IL28190A - 13-alkylgona-1,3,5(10),7-tetraenes and intermediates therefor - Google Patents

Description

28190/2 Q*3κη"»¾©-.7, (10)5, 3, 1-κa l a» ·p κ-1 onlay o»»3*a »nipm 13-Alkyl-gona-l,3, 5(10) ,7- etraenes and Intermediatos therefor' AMERICAN HOME PRODUCTS CORPORATIOff 0:26715 This Invention relates to processes for preparing gona-1 ,3,5(10) ,7-tetraenes, to intermediates for preparing these compounds, and to pharmaceutical compositions containing them.

The invention provides a process for preparing 13-aikyl-gona-1 ,3*5(10) ,7-tetraenes which comprises the sequence of reactions including: (a) oxidising a 3-Y-l3-alkylgona-1 ,3,5(10) ,8-tetraene to a 3-Y-8 , 9-ep0xy-13->alkylgona-I, 3 , 5 (¾0)-trie¾e„ ■ ;<:■■<■? (b) opening the epoxide ring to form a 3-Y-8-hydroxy-l3-alkyl- gona- ,3,5(10) ,9(11 )-tetraene, (c) selectively catalytically hydrogenating the 3-T-8-hydroxy- 13-alkylgona-1,3,5(10) ,9(H)-tetraene to give a 3-Y-8-hydroxy -13-alkylg6na-1 ,3 ,5( 0)-triene , and (d) dehydratdLng the 3-Y-8-hydroxy-l3-alkylgona-1 ,3,5(10)-triene across the 7» 8-positions to give a 3-¥-13««aikyl gona-1 ,3,5( O) ,7-tetraene, where Y is an activating group capable of activating the benzenoid ring A for electrophilic aromatic substitution* ¾ie invention is particularly illustrated by the preparation is an alk 1 group, Y is hydrogen or a group which is ortho-para directing in AHP-4056-f electrophilic aromatic substitution, X is a carbonyl, ketalised carbonyl (including thioketalised or hemithio- - methylene ketalised carbonyl), ethylidenef, hydroxymethylene, acyloxy-methylenefl alkane sulphonyloxymethylene., or an organo- hydroxy or acyloxyymet^ylene ro g of the formula hyeroTcym f rh lTSOT grouy =CR R *=t where R is a uiasubstituted alkyl, alkenyl or alkynyl group or a substituted -alk lt alkenyl or alkynyl group having the essential character of an unsubstituted alkyl, alkenyl or alkynyl group, and ^ is a hydroxy or acyloxy group the dotted line represents a S'.J'-epoxybutylene group, a 3,-hydroxybut-l'-enylene group, a 3'-hydroxybutylene group, or a but-3'-enyIene group, and the hydrogen atom in the 9-po6<4tion, where present, is in the a-configuration, in which [for example referring to Figure (I)] a gona»lt3»5ClO),8«-tetraerie (e.g. l) is oxidised to give an 8»9~epoxygona«=l,3,5(lO)-triene 0f structure (A) (e.g. II) and if desired, either the epoxy group of the 8,9-epoxy-gona-l,3,5(lO)-triene (e.g. II) is opened to give an 8-hydroxygoria-l,3»5(lO),9(H)-tetraene of structure (A), (eg. (Ill), and if desired, the compound so produced is selectively hydrogenated to give an 8-hydroxygona-l,3,5(10)-triene of structure (A) (e.g. IV); or the latter compound is obtained directly from the 8,9-epoxygona-l,3i5(lO)-triene (e.g.II) by reduction with a metal hydride particularly an alumino hydride} and then, if desired, the compound so producted, is dehydrated to give a gona-i,3,5(lO)»7-tetraene of structure (A) fe.g. V); and where the product of any of the reactions has a group X or Y other than that, desired, the desired group X or Y is formed by a subsequent operation0 28190/2 The invention also provides the novel compounds of structure (Λ) as defined above with the proviso that is an alkyl group of more than one carbon ajiom when the dotted line represents a but-3 ' -ethylene group and (a) Y is a hydroxy or an etherified or esterified hydroxy group and X is a carbonyl, ketalised carbonyl (including hemithioketalised and thioketalised carbonyl) or hydroxy-methylene group, or (b) Y is hydroxy and X is 'an ethynyl-hydroxymethylene group or (c) Y is acetoxy and' X is an acetoxymethylene group or (d) Y is methoxy and X is a methyl-hydroxymethylene group.

• It is to be understood that in the above process if a substituent that is required would interfere with any of the reactions then this group is formed subsequently b means of a suitable after-process and that any of the usual . processes of organic chemistry may be performed at any stage , where suitable and desired, such as for instance oxidation of hydroxy to oxo, reduction of oxo to hydrox 'Such as with a hydride transfer agent, estjrification of hydroxy, e.g. using an acid or its functional derivative such as an anhydride or halide or hydrolysis of ester groups to hydroxy, ketalisation or thioketalisation of oxo and deketalisation and dethioketalisatio to oxo, etherification and de-etherification and reactions of oxo groups with organo-metallic reagents to introduce organic substituents. In addition to such reactions, de-etherificatio using a Grignard reagent, e.g. an alkyl magnesium iodide, preferably at a high temperature in the range 100-200°C, and preferably thereafter quenching the reaction mixture to a low temperature below 0°' preferably using a cooling bath below -50°C , has been found a useful procedure at many stages in the present synthesis. The only structural requirements are that the steroid nucleus contains only inert functions, those which can be converted back to the startin functions or those which permitted while carbonyl and like groups which are alkylated by. Qrignard reagents are not, unless alkylation is also desired.

When the group R is an alkyl groups it is preferably lower alkyl group having up to.6 carbon atoms? examples of suitable groups are methyl and ethyl groups* 1 The group R suitably has up to 20 carbon atoms and preferably up to 5 carbon atoms. Examples of suitable alkyl groups are methyl, ethyl, propyl, especially n-propyl, iso-propyl, butyl, especially n-butyl, isobutyl, pentyl, especially n-pentyl , and cetyl.

The group Y is preferably one which is unaffected by or does not itself detrimentally affect the subsequent reactions but which is sufficiently activating to promote the openin of the 8,9-epoxy ring. Suitable groups are hydroxy and alkoxy groups (this term includes cycloalkyioxy groups), for example methoxy, ethoxy, propoxy, isopropoxy, cyclopentyAoxy and butoxy groups. Acyloxy groups can also be used.

When the group X contains an esterified hydroxy1 group, the ester portion can be derived from either an organic or inorganic acid* Preferably the organic acid is a carboxylic acid having up to 20 carbon atoms, for example, acetic, propionic, butyric, decanoic and benzoic acids. Suitable inorganic acids are sulphuric and phosphoric acids. Alkane-sulphonic acids, for example methanesulphonic acids can also of the formula -CR2R3-be used. When the group X is an organo-hydroxymethylene group/ a. it is preferably a*i-»j>gatt»Sa¾^*^»e4kyl»i¾o~ rcup having up to By the terra "substituted alkyl, alkenyl or alkynyl group having the essential character of an unsubstituted alkyl, alkenyl or alkynyl group " is meant such a group substituted by a relatively inert atom or group of the kind known and used in medicinal chemistry;, By the term "relatively inert" is meant that the atom r group is not acidic or basic and is free from active hydrogen atoms and multiple (double, triple or co-ordinate) bonds. Examples of suitable substituents are halogen atoms, for example chlorine, and alkoxy groups, for example methoxy groups.

The chlorethynyl group is a particularly suitable substituted alkynyl group.

When the group X is a ketalised carbonyl it is preferably an ethylenedibxy, propylenedioxy or 2 , 2 -dimethylpropylene dioxy group.

It will be apparent to those skilled in the art that the starting compounds can bear other usual substituents used in steroid chemistry which are unaffected by the processes of the invention such as ff 12 and 16 hydroxy groups or substituents (particularly those mentioned above for the group Y) at other positions on the A-ring of the steroid nucleus or that such groups can be introduced subsequently by methods known to the art and that compounds having such minor variations are to be considered to be within the scope of the generically named compounds by reference to which the process of the invention is defined on page 2 herein0 in claim 1 and by the general formula (A).

The oxidation 'reaction is preferably carried out at low, · •temperatures with- a per-acidt. eug0 an aikyl.or- aryl percarboxylic acid, for example peracetic acid, perbenzoic, perphthalic or m-chloroperbenzoic acid and preferably at a low temperature such, as about -20° to 0°C in a solvent of moderate polarit (e.g. benzene, toluene, chloroform, or methylene chloride which can contain a liquid alkane; a particularly suitable solvent is a benzene/hexane mixtur.-> conveniently containing an inorganic base, for example an alkali metal carbonate such as potassium carbonate or bicarbonate. Conveniently the reaction is carried ou i a liquid alk^e and. benzene or toluene in the presence of alkali metal carbonate or bicarbonate at a temperature below 10°C for a period up to 2 hours. More preferably the oxidation is conducted with m-chloroperbenzoic acid in a hexane-benzene solvent mixture or other solvent of moderate polarity in the presence of an inorganic base such as sodium or potassium carbonate at about -10° to 0°C for about 15 minutes.

An oxidation product where Y is a carboxylic acyloxy group can be subsequently hydrolysed to give a compound where Y is a hydroxy group. A suitable reagent for this hydrolysis is sodium methoxide in methanol . Likewise a product where X is a carbonyl group can be reduced e.g. with a hydride transfer agent to give a product where X is a hydroxymethylene group, a product where Y is an alkoxy group can be de-alkylated to give a hydroxy group Y, e.g. using a Qrignard reagent provided that other functional groups are not present which would be irreversibl , changed to an unwanted group as described above.

The invention also provides a process for the preparation 1 of a steroid compound of structure (A), where H, R , Y and X first-are as/defined above and the dotted line represents a 3'- hydroxybut-11 -enylene group in which the epoxy group of a 8,9-epoxygona-1 ,3,5(10)-triene of structure (A) is opened: and where the product has a group X or Y other than that desired, the desired group X or Y is formed b a subsequent operation. ' '.' A suitable reagent for this process is a weak acid, e.g. an organic carboxylic acid4 for exaaple benzole furoic o ^-chloro-^-nitroSehzoic acid or 2:4-dihitr0behzoic aoid and conveniently in a-solvent of moderate- olarity s-described above.

In this process the promotional effect of a substituent at position -3 by electron, donation is of value and is believed to arise by resonance stabilisation of a transition state or > intermediate having the character of a benzylic carbonium ion involving position -9 of the steroid nucleus. ¾us, where Y is a strongly resonance promoting group such as a hydroxy or alkoxy group benzoic acid is a sufficiently strong acid, to effect a ring opening in good yield but where Y is an acylox group benzoic acid is insufficiently strong for effective reaction and it is preferred to use a stronger acid such as 2,1f-dinitrobenzoic acid while acids intermediate in strength between benzoic and 2,1t-dinitrobenzoic acid i.e. m-chloro-benzoic ,furoic and 2-chloro-5-nitrobenzoic acids, cause ring opening to a degree relative to their acid strength. On the other hand, very strong acids such as mineral acids are to be avoided as they cause dehydration of the product or starting, material to equilenins and gana-1 ,3,5(10) ,8,1^-pentaehes regardless of the nature of Y. The epoxide ring opening reaction is preferably conducted by stirring. he epoxide i 3 ^ chloroform solution containing the weak acid for several hours. ' The invention also provides a process for the preparation of a compound of structure (A) where R, R , • . 'firsts ; . ■■,;'.!¾·'· :··.: Y, X and the dotted lines are as/ defined above in whic , a ona^l ,3t5(10) ,8-tetraene of structure (A) is epoxidised and -the suiting epoxy ring, is opened all in on stage . ■ · 'V During the oxidation reaction there is a tendency for the epoxide to rearrange or open !to the 8-hydroxygona-1 ,3,5(10) ,9(11)- tetraene for instance as shown in Example-63 and at higher temperatures such as room temperature, as shown in Examples 65 to 69, the rearrangement takes place to give substantially only the 8-hydroxygona-1 ,3,5(10) ,9( 1 )-tetraene, the reaction possibly being catalysed by the free organic carboxylic. acids present. The rearrangement or epoxide ring opening reaction without isolation of the epoxide is preferably conducted by allowing the epoxidation reaction mixture to warm up to room. temperature at which it is stirred for about to 2 hours.

The invention also provides a process for the preparation of a compound of structure (A). where R, - R - Ί , ■ · Y', X■ an'd·th·e'■ '■ "■■ ■ .■ ■ ■■. ■ ■ .■ : ' ■. · '■ '.:'.'■'·■ ; first configuration of the hydrogen atom in the 9-position are as defined above and the dotted line represents a 3'-hydroxy- butylene group, in which a 8-hydroxygona- ,3,5(10) ,9(11)- tetraene of structure (A) is selectively hydrogenated, and where the product has a group x or Y other than,:that desired, the desired group X or Y is formed by a subsequent operation.

The hydrogenation process is suitably carried out by. methods and using catalysts known to those skilled in the . art of organic chemistry, preferably in the presence of a. palladium on carbon catalyst; preferably the catalyst is pretreated with hydrogen until ptake of· the .','gas'; /is' i - . complete. A suitable solvent for the hydrogenation. rocess.. is ethanol. .·■ ■ A hydrogenation produc where X is a hydroxymethylene an group can be subsequently esterified ,by, for example ,-ajaet acid anhydride in pyridine to give a compound where X is a* carboxylic acyloxymethylene group, while a hydrogenation product where Y is an alkoxy group can be subsequently de- etherified by, for example, ethereal methyl magnesium bromide, e.g. as described above, to give a compound where Y is a' hydroxy M / group · ; - : Qgpou , and a hydrogenation product where Y is a hydroxy group and X is a hydroxymethylene group can be subsequently '-■ esterified by for example, an acid anhydride in pyridine to give a compound where Y is a carboxylic acyloxy group and X i;s a carboxylic acyloxy-methylene group. , ' The invention also provides a process for the preparation of a compound of structure (A.) where R, R , Χ,ΟΓ'Υ, and the configurati on of the hydrogen atom in the 9-position are as/ firs defined above and the dotted line represents a J'-hydroxy- butylene group in which an 8,9-epoxygona-1 ,3,5(10)-triene of . structure (A) is reduced with a metal hydride, preferably a alumino-hydride and where the product has a group X or Y other than that desired, the desired group X or Y is formed b a subsequent operation. The alumino hydride can be aluminium hydride or a complex aluminium hydride, preferably lithium aluminium hydride, and the reaction is preferably conducted at a moderately high temperature, as for instance b refluxing in a high boiling ether such as tetrahydro-furan, The invention also provides a process for the preparation 1 of a compound of structure (A) where R, R , Y, (X, and the. configuration of the hydrogen atom in the 9-position are as first defined above and the dotted line represents a but-3'-enylene group, in which a 8-hydroxygona-1 ,3,5(10)-triene of structure (A) is dehydrated, and where the product has a group X or Y other than that desired, the desired group X or Y is formed by a subsequent operation,, Suitable reagents for the dehydration reaction are acyl halides in an alcohol, for example acetylchloride in refluxing methanol, or alkane / sulphonyl halides in an organic base, for example methane sulphonyl chloride in hot pyridine . When a hydroxyl group elsewhere in the molecule is converted to a mesyl ester grouping by such treatment, the ester grouping can be converted back to a hydroxyl group by methods known to the art. A tertiary hydroxy group elsewhere in the molecule can undergo concomitant elimination giving the corresponding gona-1 »3»5(10) ,7-tetraene having an additional ethylenic bond.

Thus the invention includes the processes; in which the dehydration is carried out with an alkane, sulphonyl halide on a gona-1 »3»5(10)-trien-8,17-diol to give the corresponding' gona-1 ,3,5(10) ,7-tetraene-17-ol, 7-alkane sulphonate, in which the dehydration is carried out on a 17-% hylgona ·¾: ... ,3i5(lO)-trien-8,17-diol to give the corresponding 17- ethylidenegona-l,3s5(lO) ,7-tetraene, and in which the dehydration is carried out with an alkane sulphonyl halide on a gona-l,3,5("iO)"trien-3,8,17-triol to give the corresponding gona-ls3«5(lO){7-tetraen-3»17-cliol4 dialkanesulphonate.

The dehydration can also, for example,, be carried out. with an alkane-sulphonyl chloride, particularly methane sulphonyl chloride, in pyridine and a dialkyl formamide, e.g. dimethyl formamide whereby any free hydroxy group present becomes formylated to give the corresponding formate ester group. The formate group can be removed by hydrolysis for instance with a base such as an alcoholic metal hydroxide to regenerate the hydroxy group.

A. dehydration product (1.))where X is a carbobylic acyloxymethylene group or an alkanesulphonated hydroxymethylene group can be subsequently reduced by, e.g. a metal hydride, for example lithium aluminium hydride to give a compound where X is a hydroxymethylene group (2) where X is a carboxylic acyloxymethylene group can be subsequently hydrolysed by, e.g. acid or base, for example, sodium hydroxide in methanol to give a compound where X ; is a hydroxymethylene group, (3) where X is a carbonyl group can be subsequently reduced by, e.g. a hydride transfer agent, for example sodium borohydride to give a compound where X is a hydroxymethylene group, (4) where Y is an alkoxy group can be subsequently de-etherified by, ag, a Grignard reagent, e.g. ethereal methyl magnesium bromide or iodide for instance as described above to give a compound where Y is a hydroxy group, (5) where X is a hydroxymethylene group can be subsequently oxidised by, for example, the Oppenauer reaction or with chromic acid or dimethyl sulphoxide-acetic anhydride reagent to give a compound where X is a carbonyl group, (6) where X is an alkanesulphonated hydroxymethylene group and Y is an alkanesulphonated hydroxy group can be subsequently reduced by, for example, a metal hydride e.g. lithium aluminium hydride to give a compound where X is a hydroxymethylene group and Y is a hydroxy group, (7) where X is a carboxylic acyloxymethylene group and Y is a carboxylic acyloxy grou can.be subsequently hydrolysed by, e.g. an acid or base, for examjple, sodium hydroxide in methanol to give a compound where X is a hydroxy- methylene group and Y is a hydroxy group, (8) where Y is a hydroxy, group can be subsequently esterified or etherified to give a compound where Y is an ester or ether group, ($)) where Y is ah ether group and X is a formyloxymethylene group can be subsequently de^retherified together with deformylation for example using a Grignard reagent as described above to give a compound where X is a hydroxymethylene group and Y is a hydroxy group and ( 10) where X is a carbonyl group* or a group which is converted to such group is subsequently reacted with an organo-metallic reagent to introduce a group and such group,if an alkeijrl or an alkynyl group, is subsequently reduced by catalytic hydrogenation.

