BE653117A - - Google Patents

Description

       

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     ; STEROID COMPOUNDS PREPARATION PROCESS
AND PRODUCTS THUS OBTAINED.

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    The present invention relates to compost steroids and methods for preparing them. The present invention more particularly provides methods for increasing the progestational activity of 17O-ethyl steroids of the estrane series by substituting the estrane series. hydrogen atom in position @ of the ethylnyl group by a halogen atom.



  The present invention also relates to new intermediates and to the processes by which these compounds are prepared.



   The compounds prepared using the novel methods according to the present invention can be represented by the formula:
 EMI2.1
 where X is chlorine or bromine
According to the present invention., The progestational activity of 17Ó-etynyl-17ss-hydroxy-estra-4,9 (10) -dien-3-one is increased by replacing the hydrogen of the ethynyl group with a halogen atom, such as chlorine or bromine.

   The ethynyl compound can be obtained by reacting estradiene-

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   3,17-dione with a metal acetylide in liquid ammonia, for example, an alkali or alkaline earth metal acetylide, preferably sodium, potassium or calcium acetylide.



   In a process for replacing the hydrogen atom of the 17Ó-ethynyl group with an ahylogen atom, the starting compound, i.e. 17Ó-ethynyl-17ss-hydroxy-estra-4,9- (10) -dien-3-one is first protected at the C-3 position by an easily removable group, for example, by conversion of the compound into a ketal, an enol ether or a pyrolidin derivative by reaction with. appropriate derivative agent. The derivative is then converted to a 17ss-ether, for example a tetrahydropyranyl ether. The compound thus obtained is then transformed into an ethynylic anion which is reacted with a positive halogen.

   The series of reactions illustrating this process can be represented as follows:

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 EMI4.1
 

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 EMI5.1
 

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In the above formulas, X has the abovementioned meaning,
 EMI6.1
 3-Alkylbneoxy bridging compounds readily prepared by reaction with (interior alkylene) d1ol &.

   The ethylenedioxy derivative is prepaid by reacting the steroid with an excess of ethylene lyool in a solvent inert to the faction, consisting of a lower hydrocarbon or a halogenated hydrocarbon, such as benzene, toluene or
 EMI6.2
 ethylene bioliloride, in the presence of catalyst acids.



  Organic or inorganic acids can be used, such as toluenesulfonic acid or sulfuric acid. The strong water oowaa by-product of the reaction is continuously removed.



   In another process, a dioxolane such as
 EMI6.3
 as 2-ethyl-2-me "hyl-1,5; toioxolaaie, instead of ethylene glyool. Under analogous reaction conditions, the by-product which is the ketone formed by the decomposition of dioxolane; for example, the butanone is also eliminated on a continuous basis.



   Similarly, other oetals are prepared, such as (lower alkylene) dioxy oetals or containing up to 7 ato-
 EMI6.4
 carbon mon <Dnolic ethers can be prepared by the addition of alkyl orthoformates, such as ethyl orthohydrate and an acid catalyst, such as p-toluene aoido
 EMI6.5
 sulfonic acid, to a solution of the steroid in an inert reaction solvent, such as dioxane, and by stirring for about 1 to about 3 hours at a temperature of between about 2000 and about 35 C.

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   The N-pyrolidine derivatives are prepared by heating a mixture of the steroid and pyrolidine, preferably in slight excess, in a lower alkanolic solvent containing up to 5 carbon atoms. The mixture should be heated under reflux in an alkanol such as methanol for about 1 to 3 hours.

   The 17ss position is protected by conversion to an ether, preferably a tetrahydropyranilic ether. This can be done by mixing the steroid and dihydropyran in an inert reaction solvent or in an excess of dihydropyran and allowing the mixture to stand at a temperature between about 20 and about 35 C for about 10 to about 20 hours in. presence of an acid catalyst. Suitable catalysis include p-toluene sulfonyl chloride and 2,4-dinitrobenzene sulfonyl chloride ...



   In a variation of the base-halogen step illustrated above, the steroid, i.e. the steroid protected at Position 3 and Position 17, is converted to an alkali metal salt, preferably a salt. sodium or potassium and this compound is reacted with an N-haloacylimide such as N-bromo- or N-chlorosuccinimde. The sol can be prepared by adding an alkaline, metallic form to liquid ammonia containing a trace of a ferric salt, such as ferric chloride and then adding a solution of the steroid in an inert reaction solvent, such as than tetrahydrofuran. The reaction is completed, for example, by stirring for about 1 to about 3 hours.

   The ammonia is then allowed to evaporate and a solution of the selected N-haloacylimide in an inert reaction solvent is added.

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 The mixture is allowed to stand, preferably with stirring for 12 to about 18 hours until complete reaction is obtained.



   The product can be isolated in any suitable manner. In one process, the reaction mixture is poured into cold water and is extracted with ether.



  The organic layer is washed with an aqueous base, then it is washed with water and dried over an anhydrous drying agent, such as anhydrous magnesium sulfate. The drying agent is removed and the solvent is evaporated off, so as to give the desired product in the form of a residue: This compound can be purified by chromatography.



   In another process for preparing an alkali metal salt, the steroid and a suspension of an alkali metal amide, such as sodamide, in an inert organic reaction solvent, such as a hydrocarbon, preferably benzene or toluene and a slight excess of sulfonyl ahlogenide are heated, preferably under a nitrogen atmosphere, at a temperature of between about 80 ° C and about 100 ° for about 1 to about 4 hours. As the sulfonyl halide, it is preferred to use p-toluene sulfonyl chloride.



   The product can be isolated from the organic solvent in the same way as that which is used to isolate the same product as described in the previous paragraph.



   These two reactions can be described generically as reactions of the steroid with a source of positive halogen in the presence of a strong base,
Yet another method is available for the substitution of the hydrogen atom of the ethynyl group by

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 EMI9.1
 an atom of 14uloim $ QaJ1e that it is n6nosnairo to protect the Group 3-Oxoo 0epo dan%, It is possible to proteaer Ion eroupea by oonvaroton in a .t1uu ..., tol that the ether Danc this prooddd # le mataf composes.

   of deptirt used higher is first converted to a cther and then to a 20,21-diht \ 10 compound which is then
 EMI9.2
 
 EMI9.3
 dehydrohalogend so as to give the desired cooperation.
 EMI9.4
 form of an ether derivative,
 EMI9.5
 The reactive purchase of this component have illus% r4
 EMI9.6
 as follows!

