 g of crystallized sodium acetate in 60 cm3 is then placed. Water is added and the acetone is distilled off in vacuo. The oily deposit is taken up in methylene chloride, the solution washed with water, dilute sodium hydroxide solution, dilute sulfuric acid and water, dried and evaporated. 8.59 g of a brown oil are obtained, which is chromatographed on aluminum oxide.

   The pure fractions are obtained from the fractions eluted with benzene-ether in a ratio of 2: 1 by crystallization from an alcohol-ether mixture
 EMI16.2
    Fmethyl-1, 2,3,4,4aa, 4b, 5,6,7,9,10,10ass -dodecahydrophenanthren- 1,7-dion-4ss-ol- 1,7-dione-4B-ol are in 20 cm3 glacial acetic acid and treated with a solution of 500 mg N-bromoacetamide and 520 mg sodium acetate in 5 cm3 water at room temperature. After 6 hours, the mixture is concentrated strongly in vacuo, the residue is taken up in ethyl acetate and water and the ethyl acetate layer is washed with sodium hydrogen carbonate solution. After drying and removing the solvent in vacuo, the residue is dissolved in 7 cm3 of glacial acetic acid and stirred with 1 g of zinc dust at 70-800 for 15 minutes.

   It is then cooled, diluted with ethyl acetate, the solution is filtered to remove the remaining zinc and washed with ethyl acetate. The filtrate is washed twice with water, dried with sodium sulfate and freed from volatile constituents at a bath temperature of 70 in vacuo for 2 hours. The crude product that remains is obtained by dissolving it in 5 cms of acetone and diluting with 35 cm3 of carbon tetrachloride and chromatography on 6 g of purified fuller's earth

 <Desc / Clms Page number 17>

 (Trade name: Florex XS) and eluting with an acetone-carbon tetrachloride mixture 1: 7 in the initial fractions the methyl ketone of the formula
 EMI17.1
 from F. = 1820.



   Example 20: 10 g of 2,2-diallyl-4bB-methyl-1,2, 3, 4, 4aa, 4b, 5, 6, 7, 9, 10, 10a8-dodecahydro- phenanthrene-1, 7-dione-4ss -ol are dissolved in 300 cm3 of glacial acetic acid and 1.5 cm 3 of water and 11.0 g of silver acetate are added. 15.5 g of powdered iodine are added in portions to this reaction mixture over a period of 30 minutes with stirring, silver iodide being deposited. After the addition has ended, the mixture is stirred
 EMI17.2
 The filtrate is poured into 2 liters of water with vigorous stirring, left to stand for 2 hours, filtered off with suction and washed thoroughly with water. The residue is dried over phosphorus pentoxide and potassium hydroxide in vacuo.



  15.94 g of the crude white iodohydrin are obtained. Recrystallization from a mixture of methylene chloride and methanol gives the pure compound with a melting point of 183 - 1840 (decomposition). In alcoholic solution the compound shows an absorption maximum at 242 μm (e = 17100) and in methylene chloride solution in the infrared an OH band at 2.7411, but only the bands of the <x, B-unsaturated ketone at 5.96 and in the carbonyl region 6, 16 and The formula comes to her
 EMI17.3
 
 EMI17.4
 



   If 5 g of the crude product is treated in 160 cm3 of glacial acetic acid with 10 g of zinc dust for 60 minutes at 600, the filtrate is filtered off, the filtrate is evaporated to about 30 cm3 and the residue is taken up in methylene chloride, a solution is obtained from which after washing Water, sodium hydrogen carbonate solution and water and drying with magnesium sulfate 2.1 g of 2, 2-diallyl-4bB-methyl-l, 2, 3, 4, 4aa, 4b, 5, 6, 7, 9, 10, 10ass-dodecahydrophenanthrene-l , 7-dione-4ss-ol can be obtained.



   1.5 g of the di-iodohydrin described above with a F. = 183-1840 are dissolved in 10 cm3 of pyridine, 5.0 cm3 of acetic anhydride are added and left to stand for 3 days at room temperature. The solution is then diluted with 50 cm3 of benzene, 5 cm3 of methanol is added, after an hour it is diluted with ether and washed several times with ln-sulfuric acid, then with water, dilute sodium hydrogen carbonate solution and water. After drying and evaporation, 1.61 g of a light yellow oil are obtained, which solidifies completely when rubbed with ether. The compound can be recrystallized from ether and melts at 135-1380 with strong decomposition, which starts at around 88-900.

