DE2018087A1 - Process for the preparation of 17 alpha - propadienyl steroids - Google Patents

Description

dr. W. Schalk dipl.-ing. P. Wirth dipl.-ing. G. Dan ν en berg DR. V. SCHMIED-KOWARZIK ■ DR. P. WEINHOLD · DR. D.GUDEL

6 FRANKFURT AM MAIN

OR. ESCHENHEIMER STHASSE 39

Syntex Corporation Apartado Postal 7386 Panama / Panama

ΡΛ-367

Process for the production of
steroids

The present invention relates to a new process for the production of valuable steroidal compounds, in particular to a process for the production of steroidal l? B (-arenes.

Certain Stendverbindungen with a l7 <j (· -äthyleniscJi unsaturated side chain, in particular a 17 <> (- Propadienyl- (Allen) grouping _t and above all the Itoi Propadienylsteroide of 6,6-Difluorandrostan- and 19-nor-androstane Series according to the following formula (I) are new.

- ν ·· Wi-

009843/1833

Other 17o (-t'rppadienyl steroids have already been described. For example, the U.S. Patents 3,392,165 and 3,392,166, among others, by the Tollenden Formulas (II) »(III) and (IV) represented derivatives of cheated-, Üstr - ^ - en-, i) str-5 (10) -en and Androst- ^ - en-row:

L ... CH = C = CH,

(II)

OR '

... CH = C = CH

(III)

009843/1833

., .. CH-C—

(IV)

In these and the following formulas, R stands for hydrogen or a

2 lower alkyl group of 1-3 carbon atoms; R means hydrogen, Tetrahydrofuran-2-yl, tetrahydropyran-2-yl or a carboxylic acyl group

3
with less than 12 carbon atoms; R stands for an oxo group or the

H ₆

Group ^ .6 » '. , in which R is hydrogen, tetrahydrofuran-2-yl. Tetrahydro

K U— ·

pyran-2-yl or a carboxylic acyl group with less than 12 carbon

if. 5

atoms means ^ R is hydrogen or methyl; and R means hydrogen, lower alkyl with 1-8 carbon atoms, cycloalkyl ^ TetrahyJrofuran2-yl, Tetrahydropyran-2-yl or a carboxylic acyl group with fewer than 12 carbon atoms.

The l? I (propadienyl derivatives in the Östra-1,3,5 (10) -triene series (Formula II) have estrogenic and antiandrogenic activity and are in the

suitable for these agents for the treatment of diseases which respond to estrogenic and antiandrogenic agents, such as, for example, in the control and regulation of fertility, in the treatment of acne, benign

. 009843/18 33

Prostatic hypertrophy and hirsutis rus in cows The 17c (-Propagienylderivate der 6,6-Difluomadrostan-, 6,6-L) ii.'J uor-19-norandrostan-, Östr-5 (10) -en-, Östr-4-en- and AndrosW + -en series (formulas I, 111 and IV) show progestatic and adrenal inhibitory effects Efficacy and are suitable for treating cases related to such Address effectiveness, such as in various menstrual disorders and the control and regulation of fearfulness.

In operating in accordance with the preferred embodiments, this also applies Invention in particular for the production of the 17o (-propagienyl steroids the estrogen, estran and androstane series according to the above formulas (I), (II), (III) and (IV).

The novel process according to the invention for the preparation of these 17 ^ -propadienyl derivatives is characterized in that the corresponding 17o (- (3-halopropynyl) steroid compound together with a reagent from the group of metals with an oxidation potential between + 3iO ^ 5 and + 0.7 ^ volts (measured at 25 C. {cf. Hodgman et al "Handbook of Chemistry and Physics" the Chemical Rubber Publishing Co., Cleveland, Ohio, 42nd ed. page 17 ^ 0) ■ and salts which, when ionized, form cations with an oxidation potential between +0.61 and +0.255 volts. Include metals of the first category Lithium, potassium, sodium, calcium, magnesium, aluminum, manganese, vanadium, zinc and chromium. Salts of the second category of reagents for the invention Processes include metal halides, sulfates, and acetates, such as Chromium chloride, chromium sulfate, chromium acetate, vanadium chloride, vanadium sulfate and Vanadium acetate "

BATH ORIGINAL

The metal or metal salt reagent is at least chemically equivalent Quantities used with the steroid starting material. ZweckmäfJif * is used Excess amounts, i.e. up to a molar excess of 20-50 "In the preferred embodiments will add 1.5-20 moles of metal or metal salt reagent used per mole of starting steroid.

The reaction takes place in the presence of an organic liquid reaction medium. Appropriate media include the usual organic solvents, such as lower aliphatic alcohols such as methanol, tert.-butane oil, n-propanol, etc .; Ethers, such as D in et hy lather, ioxane, methyl propyl ether, tetrahydrofuran etc.j lower aliphatic ketones such as acetone, methyl ethyl ketone, etc .; saturated aliphatic hydrocarbons such as petane, hexane, octane etc.; aromatic hydrocarbons such as benzene, toluene, mesitylene, etc .; and carboxylic acids with less than 12 carbon atoms, such as acetic acid, propionic acid, Trifluoroacetic acid, etc.

The reaction takes place in the presence of a proton donor. Suitable proton donors include lower aliphatic alcohols such as methanol, ethanol, propanol and butanolj carboxylic acids such as kassig, propionic, butyric and hexanoic acidsj and water; or mixtures thereof. The proton donor is roughly |

stoichiometrically equivalent amounts to the amount of metal used «or Metal salt reagent present.

When using a lower aliphatic alcohol odes · * p & bxh as liquid Keaktionsmedium, this also as a proton donor Μβάθπο £ β may also be mixtures of the various proton donors or M isehunganvon Protonenapendern and other liquid Reaktiunf & odi n & ccier nä

BATH ORIGINAL

009843/1833

Mixtures of the water-miscible liquid reaction media are used , Suitable mixtures include acetone / water, dioxane / waaser, Benzene / n-propanol and toluene / acetic acid. * '"

When carrying out the reaction with metals with an oxidation potential above about +1.5 volts, such as lithium, calcium, sodium, magnesium, etc., the organic liquid reaction medium used is preferably free of active hydrogenate. Corresponding media include the aromatic solvents, such as benzene and xylene, and the ethers, such as tert-butyl ether or tetrahydrofuran. When using metals with an oxidation potential below about +1.5 volts, such as manganese or zinc, the organic liquid reaction medium used is preferably a lower aliphatic alcohol, such as methanol, ethanol or isopropanol, or a liquid carboxylic acid with less than 12 Kohl s st of f atoms η _s such as acetic acid, butyric acid and hexanoic acid. If the reagent used is a metal salt that forms a cation with the corresponding oxidation potential, then the reaction takes place in a polar organic liquid reaction medium that is inert towards this salt. These include, for example, the lower aliphatic ketones ₉ such as acetone and pentanone ₉ and the lower aliphatic alcohols, * w such as methanol and ethanol »When using the first-mentioned ketones, the proton donor preferably consists of water and acetic acid,

The EsalAion can * also be carried out, by taking a reagent from it Mieehung * a metal with the appropriate. Oxidation Potentials The metal has an oxidation potential lower than the above Grosissafl. wia copper and Q ^ ssksilb © r "used. This' sweimetalligen;.;. . Misefe? Mg © K includes @@ n-Sink-Kupfsr pairs, sodium aoalgam, Zin'kconalgam and /

BATH ORIGINAL

009843/1833

The reaction takes place at a temperature between about 20-120 ° C., preferably at the boiling point of the reaction mixture and under reflux. The reaction sufficient time is allowed to complete the reaction, i. e. for about 2-48 hours. Longer or shorter times can be applied what of the choice of reaction temperature and the reactants used depends. In a preferred process, the - if appropriate in an organic liquid reaction medium and proton donor dispersed - starting steroid compound treated with the metal or metal salt reagent on the basis of at least one mole per mole. The reaction mixture obtained is then heated for a long time with stirring. After the reaction has ended, the product is separated off and recovered from the reaction mixture using customary methods, such as filtering, decanting, Evaporation, chromatography, recrystallization, etc.