Any of the above reactions ,can, if desired, be performed on the dl- , the d- or the 1- form of the starting, material concerned.

The starting materials for the processes of the invention, Ιοθο the l3-alkyl-gona-1 ,3 ,5( 10) ,8-tetraenes are prepared as described in United Kingdom Patent Specifications Serial Nos. 991 , 59^ , and 1 ,024,911 by selective hydrogenation of the . corres onding' gonapentaeiie* .

The above described processes of the invention are illustrated in Figure (I) It is clear that instead of a keto group in the 17-• - position, as shown in Figure I, other groups which do not interfere with the desired result can be at that position. Thus, there may be in that position a hydroxy group, and alkyl and an hydroxy group, an acyloxy group, a ketal group, or other which does not interfere in the processes of the reaction. Furthermore, 10 the 17-carbonyl group can be converted to alkyl hydroxymethylene , for example, the 17ot-methyl-17P-hydroxy or 17a-ethyl-17P-hydrox /derivative by addition of the appropriate organometallic compound, : or to alkynyl hydroxymethylene, for example the 17a-ethynylrl7P- hydroxy derivative, including haloalkynyl hydroxymethylene, for 15 example the 17a-chloroethynyl-17P-hydroxy derivative, by addition of the appropriate alkali metal acetylide, to alkenylhydroxy- methylene, for example the 17a-allyl-17P-hydroxy derivative by reduction of the corresponding 17 The processes of the invention provide a novel unique, and feasible synthetic route to the corresponding natural sex hormone . equilin when the group R''* is methyl, as shown in Figure II which will now be described in more detail: The estratetraenol (VI) is converted by the processes of the invention described above through the intermediates (VII), (VIII) and (IX) to the mesylate (X). This ester is cleaved by reduction with lithium aluminium hydride and the resulting alcohol (XI) is converted by heating with methyl magnesium halide at a temperature 0 above 100°C to the estratetraene diol (XII) which is oxidised AIIP-i 056-f under Oppenauer conditions or with acetic anhydride-dimethyl sulphdxLde reagent to equilin (XIII).

Alternatively the diol (IX) is demethylated by heatin with a methyl magnesium halide as before, the resulting triol (XIV) ; is converted by heating with methane sulphonyl chloride in pyridine to the estratetraene (XV), and the latter is cleaved by lithium hydride reduction, to the diol (XII), which is oxidised as before to equilin. In a variant of this alternate route the triol (XIV) is converted to a 3,17-diacylate (e.g. 3|17-difbrmate or diacetate) which is eliminated to the corresponding estratetraene 3»17-diacylate and converted by ester hydrolysis to equilin (XIII). In another variant the diol (IX) is dehydrated by reaction with methane sulphonyl chloride in pyridine and : dimethyl formamide to give the formyl ester of the alcohol (XI) which is hydrolysed to (XI) for instance with a base.

The processes of the invention also provide a novel, unique and feasible route to compounds difficult or impossible to obtain from natural steroids, when the group R has more than one carbon atom.

The compounds of structure (A) have the inherent general physical properties of being white crystalline solids, are substantially insoluble in water, and are generally soluble, in polar organic solvents, such as dimethylacetamide# . xamination of the compounds; produced according . to the herein-after described process reveals, upon infrare ultraviolet and nuclear magnetic resonance spectrographic analysis, spectral data supporting the molecular structure hereinbefore set forth.

The aforementioned physical character taken together With the nature of the starting materials, the elemental analysis and the products obtained therefrom, further confirm the molecular structure hereinbefore set forth. ; . .·■ ' .. 28190/2 ■:' In the product of a total synthesis which has not included a suitable resolution stage the compounds. of the invention, which have the 13P configuration,will be present in racemate form, as in most of the E»ampies below. The racemates are designated as (ί) -13β-compounds using the Ho eau-Reichstein Convention approved by Fieser and Fieser, Steroids (1959) t at page 336, in which the enantioner of l3P-configuration is considered as the d-form and its antipode the enantiomer of 13 The invention also provides pharmaceutical preparations comprising one or more steroid compounds of structure (A) when prepared by the processes of the invention or novel compounds, of structure A as hereinbefore defined in association with a pharmaceutically acceptable carrier. '_ 28190/2 - /''-? The pharmaceutical preparations of the invention can be formulated in liquid or solid forms, for instance as capsules, tablets, suppositories, powders, dispersible granules, cachets and the like by combining them with conventional carriers.

Such conventional carriers include magnesium carbonate or stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax and cocoa butter,, Diluents, flavouring agents,' solubilizere, lubricants, suspending agents, binders or tablet-disintegrating agents can be employed. Powders and tablets preferably contain 5 or 10 to 99$ of the active constituent. The active steroid can be formulated with an encapsulating material with or without other carriers.

Liquid preparations such as solutions, suspensions or emulsions can also be used. Such preparations include dispersions in a pharmaceutically acceptable liquid carrier such as arachis oil or sterile water, preferably containing a non-ionic surface active agent such as fatty acid esters* >f polyhydroxy compounds, e.g. sorbitan, (for instance polyethylene oxide fatty acid esters, such as Tween 8θ) , aqueous starch in sodium carboxymethyl cellulose solution, aqueous propylene glycol or polyethylene glycol. Thus a w'ater-propylene glycol solution can be used^for parenteral injection and aqueous suspensions suitable for oral use can be made by utilising natural or synthetic gums, resins, methyl cellulose or other well-known suspending agents.

- V - AHP-.O56-f •: The compounds can be in unit dose form in which the dose unit is for instance from 0.1 to 200 mg. of each active steroid depending on the type of therapeutic desired. ■ The unit dose form can be a packaged composition, e.g. packe.ted powders, vials or ampoules, or for example, in the form of capsules, cachets or tablets or any number of these in packaged form.

The pharmaceutical preparations can also consist substantially soley of the active steroid when this is in unit dose form.

The invention is illustrated by the. following Examples, in which temperatures are in °C., infrared absorption data (IR) refer to the positions of maxima given in cm.-"'", and ultraviolet absorption data (UV) refer to positions of maxima given in i¾i ; with figures in parentheses denoting, molecular extinction coefficients at these wavelengths.

X-69 EXAMPLE 1 Potassium carbonate (28.0 g. ) was added to (-)-3^ methoxyoestra-l,3,5(lO) ,8~tetraen-17-one (28.0 g. ) in benzene (550 ml.) and hexane (150 ml.) and the mixture stirred at 0°C. Solid m-chloroperbenzoic acid (19.0 g„) was added over a period of 5 minutes and the mixture stirred for 10 minutes at 0°C, # Potassium carbonate solution (500 ml.) was then added and after stirring for minutes more, allowing it to warm up to room temperature, the organic laye was' diluted with ; ethyl acetate and washed with 5% sodium hydroxide solution, with water and with saturated sodium chloride solution. The extract was dried filtered and the solvents removed in vacuo. The resulting oil was refluxed with ether and then set aside to allow complete crystallisation to give (-)-8, 9-epoxy-3-methoxyoestra-l, 3, 5(l0)-trien-l?-one (2* .5 g.)| m.p. 132-136°} IR 17^ .

EXAMPLE 2 (-)-8,9-Epoxy-3-methoxyoestra-l,3,5(lO)-trien-17-one (3.00 g. , m.p. 127-131°) and benzoic acid (2.0 g.) i chloroform (75 ml.) was stirred at room, temperature overnight and the chloroform was then removed in vacuo. The residue in ether -ethyl acetate (1:2) was washed with saturated sodium.: bicarbonate .LSblution, with, water. '.and with- saturatedr.Sodium chloride solution, and dried After filtration and evaporation of the solvents in vacuo, the resulting colorless oil in ether was allowed to stand at room temperature and the resulting tiny colorless prisms filtered to give (i)-8-hydroxy-3-methoxyoestra-lt3,5(lO) ,9(ll)-tetraen-17-one (2.00 g. ); m.p. 1^8-150° j IR:; ^ 0 and 1 ^0 UV: 2 (1 ^00) (Found: 0 6. 8 H . .

X-69 EXAMPLE 3 To (i)-3-Methoxyoestra-l,3,5(lO) ,8-tetraen-17-one (6.00 g. ) in benzene (175 ml) and hexane (35 ml) was added potassium carbonate (6.0 g. ).: and the mixture cooled to 0° . m-Chloroperbenzoic acid (4.0 g. ) was then added and the mixture stirred for 10 minutes. The reaction was quenched by the addition of a 5 potassium carbonate solution (200 ml), and the mixture was stirred for a few minutes at room temperature; the organic layer was diluted with ether, washed with 5 sodium hydroxide solution, with water and with saturated sodium chloride solution, and dried (N 2S0^);. After filtration and removal of the solvents in vacuo, the yellow residue was covered with ether-petroleum ether, boiled and then allowed to stand giving a white crystalline precipitate of the crude product (4.7 g. ) ; m.p. 130-136°, which was dissolved in boiling benzene, treated with activated charcoal (Nuchar) and filtered while hot through Supercel. The mixture was boiled to low volume and allowed to stand at room temperature to complete crystallisation. The resulting clusters of prisms were filtered to give (ί)-8~ hydroxy-3-methoxyoestra-1 , 3 » 5(10) , 9 ( 11)-tetraen-17-one (3.63 g.); m.p. 152-155°? IH: 3^50 and 1740; UV: 259 (19,300) ; (Found*. 0,76.50; H.7.24. CigH2203 requires 0,76.48; Η.7 2*) .

EXAMPLE 4 A solution of (i)-8-hydroxy-3-methoxyoestra-l,3f 5(10), 9(ll)-fcetraen-17-spne (3.00 g. ) in absolute ethanol (100 ml) was hydrogenated in the presence of 5# palladium on carbon X-69 of the gas was complete. The solution was filtered twice through Supercel.and the ethanol removed in vacuo to · ive an oil which was dissolved in methylene chloride, treated with activated charcoal (Nuchar) and filtered through Supercel. The solvent was removed in vaouo and the resulting colorless oil covered with ether. Filtration yielded, as white crystals, (i).-8-hydroxy-3-methoxyoeetra-l,3,5(10)-trien-17-one (2.56 g.); m.p. 136-1380,· IR: 3^50 and 17^0? (Found* C,76.03; H„ 8.13. C^H^O^ requires C,75.97} H.8.05*.

EXAMPLE 5 (i)-8-Hydroxy-3-methoxyoestra-1, »5(10)-trien-17-οηβ (O.5O g. from Example ) in methanol (25 ml) was treated dropwise at room temperature with acetyl chloride (10 ml) at a rate to prevent excess sputtering of the spontaneously refluxing solvent. The solution was boiled on the steam bath until the volume of solvent was reduced to below 10 ml. The solution was allowed to stand at room temperature to deposit, as white crystals, (ί)-3-methoxyoestra-l,3,5(10) ,7-tetraen-17-one (0.37 g.)? m.p.l26-128°j IR: 17^0. (Found: C,80.68{ H,7.65. C19H22°2 re¾uires c»8o«8l» H,7.85#).

EXAMPLE 6 (ί)~8-Hydroxy-3-methoxyoestra-1,3,5(10)-trien-17-οηβ ( iOO g.) in pyridine (50 ml) was treated with methanesulphonyl chloride (20 ml).and the yellow solution heated on a steam bath in a flask fitted with a reflux condenser. Heating was continued until an exothermic reaction was initiated and spontaneous refluxing occured. Heating was discontinued until X-69 applied for ■¾· hour to complete the reaction.; The blaok mixture was cooled, treated with ice water (200 ml), and with ether which was then blown off with nitrogen.

Crystallisation was initiated by scratching and the resulting dark brown solid filtered and air dried. The solid in methylene chloride was treated with activated charcoal(Nuchar), boiled, allowed to cool to room temperature and the dark red solution filtered through Supercel. The methylene chloride was replaced with absolute ethanol by boiling on the steam bath. Cooling gave red crystals (2,7^ g.) of crude product, m.p. 129-131°. T is product in benzene was filtered through a short column of Florex. After removal of the solvent in vacuo, the residue was covered with methanol! filtration gave, as pink crystals, (-)-3-methoxyoestra-1,3, 5(10),7-tetraen-17-one (2.32 g. ) 5 m.p. 130-132°} IR: 17^0. (Found: C, 80.68} H,7.55. c1gH22° re¾ulpe* C, 80.81 } H,7.85#) .

EXAMPLE 7 (i)_13-Ethyl-3-niethoxygona-l,3,5(lO) ,8-tetraen-17-one (3.00 g.) in benzene (25 ml) and m-clilor perbenzoic acid (2.0 g. ) in benzene (25 ml) were added simultaneously with stirring to potassium bicarbonate (2 g. ) in hexane (70 ml.) at 0° over a period of 15 minutes. When addition of the reactants was complete , stirring was continued for 15 minutes at 0° . The resulting white precipitate was quickly filtered and the filtrate washed into a separatory funnel with ether. The extract was washed with sodium hydroxide, with water and with saturated sodium chloride X-69 evaporation of the solvents in vacuo} there was obtained a white crystalline solid which, in boiling hexane containing a few drops of benzene, was then filtered hot* The filtrate was boiled to bring all the solids back into solution and allowed to stand at room temperature to complete crystallisation. The resulting colourless plates were filtered to give (i)-8,9-epoxy-13-ethyl-3-methoxygona-lt3,5(10)-trien-17-one (2.l8 g. )} m.p. 125.5-127°; IB- 1730; UVr 237t277 and 286 (13,000, 1,600 and 1,600) (Found: C, 77.18, H,7.6l. C^H^O^ requires:: C.76.89; H,7.7W .

EXAMPLE 8 ;i)-13-.Ethyl-3-methoxygona-l,3,5(l0) ,8-tetraen-17-one (2^.0 g. ) in benzene (500 ml) and hexane (]A0 'ml) was treated with potassium carbonate (2*.O g. ). The mixture was stirred at 0° and then/solid m-chloroper-benzoic acid (l6.0 g. ) added over 5 minutes. The reaction mixture was stirred for 10 minutes at 0°, $ potassium carbonate solution (500 ml) was added and stirring continued for 10 minutes more; allowing the solution to warm up to room temperature. The organic layer was diluted with ethyl acetate, washed with 5# sodium hydroxide solution with water and with saturated sodium chloride solution and then dried After filtration and removal of the solvents in vacuo, the resulting oil was heated to reflux with ether and then set aside to allow complete crystallisation to give, after filtration, white crystals of (-)-8,9-epoxy-13-ethyl-3~ methoxygona-l,3,5(lO)-trien-17-one (15.0 g. ){ m.p, 120-5°.

X-69 EXAMPLE.9 ( - ) -8 , -Epoxy-3-methoxy-13-θthylgona-l, 3 , 5( 10)-trien-17-one (5.00 g.) and benzoic: acid ^(2.0 g. ) in chloroform (100 ml) was stirred at room temperature for l8 hours.

The chloroform was removed in vacuo and the residue in ether/ethyl acetate was washed with saturated sodium bicarbonate solution, with water and with saturated sodium chloride solution and then dried briefly After filtration and removal of the solvents in vacuo, the resulting yellow oil in ether was allowed to stand at 10° to allow complete crystallisation. Filtration gave, as white crystals, (i)-8-hydroxy -3-methoxy-13-ethylgona-l,3, 5(lO) ,9(ll)-tetraen-17-one (3.0 g.); m.p. 118-121° j IH: 3^50 and 1?25? UV: 258 (17,600) .

(Found: 0,76.895 Η,7 · c2o¾°3 re¾uires C.76.89; H.7.7W .

EXAMPLE 10 (i)-8-Hydroxy-3-methoxy-13-ethylgona-l,3» 5(10) , 9(ll)-tetraen-17-one (10.0 g. ; from Example 9) in absolute ethanol (2^0 ml), was hydrogenated in the presence of 5# palladium on carbon (4.0 g. ) and absolute ethanol (50 ml), which had been pretreated with hydrogen at atmospheric pressure, until uptake of the gas was complete. The solution was filtered through Supercel and the ethanol removed in vacuo. The resulting oil in methylene chloride was treated with activated charcoal (Nuchar) and filtered through Supercel. After removal of the methylene chloride in vacuo, the resulting colourless oil in boiling ether was allowed to stand at room temperature X-69 to complete crystallisation. The resulting colourless-prisms were filtered to yield (i)-8-hydroxy-3-niethoxy-13-ethylgona-l,3t5(l0)-trien-17-one (7.6 g. ) m.p. 127-129° with partial resolidification followed by m.p. 1^7-1 9°. iR.; 350 and 1740. (Found: C,76. 9} H.8.19. C2QH2g05. requires: , C, 6; 40} H, 8.3^) .

EXAMPLE 11 (i)-8-Hydroxy-3-methoxy-13-ethylgona-l ,3i5(10)-trien-17-one (2.00 g. from Example 10) in methanol (25 ml.) was treated dropwise with acetyl chloride (15 ml.) at a rate to prevent excess sputtering of the boiling solution. After complete addition, the solution was diluted with ethanol (25 ml.), boiled on a steam bath until the volume of the solution was reduced to about 15 ml., allowed to cool and was then treated with a few drops of ether to prevent cloudiness. Scratching with a glass rod and filtration gave the crude product (ΐί 5 g. )} m.p. 110-116°, which was dissolved in methylene chloride, treated with activated charcoal and filtered through Supercel. The methylene chloride was replaced with ethanol by boiling on a steam bath; the solution was then allowed to stand at room temperature to deposit, as white prism clusters, (i)-3-methoxy-13-ethylgona-l,3»5(l0),7-tetraen-17-one (1.23 g.), m.p. 110-115°} IR: 1740 (Found: C,80.68; H.7.89. C2QH2i+02 requires:. 0,81.04} H,8.l6#).

