BE623842A - - Google Patents

Description

       

   <Desc / Clms Page number 1>
   estradiol-related bteroids.



   The present invention relates to estradiol-related steroids having an alkyl group of more than 1 carbon atom in position 13, as well as processes for their preparation.



   Steroids according to the present invention are structural compounds;
 EMI1.1
 

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   where R is a hydrogen atom, an alkyl group or an acyl group, R1 is a saturated alkyl group containing at least 2 carbon atoms
 EMI2.1
 ne, R. is an alkyl group in the trin configuration with respect to R, the C ring is saturated or has an ethylenic bond ending in position 9, the C / D ring junction is in the
 EMI2.2
 a hydrogen atom in position 8 is in .4nu configuration with respect to the hydrogen atom Xi in position a..4 and any hydrogen atom in position 9 is in trans configuration with respect to that of position 8 .



   The compounds of the present invention therefore fall into three classes represented by the structures (II), (III) and (IV)
 EMI2.3
 
 EMI2.4
 where, in each case, there is a 13p.altyla group, and the corresponding enantiomorphs where I is a 13 -alkyl group.



  The term "alkyl group * as used in general herein refers to both substituted allyl groups and unsubstituted allyl groups. Thus, an alkyl group can be a straight chain group. or branched carrying or not
 EMI2.5
 8ubstants (eg methoxy or hydroxy groups). R may be, for example, a methyl, ethyl, methoxymathyl, hydro-xydthylop glyeréry or tocnzyie group, or a uci-tyl or benzoyl group.



  R is preferably an alkyl group of less than 6 carbon atoms.
 EMI2.6
 born. and preferably a methyl group. ir and Au are preferably unsubstituted alkyl groups, and preferably each contain no more than 6 carbon atoms. R1 can be
 EMI2.7
 for example, an ethyl, g-propyl, isopropyl, n-butyl or iaobutyl group. a2 can be a saturated or unsaturated alkyl group, for example a methyl, ethyl., vinyl, ethynyl, a-propyl, iso-

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 EMI3.1
 propyl, allyl, propynyl, s-butyl and 1- and 2-methallyl.



   Of particular importance are compounds in which R 1 is ethyl (i.e. 18-homo compounds), especially those in which R 2 is also ethyl, n-propyl, allyl or ethynyl.



   A process for preparing a steroid of the invention
 EMI3.2
 uses the corresponding 17-ketone of structure ('):
 EMI3.3
 which is alloyed to give tertiary carbinol. The term "alkylation" as used herein refers to the attachment of an alkyl group to the 17 carbon atone with formation of a tertiary carbinol. Preferably, the compound used for the alkylation is a compound.
 EMI3.4
 wherein the group R is an alkyl group without an active hydrogen atom, which makes the alkylation inexpensive.

   In the case where R is an acyl group and this is lost in the course of alkylation, it can be reformed by subsequent esterification of the hydroxy group at position 3. Starting materials for such a process -
 EMI3.5
 dice are described in patents 600,245 and 603 <369. Allation can be carried out using as an alkylating reagent a suitable organometallic compound which contains the alkyl group R2 which it is sought to introduce. The organometallic compound can
 EMI3.6
 be a Grignard reagent (that is to say an allJ..a. sium halide), or an alkyl derivative of an alkali metal, for example a clfcyl-lithium or an actylide or a lithium carbide, of sodium had potassium.

   Thus, the ethynyiation can be carried out under the action of acetylene and an alkali metal, an alkali metal amide or an alkali metal alcoholate. 2. :: '; .. hi.I ::::' - aluminum acetylide, which is prepared by the reaction of aluminum hydride 1i t!: I '. ;;; :: -' aluminum with acetylene, can also be used. h * 1 ': .tiC: 1

 <Desc / Clms Page number 4>

   alkylation is carried out at a suitable temperature in a suitable inert solvent, for example ether, and if a reactive group, such as the hydroxyl group, is present at the 3-position of the compound during the alkylation, an access is used. corresponding alkylation reagent.



   Compounds of the invention can also be obtained by appropriate reduction of other compounds of the invention having a higher degree of unsaturation. Thus, the compounds of structure (IV) can be prepared by reduction of the compounds of structure (11) under Inaction of alkali metals in liquid ammonia, or by reduction of compounds of structure (III) under the action of alkali metals in liquid ammonia or by catalytic hydrogenation: in each case, if the starting product contains an unsaturated R2 group, the latter may become saturated depending on the nature of this unsaturation and the conditions of reduction.

