IL38143A - Process for the preparation of 11,12-enolates of 9alpha-halo-11-keto steroids and of 9alpha,12-dihalo or 9alpha,12,12,12-trihalo 11-keto(or11-hydroxy)steroids - Google Patents

Abstract

1376123 #<SP>11</SP>-Enolates; 12-halosteroids RESEARCH INSTITUTE FOR MEDICINE & CHEMISTRY Inc 15 Nov 1971 [17 Nov 1970] 54671/70 Heading C2U The invention comprises (A) a process for the 11,12-enolization of a 9α-halo-11-oxosteroid having at least one 12-hydrogen atom, by treating it in a polar aprotic medium with a strong base; (B) a solution of a 9α-halosteroid- 11,12-enolate in a polar aprotic solvent; and (C) 9α,12,12-trifluoro-11-oxo and -11-hydroxysteroids. Thus a 9α-halo-11-oxo-12-unsubstituted steroid is converted by process (A) to a Na, K, Li or Mg enolate (the Li enolate being obtainable either directly with Buhi, or by treating an initially obtained Na enolate with LiCl, or by treating a corresponding enol ester with a lithium base). The enolate may be converted to (i) an enol ester by reaction with an acid derivative, e.g. benzoic anhydride; or (ii) an enol silyl ether by reaction, e.g. with Me 3 SiCl; or (iii) a 9α,12-dihalo-11-oxo steroid by reaction with Cl 2 , Br 2 , ClO 3 F or FOCF 3 . The 9α,12-dihalo-11-oxo steroid may be converted to (i) the corresponding 11-ol by reaction with, e.g. NaBH 4 ; or (ii) an enolate by process (A). The enolate may be acidified to give the 12-epimer of the initial 9α,12-dihalo- 11-oxo steroid, or may be converted by methods analogous to those described above to (i) an enol ester; or (ii) an enol silyl ether; or (iii) a 9α-halo-12,12-difluoro-11-oxo steroid. The latter may be reduced to the corresponding 11-ol and any protecting groups (e.g. 3-ketal, 3-enol ether and 17,20;20,21-bismethylenedioxy) removed. In the examples the starting materials for the above conversions are protected derivatives of 9α-fluorocortisone and 9α-fluoro-16α-methylprednisone. [GB1376123A]

Description

38143/3 PROCESS FOR THE PREPARATION OF 11 , 12-ENOLATES OF 9a-HAL0-l l -KET0- STEROIDS AND OF 9a, 12 OIHALO OR 9a, 12,12-TRIHALO 11 -KETO (OR 11 -HYDROXY) STEROIDS This invention is concerned with novel steroid enolates and processes for their preparation and their use as intermediates .

We have found that 11 , 12-enolates of 9a-halo-ll-keto-steroids can readily be prepared and, if necessary, isolated and further that these new compounds can serve as starting materials for a number of very useful synthetic procedures. The -new enolates may be prepared from the 9a-halo-ll-ketones by treatment with a strong base, in spite of the fact that they are oc-halo-ketones and would therefore be expected to undergo the Favorskii rearrangement with ring contraction or nucleophilic replacement of the halogen atom accompanied by transposition of the substituent from one side of the carbonyl group to the other.

The Tre enolates are preferably alkali metal enolates, more especially sodium, potassium or lithium enolates, or magnesium enolates, althoughany cation which is sufficiently electrophilic to form the enolate is suitable. As is explained below, the lithium and magnesium enolates are especially preferred due to their reluctance to undergo metathesis with keto groups in subsequent reactions and hence their avoidance of side-reactions and multiple products The 9cc-halo-ll-keto steroids are preferably 9a- chloro- and more preferably 9a-fluoro-steroids.

In addition to the 11-keto group, the steroid substrate may carry advantageously a 3-substituent which is convertible into a 3-keto group, for example an enol ether or ester group, a hydrazone or substituted hydrazone group, an oxime or alkoxime group, or a dialkylketal or cyclic ketal group such as a dioxolan group. Such groups can be converted into the 3-keto group, where this is required, by conventional means.

An unprotected 3-keto group may be present in conjunction with a 6-fluoro-1 ,4-diene system since the keto group does not then readily enolise.