The starting steroid compounds according to the invention with a 17o - (^ - halopropynyl) grouping are made from the corresponding 17 ^ - (3-Hydroxy prop iny I) compounds manufactured. This conversion takes place in the bromine and chlorine series by treating the hydroxy compound with thionyl bromide or phosphorus pentabromide or with thionyl chloride or phosphorus pentyl chloride in the presence of a tertiary amine base, such as the tertiary alkyl amines, pyridine, lutidine, etc. The reaction is carried out in any convenient order or manner at temperatures from about 0-20 C, and expediently in an organic liquid reaction medium, such as ether, benzene, etc.

The bromine and chlorine derivatives can also be prepared by treating the hydroxy compound with triphenylphosphine and Tetrabromkohlenstoff- or carbon tetrachloride in an organic Reaktionümedium such as dimethylformamide and Dioxari, boi about HO ⁰ Q. fo _r ujnjfx "nimitnn, whereupon the sinh

009 iU 3/1833

BATH ORIGINAL

- Connect 8 common extraction processes.

In the fluorine series, the hydroxy compound is combined with a hydrocarbon sulfonyl fluoride, such as benzyl sulfonyl fluoride, tosyl fluoride and mesyl fluoride, treated. In these processes, an inert hydrocarbon solvent is preferably also used, such as hexane, heptane, benhol, toluene, or an etherified or esterified alcohol such as dirnethoxyglycol. Others suitable solvents are chloroform and nitromethane. The reaction takes place at temperatures from 0 ° C. to about 150 ° C. for 1 to about 8 hours.

The 17tfi- (3-hydroxypropynyl) steroid compounds from which the 3-halopropynyl derivatives are prepared are in turn obtained by various processes. In such a process a Grignard reagent "is prepared by treatment of the product from the reaction of propargyl alcohol and dihydropyran, namely 3- (tetrahydropyran-2 -yloxypropin ^l) with magnesium and ethyl bromide in a per se known method. This reagent is then reacted with a 17-oxosteroid, whereby the corresponding 17tf- (3-tetrahydropyraTi-2 ^l -yloxypropynyl) - 'steroid derivative is obtained -2 '.. yloxy group hydrolyzed into the hydroxyl group «

In another process for the preparation of the 3-hydroxypropynyl compounds, which is particularly suitable for the estrogen series, a 17-oxo starting compound is ethinylated in a known manner, ie by treatment with potassium acetylide to form the 17o (-ethynyl-1713-hydroxy derivative . Before further reaction the 17ü-hydroxy group is preferably, for example nyran-2 -yloxy- by formation of the tetrahydro ¹ or tetrahydrofuran-2'-yloxyäthergruppe protected. In the further reaction, the Athinylgruppe-through is

Π 0 9 8 /, 3/1 8 3 3 BAD ORIGINAL

Addition of the hydroxymethyl group to replace the acidic hydrogen atom elaborated · This is done by forming the ethynyl lithium salt (by Treatment of the Ethiny! Derivative at room temperature with an equivalent Amount of an ether solution of methyl, butyl or Ph eny Hit hium) and treatment the same with an equivalent or slightly excess amount of paraformaldehyde under mild reflux in ether and subsequent hydrolysis according to the method of Schaap (Rec.Trav.Chim .; 84, 1200 (1965) and the there cited references.

The processes for making the 3-halopropynyl starting steroids are more fully described, for example, in U.S. Patent 3,029,261.

In the preparation of the 17 << - (3-halopropynyl) starting derivatives in the 6,6-difluorandrostane and 19-nor-androstane series can do the above Production methods with the corresponding ojo-difluorandrost - ^ - en ^,!? - diones and oio-difluoro - ^ - nor-androst - ^ - en ^ l ^ -diones and the 18-alkyl derivatives the same are carried out. In practice, the 6,6-difluoro group into the precursors-androst-4-en-3,17-dione and i9-nor-androst-4-en-3,17-dione or the 18-alkyl derivatives thereof are introduced. One such The method is described in U.S. Patent 3,2L9,673. This is a ^ -Acyloxy-S-fluoro-o-ketosteroid (which is known or according to the mentioned ■ Patent can be produced) with sulfur tetrafluoride to form of the corresponding 3-acyloxy-5,6,6-trifluorosteroids, which gives the 3-hydroxy-5,6,6-trifluorocompound is hydrolyzed. The latter is oxidized into the corresponding 3-keto-5,6 »6-trifluoro derivative, which is then with a Dehydrofluorinating agents, such as clay, to form the 3-keto ~, A -6,6-difluoro compound is treated.

BAD ORIGINAL 0 0 9 8 Λ 3/1833

Another method of making these 6,6-fluoro precursor steroids takes place by two successive formation of an enol ether and treatment of the same with perchloryl fluoride. This is how the output anstro- ^ -en-3,17-dione converted into its enol ether and this with perchloryl fluoride Treated to form the 3-keto-Δ -6-fluoro derivative. The same thing Process is with this compound for the formation of the 3-Keto-A -6,6-difluorprodukte repeated. The formation of the enol ether and the fluorination treatment are common reactions in steroid technology.

In the preferred embodiments, the desired, non-interfering elaborated groups on the other optional position of the molecule the new, main reaction according to the invention introduced. It will be preferred those groups that compete with the main reaction or are protected these could interfere with the preparatory processes for the main reaction could disturb. Such protection consists, for example, in the formation of the ketal or enol ethers of the 3-oxo function, which regenerates later in the reaction sequence can be.

In the case of the estrogen series, for example, the treatment of the l? O (-ethynyl-3,17β-diol derivative with a corresponding carboxylic acid anhydride, such as acetic anhydride, in pyridine selectively the 3-acyloxy-17β-hydroxy derivative. The usage an acid anhydride in the presence of the corresponding acid and an acid catalyst, like p-toluenesulphonic acid, it gives 3 »17β-uiacyloxy derivative. This diester can then be selectively, e.g., by using methanolic Potassium bicarbonate, - to form the corresponding 3-hydroxy-l? I3-acyloxy derivative to be saponified. Etherification can also be carried out according to the same procedure take place. Thus, treatment with üihydropyran delivers in the presence of a Acid catalyst, such as p-toluenesulfonic acid, p-toluenesulfonyl chloride, üinitrobenzplsulfonsäure etc., the corresponding tetrahydropyran-2-yloxy derivative.

0098 ^ 3/183 3

BATH ORIGINAL

The formation of monotetrahydropyranyl ether can be achieved through selective protection of the other hydroxyl groups, for example by formation of the structure described above

possibly

Way / with alkaline hydrolysis of these ester groups after formation of the ether take place. The 3-methoxy derivatives can also be obtained by using dimethyl sulfate and potassium hydroxide are formed in the usual manner.

Similar conventional esterification and etherification processes can be used for the other series of starting compounds according to the invention. In the production of .3i3 _t 17ß-diacylate starting materials for the inven- g

methods according to the invention can, for example, reduce the 3 »17-uioxo compounds and acylated with about 1 chemical equivalent of acylating agent. The product mixture is then chromatographed to separate off the 30-acylate-17β-ol compound. This derivative is then oxidized to the 3β-acylate-17-oxo compound. Then the Grignard method is followed to introduce the Including hydroxypropynyl group at C-17 << in the manner described above the addition of the appropriate acylating agent before work-up for the purpose of formation of the 3β »17β-diacylate-17 ^ -tetrahydropyranyloxypropijnylyer linkage. This compound is then converted into the corresponding halopropynyl derivative converted. ■ "

The 3ßjl7ß diether are formed expediently by first preparing the 3 ^ß diether and then the formaldehyde Metnode follows for producing the 17o (-Hydroxypropinylverbindungen in the above manner.