   A compound in which K is an unsaturated group and the ring C contains an ethylenic bond can be selectively hydrogenated so as to reduce the R2 group and leave the ethylenic bond of the ring intact. The catalytic hydrogenation can be advantageously carried out by stirring the compound, in solution in a suitable solvent, in a hydrogen atmosphere and in the presence of a catalyst, for example, a palladium or Raney nickel catalyst. , the compounds of structure (II) where R2 is an ethyl group, and of structure (IV) where 11- is a vinyl group, can be obtained by catalytic hydrogenation of the corresponding compounds where R2 is an ethynyl group,

       using a palladium on calcium carbonate catalyst (preferably in the presence of pyridine, if a vinyl group is to be formed) and interrupting the hydrogenation when the amount of hydrogen required for the transformation Selective conversion of ethynyl group to ethyl group or vinyl group, respectively, was taken up. The compounds of structure (III) can be obtained by acid isomerization of the corresponding compounds of structure (II).

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  In the structural formulas (I) and (V) above, ls
 EMI5.1
 13P and 13a compounds are not shown in a distinct manner: in a product obtained by total synthesis, without resolution, 'the 13ss and 13a forms will be present in an equimolecular mixture
 EMI5.2
 or in racemic form. The structures (11) to (IV) above represent the 13P forms * If the starting product is a 13ss enantiomorph (for example), the product will of course be a
 EMI5.3
 z, but in the opposite case the enantiomorph 13 can be obtained by a subsequent doubling, which can involve temporarily transforming the group R into another group. So a compound where.

   R is a hydrogen atom can be split by transforming it
 EMI5.4
 in its j, -menthoxyacetic ester, by separating the op- enantiomorphs; tically active by fractional crystallization, and by decomposing esters.



   The compounds of the invention are very important intermediates for the preparation of other valuable steroids having:
 EMI5.5
 reduced ring A, in particular 17α-alkyl-18-homo-19-nortestaitérones as described in the patents of the same date by the applicant, entitled “Steroid compounds” and “Steroid ketones”.
 EMI5.6
 



  Thus, 3-4ethyl ether of 17a. ethyl-18-homo-estradiol is a starting material for the preparation of 17a-ethyl-18-homo-l-nortestosterone, which has remarkable anabolic properties associated with androgenic activity and very low toxicity. - wheat. Compounds of the invention, where R is an acyl group, can remove hydrolysis to compounds where. R is hydrogen, and these can be transformed by etherification into compounds where R is
 EMI5.7
 an allyl group.

   The latter can be transformed directly by producing eîreh into reduced cycle steroids *
The present invention is illustrated by the following examples, in which temperatures are given in degrees Celsius.
 EMI5.8
 sius, the numerical values of infrared absorption (IR) refer to the positions of the maxima. in cà-1, and the numerical values of ultraviolet (UV) absorption refer to the positions

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 EMI6.1
 maxima, in 1..3.ta3.Ctllxa the value C. t, "ittÎléaB indicating the molecular extinction coefficient at these wavelengths.



  Add slowly, with stirring under a nitrogen atmosphere, an ethereal solution of methylmagnesium bromide (from os9 g of # agnesiucO to a solution of methyl ether of (-) - l8homo-estrone (1.0g) in benzene (50 in} * The mixture is heated under reflux for 4 hours then poured onto ice, acidified with hydrochloric acid and the aqueous phase is separated and
 EMI6.2
 extracted with ether. The combined organic phases are washed, dried and evaporated, and the residue is taken up in benzene (20 cat3, y and chromatographed on neutral alumina; by elution with bEJ1zene, then with benzene containing a small proportion of chlo reform, a crystalline product is obtained which is rechromatographed on alumina;

   the product is recrystallized from methanol to give
 EMI6.3
 ner (-) - 18-homo-17o [-methyloestradiol 3-methyl ether (0.9g), mp 142-145 ° C; UV: 79 (1.15Uj 3 IR, 34? U; (Found! C 8U, 5; Il, 9.4. Calculated for C, 21 H 30 U 2 C, 802; Ft, ge6.



