DE1618493A1 - Process for the manufacture of halogenated steroids - Google Patents

Description

16 / IB493

\ "" RAN 4104/48

ν "-: ■■■" ■ "'"' '■

F. Ho & aim-La Roche & Co. Aktieniigesellschait, Basel / Switzerland

Process for the manufacture of halogenated steroids

. This invention relates to a method of manufacture new halogenated steroids of part formula

in which R, fluorine, chlorine or bromine or a lower Alkyl group j Q, an oxo group or a 1/2-alkylenedioxy group with 2-4 carbon atoms and M the rest

TeiX of rings A and B and rings C and D of Represent the steroid framework.

Preferred compounds of the formula I are those in which the radical M represents a group of the sub-formulas II * III or IV, ... . _ ■.

IX

I. H ₃ < . J- ι H

III

IV

826

in which R _{3 is} hydrogen or fluorine; R_'hydrogen, a hydroxy, lower-alkanoyloxy or lower-alkyl group; R ₂ , hydrogen or a lower alkyl group ;. R_ and Rq xmaD, depending on one another, are hydrogen or a lower alkanoyl group; Rg is hydrogen, a lower alkyl group or an ethynyl group; R "hydrogen or a" methyl group .; Rg hydrogen or fluorine, chlorine or bromine R ₁₀ hydrogen, an α-hydroxy or lower-alkyl group; R, ^ a hydroxy group or together with R _1n a group of

0 / ■

Formula "* * _rt " ^^ ( ^lower alkyl) _o ; X a bond -. between the 1 and 2 positions i η 0 or 1; Y is a methylene, ß-hydroxymethylene, a-hydroxymethylene / or carbonyl group and Z is a methylene, ß-hydroxymethylene a ctr-hydroxymethylene or carbonyl group or if Ro Ciilor is a β-chloromethylene group, where Z is a methylene or a ^ represents hydroxymethylene group only if Rg is hydrogen - '■■'"■.. - ,.:. ■

The term lower alkyl group refers to straight-chain and branched hydrocarbon radicals with up to 8 carbon atoms, such as "methyl, ethyl, t-butyl, or n-octyl. A lower alkanoyl group is, for example, an acetyl, butyryl or capronyl group and a 1,2- Alkylenedioxy group with 2- ² I-C-atoms for example the Äethylendioxygrüppe ...'- "

Preferred compounds are those in which iL chlorine, Fluorine or a lower alkyl group with up to 4 carbon atoms represents and especially those in which R, chlorine, Represents fluorine or a methyl group. Likewise preferred compounds are those in which fluorine is an ethylenedioxy group or in particular represents an oxo group.

The process according to the invention is characterized in that a compound of the formula

in which R, and M have the above meaning, with chlorine either in the presence or with subsequent Treated addition of a proton acceptor and, if desired, converted the 3-oxo group into a 1,2-alkylenedioxy derivative.

Examples of proton aceeptors are heterocyclic nitrogen-containing bases, such as picoline or pyridine; N, N-di-lower-alkyl-lower-alkanoylamides, such as dimethylformamide or dimethylacetamide or lower alkylene oxides, such as ethylene oxide or propylene oxide into consideration. The proton acceptor can

00984A / 1826

also serve as a solvent for the steroid of the formula V used as the starting material. The reaction mixture preferably also contains other solvents. All customary inert organic solvents are suitable as such, for example ethers such as lower-alkyl ethers, for example ethyl ether or dioxane; lower alkanecarboxylic acids such as propionic acid or acetic acid, chlorinated hydrocarbons such as chloroform or carbon tetrachloride, the chlorine can be introduced into the reaction mixture by known methods, for example in the form of a solution. A solution of chlorine in a lower alkanecarboxylic acid, for example a solution of chlorine in propionic acid, is particularly suitable for this purpose. The chlorination is conveniently carried out at low temperature, preferably between about - ² K) ⁰ and room temperature, in particular zwisehen about -30 ° and about 0 ° conducted. When using starting materials with a Δ double bond, ie compounds of the formula V in which M represents a group of the sub-formula II, III or IV, * where η = * 1:> the chlorination is conveniently carried out in dimethylformamide.

Hydroxy groups contained in the starting material can be esterified after chlorination; on the other hand can also Compounds with ester groups are chlorinated. In the chlorination of compounds in which Y or Z is a ß-hydroxymethylene group represents, one expediently protects the hydroxyl group from chlorination, for example by acylation to the corresponding 11-ß-acetoxy or ll-ß-trifluoro

0088U / 182S

acetoxy derivative. The 11-ß-hydroxy group can be regenerated by conventional means after the chlorination. Reaction products of the sub-formulas I or III, in which R ₁ - represents a lower alkanoyl group, can be converted into the corresponding compounds with R, - = hydrogen by ketalization of any 3-oxo group present, reduction with lithium aluminum hydride and, if necessary, decetalization, for example with mineral acid , are obtained. However, it is preferred to prepare such compounds directly by chlorinating compounds of the formulas V or III in which R ^ is hydroxy. Other methods can also be used to protect labile groups from chlorination. .

The simple way in which the inventive chlorination process can be carried out, and the good yields that can be achieved are remarkable in that with conventional chlorination processes from 6-R - 4,6-dien-3-one steroids, in which R, the same as above, no noticeable yields of 4-chloro ~ 6-R, - ^, ö-dien - ^ - one steroids could be obtained.

The conversion of a reaction product obtained into a 5,3-alkylenedioxy derivative, i.e. the preparation of compounds in which Q represents a 1,2-alkylenedioxy group, can follow the chlorination process in a conventional manner, for example by reaction with a 1,2-alkylene glycol in

09844/1826

Presence of an acidic catalyst such as p-toluene sulfonic acid. With ethylene glycol, compounds are obtained in which Q represents an ethylenedioxy group. -_ / . ''"■,:" - ■ """."■■■;".--.""."

In a further reaction step, in one Free hydroxyl groups contained in the reaction product are esterified by known methods. Furthermore, reaction product e like 4, ö-

to the corresponding 1,2-unsaturated derivatives on per se

known way to be dehydrated.

It has been found that steroids with the structure of sub-formula I have valuable endocrinological effects. Compounds which combine the structural elements of formula I and II, where R_ denotes a hydroxyl, lower alkanoyloxy or lower alkyl group, are progestationally effective. Compounds which correspond to the sub-formulas Ϊ and IV are anti-inflammatory and tlymoilytisdi and compounds which correspond to sub-formulas I and. III correspond, where R, -hydrogen and t are a methylene, a β-hydrogen xymethylene, a β-chloromethylene or a carbony group, if Rg hydrogen is a lower-alkyl group, anabolically effective o & r, if Rg represents an ethynyl group, progestationally effective .. Compounds from the sub-formulas I, III or IV, in which Y or Z represent an α-hydroxymethylene group

009844/1828

are intermediates for the production of compounds, in which Y or Z is a carbonyl group. This conversion into the carbonyl group can be carried out in a manner known per se Wise done. Compounds from sub-formulas I and II, in which IU represents a hydroxyl group, can be esterified and compounds from sub-formulas I and III, wherein R, - is a lower alkanoyl group, can be in the corresponding free hydroxy compounds are transferred. Such compounds are therefore also intermediates.