If a mixed ester-ether compound is desired, then the monoether is used prepared in a similar manner as in the preparation of the monoacylate. then one follows the described Grignard process and ends with the acylation

before processing. The monoacylate prepared as above can also be used on etherified and the C-17β-hydroxyl group etherified. then

0 09 8.A 3 / 1.8 3-3 BAD ORIGINAL

Then one follows the described Kormaldehydverfahren for the production of the corresponding 1 ¹ ^ -Hydraxypropinyl connection »

As used herein, "carboxylishe acyl group" and "carboxylisc Aeyloxy group "refers to acyl and acyloxy groups with less than 12 carbon atoms, which can be straight, branched or cyclic. This structure can also be saturated, unsaturated or aromatic and optionally by functional groups such as hydroxyl groups or alkoxy groups up to 5 carbon atoms, acyloxy groups with less than 12 carbon atoms, Nitro groups, amino groups, halogen groups, etc., may be substituted. Such esters thus include the acetate, propionate, enanthate, benzoate, trimethyl acetate, tert-butyl acetate, phenoxyacetate, cyclopentyl propionate, amino acetate, ß-chloropropionate, adamantoate, bicyclo- ^ 2.2.2j / -octane-l-carboxylate, Bicyclo - ^^. ^ - oct ^ -en-l-carboxylate, ^ -Methylbicyclo- ^^. ^ - cot ^ -en-l-carboxylate etc. As used herein, the term "lower alkyl" refers to straight or branched chain structures. Such an alkyl group include methyl, ethyl, isopropyl, η-butyl, tert-butyl, n-hexyl, n-heptyl, n-octyl, isooctyl, etc. The term "cycloalkyl group" (see. R in the formulas above) include, for example, cyclopentyl, cyclohexyl groups, etc. borrowed 3-Ö contain carbon atoms. The term "3-halopropynyl" includes 3-bromopropynyl, 3-chloropropynyl and 3-chloropropynyl, preferably 3-chloropropynyl.

The following experiments and examples illustrate the present Invention without limiting it.

BATH ORIGINAL

copy

D Ii'UW, 3/1 8 3 3

Attempt

A solution was prepared by dispersing 29 g of Ostr - ^ - en - ^. IV-dione in (MU ecm dioxnn at room temperature with stirring. 60 ml of ethyl orthoformate and 1.8 g of p-toluenesulphonic acid hydrate were added to this. The addition was carried out in batches After the addition was complete, the resulting reaction mixture was left to stand at room temperature for 3.5 hours and then poured into 2 liters of ice-water. The entire mixture was filtered to give a crystalline material; contained a few drops of pyridine, recrystallized and gave the desired 3-ethoxyestra-3,5-dien-17-one product.

Two grams of propargyl alcohol were dispersed in 63 g of 2,3-hydroxypyran with stirring. 500 mg of phosphorus oxychloride were added batchwise to the resulting solution at room temperature with constant stirring. The reaction mixture warmed up rapidly and was cooled in ice from time to time. These conditions were maintained for 2 hours; then the temperature of the reaction mixture was allowed to stabilize at room temperature and an aqueous potassium hydroxide solution was added. The mixture was then extracted with ether and the ether extracts were distilled with gradually increasing temperatures and gradually decreasing pressures, whereby the 3-tetrahydropyran-2'_yloxypropyne product was obtained.

Under anhydrous conditions 3 * 2 g magnesium, 11 ecm ethyl bromide and 150 ecm abs, ether were mixed together at room temperature. dos as above obtained 3-Tetrahiydrop.-rnn-ii '-ylox.Tprap.inprGdulctes fiingetiOof t “The temperature of the tirhai. herisn ■ i-ru-ahum-; was on de-a U lotie point gobivaenh; then-flirdßn- 5 Hiiiutuj) tÜickt'lui.lDed in-

-mr.Je. cd ': HiiTcning auf '? ■ Lnmcrtempi: raLui- .u ;;; / i ·

■. ,, .. _ ■ "BAD

Q U 0 U /, J / 1> i J ο

-IA-

cooled and mixed dropwise with a solution of 21 g of 3-Athoxyöstra-3,5-dien-17-one, dispersed in 200 ecm of tetrahydrofuran. After the addition had ended, the reaction mixture was stirred at room temperature for 2 hours. The resulting solution was cooled in an ice bath and then ^{mixed with r} / 0 ecm acetic anhydride. This solution was left to stand for 16 hours at room temperature and then poured into an ammonium chloride / ice solution and this was extracted with ether. The ether extracts were dried and concentrated. The concentrate was chromatographed and gave a crystalline product which was crystallized from ethyl acetate / hexane / petroleum ether. Recrystallization from the same solvent mixture gave the desired 3-ethoxy-1706- (3-tetrahydropyran-2'yloxypropinyl) -17β-acetoxyestra-3 »5-diene as the product.

18 g of 3-ethoxy-17 "(- (3-tetrahydropyran-2 ^l -yloxypropynyl) -lβ-acetoxyestra-3" 5-diene were dissolved in 750 ecm of methanol at room temperature. Then 20 g of oxalic acid were dissolved in 150 ecm of water dispersed and the resulting aqueous oxalic acid solution was added batchwise to the methanol is before η Si.eroidlösung at room temperature. The resulting reaction mixture was left to stand overnight at room temperature, then neutralized by the batchwise addition of sodium hydroxide and the neutralized mixture was filtered. The filtrate was filtered under vacuum This was extracted with an ether / methyl chloride mixture, the resulting solution was dried over sodium sulfate and evaporated to a solid was recrystallized from Athylacet.at/Ilexan and gave the 17? ji- (3-Hyfiro5yp ^{i!. t} i .- »pirv! / l) -I? ü-aceto3q5röstr-4-en- 3-on-.product as crystalline i ^ eet =: - off.,

BATH ORIGINAL

ü 0 b B 4 'i / 1 H j'i -

At room temperature, a hybrid of 20 ecm from:,. Pyridine, 8 ecm freshly distilled thionyl chloride and 90 ecm abs. Tetrahydrofuran produced. To the solution obtained, _f k g of 17 ^ - (3-hydro> typropinyl) -17id-acetoxyestr-4-en-3-one, dissolved in 50 ecm of anhydrous tetrahydrofuran, were added to the solution obtained within a minute at room temperature. After the addition had ended, the reaction mixture was stirred for 35 "minutes at room temperature, then poured into ice water and the mixture obtained was extracted with ether / methylene chloride. The extracts were washed with water and dried over sodium sulphate. The dried material was evaporated to an oil and this was evaporated Chromatography silica gel, there was prepared the desired 17o (- (3-Chlorpropinyl) -17ti ^{acetoxyöstr--i} i-en-3-one as a product.

If the above processes are carried out with the corresponding 18-alkyl compounds, the products obtained are 17 "(- (chloropropynyl) -17β-acetoxy-18-methylbstr-4-en-3-one, 17ei- ( 3-chloropropynyl) -176- acetoxy-18-ethyl-oestr-4-en-3-one and 1- (3-chloropropynyl} -17β-acetoxy-18-n-propyl-cistr-J4-en-3-one. Experiment 2 .

To a suspension of 1.0 g of sodium hydride in 10 ecm of dry diethylene glycol dimethyl ether 1.0 g of 3-methoxy-1 / ib (-äthinyl-oestra-1,3,5 (10) -trien-17β-ol in lü ecm dripped in dry diethylene glycol dimethyl ether within 20 minutes. 0.9 g of 2-chlorotetrahydropyrar} was added to this mixture within 10 minutes. dripped in.

The mixture was stirred at room temperature for an additional 30 minutes and then carefully added to a cold water mixture with stirring. The organic phase was extracted with diethyl ether, dried and evaporated under reduced pressure and gave the 3-methoxy-17 ^ -ethinyl-17id-tetraliy (Jrc,;. Yran- / ⁾ . ¹ -yloxyöstr-l _f 3 »5 (10) -triene, which by recrystallization from Ar (jtori / ::.:. V; u)

0098 43/1833

can be further cleaned.

A solution of 2.5 g of phenyllithium in 25 ecm of diethyl ether was kept at room temperature, then 10 g of 3- ^ ethoxy-17 <X-äthinyl-r / i3-totrah.yriropyran-2'_yloxyöstr-1,3 »5 (10) -triene was added to obtain a solution containing 3-MethcK, y-17 ₍ ) (-äthinyllithium-17i3-tetrahydropyran-2 ^l -yloxyöstr-1,3,5 (10) -triene 3 g of paraformaldehyde was added intermittently with stirring to the solution at a rate that maintained the solution under mild reflux. When the addition was complete, the mixture was stirred for 20 hours, then poured into water and extracted with ether. The ether was extracted with water washed, dried and evaporated to give the 3 ^ ethoxy-17 ^ - (3-hydroxypropynyl) -17ß-tetrahydropyran-2'-yloxyestr-1,3,5 (10) -triene.