  KAMPLE 2.- A 3M solution of methylmagnesium bromide in ether (25 cm3) is added slowly, with stirring, under a nitrogen atmosphere, to a solution of methyl ether of (-) - 18 nor l3p-xi-propyl-estrone ('z, 14 g) in benzene (where the mixture is heated under reflux for 44 hours, a test then showing that the unchanged ketone content is negligible. After the usual treatment. , followed by recrystallization from methanol, the ether is obtained
 EMI6.4
 (J-ü? A methyl. 8-nar-131s b-propylaestradiol bzz melting point 131-134 "C; UVt 27d (2.300) j rh: 3480 no absorption due to carbonyl. Kx Iu. 3 ...



   A lithium aluminum acetylide suspension is prepared by slowly passing a stream of dry acetylene through a (saturated solution of lithium aluminum hydride (40g) in tetrahydrofurana (500cm) over 18 hours -

 <Desc / Clms Page number 7>

 
 EMI7.1
 This 413 ci suspension (te (t) -18-homo-estrone methyl ether (0.60 g) is added to a part of this suspension, the mixture
 EMI7.2
 is stirred for 5 minutes and then left for 20 hours
 EMI7.3
 at room temperature.

   The product is poured into ice-cold sulfuric acid (100 0.% 3) containing crushed ice and the
 EMI7.4
 mixture is extracted with ether; the ethereal extracts washed, dried and evaporated give a crystalline residue which is taken up in
 EMI7.5
 benzene (10 cm and adsorbed on alumina (60 gij. 'elut1on by
 EMI7.6
 a mixture of benzene and petroleum ether, gradually increasing-
 EMI7.7
 However, the benzene content up to 100 debenzene gives the starting drug unchanged (0 Il .Lob gj3 a new .lutin with benzene containing 10 ether and finally with a J! lt: lan & e 4th volume equal of benzene and ether gives the 3..meilyl ether of (-} #] i? cetiynyl. 18 nto-oesttacüa.

   (0.41 g), melting point 140-135 "infrared 350 (a broad band due to hydroxy and 3300 (a methane group); no ketone absorption, pElU 'J.r1' ': 4.



  Is added with stirring, in a slow stream of acetylene, a release to dtherm.dthrxiree of (j-7.8..nor-13p-po: r3 .. estrone (19.4 g) in di1léthy J.aeetamlde ( 30U c: m3) at an auspen-
 EMI7.8
 its lithium acetylide (26.? g, in a mixture of dioxane (332 a} and ethylenediamine (18 oa 3); stirring is continued at room temperature for b6 hours then the reaction mixture is poured in in ice water 3 1 ') * The eroddit is
 EMI7.9
 extract with ether and the washed and dried extracts are evaporated
 EMI7.10
 to give a residue which is purified by chromatography in benzene on neutral alumina;

   the solution with benzene gives a crystalline product which is recrystallized from acetone / n-hexane to give the 3-ethyl (* - ,? a-etynyl-.8-ricr-Ils - propyàoestradiisl) (11.0 g) p melting point 3.G-130 CU <280 (1.9CÎb).
 EMI7.11
 

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 EMI8.1
 



  , w. 5.-,
 EMI8.2
 Add a methyl ether solution of (-) - la-
 EMI8.3
 hD.'ll1o ... estrone (0.8 * 5 g) dfa18 a mixture of ether (40 cm) and allyl bromide (2.9 cm3) to a mixture of magnesium (0.3o2 g) and allyl bromide (Upl5 cm3) the mixture is heated gently under reflux for 3.5 hours, cooled to 5% and gradually added with a 10% solution of ammonium chloride (100 cu3.
 EMI8.4
 The ethereal phase is separated, washed, dried and evaporated; the residue
 EMI8.5
 is recrystallized from hexane to give 3 aethyl ether
 EMI8.6
 
 EMI8.7
 (+) - 1'7a-a-Llyl-la-homo-oeutradio.L (0.845 g), mp 126.1k8l ° C;

   Ulls A78, S (2000) infrared 1, it S A mixture of allyl bromide z7 g) and 51ca3i ether is heated to reflux in the presence of magnesium (0.7 gas then addi-
 EMI8.8
 titrated drop by drop over 30 minutes with an ether solution
 EMI8.9
 -18-nar-13r -propyloestrona 3-methyl (2.5 g) in
 EMI8.10
 
 EMI8.11
 ether (100 cuaj and allyx bromide (10.8 S). The mixture is stirred and heated at reflux for another 4 hours then addi- tion of ether (30 osu3) # the cooled mixture is then poured into
 EMI8.12
 an aqueous solution of ammonium chloride and the product is extracted with ether.