EXAMPLE 12 In exactly the same manner as described in Example 6, (-)-8-hydroxy-3-methoxy-13-ethylgona-l,3t5(lO)-trien-fl7-one (4.00 g. ) was reacted with methahesulphonyl chloride X-69 (20. ml) in pyridine (50 ml) to obtain from ethanol, the crude product (2 5 g« ) as red plates, m.p. 118-122°.

This product in benzene was filtered through a column of Florex arid after removal :of the benzenein. vacuo, the residue was triturated with methanol to deposit, as a pink crystalline solid, (-)-3-methoxy-13-ethylgona-I,3i5(l0) ,7-tetraen-17-one (2.17 g. )? m.p. 122- °} IB: 1730. (Found: C,8l .11; H, 8.31· c2oH24°2 re¾uires 1 C, 8l.0*j H,8.l6#).

EXAMPLE 13 (-)-3-Methoxyoestra-l,3»5(lO) ,8-tetraen-17^one, ethylene ketal (6.00 g. ) in benzene (175 ml) and hexane ( 0 ml.) was cooled to 0° and then treated with anhydrous potassium carbonate (6.0 g. ) and m-chloroper-benzoic acid (4.0 g. ). After stirring at 0° for minutes, the solution was quenched with $-aqueous potassium carbonate solution (500 ml) and then stirred a few minutes more at room temperature,. The organic layer was diluted with ethyl acetate, washed with 5 sodium hydroxide solution, with water and with saturated sodium chloride , solution and then dried (Na^O^). After filtration and removal of the solvents in vacuo, the resulting colourless oil in boiling ether was scratched with a glass rod to initiate crystallisation, to give, after standing at room temperature, as white crystals, (¾-3-methoxy-8, 9-epoxyoestra-l, 3,5(lO)-trien-17-one, ethylene ketal (5.0 g. ), m.p. 127.5-129.5°J 235 (12,200) : (Found: 0,73.59} H.7.42. <½1Η26°4 requires: C,73.66; H,7.66#).

X-69 EXAMPLE Ik ( - ) -3-Methoxy-8,9-epoxyoeetra-l, 3 » 5 (10)-trien-17-one, ethylene ketal (4.00 g. ) and benzoic acid (3.0 g. ) in chloroform (150 ml) was stirred at room temperature for 20 hours; after removal of the solvent in vacuo, the residue in ethyl acetate was washed with # potassium carbonate solution, with water and with saturated sodium chloride solution and dried After filtration and removal of the solvent in vacuo, the oil in ether was scratched with a glass rod to initiate crystallisation to give, after filtration, tiny white prisms of (i)-3-methoxy-8-hydroxyoestra-lf 3*5(10) ^ 9(11)-tetraen-17-one, ethylene ketal (2. l8 g. ), m.p. 139-1^1° ; IH: 3180 and l680; .UVt 258 (18 , 850) . (Found: G:¾V73 8QJ I¾i7.6l". .

C21H26°i re¾uires :: c « 73.66 ; H, 7.66 ) . \ EXAMPLE 15 (i )-3-Methoxy-8-hydroxyoestra-l , 3, 5(10) , 9(H)-tetraen-17-one , ethylene ketal (1.36 g. ) in absolute ethanol (75•■ml'...} was hydrogenated in the presence of 5 palladium on charcoal (0.50 g. ) and absolute ethanol (25 ml.) which had been pretreated with hydrogen at atmospheric pressure until saturation of the catalyst was complete, until uptake was complete. The mixture was Altered through jSupercel! and the ethanol removed in vacuo. The resulting oil in methylene chloride was treated with Nuchar charcoal and filtered through Supercel. After removal of the solvent in vacuo, the residue in ether was allowed to stand to complete crystallieation to give, as tiny, shiny needles ,(- )-3-methoxy-8-hydroxyoestra-l,3.5(l0)-trien-17-one, ethylenejketal (Ο.69 g.), m.p, 131-2°; IRr 3^80; (Found: C, 73.05$ Η,δ.ΙΟ, C fi O requires: X-69 EXAMPLE 16 (i)-3-Methoxy-8-hydroxyoestra-l,3,5(3.0)-trien-17-όηβ, ethylene ketal (I.50 g. ) in pyridine (15 ml) was treated with methane sulfonyl chloride (7 ml.) and the solution heated on a steam bath until a vigorous exothermic reaction caused reflux of the solvent; the heat was then removed until the reaction subsided. Then heat was applied again for a period of 15 minutes more to complete the reaction. The reaction mixture was cooled to room temperature and treated with ice-water and ether. The ether layer was blom off with nitrogen; after filtration and air-drying, the resulting solids in methylene chloride was treated with Nuchar charcoal and filtered through Supercel. The solvent was removed in vacuo and the resulting yellow oil boiled in methanol; the mixture was allowed to stand to crystallise . to give a slightly yellow crystalline solid (0.90 g. ) m.p. 106-109°.

This product in benzene was passed through a short column of Florex XXS. The benzene eluent was evaporated in vacuo to give an oil which triturated with methanol yie;ldedi ; as -sllLghtlyl yellow pr'i¾'ms, '* (--)-'3-raeth¾rxyoestrarl«i 5¾5(·1ϊ)¾^ ^r en-^oaiejfi ethy^e'ne! keifcal ·Χρ.·· 7:·«β .) -· m.j), 'H9¾L£1°! (Found:) C, 77.07? fi, 7.87. C^H^O^ requires r C, 77.27; H, 8.0351.), EXAMPLE 17 (-)-3-Methoxy-13-ethylgonaTl,3i5(lO) |8-tetraen-17-one, ethylene ketal (12.0 g. ) in benzene (250 ml) and hexane (70 ml) was cooled to 0° and then treated with stirring with potassium carbonate (12.0 g. ) and m-chloroperbenzoic acid(8.0 g. ). Stirring was continued at 0° for 7 minutes; x-69 the mixture was quickly quenched by adding 5$ potassium carbonate solution (300 ml) and stirring continued for a few minutes at room temperature. The organic layer was diluted with ethyl acetate, washed with 5# sodium hydroxide solution, with water and with saturated sodium chloride solution and then dried (Na^O^). After filtration and removal of solvents in vacuo. the slightly yellow residue was triturated with boiling ether and allowed to cool to complete crystallisation to give, as white prisms, the crude product (10.9 g») n p. 162-166°. A sample (1.90 g. ) was purified for analysis by dissolving it in boiling benzene diluting with hexane (twice the volume of benzene), boiling the solution on a steam bath to one-half volume and then allowing to cool to deposit, as large colorless prisms, (-)-3*»methoxy-13-ethyl-8,9-epoxy-gona-l,3,5(10)-trien-17-one, ethylene ketal (I.70 g.), m.p. I75-I780; UVc 235.5 (12,900). (Found: 0,7^.18} H, 7.82. C2^lZ°h re¾uires:- c» 7½.13i H» 7.93*).

EXAMPLE 18 (I)-3-Methoxy-8,9-epoxy-13-ethylgona-l3»5(lO)-trien-17-one, ethylene ketal (9.00 g, ) and benzoic acid (5.0 g«) in chloroform (200 ml) was stirred at room temperature for 2k hours. The solvent was removed in vacuo and the residue in ethyl acetate/ether was washed with potassium carbonate solution, with water and with saturated sodium chloride solution and then dried (Na.,S0^). After filtration and evaporation of the solvents in vacuo , the resulting oil in boiling ether was allowed to cool and crystallisation was romoted b scratchin to ive as white shin lates X-69 tetraen-17-one, ethylene ketal (6.1 g. ),m.p, 1^5·7°| IR:: 3390 and I66O5 UVs 260 (19,200), (Found: C, 7 .01; H, 7; 1. G2zEzS° requires?: C, 7^.13: H, 7.92#).

EXAMPLE 19 (-)-3-Methoxy-8-hydroxy-13-ethylgona-l,3,5(10) , 9(ll)-tetraen-17-one, ethylene ketal (6.00 g. ) in absolute ethanol (200 ml) was hydrogenated in the presence of 5$ palladium on charcoal (3.0 g0) and ethanol (50 ml) which had been pretreated with hydrogen at atmospheric pressure until saturation of the catalyst was complete, until uptake of gas was complete. After filtration through Supercel and removal of the ethanol in vacuo, the resulting oil in methylene chloride was treated with Nuchar charcoal. The mixture was filtered through Supercel and the solvent removed in vacuo 5 the residue in hot ether was allowed to stand to complete crystallisation to give, as fine white crystals , (~)-3-methoxy-S^hydroxy-13-βth lgona-1,3,5( 0)- rien-17-one, ethylene ketal ( .20 ge), m.p0 I66-80? IR: 3600 (Foundi: C„ 73.62? H, 8.58. requires: C,73.71? H,8.V#).

EXAMPLE 20 ( j^^Methox ^S-h dro y^lJ^eth lgona-l^, 5(10)°trien« 17-one0 ethylene ketal (1.50 g. ) in pyridine (13 ml) was treated with methanesulphonyl chloride (7 ml) and heated on a steam bath until a vigorous exothermio reaction caused reflux of the .solventj the heat was then removed until the reaction subsided. The heat was then reapplied for a period of 15 minutes more to complete the reaction. The ^ X-69 and ether added, the ether layer blown off with nitrogen; it was then filtered and the resulting solid air-dried* This solid in methylene chloride was treated with Nuchar charcoal and filtered through Supercel. After removal of the solvent in vacuo, the resulting yellow oil was boiled in methanol and then allowed to crystallise to give a yellow crystalline solid (1.20 g. ), m.p. 128-131°« which was dissolved in benzene and passed through a short column of Florex XXS. After removal of benzene in vacuo, the resulting oil was covered with methanol to give, as fine" pale yellow crystals, (£)-3-methoxy-13-ethylgona-1,3*5(10),7-tetraen-17-one, ethylene keta¾m.p. 131-(0.92 g.)t (Founds C, 77.70; H, 8.14. C22K2Q03 requires:: C, 77*6l; H,8.29#).

EXAMPLE 21 (-)-3-Methoxyoestra-1,3»5(10) ,8-tetraen-1?β-ol (3.00 g.) in benzene (100 ml) and hexane (30 ml) was treated with anhydrous potassium carbonate (3*0 g. ) and the mixture cooled to 0°J; m-chloroperbenzoic acid (2.00 g„ ) was added and stirring continued at 0° for 3*5 minutes more. The reaction mixture was quenched by adding a potassium carbonate solution (200 ml). The organic layer was diluted with ethyl acetate, washed with 5$ sodium hydroxide solution, with water and with saturated sodium chloride solution and dried After filtration and removal of the solvents in vacuo. the residue was covered with ether, triturated and then allowed to stand at room temperature i - - X-69 methoxy-8,9-epoxyoestra-l,3,5(lO)-trlen-17P-o!l. and (i)-3-methox oestra-l,3,5(10),9(11)-tetraene-8,17β-diol (1.95 g.); n p. 159-167°.

EXAMPLE 22 (i)-3- ethox oeatra-1,3»5(10) ,8-tetraen-17"Ol (9»0.g. ) in benzene (250 ml) and hexane (25 ml) was cooled to 0°' and treated with potassium carbonate (9«0 g). m-Chloroperbenzoic acid (6.0 g.) was added with stirring and stirring continued at 0° for 15 minutes. The reaction mixture was quenched with $ potassium carbonate solution (250 ml) and then stirred for 15 minutes at room temperature. The organic layer was diluted with ethyl acetate, washed with # sodium hydroxide solution, with water and with saturated sodium chloride solution and dried (Na2S0^).. After filtration and removal of the solvents in vacuo, the resulting oil in hot ether was allowed to stand to complete crystallisation to give, as fine* white crystals , (i-)-3-methoxy-8,9-epoxyoestra-l,3»5(lO).-trien-17-Ql and (£)-3-methoxyoestra-1,3,5(10),9(ll)-tetraene-8,17P-diol (5.57 g.)} m.p. 1^7-1^9°· The mother liquors from the above filtration contained mostly the non-crystalline epoxide and were evaporated in vacuo to yield material suitable for conversion to the pure (i)-3-methoxyoestra-l,3»5(10)| 9(ll)-tetraene-8,17 -diol as described in Example ZK.

EXAMPLE 23 The mixture of products from Example 21 (1.87 g. ) and benzoic acid (1.0 g. ) in chloroform (50 ml) was X-69 of the chloroform in vacuo , the residue in ethyl acetate was washed with % potassium carbonate solution, with water and with saturated sodium chloride solution and then was dried (Na^SO^). After filtration and removal , the resulting oil in ether was allowed to stand to complete crystallisation to give, as prismatic needles, (£)^-methoxyoestra-l, 3,5(10) ,9(11)- tetraene-8,17p-diol (1 2 g.). m.p. .173 6°; IR*- 3^20, 3260 and 1635? UVs: 259(16,^00), , ; : ,. ,.· . , ,. ..

EXAMPLE 2k The mixture of title products from Example 22 ( .00 g. ) and benzoic acid (3.0 g. ) in chloroform (100 ml) was stirred at room temperature overnight. After removal of chloroform in vacuo, the residue in ethyl acetate was washed with # potassium carbonate solution, with water and with saturated sodium chloride solution and dried After filtration and removal of the solvents in vaouo. the resulting oil in boiling ether was allowed to stand at room temperature to crystallise to give, as colourless prisms, (i )-3-methoxyoestra-l, 3 , 5 (10) , 9 (11)-tetraene-8 , 17P-diol (3.^3 g.), m.p. 176-178°; IRs 3^50, 3260 and 1630; UVt 259 (18,000) . (Founds C, 75.66; H,8.0 . C^H^O^ requires C, 75· 975 H,8.05#) .

The residue from the mother liquors from Example 22 (which contain mostly the non-crystalline epoxide) in chloroform (100 ml) containing benzoic acid ( f0 g. ) was stirred at room temperature for 3 days. The solvent was removed in vaouo and the residue was worked up exactly as described above to yield crude (¾- 3-methoxyoestra- x-69 l,3,5(lO) ,9(ll)-tetraene-8,17p-diolj (2.35 g.) m.p. 150-153° which wae purified by dissolving it in boiling methylene chloride and allowing the solution to stand to deposit, as a fluffy white solidj (-)-3-methoxyoestra-1 , 3 , 5( 10 ) , ( 11)-tetraene-8 , 1?β-<ϋο1 (1.52 g.) m.p. 173-175°.

EXAMPLE 25 (l)-3_Methoxyoestra-l,3,5(lO) ,9(ll)-tetraene-8,17P-diol (3.75 g. ) in absolute ethanol (100 ml) and tetrahydrofuran (10 ml) was hydrogenated in the presence of palladium on charcoal (2.0 g. ) and ethanol (50 ml) which had been pretreated with hydrogen at atmospheric pressure until saturation of the catalyst was complete, until uptake of the gas was complete. After filtration through Supercel and removal of the solvents in vacuo, the resulting oil in tetrahydrofuran was treated with Nuchar charcoal. The mixture was filtered through Supercel and the solvent removed in vacuo, the residue was boiled with ether and set aside to complete crystallisation to give, as a white fluffy crystalline solid, (i)-.3_methoxyoestra-l,3,5(l0)-trien-8,17P-diol (3.26 g. )| m.p. I78-I8O0; IH:: 3360 and 3280. (Found: C, 5.30; H, 8.39. C19H26°3 requires? 0,75 6; H, 8.67*).

EXAMPLE 26 (t) -3-Methoxyoestra-l, 3 , ( 10)-triene-8,l?p-diol (1,00 g.) in pyridine (10 ml) was treated with methanesulphonyl chloride (5 ml) and the solution heated on a steam bath until the vigorous exothermic reaction X-69 caused reflux of the solvent; the heat was removed until the reaction subsided. The heat was reapplied for a period of 15 minutes more to complete the reaction. The reaction was cooled to room temperature, treated with ice-water and ether, blown with nitrogen to remove the ether layer and the resulting solid filtered and air-dried. This solid in methylene chloride was treated with Nuchar charcoal and filtered through Supercel.

The solvent was replaced with absolute ethanol by boiling on the steam bath and the mixture was allowed to stand to complete crystallisation, to give the crude product, as an off-white crystalline material} m.p. 137-139°. A sample (0.72 g.) in benzene was passed through a short column of Florex XXS. After evaporation of the benzene in vacuo and trituration of the .resulting oil with methanol , there was obtained,as a white crystalline solid , (¾-3-methoxyoestra-l,3, (10),7-tetraen-17P-ol, methane sulphonate (0.6l g. ), m.p. 138-140°. (Foundt-C,66.535 H, 7.11? S, 9.2. C2oH26¾S re¾uirest- c» 66.27; H,7.23; s, 8.9#).

EXAMPLE 27 (ί)-3-Methoxy-13,17odiethylgona-l,3,5(10),8-tetraen-17β-ο1 (12.0 g. ) in benzene (250 ml) was treated with anhydrous potassium carbonate (12.0 g. ) and hexane (70 ml) and the mixture cooled to 0° . m-Chloroperbenzoic acid (8,0 g) was added with stirring and the solution stirred at 0° for 8 minutes. The reaction mixture was quenched with potassium carbonate solution (250 ml) and stirred for 10 minutes . The organic layer was diluted with ethyl X-6 acetate, washed with 3% sodium. hydroxid solution, with water and with saturated sodium chloride solution and dried After filtration and removal of the solvents in vacuo, the gummy solid was triturated with ether and allowed to stand to complete crystallisation 'to give, as white shiny plates, (£)-3-raethoxy-8, -epoxy- 13,17α-diethyl ona-lt3,5(10)-trien-7-ol (11.5 g.) m.p. 17-152' IR: 3».480} UV: 235 (12,300). A sample from a previous preparation gave the following analysist Found! 0, 6.84} H, 8.47. C22H30° re¾uiree:: c» 77.15? H, 8.83#.

EXAMPLE 28 (i)-3-Methoxy-8,9-epoxy-13,17a-diethylgona-l,3t5(10)- trien-17-ol (11.5 g. ) and benzoic acid (8.0 g) in chloroform ( Ο ml) was stirred at room temperature for 24 hours,, washed with % potassium carbonate solution and dried (NagSO^ .