Particularly preferred compounds which, according to the invention Processes that can be produced are those of the formula

. H ₃ C

VI

Cl

in which R ₁ , R ₂ , R ^, X and η have the same meaning as above and R 'represents hydrogen, a lower alkanoyloxy or lower alkyl group.

009844/1826

These compounds are distinguished by their pronounced progestative activity; Of these compounds, those in which R, chlorine and Rh represent hydrogen or a methyl group are particularly preferred. The substituent R ₂ ^ can have either α or β configuration * Particularly preferred are compounds in which R 1 is hydrogen or a lower alkanoyloxy group.

Another preferred group of c. Available compounds are those of the formula

VII

Cl

in which R, R ", X and η have the same meaning as above; Y represents a methylene, β-hydroxymethylene or carbonyl group and R _{12 represents} hydrogen or a lower alkyl group. ·

Compounds are androgenic and anabolic. ₀ Particularly

Good compounds of the formula VII are those in which R. «a - or A @ fchy! group representsί darubt ^ hixiaus diej

0 @ B447 1

Compounds in which R- chlorine and those in which η = 0 is.

Another preferred group of those obtainable according to the invention Compounds are.Compounds of the formula

• H ₃ O

¥ 111

Jl R ₁

in the R., R ₁ -, R "and Y, the same meaning as above χ O j ±

and IL, represents an ethynyl group.

These compounds have a progestational effect. Those compounds of the formula VIII in which R _{1 is} chlorine are preferred.

Another preferred group of those obtainable according to the invention Compounds are the compounds of the formula

IX

in the

* ^x

ⁿ the same

, R, R _g , R- _o ,

Meaning As above havei. _; and Z represents a methylene, β-hydroxymethylene or carbonyl group or, if Rn is chlorine, a β-chloromethylene group ", where Z, represents a methylene group only when Rg is hydrogen ". ... . ■ ..- ..; '^; . ■. ;;

These compounds are anti-inflammatory and thymolytic. Preferred compounds of the formula IX are those in which Rq is hydrogen or an acetyl group and those in which Z is a carbonyl or β-hydroxymethylene group, and those in which R _{10 is} hydrogen, an α- or β- Represents methyl or α-hydroxy group and those in which R _{1 is} chlorine.

0 08844/1828

The compounds of the formula

group; R 'is a lower alkyl group and

in the R _{1 iL} hydrogen or a lower alkanoyl

r fluorine,

xO

Mean chlorine or bromine,

are new compounds and represent intermediates for the Manufacture of ^, o-disubstituted- ^ ö-diene steroids of the Formula I.

The compounds of the formula X can through a 5-stage Process from compounds of the formula

• H ₃ O

OR ₁₄

XI

009844/1826

in.der R, jv- and BJ ₁ , have the same meaning as above. ■: -

In the first stage of this process, the connection is made Formula XI is dehydrated according to methods known per se, for example with 2,3-DiChIQr-S, ö-dlcyanobenzoquinone oxide a compound of the formula ■

- - - - H ¹ 155

XII

in the R ₁₁ , and Ri, - have the same meaning as above.

The compound of the formula XII is then selectively oxidized by methods known per se, for example with mono perphthalic acid, and yields a compound of the formula

& 0 98L4 4 / 1SL2B

XIII

in Ry ₁ , and L, have the same meaning as above.

Treatment of a compound of formula XIII in acidic? Solution how in acetic acid, with a hydrogen halide then gives a compound of the formula X. Other starting compounds of the formula V can be prepared in the same way.

Compounds of the formula

H ₃ C

H ₃ C

- ·· ~ CH3

xrv

009844/1826

in which R ₁ ^ hydrogen or acetyl represents an acetyl group, ^ '.' ■ - / ■ "-."":.

In addition to their convertibility into compounds of the formula I, they are of value because of their endocrinological activity. The compound of the formula XIV, in which Rg represents hydrogen, is anabolically and androgenically effective, the compound of the formula XIV, in which R ₁ ^ represents an acetyl group, is antlandrogenic. The latter connection can be converted into the former and

from the corresponding ö-chloro - ^ - methoxy-j ^ S-diene steroid by treatment with t-butyl chromate, manganese dioxide or a similar oxidizing agent. getting produced. In in the same way, other 6r-ehlor-4,6 ~ dien- "5-Oh compounds of the formula V from the corresponding ö-chlorine - ^ - methoxy-5,5 "-α1βηβη getting produced. The latter, in turn, can be obtained from 6-chloro-4-en-; 5-one = Stei? Oideh by treatment with trimethyl o-formate can be obtained. The methods described in this section can be carried out in a manner known per se carried out.

Compounds of formula VI in which Rl ^ is hydrogen can be converted into compounds of formula VI in which Rl is a hydroxy group. That can for example take place in that it is a compound of formula VI wherein El is hydrogen and Q, a Öxogruppe / Essigsäur with eanhydr id and treated perchloric acid, the enol acetate of the general formula '

- XO -

16Ί8Λ93

xv

Cl

in the R, R _? , X and ή have the same meaning as above,

receives.

Treatment of the enol acetate of formula XV with unbuffered Peracetic acid then provides a compound of the formula VI in which R * represents a hydroxyl group. According to a different method treating a compound of the formula XV with buffered peracetic acid to give a compound of the formula

• CH ₂ -R ₂

Cr OCCH ₃

XVI

098U / 1826.

'in the B ,,. PL, X and η have the same meaning as have up. -

By acid or base hydrolysis, a compound of Formula XVI into one of the formula VI in which R 'is a hydroxyl group represents, are convicted.

The compounds available according to the invention are at a selectivity of action characterized by minimal side effects highly endocrinologically effective. The process products, i.e. the compounds of the formulas or the sub-formulas I-IX and 14 can be used as medicaments, for example in the form pharmaceutical .Preparate use, which they in Mix with one for the .enteral, percutaneous or parenteral Application of suitable pharmaceutical, organic or inorganic inert carrier material, such as .z.B. Water, gelatine, Gum arabic, lactose, starch, magnesium stearate, Contains talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, coated tablets, suppositories, capsules; · in semi-solid form, e.g. as ointments; or in liquid form, e.g. as Solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliary materials, such as preservatives, stabilizers, wetting agents or emulsifiers, Salts to change the osmotic pressure or

Buffer. You can also find other therapeutically valuable ones Contain substances. ■ "'■.'

009844/1826

In addition to internal administration, the compounds with progestative activity, i.e. the compound of the Formula VI and VIII or the compounds with anti-flaminatory Activity, i.e. the compound of the formula IX can also be used locally, for example as ointments. The endocrinological active compounds of formulas L-IX and XIV can be used as feed additives and for this purpose with conventional feed or feed premix.