   The compound comes the formula
 EMI17.5
 

 <Desc / Clms Page number 18>

 
 EMI18.1
 the bands at 5, 76 and 5, 97 do not show any CO bands, and the band of a free hydroxyl group is also absent.



   If this acetate is treated in the manner indicated above with zinc in glacial acetic acid, an oily, iodine-free product is obtained from which, by crystallization from a mixture of acetone and ether, a
 EMI18.2
    - 960hydrophenanthren-1, 7-dione are dissolved in 50 cm3 of glacial acetic acid and 0.5 cms of water and 1.9 g of silver acetate are added. Then 2.72 g of powdered iodine are added in small portions within 60 minutes. The iodine is immediately decolorized with every addition, with simultaneous deposition of silver iodide. After the addition is complete, stirring is continued for 30 minutes, then suction filtered through a glass suction filter and the filtrate is poured into 500 cm3 of water.

   After 15 minutes the precipitate is filtered off with suction, taken up in a mixture of ether and methylene chloride and the solution is washed with water, sodium hydrogen carbonate solution and water, dried and evaporated. 3.5 g of a pale yellow, oily residue are obtained, from which 3.0 g of the di- iodohydrin acetate described in the previous example with a melting point of 135-1380 (with decomposition from 880) are obtained by crystallization from ether.
 EMI18.3
    22: 3, 14g 2, 2-diallyl-4bss-methyl-l, phenanthrene-l, 7-dione-4ss-ol are tert in a mixture of 5 cm3 of glacial acetic acid and 50 cm3. Butanol heated to solution and then cooled to 25. A solution of 1.65 g of N-bromoacetamide and 1.65 g of sodium acetate in 10 cm3 of water is added to this solution, the temperature rising to 30.50.

   After 10 minutes, hypobromous acid can no longer be detected in the reaction solution. A solution of 1.65 g of N-bromoacetamide (80%) and 1.65 g of sodium acetate in 10 cm3 of water is then added again at 300. The temperature rises to 340. After 2 hours the hypobromous acid is consumed.



  The partially already crystallized reaction product is completely precipitated by carefully adding 50 cm3 of water, suction filtered, washed with water and dried. In this way, 2.9 g of the reaction product of the formula are obtained
 EMI18.4
 which, after dissolving from methylene chloride-ether, melts at 206-208 with decomposition.



   In an analogous manner, one wins when using tert. Butyl hypochlorite instead of N-bromine
 EMI18.5
 
 EMI18.6
 
 EMI18.7
 briefly heated. 17.9 g of the di-iodohydrin described in Example 21 are added to the cooled mixture with stirring. The mixture is refluxed for an hour and then the excess is destroyed

 <Desc / Clms Page number 19>

 Lithium aluminum hydride by slowly adding ethyl acetate. In addition, a further 800 cm3 of ethyl acetate are added to the reaction mixture and then just enough saturated aqueous sodium sulfate solution that the sludge can be separated from the organic solution by suction filtration.

   It is rewashed with ethyl acetate, the tetrahydrofuran is removed from the filtrate by concentration, diluted again with ethyl acetate, washed with water, then with thiosulfate solution, dried with sodium sulfate and, after removal of the solvent, a mixture of the 3-position epimeric oxy compounds of the formula is obtained
 EMI19.1
 as a colorless foam.



   The bromohydrins or chlorohydrins described in Example 22 can also be reduced in an analogous manner to the dehalogenated compound described above.



   10 g of this mixture of epimeric oxy compounds are dissolved in 50 cm 3 of ethyl acetate, 120 cm of chloroform, then 60 g of active manganese dioxide are added. The reaction mixture is stirred for 20 hours at room temperature. After filtering off the manganese oxides and concentrating the filtrate, a crystallized compound of F. = 171 - 1730 is obtained by dissolving in ether. In the UV spectrum at 241 m it shows an absorption maximum te = 15,900) and in the infrared bands at 2.75 and 2, 90p (OH) and at 5, 98 and 6, 17 li (ci, 6-unsaturated ketone) and has the formula
 EMI19.2
   8.4 g of this last compound are heated in 200 cm3 of pyridine and 100 cm3 of acetic anhydride in a bath of 80 for 5 hours.