After filtration and removal of the chloroform in vacuo,the residue was triturated with ether to give, as a white crystalline solid, (ί)-3-methoxy--13»17ot-diethylgona-l,3t5(lO) , 9(ll)-tetraene-8,17P-diol (6.5Ο g.) m.p. l6l-4°; IR : 345Q, 336Ο and 1640; UV: 26l(l8,200). (Foundt C, 77.l8f H,8.77j requires:: C,77.15; H, 8.83¾.) EXAMPLE 29 (i)-3-methoxy-13,17a-diethylgona-1,3»5(10) ,9(11)- tetraene-8,17|3-diol (4.00 g.) in absolute ethanol (100 ml) and tetrahydrofuran (100 ml), was hydrogenated in the presence of 3 palladium on charcoal (2.00 g. ) and ethanol (50 ml) which had been pretreated with hydrogen at atmospheric pressure until saturation of the catalyst was complete, until uptake of the gas 'was; complete. After filtration through Supercel and X-69 chloride was treated with Nuchar charcoal, filtered through Supercel and the -solvent removed in vacuo.

The residue in boiling ether was allowed to stand to crystallise to give, as colourless prisms9 (-)-3-methoxy-13 « 17a-diethylgona-1 , 3 « 5 (10)-triene-8,17p-diol (2.50 g.) m.p. 156-8.5; IR: 3510.

(Found:. C, 76.55» H, 9.07. C^H^O-j requires: C, 76.70; H, 9.36#) .

EXAMPLE 30 ( ) -3-Methoxy-13117a<-diethylgona-1 , 3 » 5 ( 10)-triene-8,17 -diol (1.00 g.) in pyridine (12 ml) was treated with methane sulphonyl chloride (5 ml) and heated on a steam bath until a vigorous exothermic reaction caused reflux of the solvent; the heat was then removed until the reaction had subsided. The heat was reapplied for a period of 15 minutes more to complete the reaction. The reaction mixture was cooled to room temperature, treated with ice-water and ether and the ether layer blown off with nitrogen; the resulting solid was filtered and air-dried. The solid in methylene chloride was treated with Nuchar charcoal and filtered through Supercel. After removal of the solvent in vacuo, the resulting oil was contacted with ethanol; the resulting crystalline material gave in two crops, the crude product (O.M g. ) m.p. 105 -110°. The combined two crops in benzene were passed through a short column of Florex XXS. The benzene eluent was evaporated in vacuo and the resulting yellow oil triturated with methanol to give, as a slightly yellow X-69 7,17(20)-pentaene (0.33 g.) m.p. 110-112°; (Found: C, 85.12; H, 8.89, C22H280 re¾uiree i Cf 85.66; H, 9.150).

EXAMPLE 31 (i ):-3-Methoxyoestra-l,3i 5(10) , 8-tetraen-17 -ol (15.0 g. ) in pyridine (50 ml) and acetic anhydride ( O ml) was allowed to stand at room temperature overnight. The reaction was poured into ice-water and the resulting white crystalline precipitate filtered and air-dried.

This solid in methylene chloride was treated with Nuchar charcoal and filtered through Supercel. The methylene chloride was replaced with absolute ethanol by boiling on a steam bath and the mixture allowed to stand to complete crystallisation to give, as shiny plates (-)-3-methoxyoestra-l,3»5(l6) ,8-tetraen-17P-ol, acetate (15.3 g.) m.p. 119-121°; IR:: V? and 1635? UVR 276 (17200) (Found:: Ct 77.01j H, 7.830. c2iH26°3 re¾ulres ' 0,77· 271 H, 8.030).

EXAMPLE 32 ( - ) -3-Methoxyoestra-1 , 3 , 5 ( 10 ) , 8-tetraen-17β-ol, acetate (6.00 g. ) in benzene (125 ml/ and hexane (35 ml) was cooled to 0° , treated with anhydrous potassium carbonate (6.0 g. ) and m-chloroperbenzoic acid Ct.O g. ) and stirred at 0° for .5 minutes. The reaction mixture was quickly quenched with 50 potassium carbonate solution (25Ο ml) and then stirring continued for a few minutes at room temperature. The organic layer was diluted with ether, washed with 50 sodium hydroxide solution, water X-69 (NagSO^). After filtration and removal of the solvents in vacuo , the resulting colorless oil in ether was allowed to stand to crystallise to give, as prismatic needles, (=)-:3-methoxy-8,9-eopxyoestra-l,3,5(lO)-trien-17P-ol, acetate (3.51 g.) m.p. 118-21°} IR: 17^0; UV:.235 (13,100).

(Found i C, 73.72? H, 7.33; C^R^gO^ requires: C, 73.66} H, 7.66%) .

EXAMPLE 33 (-)-3-Methoxy-8,9-epoxyoestra-1,3j5(10)-trien-17β-ο1, acetate ( .OO g„ ) and benzoic acid (2.0 g. ) in chloroform (150 ml) was stirred for l8 hours, and the solvent removed in vacuo. The residue in ethyl acetate was washed with 3% potassium carbonate solution, with water and with saturated sodium chloride solution and dried (Na2S0^). After filtration and removal of the solvent in vacuo, the resulting oil was triturated with ether to give, as. a white crystalline solid, (i)-3-methoxyoestra-1,3,5(10) ,9(H)-tetraene-8,17β-diol, 17-acetate (3.37 g.)},. m.p. 17^-6°5 IR: 3600, 1720 and I63O5 UV: 258 (I76OO) (Found: G, 73.35? H, 7.69.

C21H26°* re(luires c» 73.66} H„ 7.66#).

EXAMPLE 3f (ί)-3-Methoxyoestra-1,3, 5(10) ,9(11)-tetraene-8,17β-diol, 17 acetate (2.53 g. ) in absolute ethanol (I50 ml) and tetrahydrofuran (50ml. ) was hydrogenated in; the presence of % palladium on charcoal (1.0 g. ) and ethanol (50 ml), which had been pretreated with hydrogen at atmospheric pressure until saturation of the catalyst was complete, X-69 until uptake of the gas was complete,, After filtration through Supercel and removal of the solvent in vacuo, the resulting oil in methylene chloride was treated with Nuchar charcoal, filtered through Supercel and the solvent removed in vacuo, The residue in benzene-hexane (1:1) was allowed to stand to complete crystallisation to give, as a white crystalline solid, (- -3-methoxyoestra-l,3, 5(10)-triene-8,17P-diol, 17-acetate (1.83 g. ) m.p, 13* °I IH: 3^60 and 1720.

EXAMPLE 35 (I )«-3-Methoxyoestra-l, 3 , 5(lO)-triene-8 , 17β-ά1ο1 (3.20 g.) in pyridine (15 ml) and acetic anhydride (10 ml) was allowed to stand at room temperature overnight and was then poured into ice-water. A little ether was added to facilitate crystallisation; after blowing off the ether with nitrogen and filtration, there was obtained a white crystalline precipitate. After drying,, this solid in methylene chloride was treated with Nuchar charcoal and filtered through Supercel.

The methylene chloride was removed in vacuo and the resulting colourless oil in boiling hexane treated with a small amount of benzene to remove cloudiness. After standing at room temperature, there was obtained, as colourless prisms, (-)-3-methoxyoestra-l,3,5(lO)-triene-8917 -diol, 17-acetate (2.71 g.), o m.p. 1^0.5-1^ . ; IR:; 3^60 and 1725. (Found: C, 73.171 H.8.04. C21H28° re¾uires: c« 73.32? ,H, 8.19S*) e EXAMPLE (i)-3-Methoxyoestra-l ,3 » 5(10)-triene-8 , 17β-<ϋο1, 17-acetate ( . O g. ) in pyridine (25 ml) was treated with methane X-.69 the heat was then removed until the reaction had subsided. The heat was reapplied for 15 minutes to complete the reaction. The reaction mixture was cooled to room temperature, treated with ice-water and ether and the ether layer blown off with nitrogen; the resulting solid was filtered and air-dried. This solid in methylene chloride was treated with Nuchar charcoal and filtered through Supercel.

After removal of the solvent in vacuo, „the yellow oil in methanol was allowed to stand to complete crystallisation to give an off-white crystalline precipitate (2.57 g«) πι·Ρ· 1θ6-1θ8°. A sample (0.75 g«) was purified by dissolving it in benzene and passing it through a short column of Florex XXS.

After evaporation 0f the benzene eluent in vacuo. the resulting oil in methanol was allowed to stand to crystallise to give, as a fine white crystalline material, (i)-3-methoxyoestra-l,3,5(lG) ,7-tetraen-17 -ol, acetate (0 0 g.) m.p. 115-8° ; IR: 17 0) .( Found:. C, 76.97} H, 7.85#. C21H26°3 requires: C, 77.27? H, 8.03#).

EXAMPLE 37 d- (-)-3-Methoxyoestra-l,3,5(lO) ,8-tetraen-17P-ol (3.00 g. ) in benzene (100 ml) and hexane (25 ml) was .cooled to 0° treated with potassium carbonate (3.0 g. ) and m-chloroperbenzoic acid (2.00 g. ) and stirred at 0° for 10 minutes. The reaction mixture was quenched with 5% potassium carbonate solution ( 0 ml) and stirred for a few minutes more at room temperature. The organic layer was diluted with ethyl acetate, washed with 5# potassium X-69 sodium chloride solution, and dried After filtration and removal of the solvents in vacuo, there was obtained, as a non-crystallisable oil , d-3-methoxy-8,9-epoxyoestra-l,3,5(lO)-trien-17P-ol and d-(-)-3-methoxyoestra-1 , 3 , 5 ( 10 ) , 9 ( 11.)-tetraene-8 , 17β-diol. The oil was not further purified but was next converted to pure d-(-)-3-methoxyoestra-1 , 3»5(10) ,9(ll)-tetraen-8,17P-diol as described in Example 38.

EXAMPLE 38 The oily mixture from Example 37 and benzoic acid (2.00 g, in chloroform (100 ml) was stirred overnight at room temperature. After removal of the. solvent in vacuo, the residue in ethyl acetate was washed with % potassium carbonate, with water and with saturated sodium chloride solution and dried ( a^O^). After filtration and removal of the solvent in vacuo the resulting oil in benzene was allowed to stand to complete crystallisation to give, as white crystals, d-(-)-3-methoxyoestra-l,3t5(l0) , 9(ll)-tetraene-8t17 -diol (2.08 g.); m.p. 130-2°; IR: 3330 , and 16355 U : 258.5 (16,350) ; Ca]D26j-1 .7° (Ο»1»00; dioxane).

EXAMPLE 39 d-(-)-Methoxyoestra-1 , 3 , 5 ( 10 ) , 9(H)-tetraene-8 , 17β-diol (I.98 g.) in absolute ethanol (100 ml) was hydrogenated in the presence of palladium on 'charcoal (1.00 g. ) and ethanol (25 ml) which had been pretreated with hydrogen at atmospheric pressure until saturation of the catalyst was complete, until uptake of the gas was complete. After filtration through Supercel and removal of the solvent in vacuo, the re"sulting oil in tetrahydrofuran was treated X-69 with Nuchar charcoal, filtered through Supercel and the solvent removed in vacuo. The residue was triturated with benzene and allowed to stand to complete crystallisation to give, as a white crystalline solid, d-(+ )-3-methoxyoestra-l,3,5(lO)-triene-8,17P-diol (1.70 g. ) m.p. l 6-8°] IB: 3315*. [a]p5 + 32° (C=l, dioxan); (Found: C, 75.62; H, 8 θ#.

C19H26°3 re(luires: c« 75 6; H, 8.67%) .

EXAMPLE *t0 d-(+) -3-Methoxyoestra-l, 3 , 5( 10)-triene-8 , 17β-diol (I.50 g. ) in pyridine (15 ml) was treated with methane sulphonyl chloride (7 ml) and the solution heated on a steam bath until a vigorous exothermic reaction caused reflux of the solvent. The heat was removed until the reaction subsided and then the heat was reapplied for minutes more to complete the reaction. The reaction was cooled to room temperature and then ice-water and ether added; ; the ether layer was blown off with nitrogen and the resulting solid filtered and air-dried . The solid in methylene chloride was treated with Nuchar charcoal, filtered through Supercel and the solvent removed in vacuo ; the resulting oil was triturated with methanol to give, as a light yellow crystalline material, d-(+) -3-methoxyoestra-1 , 3 » 5 ( 10 ) methane sulphonate (I.38 g.)? m.p. 150-2°·, [a]^ -if 105° (C=l, dioxan).

X-69 EXAMPLE kl (1)-3-Methoxyoestra-l,3,5(lO) ,7rtetraen-17P-ol» methane sulphonate (1.00 g.) in tetrahydrofuran (25 ml) was added dropwise to lithium aluminium hydride (1.00 g, ) in tetrahydrofuran (25 ml) under nitrogen. After complete addition (15 minutes)! Ί the reaction mixture was refluxed under nitrogen for 2.5 hours. After cooling to room temperature, the mixture was carefull treated dropwise with ethyl acetate (15 ml), water and then dilute acetio acid-and was then extracted with ethyl acetate} the extract was washed with saturated sodium bicarbonate solution, with water and with saturated sodium chloride solution and dried (NagSO^). After filtration and removal of the solvent in vacuo, the resulting oil in a small amount of ether was treated with petroleum ether to cloudiness. The solution was seeded and allowed to stand to complete crystallisation to give, as off-white prisms, (i)-3-methoxyoestra-l,3,5(l0) (0. ^ g.)| m.p. 121-*t°j IR* 3280.

EXAMPLE Z (¾- Methoxyoestra-l,3,5(lO) ,7-tetraen-17P-ol, acetate (0.70 g.) was added to warm sodium hydroxide (O.5O g») in anhydrous methanol (20 ml). The mixture was stirred and warmed until all the solid dissolved. The reaction mixture was stirred at room temperature for O.5 hours and then water was added; the resulting precipitate was filtered and air-dried. The' solid X-69 and filtered through Supercel. After removal of the solvent in vacuo , the resulting colourless oil in a small amount of benzene was diluted with an equal volume of hexane. The solution was seeded and set aside to complete crystallisation to give, as white needles cluster (i)-3-methoxyoestra-l,3t5(10) ,7-tetraen-17p-ol (0,37 g.); m.-p. 126-8°; IRr 3280.

(Foundr C, 80 7. H, 8.59· re¾uires !: C, 80.2*; H, 8.51#) .

EXAMPLE k3 (i)-3-Methoxyoestra-l, 3 » 5(10) , 7-tetraen-17-one (2.08 g. ) and methanol (50 ml) was treated with sodium borohydride (2.0 g.) in small portions over a period of one hour . After complete addition, the reaction mixture was stirred at room temperature for one hour more and then water was added. After seeding, filtration of the resulting precipitate and air-drying, there was obtained (i)~3-methoxyoestra-l,3,5(l0) , -tetraen-17 -ol (2.00 g)| m.p. 121-· .

EXAMPLE ¥ d(+ )-3-Methoxyoestra-l, 3 , 5 ( 10) , 7-tetraen-17P-ol, methane sulphonate (1.30 g. ) in tetraJtiydrofuran (25 ml) was added dropwlse to lithium aluminum hydride (1.30 g. ) in tetrahydrofuran (25 ml) under nitrogen. After complete addition (15 minutes), the reaction mixture was refluxed under nitrogen for 2.5 hours. The mixture was cooled to room temperature, carefully treated with ethyl acetate, water and dilute acetic acid and was then extracted with eth l acetate the extract was washed with X-69 saturated sodium bicarbonate solution, with water and with saturated sodium chloride solution and dried (N&^SD^). After filtration and removal of the solvent in vacuo, the resulting oil was cooled and scratched to give a partially crystalline solid, which dissolved in a small volume of benzene, was passed through a short column of Florex XXS. The benzene eluent was evaporated in vacuo ; the resulting colourless oil in a small amount of benzene was diluted with hexane and seeded to give, as white feathery crystals, d~(O-3-methoxyoestra-1,3,5(10) ,7-tetraen-17P-ol (0.71 g.)j m.p. 80-2°; IR; 32805 [ ^ + 168° (Q=l5 dioxan). Second, crops were obtained from the above mother liguore as a white / crystalline solid (170 mg. ) m.p. 79-82°.

EXAMPLE h5 ( - ) -3-Hydroxyoestra-1 , 3 » ( 10 ) , 8-tetraen-17-one, acetate (6.00 g. ) in benzene (125 ml.) and hexane (35 ml.) was cooled to 0° and treated with potassium carbonate (6.00 g») and m-chloroperbenzoic acid ( .0 g. ) Stirring was continued for two hours, the reaction mixture was quenched with 5$ potassium carbonate solution (250 ml.) and then stirred for a few minutes. The organic layer was washed with 5# sodium hydroxide solution, with water and with saturated sodium chloride solution and then dried (Na>jS0^);. Filtration and removal of the solvents in vacuo gave a red oil, which, dissolved in ether, was allowed to stand to crystallise to give, as orange prism clusters, the crude product (3.88 g.); m.p. 155-160°. Ai sample X-69 to give,as slightly orange platelets, (*)-3-hydroxy-8,9-epoxyoestra-l,395(lO)-trien-17-one, acetate (0.33 g.)j m.p, 166-9°; IR: 1 ^0; UV: 228 (10,100) : (Found:. C, 73.0?; H, 6.48* ¾0H22¾ requires; C, 73.60; H, 6.79#>.

EXAMPLE 6 (ί)--3=Hydroxy-8 ,9-epoxyoestra-1 ,3 , 5(10)-trien-17-one, acetate (0.326 g. ) in sodium methoxide O.090 g. ) in methanol (10 ml.) was stirred for 10 minutes and then the methanol was removed in vacuo. Water (100 ml.) was added to the residue and then solid ammonium chloride in small portions until the mixture is nearl neutral. The mixture was extracted with methylene chloride; the contact was dried (^ 30^), filtered and solvent removed in vacuo to give a dark oil, which was covered with benzene and allowed to crystallise to give, as a dark crystalline solid (-J^-hydroxy-S^-epoxyoestra-l^iSdOj-trien-^-o e (0.150 g. ); m.p. 182-5°; IR: 3280 and 1725? UV:.223 (7,300) .