If a 3-keto-l ,4-diene is used, a 1 , 3, 5-enolate is usually formed first but will rearrange to the 1 4 desired 11 , 12-enolate with regeneration of the Δ ' -3- keto system if the base is a sodium or potassium base and is added slowly to the steroid.

Double bonds may be present, for example at the 1, 2-, 3,4-, , 5- and/or 16 , 17-positions and alkyl groups, for example methyl groups, may be present at the 6- and/or 16-position, (in the a- or β-configuration) , or in the 10- or 13-position. Halogen atoms may be 12,-present at the 6-j or 16-position. The 17-position may carry a keto group or alternatively a hydrogen atom, a hydroxyl group or an acyloxy group together with a hydrogen atom or an aliphatic group, preferably with 1-8 carbon atoms, which may, for example, carry one or more keto and/or hydroxy or acyloxy substituents , provided that any hydroxy groups or keto groups are protected, for example as esters or ethers or as ketals, hydrazones, or dioxolans respectively. The corticoid side chain ( 17a-hydroxy-17p- hydroxyacetyl) is especially valuable and may advant¬ ageously be protected by a bis-methylene dioxide grouping or the formation of 17 , 21-diesters or orthoesters. Where esters of hydroxyl compounds are used, these are preferably derived from aliphatic acids having 1-6 carbon atoms, e.g. acetic or propionic acid, or aromatic acids such as benzoic acid. Hydrazone derivatives include, for example, dialkyl hydrazones such as dimethylhydrazone , or semicarbazide . Alkoximes include for example, methoximes.

The new enolates may be prepared by 11,12- enolisation of a corresponding 9a-fluoro-ll-keto steroid by treatment in a polar, aprotic medium with a strong base, for example an alkali metal hydride, aralkyl amide -aluminium-hydride ,- amide , -alkylamide / silyla ide , an alkali metal acetylide or substituted acetylide, &lkyl or amine-sol vated al l al i metal mcrdiiirerd/ alkyl . A sodium or potassium triarylmethy1 can also be used where the 3-keto-A 1 ' 4-system is present; in that case alkali metal exchange with the 11-keto group yields the desired 11 , 12-enolate . Such reagents do not, however, normally form an 11, 12- enolate directly. The strong base should, of course, be a stronger base than the desired enolate; that is the protonated derivative from which the base is derived, for example an amine or acetylene, should be a weaker acid than the enol form of the 11-ketone.

The alkali metal base may, for example, be a sodium, potassium or lithium derivative. In aral fcyl amides alkylamides,br alkylsilylamides the amine portion 1 2 1 2 can be defined as NR R where R and R , which may be the same or different, are alkyl groups or trialkyl- silyl, triaralkyl or triarylsilyl groups. The alkyl groups in such compounds advantageously have 1-6 carbon atoms and may, for example, be methyl, ethyl, propyl or hexyl groups.

Branched alkyl groups such as isopropyl groups are preferred in the alkylamides. Aralkyl groups are preferably monocyclic groups with 1-6 carbon atoms in the alkyl portion, for example benzyl or phenethyl groups. Aryl groups are preferably monocyclic, for example phenyl or tolyl groups. The branched alkylamides and the silylamides, and particularly diisopropylamides and bis-trimethyl- silylamides, give the most satisfactory results from the point of view of reactivity and cleanness of reaction. Lithium diisopropylamide is especially useful. It is also convenient to use a mixture of a lithium alkyl, e.g. butyl lithium, with an amine such as diisopropyla ine.

Triarylmethyl groups preferably carry monocyclic aryl groups such as phenyl or tolyl groups. Alkali metal alkyls include, for example, butyls, such as lithium butyl. There are preferably 1-5 carbon atoms in each alkyl group.

The formation of the 11,12 enolate from the 11-one is effected in a polar, aprotic medium, preferably a solvent serving to solvate alkali metal cations. Suitable solvents include ethers and cyclic ethers such as tetrahydro furan and dimethoxyethane , amides such as tetramethylurea, dimethylformamide, dimethylacetamide, hexame hylphosphoramid and N-methylpyrrolidine and sulphones and sulphoxides such as sulpholan and dimethylsulphoxide. In general an amide or ethereal solvent is preferred.

Completion of the reaction may be monitored by removing an aliquot from the reaction mixture, treating it with benzoic anhydride and determining the product composition by n.m.r. or thin layer chromatography.