   After evaporation of the ethereal extracts, washed and dried, a gum is obtained which is recrystallized from methanol to
 EMI8.13
 give 3-methyl ether of (!) -170-811) '1-18 -nûr-13p- -propyl- estradiol (2.5 gases, part of the product recrystallized from n-hexane melts at 8U-0 .C; uw; 280 (2,000); g I # ia 3535, 1640, 'ü0g (Found; C, 8i., O | ti, 9.1. Calculated for CH340 C, 81.3; H, 9, ï ,. tJ # MPË 7.
 EMI8.14
 200 carbs of lithium acetylide suspension are added.
 EMI8.15
 aluminum of example i to a solution of (!.) - 8-dehYdro-J.8-homo-oestrone methyl ether (5.0 g) in tetrahydrofuran (10 c '), and the mixture is heated at reflux for 4 hours.
 EMI8.16
 



  Ice water is then added, with stirring, followed by sulfuric acid 3 to dissolve the precipitate obtained and the product is treated.
 EMI8.17
 Z

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 EMI9.1
 with ether in the usual manner to give (j -.- dehydr4-lcethyny7.-18-nomo-estradiol 3-raethyl ether (5, U gas UV: 276 (13.300). a solution of methyl ether of C * j-3- deïtydro-.L8-horao-estrone (2 g) in aniline (300 cm) egt added, in an acetylene atmosphere, to a suspension of acetylide of
 EMI9.2
 lithium. (<< b6enu from a.n: technical lithium hard, 50 a) without aniline (500 cm). Acetylene is bubbled through the 1 3elan-
 EMI9.3
 age by shaking it for 3 days.

   Water is then added and
 EMI9.4
 the mixture is extracted with ether, the ether extracts are separated from the aniline by washing with 10) sulfurized acid and the product is isolated to give 3-methyl ether of (-) - 8 - dhydro-1Tu-thyny.-1-hoao-oestradio. in the form of a gum (88 g) j ittî 3630, J3UO. jd, (s .r To a stirred suspension of lithium acetylide (42.4f {) in
 EMI9.5
 
 EMI9.6
 a mixture of dioxane (40 3), ethylhedianine (10 and 1 dimethylacetajflide (50 cm 3) is added, in an acetylene atmosphere, a solution of 3-metylic etiier of (j..8dénydro-3.8-horo. csstradal (ot>, 6 g) ttans uimethylacetauid (450 cm).

   stirring is continued for a further 20 hours in an acetylene atmosphere and a mixture of
 EMI9.7
 reaction mixture is poured onto crushed ice and extracted with benzene
 EMI9.8
 the evaporation of the washed and dry extracts gives a crude zero which is dissolved in methanol (450 au}, and the solution is
 EMI9.9
 charcoal treated and filtered. After concentration of the filtrate at
 EMI9.10
 300 cl, we add water (45 3) and we cool 1. aelanse to precipitate the i-metnyl ether of (!) - a-denydro-11- etbynyl-18-hoo-oestraa101 (02, 4g) which is recrystallized from methanol, melting point 10-ju "; uv: 278 (16.1UO) | iRs38S 2830, 2UeU; (Found: Z, 82, os Tri, 8.1.

   Calculated for C ,, Ó2: C, 82 # 3; Jie 6.3). â.lili rt, 10.- a stirred suspension of lithium carbide (2e5 g) in

 <Desc / Clms Page number 10>

      
 EMI10.1
 a mixture of dioxane (40 gases, ethylenediamine (10 orrez and dimét3yrlacétaruide (50 eu-3) p is added, in an acetylene atmosphere, a solution of 3-methyl ether of (-) - 8- <1hydro -18-homo-estradiol (5 L) in dimethylacetaimide (50 eru) Stirring is continued for a further 20 hours in an acetylene atmosphere.
 EMI10.2
 



  My reaction mixture is poured onto crushed ice and extracted thoroughly. The evaporation of the washed and dry extracts gives an oil which is dissolved in methanol (50 car), and the solution is
 EMI10.3
 treated with charcoal (o g) and filtered. The filtrate is concentrated to
 EMI10.4
 half of its volume, added with water (o cm3, and the mixture is cooled to precipitate the (-) - 8- dehydro-17 <] t-ethynyl-18-hojno-oesH 'J-llâthyl ether adiol (4.2g), melting point, ü, i ... ü3 "C after recrystallization from methanol; U1: 278 (16.100) IR: 3580, 32SOr 2830, 2080.