EXAMPLE 7 (i)„3-Methoxyoestra-l,3,5(lO) ,8-tetraen-17 -ol (2^.0 g. ) was treated with 3M-ethereal methylmagnesiuni iodide (350 ml.) and heated, under argon, tc l60°, the mixture was kept at l60° for 5 hours and was then illowed to cool. The mixture was covered with a layer of white mineral oil and then further cooled by immersion in a methanol-ice bath. Ice-water was added and the mixture vigorously stirred. The solution was acidified with dilute acetic acid, filtered, washed with petroleum ether and air-dried to give a yellow solid which, X-69 was boiled to remove the methanol and then it was allowed to stand at -10° to complete crystallisation to give the crude product (12.5 g. ) 5 m.p. 218-21°; IB:.350 and 3l80; UV:.2?2 (14.115). A portion (0.37 g. ) was dissolved in methanol, treated with Nuchar charcoal and filtered through Supercel. The methanol in the filtrate was replaced with ethyl acetate by boiling on a steam bath, to give, as off-white prisms, (i)-oestra— 1,3,5(10),8-tetraene-3,17P-diol (0.20 g.); m.p. 215-7°5 IR: 3450 and 3160; UV:; 275 (l6,200). (Found: C, 79.62; H, 8.16; C18H22°2 e¾uir EXAMPLE 49 ( )-Oestra-1,3,5(10),8-tetraene-3,17 -diol, diacetate (2.10 g. ) in benzene (50 ml.) and hexane (15 ml.) was X-69 and m-chloroperbenzoic acid (1.50 g.) were added and the reaction mixture stirred for two hours; 3# potassium carbonate solution (15O ml.) was added and the stirring continued for a few minutes longer.

The organic layer was diluted with ethyl acetate, and washed with sodium hydroxide solution, with water and with saturated sodium chloride solution and then dried After filtration and removal of the solvents in vacuo, the resulting oil in ether was allowed to stand to crystallise to give (i)-8,9-epoxy-oestra-l,3,5(10)-trien-3,17P-diol, diacetate.

EXAMPLE 50 (t)_3_Methoxyoestra-1,3,5(10) ,7-tetraen-l?β-οΐ (2.00 g. ) was added to 3M-ethereal methylmagnesium bromide (70 ml.) and heated, under argon, to 185°.

The reaction mixture was kept at this temperature for 1.5 hours and was then allowed to cool to room temperature. The reaction mixture was further cooled in an ice-salt bath and was then quickly quenched with ice-water. The mixture was acidified to pH7 with hydrochloric acid, filtered and air-dried to give a yellow solid which, dissolved in tetrahydrofuranwas treated with Nuchar charcoal and filtered through Supercel. After removal of the solvent in vacuo, the resulting yellow oil iwa contac ed wi;th methylene chloride .-and· the resulting yellow solid filtered to give (i5,-oestra-li3t5ClO)f7"tetraene-3il7-diol (0#95 g.)j m.p.V210-3°, -.a portion (O.35cg.)of which in methanol was treated with Nuchar charcoal and boiled; after filtration through Supercel the methanol was replaced , .

X-69 and the solution allowed to stand to crystallise to give, as white, leafy crystals, the pure compound (0.20 g. ) m.p. 220-2°; IR: 3390 and 3220; (Found:: C, 79.68; H, 8.13. Cl8H22°2 re(luires: c»79.96; H, 8.20#).

EXAMPLE 51 (i)-Oestra-l,3,5(10),7-tetraene-3,17P-diol (200 mg.) in methyl ethyl ketone (20 ml.) and benzene (30 ml.) was refluxed under nitrogen into a water separator; aluminum isopropoxide (1.0 g. ) in dry benzene (10 ml.) was added and refluxing continued for 2 hours. The reaction mixture was then treated with aluminum isopropoxide (1.0 g, ) In dry benzene (10 ml.) and refluxing continued for *t hours more.

After cooling and standing overnight, the reaction mixture was treated with water and the pH was reduced to 7 with acetic acid. The mixture was extracted with ethylacetate and washed with water and with saturated sodium chloride solution and then dried (Na2S0^). After filtration and removal of the solvents in vacuo, the resulting partially orystalline oil was triturated with ether to give, as yellow prisms, (-)-3-hydroxyoestra-1,3,5(10) ,7-$etraen-17-one (98 mg. ); m.p. 213-6°; IR: 330 and 1725. The IR spectrum (tetrahydrofuran) and NMR spectrum (CD Cl^) were identical to the corresponding spectra for the natural product, equilin.

EXAMPLE 52 3M-Ethereal methylmagnesium iodide (30 ml. ) was added to d(+)-3-methoxyoestra-l,3,5(10),7^tetraen-17-ol (0.80 g.) and, under an atmosphere of argon, heated tc l60°. The reaction mixture was kept at this temperature for 2 hours X-69 mixture waa cooled further by immersion in a methanol-ice bath, and was quickly quenched by acidification to ph7 with dilute^acetic acid.' Filtration and air-drying gave a yellow solid, which, dissolved in tetrahydrofuran, was treated with Nuchar charcoal, filtered through Supercel and the solvent removed in vacuo* The resulting yellow oil in a small amount of methylene chloride was diluted with ether to give, as. a yellow crystalline solid, in two crops, the crude product (θ θ g. ) j m.p. 200-3° with pre-softening at l65°? a portion (210 mg. ) was recrystallised' from boiling 30$ ethanol to give, as long off-white needles, d-(+)-oestra-l,3,5(10) ,7-tetraen-3,17P-diol (I60 mg.)j m.p. 200-3°; IR: 3230 and 3160.

EXAMPLE 53 d(+)-oestra-l,3|5(10),7-tetraene-3,17-diol (3OO mg.) in methyl ethyl ketone (25 ml.) and benzene (35 ml.) was refluxed under nitrogen into a water separator. Aluminum isopropoxide (1.0 g. ) in dry benzene (10 ml.) was added and refluxing continued for 2 hours. More aluminum isopropoxide (1.0 g. ) in dry benzene (10 ml.) was then added and refluxing continued for *t hours more. After cooling and standing overnight, water was added and the pH reduced to 7 with acetic acid. The mixture was extracted with ethyl acetate, washed with water and with saturated sodium chloride solution and then dried (Na^SO^). After filtration and removal of the solvents in vacuo, the residue was triturated with ether to give d-(+)-3-hydroxyoestra-l,3,5(l0) ,7-tetraen-17-one (equilin).

X-69 EXAMPLE 5^ 3M-Ethereal methylmagnesium bromide (100 ml. ) was added to (-)-3-methoxyoestra-l,3,5(l0)-triene-8,17β^ΐο1 (*.00 g.) and the mixture, under argon, was heated to l85° and then kept at this temperature for 1.5 hours. After being allowed to cool, the mixture was further cooled by immersion in an ice-salt bath and then was quickly quenched with ice-water followed by acidification to pH7 with dilute hydrochloric acid to give after filtration and air-drying, a yellow solid, which dissolved in tetrahydro-furan,was treated with Nuchar charcoal and filtered through Supercel. Removal of the solvent in vacuo gave a dark oil which,dissolved in methylene chloride, was cooled and scratched with a glass rod to promote crystallisation to give, as yellow prisms, the crude product (0.33 g. )} m.p. 163-^°; IR: 3280. A sample (3OO mg. ) in methanol was treated with Nuchar charcoal and filtered through Supercel. The methanol was replaced with ethyl acetate by boiling on a steam bath} then the mixture was allowed to stand to complete crystallisation to give, as a crystalline solid, (-)-oestra-l,3»5(lO)-triene-3,8, ^--triol (130 mg. ); m.p. l86-8° (decomposition); IR: 3l80 (broad OH).

, EXAMPLE 55 (±)-Oestra-l,3,5(10)-trien-3,8,l?p-triol (1.00 g. ) in pyridine (12 ml.) was treated with methanesulphonyl chloride (5 ml.) and was heated on a steam bath until t.

X-69 the reaction subsided and then heat was applied for 15 minutes longer to complete the reaction. Cooling to room temperature, treating with water and ether, blowing off the ether with nitrogen, filtering and air-drying gave a crystalline material which, dissolved in methylene chloride, was treated with Nuchar charcoal and filtered through Supercel. After removal of the solvent in vacuo, the residue was triturated with methanol to give (-)-oestra-1 , 3 , 5 ( 10 ) , 7- 1etraene-3 , 17P-diol, dimethane sulphonate.

EXAMPLE 36 Lithium aluminum hydride (1.00 g. ) in tetrahydrofuran (25 ml.) under nitrogen was treated dropwise with (i)-oestra— 1 , 3 , 5 ( 10 ) , -tetraene-3 , 17β-diol, dimethanesulfonate (0,50 g. ) in tetrahydrofuran. The mixture was refluxed under nitrogen for 3 hours and was then allowed to cool to room temperature. The mixture was carefully treated dropwise with ethyl acetate, water and then dilute acetic acid, and then was extracted with ethyl acetate; the organic layer was washed with saturated sodium bicarbonate solution, with water and with saturated sodium chloride solution and then dried (ife^SO^). After filtration and removal of the solvent in vacuo, the residue was triturated with ether to give (-)-oestra-l,3,5(l0) ,7-tetraene-3|17P-diol.

EXAMPLE 57 (i)-Oestra-l,3,5(lO)-triene-3,8,17p-triol (0.50 g. ) in pyridine (5 ml.) and acetic anhydride (2 ml.) was X-69 allowed to stand at room temperature overnight. The reaction mixture was then poured into water, filtered and air-dried to give a crystalline solid, which dissolved in tetrahydrofuran, was treated with Nuchar charcoal, filtered through Supercel and the solvent removed in vacuo. The residue was triturated with benzene/hexane to give (i)-oestra-l,3, 5(lO)-triene-3,8,17p-triol, 3,17-diacetate.

EXAMPLE 58 (i)-Oestra-1 , 3 , 5(10)-triene-3 , 8,17 -triol, 3,17 -triol, 3, 17-diacetate? (l.OO g. ) in pyridine (12 ml. ) was treated with methanesulphonyl chloride (5 ml.). he solution was heated on a steam bath until a vigorous exothermic reaction caused reflux of the solvent. The heat was removed until the reaction subsided, and then was reheated for 15 minutes more to complete the reaction. After cooling to room temperature, water and ether were added and the ether blown off in a streamof nitrogen. Filtration and air drying gave a solid, which dissolved in methylene chloride, was treated with Nuchar charcoal, filtered through Supercel and the solvent removed in vacuo. The residue was triturated with methanol . )¾0estfar¾,3,r5(10),,7Ttetraene- 3¾1 P*dipi,, Id'iacetaite.. ' ' , 1:/·'·-·■;. '.acc t> o.

. EXAMPLE 59 (1)-0estra-l, 3 , 5(10) , 7-tetraene-3*17P-diol, diacetate (O.5O g. ) and .sodium hydroxide. tOAO ,g. in methanol . (10 ml. ) was boiled on a steam bath for 15 minutes. The solution was dilute acetic acid to give (+)-oestra-l, 3 ,5( 10) ,7-tetraene-3 , 17-diol.

EXAMPLE 60 ■ . ; To pre-hydrogenated 2% palladium/calcium carbonate in benzene ( 100 ml.) was added dl-3-tnethoxyoestra-l,3 »5( 10) ,8 ,1 - pentaen-17- EXAMPLE 61 dJL-3-Methoxy-l3-ethylgona-l, 3 , 5( 10) ,8-tetraene-17P-ol ( 10.00 g.) in benzene (300 ml.) and hexane ( 70 ml.) was cooled with an ice-bath.

Anhydrous potassium carbonate ( 10.0 g.) and m^chlorperbenzoic acid ( 8.0 g.). was added and the cooled mixture stirred for exactly 5 min, . the reaction was quickly quenched with 5¾ potassium carbonate solution (¼00 ml.). After stirring the layers were separated and the organic layer diluted with ethyl acetate, washed with water and saturated ·. sodium chloride and dried (Na^SO^) . The mixture was filtered and the solvents evaporated in vacuo to give a product which crystallised on standing from ether to give dl-3-methoxy-8 ,9-epoxy-13-ethylgona-li 3 »5( 10) - trieh-17P-o ( 8. o g.); m.p. l* 0-5° ; IR: 3^00; UV: 235 ( 12,300) . -5h - EXAMPLE 62 dl-3-Methoxy-8 ,9-epoxy-l3-ethylgona-1 ,3,5( 10)- trien-17-οηθ ( 1 .82 g.) and methanol ( 100 ml.) was treated s quenched by added potassium carbonate solution (600 ml.); after stirring the layers were separated. ¾te organic layer was diluted with ethyl acetate, washed with 5% sodium hydroxide, water and saturated sodium chloride solution and then dried The mixture was filtered, the solvents removed in vacuo and the residue,in ether, was allowed to stand at 10°.

Filtration gave dl-3-methoxy-8,9-epoxy- 3-ethylgona-1 ,3 ,5, (10)- trien-17 -ol ( 10. ^5 g. ) ; m.p. 130-13^°. The filtrate was diluted with petroleum ether and filtered to obtain a crude product (3O.5 g.) m.p. 135-8° of which a sample (3·35 g«), in methylene chloride was treated with Nuchar charcoal and filtered through super cel. ¾e solvent was replaced with isopropanol by boiling, and the mixture then filtered to obtain dl-3-methoxy-13-ethylgona- 1 ,3»5(lO) ,9(11)-tetraene-8,17P-diol (2.20 g.); m.p.

IR: 3330; UV 260 ( 17 ,700) .

EXAMPLE 6k dl-3-Methoxy-8 , 9-epoxy-13-ethylgona-l, 3 ,5 ( 10)-trien-17P-ol (8.00 g.)fbenzoic acid (6.00 g.) and chloroform (150 ml.) was stirred at room temperature overnight. The chloroform was removed in vacuo, and the residue, in ethyl acetate, washed with potassium carbonate solution, water, and saturated sodium chloride and was then dried . After filtration and removal of the solvent in vacuo , the resulting oil, in ether, was allowed to stand to complete crystallisation. Filtration gave the crude product (2.38 g.) m.p. 83-88° (solvate), a sample of which, in methylene chloride, was treated with Nuchar charcoal, filtered through super cei and then the solvent was replaced with isopropanol-heptane b boiling. The resulting solid was filtered to give dl-3-methoxy-13- 13-ethylgona-l,3,5(10) ,9(ll)-tetraene-8,17 -diol m.p.85-88° (solvate).

L EXAMPLE 66 . d(-)-3-Methoxyoestra-1 ,3 ,5( 10) ,8-tetraen-17 -ol (60.0g. ) in benzene ( 1 . litres) was treated with hexane (200 ml.). The stirring solution was cooled in an ice-bath to 10° and then anhydrous potassium carbonate (50 g.) and m-chloroperbenzoic acid (4-3,0 g. of 85% assay) was added.The temperature rose to about 26° then dropped again to 18°. After 15 mins,a starch iodide test showed that all of the peracid had been consumed.

The ice-bath was removed and stirring continued at room temperature for 45 mins. the reaction was quenched with 5% potassium carbonate solution ( 1 litre), the residue stirred and filtered to give a white crystalline solid which was washed with ethyl acetate and water and then dried (P2O5- vacuum) to give d<.-)-3-methoxyoestra-1 ,3 »5( 10) ,9( 11)-tetraene-8 , 7P-diol.

The layers from the above mother liquors were separated and the extract well washed with $ sodium hydroxide solution, water and brine-,. The dried ethyl acetate extract (Na2S0^) was filtered the: solvents removed in vacuo ; the residue was triturated with benzene and stored at 10° to obtain some further product ( 11.5 g») The combined product (57.5 g. » 90 ) had m.p. 128-131°. The analytical sample (from benzene) had m.p. 13 -136° ; [α]2^ -22° (C = 1 , dioxahe); IR: 3330 ; UV: 258 ( 16 ,5 0) . (Found: C, 75.93 ? H, 8.19 , C19H2i P3 requires: C, 75-97 ; H, 8.07%) .

EXAMPLE 67 dl-3-Hydroxyoestra- ,3 ,5( 10) ,8-tetraen-17-.one (3 5 g. ) ,ethyl acetate (200 ml.) and tetrahydrofuran (30 ml.) were, cooled i an ice bath; anhydrous potassium carbonate (3·· Og) and then m-chloroperbenzoic acid (2.78 g.) were added and the cooled solution stirred for 0.5 hr. The ice bath was removed and the mixture stirred for 1 hr. at room temperature. The reaction was quenched with saturated sodium bicarbonate solution (200 ml.)} the layers separated, the extract. washed with 3% potassium carbonate, water and saturated sodium chloride and then. dried (Na^SO^) . Filtration and evaporation of the solvent in vacuo gave an oil which in methylene chloride was diluted with ether, filtered and dried to give dl-3',8-dihydroxyoestra-1 ,3 ,5( 10) ,9( 11 )-tetraen-17-one ( 1.50 g.) m.p. 207-210; IR: 3330, 1720 ; UV: 260 ( 1i ,600) .

EXAMPLE 68 dl-0stra-1 ,3 ,5( 10) ,8-tetraene-3 , 17P-diol (2.00 g.) in tetrahydrofuran (75 ml.) was cooled in an ice-bath; m-chloro-perbenzoic acid ( 1.50 g.) was added and the mixture stirred at room temperature for 1 .25 h. The reaction was quenched by adding saturated sodium bicarbonate solution, the mixture extracted with ethyl acetate, and the extract washed with saturated sodium bicarbonate and saturated sodium chloride solution and dried (N&^SO^) . Filtration, evaporation of the solvent in vacuo , trituration of the residue with methylene chloride and filtration gave dl-ostra-1 ,3 ,5( 10) ,9( 11 )-tetraene-3 ,8 , 17β-ίΓΐο1; m.p. 160-1630 (solvate); IR: 3330 ; UV: 259.