Sodium or potassium enolates are, in general, more readily prepared by the above method than lithium enolates but tend to undergo methathesis with other ketones whereby the enolates of the latter are formed and enter simultaneously into subsequent reactions. Thus, for example, although it is often convenient or synthetically advantageous to prepare the sodium 11 , 12-enolate, this enolate must be fluorinated rapidly and in very dilute solution or otherwise it undergoes metathesis with the product 9 , 12-difluoro-11-keto steroid to afford a mixture of 9-fluoro -11-keto steroid and 9, 12-difluoro -11, 12-enolate . This, of course, leads to the isolation of mixtures of mono-, di- and tri-fluorinated ketones and spoils the reaction from a preparative point of view. Lithium or magnesium enolates do not rearrange quickly enough to present this difficulty and it has been found surprisingly and fortunately that it is possible to convert the easily formed sodium enolate into a lithium enolate by simple expedient of treating the former in solution with a solution of lithium chloride e.g. in tetrahydrofuran. A rapid cation exchange ensues and sodium chloride is precipitated leaving behind a solution of the 11 , 12-lithium enolate which may then be fluorinated without difficulty. This same process may indeed be useful when carrying out other reactions which lead to substitution of the enolate at the 12-position.

Where a lithium enolate is required it is also some-r times convenient to cleave an 11,12-enol ester, e.g. the benzoate, with a lithium base such as an alkyl, amide or hydride. It is also possible to cleave a Δ^^^-11-tri alkylsilyloxy ether with an alkyl lithium. A magnesium enolate may be generated by cleavage of a Δ^^^-ΙΙ-trialkylsilyloxy ether or ester with a Grignard reagent for example an aliphatic, araliphatic or aromatic magnesium halide .

The solutions of the new 11 , 12-enolates in polar, aprotic solvent media are very versatile reagents and constitute a further feature of the invention. The enolates themselves in general, relatively unstable out of solution and there is normally no advantage in isolating them before subsequent reactions are effected, such as formation of enol ethers and esters or 12-halides.

In general, 12-halogenated steroids show enhancement of physiological activity as compared with un-substituted analogues, particularly in the corticoid field where the products are antiinflammatory agents, and in the 20-ketopregnane and oestrane field where the products exhibit progesterone-like activity.

Enol esters may be produced by reacting the enolate with an acylating agent, e.g. a reactive derivative of an acid, e.g. a halide or, more particularly, an anhydride of an organic acid such as an aliphatic, araliphatic or aromatic acid, e.g. acetic, propionic or benzoic acid.

Enol silyl ethers may be prepared by reaction with an etherifying reagent, e.g. a dialkyl or trialkyl silyl halide such as trimethyl onochloro-silane or dimethyldichlorosilane . 12-Halogenation may be effected by reaction with a source of positive halogen, for example molecular chlorine or bromine. It is particularly useful to introduce a 12-fluorine atom by reaction with an electrophilic fluorinating agent such as perchloryl fluoride, or a hypofluorite reagent such as trifluoro-methyl hypofluorite.

Electrophilic fluorinating agents such as perchlory fluoride give initially 9a-halo- 12- fluoro- 11-ketos teroids . These latter compounds may, however, be further converted to their 11 , 12-enola t s which can then be further reacted with halogeneting reagents to give the corresponding 9a- -12,12-;<-- trihalo -11-ketosteroids .

The 9 , 12-dif luoro Δ(11,12) enolates may also be treated with acid to afford 9 , 12-difluoro 11-keto steroids isomeric with the parent 9 , 12-dif luoro 11-keto compound. Direct perchloryl fluoride fluorination of the 9-fluoro Δ(11,12) enolate leads to the thermodynamically more stable 9 , 12-difluoro ketone^ which on enolization and protonolysis is isomerized to the thermodynamically less stable derivative.

The 9-halo-12-f luoro-ll-ketosteroids initially prepared may, for example, be reduced to the corresponding 11-hydroxysteroids , e.g. by conventional methods. Thus, for example, 9a , 12 , 12- trifluorocortisone 17a , 20 : 20 , 21-bismethylene dioxide 3-ethylene ketal may be reduced to give the corresponding Cortisol, for example using a borohydride reducing agent such as sodium borohydride.