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 EMI10.1
 
The 17ss-tetrahydropyranyloxy derivative is formed in the same manner as described above. It is then converted to a dihalosteroid.

   The dihalosteroid thus formed. is most easily referred to as a derivative of préganne and this nomenclature is adopted in this memo,
The 1? $ - ether thus prepared is then dihalogenated in the ethynyl group. A suitable method by which the halogenation is effected is the di-reote halogenation using a molecular halogenating agent, such as

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 chlorine or bromine.

   In this process, a solution of the steroid in an inert organic reaction solvent, preferably a halogenated lower hydrocarbon, such as chloroform or methylene bichloride is mixed, preferably by slow addition, to a solution of the halogen, of .preference, in the same solvent. The reaction is a reaction (it routs at low temperature and it is best to keep the temperature between about -10 0 and about 10 during the formation of the 20,21-dihalo steroid.



   The product can be isolated by any suitable method. In a suitable method, the reaction mixture is first washed with an aqueous base, such as saturated sodium bicarbonate solution, and is then lifted with water. The organic layer is separated, dried over an anhydrous drying agent, such as anhydrous sodium sulfate, filtered and the solvent removed therefrom to give the desired product as a residue.



   The 20,21-dihalo compound can also be prepared
 EMI11.1
 by treating the steroid with an lt-haloacylimide such as I3-oh.arosuco: in: itaida or H-bromosuccil1.imide in the presence of an alkali metal halide, preferably lithium chloride or bromide, of sodium or potassium. The temperature of the reaction is not critical. For the sake of convenience, it is preferable to mix the ingredients in an inert reaction solvent of the type described above with respect to the reaction with the molecular halogen.
 EMI11.2
 at room temperature, it is 20 ° C to 30 ° C. The reaction is GtSn6rnlc; H: mt tel'lainúe in about 10 minutes and about 4 hours.

   For reasons of economy, it is preferred to use an oxcù icGer, - ,, that is to say a cxooa molar

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 up to 10%, of the halogenating agent in order to ensure as complete a reaction as possible of the steroid. This is not essential, however. The product can be recovered in the same way as that described in the previous paragraph.



   The best yields are obtained in this process by using mixtures of the N-haloacylimide and the alkali metal halide which are prepared and collected together. For example, a mixture of N-bromosuccinimide and potassium bromide can be obtained by coprecipitation from a lower alkanol solvent. The precipitate is formed by adding molecular bromine to an equimolar mixture. re of suocinimide and potassium hydroxide in an alkanol such as methanol.



   The 20,21-dihalo steroid is then dehydrohalogenated with a strong base in an inert reaction solvent. The blocking group in position 17 is then removed to give the desired product. The reaction is carried out by treating the steroid at an elevated temperature, for example, at a temperature of between about 75 and about 120 C, in an inert organic reaction solvent, preferably a lower halogenated hydrocarbon, with a solution. of an alkali metal lower alkoxide, such as potassium t-butoxide, preferably in the same solvent.



  It is easiest to simply take up the reactants in a solvent whose boiling point is between the above-mentioned limits and to heat under reflux for about 3 to 5 hours. The reaction mixture is then acidified, for example, by the addition of an aqueous mineral acid. such as dilute aqueous hydrochloric acid, at a temperature between about 20 ° C and about 35 ° C. for about

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 8 to about 16 hours,
The resulting product can be cut again as described above for the dihalo compound.



   The hydrogen atom of the ethynyl group can also be replaced by a halogen atom by first reacting the ethynyl compound with a heavy metal lower alkanoate, such as mercuric acetate, to obtain the salt. of corresponding disteroid metal which upon treatment with molecular halide gives the desired product. This process can be illustrated as follows:
 EMI13.1
 
The heavy metal salt, for example the mercury or silver salt, is formed by reaction between the steroid and a selected heavy metal aloanoate in a basic organic solvent, for example, a (lower alkyl) amine, preferably butylamine.

   A solution of the steroid in the chosen solvent should be added to a solution of the salt in

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 the same solvent at a temperature of between about 20 ° C and about 35 ° C. There is an initial development of heat and when this release of heat ceases, the desired product can be isolated.



     A suitable isolation method is to add the reaction mixture to a cold dilute aqueous mineral acid such as 0.3N to 1.0N sulfuric acid. The product is recovered from the aqueous mixture by attraction with a non-organic solvent. miscible with water, such as ethyl acetate, this removing operation followed by the removal of the solvent.



   The metal salt of the steroid is converted to the desired 17O-halothynyl steroid by reaction with molecular halogen. This conversion is carried out by adding a solution of the selected moleal halogen in an inert organic reaction solvent to a solution of the heavy metal salt of the steroid in preferably the same solvent. The reaction is terminated by stirring for about 10 minutes to about 1 hour after the addition. As suitable solvents, mention may be made of solvent aromatic hydrocarbons, such as benzene, toluene and xylene. Among these compounds, please use benzene.



   The product can be recovered by evaporating the solvent in vacuo and it can be purified by chromatography.



  For example, the residue is taken up in petroleum ether containing up to 10% by weight of benzene and then washed in a charcoal column containing one part to 10 of charcoal supporting 10% palladium. . The purified product is recovered by removing the solvent.

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   A number of new and interesting intermediates are prepared by the methods according to the present invention.
 EMI15.1
 vention, Among oetix-cil there may be mentioned 3-ketal, 3-enol ether and 3-PYrrolidinîques derivatives of 1'la-t, tY ,, ynyl and l7-haloÓthynyl-17P-tétrahydropyranyloxy-aatrn-5 (10) t9 (11). dibn-3-one which can be represented by the following functions
 EMI15.2
 in these formulas THP represents a tetrahydropyranyl group, R is a lower alkyl radical and Y is halogen, chlorine or bromine,
Other new compounds are the 17ss- drifts
 EMI15.3
 20,21-dihalo-pregna-'4t9t20-tren-3'-one tetrahydropyranyloxy which may be represented by the formula;

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 EMI16.1
 In these formulas THP and X have the meanings indicated above.



   The heavy metal salts of the steroids prepared according to the present invention are also new. Those are
 EMI16.2
 heavy metal salts of .α-ethynyl-7.7-hydroxy-esra-.4 g-dien-3-ones and may be represented by the formula:
 EMI16.3
 in this formula M is a heavy metal such as mercury or silver.