  .1.tE..t, .... ±
To uagnesium (20 g) covered with tetrahydrofuran (50 cm3) we add several cubic centimeters of a solution of allyl bromide (11, 8 g) in tetrahydrofuran (225 cm3) and we prime
 EMI10.5
 the reaction by crushing a fragment of = agnes:

  L4with a glass bar and adding a small crystal of iodine. when the reaction has started, the remainder of the solution of allyl bromide in tetrahydrofuran is added slowly over 30 minutes, followed by addition of
 EMI10.6
 dropwise, over 45 minutes, a solution of 3 u tnyl ether of (-) - 8-denydro-o-nomo-esttone (50 g) in tetrahydrofURane (1 liter) and allyl bromide (2kO g). The mixture is heated at reflux for 3 hours, cooled to z and treated with a 20% aqueous solution of ammonium chloride with vigorous stirring.



  The separated organic pnase is then extracted with ether and the real obtained after evaporation of the washed and dried extracts is redesigned.
 EMI10.7
 crystallized from n-hexane to give ether J ... metHy11que du (:,? a-allyl-¯aéhyaro-18-hoao-estrdiol (51 g), melting point 23-125 "C! UV: 230 (18..süü; LH: 3470, 2V2U, 1630, 1610, 1570, 1500; Found C, 81.55; tut, 8.8.

   Calculated for C3H3üJxs C, 81.6, 0), 8,, 97)

 <Desc / Clms Page number 11>

 
 EMI11.1
 1JCKt'L -A solution of methyl eter of (") - @ - 'dTydro-l3- nor-13iJ-.û-ijropyioes throne (', U) in aniline (i cm) is Rou-
 EMI11.2
 tee, with stirring in an acetylene atmosphere, to a suspension
 EMI11.3
 littiiua acetylide (obtained from 1 g of litait) in aniline (or ct3). bpus agitation, we pass for 26
 EMI11.4
 hours a vigorous flow of acetylene through the mixture- After!
 EMI11.5
 treating the mixture as in Example 6, we obtain the J-mthyJ.ique eter with (*}. s-daydrol.9a-ethyny7..8-nor-.t3 -prapy.Locat: a-diol under the form of a red 6cim (0 g), 1H: 3570 # 3280.



  Is added, with stirring, in an ketylene atmosphere, a solution of II1Jthyl1'1Ue ether of (*) - 13p - butyl-.Méydra-18-nor-estrone zij, 5 g) in aniline (J5 cmj to leaedt7jlure of lui- thima (obtained from 4 g of aiiaure of teckmic .l1tnlUl11) in aniline (55 cm) #bous stirring, we pass for 40 hours
 EMI11.6
 res a stream of acetylene in the mixture. After cotcae treatment in Example 8 # the 3-methyl eter of (-) - 13j> -jj- butyl-y-dényaro 17a-ethynyl-lB-noroestradlol is obtained in the form of a gull wheel (J , 7g) 1K: 3415, 3250e 2180.



  X, 1'rk '..



  % n stirring, in an acetylene atmosphere, iitriioii acetylide (3.5 g) in a mixture of dioxane (10 <aa) is added
 EMI11.7
 
 EMI11.8
 of ethylene diauine (10 e: u3? and of climetaylac4taaide (aU cia3) to a solution of methyl ether of there (t) -9-idehydro-18-horao-estrone (3.5g) in dlinétnylacetamide (100 c31 * The mixture is stirred overnight at ordinary temperature then poured onto crushed ice and extracted with 3. ether. The washed and dried extracts are evaporated to give a residue which is chromatographed on alerd on water. activated fuller's earth, recrystallized in a n6-. lane of methanol and water and then in a mixture of ethyl acetate and itexane to give the ether -.ra6, iyique of (-) - 9-dehydro-17a- j etiy.t.-18-.uomo..oestra3ol, fusion poiu llt-11 "4 :; tJY: 263 (20 * 400) j 1:

   3570, 32â0.

 <Desc / Clms Page number 12>

 
 EMI12.1
 



  LXI! K4eLE l-.!. The J-Aathy11que ether of {: j¯17a-6tliynyl-18-hota = -oestradiol {t?, 5U 9p the product of Example 3) in solution in anhydrous dioxane ( 1U cia3) is a6itated in a hydrogen atmosphere at atmospheric pressure in the presence of a 5% palladium-on-carbon catalyst (0.05 g) until the end of uydrogen absorption.



  After filtration and separation of the solvent, the (-) 17-ethyl-18-iioiao-aestraciioi-ethyl ether is obtained in crystalline form, (0.45 g), melting point 1k-ll.y4. ; bed! zij0.