1 g of 3-methoxy-17 (Y- (3-hydroxypropynyl) -17β-tetrahydropyran-2 ^l -yloxyestral, 3 »5 (10) -triene was dispersed in 50 ecm of anhydrous ether at room temperature with stirring ⁰ C. batchwise 1.5 cc of purified thionyl chloride was added, the mixture obtained then for 6 min at 0 C ₀ allowed to stand and with aqueous sodium bicarbonate and then washed with water. the washed material was evaporated dried over sodium sulfate and evaporated to dryness to give the 3- Methoxy-17 ^ - (3-chloropropynyl) -17ß-tetrahydropyran-2 '-yloxyöstra-1,3 »5 (lu) -triene as a product which is recrystallized from ether / ethyl acetate.

To a solution of 1 g of 3-methoxy-176 ('- (3-chloropropyn.yl) -17 ^ -tetrahydropyran-2'-yloxyöstra-1,3 »5 (10) -triene in 30 ecm acetic acid was 0.5 ecm 2N hydrochloric acid added, the mixture left to stand for 5 hours at room temperature, then diluted with ice water and extracted with methylene chloride. The K extracts

BAD ORlGlNM-00 9 843/183 3

Were washed neutral with water, dried over sodium sulfate and evaporated to dryness and gave the 3-methoxy-17Ö (- (3-chloropropynyl) -Ö3tra-It3 »5 (Iu) -trien-l ^ ß-ol, which is obtained from acetone / Hexane was recrystallized Experiment 3

1 »5 g of 17 <^ - (; 3-hydroxypropynyl) -estr-4-en-1 ^r / ü-ol-3-ori were dissolved in 75 ecm of toluene and the solution obtained was gfsmiseht with 2 g of benzenesulfonyl fluoride. Then the temperature of the reaction mixture rose to 80-90 ° C. for K hours. After this reaction time, the mixture was cooled and poured into ice water. The organic layer was washed with a sodium bicarbonate solution and then with water and dried over sodium sulfate. The solvent was evaporated and the residue was recrystallized from ether; in this way one obtained the l '^ - (3-i ⁱ * luorpropinyl) -estr- ⁱ J' -. en-17ß-ol-3-one.

attempt ^l y

5 g 17o (- (_ 3-hydroxypropynyl) -17ß-acetoxyöstr- ⁱ (-en-3-one were intermittently added to a mixture of 6 g Tripheny phosphine, 2 cc of carbon tetrachloride and 50 cc Dimethylformainid under stirring at room temperature The resulting!. mixture was heated to 110 ⁰ C. and held for 15 minutes at this temperature, then poured into iSiswasser and the aqueous mixture with methylene chloride / ether the extracts were dried and evaporated to give the 17e. ^ - (3-Chlorpropinyl) -17Ü- acetoxyöstr - ^ - en-3-one as a product.

Attempt 5

Experiments 1, 2 and 4 gave 17jA- (3-bromopropynyl) -androst ~ 4-en-17to-ol-3-one, by using thionyl bromide instead of thionyl chloride in experiment 1 and 2 and carbon tetrabromide instead of carbon tetrachloride in trial ^ used .. By using the appropriate output connections the corresponding 18-methyl, ethyl and propy derivatives are obtained, Dia

0.09-8.4 3/1833 'BAD ORIGINAL

-Ib-

Processes are also used for the preparation of the 17 ^ - (bromopropinyl) -fierivato Estrogen and estran raw materials are suitable.

Seek 6

To a suspension of 1 g of Ostr - ') - en-3,17-dione in ' /, 5 ecm was ;. ^r ; orl.'reiem, peroxide-free dioxane were 1.2 ecm freshly distilled. Ethyl orthophonate and 0.8 g of p-toluenesulfonic acid were added, the mixture was stirred at room temperature for 15 minutes and then left to stand at room temperature for 30 minutes. Thinly 0.8 ecm of pyridine and then water were added until solidification. The solid was filtered off, washed with water and air-dried to give 3-ethoxy-oestra-3 »5-clien-17-one, which was recrystallized from acetone / hexane.

A stream of ferchloryl fluoride was passed for 5 minutes through a solution, cooled to 0 C, of 1 g of 3-ethoxyestra-3,5-dien-17-one in 25 ecm of dimethylformamide. After slowly reaching a temperature of 20 ° C., the solution was poured into water and extracted with ethyl acetate. These extracts were washed neutral with a saturated aqueous sodium bicarbonate solution and then with water, dried over sodium sulfate and evaporated to dryness. Then, the residue to separate the 6 (-fluoro- was and OSS Fluorisomeren to alumina chromatograph ie rti The predominant ό / 3-fluoro isomer was dissolved in 50 cc of glacial acetic acid by this solution 2k hours at I5 C, a dry stream of hydrogen chloride was passed "The mixture was poured into cold water and the solid that had formed was filtered off, washed with water and dried; this gave 6 ^ -Fluorö3-br-V-en-3,17-d.ione, which was recrystallized from acetone / hexane"

BATH ORIGINAL

009043/183 3

To a suspension of 1 g of 6 ^ -Fluoröstr - ^ - en-3,17-dione in 7.5 ecm of anhydrous, peroxide-free dioxane were 1.2 ecm freshly distilled. Ethyl orthoformate and 0.8 g of p-toluenesulfonic acid were added and the mixture was added for 15 minutes at room temperature stirred and then left to stand for 30 minutes at room temperature. Then 0.8 ecm of pyridine and then water were added until solidification The solid was filtered off, washed with water and air dried and gave the 3-ethoxy ~ 6-fluorostr-3 »5-dien-17-one, which was obtained from acetone / Hexane was recrystallized.

Through one on OC. cooled solution of 1 g of 3-Ätboxy-6-fluorostr-3,5-dien-17-one a stream of perchloryl fluoride was generated in 25 ecm of dimethylformamide for 5 minutes directed. After slowly reaching a temperature of 20 C., the Poured solution into water and extracted with ethyl acetate. The extracts were neutral with saturated aqueous sodium bicarbonate solution and then with water washed, dried over sodium sulfate and evaporated to dryness. Juann the residue was chromatographed on alumina and gave the 6,6-Difluoröstr-4-en-3,17-dione, which was recrystallized from acetone / hexane.

In a similar way, 6,6-difluorane ± Ost ^J + -en-3,17-dione, 6,6-difluor-18-methylöstr- ⁱ f-en-3,17-dione, 6,6 -Difluor-18-methylandrost-4-en-3 _t 17-dian, 6,6-Difluor-18-äthylöstr - ^ - en-3,17-dione, oo-Difluor-IS-äthylandrost - ^ - en ^, 17-dione, 6,6-difluoro-18-propylöstr - ^ - en-Sι17-dione and 6,6-difluoro-l8-propylandrost - ^ - en-3,17-dione.

BATH ORIGINAL 009843/1833

Try 7

A solution of 2 g of 6 "6-Difluoröstr- ^z 1-en-3,17-dione in 2 ecm anhydrous tetrahydrofuran was cooled to -75 ° C. in a bath of dry ice and acetone and treated with a previously cooled solution of 0, 6 g lithium aluminum tert-butoxide treated in 20 ecm anhydrous tetrahydrofuran. After the reaction mixture had been refluxed for 15 minutes, it was cooled, poured into ice water and extracted several times with ethyl acetate. The extracts were washed neutral with water, dried over anhydrous sodium- ^ sulfate and evaporated to dryness to give 6,6-difluorostr- ^; + ~

en-3β, 17β-diol _o

A mixture of 3 g of 6,6-Difluoröstr-4-en-3ß »17ß-diol, 10 ecm of pyridine and 0.9 ecm of acetic anhydride was left to stand for 15 hours at room temperature left, then poured into ice water and the solid formed filtered off, washed with water and dried; in this way one obtained 3ß, 17i3-diacetoxy-6,6-difluoröstr - ^ - en; 3ß-acetoxy-6,6-difluorostr-4-en-17ß-ol and 6,6-difluoro-17ßacetoxyostr-4-en-3ß-ol 9 which were separated by chromatography on alumina.