   EXAMPLE 1
 EMI16.4
 To a solution of 1 g of 17 - ± thynyl-17 # -hydroxy-439-estxad3.ene.-3-one dissolved in 75 ml of benzene, 7 $ 5 ml of ethylene glycol are added together with 50 mg of bzz toluene sulfonic acid. The reaction mixture is heated under reflux with a water separator for 20 hours. The reaction mixture is cooled and a bicarbonate solution is added, the reaction mixture then being extracted with ether. The combined extracts are washed with water,

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 EMI17.1
 dried over sodium sulfate and evaporated to alcoholic strength to give 3-etlenodioxy-17'-thynyl'-17P''hydroxy'-: A), 9 (11-e atradine.



  BXHIJPLE 2 ..



  3 N1 of pyrrolidine are added to a solution of 2.7 g of l7ac-dthyny3.-17-hydroy. 9-satxadins - ona in 30 ml of methanol, The solution is heated under reflux under a nitrogen atmosphere for 1 hour. The solution is reduced in volume in vacuo, taking care to exclude moisture. The product crystallizes on cooling and is recrystallized.
 EMI17.2
 read so as to give 3-N prrrol3dylj-.7a-étlyny .-. 7 ^ hydxoy-3, - (10.9x1) -estxatr3.ene, normally pure, Ei, ''. 'TE 3, A mixture of 1 g of 17 -dthynyl-17P-hydroxy-4 # 9 * - estradiene-3-onep 100 mg of p-toluene sulfonic acid monohydreoé and 20 ml of 2-dthyl-2-methyl- 103-dioxolane is heated and the butanone released,

   is mixed with the dioxolane reagent, then slowly distilled through
 EMI17.3
 a small Claisen-Vigreux column at atmospheric pressure for 5 hours. The cooled reaction mixture -
 EMI17.4
 is diluted with benzene, washed successively a. using a 5% aqueous solution of sodium bicarbonate and using water, dried over sodium sulfate and concentrated to
 EMI17.5
 to dryness. Crystallization gives 3-'ethylenedioxy-.? A-thynyl-1.7hydroxy-5 (7.Oa, 9 (1,1) -eatradiene, Ex21, tPL-4.



  4'a solution of 100 mg of 1.7t-ethyny.-1? -Hydroay.



  4, 9 - eetxadine-3-one in 3 ml of dioxane add 2 al of ethyl orthoformate and 10 mg of 2 # 4-dinitrobonzene acid

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 EMI18.1
 âulfonitlue. Lo 'reaction mixture is stirred at room temperature for 3 hours and 1 ml of pyridine is added, this addition being followed by the dropwise addition of 5 ml of water. The aqueous phase is separated and extracted with benzene. The organic extracts are washed with sodium bicarbonate solution and then with water until the washings are neutral.

   The organic phase is dried over sodium sulfate and concentrate
 EMI18.2
 in vacuo to give 3-etlioxy-17 -ethynyl-175-y & roy''3t5 (10), 9 (II) -estrtrieno. 1 due $ -ébhjléxiedioXy-17 -éthynyl-175-hyùroxy- is dissolved in 5 ml of freshly distilled 2,3-dihydropyran, 0.1 g of chloride of
 EMI18.3
 p -tùluùnei> ùlfonylv and the mixture is left to stand for 14 hours at room temperature.

   100 ml of ether are added: and the mixture is washed successively with a normal aqueous solution of sodium hydroxide and water, the ethereal layer is dried over magnesium sulfate, filtered and the filtrate.
 EMI18.4
 is evaporated to give substantially pure 5-% hylenedioxyl-dthynyl-1µ-hfidroxy-5 (10), 9 (11) -es-trcdene-17) -ereetral% yàro-pyranyl ether.



   By repeating the procedure described above
 EMI18.5
 but starting from 3- (N-pyrrolidyl) -17 -6% hynyl-17µ-ùydioxy- 3e5 (10) t9 (II) -estratriene and 3-ethoxy-17a-ethynyl-17Phyàroxy-3,5 (EG) , 9 (? 1) -ea% raEriene instead of 3-ethyllenedioxyl7 "-Óthynyl-17-hydrox-5 (10), 911) -estradiene, we obtain ether 3- (X-PYrrolïdYl) -17g- EtIlYnYl-17p-hydroxy.-3s5 (10) 9 "9 (11) -eatratrièna-17tetruhydropyranyl and 3-ethoxy-17 -ethynyl-17-11ydoxY-3t5. <10), 9 (11) -vstoeatriene.

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   EXAMPLE 6
30 ml of liquid ammonia are placed in a three-necked flask which has been cooled in dry ice, which flask is equipped with a stirrer, an inlet tube and an outlet tube.

   78 mg of metallic potassium are added in small pieces. A trace of crystalline ferric chloride is added and the mixture is stirred until the blue color disappears. Then 788 mg of ether are added
 EMI19.1
 3-ethoxy-1? A-ethymy.-3, 5 (10 d, 9 (-1) - $ e'ratx3, enow3.? -. Tetrahydro pyranyl in 10 ml of tetrahydrofuran. The mixture is stirred for 3 hours and the ammonia is allowed to evaporate overnight under a slow stream of nitrogen, taking great care to exclude all moisture and oxygen.

   Then 50 ml of dry tetrahydrofuran are added and the mixture is stirred! so as to give a suspension of the potassium salt of
 EMI19.2
 3-Ethoxy-. Ta-ethynyl-, 5 (.0), 9 (11) -. estratriñe 17P-tetrahydropyrany7 ether, which is used without further purification. By repeating the procedure described above but starting with lithium, sodium and calcium instead of potassium, the corresponding lithium, sodium or potassium salt is obtained, repeating the procedure described above,
 EMI19.3
 but using 3-ethylenedioxy-17ct-ethynyl'- 5 (.J) s (lâ.) - eatrac.ene .. 'l-té'rahydropyrazy.ique ether and ether - (N-pyrraaidy .) .- ÏJ.? A-ethynyl-3,5.) R9 .-) - estratr.

    ne-17p-tetrahydropyranyl instead of 3-ethoxy-17a-ethynyl-17fi-hyàr'oxµ-5.5 (10), 9 (11) -eBtratriéne tètrahydropyr M li ether. that, one obtains the metal salt of the ether 3-ethylnedioxy.1? a-etynYl (10) 97.1) -estradine-1 "-tetrahydropyrany.ique and the metal salt of the ether 3- (N -pyrro.idyl) - ,? a.-ethynyl-3, (10) 91.) - estratriene-1? rtetrahydxopyrany.3que corresponding,

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   EXAMPLE '-. Has a suspension of ether potassium salt 3-
 EMI20.1
 Ethoxy-.7a-cthynyl-3, 5 (10) to 9 (11) -eatratrin-1? -tetrahydropyranyl in tetrahydroeuran a solution of P..ahlorosuoa3: nim.de in carbon tetrachloride is added. The mixture is stirred at room temperature for approximately
 EMI20.2
 18 hours. The whole reaction mixture is poured into water and extracted with ether.