EXAMPLE 69 ' : dl-3-Cy¾lopentyloxyoestra-1 ,3 ,5( 10) , 8-tetraen-l7P-ol (3.00 g.) in benzene (75 ml.) and hexane (20 ml.) was cooled in an ice-bath, anhdrous potassium carbonate (3.0 g.) and m-chloroperberizoic acid (I.80 g.) was added and the cooled reaction mixture stirred for 0.5 hr. ¾e ice-bath was removed' and the mixture stirred a!t room temperature for 2 hr. before quenching the reaction with 3% potassium carbonate solution ( 100 ml.). ' The mixture was diluted with ethyl acetate the layers separatedtthe extract washed well With 3% potassium -carbonate , .water and .saturated sodium chloride solution and then dried. (NaSO^). Filtration and removal of the solvents in vacuo gave am oil which,in ether was scratched to induce crystallisatinn, triturated and filtered to obtain the crude product .36 g.) m.p. 1^0-142°, which, in tetra-hydrofuran, was treated with Nuchar charcoal, and filtered through super cel. After removal of the solvent in vacuo , the oil, in ether^was seeded and allowed to stand to crystallise. Filtration gave dl-3-cyclopentyloxyoestra- 1,3,5(10), 9(11 )-tetraene 8 , 17P-diol (0.70 g.) m.p, 1Η-1½6°; IR: 3 00 ; UV 260 ( 18,^00). (Found; C,77.93 ; H^O C23H30°3 re<*uires c « 77.93 ; H, 8.53#).

EXAMPLE 70 ^-Oestra-1,3,5(10) ,8-tetraene-3, l7P- EXAMPLE 7 dl-8 , 9-Epoxy-3-hydroxyoestra-1,3,5O0)-trien-1 -one,acetate (250 mg.) and 2,^-dinitrobenzoic acid (250 mg.) in chloroform (20 ml.) was allowed to stand at room temperature overnight; the solvent was removed in vacuo and the residue, in ethyl acetate,was washed the 9(11)-tetraen-l7-one,3-acetate. IR:3390,1760, T74o,UV: 252,(13^00).

EXAMPLE 72 dl-3-Methoxy-8¾9-epoxy-13-ethylgona=-l,3¾5(10) ~trien-17-one (1.00 g.) was added to lithium aluminium hydride (2.0 g.) and tetrahydrofuran (60 ml„) and the mixture refluxed for 20 nr.

After cooling to ropm temperature, the material was decomposed by the careful dropwise addition of ethyl acetate, then water followed by dilute hydrochloric acid; the mixture was extracted with ethyl acetate and the extract washed with water, saturated sodium chloride and then dried (ΝΒ230^) „ Filtration and remo al of the solvent in vacuo gave an oil, which in ether, was filtered to obtain dl-3-methoxy-13-ethylgona-l53,5(lO)-trien-=8,17 -diol EXAMPLE 73 dJL-3-Methoxy-8,9-epoxy-13-ethylgona-l, s5(10)-trien-r^-ol (1.00 g.) was added to lithium aluminium hydride (2.00 g0) and tetrahydrofuran (60 ml.) and the mixture refluxed for 20 hr. After cooling to room temperature, the mixture was decomposed by the careful dropwise addition of ethyl acetate, then water followed by dilute hydrochloric acid. The mixture was extracted with ethyl acetate and the extract washed with water, saturated sodium chloride solution and then dried (Na2S0^) „ After filtration, and removal of the solvent in vacuo, the resulting oil, in ether, was filtered to obtain dl-3-methoxy-13-ethylgona-l,3,5(l0)-triene-8,17P-diol (0.12 go) ιη. .191-^0.

EXAMPLE 7^ dl-3-Methoxy-13-ethylgona-l,3,5(10) ,9(11)-tetraene-8,17 «=diol (27.00 g.) in ethanol (250 ml.) was added to pre-hydrogenated % palladium on carbon (10.0 g.) and ethanol (100 ml.) and the mixture shaken with hydrogen at one atmosphere until uptake of the gas was complete. The mixture was filtered through super eel and the solvent removed in vacuo. The residue, in warm tetrahydrofuran was treated ) in ethanol (50 ml.) was added to pre-hydrogenated 596 palladium on carbon (0.50 g.) and tetrahydrofuran (20 ml.). The mixture was treated with hydrogen at one atmosphere until uptake of the gas was complete. The solution was filtered through super eel, and the solvents removed in vacuo ; the residue in tetrahydrofuran was treated with nuchar charcoal, filtered through super eel and the solvent removed in vacuo to give an oil which, in methylene chloride, was filtered to obtain dl-3,8-dihydroxyoestra-l,3,5(10)-trien-17-one (0.80 g.) m.p. 230-233°; IR: 3^00, 3200, 1725.

EXAMPLE 76 - dl-Oestra-l,3,5(10) ,9(lD-tetraene-3,8,17P-triol (4.1 g.) in -ethanol (200 ml.) was added to pre-hydrogenated 5¾ palladium carbon (i.O g.) and ethanol (5Q ml.)and shaken with hydrogen until uptake of. the gas was complete. The mixture was filtered through super eel, the solvent removed in vacuo and the residue, in tetrahydrofuran, treated with nuchar charcoal, filtered through super eel and the tetrahydrofuran removed in vacuo. The residue was boiled with chloro- form, cooled and filtered to give dl-oestra-l,3,5(10)-triene-3,8,17 - .: triol (1.86 g) m.p. 219-220°.

EXAMPLE 77 dl-Oestra-l,3,5(lO) ,8-tetraene-3, 17P-diol (10.0 g.) in tetrahydrofuran (150 ml.) was cooled in an ice-bath and then m-chloroperbenzoic acid (7.5 g.) added.

AJ0P^AO56-f After stirring the ice-bath was removed and then stirring continued at room temperature for 1.5 hr. The reaction was quenched by adding saturated sodium bicarbonate solution (200 mi.) and the mixture extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate, water and saturated sodium chloride solution and then dried (Na^SO^) ΐ -. After filtration and removal of the solvent in vacuo the oil, in ethanol (150 ml.), was added to pre-hydrogenated 5% palladium on carbon (3.0 g.) and ethanol (50 ml.) and the mixture treated with hydrogen until uptake of the gas was complete. The mixture was filtered through super eel, the solvent evaporated in vacuo and the residue, in boiling methanolic-tetrahydrofuran, treated with nuchar charcoal, filtered .through super eel and the solvents removed in vacuo. The residue was boiled with chloroform containing a small amount of tetrahydrofuran and the allowed to cool to fully crystallise to give after filtration, dl-oestra-l,3,5(10)-triene-3,8,17P-triol (8.0 g.); m.p.255-2580.

. EXAMPLE 78 % Palladium on charcoal ( 10.0 g.) in ethanol (100 ml.) was pre-treated with hydrogen at one atmosphere until the catalyst was saturated. d( -) -3-Methoxyoestra-l ,3 ,5( 10) ,9( 11) -tetraen-8 , 17P-diol (3O.O g.) in ethanol (750 ml.) was added and treatment with hydrogen continued until uptake of the gas was complete (2500 ml.). The mixture was filtered through super eel, the solvent removed in vacuo and the residue , in tetrahydrofuran treated with Nuchar charcoal.

After filtration through super eel and removal of the solvent in vacuo the residue was triturated with benzene and allowed to stand to complete crystallisation to give, after filtration a white crystalline : solid , in several crops of d(+) -3-methoxyoestra-l,3»5(10)-trien-8,17 diol (26.7 g) m.p.1^8-152°. The analyticalsample(from benzene) had m.p .

AHP«4056-f EXAMPLE 79 dl_3_Methoxy-8-h drox besira-1 ,5 ,5( I0)-trien- 7-one ( 1 ,00 g.) in dimethylformamide ( 10 ml.) and pyridine (5 ml.) was trated with methane sulphonyl chloride(2 ml.). The solution was quickly warmed to 85-90° (under argon) and kept at this temperature for 10 min. After cooling the mixture was pouted into water, and the precipitate filtered and air dried This solid, in benzene, was passed through a short column of Florex (XXS, the benzene removed in vacuo and the product cr stallised from 95% ethanol. Filtration gave the crude product (0.70 g.) m.p. 125-8° , a sample (0.60 g.) of which i ether, was passed through a column of 10% silver nitrite- impregnated alumina. The solvent was removed in vacuo and the residue crystallised from 95 ethanpl to obtain dl-3-methoxy- oestra-1 ,3 ,5( 10) ,7-tetraen- 7-one (0.46 g.) m.p. 129 132 , EXAMPLE 80 dl-3-Methoxy-oestra-1 ,3 ,5(lO)-triene-8 , 17P-diol (5.00g. ) /in/ dimethylformamide (60 ml.) and pyridine ( 1*+ ml.) was treated ' with methane sulphonyl chloride (8 ml.;) and.the*,solution heated /under argon to 85° for 15 min. The mixture was cooled and poured into water. After filtration and air-drying, the resulting solid, in benzene, was passed through a short column of Florex XXS and then through a column of 10% silver nitrate impregnated alumina. The solvent was removed in vacuo and the residue crystallised to give the crude product; m.p. 120-122°, a sample ( 1.00. . ) of which in methylene chloride, was treated with nuchar charcoal, filtered (super eel) .'and the methylene chloride replaced with isopropanol by boiling. The resulting white crystalline solid was filtered to give dl-3-methoxyoestra-1 ,3 ,5( 10) ,7-tetraene-17P-ol, formate (0.86 g.); m.p. 123-5°; IR'- 1 25 (Found: C, 76.69 ; H, 7-57 (C2QH2i 03 requires C, 76.89 -, H, 7.7W .

EXAMPLE 81 : dl-3-Methoxy-l3-ethylgona-l ,3,5( 10)-trien-8, 17P-diol (5.00 ^. ) in dimethylformamide (55 ml.) and pyridine ( 10 ml.) was treated with methane sulphonyl chloride (6 ml.). The solution was heated to 95° for 30 rain, cooled and poured into water. After filtration and air-drying, the material, in benzene, was passed through a column of Florex X S« the solvent removed in vacuo and the residue crystallised from methanol. Filtration gave the crude product (2.73 g») m.p. 111-^°, a sample (2.65 g. ) of which, in benzene, was passed through a column of 1056 silver nitrate-impregnated alumina, the solvent removed in vacuo and the residue crystallised from ethanol to give,after filtration, dl-3-methoxy-l3-ethylgona-1 ,3 ,5( 10)-7-tetraen-17P-ol, formate (I.83 g.); m.p. II7-80 ; IR: 17 0; (Found: C, 77^ . H. 7.70.

C21H26°3 re¾uires: C, 77.27 ; H, 8.03%) .

EXAMPLE 82 d-(+)_3_Methoxyestra- ,3 ,5( 10)-trien-8 , 1?£-diol (23.5 g.) in dimethylformamide (320 ml.) was treated with pyridine (6k ml.) and methane sulphonyl chloride (kO ml.) and heated quickly under argon (or other inert gas) to 85°. The mixture was kept at 85° for 10 min. , then quickly cooled to room temperature. The mixture was decomposed by pouring it into ice-water and the crystalline precipitate filtered and air dried; the solid in benzene (warming is necessary); was passed through a short column which consisted of a upper layer of Florez XXS and a lower layer of 10$ silver nitrate-impregnated alumina. The benzene was removed in vacuo and the resulting oil, in 95 ethanol (Warm), allowed to stand to fully crystallise. Filtration of the resulting white crystalline solid gave d(+)-3-methoxyestra-1 ,3 ,5( 10) ,7-tetraen- 17P-ol, formate 08.0 g.) m.p. 1^7-150°; the analytical sample (from 95# ethanol) had m.p. 15^-156° ; [ The methylene chloride was replaced with isopropanol by boiling, (steam bath), and the mixture seeded and allowed to complete crystallisation. Filtraction of the resulting long, fine needles gave d(+)-3-methoxyoestra-l,3,5(lO) ,7-tetraen-17P-ol (0.70 g.) m.p. 136-138° [a D + 208° (C=l, dioxaneV; IR: 3550; UV: 222 (76ΟΟ).

Found: C, 80.00; H,8.25- CigH2^02 requires: 0,80.2^; H,8.51%) EXAMPLE 87 Ethereal methyl magnesium iodide (250 ml}!3M) was added to dl-3-methoxyoestra-l,3»5( 10) ,8-tetraen-17 -ol (30.0 g.) and heated . under argon to 165°; the temperature was kept between 166-170° for 2.5 nr. The mixture was cooled to room temperature and then the flask was immersed in a dry-ice acetone bath. Tetrahydrofuran (500 ml.) and ethyl acetate (300 ml.) were added, the bath removed and the mixture stirred to fully decompose it. Water (100 ml.) and saturated ammonium chloride solution (*t00 ml.) and filute acetic acid were added to neutrality. The mixture was extracted with ethyl acetate, the extract washed with water and saturated sodium chloride solution and ::..AHP-i 056-f then dried (Na,,SO^) . Filtration and removal of the solvent in vacuo gave a residue which, was treated in hot tetrahydro-furan, with Nuchar charcoal, filtered through super eel and the solvent removed in vacuo. Crystallisation from chloroform gave dl-oestra-l,3,5(10) ,8-tetraene-3,17 -diol (17.5 g) m.p.21^-216° .

EXAMPLE 88 dl-3-Methoxy-13-ethylgona-l,3,5( 10) ,8-tetraen-17P-ol ( .O g) was covered with ethereal methyl magnesium iodide (^00 ml?3M) and heated under argon to 160° (oil bath). The oil bath temperature was kept at 160 -165° for 3 hours, and the mixture allowed to cool to room temperature. The flask was immersed in a dry-ice-acetone bath, and then tetrahydrofuran (500 ml.) and ethyl acetate (500 ml.) were added. The bath was removed and the mixture stirred until decomposition was complete. Water, 10% ammonium chloride solution (500 ml.) and dilute acetic acid were added to neutrality. The mixture was extracted with ethyl acetate, and the extract washed with saturated sodium bicarbonate solution, water and the saturated sodium chloride solution and then then dried . Filtration and removal of the solvents in vacuo gave a residue which was triturated with ether. Filtration gave the crude product (35.5 g) m.p,177-l80° a sample (2.00 g) of which in tetrahydrofuran, was treated with Nuchar charcoal, filtered through super eel and the solvent replaced with isopropanol. The resulting crystalline solid was filtered to give dl-13-ethylgona-l,3,5(10) ,8-tetraene-3, ^-diol (1.78 g) as the isopropanol solvate; m, p.118-120° (loss of isopropanol) then l83-l8*f0;IR: 3310, 3l60; UV: 270 (15000) . (Found: C,76.58; H,9.07. c1Q 2 °2' C3H8° re¾uires C,76.70? Η.9.3Φ .

EXAMPLE 89 d(-)-3-Methoxyoestra-l,3,5(10) ,8-tetraen-17 -ol (15=0 g.) was covered with ethereal methyl magnesium iodide (l60 ml:3-M) and heated- under argon to 165° (oil-bath). The oil-bath tempera-ture was kept at 165-170° for 3 hr. and then was; cooled to room temperature. The flask was cooled further by immersion in a dry-ice-acetone bath and then tetrahydrofuran and ethyl acetate were added. The bath was removed and the mixture stirred until the product was decomposed. Water, saturated ammonium chloride solution, and dilute acetic acid were added to neutrality. The mixture was extracted with ethyl acetate, the extract washed with water and saturated sodium chloride solution and then dried (Νβ2≤0ί+) . Filtration and removal of the solvent in vacuo gave a residue which, in chloroform, was allowed to stand until fully crystallised.

Filtration gave the crude product (1^.0 g) m.p.115-121° (loss of chloroform), a sample (1,5 g) of which,in tetrahydrofuran, was treated with Nuchar charcoal, filtered through super eel and the solvent replaced with ethanol by boiling. The solution was diluted with an equal volume of water, scratched and allowed to stand to crystallise. Filtration gave solvated d-oestra-li3,5(i0) 8-tetraene-3, g) mVp.135-139° .'"(loss fof water)'ϊ=®ίί≥7&<ΐΛί9∞Ύϊί<£} V;0. •(C^l,diqxane) . (Found,: ,,?8. 9; 'H,8;2 i. ¾¾2¾ 1/6'·Ι¾0 requires C,78.91; H,8.2*»#).

EXAMPLE 90 dl-3-Methoxyoestra-l,3,5(l0) ,8,l^-pentaen-17 -ol (5.00 g.) was covered with ethereal methyl magnesium iodide (3 M) and the mixture heated under argon to 170° (oil-bath). The oil-bath temperature was kept at 170° for 2.5 hr. and then cooled to room temperature. The flask was cooled further by immersion in a dry-ice-acetone bath.

Tetrahydrofuran and ethyl acetate were added and then the bath removed. After stirring to decompose the product, water, saturated ammonium chloride solution and dilute acetic acid added to neutrality.

.. The mixture, .was extracted wit ethyl acetate, the extract washed .with water and saturated sodium chloride solution and then dried Filtration and removal of the solvent in vacuo gave a residue which, in methanol, was allowed to 'stand to fully crystallise. Filtration gave, as a methanol solvate, ^~oestra-l,3,5(lO) ,8,l^-pentaene-3 7P^diol (2.07 g.) m.-p. 110-113° (loss of methanol); UV: 311 EXAMPLE 91 dl-Oestra-l, 3,5(10) ,8, l^pentaene-3,17 -diol (1.50 g.). in tetrahydrofuran (25 ml.) was added to pre-hydrogenated 2% palladium ■ on calcium carbonate (0.50 g.) and tetrahydrofuran-ethanol (50-10 ml.) and treated with hydrogen until uptake of the gas was complete « The mixture was filtered through super eel, the solvents removed in vacuo and the residue, in tetrahydrofuran, was treated with Nuchar charcoal, . filtered through super eel and the solvent removed in vacuo i The resulting oil, in ether, was allowed to stand to fully crystallise.

The resulting pripms were filtered to give dl-oestra-l,3»5(lO) ,8- tetraene-3,17P-diol (0.69 g.) m. p.210-213°; UV: 276 (13,600) .