^ A solution of 6 g of 3β-acetoxy-6,6-difluorostr-4-en-17β-ol in 120 ecm of pyridine

was added to a mixture of 6 g of chromium trioxide in 20 ecm of pyridine, the reaction mixture was left to stand for 15 hours at room temperature, diluted with ethyl acetate and filtered through Celite diatomaceous earth. The / filtrate was washed well with water, dried and evaporated to dryness and gave 3β-acetoxy-6,6-difluorostr- ⁱ + -en-17-one, which can be further purified by crystallization from acetone / hexane can.

BAD ORiGINAL

00 9843/1833

The derivative thus obtained was treated according to the procedures of Experiment 1, paragraph 3 and k-, and gave the 3ß, 17i3-diacetoxy-6,6-difluoro-l? ^ - (3-hydroxypropinylj-oestr - ^ - en, the was converted into the corresponding 17β (- (3-halopropynyl) derivatives by the procedure of Experiment 1 (paragraph 5) - ». 3 and 5. Thus 3β» 17β-diacetoxy-6,6-difluoro-17ei- ( 3-halopropynyl) -androst-4-en.,

By using a different carboxylic acid anhydride in the above procedure the corresponding diacylates were obtained, e.g. the propionates, JJenzoabe,

Pentanoates and adamantoates, such as

3ß »17ß-Dipropio nyloxy-6,6-difluor-17p (- (3-halo'genpr opinyl) -19-nor-andro st-Λ-βη, ζ 3ß» 17ß-acetoxy-6,6-difluor -17il- (3-halopropynyl) -IS-ethyl-oestr-^ - en, 3ß, 17ß-Dipropionyloxy-6,6-difluoro-17öi- (3-halopropynyl) -androst- ⁱ f-en, 3i3,17ß -Dibenzoyloxy-17oi- (3-halogenpropinyl) -östr - ^ - en _t '

3ß, 17ß-Diberizoyloxy-17i (- (3-nalogenpropynyl) -18-methylandrost- ⁱ -en and 3ß, 17ß-diadaraantoyloxy-17i (- (3-halopropynyl) -18-ynethylestr-5 (10) -en. Trial 8

A solution of 1 g of sodium borohydride in 300 ml of water was added to an ice-cold solution of 1 g of 6 _t 6-Difluoröstr-4-en-3,17-dione in 120 ecm of methanol Λ

and then left the mixture to stand at room temperature for 16 hours. The excess reagent was decomposed by the addition of acetic acid and the solution then concentrated to a small volume under vacuum and diluted with water. The product was extracted with ethyl acetate and the extracts washed with water / water, dried and evaporated; in this way one obtained o, 6-difluorostr-4-en-3fl, 17u-diol, which can be purified by UmkristaMsabion from acetone / hexene woiter.

BATH ORIGINAL

0098 437 1833

To a suspension of 1.0 g of sodium hydride in 10 ecm of dry diethylene glycol dimethyl ether was slowly added 1.0 g of 6,6-difluorostr- ' ^/ 4-en-3β, 17u-diol in 10 ecm of dry diethylene glycol dimethyl ether under a dry S ticks to ff atmosphere added dropwise within 20 minutes. 0.9 g of 2-chlorotetrahydroryran was then added dropwise to this mixture in the course of 10 minutes. The mixture was stirred at room temperature for a further 30 minutes and then carefully added to an ice / water mixture with stirring. The organic phase was extracted with diethyl ether, dried and evaporated under reduced pressure; thus obtained 3 [beta] 17 [beta] -bis (tetrahydropyran-2'_yloxy) -6,6-difluorostr-4-ene, 3 [beta] -etrahydropyran-2'-yloxy-6 »6-difluorob`str-^ - ene-^ ß -ol and 6, o-difluoro-17ß-tetrahydropyran-2'-yloxyöstr - ^ - en-Oß-ol, which were separated by chromatography on clay.

By using di-diofuran in the above procedure, the corresponding ones were obtained Tetrahydrofuran ^ '-yloxyderivateo

A solution of 6 g of 3β-tetrahydropyran ~ 2 ^l -yloxy-6,6-difluorostr-4-en-17i3-ol in 120 ecm of pyridine was added to a mixture of 5 g of chromium trioxide in 20 ecm of pyridine, the reaction mixture for 15 hours at room temperature left to stand, diluted with ethyl acetate and filtered through Celite diatomaceous earth. The filtrate was washed with water, dried and evaporated to dryness and gave 3β-tetrahydropyran- ^{21-yloxy-6,6-di-fluorostr-1} -en-17-one, which can be further purified by recrystallization from acetone / hexane can.

BATH ORIGINAL

003843/18 3 3

. - 23 -

A slow stream of purified acetylene was continuously injected for one hour into a solution of 1 g of lithium alurainiurahydride in IuU ecm anhydrous tetrahydrofuran. JJann was added 1 g of 3 ^ ^r -Tet sih.ydropyran ^{l-2-yloxy-6,6-difluoröstr-4-en-17-one} in 10 cc of tetrahydrofuran was added and the reaction mixture stirred k hours at room temperature. Thinly 8 ecm of water were added and the mixture was stirred for 30 minutes, filtered and the organic filtrate was evaporated; 3β-Tetrahydropyran-2'-yloxy-6,6-dif'luor-17o (-äthinylöstr-4-en-17β-ol _1, which was recrystallized from acetone / hexane, was obtained in this way.

3ß-Tetrahydrofuran-2 ^l -yloxy-6,6-diflaor-17o <-äthinylöstr - ^ - en-l'7ß-ol was prepared in a similar manner.

The 3.beta.-Te'trahydropyran-2 thus produced ^{l-yloxy-6,6-diluor-17i} (- äthinylöstr-4 "en-17-ol and 3L3 tetrahydrofuran-2 ^{1-yloxy-6,6-difluoro} -17 ^ -äthinylöstr-4-en-17ß-olverbindungen were then treated according to the method of experiment 2 (paragraph 3) and then halogenated according to experiment 2, 3 »^ or 5, whereby 3ß-T ^e trahydropyran-2 ^l _yloxy- 6,6-difluoro-17 (K- (3-halopropynyl) -östr- ⁱ i- en-17.beta.-ol and 3.beta.-tetrahydrofuran-2 ¹ _yloxy-6,6-difluoro-l7 ^ - (3-halopropynyl) estr -4-en-17 _{i:) - o} i received.

The 3β-monoethers produced in this way can then be prepared according to Experiment 7 mixed ester / ether derivatives are acylated. So one got e.g .:

3ß-Tetrahydropyran-2 '-yloxy-6 _f 6-difluoro-17 ^ - (3-halopropynyl) -17ß-acetoxyostr-4-en,

3.beta.-tetrahydrofuran-2-yloxy ^{l-6,6-difluoro-17o} (- (3-halopropynyl) -17ß-acetoxyöstr- + ² -en,

3ß-Tetrahydropyran-2 '-yloxy-6,6-difluoro-17o (- (3-halopropynyl) -17ß-acetoxy androst - ^ - en,

• 0 0 9 8 Λ 3/1 8 3 3 BAD ORIGINAL

- 2k -

3ß-Tetrahydrofuran-2'-yloxy-6,6-difluoro-1 7d ~ { 3-halO £ enpropiny1} -1713-acetoxyandrost-4 ~ en,

3ß-Tetrahydropyran-2 "-yloxy-6,6-difluoro-17a (- (3-halopropynyl) -17ß-propionyloxyestr-Λ-βη _f

3ß-Tetrahydrof uran-2'-yloxy-6,6-dif luDr-17e <- (3-halogenpropiny 1) -17f3-propionyloxyöstr-4-en,

3ß-Tetrahydropyran ~ 2'-yloxy-6,6-difluoro-17 (j (- (3-halopropynyl) -17ß-propionyloxyandrost - ^ - en,

3β-Tetrahydrofuran-2'-yloxy-6,6-difluoro-17FI- (3-halopropynyl) -17β-propionyl ■ oxyandrost - ^ - en,

3.beta.-Tetrahydropyi'an-2 '~ yloxy-6, 6-dif luor-l / ^ - (3-halopropynyl) r-17-caproyl

oxyostr-i) - en,

3ß-Tetrahydrofuran-2 · -ylo3ty-6,6-difluoro-17a (- (3-halopropynyl) -17ß-caproyloxyöstr - ^ - en ₉

3ß-Tetrahydropyran-2 '»yloxy-6 ₉ 6» difluoro-17 <j (- (3-halopropynyl) -! "Flj-capropyloxyandrost-4-en,

3ß-Tetrahydrofuran-2 ¹ yloxy-6,6-difluoro-17 _e (- (3-halogenpropinyl) -l7ß-caproyloxyanstrost - ^ - en etc "

Attempt9

By treating 3ß-acetoxy-6,6-difluoro-17-one according to paragraph 5 of Experiment 8, 3ß-acetoxy-6,6-difluoro-17 /> (- äthinylb'str-4-en -17ß-ol.This derivative was then etherified according to paragraph 2 or 3 of Experiment 8, whereby the corresponding 3ß-acetoxy-6,6-difluoro-l '? B (-äthinyl-17ß-tetrahydropyran-2 ^l -yloxyöstr- ^ -en or «3ß-acetoxy-6,6-difluoro-17e ^ -äthinyl-17ß-tetrah / drofuran-2 '-yloxyöstr - ^ - en received

The above procedures can be performed with the other 3β ~ starting acylates described above have been carried out.