   The ethereal extracts are 1 avé with a saturated aqueous solution of sodium bicarbonate and then with the aid of water, The ethereal extract is dried.
 EMI20.3
 over sodium sulfate, filtered and evaporated to dryness. The oily residue is filtered through aluminum oxide to give another oil which is ohromatographed on activated alkaline alumina; Elution gives ether
 EMI20.4
 3-ethoxy - 1? A-chlnroethynyz-3,5 (10j, (li) -eatratriene-Z? - ,,, tetrahydrapyranyl3.que, .. ', By repeating the procedure described above,' 'but using! {- c1! Dl'OJ:! tosuccinimide instead of N- chio "'roeucc.nim.de gives ether.3-ethoxy..1? a-bramoethy .. nyl-3 , 5t1), 9 (11) -estratr.iene-1? -TetrahydrapyranylicPue.



  By repeating the procedure described above but starting with a metal salt of 3-ethylene ether, ioxy-17% Eynyl-5 (, 0) 9 (1j-eetradien-1? -tetrahydrapyranyl and a metal salt of 3- (N-PYrrolidy.) - 17a-ethynyl-3,5 (.0) 9 (J ..) -: estratriene-17P-tetrahydropyranyl instead of a metal salt of 3-ethoxY-17a-6thynyl-335 (10) 09 (II) -estratriene-17P-t6tral'YclroPYranYliquQi the ether is obtained; -ethylene- di, oxy-1? a-ha7 .oéthny.-5 (1n), g (.a) -eetradiene-.1? -tetrahydxopy- ranyl ether and 3- (N-pyrrol.dyl) .-.? a-halcethynyl-3,5 (ln ) .. 9 (llj-estratribne-17p-tetrahydropyranylic corresponding,

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 EXAMPLE 8.
 EMI21.1
 



  A solution of ether 3-u "tlioxy-17 -dtliynyl- # 5.) ..- atxatxna-.?.ttaydrapyxatrà..cua (0.2 mole) is added, while stirring vlaourousemoiitt to a suspension of Ot2 mole of sodanide in boxizene and then slowly added a solution of 41.9 g (0.22 mole) of p-to.uénssul "an5rle chloride in 100 ml of bonzënet 4 after heating under reflux for 1 hour, the The same mixture is deoonposed with dilute hydrochloric acid and the benzene layer is added, washed with a saturated aqueous solution of sodium bicarbonate and then with water.

   The benzene extract is dried over sodium sulfate, filtered and concentrated in vacuo to give an oily residue which is filtered through aluminum oxide, so as to give another zero which is
 EMI21.2
 chromatography on activated alkaline alumina, The elution - denotes ether 3-thoxy-x'a-ohloro thynyl-3, 5 (24 i, 9 (..

   estratriene-17p-tetrahydropyranyl, By repeating the procedure described above but starting with p-toluene sulfonyl bromide instead of p-toluene sulfonyl chloride, ether 3-
 EMI21.3
 ethoxy -.? c-bromoethynyl-3,5 (.0), 9 (1.) estratxieno-7.? - tdtra-hydropyranyl,
By repeating the procedure described above,
 EMI21.4
 but starting from ether -thylnedioy ...? a-6tïyny.-5 (1.4), - 9 (II) -estradiene-17p-tetrahydropyranyl and ether (11-pyr-rolidy.) - 1,? a -ethynyl-3,5 (-0) 9 (il) -eatxatriene-1? -ttrahydropyranyl instead of 3-ethoxy-17a-ethynyl-3,5 (10), 9 (11) -estratriene-1 ? -tétxahydropyrany7.ique, one obtains the ether -ethyléned.oxy.-17a-halothynyl- (lti, 9 (..)

   

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 EMI22.1
 estraàLene-1? fi-% ± trahyàropyrRhyligua at ether 5- (1; -pyrr0- 1 idyl) -17t <. "httl0ëtnynyl, 5 (10), 9 (ll) - 'MtratxiBne'-17P-ttra- iiydropyranyliquo oecxQspondMts, ¯ f! * A solution of 400 mg of ether µ-é% hoxy-17ù-0hloro-) ùthynyl-3,5 (10), 9 (11) -estra% rene-175-% et> al1¯ vdrory> anylique dune 40 ml of methanol, 0) 8 ml of concentrated hydrochloric acid are added and the reaction mixture is stirred until
 EMI22.2
 leyideràuin at room temperature. The methanol is then - driven off under reduced pressure, water is added and the mixture
 EMI22.3
 t ', 1actioel is extracted with ether.

   The combined ethereal extracts are washed with water and dried over sodium sulfate, filtered and evaporated so as to give
 EMI22.4
 17 -ohloroethynyl-17fi-hydroxy-4,9-estradiene-5-one.



  By repeating the procedure described above, starting with ether '... thoXY ",, 17rx..bromoethynyl..3.5 (10), ...