EXAMPLE 92 ' '..'-·■ dl-3-Methoxyoestra-l,3,5(lO)-triene-8,17 -diol (3.00 g)was ^covered with ethereal methyl magnesium iodide (50 ml;3M) and the mixture heated under nitrogen to 165° (oil-bath). The oil-bath was kept at 165-170° for 2.5 hr. and was then cooled to room temperature. The mixture was cooled further by immersing the flask in a dry-ice-acetone bath . and then tetrahydrofuran ( 100 ml. ) and ethyl acetate (100 ml.) were ■ added. The bath was^ removed and the mixture stirred until decomposition was complete. Water (50 ml.), and saturated ammonium chloride (200 ml.) were added and the mixture extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and then dried (Na^SO^) . Filtration and removal of the solvents in vacuo V. gave a residue which, in warm tetrahydrofuran, was treated with Nuchar charcoal, filtered through super eel and the solvent removed in vacuo » The residue was crystallised from chloroform to give the crude product (1„ 15 g) m»p0221-225° , which, in boiling methanol-tetrah'ydrofuran (1: 1) , was filtered hot through s per eel, the solution boiled to low volume and allowed to stand to deposit dl-oestra-1 ¾ 3 ,5 ( 10) -triene-38V 17 -triol (0„65 g) m.p0 25^-256°; IH: 3390, 3200.

(Found: C, 75.03; H,8„15o Η,δ.,39%) EXAMPLE 93 /"' was covered with ethereal methyl magnesium iodide (60 mis 3M) and heated under nitrogen to 165° (oil bath) „ The mixture was kept at 165-170° for 2 hr. and was then cooled to room tempera-ture. The flask was cooled further by immersion in a dry-ice-acetone bath. Tetrahydrofuran and ethyl acetate were added, the bath removed and the mixture stirred until decomposition was complete. Water, ammonium chloride solutio and dilute acetic acid were added to neutrality. The mixture was extracted with ethyl acetate, the extract washed with water and saturated sodium chloride solution and then dried (Na2S0^) „ Filtration and evaporation of the solvent in vacuo gave a residue whicfr in tetrahydrofuran, was treated with Nuchar charcoal, filtered through super eel and the solvent removed in vacuo» The oil was crystallised to give dl-oestra-l,3,5(lO) ,7-tetraene-3,17P-diol (3o60.g). m„p.213-5°? IR: 3*+10, 31^0 EXAMPLE ΟΛ \ dl-3-Methoxy-.l3»ethylgor)a~1 ,3 ,5( 10) 97»tetraen-17P-ol (3«δ5 go) was covered with ethereal methylmagnesium iodide (50 ml0 3M) and heated under argon to 165° (oil bath). The oil-bath was kept at 165-170° for 3 hre. and then the mixture was cooled- to room temperature.. " The'-flask was cooled further by immersion in a dry-ice-acetdne bath and then tetrahydrofuran (100 ml„ ) and ethyl acetate (60 mle) were added, ¾e bath was removed and the mixture stirred until decomposition was complete,, Ethyl acetate (60 mle), water (50 ml.), saturated ammonium chloride solution (100 ml.) and dilute acetate acid was added to neutrality., ¾e mixture was extracted with ethyl acetate, and the extract washed with water and saturated sodium chloride solution and then dried Filtration and removal of the- -solvent in vacuo gave a residue, which, ;¾j tetrahydrofuran,?was treated with uchar charcoal, filtered thfeugh super eel and the solvent removed in vacuo„ The residue was crystallised from isopropanol to give dl_l3_ethylgona- s 55( '10) ,7-tetraene-3il7 -" iol (2e86. ge). m.pe 212-216°0 The analytical sample (from isopropanol), isolated as an isopropanol solvate, had n po 218-220°; IR: 3370, .3160 (Found: C, 77.11 ; H, 9°01 „ C^H^O^ C^HgO requires C, 76.70; H, 9 ;36 ) EXAMPLE 9 Ethereal methylmagnesium iodide (200 ml0; 3 M) was added to d-(+)-3-methoxyoestra-1 ,3 ,5( 10) ,7-'tetraen-17 -ol and the mixture was heated under argon (or other inert gas) to 165°« The temperature was kept at 165-170° for 3 hr. and the .mixture then cooled to room temperature, and then to -78° by immersion in V Al&a¾¾>56-f a dry-ice acetone bath. Tetrahydrofuran (^00 ml.) was added and the mixture partly decomposed; ethyl acetate (200 ml. ) was added and the bath removed. Stirring was continuous and the mixture warmed up and decomposed,, Small quantities of water ( 10-20 ml.) were occasionally added* using the dry. ice bath to keep the temperature well below room temperature. When the mixture was completely decomposed, saturated ammonium chloride solution and then dilute acetic acid solution were added to neutrality. The mixture was well extracted with, ethyl acetate,the extracted washed with water and with saturated sodium chloride and dried β Filtration and removal of the solvent in vacuo gave a residue which, in tetrahydrofuran, was treated with Nuchar charcoal and filtered through super cele' The solvent was removed in vacuo and the resulting oil, in chloroform, allowed to stand to crystallise (-10°) ; the white crystalline solid was filtered to obtain the crude product ( 12.3 i») m.p. 172-173° ; 0]D + 188° (C = 1 , dioxane). a sample of which in hot isopropanol, was diluted with water to give, as fine white needles, (d^(+)-oestra-1 ,3 ,5( 10) ,7-tetraene-3, 17Prdiol (d(+)-17 -dihydroequilin), m.p. 17^- 7 ° ; [α]^+ 211° (C = 1 , dioxane^; IE ■ 33^0 , 3180, UV: 222 (8250) .

EXAMPLE 96 Ethereal methyl magnesium iodide; 60. ml.; 3M) was added to d-(+)_3-methoxyoestra-1 ,3 ,5( 10) ,7-tetraen-17 -ol, formate (3.00 g. ) and heated under argon (or other inert gas) to 165°. The . temperature was kept at 16 -1 0° for 3 hr. The mixture was cooled to room temperature, and then to -78° by immersion in a dry ice-acetone bath. Tetrahydrofuran (100ml.) was added, the mixture stirred and then treated with ethyl acetate (60 ml.) After removal of the bath, stirring was continued as the mixture warmed up and decomposed. Small quantities^ of water were added from time to time to speed up the decomposition, using the cold bath to keep the temperature well below room temperature. When decomposition was complete, water (50 ml.) and then saturated ammonium chloride solution (100 ml.) and dilute acetic acid were added to neutrality. The mixture was extracted with ethyl acetate, the extract washed with water and saturated sodium chloride and then dried (N&^SO^), Filtration and removal of the solvent in vacuo gave an oil which, in tetrahydrofuran was treated with Nuchar charcoal and filtered through super cel. ¾e solvent was removed in vacuo, the yellow oil, in chloroform was allowed to stand to give, as a white crystalline solid ά-(+)-οβ3^-1,3,5 0),7-ΐβΐΓΒβηθ-3,17β-άίο1[ά(+)- 7 -ά^άΓοε¾^ϋη] (1.55 g.) m.p. 170-172°; [oc]^ + 195° (C = 1, dioxane) and second crops of O.50 g; m.p. 165-169°.

EXAMPLE 97 dl-Oestra-1 ,3,5(10) ,7-tetraene-3,17 -diol (3. 2 g.) in methyl ethyl ketone (60 ml.) and benzene (100 ml.) were refluxed under a water separator for 1 hr. and 10 ml. of distillate removed.

Aluminium isopropoxide (3.0 g. ) was added and refluxing continued for 3·5 hr. The mixture was cooled to room temperature, water (100 ml. ) and dilute hydrochloric acid added until the pH was 6. replaced with isopropanol b boiling on a steam bath. The solution was seeded and allowed to stand at 10° to fully crystallise. Filtration gave as white plates, d-(+)-3- hydroxyoestra-1 ,3,5(10) ,7-tetraene-17-one [d(+)-equilin] (5.08 g.) m.p. 236-239°; IR: 3300, 1720 [o]^ + 282° C = 1 dioxane). ¾e mother liquors from above deposited a total of 1.27 g. of second crops which upon purification as above gave a further 0.6^ g. of d(+)-equilin; m.p. 232-23^°.

EXAMPLE 100 d(+)-3-Hydroxyoestra-1,3,5(lO),7-tetraen-l7-one (2.00 g.) was added to sodium methoxide (0.60 g.) in absolute ethanol (30 mli) Cyclopentyl bromide (2.5 g. ) was added and the solution refluxed for 2 hr. The mixture was cooled to' room temperature, and water and ethyl acetate added. Filtration gave the crude product (0.91 g*). More crude product was obtained from the filtrate by washing the organic layer with water and saturated sodium chloride solution, drying (Na2S0^) filtering and evaporating the solvent in vacuo. The combined solids, iA methylene chloride Were treated with Nuchar charcoal and filtered through super eel, The solvent wa,3 replaced with isopropanol by boiling, cooled and allowed to stand to fully crystallise. Filtration gave d-(+)-3-cycloptentyloxyoestra-1 ,3,5(10) ,7-tetraen-17-one (1.70 g.), m.p. 190-192°¾ IR: 1?25; [a]2^ + 2^7° C = 1, Chf).

(Found: C, 82.1^ H, 8.7L O^^O^ requires C, 82.10; H, 8.356 · EXAMPLE 101 dl-3-Hydroxy-l3-ethylgona- ,3,5(10) ,7-tetraen-17-one (½.00 g.) was added to sodium methoxide (1.00 g.) in absolute ethanol (100 ml.).

Cyclopentyl bromide (5.0 g.) was then added and the mixture refluxed for 5 hr. and then cooled to room temperature. Water (300 ml.) was added and the mixture extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solutiin and then dried (NaSO^). Filtration and removal of the solvent in vacuo gave an oil which, in benzene, was passed through a column of 0.¾silver nitrate impregnated alumina; the solvent was removed in vacuo and the residue, in methylene chloride, treated with Nuchar charcoal, filtered through super eel and the solvent replaced with isopropanol by boiling. Cooling and standing caused the deposition of dl-3-cyclopentyloxy-13-ethylgona- 1,3»5(lO) ,7-tetraen-l7-one (2.00 g.); m.p. 13^- 36°. IR: 1730 . (Found: C, 82.25; H, 8.90. Q2^QQZ requires C, 82.2V, H, 8.63#) .

EXAMPBE 102 dl-0estra-1 ,3«5(l0) t8-tetraene-3,17P-diol (5.00 g.) was added to sodium methoxide (1.50 g.) in absolute ethanol (100 ml.) and then cyolopentyl bromide (5.0 g.) was added. After refluxing for 2 hr. <·.''.· the mixture was cooled, the ethanol removed in vacuo and the residue decomposed with water and ethyl acetate. The extract was washed with Water and saturated sodium chloride solution and them dried ,^a.^>0^).

After filtration and removal of the solvent in vacuo, the residue, in methylene chloride, was treated with Nuchar charcoal, filtered through super eel and the solvent replaced with isopropanol by boiling; Cooling and standing caused the deposition of the prude product (½.3 g.) m.p. 117-121°, a sample (1.00 g.) of which, in methylene chloride, was subjected to the above purification procedure - . to obtain solvated dl-3-cyclopentyloxyoestra-1 ,3«5(1Q) .8-tetraen-l7P-ol (O.80 g.); m.p. 12^-126°; IR: 3360; UV: 2?8 (17,800) . (Found: C, 79.97 ; H, 8.92. C^H^^. ¾ C^igO requires< C, 79.8^ H, 9.30#) .

EXAMPLE 03 Through dl-3-methoxyoestra-1 ,3 ,5(10) ,7-tetraen- 7-one ·0 g» ) in dimethylacetamide (75 ml») was bubbled purified acetylene ,the solution was saturated lithium acetylide-ethylene-diamine ( 1.0 g. ) was added and the mixture stirred under acetylene for hr. Another charge of lithiun acetylide-ethylehediamine (1 »0 g.) was added and stirring continued overnight. The mixture was poured into water, extracted with ether and the extract washed with water, dried , filtered and the solvent removed in vacuo, to give a residue which, in benzene was filtered through a column of Florex XXS , the solvent evaporated in vacuo and the residue crystallised from methanol to obtain dl-3-methoxy-17 EXAMPLE 0^ Acetylene was bubbled through dl- 3-methoxy- 3-eth.ylgona-1 ,3,5(1.0) ,7-tetraen-l7-one (2.0 g.) in dimethylacetamide (50 ml.) until it is saturated (0.5 nr.) Lithium acetylide-ethylenediamine (1.0 g.) was added and the mixture stirred under acetylene for 5 nr. at room temperature. After standing overnight, the mixture was poured into water, extracted with ether, the extract washed with - - water and then dried (Na^SO^). After filtration and evaporation of the solvent in vacuo, the residue was crystallised from methylene chloride-hexane to give dl-3-methoxy-l3-ethyl-17a-ethynylgona-1 ,3,5(10) ,7-tetraen-17P-ol (0.875 g.); m.p. 1i8-151°5 IR: 3^10, 320. The analytical sample (from isopropanol-hexane) had m.p. 153-155°· (Found: C, 81.61 ; H, 7.85. C22H26°2 re1uires: c> 81.95; H, 8,13$).

EXAMPLE 105 d-3-Cyclopentyloxy-oestra-1 ,3,5(10)-7-tetraen-17-one (2.00g.) in dimethylacetamide (50 ml.) was saturated with acetylene. Lithium acetylide-ethylenediamine (1.0 g.) was added , the mixture stirred under acetylene for 5 hr. at room temperature, poured into water, extracted with ether and the extract washed,dried (Na^SO^) , filtered and the solvent evaporated in vacuo. The residue was crystallised from benzene-hexane to obtain d-3-cyclopentyloxy-17arethynylestra-1 ,3,5(10) ,7-tetraen-l7P-61.

EXAMPLE 106 -3-Cyclopentyoxy-l3-ethylgona-1 ,3,5(10) ,7-tetraen-l7-one (3.OO g. ) in dimethylacetamide (75 ml.) was saturated with acetylene and then, treated with lithium acetylide-ethyleitediamine (2.0 g. ).

The mixture was stirred under acetylene overnight at room temperature poured into water, and the extract washed, dried, filtered and the solvent evaporated in vacuo. The residue was crystallised from benzene-hexane to obtain dl-3-cyclopentyloxy-13-ethyl-17x-ethynyl-gona-1 ,3,5(10) ,7-tetraen-l7P-ol.

EXAMPLE 107 dl-3-Methoxy-l7a-ethynyloestra-1 ,3,5(10) ,7-t.etraen-l7P-ol (0.50 g.) in benzene (30 ml.) was added to pre-hydrogenated 2% palladium oxide on calcium carbonate (0.20 g.) and benzene (25 nil.) and was treated with hydrogen until uptake of the gas was AEE fp5 -f complete. After filtration and removal of the solvent in vacuo the residue was crystallised from methanol to give dl-3-methoxy-l7a-ethyloestra-i ,3 ,5(10) ,7-tetraen-1? -ol (θ 6θ g.); m.p. 167-169°; IR: 3390. (Found: C, 80.29; H, 8.93. C21H28°2 requires: C, 80.735 H, 9*03%).

EXAMPLE 08 ^-3-Methoxy-13-ethyl-l7a-ethynylgona- ,3 ,5(10) ,7-tetraen-17β-ο1 (0.515 g.) in benzene (50 ml.) was added to a pre-hydrogenated 2% palladium oxide on calcium carbonate (0.20 g.) and benzene (25 ml.) and treated with hydrogen until uptake of the gas was complete. After filtration and removal of the solvent in vacuo, the residue was crystallised from methanol to give ^-3-methoxy-13 t 17a-diethylgona-1 ,3 ,5( 10) ,7-tetraen-17 -ol (0.Ή g.) m.p. 130-1320·, IRL 3^0. (Found: C, 80.765 H, 9. . C22H30°2 requires C, 80.93 ; H, 9.26#) .

EXAMPLE 109 d-(+)_3-.Methoxyoestra- ,3 ,5( 10) ,7-tetraen-17P-ol (0 3 g.) in dimethylsulphoxide (6 ml.) and acetic anhydride ( 2ml. ) was allowed to stand overnight. The mixture was poured into water, and the resulting precipitate filtered and air-dried. The solid, in benzene, was passed through a column of 10$ silver nitrate-impregnated alumina. The benzene was removed in vacuo the residue, in methylene chloride, was treated with Nuchar charcoal and the mixture filtered through super cel. The solvent Was replaced with absolute ethanol by boiling, and the mixture cooled and allowed- to stand to cmppfcte crystallisation. Filtration gave the crude product (0.24 g. ) m.p. 156-158°, which was re- A o5 - erystalllsed from methanol to obtain d(+)-3-methbxyoestra-1.3»5(10),7-tetraen-17-one (0.2G g.) m.p. 1 9-161°; IR: 1735? Co]^ + 277°(C = 1, Chf.).

Claims (9)

1. HAVING NOW particularly described and ascertained the nature of our aald invention and in what manner the same is to be performed, we declare that what we claim is: ^ ■ N 1. A process for preparing 13-alkylgona-l , 3,5(10) ,7- tetraenes which comprises the sequence of. reactions including: (a) oxidising a 3-Y-13-alkylgona-l, 3,5(10) ,8-tetraene to a 3-Y-8,9-epoxy-13-alkylgona-l,3,5(10)-triene, (b) opening the epoxide ring to form a 3-Y-8-hydroxy- 13-alkylgona-l, 3 , 5 ( 10 ) , 9 ( 11)-tetraene , (c) selectively catalytically hydrogenating the 3-Y-8- hydroxy-13-alkylgona-l,3,5(10) ,9(ll)-tetraene to give a 3-Y-8-hydroxy-13-alkylgona-l,3,5(lO)-triene, and (d) dehydrating the 3-Y-8-hydroxy-13-alkylgona-l,3,5(10)- triene across the 7i8-positions to give a 3-Y-13-alkylgona- 1, 3 , 5 ( 10 ) , 7-tetraene, where Y is an activating group capable of activating the benzenoid ring A for electrophilic aromatic substitution.