   It is then concentrated in a vacuum and the oily back
 EMI19.3
 The acetyl compound of the formula which melts at 1360 is obtained by stirring the crude product with ether
 EMI19.4
 which in the IR at 5.76 / l shows a band typical for esters. 5 g of this acetyl compound are dissolved in 100 cms of glacial acetic acid, a solution of 5 g of chromium trioxide in 4 cm3 of water and 65 ems of glacial acetic acid are added and the mixture is kept at a temperature of 330 for 20 hours. 100 cm3 of methanol are then added and, after the excess chromic acid has been reduced, the solution is strongly concentrated in vacuo. The residue is dissolved in 300 cms of methanol, 30 ems of conc. Hydrochloric acid was added and the solution was refluxed for 2 hours.

   After adding 15 g of crystallized sodium acetate, the mixture is concentrated in vacuo to a small volume, diluted with chloroform and water and the chloroform

 <Desc / Clms Page number 20>

 pushes one after the other with water and sodium hydrogen carbonate. The crude product obtained by concentrating the chloroform solution is obtained by chromatography on purified fuller's earth and eluting. with a mixture of acetone and carbon tetrachloride in a volume ratio of 1: 7 the compound dci formula
 EMI20.1
 which melts at 1820 and is identical to the compound described in Example 23.



   Example 24: To 2.0 g of 4bss-methyl-7-ethylenedioxy-1,2,3,4,4aα, 4b, 5,6,7,8,10,10ass-dodeca-hydrophenanthren-1-one-4ss -ol in 200 cm3 of dioxane is added with stirring in a nitrogen atmosphere 96 cm3 of a solution of 6.4 g of potassium in 192 cm3 of tert. Butyl alcohol. Then 10 cm3 of methallyl iodide are added and stirring is continued for one hour at room temperature. Then another 96 cm3 of the above potassium tert. Butylate solution, 10 cm of methallyl iodide are added and the reaction mixture is slowly heated within 45 minutes until the internal temperature is approximately 700. A strong deposition of potassium iodide is observed. It is allowed to cool again to 20 for one hour, diluted with 400 cm of benzene, filtered and the filtrate is washed once with 50 cm3 of water.

   The dried organic solution is then evaporated to dryness in vacuo. 28.2 g of a light brown oil are obtained.



   A sample of this oil is rubbed with hexane, whereby it almost completely solidifies. The pure 2,2-dimethallyl-4bss-methyl-7-ethylene-dioxy-1,2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10aB is obtained by recrystallization from hexane and aqueous methanol -dodecahydrophenanthren-l-on-4ss-ol from F. = 84-860. In the infrared spectrum, this compound shows the 1-ketone band at 2.76 li, the methallyl double bond at 6.08 and the ethylene ketal band at 9.111 / l.



   The bulk of the crude ketal is dissolved in 250 cm3 of hot glacial acetic acid, 170 cms of water are added to the solution and the bath is kept at a bath temperature of 90-950 for 90 minutes. It is then evaporated to dryness in vacuo, the residue is dissolved in 300 cm3 of ether, the solution is then repeatedly washed with 0.5N sodium hydroxide solution
 EMI20.2
 
50 cms of ether crystallize. 18.5 g of the recovered pure compound melts at 127.5 - 1290 and shows a strong absorption maximum at 239 μm in alcoholic solution (e = 15700). This methylene chloride solution shows the following bands in the infrared: 2.76 o (OH), 5, 87 fi (1-ketone), 5, 97; ; and 6.16 u (α, β-unsaturated ketone), inflexion at 6.08 each (methallyl double bonds).



   Example 25: 32.9 g of the dimathallyl diketone described in Example 24 having a melting point of 127, 5-129 are dissolved in 150 cm3 of glacial acetic acid and 450 cm3 of chloroform and heated for 2 hours 43 minutes at -15 to -190 with rapid stirring with an ozonated oxygen stream which supplies 62.5 mg of ozone per minute. The oxygen is then displaced from the reaction vessel by passing nitrogen through it, about 40 g of water-moist zinc dust activated by means of dilute acetic acid is added, the temperature being kept below 00. The decomposition of the ozonides formed is completed by adding dilute cold alcohol (obtained from 50 g of ice and 50 cm3 of alcohol).