  9 (11) -eotratriànQ17..tétrahydropyranyliqueJ ether 3-ethyl enedicxy-17 -cliloroé% hynyi-5 (10), 9 (11) -estradiéne-17fiet ² t6tre, hydropY). '8nyli, (:!. Ue , (dT é'cher 3-6thylenedioxy-17 ,, - bromoethynyl-5 (10), 9 (II) -estradian-.17p-tetrahydropyrari.ylique, ether 5- (Îl-pyrtnlià6'l) -17 - ohloroé% hy'nyl-3,5 (10), 9 (11) -es% ratriéne- 17-tútruhydropyrany1iqut ether 3 - (. i-PYrrolidYl) -17g-bro- 'moet} lynyl-3,5 ( 10) t9 (11) -estratriene-17-tetrahydropyranyl instead of 3-ethoxy-17 -chloroethynyl-3,5 (10) t9 (ll) - estratriene-17-tetrahydropyranyl ether, 17-halo-Jthynyl- is obtained. Corresponding 17-hydroxy-4.9- & stradiene -; - Example 10.
 EMI22.5
 



  To a solution of 17ct-ethynyl-4t9 "estradiene-3-Qne-17-t6traldropyranyl ether in chloroform which is cooled to 0 ° C. is added dropwise while stirring a solution of chlorine in chloroform. . The solution

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 is washed with a saturated aqueous solution of sodium bicarbonate and with water, dried over sodium sulfate and evaporated to siucency so as to give
 EMI23.1
 20,.-d.ah.oro-4, 9 r, 1-nornrwnatx.ne-3.-one-.7-tetrahydropyranyl ether which can be used without further purification.



   By repeating the procedure described above but using bromine instead of chlorine, ether is obtained.
 EMI23.2
 2t3, 21-d.bramo-4, 2C-19-nor-pre; natx.ne-3-one tdtraliydropy-1 ranyl, EXAMPLE 11
 EMI23.3
 400. .7a - thyny.-4 9-estrad.ene-3 - one-17tetrahydropyranyl ether are dissolved in 10 ml of carbon tetrachloride and a mixture of 205 mg of i-bromc, uca.n3.miùo at 61 1; 1 (containing 125 mg of oe n-brotlosuccinimide and 80 l.: Of potassium bromide) are heated under reflux for 14 hrs. The mixture is cooled and filtered, the filtrate is washed with a @ de. with a saturated aqueous solution of sodium bicarbonate and then with water.

   The carbon tetrachloride solution is then dried over sodium sulfate, filtered and
 EMI23.4
 porée so a. give substantially pure 20,21-dibromo-4., 9,20-19nor-prna.trene-3-one-i-ttrahydxopyxajxyltether.



  2n. 1 and the procedure described oi-desxun maiz using sodium bromide or lithium bromide instead of potassium bromide, the same product is obtained !.



   Likewise, using an alkali metal chloride
 EMI23.5
 in the presence of 3: - ehlorouuec.niuide instead of an alkali metal bromide in the presence of H-broTJ1oDuociuirnidet one obtains the ether 20,, d, a, oo- x, G-1.t.tor-yfc , 'tt'L7e''toâo.ew7tù% Tlli13'di QpyraÎlyli4uo *

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 EMI24.1
 N-halosuccinimide / alkali metal halide 1 mixtures as used above can be prepared as; 65 g of potassium hydroxide are added to a mixture of 200 ml of methanol and 400 ml of water. The solution is cooled to 0 ° C. and 99 g (1 mole) of sucoinimide are added, with vigorous stirring. As soon as any insoluble material is removed by filtration, 160 g (91 moles) of bromine are added rapidly and with stirring.

   The precipitated mixture
 EMI24.2
 N-bromoeuccinimide-potassium bromide is filtered off, washed with 3 100 ml portions of methanol and dried over phosphorus pentoxide in vacuo. The yield is.
 EMI24.3
 150 g. The content of N-bromo-auccinimide is determined by iodometrics and the content of potassium bromide is determined by reduction to ash with perchioric acid.
 EMI24.4
 E.J # MPLE 12. "-
Potassium is dissolved in t-butanol. The t-butanoi is distilled off under a nitrogen atmosphere and under reduced pressure and is replaced by dry benzene in which
 EMI24.5
 a solution of 20,21-alahloio-4,9,20; 19-noi-prregnatriene-3-one-17P-tetrahydropyranyl ether in benzene is added.



  The mixture is heated under reflux for 4 hours and after cooling it is acidified with hydrochloric acid, aqueous (4N) and stirred overnight. The benzene layer
 EMI24.6
 that is washed with saturated aqueous sodium bicarbonate lolut1on and water, washed over sodium sulfate and evaporated to dryness in vacuo to give l. 'a-ahlaroëthynyl -.? S-hydroxy- ° r9-estradiene-one.

 <Desc / Clms Page number 25>

 By repeating the procedure described above
 EMI25.1
 nuia starting from ether 20,1.-d3.lxoaa-, 9,0-.9-nox-prdgnatrine - on $ -ï'R-tetrah3raropyrrnyliuo, instead of ether 20921dàoh, aro- $ 9 a - -nor-prdgnatr.èo-onol7-tdtrab.ydropyru nylique, we obtain 1? a-brom.o; th3'n3'1¯.? hydrocy-4 9estradiene-3-one * X.:b'2 13 .



  A solution of 17a-ctlayyyl-.?-ydxoxy-4.9^dta-diene -'- o1e in 10 ml of n-butylamine is added to a so.u-. tion of mercuric acetate in 15 ml of the same solvent. After 2 minutes, when the evolution of heat has ceased, the mixture is poured into 50 ml of 0.5 N glaoated sulfuric acid and the neutral fraction is extracted with ethyl acetate.
 EMI25.2
 



  The ethyl acetate extract is SeOAe over sodium sulfate and evaporated to dryness. The residue is reoriatalliated in benzene so as to give di (17 - ± thynyl-17fihydroxy * -4t9-'e8tradiënG-3-ono) mercury # E7 ,.



  To a stirred solution of at. (,? A. Dtyzrl..xp..h3'a.'oY ^ 4.9 - sstradiana-3-ane mercury in 150 ml of benzene is added dropwise a solution of 1.81 g of bromine in 20 ml of benzene. A red tint persists after 80% of the bromine has been added. When the addition is complete, the mixture is stirred for a further 10 minutes and the solvent is removed in vacuo at 60 C.

   The residue is extracted several times with a cooled mixture of light and good petroleum.
 EMI25.3
 senna and the extract is freed from the metal bromide by passing through a short column of charcoal containing one part to 10 of charcoal supporting 10% palladium. Evaporation of the eluate followed by the recirstal-

 <Desc / Clms Page number 26>

 
 EMI26.1
 binding in ethyl acetate, gives 17e-bromoethynyl-17P ** hydroxy-419-e8tradiene-'3-'one <Using the oi-dessua procedure, but using chlorine in tetrachlo-ure. carbon, instead of bromine in benzene, one obtains 17 -obloroé% hynyl-17µ-hydroxy-4'9-est & dien9 '<3' <6s.e.