Although the administration of the endocrinologically effective Compounds obtainable according to the invention is to be adapted to the individual needs, compounds which are progestatively are effective, i.e. those of the formulas VI and VIII in Daily doses of about 0.005 mg / kg to about 0.15 mg / kg are administered internally. For androgenic and anabolic compounds, ie. those of formula VII and XIV come with ' internal administration daily doses of about 0.15 mg / kg to about 1.5 mg / kg are possible. Anti-inflammatory and thymolytic active compounds, i.e. those of the formula IX, can be administered internally in daily doses of about 0.005 mg / kg to about 0.3 mg / kg administered.

In the following examples the temperatures in degrees Celsius specified. If they are not known, the starting compounds can be prepared by methods known per se will.

0098.44 / 1826

\ example 1

To a solution, cooled to 0 °, of 2.03 g of 17a-acetoxy-6-chloro-pregna-4,6-diene-3,20-dione in 20 ml of dimethylformamide and 10 ml of ether, 5.39 ml of a 1.015 M Given a solution of chlorine in propionic acid. The mix will Left to stand for 12 hours at 0 °, whereupon another 0.3 ml of the Chlorine solution are added, the mixture is then added Left to stand at 0 ° for 2 hours.

The reaction mixture is poured into 300 ml of water and the resulting mixture is extracted three times with ether / methylene chloride (2.5: 1). The organic layers are washed once with 5% sodium bicarbonate solution and once with brine. The layers are combined, dried over sodium sulfate, and evaporated under reduced pressure. "The remaining oil is triturated with ethyl acetate. This gives crude ITa-acetoxy - ^ / ö-dichloro-pregna-tyiö-dien ^ iäO-dione, which, after further crystallization from chloroform-ethyl acetate, has a melting point of 237-239.5 ° (colorless crystals), [a] | ⁵ + 135, ° (C = 1.03 in CHCl-.). '

According to the procedure described above, the following is chlorinated:

a) 21-Acetoxy-11ß, 17a-dihydroxy-6-chloro-pregna- ² } ·, 6-diene--3,20-dione, it is formed

009844/1826

dien-3 * 20-dione.

b) 21-acetoxy-11ß, 17a-dihydroxy-6,9a-difluoro-16a-methylpregna-4,6-diene-5,20-dione, 21-Acetoxylß, 17a-dihydroxy-4-chloro-6,9a-difluorο-1βα-methylpregna-4,6-diene-3i20-dione is formed.

c) β-fluoro-11ß, 17a, 21-trihydroxy-pregna-1,4,6-triene-3,20-dione, 4-chloro-6-fluoro-ll3, 17 ", 21-trl- is formed. hydroxy-pregna-1,4,6-triene-3i20-trione.

d) e-chloro-LLSs, 17a, 21-trihydroxypregna-l, 4,6-trien ->, 20-dione, there is produced 4 _J-dichloro-6 LLSs, 17a, 21-trihydroxypregna-1,4, β-triene-5,20-dione.

Example 2

To a solution, cooled to 0 °, of 1.16 g of 6-chloro-17a-acetoxy pregna-4,6-diene-3,20-dione in 10 ml alcohol-free Chloroform is quickly added. 0 ° 3.4 ml of a 0.817 M solution of chlorine in dry carbon tetrachloride. This solution is left to stand at 0 ° for 18 hours. The solvent is at evaporated under reduced pressure, the residue with 25 ml of heptane added and the solvent evaporated again under reduced pressure. This operation is repeated again. Of the 4 ml of dry pyridine are added to the residue, the solution then heated on the steam bath for 5 minutes. The solution will be

009844/1826

Left to stand overnight at room temperature (with crystallizes pyridine hydrochloride from the reaction mixture). 50 ml of chloroform are added to the pyridine solution and then becomes extracted twice with 50ml IN hydrochloric acid each time. The watery Layer is extracted with 25 ml of ether. Combine the organic layers, dry over magnesium sulfate and evaporated under reduced pressure. Add to the residue 25 ml of heptane ^ evaporated under reduced pressure: and repeated this operation. 4,6-DichlQr-17a-acetoxy-pregna-4,6-diene-3i20-dione is made twice from methylene chloride-ethyl acetate recrystallizes and melts at 241-245 °.

Be game ~ b

To a solution, cooled to -2 °, of 6-chloro ~ 17a, 21 = di ~ hydroxy-pr @ gna = 4 _i 6 = diene = 3ill * 20 ° trione-21-acetate in 16 ml of dry dimethylformamide and 10 ml of ether 4.0 ml of a 1 * 05 M solution of chlorine in propionic acid are added. The reaction mixture is left to stand first for 10 hours at -2 °, then for 5 hours at room temperature ^1. It is poured into 100 ml of water and extracted with methylene chloride * The organic phase is ^{washed twice with Seiger 1} sodium carbonate solution and once with sodium chloride solution. It is dried over sodium sulfate and evaporated. The residue gives, recrystallized three times from methylene chloride ether, 4 _i 6-dichloro = '17, 21-dihydro3cy-pregna = 4.6 = diene-3,11,20-trione = 21 ° aeetatiMelting point 257.5-259 * 5 °

/ 1IiS: ■ - ■ '

- • 22 -

Example 4

To a solution, cooled to 0 °, of 0.60 g of 17β-acetoxy-6-chloro-17ffi-methyl-androsta-4,6-diene-3, ll-dione. 2.0 ml of a 0.98 M solution of chlorine in propionic acid are added to 6 ml of dimethylformamide and 3 ml of ether. The reaction mixture is left to stand for 12 hours at 0 °, then it is diluted with 100 ml of water and the resulting mixture is extracted three times with ether / methylene chloride. The organic layers are washed once with 5% sodium bicarbonate solution and once with brine. The combined organic phases are dried over sodium sulfate, then _s under reduced pressure and evaporated to dryness. The residual oil is triturated with ether / hexane, giving crude 17-acetoxy-4,6-dichloro-17a-methyl · androsta-4 _j, 6-dlen ° '3pll = dione _i which after recrystallization from methylene chloride / ether has a melting point of 209-211 ° feist (colorless crystals), 1 &) ψ + 341.5 ° (C = 0.523 in

According to the above process, chlorination is carried out;

= Acetoxy-6 ° chloro-17a-methyl-androsfca-4,6-dien-4-one, 17ß-acetoxy-4,6-dichloro-17ayl = androsta - 4,6-dien-3-one _e

> 17ß-hydroxy-17a-methyl-androeta-4 _Ä 6-diene

/1

j5, ll-dlon, 4,6-dichloro-17ß-hydroxy-17a-methyl-androsta-4,6-diene-5, ll-dlon is formed.