  After a reaction time of 15 - 20 minutes with the zinc, the mixture is diluted with about 500 cm3 of ethyl acetate, the zinc is filtered off and washed with ethyl acetate. The aqueous layer is separated off from the filtrate and the latter is extracted with ethyl acetate. The organic layers are washed one at a time with a mixture of 250 cm3 of saturated sodium hydrogen carbonate solution and 100 cms of saturated saline solution. After drying with sodium sulphate, the combined organic solutions are freed from solvents if possible at a bath temperature of 700 in vacuo by keeping the residue under vacuum for 1-2 hours at 700 after the majority of the solvents have been distilled off.

 <Desc / Clms Page number 21>

 The resulting cyclic enol ether of the formula
 EMI21.1
 crystallizes out in the warmth.

   The crystallization is completed by adding a little ethyl acetate. The compound melts at 1820 and shows a maximum in the UV at 238mu (= 18150).



  The IR spectrum is characterized by the lack of an OH band and by bands of approximately equal strength at 5, 85 and 5, 97 left.



     Example 26: 19 cm3 of solvent are distilled off in a stream of nitrogen from a solution of 1 g of the cyclic enol ether described in Example 25, having a melting point of 1820 in 74 cm3 of absolute thiphene-free benzene and 37 cm of methylethyldioxolane distilled over lithium aluminum hydride. A hot solution of 110 mg of p-toluenesulfonic acid in 85 cms of benzene is then added, which is dried by distilling off a few cm3 of benzene and replacing the distilled benzene with dry, fresh benzene.

   A total of 203 cm3 of solvent are then distilled off over the course of 4 hours through a Vigreux column, after 65 cm3 of solvent have been distilled off, the volume of the reaction mixture is increased by slowly adding 46 cm3 of absolute benzene, then a mixture of 21.5 cm3 of methylethyldistilled over lithium aluminum hydride. dioxolane and 24.5 cm3 benzene and finally another 46 cm3 benzene is kept constant. The contents of the flask are then cooled and poured onto 40 cm3 of semi-saturated sodium bicarbonate solution. After shaking out twice with benzene, washing the organic solutions with 40 cm3 of semi-saturated sodium bicarbonate solution and water, these are dried and evaporated in vacuo.

   The solution of the residue in 10 cm3 of benzene is chromatographed on 36 g of aluminum oxide (activity II). The first benzene eluates contain 350 mg of the monoketal of the cyclic enol ether of the formula
 EMI21.2
 recrystallized from acetone-ether and 1 drop of pyridine melts at 155-1570. The later benzene fractions contain 430 mg of unchanged starting material.



    Example 27: 3g of 2,2-dimethallyl-4bss-methyl-7-ethylenedioxy-1,2,3,4,4aα, 4b, 5,6,7,8,10,10ass- - dodecahydrophenanthren-l-one- 46-ol are dissolved in 30 cm 3 of methanol and 30 cm of ethyl acetate and strongly cooled. At -10, a stream of oxygen containing 20 mg of ozone per minute is started with rapid stirring. The temperature is now reduced to -65 within 3 minutes and then slowly further reduced to -750. Treatment is carried out with ozone-containing oxygen of the specified concentration for a total of 51 minutes.

   The oxygen is then displaced by nitrogen, about 15 g zinc dust activated by means of dilute acetic acid and washed with 50% alcohol is added at -50 to -100, and then a mixture of 25 cm3 water, 25 cm * alcohol, 10 cm3 acetic acid and 20 cm3 pyridine. After 15-20 minutes, the unused zinc is filtered off and washed with benzene. The filtrate is washed neutral with saturated sodium hydrogen carbonate solution and the organic solution is dried with sodium sulfate and concentrated in vacuo. This is what you get when it cools down

 <Desc / Clms Page number 22>

 2, 2-Diacetonyl-4bss-methyl-7-ethylenedioxy-l, 2, 3, 4, 4act, 4b, 5, 6, 7, 8, 10, 10ass-dodecahydrophenanthren- - 1-one-4ss-ol of the formula
 EMI22.1
 in colorless crystals from F. = 1830.

   A further amount can be obtained from the mother liquor by chromatography on aluminum oxide and eluting with benzene.



   By heating this compound in benzene with the addition of glacial acetic acid and pyridine, the dehydration product of the formula described in Example 26 is obtained
 EMI22.2
 Example 28: 2.146 g of the cyclic enol ether of the formula described in Example 25
 EMI22.3
 vom F. = 1820 are dissolved in 250 ems benzene and traces of moisture are removed by distilling off 50 CM3 benzene. Then you give a solution of potassium tert prepared as follows. Butylate in 150 cm3 of benzene to: 500 mg of potassium metal are tert in 50 ems. Butyl alcohol is dissolved and the solution is evaporated to dryness in vacuo. Then 100 cm3 of benzene are added, the last residues of butyl alcohol are evaporated to dryness again in vacuo, taken up in 150 cm3 of benzene and heated to the boil.