   By repeating the procedure described above but starting with the corresponding silver acetylide instead of
 EMI26.2
 meroure taoetylide. we get the same product. ro.'VENDI, 9AT IOlTf6 ...



  1.- Method to increase the progestational activity of 179-dthynyl st44roids of the estrane series. oaraotëpi-! se in that the hydrogen atom of the ethynyl group is replaced by a halogen.



   2. - Process for increasing progestational activity
 EMI26.3
 of 17 -ethynyl steroids of the estranet series characterized in that the hydrogen atom of the ethyny- group is replaced
 EMI26.4
 Io by ùu b'.t'QtIll3.



  3, Proceeds to increase the progestagenic activity of 179-ethynyl 4% estranium series, caraoterized, by replacing the hydrogen atom of the ethynyl group by chlorine: ''
4.- Proceeds to increase progestational activity
 EMI26.5
 of 17 -ethynyl steroldea of the estrane series, caraoteri.-:

   Born in that a 3-elkylenedioxy derivative of a 17a-etliynyl-17P-liydroxy-ootra-4i9-dibn-3-one is formed, in this. that said derivative is reacted with dihydropyran, in that the β-tet5ahydropyTanyliguo ether thus obtained is made to react with a
 EMI26.6
 alkali metal in liquid ammonia, in that the alkali metal salt thus obtained is reacted with an N-halo.

 <Desc / Clms Page number 27>

 
 EMI27.1
 acylimide and in that the 17o: '- haloethynyl compound is hydrolyzed. of, way to eliminate the alitylénodioxy and tatra groups
 EMI27.2
 hydropyranyl.
 EMI27.3
 



  5.- Process for increasing the progestational activity 4a 17 -ethynyi staroldes of the estrune series, characterized in that one reacts a 17cc-ethynyl-17p'-hydroxy-cstra- '4,9-diônL5- one with ethylene slyool, in that the 3'-ethylenedioxy compound thus obtained is reacted with dihydropyran, in that the 17-tetrahydropyranyl ether is reacted.
 EMI27.4
 as thus obtained with sodium in liquid ammonia, in that the sodium salt thus obtained is reacted with
 EMI27.5
 ri-chlorosucciniiiiide and in that the l7ahaloethynylic compound thus obtained is hydrolyzed so as to eliminate the thy7 nedà.o; r and tJtta1iydrcpàrmùiyl groups.



  6.- rrocedd to increase the progestational activity of 17a-ethynyl stcroidds of the estranium s; xe, oaiaotéii- jé in that one makes z, àajin a 17 -ethynyl-17fi-hyàroxy-ea% ra - 4,9-dien-3-one with 2-thy7.-2-nthyl .-., - dioxolane, in that the compound 3-thylrtedioxy thus obtained is reacted with dihyarh3rrane, in that the 17-tetrahydropyranilic ether thus obtained is reacted with sodium in liquid ammonia, in that the sodium salt thus obtained is reacted with il-clilorozucoiniiùiùe and in that the coiZ is hydrolyzed, -, os, 7i ioe-1: aloétliô n: rligue r.inzi obtained in such a way as to eliminate the ethylcnedioxy groups Jt t-trElyü.rOpy.-
 EMI27.6
 ranyle.
 EMI27.7
 



  7, - Proceeds to: j: entar the progestational activity of 17a-6thynyl steroides of the estrane series, characterized in that one forr-you an enolic deleter of a 3.?a-thynyl-173iyd : o ty-estza- $ ¯dièn-3-o2ae, in 00 that said uther is reacted with trihydropyran, in that one makes dthcr iGnzir
 EMI27.8
 

 <Desc / Clms Page number 28>

   17-tetrahydropyranilic thus obtained with an alkali metal in liquid ammonia, in that the alkali metal salt thus obtained is reacted with an N-haloacylimide and in this
 EMI28.1
 that the compound '' Ta.hal.oéthynyl3cue obtained is hydrolyzed in order to regenerate the 3-oxo- and 17P-hydroxyl groups.



   8.- Procedure for increasing progestational activity
 EMI28.2
 of 17α-ethynyl sterols of the estrane series, aaraetéx3gé, in that a .7α-ethynyl, .1? -hydraxy: estra-4,9-dien-3-one is reacted with. ethyl orthoformate, in that the 3-ethoxyenolic ether thus obtained is reacted with dihydropyran, in that the 17-tetrahydropyranilic ether thus obtained is reacted with sodium in liquid ammonia, in that the sodium salt obtained is reacted
 EMI28.3
 with ii-ahiorosuàainimide and in that the obtained 17α-chloroethynyl compound is hydrolyzed in order to regenerate the 3-oxo'- 'and 17P-hydroxyl groups.



   9.- Method for increasing the progestational activity of 17α-ethynyl sterols of the estrane series, characterized
 EMI28.4
 in that a 17 -ethyny] -17p-hydroxy-estra-4,9-dien-3-one is reacted with pyrrolidine, in that
 EMI28.5
 reacting the 3- (N-pyrrolidinyl) compound obtained with dihydropyran, in that the obtained 17-tetrahydropyranil ether is reacted with an alkali metal in liquid ammonia, in that it is made react the alkali metal salt thus obtained
 EMI28.6
 with a ii-haloacylimide and in which the 1Ta-hal.athynyl compound obtained is hydrolyzed in order to regenerate the 3-oxo and 173-hydror groups: y.e.



  10.- Process for increasing the progestational activity of L7a-ethylwnyl steroids of the sarie'de estrane, characterized in that reacting a 17 -ethynyl-17p-hydroxy-estra-

 <Desc / Clms Page number 29>

 
 EMI29.1
 4t9 '-' din-5-ono Mreo of pyrrolidinc, in that the compound obtained is made with dihydropyrano, in that the - \ $ 1her 17-tetrahYdroJfy;: a111que obtained with aodiua toinx liquid ammonia, in that the sodium salt thus obtained is reacted with Ï! -chlorosuocinimide and in that the compound is hydrolyzed 17 <t-haloethrnyliquo obtonu afi;

  i do ejadnérde los groupas 3 "oxc- 'and 170-
 EMI29.2
 hydroxyl,
 EMI29.3
 11.- Proceeded to increase progoetntive activity!
 EMI29.4
 
 EMI29.5
 of 17 -6thynyl stéro'Cdea of the series of Itentranc, oaraoterized in that one forms a derivative 5-alltylidene toioxy of 170e-ôthynyl- 17µ-hyEroxyeBtra-4 + 9 = alien-3-one, in that one makes Really said derivative with dillydropyran, in that the ether L7-% 1t> allyàropyoeciniliçue thus obtained is combined with an alkali metal amide and an ouleonyl halide, and in that! hydrolyzes the resulting 17α-halo3thynyl compound in order to regenerate the µ-oxo- and 7p-hydroxyl groups.