The following Examples are given by way of illustration only: all reaction were effected using freshly distilled solvents under an atmosphere of argon:- Example 1 Preparation of 9a-fluorocortisone 17a , 20 ; 20 , 21-bismethylene- dioxide 3-ethylene xketal 11 , 12-enol benzoate. 9a-Fluorocortisone 17a, 20 : 20 , 21-bismethylene dioxide 3-ethylene ketal (400 m . ) was dissolved in freshly distilled hexamethylphosphoramide (H.M.P.A.) under an atmosphere of argon and a 20% suspension of sodium acetylide in hexane (0 . 8 ml.) was added. The mixture was stirred for fifteen minutes and then benzoic anhydride (0 .8 g. ) in H.M.P.A. ( 10 ml.) added; the solution was stirred for five minutes more and poured into water. The aqueous solution was extracted with ether and the ether layer separated and dried (MgSO^). Evaporation of the ether layer to dryness gave an oil containing excess benzoic anhydride and the product .

Chromotography on alumina and elution with benzene gave 250 mg. ) of title product as a clean colorless oil which could only be induced to crystallize in very poor yield. It was however pure to t.l.c. and N.M.R.

I.R. Absorption maximum Carbonyl stretch 1745 cm V.S.

C-0 stretch 1250 cm"1, V.S.

N.M. R. 5 proton multiplet 7 -8 $ , 1 proton doublet at 6. 55£(J = 2 . 5 cps.) 19 methyl 1. 25 $ , 18- methyl at 1. 05 Example 2 Preparation of 9g-fluorocortisone 17a, 20 : 20 , 21-bismethylene dioxide 11,12- enol benzoate 3-methyl enol-ether (i) Hexamethyldisilazane (400 mg. ) was dissolved in a 4:1 mixture of benzene and H.M.P.A. and 2 mg, of triphenyl-methane added as an indicator. n-Butyl lithium was then added until a pale pink colour indicated a small excess.

Half this solution was then added to 9a-fluorocortisone 17a, 20 : 20, 21-bismethylene dioxide 3-methyl enol-ether, (200 mg. ) the solution stirred for fifteen minutes and benzoic anhydride (400 mg. ) in H.M.P.A. (5 m].) added. The reaction products were poured into water, extracted with ether and the ether layer separated and dried (MgSO^). Evaporation of the ether and chromatography of the residue gave 110 mg. of title compound as a colourless oil which could not be crystallized .

I. R. Absorption maximum Carbonyl at 1745 cm 1 , V.S.

C-0, 1250 cm'1, V.S.

N.M. R. 5 proton multiplet 7.8 , 1 proton doublet 6.55 (J = 2.5 cps) 19 methyl 1.18 i, 18 methyl 1.05 S Example 3 Preparation of 9q-fluorocortisone 17a, 20.20 ,21-bismethylene-dioxide 11,12-enol benzoate 3-methyl enol-ether (II) 9a-Fluorocortisone '17a, 20 : 20, 21-bismethylene dioxide 3-methyl enol-ether (400 mg.) Was dissolved in tetrahydrofuran (T.H.F.) (10 ml.) and sodium bistrimethylsilyl amide (400 mg . ) in T.H.F. (10 ml.) added. The solution was stirred for five minutes and benzoic anhydride (520 mg. ) in T.H.F. (10 ml.). Work-up as in Example 1 gave 320 mg. of title compound as a colourless oil.

Example 4 Preparation of 9cc-Fluoro- 17cc , 21-dihydroxy-16a-methyl-3 , 11 , 20-trioxopregna-l ,4-diene 17 , 20: 20 , 21-bismethylene dioxide 11,12-enol benzoate. 9a-Fluoro - 17a, 21-dihydroxy-16a-methyl-3, 11 , 20-trioxo -pregna-l,4-diene 17a, 20:20, 21-bismethylene. dioxide (400 mg#) was dissolved in T.H.F. (10 mL ) and sodium bistrimethyl silyl amide (400 mg . ) in T.H.F. (10 ml.) added over two hours. Benzoic anhydride (520 mg. ) in T.H.F. (10 ml.) was added and the solution was worked up as in Example 1.

Chromatography on alumina gave 180 mg. of the title compound as a crystalline product.