  J.-LR ..



  A solution of J-methyl ether of (-) -17u-alXyl-18-.homo-estradiol (0.87 g, the product of Example 5) in ethanol (110%) is stirred. in hydrogen zatosphere under atmospheric pressure in the presence of a palladium-on-carbon catalyst until absorption of the urogen is complete. after wire-
 EMI12.2
 tration and evaporation of the solvent, a residue is obtained which is re-
 EMI12.3
 crystallized from hexane to give () - 18-nomo-17ct-α-propyloestradiol 3-methyl ether (0.745 g), mp 1-3-12 g "C;

   UVt j, 79 (1.950). j \: JJ!: - 1J? J..t .. 17.- The 3-¯étbYl1que ether of {} -1iu-allyl-18-nor-131; - proyJ.oestrad101 (, 91 g, the product of example 6) is hydro- hampered in eDanol (50 cm.3) under atloshereal pressure in the presence of a bzz catalyst of palladium on carbon (1 g} * After filtration and evaporation, a residue is obtained which is recrittalized in methanol to give (fi) α3t, α-bis -prapyl-18..noroestradio 3-xaethyl ether, mp 85-4-C; uvt Z80 (17U);

   liit 3450. jbJ # MFjbR 18. - The $ t <er 3-methyl of (-) - 8-dehydro-17a-etbynyl-184homoestradiol (i, 9 i, the product of Example 7) in benzene (100 cc) is stirred in hydrogen under atmospheric pressure in the presence of a catalyst pre-reduced to 2 of palladium on

 <Desc / Clms Page number 13>

 
 EMI13.1
 calcium carbonate (016 gas, until the end of absorption! Jtion of hydrogen
 EMI13.2
 ne * Hydrogenation ceases when the amount of lUr36e required for selective saturation to the ethyl group has been absorbed.
 EMI13.3
 After filtration and evaporation with solvent a residue is obtained.
 EMI13.4
 Crystalline which is recrystallized from metilanol to give the 3-.athyl eter of t) .. rlcieayciro-1? a..itcyl-13-itc-estradical.



  (1, gi, melting point 13V-140vU $ UV: 'l6 (15. 5uU); ¯ IR: - 3565j JLK-Rth. 1'- t'6tcrer> -! 4étny J.14.'1. Du ( -) - i7a-tiilyi-8-dehydro-m- homo-oestraaioj. (50 g, the product of Example 11} in benzene (5 or cil3) is stirred with a pre-reduced catalyst to 2 * of palladium on carbonate of calcium (<< 5) at 5'C in a hydrogen atmosphere
 EMI13.5
 until absorption of one molecular equivalent of hydrogen (3.6 l).
 EMI13.6
 after filtration of the catalyst and evaporation of the solvent, a residue is obtained which is recrystallized from n-hexafte to give the J! I16t ± 1Y lic ether to (*) - t3-denyaro-lc-raa: xo-17a -propyloestraaiol (4Ug), melting point 13? -l.sY c :; uv; 78 (16.8uO); I: J) 40, 28tOe 16UUe .5u, 150u. 2u.



  . ,, '6tuer 3-: atny.isue du (-) - 8- (iénydro-17a-étnynyl-18-nor-' 13, -g-royloestruà.iol (1 g, the product of Example 12) in benzene (-100 cita) is stirred in a '.lY <1roene atmosphere under at: cosmetic pressure in the presence of a catalyst prereduced to 2, b of pailaaiuiti on calcium carbonate (0.35 g) .... 'l1dJ:' ol \ <mat1on is discontinued after absorption of the amount of 1dro & èr.e required for the selective saturation of the 6thynyl group; after filtration and
 EMI13.7
 evaporation, a residue is obtained which is recrystallized from
 EMI13.8
 tnanol to give (-) - 3-daydro 17a-etayl-1-nor-13p-n-propyloestractiol 3-methyl eter (0.5 g), mp 16-198; uv:

   Mis (14.7uut; ln: 3570. t.Á "lt1 iritner 3-Aethylique du (=) - i3p - buty .-- dhydro-17a-. Ét'4iyny.L-1; 6-noroestraaiol ( 3.7 g, the product of Example 13) in benzene (15J c = 3) is stirred in a û atmosphere. * 'AyaT0bns under the