  12.- Process to increase proGestfttiva activity! of 17 <t-'ethynyl sturoldes ue ia sdrio de i estrnne, cM ': <otri <{6 in that a 170th-e% iqnyl-17p-iiydroxyon% r; -4,9dien-3 is reacted -one with ci% which is reacted with the ethylene compound) .. '7 {(11n131 obtained with dihydropyran, in that the 1'l-% ± traliyàro-pyranyl ether is reacted as well obtained with sodanide and P-toluene sulfonyl chloride and hydrolyzing the 17α-chloroethynyl compound to regenerate the 3-axis and 17-hydroxy groups.
 EMI29.6
 



  13.- Procedure for increasing progestational activity
 EMI29.7
 of 17α-ethynyl steroids of the estrane series, characterized in that an el10lic ether of 17o-ÓthYl1yl..17hydro; y-estra-4,9-dien-j-one, in this that we react to said

 <Desc / Clms Page number 30>

 
 EMI30.1
 ether t, Vf1C du 011 what one. reacts the 17-fetrahydropyranilic ether thus obtained with an alkali metal acid and a sulfonyl halide and hydrolyzes the 17 "-haloothynyl compound thus obtained to regenerate the 3-oxo- and 17-hydroxyl groups.
 EMI30.2
 



  14.- Method to increase progestational activity
 EMI30.3
 de 17 '&' "uthynyl a% ± rvsdes ùo la. o.loeioe du 1'Ettanet C: It \: t.'aot6x-: 1. $ d an or tU \ 1 Ol makes eu * a6le nuo l? K -4Hiyyl '-' l? *. 'Hydroxy-9at'E'a- 4t9-di11-5-une with deethylse in that the resulting ether is reacted with dthydropytane, e1. the 17 '-' ttahydro'pyreniliquc ether thus obtained is reacted with sodamide and P-tolubnesulfo-ally chloride and in that the 17 "-Qhlooethynyl compound thus obtained is hydrolyzed in order to regenerate the grou.

   p3 5-oxo- and 1? µ - hjtàroXyla, 15t- Method for increasing the progestational activity of 17-thY1Yl stro1des of the Ilestrane series, characterized in that a 17c.-9tliynyl-17p'- is reacted. hydroxy-eatra-4,9- 'dibn-3-one with pyrrolidine, in that the compound 5- (N-pyrrolidinyl) thus obtained is reacted with dihydropyrana, whereby the compound is reacted. 17-tetrahydropyranilic ether as well
 EMI30.4
 obtained with sodamide and p-toluene sulfo chloride
 EMI30.5
 nsrle and in that the 1qa-chlo-zoet-hynyl compound obtained is hydrolyzed in order to regenerate the 3-oxo and 17P-hydroXy- groups.
 EMI30.6
 the.



  16.- Proceeds to increase progestational activity
 EMI30.7
 - De'17ec-ethynyl stêrolçles of the estrane series, characterized '..in .. that one reacts a 17 -etl, .Ynyl-17P-hYdroXY-estra-4t9dle'n-3-ohe with dihydropyiane, in that the ethoi, tetrahydropyranyl thus obtained is reacted with mole bromine. - 'c'ulaire> in that it is subjected thus

 <Desc / Clms Page number 31>

 
 EMI31.1
 obtained in a dehydnobromination by reaction with a lower alkali metal alkoxide and in that it is hydrolyzed to regenerate the group .7-h: doxyl.e, z.'1 * .- Process for <:. 1 "±; JJlenter the progestational activity of 1.7α-ethynyl steroids of the estrane series, characterized in that a 1? a-t'riyny.-1? -hdroty.-ertao- 4,9-dien- is reactivated. 3-one with dihydropyran, in that we make 611 [;

  ir
 EMI31.2
 tetrahydropyranilic ether thus obtained with chlorine
 EMI31.3
 molecular, in that the 20,21-dichloroprgnatriena is subjected
 EMI31.4
 
 EMI31.5
 thus obtained to a de-hydrochlorination by reaction with a
 EMI31.6
 ,
 EMI31.7
 lower alkali metal alkoxide and hydrolyzed to regenerate the 17! 3-hydroxyl group.
 EMI31.8
 
 EMI31.9
 



  .8 * - Method for increasing the progestational activity of 17α-ethynyl sterols of the estran series, characterized in that a 17α-dtl ', Yy'Yl-17P-lYdroXY-estra- is reacted.
 EMI31.10
 
 EMI31.11
 °, g-â.n-3-one with dihydropyran, in that we make r00.:.;1:1: 'tetrahydropyr ± tltilic ether thus obtained with mole broiae'-'! culaire, we subject the 20,21-àibroiTiopréànatriône thus obtained to a dehydrobronuration 1> ù, r reaction with t-butoxide of pata5sztk. and in that it is hydrolyzed to regenerate the 17p-hydroxyl group.



  19.- Proceeds to increase the progestational activity of 17tï-ethynyl steroids of the esta.ane series, carcct6ri3é!
 EMI31.12
 
 EMI31.13
 in that we fs-it i, éejà.4> a 17 -6 hliàrnyl-17µ-liydroxy-eJtra- 4,9-diùl1.-3-one with dihydropY1. '! U16, in cc which is made . 1,: .. '0: 1011' 11 ether ttr.izyd.xol5rimzil.:ue thus obtained with chlorine tlo10culail'e, in that one sounet the 20t21-diohloroprcguatriene #li; if obtained at a ù!; D : yÙl'ochlol.'1.1 ': ". tion pure xt: scti.ozr with 4-buto.% - potassium ydo çi m'. ce ;; i; 'Ji <nydrolysu to rcgdnure the eJ ..' V1 .11JO 17-hydro :: yle.