c) 17α-ethynyl-6-chloro-17β-hydroxy-19 ⁱ -nor-androsta-4,6-dien ~ 3-one, 17α-ethynyl-4, β-dichloro-17β-hydroxy-19-nor is formed -androsta-4,6-dien-j-on.

d) 17ß-acetoxy-17α-methyl-β-chloro-19-nor-androsta-4,6-dxen-3-one, 17ß-acetoxy-i7a-methyl-4,6-dichloro-19-nor-androsta-4,6-dien-3-one is formed. ·

The 17ß-acetoxy-6-chloro-17a-methyl-androst-4 _Jί 6-dIen-5, ll-dlon used as starting material can be prepared as follows:

A solution of 25 g of 17β-hydroxy-17a-methyl-androst-4-en-5jll-dione in 125 ml of anhydrous Pyridih and 125 ml Acetic anhydride is refluxed for four hours. The reaction mixture is cooled and washed with one liter of ether-methylene chloride (2.5s1) diluted. The solution appears twice with 1 N hydrochloric acid, twice with 5 ^ strength sodium bicarbonate solution and washed once with water. The organic layer will dried over sodium sulfate, then under reduced pressure concentrated. The residue is on an empty short column purified from synthetic magnesia silica gel (Plorisil), the product being eluted with benzene. The eluate is

0 00844/1828

concentrated under reduced pressure and the residue crystallized from ether-hexane. 17β-Acetoxy-17a-methyl-androst-4-en-3, ll-dione, melting point 188-190 °, [α] ψ + 170 ° (C = 1.0 in-CHCl,) is obtained.

A gentle stream of hydrogen chloride is passed through a solution of 10.0 g of 17β-acetoxy-17oc-methylandrost-4-en-3, ll-dione in 150 ml of anhydrous dioxane for 10 seconds. The same stream of anhydrous hydrogen chloride is passed for 10 seconds through a solution of 6.95 S 2,3-dichloro-5,6-dicyanobenzoquinone in 10 ml of anhydrous dioxane. The two dioxane solutions are then combined and hydrogen chloride is bubbled through the resulting mixture for 90 seconds. The reaction mixture is left to stand for 35 minutes at room temperature and the precipitate formed is filtered off. The piltrate is concentrated to approx. 50 ml under reduced pressure and then diluted with 1 liter of ether-methylene chloride (2.5: 1). The organic solution is separated off, washed twice with dilute sodium hydroxide solution (IN) and once with water. The organic layer is dried over sodium sulfate and then evaporated under reduced pressure. The residue is purified from synthetic magnesia-silica gel in a short column, the 17β-acetoxy-17qc-methyl-androsta-4,6-diene-3, ll ^ dione being eluted with benzene and ethyl acetate. The eluates are combined and evaporated. The residue is crystallized from methylene chloride / ether, 17ß-acetoxy-17a-methylandrosta-4,6-diene-3, ll-dione, melting point 182-184 °, (. C = 1.0 in CHCl3). "

009844/182 «

1618483

To a solution of 4.7 g

^ ö-dienK ^ ll ^ dione in 940 ml of methylene chloride and 225 ml of ether are given 125 ftl of a 0.8 molar monoperphthalic acid solution in ether. The reaction mixture is left to stand still for 41 hours at room temperature and then diluted with 1.4 liters of ether. 15ie orgahisähe Sohloht is separated, washed twice with hydrochloric lö $ soda solution, washed twice with water and twice with KochsalzlösunggewaschenY VM ^ organic layer before mindertem about Katriums ^ l £ a & dried, and ver * · pressure. conc. After further crystallization from methylene chloride / ether, the product has a melting point of 255.5 ^ 2 ^ ^^, 1 «l | ⁵ -: t ^ 3 ^P (G- 0.75 in CHCl ^)

By a solution of 2.5 ¹ I g

androst - ^ - en- ^ ill'-dione in 110 ml of glacial acetic acid is used at Room temperature passed for 10 minutes of hydrogen chloride. The solution will then stand for 3 hours at room temperature left, then diluted with 700 ml of cold water. The reaction mixture is extracted three times with ether / methylene chloride (2/5: 1). The organic layers are washed twice with 5 ^ -iger Sodium bicarbonate solution, once with water and once with Saline solution washed the combined organic layers are dried over sodium sulfate and under reduced · · Focused pressure. The residue; is attached to a column of 30 g

chromatographed synthetic magnesia silicate gel. The product is eluted with benzene / ethyl acetate and the resulting crude product is crystallized from methylene chloride / ether. The resulting ^ ß-acetoxy-o-ehlor- ^ a-methyl-androst-4,6-dlen-3, "ll'-dlott melts after further crystallization from ether / hexane at 137" 3-139 ** t " 3 ²⁵ + 209 ° (C = 0.71 in CHCl ₃ ).

Example 5

5.0 ml are added to a solution, cooled to -10 °, of 2.0 g of IYa-acetoxy-6-methyi-pregna-4,6-diene-j5> 2Q-dione in 21 ml of dimethylformamide and 10.5 ml of ether a 1.15 M solution of chlorine in propionic acid. The mixture is left to stand first for β hours at 0 °, then for 14 hours at 20 °. The reaction mixture is poured into 200 ml of water, then extracted three times with ether-methylene chloride (2.5 μl). The organic layers are washed once with 5% sodium bicarbonate solution and once with brine. The combined organic layers are dried over sodium sulfate and evaporated under reduced pressure. The residue is extracted three times from methylene chloride /

Aether crystallizes. Lta-acetoxy - ^ - chloro-ö is obtained

with a melting point of 217.5 * 218.7 ° «

Example 6

A solution of 0.439 S 4.6 is subjected aoetQxy-pregna> «4.6" diene-3,20-diQn, 0.03 S p-toluenesulfonic acid

and 2.5 ml of ethylene glycol in 15 ml of dry benzene one

slow distillation (1.5 hours). 0.8 ml of ethylene glycol, 8 ml of benzene and 0.005 g of p-toluenesulfonic acid are now added and a slow destination is carried out again (2 hours). It is cooled and diluted with 50 ml of ether and 40 ml of 5% sodium bicarbonate solution. The organic layer is washed once with 5% sodium carbonate solution and once with water. It is dried over sodium sulfate, concentrated and the residue is crystallized after the addition of ether. After recrystallization twice from methylene chloride ether, the 4,6-Diehlor-17a-aeetaxy-pregna-4,6-diene-5,20-dione 5,3-ethylene ketal has a melting point of 266.5-268 °, [aJ _D +78.16? (G = 0.99 in CHCl ₅ ).