BAD ORiGiNAL

C) Il 9 ß / * 3/1833

example

5g 17 ^ - (3-Chlorpropinyl) -17ß-acetoxyöstr-'4-en-3 ~ one, 25 g of zinc dust and cc of glacial acetic acid were mixed together at room temperature under stirring and the obtained mixture for 2 hours under constant agitation at 5O ⁰ C . mentioned. After this time it was filtered through gelite, the filtrate collected and concentrated to a small volume under reduced pressure. The concentrate was cooled and diluted with ice water to precipitate a solid material. The solid was nitrated and recrystallized from acetone / hexane and gave the 17fl (-propadi8nyl-17i3-acetoxyestr-4-en-3-one. Example 2

¹ g of 17i / - (3-chloropropynyl) -androst-4-en-17-ol-3-one was dispersed in 50 ecm of ethanol at room temperature. 3 g of copper sulfate were in 20 ecm of water

dispersed, and to the aqueous solution obtained, 5 g of zinc dust was added. The zinc-copper powder formed from this suspension was added intermittently to the ethanolic steroid solution at room temperature. When the addition was complete, the reaction mixture was heated to the boiling point and refluxed for 16 hours. Then, the filtrate was filtered through CeIite, collected and evaporated to dryness and the residue crystallized from acetone / hexane} there was prepared the 17oi ^{Propadienylandrost--i} i-en-17-ol-3-one. Example 3

By dispersing 2 g of 3-methoxy-17 _i (- (3-fluorpropinyl) -estr-l, 3i5 (10) -triene-l7ß-ol in 10 cc of benzene at room temperature with stirring to obtain a steroid solution 5 g of finely divided. metallic sodium was dispersed in 200 ecm benzene and 5 oem isopropanol and the dispersion obtained was added batchwise to the steroid solution at room temperature. The temperature of the mixture obtained was raised to the boiling point and refluxed under a nitrogen atmosphere for 24 hours carefully removed by filtration and the

• 009843/1833

BATH ORIGINAL

The remaining solution was washed with 5 ecm of methanol and then with 5 ^cc m of water. The organic layer was separated, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was recrystallized from methanol / benzene and gave the 3-methoxy-17e (-propadienylÖ3tra-1,3,5 (10) -trien-l-ii-ol as product.

Example ^

A steroid solution was prepared by dispersing 1 g of 6,6-difluoro-17 ^ - (3-chloropropynyl) oestr-4-en-17ß-ol-3-one in 200 ecm of acetone. 6p ecm ^ of a freshly prepared solution of chromochloride (Rosenkranz et al, J.Am.Chem.Soo. 72- _f kO77 (195O)) were added to the steroid solution, intermittently at room temperature, the entire mixture being kept under a nitrogen atmosphere became. 5 minutes after the addition, the acetone was removed under reduced pressure and water was added to initiate the precipitation. The precipitated solid was collected and dried over sodium sulfate and then recrystallized from acetone / hexane -4-en-17β-ol-3-one as product, Example 5

2 g of 17 ^ - (3-bromoprpiny! 0-oestr-5 (10) -en-17ß-ol-3-one were dispersed in a mixture of 50 ecm methyl ethyl ketone and 10 ecm water at room temperature with gentle stirring The mixture thus prepared was heated to boiling point and refluxed for 8 hours, then cooled and poured into water, then the aqueous mixture was extracted with ethyl acetate, and the extracts were separated and recovered, then they were dried over anhydrous sodium sulfate and then evaporated to dryness the residue remaining after evaporation residue was / umkrietallislert Heitan from Aöeton to give the 17 ^ (-. Propadienylöatr-5 (10) -en-17.beta.-ol-3-one as a product _{SSAD O} r _igwl.

009843/1833

Example 1 6 to 16

According to the invention, the following reactions were carried out:

By reacting l '^ - (3-i ^{| 1} luorpropinyl) -17ß-acetox.y-18-methylandrost-4-en-3-one and zinc dust with ethanol as the liquid reaction medium and proton donors according to the method of Example JL were obtained 17 <^ - Propadienyl-17ü-apetoxy-18-methylandrost - ^ - en-3-one as a product. ■

By reacting 17 <j (f (3-chloropropyne _i yl) eth--l8, ylöstr - ^ - en-17l; J-ol-3-one and metallic potassium in benzene and t-butanol according to procedure of Example 3, 17d (-propadienyl-18-äthylöstr-4-en-17ß-ol-3-one was obtained as the product.

By reacting l'7i (- (3-fluoropropynyl) -17ß-tetrahydrofuran-2 ^l -yloxyestetrali3i5 (10) -trien-3-one and metallic calcium in aqueous dioxane at a temperature of 70 G. according to the method of Example 3 was obtained - ^ nan the corresponding 17 ^ -propadienyl-17ß-tetrahydrofuran-2 ^l -yloxyöstra-1,3,5 (lü) -trien-3-ol as a product.

By reacting 17o (- (3-bromopropynyl) -17ß-propionyl-oxy-18-n-propylestr-5 (10) -en-3-one and metallic magnesium in tetrahydrofuran which contained 10 i tert-butanol, and Heating to reflux according to the procedure of Example 3 gave the 17o (-propadienyl-17ß-propionyloxy-18-n-propylöstr- ' ⁱ 4-en-3-one as the product.

By reacting 17 _< j (- (3-chloropropynyl) -18-isopropylestr-1,3,5 (10) -triene-3,17β-diol and metallic manganese in a 9: 1 medium of isopropyl ether and isopropanol according to the procedure from Example 3, the corresponding 17fl (-propadienyl-18-isopropylöstra-1,3,5 (lu) -triene-3,17ß-diol was obtained as a product.

00 9 8Λ 3/18 3 3

BAD ORIGINAL

By converting 3-ethoxy-1 ^ - (3-fluoropropynyl) -17ß-propionyloxyestra-1 »3i5 (lü) -triene and zinc dust in a propionic acid medium at 50 G · according to The procedure of Example 1 gave the 3-ethoxy-l ^ (- propadienyl-17i3-propio ·· nyloxy-18-methylestr-1,3,5 (10) -triene as the product.

By reacting 17 ^ - (3-BrompropinyJ.) - 17W-butyryloxy-18-isopropylandrost- ^ -en-3-one and zinc dust in a methanol medium according to the method of Example 1 obtained the 17K ~ propadienyl-17ß-butyryloxy-18-isopropylandrost- ^ · - en-3- " on as a product.

By reacting 17 ^ - (3-chloropropynyl) -17ß-acetoxy-18-methylöstr- ' ⁱ »-en-

t or Ul y
3-one and vanadium-III-sulfate in an aqueous acetone medium under a nitrogen atmosphere according to Example 4 gave the corresponding 17W-propadienyl-17β-acetoxy-18-methylostr4-en-3-one ^: as a product.

By reacting 3-methoxy-17 <? C- (3-fluoropropynyl) -17i3-tetrahydropyran-2 ^l yloxyöstra-1,3 »5 (10) -triene and chromoacetate in aqueous diethyl ketone and η-hexane according to the method of example 5 the corresponding 3- ^ ethoxy-17 «i-propadienyl-17ß-tetrahydropyran-2 ^l -yloxyöstra-1,3,5 (lü) -triene was obtained as a product.