   The hot solution is added directly to the solution of the methyl ketone regardless of the undissolved components. The reflux is continued in a nitrogen atmosphere for 4 hours.



  After cooling, the mixture is washed with water, sodium hydrogen carbonate solution and water, dried and evaporated to dryness in a vacuum.



   1.95 g of a residue are obtained which crystallizes completely on addition of a little acetone and shows a molar extinction e of 25,500 at 236 μm. The crude product is purified by filtration through 60 g of aluminum oxide (activity II), benzene and ethyl acetate being used as the eluent. 1.4 g of the pure d1- # 4,14,18-3,16-dioxo-11ss, 18a-oxido- 18a-methyl-18-homo-androstatriene of the formula are obtained

 <Desc / Clms Page number 23>

 
 EMI23.1
 from F. = 194-196. In an alcoholic solution it shows a strong absorption maximum at 236 μm (e = 33500).



   In the infrared spectrum the compound in methylene chloride solution shows the band of the (x, ss-unsaturated
 EMI23.2
 strong double bond at 6, 19 left



     Example 29: Ig of the cyclic enol ether of F. = 1820 described in Example 25 is dissolved in 100 cm 3 of methanol while nitrogen is passed through and heating. Add 10 g of potassium hydroxide (in cookies) through the cooler and dissolve while swirling. The reaction mixture is heated to gentle reflux for 20 hours while passing nitrogen through. After cooling, carbon dioxide gas is passed into the reaction mixture until it is saturated and, after adding 100 cms of ethyl acetate, the carbonates which have crystallized out are dissolved using water. The aqueous layer is separated from the organic layer and the former is extracted with ethyl acetate. After drying with sodium sulfate, the solvents are distilled off in vacuo. The crude product is dissolved in benzene and filtered through an approximately 2 1/2 cm thick layer of fuller's earth to decolorize.

   When the filtrate is concentrated, the d1- # 4,14,18-3,16-Dixo-11ss, 18a-oxido-18a-methyl-18-homo-androstatriene described in Example 28 crystallizes in pure form out.



     Example 30: 1 g of the monoketal of the cyclic enol ether of F. = 150-1520 described in Example 26 are dissolved in 60 cm3 of warm methanol under nitrogen and 6 g of potassium hydroxide are added through the condenser. The reaction mixture is heated to gentle reflux for 14 hours. Working up is carried out as in Example 29 using carbon dioxide gas, ethyl acetate and water. From the benzene solution purified in the manner described with fuller's earth, by concentration, the dl-A '"'" - -3-ethylenedioxy-11ss, 18a-oxido-16-oxo-18a-methyl-18-homo-androstatriene is obtained as a colorless oil, which crystallizes in leaves of F. = 160-161 when stirred with ether and pentane. It has the formula
 EMI23.3
 and has a maximum of 232 mg (e = 17100) in alcoholic solution.



   The monoketal described in Example 26 can also, according to the information in Example 28, with potassium tert. Butylate are cyclized. The above-described dl-A5, 14, 18-3-ethylenedioxy-llss, 18a-oxido-16-oxo-18a-methyl-18-homo-androstatriene is obtained in a yield of 75 to 80%.



   Example 31: From a solution of 1.1 g of d1- # 4,14,18-3,16-Dioxo-11ss, 18a-Oxido-18a-methyl-
 EMI23.4
 dried by distilling off benzene and replacing the distilled benzene with fresh, dry benzene. A total of 249 cm3 of solvent are then distilled off over the course of 5 hours.

 <Desc / Clms Page number 24>

 - dioxolane and 24.5 cm3 benzene and finally 92 cm3 benzene constant. After the contents of the flask have cooled down, semisaturated sodium bicarbonate solution is poured onto 40 cm3 and extracted twice with benzene.

   The benzene solutions are then washed successively with 40 cm3 of semi-saturated sodium bicarbonate solution and water. The residue from the dried and evaporated benzene solutions is then dissolved in 10 cm3 of benzene and chromatographed on 36 g aluminum oxide (activity II).