Example 7

To a solution, cooled to 0 °, of 0.698 g of 6-fluorine-7,21-dihyäroxy-pregna-4,6-diene-5, ll, 20-tripn-21-acetate 2.95 ml of a 0.8l5 are added to 10 ml of alcohol-free chloroform molar solution of chlorine in dry carbon tetrachloride. The mixture is left to stand at 0 ° for 18 hours. The solvent is evaporated off under reduced pressure and given to the residue Given 25 ml of heptane. The solvent is again evaporated off under reduced pressure and the residue is dissolved in 2 ml -dry I * yridine. After standing for 24 hours at 25 ml of 1N hydrochloric acid are added to the pyridine solution at room temperature and extracted with chloroform. The chloroform layer

the aqueous ones are washed twice with 10 ml of 1 · N hydrochloric acid each time The layers are extracted with 50 ml of ether. The united organic Phases are dried over magnesium sulfate. That

. The solvent is removed under reduced pressure and the residue is crystallized from methylene chloride-ethyl acetate. The ■ ^ -Chlor-6-flubr-17,21-dihydroxypregna- ¹ l-, 6-diene-3, ll, 20-trione-21-acetate melts at 245 - 247 ° (be * l 226 ° sintering.) . Additional product can be obtained by evaporating the mother liquor and recrystallizing the resulting residue.

Example 8 · '

To a suspension of 1.0 g of 4,6-dichloro-17oc-hydroxypregna-

'" t ·' - 4,6-diene-3> 20-dione in 15 ml of caproic acid is added while stirring 4.0 ml of trifluoroacetic anhydride and stirred for 16 hours at room temperature. The reaction mixture is then poured into 100 ml of a cold 5 $ - dgen sodium bicarbonate solution and extracted the resulting mixture three times with ether-methylene chloride (2.5il). The organic layers are washed twice with 0.5 N sodium hydroxide solution and once with brine, combined, dried over sodium sulfate and evaporated.

The residue is dissolved in benzene / hexane (2: 1) and chromatographed on 15 g of synthetic magnesia-silica gel (Plorisil). It is eluted with benzene, 30 ^ ethyl acetate in benzene and finally with ethyl acetate. The eluates are evaporated,

009844/1826

the residue triturated with ether,! ^ crystallization from methylene chloride / ether gives ^ o-dichloro-rfa-hydroxy-pregna 4js6-diene-3,20-dione-caproate with a melting point of 118.5-120 ^& Jp + 115.56 * ( G = 0.98 in CHCl ₅ ) *

•,; V '- Beisiedt §' '-.-' - '■: - "; - Ί--' ■ '.-';,

To a ^ r aöf / Ο » ⁰ geköhiteni LSsmn-g ν <« ϊ Q> 6ö g fJT aridrösta ^ 4 _# i-äi £ ffiO

and 5 ml of ether giÄfe "MARKETS 2 ₀ U'mi #ine _# solution of chlorine in fröpiöEEsSure ·" fefö ilsst> StunieB at stand * Bas Reaktionsgemisöfe vtträ with löö ml; Waters; Aaraiif is extracted three times with ether / methylene chloride ⁵ (2.5 ^ 1}. The organic layers are washed once with 5% sodium bicarbonate solution and once with saline solution. The combined organic phases are dried over sodium sulphate and evaporated The remaining oil is dissolved in benzene and placed on a column of 5 g of synthetic magnesia silica gel, föivFisilj röbtfoma & ch ' grapMert * The benzene and ethyl acetate elements are combined and evaporated to dryness * to one äüfc 0 ^& sensed Iiösuhg of Küökständes in 6 ml of dry dimethylformamide and Jf ml of ether is added 2 ml of a 0/05 M iM & mg of 0felor in propionic acid * the mixture is left 12 hours ^ at O ^ stöhen> and verdüönt thereon with 1Ö0 BiI water * the The organic phases are extracted three times with ether / methylene chloride (2> 5i 1)

161S4S3

are once with 5 ^ sodium bicarbonate solution and once with saline solution; washed. Dry the combined organic; Layers over sodium sulfate and evaporate under reduced; Briick a "laugh trituration, the residue crystallized with crude ITfi-koetoxy-k * 6- &lchlox" ~ idrttstea- ^ iS-dlen- ^ ll-dlon, which after repeated crystallization from methylene & chloride / ether colorless crystals - with the melting point 209-211 * yields, EaJ ² S ₊ 541.5 «(£ = 0.52 in

Example. IO

2® of an auC -ICP filled and protected from atmospheric • solution; of 5.0 g of e-chloropregna - ^^ ö "-dlen-3> 2O-dlon in 30 ml of dichloromethane and 250 ml of ether are added 15.8 ml of a 1.1 M solution of chlorine in propionic acid. Mix well * Let about power at 0 ° Sthen, 100 ml of benzene and concentrated to about 200 ml in vacuo. then 8 ml Pyridln% are added. He resulting solution is kept for 5 hours at # Ö ^O>, then poured into water. The organic phase and an ether extract of the aqueous layer are combined and washed successively with water, 2N hydrochloric acid, water, 5% sodium bicarbonate solution and again with water, dried over sodium sulphate and evaporated . adsorbed on 125 S Sllicagel with ueen first benzene fractions impolares - "---- · -. ■ r--

Eluted material containing later benzene fractions crystalline parts. These latter fractions are combined and give 4,6-dichloro-pregna-4,6-diene-3,20-dione crystallized from ethanol and hexane in colorless crystals;

Melting point 127-130 °, λ ° ^{2Η 50Η} 299 mji, (£. 18,000);

Max ·

Example 11

A solution of 1.00 g of 4,6-dichloro-pregha-4 _J , 6-diene-3,20-dione in 10 ml of carbon tetrachloride is cooled to 10 ° with exclusion of moisture, and then with a mixture of 0.1 ml of 70 ^ -ige perchloric acid and 2 ml acetic anhydride added within 10 minutes. The mixture is stirred for a further 60 minutes, then the solution is diluted with 100 ml of ether, washed with 5% sodium bicarbonate and with water. The solution is dried and concentrated to an oily consistency. The resulting 20-acetoxy-4,6-dichloro-pregna-4,6,17 (20) -trien-3-one is pure enough for further implementation. \

To a solution of 20-acetoxy-4,6-dichloropregna-3,6,17 (20) -trien-3-one (from 0.50 g 4,6-dichloro-pregna-4,6-dien-3,20-dione prepared according to the above process) in 2.5 ml of benzene is added 0.5 ml of 40 ^ peracetic acid. After 4 days 5 ml of 10 ^ strength sodium sulfite solution are added and the mixture is stirred vigorously. The reaction mixture is diluted with ether, washed with water, dried and evaporated. The residue is in

- · ■■ —- ■■ "" 0.098 * 4 / te2S ■ "■:" _r - ^! - "- ·.

Benzene dissolved, adsorbed on silica gel and eluted with 5% ether in benzene. Crystallization from ether gives coc-hydroxy-4,6-dichloropregna-4,6-diene-3,20-dione.