 <Desc / Clms Page number 32>

      



  20. - Proceeds to increase progestational activity '
 EMI32.1
 of 170e-ethynyl et6rordes of the estrane series, characterized in that one reacts a .7a.ethynyl --.'- hydroxy-estra-4,9-diene with dihydropyran, in that one reacts. reacts the tetrahydropyranilic ether thus obtained with an N-haloacylamide and an alkali metal salt, in that the
 EMI32.2
 2021-dihalaprtsgne.trïne thus obtained to a dehydrohalogena-.

   tion by reaction with a lower alkali metal alkoxide
 EMI32.3
 and in that hydrolysis to regenerate the 17p-hydroxyl group., i 21, - Method for increasing progestational activity
 EMI32.4
 of 170e-ethynyl steroids of the estrane series, characterized in that a 17β-ethynyl-17p-hydroxy-estra-4,9-ien-3-one is reacted with di2iydropyran, in by reacting the ether-tetrahydropyranilic thus obtained with N-chlorosuccinimide and an alkali metal chloride, subjecting the 20,21-dichloropregnatriene. thus obtained to dehydrochlorination by reaction with potassium t-butoxide and hydrolyzed to regenerate the 17ss-hydroxyl group.



   22.- Method for increasing the progestational activity of 17Ó-thylnyl steroids of the estrane series, characterized
 EMI32.5
 in that a 17 -ethynyl-17 # -hyàroxy-estra-419-dibli-3-orie is reacted with dihydropyran, in that the tetrahydropyranl ether thus obtained is reacted with N-bromo- succinimide and an alkali metal bromide, in that the 20,21-dibromopregnatriene thus obtained is subjected to dehydrobromination by reaction with potassium t-butoxide.



     23.- Procedure for increasing progestational activity
 EMI32.6
 cie 7,7α-ethynyl. et6o1des of the estrane series, characterized in that a 170e-ethyn> rl-17P-hydroxjr-extra-

 <Desc / Clms Page number 33>

 
 EMI33.1
 4,9-diun-5-o> too! Tveo an initial heavy metal aloanol and in that the obtained cor.1poaJ oinvi is reacted with molecular chlorine and 24.-? 10aed to increase the proanlative activity of 17 "- & trnyl et6ro! of the iaric de 1'istrmio, eurot, e4 in that one makes ràajii a.? atkynyï -.?- ydxo, xy-estrss.-4.9.
 EMI33.2
 
 EMI33.3
 din-one with an elkanoate 1nj = ôà.ieui% of heavy actal and in. ' ae that the aino1 compound obtained is reacted with bromine III 0160u1a11'e.



  25.- 9roaédô to increase the progeotative activity of l7a-ethynyl stó1 "o! Des of the series as estrane, onroot6r1aé in that one reacts a.? A-ttl.yny7.-17-xxydxo :, y.-estru4,: di.n-3one with do the aaéiate mercuriquo and in what we do
 EMI33.4
 reacting the compound thus obtained with molecular chlorine.
 EMI33.5
 



  26.- Method for au; .2eutur the progestational activity of 17 -ethynyl st6roldes of the surie of ol3truno, carc: .ctúr1sÓ in what we do;: C ': at; ir a 17 -é% hyn % 1-17) -hydroxy-estri-, 4,9-dien-µ-on; with aoea% ate serouric and in that
 EMI33.6
 
 EMI33.7
 reactivate the a0mpox6 thus obtained with uo1éuluiG brorae.



  27.- 3 to. ether) -n11quo ut derivatives, -pyrrolidinics derivatives of 17cx-Óthynyl and 17 -haloôthynyl-17µtétrah.ydrpyrza.y.oxy-estre-5 10? f (1w i-dï, n -.3-.ozaes.



  28.- 3-'ethyleneâioxy-17p-tetrfhydropyranyloxy-17K-> 'hyny.7,' eSt'c - \ - I fl ^ J -, "(i..tXlE. ', 29.- 5-ôtiiyiénedioxy-170 -tetraiiydropyraiiyloxy-17 - brono c; tynyl-e srs-5 i Jb if 9. i dbne, 30.- -thylzedioy.-x7 - '' r; hydxopyrsznyloay-.?ach.oxoc:hyny.-.estra-57.0 ) r9 (1.) dii: ne.



  31 .... 5-é% lioi; y-17fi- # étnaliyànopyriKnyloxy-170e-h; .ao- ethyny.-estr - f 5 (1?, 9 C .1 -tr.ne,
 EMI33.8
 
 EMI33.9
 32.- - :: thoxy - 173 - ttroîiydropyrdnyloxy -.? A-ehloroethynyl-estxu-f5-Q) f9Z1) -txiènn,

 <Desc / Clms Page number 34>

 
 EMI34.1
 . "ât: czor? tx.aydxcrzxzylox;.? e-bromocitzyty-.aatxa-3i - () 9 (i t .. 'xzQ.



  34.-. 3- (1T-pyrrolidinyJ.) - 17p-td% roliydropyranyloxy- 17? GC "" hsl.O Câ'rhyu2àT ,, ^ "f3e'.i ', 7.'F," T y .i. (É! (. "" tri'âne.



  35 * - 'ia? Sa, la.y, .. twtrahydropyrayloxy-,? R-ah.oxatkzyxzy.-atxa a t 2 a-txina.



  36t ") - (N-pyrrolidinyl) -17P-tetrahydropyrany1oxy-,? X M âaz; iomLéfiziyn, les tra-3 5 9i 1z 'x..a 37 .'-, 21ü.halt3.? - tetWiydropyxanyloxy, pe ; ra- 9: "tr: inaoraa, µ8, - 20,21-diohloro-17 # -tetrahydropy> auyloXy-pregna-4, 9, 20-trien-3-one.



  39.- 20,21-dibiono-17p-tetrahydropyranyloxy-prégna-4 J s' '^ -' xi.3..ano.



  40 <- Heavy metal salts of 17 -e% hynyl-17µhyxox; ,, r.-aLrm4 9-d.n.3-ona.



  41.- Mercury salt of 17u-ethylnyi-17µ-hydroxyatxaMA., 9dixz.3 wona, 4. "Salt d create 17 -ôthynyl-17fi-liYdr0XYoztru-4,9-diôn-1-ona,