 <Desc / Clms Page number 14>

 
 EMI14.1
 atmospheric pressure in the presence of a 21a catalyst of palladium on calcium carbonate (1.2 g) until absorption of the amount of hydrogen required for the selective saturation of the etnynyl group. The red gum (3.7 g) obtained by filtration and evaporation is recrystallized from methanol to give, to
 EMI14.2
 the raw state, 3-methyl ether of j..p D-buiyl-8-df, ydro-17x etoyl18-nor-estradiol (, '/ gJl a part of the product is further recrystallized from acetonitrile. aqueous to give pure composa, melting point 7:

  -76 U1t 3 2ir3 (15 * WU); TH3 3J70. l! .Xl! l4.t 'J..1'.i 22tT The 3-methyl titer of- (!) - 9-dei-tydro-17cz-ethynyl-18-iloilo. estradiol (1 g, the product of Example 1b cans of benzene (15 cm3) is added to a suspension of a pre-reduced 2% palladium on calcium carbonate catalyst (0.3 g) in benzene
 EMI14.3
 (read C1I13) and the mixture is stirred in a hydrogen atmosphere until this 2 hydrogenous molecular equivalents ('7Ucm) is absorbed. ye Catalyst is filtered and the solvent is evaporated to give ether J-lIlétayllque du C't) - '1-dihydro-17a-6tnyl-ld-nolllo-oestrfld1ul which is recrystallized from mero101, melting point 112-117 VS; UVJ t45 (16.1U0).



  .I! J'J! .. u-; J .. 2 ..: Liquid onlac (400 in) is added with stirring to a solution of 3-methyl ether of (-) - 8-dényarōl7a-ëtnyl i8-hamo-oestraaiol (13, 3 g, the product of Example. 3 d in aniline (. Or com) then in lithium (5.0 g) ei small fraentsj after 1 hour of stirring, azruuonlcu chloride is added in excess, then water and the mixture is extracted with ether. The ethereal extracts are washed successively with water, then with 10% sulfuric acid to completely separate the aniline, with water. water and with sodium bicarbonate solution,

     and finally dried. The crystalline residue obtained after evaporation is re
 EMI14.4
 crystallized from etnano- to give () -1? a-etayl-ld-ao 3-smthyl ether: no-.oestradi.ol. (1.1.1 S) o melting point 1 $ 2-1 "C; UV: <! 80, Zd..3 (1tx, 148u); Ilt: 34 $ U.

 <Desc / Clms Page number 15>

 
 EMI15.1
 LXjaPLË 2 ..-. Lithium (2.0 g) in small fragments was added with stirring.
 EMI15.2
 (-) 4-deiydro-17a-ethyl-18-nor- l3p-n-propyi-estradiol 3-methyl ether (le2ZZe the product of the example deer gas a mixture of liquid amuaoniac (i20 cm) and aniline (65 cm 3) After the blue color has disappeared, excess ammonium chloride is added, followed by water, and the mixture is extracted with ether.



  The ethereal extracts are washed successively with water, with 10% sulfuric acid, with water, then bagged and evaporated. The residue cris-
 EMI15.3
 Tallin obtained is recrystallized in aqueous acetonitrile to give .'éther- -môtny3..that (t) -7.'la-étïl-ld-nar-13 -, - prapy, ottstra- diol (Oe9 gis melting point Y4-95uC; IRt 3365. BJUMPJ.E 25.- Cn adds, while stirring, lithium (le5 g) in small particles to 3-metnyl ether of (-) - l3-n -but / lS-ctéhydro-l7ct-6thyl-19-nor-estradiol (202 g, the product of Example 21) in a mixture of liquid acmoaiac (110 cm) and aniline (70 after 2 hours of Stirring, excess acuonium chloride is added, followed by water.

   The product is treated by the process of the previous example to give a red gum which is recrystallized from; methanol; the crystalline product is boiled with methanol (20 char) and the mixture is then left at room temperature overnight * By filtration, the 3-methyl ether is isolated.
 EMI15.4
 lic (*): 3.31 g-butl-3,7a-ethy7318 zrarrssstradio7, crude (1.57 g), contaminated with a small amount of the starting material, melting point 70-85 "C; Uy: 278 (3.jtlU); 1H: 360.