Example 12

A solution of'20-acetoxy-4,6-diohlorpregna-4,6,17 (20) -trien-3-one (from 0.150 g of 4,6-dichloropregna-4,6-diene-; 2,20-dione prepared by the method of Example 11) in 8.0 ml Benzene is added with stirring over a period of 5 minutes to a mixture of 2.0 ml of 40% peracetic acid and 80 mg Given sodium acetate. The mixture is stirred at room temperature for 1> hours, and then 10 ml of ice water and 2Ό ml of 10 ^ -iges Sodium sulfate too. The organic layer is treated with ether thin, washed with water, dried over sodium sulfate and evaporated to an oily consistency; the resulting 20-acetoxy-17a, 20-oxido-4,6-dichloropregna-4,6-dien-3-one is pure enough for further implementation.

A solution of 20-acetoxy-17ai20-oxido-4,6-dichloropregna-4,6-dien-3-one (from 0.25 S 20-acetoxy-4,6-dichloropregna-4,6,17 (20) -trien-3-one prepared by the above process) in 15 ml of tetrahydrofuran and 5 ml of IN hydrochloric acid Stirred β hours at room temperature and then poured into ice water. The amorphous precipitate is filtered off and removed benzene solution on synthetic magnesia silica gel (Florisil) adsorbed. Elution with benzene provides ■

■ 009844 / 1828-

_. " the end Aether crystallizes. ".

^; .. \ Example 15 - - ' -% \

A mixture of. 20-ac
pregna-4,6-diene -> - Qn (from 0 * 25 gpregnaM * 6jrl? (2Q) -t2 ^ enK> * om prepared according to the method of Example 12}, 20 ml methanol / and 30Ö mg sodium carbonate Monohydrate is stirred at dimmer temperature for 2 hours. 25 ml of ice water are added. dien ^ iS-Q dio-n.: ■ "" .. _: ^;

Example 14 ■; ■>;

To a 1 x 5 g of 6-chloro-lfßacetoxy-lT-methyl-andrQsta- ^ e-dien-S-one in 15 ml of dry dimethylformamide and 10 ml of ether are added 3 ^ 2 ml of a 1 * 4 M solution of Ohlor in propionic acid, Μφ, the mixture first leaves for 2 hours at Q °> _t: then 12 hours at 25 °.

The reaction mixture is poured into 100 ml of cold water and the resulting mixture is extracted three times with ether-methyl chloride (2.5: 1). The organic layers are washed with

Sodium bicarbonate solution and saline solution, dried ^: ■ over sodium sulfate and evaporated under reduced pressure. The residue is dissolved in benzene and chromatographed on 15 g of synthetic magnesia silica gel (Florisil). The benzene and ethyl acetate eluates are evaporated and the residue is crystallized once from methylene chloride / ether and three times from methanol. The 4,6-dichloro-17 ^ -acetoxy-17-methylandrosta-4,6-dien-j5-one has a melting point of 14-146 °, · [a] ^ ⁵ + 158.9 ° (C = 0 , 53 in CHOI,) «

The starting material can be prepared as follows;

To a solution of 10.0 g of 3-ethoxy-17β-acetoxy-17ecmethyl-androsta-3,5-diene a solution of 6.0 g of sodium acetate in 60 ml of water is added to 500 ml of acetone. The mixture will cooled to 5 ° and .inhalt of 5 minutes with 4.3 g of N-chlorosuceinimide and then quickly mixed with j5j5.6 ml of glacial acetic acid. The reaction mixture is stirred for 75 minutes at 5 ° and then diluted with 750 nil of water. It is extracted three times with Ether-methylene chloride, (2, SjI) washes the organic layers with 5% sodium bicarbonate solution and with water, dry over sodium sulphate and evaporate. The residue is in Benzene dissolved and attached to a column of] 5QQ g of synthetic Magnesia-Silioagel (Plorisil) chromatographed. One unites the benzene and ethyl acetate eluates and evaporate. Crystallization the residue from acetone-hexane gives 6β-chloro-17β ~ aoetoxy- * 17a-methylandrast-4-en-3-one with the melting point

008844/1828

158 °, which is sufficiently pure for the next level.

To a solution of 4.5 g of 6ß-chloro-1? Ss-acetoxy-17a « methylandrost - ^ - en - ^ - on in 25 ml of dry dioxaii is given 5.0 ml of tri-ethyl ortho-amelate and 0.20 g of p-toluenesulphonic acid. The mixture is stirred for βθ minutes at room temperature and then diluted with a solution of 50 ml of water and 2 ml Pyridine. The mixture is stirred for 50 minutes at room temperature and filtered the resulting precipitate> washes it with water and crystallized from approximately 20 ml of acetone containing 1 ml of pyridine. The 6-chloro-3-methoxy-17β-acetoxy-17a ~ obtained Methylandrost-5i5-diene has a melting point of 135-155 * 5 °.

To a solution of e-chloro-J-methoxy-lTß-acetoxy-lTocmethylandrost-3>, 5-diene in 2.4 liters of carbon tetrachloride 810 ml of a solution of tert-butylchromate are added with stirring (manufactured according to E, Heusler and A. Wettstein, HeIv. Chim. Acta 25;,. 289 (1952) in carbon tetrachloride, 81 ml thereon Ethic anhydride. The resulting mixture is then kept for 12 hours Reflux, cools; gives a solution of 243 g of oxalic acid in Add 2 liters of water and stir for another 2 hours. The chilled solution is extracted with 3 liters of chloroform, the organic phase is separated and washed with water, 5 $ sodium bicarbonate solution and finally with saline solution; washed. It is dried over sodium sulfate and evaporated. The residue will dissolved in benzene and attached to, 1 kg of synthetic magnesia silica gel

009844/1826

(Florisil). It is eluted with 4.5 1 10 $ ethyl acetate in benzene and 1.5 1 20 $ ethyl acetate in benzene, the combined fractions are evaporated, soldered in ethyl acetate and crystallized; The 6-chloro-17ß-aoetoxy-17-methylandrosta-4,6-diene -> - one, melts at 16-162.5 ° f «^ ⁵ + 25 * 8 ° (C _0.53 in CHCl,) .

Example 15

To a solution, cooled to -2 °, of 1.57 S 6-chloro-17β-hydroxy-i7-methylandrosta-4,6-dien-3-one 6.0 ml of one are added to 15 ml of dry dimethylformamide and 10 ml of ether 0.9 M solution of chlorine in propionic acid. Leave for 12 hours stand at 0 ° and then for 5 hours at 25 °.

The reaction mixture is poured into 100 ml of water and then extracted three times with ether-methylene chloride (2.5: 1). The organic phases are washed twice with 5% sodium carbonate solution and once with sodium chloride solution, dried and evaporated. The residue is crystallized four times from methylene chloride / ether. The 4,6-dichloro-17 {3-hydroxy-17-methylandrosta-4,6-dien-5-one melts at 156-157.5 °, [aj ^ ⁵ + 167.6 "(C = 0.55 in CHCI3).