  First, the d1- # 5,14,18-3-ethylenedioxy-11ss, 18a-oxido-16-oxo-18a-methyl- - 18-homo-androstatriene of the formula is eluted with benzene
 EMI24.1
 It is identical to the compound described in Example 30 in terms of melting point and mixed melting point. There is still unreacted starting material in the later benzene fractions.

** WARNING ** End of DESC field may overlap beginning of CLMS **.

 

Claims (1)

PATENT CLAIMS: 1. Process for the preparation of IIB-oxy-16-oxo-steroids. with a natural configuration at carbon atom 13, which have a bridge consisting of 2 carbon atoms leading from this carbon atom to the 11ss hydroxyl group, characterized in that compounds of the formula EMI24.2 wherein Ri is a free or esterified oxy group or a protected oxo group and R is a free or esterified ss-oxy group, disubstituted in the 2-position with a compound of the formula halogen-CH-Y, in which Y is a free or functionally modified carboxyl or Is acetyl group or together with -CH- is an allyl, methallyl or propargyl radical, in the compounds obtained with the following partial formula of ring C EMI24.3 optionally converts the substituents -CHz-Y in the 2-position into acetic acid-acetaldehyde or acetonyl radicals in any order, reacts the 0-position substituent in the 2-position with the oxy group in the 4ss-position, the a-position substituent If necessary, it is converted into an acetonyl radical in the 2-position and this is condensed with the keto group in the 1-position to form a 5-ring. <Desc / Clms Page number 25> 2. The method according to claim l, characterized in that an allyl halide, in particular allyl bromide and allyl iodide, is used as the compound of the formula halogen-CHz-Y. 3. The method according to claim 1, characterized in that a methallyl halide, in particular methallyl bromide and methallyl iodide, is used as the compound of the formula halogen-CH-Y. 4. The method according to claim 1, characterized in that in compounds with the partial formula of the ring C EMI25.1 by selective ozonization, the allyl residue in the ss position is first degraded to an acetaldehyde residue and this is converted into the cyclic enol ether grouping -O-CH = CH- between carbon atoms 48 and 2ss or to a carboxymethyl residue of the formula -O-CO- lactonized with the 4-oxy group CH2 oxidized. 5. The method according to claims 1 and 4, characterized in that in compounds with the partial formula of the ring C EMI25.2 the a-position allyl radical is converted into a halohydrin of the following partial formula by addition of hypohalous acid: EMI25.3 EMI25.4 EMI25.5 EMI25.6 EMI25.7 EMI25.8 <Desc / Clms Page number 26> 6. The method according to claims 1 and 4, characterized in that in compounds with the partial formula of the ring C EMI26.1 EMI26.2 EMI26.3 EMI26.4 EMI26.5 EMI26.6 EMI26.7 Allyl radical converts. 7. The method according to claim 1, characterized in that in compounds with the partial formula of the ring C EMI26.8 EMI26.9 EMI26.10 brings the acetonyl residue in the ss position to reaction by dehydration with the 4B-oxy group, cyclic enol ethers of the partial formula of the ring C <Desc / Clms Page number 27> EMI27.1 can be obtained. 9. The method according to claim l, characterized in that 2 (x-acetonyl-4ss-oxy-polyhydrophenanthren-l-ones, which have a 2-carbon bridge starting from carbon atom 2 to the 4 oxy group, to A14. 16- Oxo-steroids cyclized. 10. The method according to claim 9, characterized in that the 2cx-acetonyl-48-oxy- - polyhydrophenanthren-1-ones, alkaline condensation agents are allowed to act and water is split off from the 14-hydroxy-steroids which may be formed. 11. The method according to claims 9 and 10, characterized in that the cyclization with potassium tert. Butylate performs in an anhydrous medium. 12. The method according to claims 9 and 10, characterized in that the cyclization is carried out with alcoholic potassium hydroxide solution. 13. The method according to claims 9 to 12, characterized in that 2cx-acetonyl -48- oxy-polyhydrophenanthren-1-ones with a bridge of the formula -O-CO-CHz- leading from carbon atom 4 to carbon atom 2 for the cyclization used. 14. The method according to claims 9 to 12, characterized in that Sct-Acetonyl- - 4ss-oxy-polyhydrophenanthren-l-ones with a bridge of the formula leading from carbon atom 4 to carbon atom 2 EMI27.2 wherein R is a hydrogen atom or a methyl group, used for the cyclization.