2. A process for the preparation of ε steroid compound of struc 1 . where R is hydrogen or an alkyl groupjR is an alkyl group, Y is hydrogen or a group which is ortho-para directing in electrophilic aromatic subsitution, X is a carbonyl ketalised carbonyl, (including hemithio- ketalised and thioketalised carbonyl), 2 R is an unsubstituted alkyl, alkenyl or alkynyl the essential character of an unsubstituted alkyl, alkenyl or alkynyl group, and is a hydroxy or acyloxy group, the dotted line represents a 2',3'-epoxybutylene group, a 3,-hydroxybut-l'-enylene group, a ' -hydroxybutylene group or a but-3'-enylene group, and the hydrogen atom in the 9-position, where present, is in the cc-configuration, in which a gona-l,3,5(10) ,8-tetraene is oxidised to give an 8,9-epoxygona-l,3»5(10)-triene of structure (A), and if desired the epoxy group of the 8,9-epoxy-gona-l, 3,5(10)-triene is opened to give an 8-hydroxygona-l, 3,5(10) ,9(lD-tetraene of structure (A), and then, if desired, the compound so produced is selectively hydrogenated to give an 8-hydroxygona-l,3,5(10)-triene of structure (A), and then, if desired, the compound so produced is dehydrated to give a gona-l,3,5(10) ,7-tetraene of structure (A); and where the product of any of the above reactions has a group X or Y other than that desired, the desired group X or Y is formed by a subsequent operation. A process according to Claim ί in which Y is a hydroxy or alkoxy group or other group capable of activating the benzenoid ring A for electrophilic aromatic substitution. A process according to Claim 3, in which Y is an acyloxy group. A process according to Claim 3 n which Y is a methoxy or acetoxy group. A process according to any one of the preceding claims in which the oxidising agent is an aryl-percarboxylic acid. A process according to Claim 6, in which the arylr-percarboxylic acid is m-chlor¾erbenzoic acid. A process according to any one of claims 1 to 5 in which the oxidising agent is an alkyl percarboxylic acid. A process according to any one of Claims 1 to 7 in which the oxidation product is a compound where Y is a carboxylic acyloxy group and is subsequently hydrolysed to give a compound where Y is a hydroxy group. A process for the preparation of a steroid compound 1 of structure (A) where R,R » Y and X are as defined in Claim 2 and the dotted line represents a 3' -hydroxy-but-1' -enylene group in which the epoxy ring of a 8,9-epoxygona-l,3i5(10).-triene of structure (A) is opened; and where the product has a group X or Y other than that desired, the desired group X or Y is formed by a subsequent operation. A process according to any one of Claims 1 to 5 and 10,in which the epoxy ring is opened by contacting the 8,9-epoxygona-l,3i5(10)-'triene with an organic carboxylic acid. A process according to Claim 11, in which the organic carboxylic acid is benzoic acid. A process for the preparation of a compound of structure (A) where R,R-, Y, X and the dotted line are as defined in Claim 9i in which a gona-1,3»5(10) ,8-tetraene of structure (A) is epoxidised and the resulting epoxy ring is opened in one stage. A process for the preparation of a compound of structure (A) where R,R , Y, X and the configuration of the hydrogen atom in the 9-position are as defined in Claim 2 and the dotted line represents a 3' -hydroxybutylene group, in which a 8-hydroxygona-l,3,5(lO) ,9» (ll)-tetraene of structure (A) is selectively hydrogenated, and where the product has a group X or Y other than that desired, the desired group X or Y is formed by a subsequent operation. A process according to any one of Claims 1 to 5 and l , in which the selective hydrogenation is carried out in the present of a palladium on carbon catalyst. A process according to any one of Claim 1 to 5i Ik and 15, in which the hydrogenation product is a compound where X is a hydroxymethylene group and is subsequently esterified to give a compound where X is an acyloxymethylene group. A process according to any one of Claims 1 to 5» Ik and 15 in which the hydrogenation product is a compound where Y is an alkoxy group and is subsequently de-etherified to give a compound where Y ix a hydroxy group. A process according to any one of Claims 1 to 5» and 15, in which the hydrogenation product is a compound where Y is a hydroxy group and X is a hydroxymethylene group and is subsequently esterified to give a compound where Y is an acyloxy group and X is an acyloxymethylene group. ΑΗΡ-^056-ί1 19* A process for the preparation of a compound of 1 structure (A) where R, R , Y, X and the configuration of the hydrogen atom in the 9-position are as defined in Claim 2 and the dot¾∑ed line represents a but-3' -enylene group, in which a 8-hydroxy- gona-l,3,5(10)-triene of structure (A) is dehydrated, and where the product has a group X or Y other than that desired, the desired group X or Y is formed b a subsequent operation. 20. A process according to any one of Claims 1 to 5 and 19 in which the dehydration is carried out with an acyl halide in an alcohol or with an alkane sulphonyl halide in an organic base. 21. A process according to Claim 20, in which the dehydration is carried out with acetyl chloride in methanol. 22. A process according to Claim 20, in which the dehydration is carried out with methane sulphonyl chloride in pyrid^. 23· A process according to any one of Claims 1 to 5» 19, 20 and 22, in which the dehydration is carried out with an alkane sulphonyl halide on a gona-1,3» 5(10)-trien-8, 17-diolto give the corresponding gona-1 ,3,5(10) ,7-tetraen-1?-ol, alkane sulphonate. 24. A process according to any one of Claims 1 to 5 and 19 to 22, in which the dehydration is carried out on a 17-ethylgona- ,3t5(lO)-trien-8,17-diol to give the corresponding 17-ethylidenegona-1 ,3»5(10) , 7-tetraene. 25» A process according to any one of Claims 1 to 5 » 19 »20 and 22 , in which the dehydration is carried out with an alkanesulphonyl, halide on a gona-1 ,3» 5( 10)-trien-3»8, 17-triol to give the corresponding gona-1 ,3»5( 0) ,7-tetraene-3, 17-diol,di-alkanesulphonate. 26. A process according to an one of Claims 1 to 5 and 19 to 23, in- which the dehydration product is a compound where X is a carboxylic acyloxymethylene group or an alkanesulphonated hydroxymethylene group and is subsequently reduced to give a compound where X is a hydroxymethylene group 27· A process according to any one of Claims 1 to' 5 » 20 and 21 , in which the dehydration product is a compound where X is a carboxylic acyloxymethylene group and is subsequently hydrolysed to give a compound where X is a hydroxymethylene group. 28. A process according to any one of Claims 1 to 5 and 9 to 22, in which the dehydration product is a compound where X is a carbonyl group and is subsequently reduced to give a compound where X is a hydroxymethylene group„ 29. A process according to any one of Claims 1 to 5 and 19 to 25, in which Qehydration product is a compound where Y is an alkoxy group and .is sub- . sequently de-etherified to give a compound where Y is a hydroxy group. 30. A process according to any one of Claims 1 to 5 i 19 to 22 , in which the dehydration product is a compound where X is a hydroxymethylene group and AHP-4056-fl is subsequently oxidised to give a compound where X is a carbonyl group,, '**-·■ 31 . A process according to any one of Claims 1 to 5 » 19 ,20,21 and 25 , in which the dehydration product is a compound where X is a alkanesul- phonated hydroxymethylene group and Y is an alkanesulphonated hydroxy group and is subsequently reduced to give a compound where X is a hydroxymethylene group and Y is a hydroxy group, 32. A process according to any one of Claims 1 to 5 and 19 to 21 , in which the dehydration product is a compound where X is a carboxylic acylqmy- methylene group and Y is a carboxylic acyloxy group and is subsequently hydrolysed to give a compound where X is a hydroxymethylene group and Y is a hydroxy group. 33· A process according to any one of the preceding 1 claims, in which R is a lower alkyl group having up to 5 carbon atoms0 3^. A process according to any one of the preceding 1 claims, in which R is a methyl groupe 35· A process according to any one of Claims 1 to 33» 1 in which R is an ethyl group. 36. A process according to any one of the preceding claims, in which R is hydrogen or a methyl group. 37· A process according to any one of the preceding claims, in which the starting material is the d-isomer. AHP-½56-fl 38. A process for preparing a steroid compound according to Claim 2 , substantially as described herein and shown with reference to any of Examples 1 to JO, 32 to 46 and 49 to 59· of formula A as' defined in Claim 2 39· A steroid compound/whenever obtained by a process according to any preceding claim or its obvious chemical equivalents o 40. A process according to any one of Claims 1 to 8 in which the oxidation product is a compound where X is a carbonyl group and is subsequently reduced to give a compound where X is a hydroxy- methylene group- 41 . A process according to any one of Claims 1 to 8 in which the oxidation product is a compound where Y is an alkoxy group and is subsequently dealkylated to give a compound where Y is a hydroxy group« 42. A process according to Claim 41 , in which the demethylation is carried out with a Grignard reagent provided that other functional groups which are irreversibly changed thereby to an unwanted group are not present. 43o A process according to Claim 42 , in which the reaction product is worked up by a process comprising quenching the reaction mixture at a low temperature. i AHP-i+056-fl A modification of the process of Claim 2 for the preparation of a steroid compound of η where R is hydrogen or an alkyl group, R is an alkyl group, Y is hydrogen or a group which is ortho-para-directing in electrophilic aromatic substitution, X is a carbonyl, -methylene ketaiised carbonyl, ethylidene', hydroxymethylene , acyloxymethylene, alkane sulphonyloxymethylehe . " \: 2 f."5 - or acyloxy-meth ^ e .·.·. ':. ""CR ~ » or an organj^ydroxym^b^^^oup,.,^^ group of th© formula/ where R 2 is an unsubstituted alkyl, alkenyl or alkynyl group or a substituted alkyl, alkenyl or alkynyl group having the essential character of an unsubstituted alkyl, alkenyl or alkynyl group and ^ is a hydroxy or acyloxy group, the dotted line represents a 2' ,3' -epoxybutylene group, a 3'-hydroxybutylene group or a but-3'-enylene group and the hydrogen atom in the exposition, where present, is in the a-configuration, in which a gona-1 ,3»5(10) ,8-tetraene is oxidised to give an 8t9-epoxygona-1,3i5(10)- triene of structure (A); and if desired the epoxy group of the 8,9-epoxy gona- ,3»5( 10) -triene is opened by reaction with a metal hydride to give an 8-hydroxygona-1,3,5(10)-triene of structure (A) in one step and then if desired, the compound so produced is dehydrated to give a gona-1 j3f5(10) ,7-tetraene of structure (A); and where the product of any of the above reactions has a group X or Y other than that desired, the desired group X or Y is formed by a subsequent operation. A process for the preparation of a compound 1 of structure (A) where R, R , Y and X and the configuration of the hydrogen atom in the 9-position are as defined in Claim 2 and the dotted line represents a J'-hydroxybutylene group in which an 8,9-epoxygona-1 ,3,5(10)-triene of structure (A) is reduced with a metal hydride and where the product has a group X or Y other than that desired, the desired group X or Y formed by a subsequent operation. A process according to Claim k or Claim k$ in which the reduction is with an alumino-hydride. A process according the Claim 19 in which the dehydration is carried out with an alkane-sulphonyl chloride in pyridine and a dialkyl formamide whereby a free hydroxy group present is converted to a formyloxy group. A process according to Claim k in which the formyloxy group is hydrolysed to a hydrox group. ^9· A process according to any one of Claims 1 to 5 and 10 to 25 in which the dehydration product is a compound where Y is a hydroxy group which is subsequently esterified or etherified to give a compound where Y is an ester or ether group. 50. : A process according to Claim 29 in which the de-etherification is carried out with a Grignard reagent provided that other functional groups which are irreversibly changed thereby to an unwanted group are not present. 1. A process according to Claim 50 in which the reaction product is worked up by a process comprising quenching the reaction mixture at a low temperature. 5?. A process according to Claim 50 or Claim 51 in which the dehydration product is a compound where Y is an ether group and X is a formyloxy- methylene group in which demethylation is accompanied by deformylation to give a compound where X is a hydroxymethylene group and Y is a hydroxy group. 53» A process according to any one of Claims 19 to 25 in which the dehydration product is a compound where X is a carbonyl group or is a group converted to such groups which is subsequently reacted with an organo-metallic reagent to introduce a group H 2. 5^. A process according to Claim 53 in which the group R 2 is an alkyl, alkynyl or haloalkynyl group. ΛΗΡ- 056-fl 28190/2 t 2 55· A process according to Claim 3 in which the group R is subsequently reduced by catalytic hydrogenation. 5β. A process according to Claim 30 in which the oxidation is conducted with dimethyl sulphoxide-aceti anhydride· 7· Λ process for preparing a steroid compound according to Claim 2 substantially as described herein and shown. with reference to any one of Examples 61 to 89 and 9 to 109· 58. A steroid compound of formula A as defined in Claim 2 whenever obtained by a process according to any one of Claims O to 57 or its obvious chemical equivalente 59· A steroid compound of structure (A) given in Claim 2 1 where R is hydrogen or a lower alkyl group, 8 is an alkyl group of up to carbon atoms, Y is a hydroxy group or an esterified or etherified hydroxy group, X is a carbonyl, ketalised carbonyl (including hemithioketalised carbonyl and thioketalised carbonyl) , ethylidene-methylene, hydroxy- methylene, acyloxymethylene, alkane-sulphonyloxymethylene or an organo-hydroxy or acyloxy methylene group of the 2 3 2 formula -CR R -, where R is an unsubstituted alkyl, alkenyl or alkynyl group or a substituted alkyl, alkenyl or alkynyl group having the essential character of an unsubstituted alkyl, alkenyl or alkynyl group, and R"^ is a hydroxy or acyloxy group, the dotted lines represents a 2 ' ,3'-epoxybutylene group, a 3f-hydroxybut-1 '-ejiylene group, a 3'-hydroxy-butylene group, or a but-3 ' -enylene group, and the hydrogen atom in the 9-position, where present, is in the a-configuration, R being an alkyl group having more than one carbon atom when the dotted line represents a but- 3·'—ethylene group and (a) Y is a hydroxy or an etherified or esterified hydroxy group and X is a carbonyl, ketalised carbonyl (including hem thioketalised and thioketalised carbony.1) or hydroxy-methylene group, or (b) Y is hydroxy , *.'·' and X is an ethynyl-hydroxymethylene group or (c) Y is acetoxy and X is an acetoxymethylene group or id) Y is rnethoxy and X is a rnethyl-hydroxymethylene group, 60* A steroid compound according to Claim 59, where Y is a hydroxy, alkoxy or acyloxy group. 61 . A steroid compound according to Claim 60 where the acyloxy group is an acetoxy group or a methanesulphonated hydroxy group. 62. A steroid compound according to any one of Claims 59 to 6 1 where R is a methyl group. 65. A steroid compound according to any one of Claims 59 to 61 1 where R is an ethyl group. 6'+. A steroid compound according to an one of Claims 59 to 65 where X is an ethylenedioxy-methylene group. 65· A steroid compound according to any one of Claims 59 to 63 where X is an acetoxymethylene group, formyloxymethylene group or a methanesulphonated hydroxymethylene group. 66. A steroid compound according to any one of Claims 59 to 65 2 where R is an unsubstituted alkyl, alkenyl or alkynyx group having up to 5 carbon atoms. 67. A steroid compound according to Claim 66 , where R is an 3 ethyl or ethynyl group and R is a hydroxy group. 68. A steroid compound according to any one of Claims 59 to 67, where R is hydrogen. 69· A steroid compound according to any one of Claims 59 to 61 and to 68 v/here R is an ethyl group and the dotted line represents a but~3'-enylene group. 70. 13p- thyl-5-methoxygona- , 3, 5(10) , 7-tetraene-'i7-one. 1 . 13p-Ethyl-3-methoxygona-1 ,3, 5(10) , 7-tetraen-17-one, ethylene ketal. - - 72. 13β ; 1 ~Diethyl-3-methoxygona-1 , 3 , ( 10) , , (20)- entaene. 73· 3-l'iethoxy-8a,9a-epoxy-oestra-1 7 . 8α, 'ί 7β-Dihydrcxy~3-methoxy-oestra--1 ,3, 5(10), 9(H)- tetraene. 75. 8α , 17P-Dihydroxy-3-methoxy-oestra-1 , 3 , 5 ( 0)-triene. 76. 8a , 7 -Dihydroxy-13 -ethyl-3-methoxy-gona-1 ,3,5( 0)- triene. 77. 13P-3tbyl-3-methox gona-1,3,5(l0) ,7-tetraen-17 -ol, 78. 13p-Ethyl-17a-ethynyl-3-methoxygona-1,3,5( O) ,7-tetraen- 17'β-οΐ. 79. 3-Methoxy-oestra-1,3,5( p),7-tetraen-17 -ol,17-acetate. 80. 3-Methoxy-oestra- ,3,5(10) ,7-tetraen-17P-ol,17-formate. 81. 13 -Ethyl-3-methoxygona-1,3,5(lO),7-tetraen-17P-ol,17- formate· 82. 13 -Ethyl-3-hydroxygona-1,3,5(lO) ,7-tetraen-17P-ol. 8

3. 3-Methoxy-oestra-1 ,3,5(10) ,7-tetraen-17 -oI, 17-methane sulphonate. 8

4. Oestra- , 3 , 5 ( 10)-triene-3 , 8α- 7β-ΪΓ ο1. 8

5. 13 -Ethyl-3-methoxygona-1,3,5(lO),7-tetraen-17-one, 17,17- ethylene ketal. 8

6. 13 -Ethyl-3- ydΓox gona-1 ,3,5(1 ),?-tctraen-1 -one. 8

7. 3-Cyclopentyloxy-oestra-1 ,3,5(10), 9(11)-tetraene-8a , 7β- diol. 8

8. 3-Cyclopentyloxy-13P-ethylgona-1 ,3,5(10) ,7-tetraen-17-one. 8

9. 3-0yclopentyloxy-17a-ethynyl-17P-hydroxy-13P-ethylgona- 1 ,3,5(10) ,7-tetraene. 90. A steroid compound as claimed in Claim 59 substantially as hereinbefore described and shown, particularly with reference to any one of Examples 1 to , 7 to 15, 17 to 30, 32 to o, 5, ½, 49, 55, 57 and 58. ΑΐΐΡ- ο56-η. 91. A steroid compound as claimed in Claim 59 substantially as hereinbefore described and shown, particularly with reference to any one of Examples 61 to 78, 80 to 82, ok , 85, 92, 98 , 101 , 103 to 108. 92. A steroid compound according to any one of claims 59 to 89 in which the compound is predominantly in the d-form. 93· A pharmaceutical preparation comprising a steroid compound claimed in any one of claims 39 and 58 to 92 in association with a pharmaceutically acceptable carrier. For the Applicants