The starting material can be produced as follows: "

009844/1826

To a solution cooled to Q °; 20.0 g of lithium aluminum hydride in 1 liter of ether are rapidly added to a solution of 25.0 g of 6-chloro ^ 7 ~ a ^ 4> 6-diene -> - one in 2 liters of ether while stirring. The mixture is stirred for 10 minutes 0 ° further and allow the temperature to rise to room temperature within an hour. The oil is then cooled again to 0 ° and 100 ml of ae ^ byl & cetät _; Then add 250 ml of saturated sodium sulphate solution within 10 minutes. The reaction mixture is heated to room temperature and filtered through a layer of filter aid and the precipitate is washed with ether and methylene chloride. The filtrate is washed with water, dried over sodium sulfate and / or evaporated. A colorless residue results, which is dissolved in 250 ml of dry dioxane. A suspension of 20 g of ^, ^ - dichloro-Siß ^ diQyano · * benzoquinone in 210 ml. The resulting Iliedersehlag abfiltrierty WDRD washed with dioxane and evaporated to dryness Piltrat "The Residues and, lösfrjßan in 1 liter Äether-Methylenehlorid (2.5: 1) and this solution is washed three times with sodium hydroxide solution _A l # Totelmenge ^ liters, Man the organic phases combine, dry over sodium sulfate and evaporate. The residue is dissolved in benzene and chromatographed on 200 g of synthetic magnesia silica gel (Florisil). It is eluted one after the other with benzene, 500 ml of 20% ethyl acetate in benzene and 250 ml of ethyl acetate in benzene, the eluates are combined and: evaporated.

The precipitate is crystallized from methylene chloride / ethanol

Additional product can be obtained from the mother liquor. After recrystallization from ethanol, the compound melts at 166-167.5 °. ''

Example l6

To a solution of 4.5 g of 4,6-dichloro-17β-hydroxy-17-methylandrosta- * 4,6-dien-5-one in 110 ml of dry amyl alcohol. 10.5 E of selenious acid and 4, 5 ml of acetic anhydride and the mixture is heated to reflux temperature. Over a period of 48 hours, another 4.0 g of selenous acid are added. After the mixture has been refluxed for a total of 60 hours, it is cooled, diluted with chloroform and filtered The filtrate is washed with 5% sodium bicarbonate solution 1N hydrochloric acid and water. The organic phase is dried over sodium sulphate and evaporated. The residue is dissolved in benzene and omatographed on 50 g of synthetic magnesia silica gel (Florisil). It is eluted with benzene and ethyl acetate in benzene, the eluates are combined and the residue is crystallized from methylene chloride / ether: 4,6-dichloro-17β-hydroxy-17-methylandrosta-l, 4,6-trien-3-one is crystallized again from the same solvent system, melting point 225-226.5 ° ία} ²⁵ + 6.4 ° (C = 1 * 06 in CHCl,).

D .. ■ s

^: "" - ^: · '"■■ *:. Example 17 ;

^: To a solution, cooled to -8 °, of 87.0 g of 6-chloro-17a-hydroxypregna-4,6-diene-3,20-dione in a mixture of 870 ml of dimethylformamide dried over calcium hydride and 4 ^ 5 ml of ether 356 ml of a 0.95 M solution of chlorine in propionic acid. It is left to stand first for 14 hours at 0 °, then for 6 hours at 25 °. The reaction mixture is poured into 3 liters of water, then extracted three times with ether-methylene chloride (2.5: 1). The organic phases are washed twice with 1.5 liters of 5% sodium bicarbonate solution and once with 2 liters of sodium chloride solution. The combined organic layers are dried over sodium sulfate and evaporated under reduced pressure. The remaining oil is dissolved in benzene / hexane (2: 1) and chromatographed on 1100 g of synthetic magnesia silica gel (Florisil). It is eluted successively with 2 liters of benzene / feexan (residue 0 mg), 1 liter of benzene (residue 18 mg), 1 liter of benzene with 2% ethyl acetate (32 mg), 1 liter of benzene with 5% ethyl acetate (5.92 g , not crystalline), 500 ml of benzene; with 10% ethyl acetate (19.0 g), 1.5 liters of benzene with 20 $ ethyl acetate (54.1 g) and 1 liter of benzene with 40 $ ethyl acetate (16 g). result in fractions which crystallize after trituration with ether.

The combined solids are extracted three times from methylene chloride / ether recrystallized, and yield 4,6-dichloro-17a-hydroxypregna-4,6-diene-3,20-dione from melting point 159.5-

009844 / 182f

l6l ° [α J ψ + 185.4 ° (C = 0.5 in CHCl ^),

Example 18

Add to a suspension of 27 * 0 g of 4,6-dichloro-17a-hydroxypregna-4,6-diene-3,20-dione 27.0 g of p-toluenesulfonic acid in 1350 ml of glacial acetic acid and 270 ml of acetic anhydride, stirred the mixture until the pesticide has completely dissolved, and lets stand for β hours at room temperature. The reaction mixture is poured into 7 l of water, the precipitate is after Filtered for 30 minutes and washed well with water. The damp The product is dissolved in approximately Γ liters of methylene chloride, dried over sodium sulfate and the solution concentrated to approx. 200 ml under reduced pressure. The helsse solution will be concentrated further with the simultaneous addition of 150 ml of ethyl acetate, the 4,6-dichloro-17a-acetoxy-pregna-4,6-diene-3,20-dione fails. Melting point after recrystallization. sation from the same solvent 241.5-243 °.

Example 19

An ointment can have the following composition:

990 g per kg of Vaseline

4,6-dichloro-17a-acetoxypregna-4,6-diene-3,20-dione Ig

0 0 98U / 182B

1618483

Gelatine cheese soap can have the following sasara composition:

■■■■■ '■ .- "" ^: "-. ''-■" - ■■'.: .-; v ^: Per capsule

Lactose "'. - .. \ Corn birch.

0.5 ing J 180.0 mg mg 6.0

225.0 ing

Tafoletteri can be set like föigfe ssusanimen:

Lactose, spray dried

Corn starch ■■ ,. "

Calcium stearate Total weight

Example

■ * o mg m , 0 mg > ö mg 1 m $ 100 , 0 mg

One suitable for animal feed; 12.5 ^ premix can

have the following composition:

4, ö-Bichlor-lTa-acet Qxypregna-4,6-diene-3,2Q-dione 125 g

Weisenkeimmehi 8 "3Ig

Drew-Oei l ^ OQ (a mixture of glycerol triesters of fatty acids of low molecular weight (e ^ -Cig) 44 g

Total weight ". 1000 g

You can add this premix to commercial chicken feed at a ratio of 1 kg per ton ("WirkT substance content $ 0.0125) * This feed can be used as a Mash, on the other hand, can be administered in pill form. Yom The above mix can add such amounts to chicken feed that the drug concentration is $ 0.0005 to $ 0.05. · '·

Example 23

A $ 6 premix for animal feed can have the following composition:

4,6-dichloro-17a-acetoxypregna-4,6-diene-3,20-dione 60g

Wheat germ flour 836 g

Drew Oil 1400 44 g

Total weight 1000 g

This premix can be used in commercial chicken feed Ratio of 1 kg per ton are added (active ingredient content $ 0.006). The feed can be mashed or in Administered in pill form. /

Such amounts can be added to chicken feed from the above vorgemiseri be given that the drug concentration ■ is $ 0.005 to $ 0.05.