  ! X !!.: I1! - '. L, l !: r; Ç - li'éther 3-môt, yli.qua du (,) 9-ihydra-17a-étïar; .- 18-ha: o- estratl101 (0.3 g, the product of example: 2) in ethanol (150 eln3) is stirred in a hydrogen atmosphere under the atomic pressure, whereas in the presence of a catalyst at 10> of palladium on charcoal; 25 u3 of hydrogen are absorbed, the theoretical amount for saturation under the conditions considered being 22 cc. After

 <Desc / Clms Page number 16>

 filtration and evaporation a residue is obtained which is recrystallized from ethanol to give (-) - 17o-ethyl-18-homo-estradiol 3-methyl ether, melting point 160-161 C); UV: 79 (2.410).


    

Claims (1)

R E V E N D I C A T I O N S 1.6 Steroid compound of structure: EMI16.1 or. R is a hydrogen atom or an alkyl or acyl group, R1 is a saturated alkyl group containing at least 2 carbon atoms, R2 is an alkyl group in trans configuration with respect to R1, ring C is saturated or contains a bond ethylenic terminating in position 9. the cyclic junction C / D is in trans configuration, any hydrogen atom in position 8 is in anti configuration with respect to the hydrogen atom H in position 14, and any hy atom - drogene in position 9 is in the trans configuration with respect to that of position 8. 2. A compound according to claim 1, characterized in that R1 and R2 are unsubstituted alkyl groups. 3.- A compound according to claim 2, characterized in that R1 and R2 each contain not more than 6 carbon atoms * 4'- A compound according to claim 2 or 3, characterized in that R1 is an ethyl group. 5. A compound according to claim 2 or 3, characterized in that R1 is an n-propyl or n-butyl group. 6. - A compound according to either of the claims 2 to 5, characterized in that R2 is an ethyl group or an ethynyl group. 7. A compound according to either of claims 2 to 5, characterized in that R2 is a methyl, n-propyl or allyl group. <Desc / Clms Page number 17> 8. A compound according to any of claims 2 to 7, characterized in that R is an alkyl group containing less than 6 carbon atoms. 9. A compound according to claim 8, characterized in that K is a methyl group * 10. A compound according to either of claims 2 to 9, characterized in that the ring C is saturated. 11.-. Compound according to one or the other of claims 2 to 9, characterized in that the ring C contains an ethylenic bond in position 8.9 or in position 9.11. EMI17.1 .12.- 3-alkyl rtner of 18-homo-α-methyloestradiol, or the corresponding 8- or 9-dehydro compound- 13.- 3-alkyl ther of 17āethynyl-13-hoiao-oestradiol, or compound 8- corresponding oubkléhydra. 14.- 17a-ethyl-18-hMO-estradiol 3-alkyl bther or corresponding & or 9-dehydro compound. 15.- 17a-allyl-1S-homo-estradiol 3-alkyl ether or the corresponding 8- or y-dehydro compound. 16. 18-homo-17a-n-propyloestradiol 3-allyyl ether or the corresponding 8- or 9-dehydro compound. , 1? ... 17a 3-alkyl kther, .. ethyl7.8-nor1.3 -propy, or butyl-oes -traaiolp or the corresponding 8- or 9-dehydro compound * lu.- 3-alkyl etner 17α-ethynyl-18-nor-13-n''propyl- or butyl-estrad3cl, or the corresponding 3- or 9-dehydro compound. 19. - 2; ther 3-alkyl of .7a-al.7.yl-, methyl- or -prOPY1-l la-nor-13; -n-rOPY1-estradioll or corresponding 8- or 9-dehydro compound . u.- Process for the preparation of a steroid compound according to any one of claims 1 to 11, characterized in that a corresponding compound of structure: <Desc / Clms Page number 18> EMI18.1 is alaylated using a reagent which provides the R2 group. 21.- A method according to claim 20, characterized in that R is an alkyl group. 22. A process according to claim 20 or 21, characterized in that the alkylation is carried out using an organometallic compound, 23.- A method according to claim éé; characterized in that the alkylation is carried out *, using an Urignard reagent or an alkali acetylide 24.- Process for the preparation of a compound according to claim 10 or 11, where R2 is an alkyl group saturated with at least 2 carbon atoms, characterized in that the corresponding compound, where R2 is an alkyl group unsaturated, is hydrogenated to reduce the R2 group. 25.- Process according to claim 24, characterized in that the reduction is carried out by catalytic hydrogenation. 2b.- Process for the preparation of a compound according to claim 10, characterized in that a corresponding compound according to claim 11 is reduced by the action of an alkali metal in liquid ammonia * 27.- Process for preparing a compound according to claim 10, characterized in that a corresponding 9-dehydro compound according to claim 11 is reduced by catalytic hydrogenation.