By reacting 3-ethoxy-17o (- (3-chloropropynyl) -1, 3 »5 (10) -trien-17i3-ol and sodium amalgam in n-butyric acid according to the method of Example 2 , the corresponding 3-ethoxy ~ 17 was obtained << - propadienylÖstra-1,3t5 (10) -trien-17i3-ol as product.

By reaction of 3 [beta] 17 [beta] -diacetoxy-6,6-difluoro-17 * ("(3-chloropropynyl) -androst-4-en and chromoacetate in acetate and water according to the method of Example ^ f, the 3ß »17ß-Di®cetoxy-6,6-difluoro-l / ii-propadienylandrost-4-

en as a product. __._ _A

BATH ORIGINAL

009843/183 3

According to the above procedures, the following compounds were prepared, avoiding the use of an acid as the liquid reaction medium or proton donor for the ether derivatives; · 3ß | 17ß-bis (tetrahydroypran-2 '-yloxy) -6, ö-difluoro - ^^ - propadienylöstr - ^ - en, 6,6-difluoro-17 ^ -propadienyl-17ß-acetoxyöstr- ¹ f-en-3- on _r 6,6-difluor-17 ^ (- propadienyl-l 7J3-propionyloxyandrost - ^ - en-3-one, 6,6-difluor-17j (-propadienyl-l 7ß-benzoyloxyö str - ^ - en- 3-t> n, 6,6-difluoro-17e (-propadienyl-17ß-adaman toyloxyöstr - ^ - en-3-one, 3ß-propionyloxy-6, '6-difluoro-17 <(-. Propadienylandrost-4- en-l7ß-ol, 3ß, 17ß-B i s- (adamant oyloxy) -6,6-d if luor-17e (-prop adie nylös t r - ^ - en »3ß- (ß ^ hlorpropionylox ^ -6, 6-difluoro-17 | (-propadienyl-17ß-tetrahydrofuran-2'-yloxyandrost-4-βη,

3ß-Butyryloxy-6,6-difluoro-17tf (-propadienyl-17ß-tetrahydropyran-2 ^l -yloxyandrost-4-en,

3ß-Tetrahydropyran-2 ^l -yloxy-6 ₀ 6-difluoro-17 ^ -propadienyl-17ß-oaproyloxyöstr - ^ - en, '

3ß-Tetrahydrof uran-2 ¹ -ylo3y-6 _t 6-dif luor-17o (-propad ienyl-17ß-caproyloxyöstr - ^ - en »

3ß-Tetrahydroypran-2'-yloxy-6,6-difluoro-17 ^ -propadienyl-17ß-heptanoyloxyandrost - ^ - en and .

3β, 17β-D ipen tanoyloxy-5,5-dif luo r-17 ^ -pro padienylöa tr-4-en.

The C-3ß worked out after the main reaction as follows:

Example ! £

A solution of 1 g of 17 / propadienylandrost- ^/ 4-en-17β-ol-3-one in 50 ecm of tetrahydrofuran was added within 30 minutes with stirring to a suspension of 1 g of lithium aluminum hydr in 50 ecm of anhydrous tetrahydrofuran and this mixture 2 Heated to reflux for hours. Then 5 ocm. Ethylaoetai and 2 ecm of water were carefully added.

'. QQ98 A3 / 1833 BAD ORIGINAL

sulfate was added, the mixture was filtered and the solid thus collected was washed with hot ethyl acetate. Then the combined organic solutions were evaporated to give 17ci ^{Propadienylandrost--2} f-en-3i3,17ß-diol, which can be further purified by recrystallization from acetone / hexane.

In a similar way, the other, according to the invention prepared 3-oxo

derivatives with a 17 «(- propadienyl group, e.g. to the following 3Ö-hydroxyl compounds reduced:

-Propadienyl-17ß-acetoxyostr-5-en-3ß-ol,
17 ^ -P ^r ° padienyl-17ß-propionyloxyandrost-4-en-3ß-ol, 17rf-Propadier \ yl-17ß-benzoyloxyandrost-4-en-3ß-ol, 17i (-propadi! 8nyl-17ß-adamantoyloxyöstr- ⁱ i-en-3β-ol, 6,6-difluoro-17 # (- propadienylestr-4-en-3β | 17β-diol and 6,6-difluoro-17i / -propadienyl-17β-03 -chlorpropionyloxy) -androst - ⁱ f-en - 3ß-ol

Example 18

2 ecm of dihyropyran were added to a solution of 1 g of 17 ^ -propadienyl-17ß-caproyloxyandrost-4-en-3ß-ol in 15 ecm of benzene. To remove moisture, about 1 ecm was distilled off} 0.4 g of p-toluenesulfonyl chloride was then added to the cooled solution. This mixture was left to stand for 4 days at room temperature, then washed with aqueous sodium carbonate solution and with water, dried and evaporated. The residue was chromatographed on neutral alumina, eluting with hexane; This gave 30-tetrahydropyran-2 ¹ -yloxy-17o ^ -propadienyl-17ß-caproyloxyandrost-4-ene, which was recrystallized from pentane.

BATH ORIGINAL

009843/1833

20 ecm of dihydrofuran were added to a solution of 1 g of propadienylandrost-Jf-en ^ ß. ^ Ss-diol in 20 ecm · • benzene. To remove moisture, 5 ecm were removed and the mixture was then allowed to cool to room temperature. To the cooled mixture, 0.2 g of freshly purified p-toluenesulfonyl chloride was added. The mixture was stirred for Zk hours at room temperature and then poured into an excess of 5% aqueous sodium bicarbonate solution. The product was extracted with ethyl acetate, the organic solution washed neutral with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The oily residue crystallized after the addition of ether and yielded the 3 ^ß »17ß-bis- (tetrahydrofurane-2 ^l -yloxy) -17fl (-propadiehylandrost- ¹ f-en. ^

Similarly, were the tetrahydropyranyl and tetrahydrofuranyl ethers of the 17 <j (-propadienyl compounds according to the invention, e.g.

3ß-Tetrahydropyran-2'-yloxy-17fl (-propadienyl-17ß-acetoxy-18-methylandrost- ^ -en,

3ß-Te trahydrofuran-2 · -yloxy-17ii-prpadieny 1-17ß-heptanoylo3Eyös tr-5 (10) -en, 3ü _f 17ß-bis- (tetrahydropyrane ¹ -yloxy) -17 ^ '- propadienyl-18-ethylandrost - ⁱ l-en _l

3ß-TetrahydΓoypran-2'-yloxy-17j5l-'Propadienyl-17ß-adamantoyloxy-18-methylostr-4-en _t and

3β, 17β-bis (tetrahydropyran-2 ^l -yloxy) -6,6-difluoro-17 # i-propadienyl-18-ethylandrost - ^ - en.

Example 18

A mixture of 1 g of 17 # (- propadienyl-17β-acetoxyöstr- ^ en-3β-ol, k ecm pyridine xind 2 ecm acetic anhydride was left to stand at room temperature for 15 hours, then poured into ice water and the precipitate formed was filtered off and washed with water and dried; in this way 3 [3] 17 [beta] -diacetoxy-l ^ (-propadienylostr-4-ene was obtained, which can be further purified by uracrystallization from acetone / hexane.