Example 5 Reaction of the sodium enolate of 9q-fluorocortisone 17a, 20: 20, 21-bismethylene dioxide 3-ethylene ketal with perchloryl fluoride . 9a-Fluorocortisone 17a, 20 : 20 , 21-bismethylene dioxide 3-ethylene ketal (500 mg . ) was dissolved in T.H.F. (10 ml.) and sodium bistrimethyl silyl amide (500 mg . ) in T.H.F. (10 ml.) added. The solution was stirred for five minutes, cooled to 0°C and perchloryl fluoride passed in until a potassium iodide trap indicated an excess. Argon was then passed through the solution for twenty minutes to remove dissolved perchloryl fluoride, the solution poured into a potassium iodide/ice mixture, the iodine produced removed with sodium thiosulphate solution, the mixture stirred until all the ice melted and the product filtered off. Product analysis showed it to contain approximately equal amounts of mono, di and trifluoro cortisone 17a, 20 : 20, 21-bismethylene-dioxide 3-ethylene ketal.

Example 6 Preparation of the lithium enolate of 9a-fluorocortisone 17a, 20 : 20 , 21-bismethylene dioxide 3-ethylene ketal and its reaction with perchloryl fluoride 9a-Fluorocortisone 17a, 20 : 20, 21-bismethylene dioxide 3-ethylene ketal (500 mg.) was treated with sodium bistrimethyl silyelamide as before and then lithium chloride (100 mg. ) in T.H.F. (5 ml.) was added. Sodium chloride was precipated and the lithium enolate formed. This was reacted with perchloryl fluoride and work up asii Example 5 gave 360 mg . of 9α,12β-difluorocortisone 17a, 20: 20, 21-bismethylene dioxide 3-ethylene ketal .

M.Pt. 260- 262°C I.R. Absorption maximum 1750 cm ^ N.M.R. 1/2 proton doublet (J = 5 cps.)6.03^, 19 and 18 methyls at 1.3 and 0.855 ANALYSIS C25H320?F2 Req: % C = 62.2 H = 6.64 F = 7.88 Found: 62.42 6.63 7.29 Example 7 Preparation of 9a, 12, 12-trifluorocortisone 17a, 20 : 20 , 21-bis-methylene dioxide 3-ethylene ketal . 9a, 12β -difluorocortisone 17a, 20 : 20, 21-bismethylenedioxide 3-ethylene ketal (500 mg ) was dissolved in T.H.F. (10 ml. and sodium bismethyl silyl amide (500 mg. ) in T.H.F. (10 ml.) added. The solution was cooled to 0°C and perchloryl fluoride passed in. Work up as in Example 5 followed by crystallization gave 210 mg. title compound.

M.Pt. 239- 245° [ ]D = -87.4° (approximately) I.R. Absorption maximum 1755 cm ANALYSIS: C^H^O-^ Req:70 C = 59.9 H = 6.25 F = 11.38 Found: 59.7 6.7 12.20 Example 8 Reduction of 9 , 12 , 12-trifluorocortisone 17 , 20 : 20 , 21- bismethylene dioxide 3-ethylene ketal 9a , 12 , 12- trifluorocortisone 17a , 20: 20 , 21-bismethylenedioxide 3-ethylene ketal (500 mg. ) dissolved in T.H.F. (3 ml. and 2-propanol (2 ml.) and sodium borohydride (200 mg.) in water (2 ml.) was added. The solution was allowed to stand for 90 minutes at room temperature, poured into water (50 ml.) and extracted with 2 x 10 ml. of ether. The ethereal extract was washed with 570 sodium bicarbonate solution, saturated sodium chloride solution and dried with sodium sulfate. Evaporation to dryness and crystallization from methylene chloride/methanol containing 0.1% pyridine gave 280 mg. of 9 , 12 , 12- trifluorocortisol 17α , 20: 20 , 21-bismethylene dioxide 3-ethylene ketal.

M.Pt. 239-240°C.

Analysis: %C %H %F C25H33°7F3 recluires: 59.75 6.62 11.34 Found: 59.76 6.98 11.08 Example 9 Preparation of 9a , 12 , 12-trifluorocortisol 17a , 20 : 20 , 21-bismethylene dioxide 9a, 12, 12- trifluorocortisol 17a , 20 : 20 , 21-bis-methylene dioxide 3-ethylene ketal (200 mg.) was dissolved in 1% HCl in acetone and allowed to stand for an hour at room temperature. Water was added, the product filtered and recrystallization from methylene chloride/ether gave 110 mg. of 9a, 12, 12-trifluorocortisol BMD.