Example 24 An ointment can be composed as follows:

* 4, o-dichloro-lYa-acetoxypregna - ^, 6-

diene-3,20-dione 0.1 Stearic acid 13.50 Light mineral oil 1.35 Sorbitan monostearate 2.25 Methyl p-hydroxybenzoate 0.08 Propyl p-hydroxybenzoate 0.02 Sorbitol 4.50 Polysorbate 60 (polyoxyethylene 20-sor-
bitane monostearate) i, 6o Distilled water "q.s.äd 100.00 pH - about - 5.1

Example 25

A consume in liquid form can have the following composition exhibit:

4,6-dichloro-17a-aoetoxypregna-4,6-diene-3,20-dione 25 g

Polysorbate 80 (polyoxyethylene 20-sorbitan monooieate) 400 g

Propylene glycol 575 g

009844/18 ^ 6

; Ί6ΊΒ493

Example 26

53 ml of a 1 molar solution of chlorine in Propionic acid. The reaction mixture is left overnight at 0-5 °, then 6 hours at room temperature, diluted with water and extracted with an ether / methylene chloride mixture (2.5: 1). After working up, the organic phase yields 25.5 g of crude product which is chromatographed on 1250 synthetic magnesia silica gel (Florisil). It is eluted with benzene and benzene-ethyl acetate mixtures. From the initial fractions (benzene with 2 $ ethyl acetate) 1.6 g of a product are obtained which contains 2a, 4,6-trichloro-17a-acetoxy-pregna-4,6-diene-5,20-dione. The other fractions provide 7 * 35 g ^ iö ^ ö

Renewed chromatography of the 1.6 g fraction of Silicage.1 with the same solvent system as above gives 0.64 g of "crude 3α, 4,6 ¹ 3? Richlor-17α-acetoxy-ρregna-4,6-dien-3 , '20-dipn, which is triturated with ether and then recrystallized from methylene chloride / ether. Colorless crystals, melting point 220-226 ° (decomp.) [Aj | ⁵ + 135 ° (in chloroform);> _max = 301 ταμ, E = 17100 (in ethanol). '.

009844 / 182t

Example 27

A solution of 4 g of 4.6
Diene-3,20-dione in 40 ml of glacial acetic acid is mixed with 10.6 ml of a 0.948 molar solution of chlorine in acetic acid at room temperature in the course of 10 minutes. The reaction mixture is left to stand at room temperature overnight, then diluted with water and extracted with methylene chloride. The crude product, 4.3 g, is chromatographed on silica gel with benzene as the eluent. The initial fractions give 1.97 g of 2a, 4,6-trichloro-17a-acetoxy-pregna-4,6-diene-3,20-dione, which is recrystallized from methylene chloride / ether. Melting point 228-235.5 ° (dec.).

A solution of 1.2 g of 2a, 4,6-trichloro-17a-acetoxy-pregna-4,6-diene-3,20-dione in 25 ml of dimethylformamide is added with 0.25 S. Lithium chloride heated to reflux for 30 minutes under nitrogen. The reaction mixture is poured into water and with Extracted methylene chloride. The extract is worked up and the evaporation residue obtained is mixed with 30 g of aluminum oxide with benzene and benzene / methylene chloride as eluent. 0.81 g of 4,6-dichloro-17α-acetoxy-pregna-l, 4,6-triene-3,20-dione are obtained, Melting point 228-229 ° (from methylene chloride / benzene)

Ä + 18 ° (in chloroform) j> _mQV - 233-23 ^ ημιΕ- 12600;

υ max

260-263 ιημ, £ = 7900 and 308 mM, £ »9220 (in ethanol).

009844/1 ^ 26

Claims (1)

Claims 1. Process for making new halogenated steroids the partial formula in which R _{1 is} fluorine, chlorine or bromine or a lower alkyl group; Q, an oxo group or a 1,2-alkylenedioxy group with 2-Λ carbon atoms and M represent the remaining part of rings A and B and rings C and D of the steroid skeleton,
characterized in that one is a compound of the formula 009 * 44/1026 In the JL and M have the above meaning, with chlorine either in the presence or with subsequent Treated addition of a proton acceptor and, if desired, converted the 3-oxo group into a 1,2-alkylenedioxy derivative. 2. The method according to claim 1, characterized in that that Q represents an oxo group and M and R have the same meaning as in claim 1 have. 5. The method according to claim 1, characterized in that Q represents a 1,2-alkylene dioxy group and M and R _{1 have} the same meaning as in claim 1. 4. The method according to claim 1-3, characterized in that that the starting compound is a compound of the formula V, in which M represents a group of sub-formulas II, III or IV. K ₂ -R ₂ II 009844/18 * 6 III ίο j IV R ₁ - and in. where R _{2 is} hydrogen or fluorine; R, hydrogen, a hydroxy, lower-alkanoyloxy or lower-alkyl group; R ^ hydrogen or a lower © alkyl group, Rq independently of one another is hydrogen or a lower alkanoyl group; Rg hydrogen, a 'lower alkyl group or an ethynyl group; R is hydrogen or a methyl group; Rg hydrogen or fluorine, chlorine or bromine; R ^ _{0 is} hydrogen, an _{α-hydroxy or lower-alkyl groupj R 1} - a kydroxy group or, together with R _10, a group of formula C (lower alkyl) ₂ ; X a bond · / 1820 ; between the 1 and 2 positions; η O or 1; Y is a: methylene, β-hydroxymethylene, α-hydroxyraethylene ^,; or carbonyl group and Z is a methylene * ·, ß-Hydroxymethylene group, oc-hydroxymethylene or carbonyl group or, if Rq is chlorine, a β-chloromethylene group, where Z is a methylene or α-hydroxymethylene group only when R. _{Q is} hydrogen; 5. The method "according to claim 1-4, characterized in that that in a further reaction step, free hydroxyl groups contained in a reaction product are esterified. 6. The method according to claim 1-5, characterized in that that obtained ^, ö-dichloro-lTa-methyl-lTß-hydroxy-andrösta-4,6-dien-3-one or ^ e-dichloro-lTa-acetoxy-pregna- ^ ö-diene-3,20-dione dehydrated in a further reaction step in the l (2) position. 7. The method of claim 1-5 $ characterized in that one is a reaction product of the formula. CK ₂ -R2. · Q = O
H ₃ C VI ■ - ■ & - ■ 1618Z.93 in which R 1 is hydrogen and R ₁ , R 0 and X are the same as in claim X;
hydroxylated in the 17-position. - 009844/18 ^ 6