009843/1833 BATHROOM ₀ R, G, w

In a similar way, the corresponding 3ß- ^l! 'Ster of the other 17ci-P ro pad ienyl products according to the invention by using the corresponding starting compounds and customary acylating agents, such as: 3ί3-trimethyl * acetoxy-17ί (-propadienyl-17ß-aöetoxyöstr- ^ί ^ -βn, 3ß, 17ß- Dipropionyloxy-17d (-propadienylandrost- ⁱ l-en,

3ß-Butyryloxy-6,6-difluoro-17ei-propadienyl-17ß-tetrahydropyran-2 ^l -yloxyöstr- 4 ~ en, ·

3ß-Pentanolyoxy-17fl (-propadienyl-17ß-Äcetoxyöstr-5 (10) -en, 3ß, 17ß-Bis- (benzoyloxy) -17 / -propadienylandrost- ⁱ l-en and 3ß-acetoxy-6,6-difluoro- 17 ^ -propadienyl-17ß-PΓopionyloxyandrΌst-4-en.

example 20th

According to the above process using the 3-hydroxyl derivatives from the starting compound, the corresponding 0-3-substituted derivatives of the 17ci-propadienyl products of the estrogen family were prepared. According to the main reaction according to the invention, the starting compound can be formed by conventional hydrolysis of the protective group, for example a tetrahydropyran-2'-ylo ^ r group, with acid hydrolysis. So the following 3- ^su t> ^s t ^a tuated compounds of this series were made:

3-acetoxy-17i (-propadienyl-17ß-tetrahydropyran-2'-yloxyöstra-1,3,5 (10) -triene, 3,17ß-diacetoxy-17 # (- propadienylöstr-1,3t5 (10) -triene, 3,17β-bis (benzoyloxy) -17i <'- propadienyl-18-ethyletra-1, 3,5 (10) -triene and

3-C aproyloxy-17 ^ -propadienyl-17ß-te trahydrof uran-2'-y loxy-18-propylö s tral, 3,5 (10) -triene,

The following 6,6-difluoro-17 * (- propadienylandröst - ^ - ene and 19-nor-derivatives produced:

BATH ORIGINAL

0 098A3 / 1833

- 33 - 3i3,1713-Üiacetoxy-6,6 ^ ifluor-17 << - propadier \ yl - 18-n-proR5rlöstr - ^ - en, '3ί8,17ß-Diace to3qy-6 _t 6-difluor-17fli -pro padienyl-ie-raethylostr- ^ - en, 3f31, 7i3-diacetoxy-6,6-difluor- ^ oi-propadienyl-IS-ethylandrost- ^ - en, 3Ö, 17ß-Dipropiqnyloxy, 6,6-difluor -17 ^ -propadi enylö str-Λ-βη, 3i3,17ß-Dipropinyloxy-6,6-difluoro-17ei-propadier \ yl-18-methylandro st-4-en,

313,17i3-bis (tetrahydropyran-2 '-yloxy) -6,6-difluoro- ^ cf-propadienyl-ie-isopropylöstr - ^ - en, ■ ·

3ß, 17i3-bis (tetrahydro pyran-2 -yloxy) -6,6-difluoro-17o (-propadienyl-androst-

313,17M-BIs- (te trahydrof uran-2 '-yioxy) -6,6-difluoro-1 ' M- propadienyl-18-ethylandroate-'t-en,

3ß, 17ß-bis (tetrahydrofuran-2'-yloxy) -6,6-difluoro-17 ^ -propadienyl-18-ethyl estr - ^ - en,

6,6-Üifluor-17i (-propadienyl-17-propionyloxyöstr-4-en-3> -one _f "6,6-D if luor-17i (-propadienyl l-7.beta.-butyryloxyö STR ⁱ i-en-3 -one, 6,6-Difluoro-17oC-propadienyl-17ß-pentanoyloxyöstr - ^ - en-3-one _t 6,6 Difluoro-17e (-propadienyl-17ß-pentanoyloxyandrost - ^ - en-3-one, 6,6 -Uifluoro-17 () (- propadienyl-17ß-hexanoyloxyöstr- ⁱ l-en-3-one, 6,6-difluoro-17 # (- propadienyl-17ß-heptanoyloxyandrost- ⁱ l'-en-3-one, 6 , 6-Dif luor-17o (-propadieny 1-17ß-caproyloxyöstr - ^ - en-3-one, 6,6-Dif luor-17j (-propadieny 1-17ß-benzoyloxyandro st - ^ - en-3-one, 6.6 * Dif luor-17 <(- propadienyl-17-adamantoyloxyöstr - ^ - en-3-one, 6,6-difluoro-17e (-propadienyl-17ß- (g-chlorpropionyloxy) -Ö8tr- ⁱ i s -3-one, 6, 6 ^ difluoro-17 | f-propadienyl-17 [beta] -trl-methylacetoxyandro8t-4-en-3-one and 6,6-difluoro-17 <-prppadienyland <> 8t-4-en-17 [beta] -ol -3-on.

009843/183

Claims (1)

Patent claims "., -) Process for the preparation of 17« C-propadienyl compounds of the following formulas: ... CH = C = CH, F 'P ... CH = C ^ CH, ORIGINAL INSPECTED 0U98U / 1833 -35 - ..CH = C = CH, in which R represents a hydrogen atom or a lower alkyl group of 1-3 2
Carbon atoms; R is hydrogen, tetrahydrofuran ^^ yl, tetrahydropyran-2-yl or a carboxylic acyl group with less than 12 carbon 3. H atoms means; R represents an oxo group or the group _D 6 _n I , in Λ U mm » which R denotes hydrogen, tetrahydrofuran-2-yl, tetrahydropyran-2i.yl or a carboxylic acyl group having fewer than 12 carbon atoms; R represents hydrogen or methyl} and R ^ represents hydrogen, a lower alkyl group with 1-8 carbon atoms, a cycloalkyl group, tetrahydrofuran-2-yl, tetrahydropyran-2-yl or a carboxylic acyl group with fewer than 12 carbon atoms, characterized in that a 17ef ~ (3-halopropynyl) steroid with a reagent from the group of metals with an oxidation potential between + 3.0 * 4-5 and 0.7 ^ volts and salts which, after ionization, form cations with an oxidation potential between -K ), 61 and +0.255 volts, where the halogen atom is bromine, chlorine or fluorine. 0 098 A3 / 183 3 2. - Method according to claim 1, characterized in that it is in an organic liquid reaction medium and in the presence of a proton donor is carried out. 3 · - Method according to claim 1 and 2, characterized in that it is at one Temperature, from about 20-120 C. is carried out. 4.- The method according to claim 1 to 3, characterized in that as metallic Reagent potassium »calcium, sodium or zinc is used. 5 · - Method according to claim 1 to 3, characterized., .That as a metal salt reagent Chromochloride is used. 6.- The method according to claim 1 to 3 »characterized in that the metal reagent a Zinlc-copper pair is used. 7. Process according to claims 1 to 6, characterized in that a 17 (- (3-chloropropynyl) steroid is used as 17 </ - (3-halopropynyl) steroid. 8. Process according to claims 1 to 7 , characterized in that 17e ^ -Propadienyl-17ß-acetoxyöstr- ^ - en-3-one from 17 "(- (3-chloropropynyl) -l7ß-acetoxyöstr- ¹ i-en-3-one is produced. P 9 · - Method according to Claims 1 to 7 »characterized in that a 6,6-Di- ' fluorine-17e (-propadienylöstr-4-en or a 6,6-difluoro-17o (-propadienylandrost-A-t »n is manufactured as a steroid product. 10 · - Process according to claims 1 to 7, characterized in that as a steroid product 6,6-Difluor-17 / -propadi8nyl-17ß-s, cetoxyöstr ^ -en-3-one is produced 009843/1833 11, - compounds of the formula: in which R stands for hydrogen or a lower alkyl group with 1-3 carbon 2
material atoms stands; R hydrogen, tetrahydrofuran-2-yl, tetrahydropyran- 2-yl or a carboxylic acyl group with fewer than 12 carbon atoms 1 H < • } K denotes an oxo group or the group _B 6 _n I , in which R Hydrogen, tetrahydrofuran- ^ yylj tetrahydropyran-2-yl or a carboxylic if Acyl group with fewer than 12 carbon atoms means} and R means hydrogen or methyl. 12.- Compounds according to Anspruoh 11, characterized in that dai3 R for water 3
substance and R stands for an oxo group. . 2
13 · - Compounds according to claim 11 and 12, characterized in that R for Il
Hydrogen and R stands for hydrogen. 2
1 ^ »- connections according to claim 11 urtd 12, characterized in that R for L.
Acetyl and R represents hydrogen. 15 · - Compounds according to claim 11 and 12, characterized in that R for is a carboxylic acyl group, having fewer than 12 carbon atoms and R is hydrogen. 009843/1833. - 38 - 16. Compounds according to claim 11 and 12, characterized in that R ^{c stands} for hydrogen and R for methyl. 17 - compounds of the formula: ... .CH = C = CH, in which R is hydrogen or methyl, and the 170-acetate and 18-methyl derivatives thereof. The patent attorney: 0 0 9 8 Λ 3/1 8 3