M.Pt. 286-290°C.

Example 10 Preparation of 9a , 12 , 12- trifluorocortisol 9a , 12 , 12- trifluorocortisol 17a,20:20,21-bis-methylene dioxide (90 mg.) was dissolved in concentrated HC1 (1 ml.) and shaken for one minute. Water was added, the precipitate filtered off and crystallization from pyridine/methanol gave 38 mg. of 9a, 12, 12-trifluorocortisol.

M.Pt. 260-266°C.

Example 11 Preparation of 12 -bromo-9a-fluorocortisol 17a, 20:20, 21-bismethylene dioxide 3-ethylene ketal 9a-Fluorocortisone 17a , 20: 20 , 21-bismethylene dioxide 3-ethylene ketal (1 g.) dissolved in THF (15 ml.) and sodium bistrimethyl silyl amide (1 g.) in THF (15 ml.) added. The solution was stirred for 5 minutes, lithium chloride (200 mg.) in THF (20 ml.) was added and the solution stirred for a further 5 minutes. Bromine (0.25 ml.) was added, the solution poured into water, extracted with ether and worked up.

The crude mixture was treated with sodium borohydride in THF/water/isopropanol for one hour, extracted with ether and worked up. Chromatography gave 410 mg. of 12p-bromo-9a-fluorocortisol BMD 3-ethylene ketal. M.Pt. 184-5°C Analysis : Found: % C = 54.98 H= 6.30 F= 3.48 Br = 14.4 Required: 55.05 6.28 3.48 14.65 Example 12 Preparation of 9oc-fluorocortisone 17a .20 : 20 r 21-bis-methylene dioxide 3-ethylene ketal A"*""*" trimethylsilyl enol-ether (a) Preparation of n-butyl lithium/di-isopropylamine reagent n-Butyl lithium (10 m.mol:2.38M solution in hexane) was added to THF (5 ml.) containing 2 mg. of triphenylmethane as an indicator. Di-iso-propylamine (10 m.mol) in THF (5 ml.) was added and the solution stirred for 5 minutes. It was then used as such. (b) Use of reagent: 9a-Fluorocortisone 17a , 20 : 20 , 21-bismethylene dioxide 3-ethylene ketal (460 mg.) was dissolved in THF (25 ml.) and the n-butyl lithium/ diisopropylamine solution prepared above was added until there was a permenent pink color. Trimethyl-silyl chloride (0.12 ml.) was added, the solution poured into ether and worked up. Crystallization from ether gave 410 mg. of 9a-fluorocortisone BMD 3-ethylene ketal Δ"^ tri ethylsilyl enol-ether.

M.Pt. 176-8°C [a] = -124.6° Analysis: Found: % C = 62.91 H= 7.8 F= 3.69 Required: 62.9 7.8 3.55 (c) The same reaction using/ 12p-difluoro cortisone 17α , 20 : 20 , 21-bismethylene dioxide 3-ethylene ketal gave 9 , 12-difluorocortisone BMD 3-ethylene ketal Δ11 trimethylsilyl enol-■ether.

M.Pt. 174-■6°C [a]D = ■ -116° Analysis : 7oC %H %F Found: 60.88 7.16 6.52 Required: 60.84 6.93 6.87

Claims (1)

1. WHAT I S CL IMED I S : 38143/3 1. A process for the 11 , 12-enol isation of a 9a-halo-ll- ¾i keto-steroid in which the 9a-halo-ll-keto-steroid is treated in a. polar, aprotic medium with a strong base, and if desired, reacting the 11, 12-enolate with a source of positive halogen to form a 9 «, 12-dihalo-ll-keto-steroid or 9a , 12 , 12 trihalo- 11-keto steroid, a 9 o~hsilG-12-fluoro-ll-keto steroid formed - as initial product being, if desired, reduced to the correspondin 11"hydroxys teroidb 2. A process as claimed in claim 1 in which the base is an alkali metal hydride, an alkalimetal aluminium hydride, an alkalimetal amide, alkalimetal alkylamide, alkalimetal aralkylamide , alkalimetal silylamide, alkalimetal acetylide or substituted acetylide, anr alkalimetal alkyl or amine-solvated alkalimetal alkyls-. 3. A process as claimed in claim 2 in which the alkali metal is sodium, potassium or lithium. 4. A process as claimed in claim 2 or claim 3 in which the alkalimetal alkylamide, alkali metal aralkylamide, or alkalimetal 1 2 1 2 silylamide is of the formula M R R where R and R which may be the same or different are alkyl groups or trialkylsilyl , triaralkyl or triarylsilyl groups and M is an alkali metal. 5. A process as claimed in claim 4 in which any alkyl group or any alkyl portion of any aralkyl group present in the base has 1-6 carbons. 6. A process as claimed in claim 5 in which any aryl groups present in the base are monocyclic. in which the base is an alkali metal diisopropylamide or bistrimethylsilylamide . 8. A process as claimed in claim 2 or claim 3 in which the base is an alkali metal alkyl with 1-5 carbon atoms . 9. A process as claimed in any of claims 1 to 8 in which the medium is an ether, cyclic ether, amide, sulphone or sulphoxide. 10. A process as claimed in claim 9, in which the medium is tetrahydrofuran, dimethoxyethane , tetra-methylurea, dimethylformamide , dimethylacetamide , hexamethylphosphoramide , N-methylpyrrolidone , sulpholan or dimethylsulphoxide .. 11. A process as claimed in any of the preceding claims in which a lithium enolate is prepared by treating a solution of an initially obtained sodium enolate with a solution of lithium chloride, the unwanted sodium chloride being precipitated,, 12. A process as claimed in any of claims 1 to 11 in which the steroid possesses any of the following characteristics: a 3-substituent which is convertible into a 3-keto group; a 3-keto group in conjunction with a 6-fluoro-1 , -diene system; double bonds in the 1,2-, 4,5- and 16 , 17-positions ; alkyl groups in the 6-, 10-, 13- and 16-positions ; halogen 12-atoms in the 6->/and 16-positions ; a 17-keto group; a 17-hydrogen atom, a 17-hydroxy group and a 17-acyloxy group together with a 17-hydrogen atom or 17-aliphatic group which group may carry one or more protected keto and/or protected hydroxy groups. 13. A process as claimed in claim 12 in which said protected keto groups or said substituents convertible into keto groups are ketals, hydrazones or substituted hydrazones, enol ethers or esters, or oximes or alkoximes . 14. A process as claimed in claim 12 in which said protected hydroxy groups are ethers, esters or ketals . 15. A process as claimed in any of the preceding claims in which the enolate obtained is converted into an enol ester by reaction with a reactive derivative of an acid. 16. A process as claimed in claim 15 in which the reactive derivative is a halide or anhydride of a carboxylic acid. 17. A process as claimed in any of claims 1 to 14 in which the enolate obtained is converted into an enol silyl ether by reaction with a dialkyl or trialkylsilyl halide. 38143/2 18. A process as claimed 1n claim 1 In which the source of posi ti ve halogen 1s molecular chlor ne or bromine, perch! oryl fluoride or a hypofluorite fluor natlng agent. 19. A process as claimed In claim 18 In which the hypofluori te fluorinatlng agent 1s ti fluoromethyl hypofluor te. 20. A process as claimed In any of cl aims 1 or 19 n which the 9 21. A process as claimed In any of claims 1 or 18tP 20 1n which the »no1ate Is the lithium enolate. 22. A process as claimed 1n any of claims 1 or 18 to 21 In which the 9a -halo-12-fluoro-ll-ketostero1d Initial ly prepared 1s reduced to the corresponding 11 -hydroxys terold. 23. A process as claimed In any of the preceding claims substantially as herein described. 24. A process for U ,12-eno11sat1on of 9 a -halo-11-ketosterolds substantially as herein described In any of Examples I- 7, 11 and 12. 25. A process for the preparation of 9 α ,12-dlhalo-ll-ketosterolds substantially as herein described In any of Examples 6, 7 and 11 . 26. 9 a ,12-D1halo-1l -ketosterolds and 9a ,12 ,12-trihalo- II - ketosterolds whenever prepared by a process as claimed In any of claims 18 to 26. 27. A solution of 9 a -halostero1d-1l ,12-enolate when prepared by a process as claimed In any of cl aims 1 to 17. 28. A solution of a 9a -ha1ostero1d-1l ,l2-eno1ate 1n a polar aprotlc solvent. COHEN ZEDEK & SPISBACH Read. Patent Attorneys