DE1643023C3 - Process for modifying the 11-position of a 9-alpha-halogen steroid of the pregnane or androstane series - Google Patents

Description

2. The method according to claim 1, characterized in that ■

draws that the 9 "-halogen-II /? -X-steroid in ao

The presence of water is treated with the reagent YZ. The invention relates to a method for Abwand-

3. Method according to one of the preceding long the 11-position of a 9 ″ -halogen steroid Claims, characterized in that the pregnane or androstane series, which is characterized by the 9'-position halogen, is chlorine. it is noted that in a corresponding 9a-halogen

4. The method according to any one of the preceding II /? - X-steroid, wherein X is a group included in Claims, characterized in that the SuI presence of a strongly nucleophilic anion from the fonyloxy group a substituted or unsubstituted position to which it is attached, in the form of an anion Eliminated hydrocarbon sulfonyloxy group with leaving and preferably a halogen atom or a up to 20 carbon atoms, preferably tosyl- 30 sulfonyl group, but then not an iodine atom if oxy group, is. the halogen atom in position 9 * is iodine, the sub-

5. The method according to any one of the preceding tucnt X by treatment with a reagent of Claims, characterized in that Y Hy- general formula YZ, in which Y is a strongly nucleodroxyl, azide or halide, philic anion and Z is a cation, against Y

6. Method according to one of the preceding 35 is exchanged.

Claims, characterized in that Z was sub outgoing group "is corresponding to the

"Rrstoff, ammonium, alkali metal or alkaline earth- Meaning d * s in the English-language literature

metal is the common expression »leaving group« a group

7. The method according to claims 5 and 6, understood that in the presence of a strongly nucleophilic characterized in that the reagent YZ water or 4 ° anion from the position to which it is attached in «Exits in alkali metal azide or halide, preferably in the form of an anion. B. 9a, ll /? - is disodium azide or sodium chloride. chlor-löa-methyl-l ^ -pregnadien-na ^ l-dioI-S ^ O-di-

8. The method according to one of the preceding on-21-disodium phosphate or 9a-chloro-110-p-toluene-claims, characterized in that the sulfonyloxy-loa-methyl-l ^ -pregnadiene-not ^ l-diol-9ot-halogen -110-X-steroid one at C-21 by 45 3,20-dione-21-disodium phosphate in water, so will Hydroxy, lower alkanoyloxy or lower alk- the 11 / S-chlorine atom or the 11/3-p-toluenesulfonyloxyoxycarbonyloxy with preferably up to 10 carbon groups separated from the steroid nucleus and replaced by hydrogen atoms or by alkali metal phosphodoxyl and thus 9 « -Chlor-16Ä-methyl-pΓedniryloxy substituted 9 "-halogen-II /? - X-pregnan solon-21-uatriumphosphat, a strong inflammatory disease. so inhibiting agent, formed. Equivalent to the

9. Process according to any of the foregoing preferred leaving groups Claims, characterized in that one group such as substituted carboxyl, sulfate, 9 ", ll /? - dichloro-16 (" or 0) -methyl-1,4-pregna-chlorosulfite, chlorophosphite and the like. diene-17 «, 21-diol-3,20-dione-21-disodium phosphate, the halogen emerging at the C-II can be fluorine, 9a-bromo-110-chloro-16 «-methyl-1,4-pregnadiene-55 be chlorine, bromine or iodine.

17a ^ l-diol-3,20-dione-21-disodium phosphate, a fall under the term "sulfonyloxy group"

9 «-Chlor-II /? - tosyloxy-4-pregnen or a 21-low hydrocarbon sulfonyloxy groups with up to

rigalkanoate or 21-alkoxycarboxylate thereof, 20 carbon atoms, such as alkylsulfonyloxy, e.g. B.

especially a 9a-chloro-II /? - tosyloxy-16 «-me- methylsulfonyloxy (= mesyloxy) or ethylsulfonyl-

ethyl-M-pregnadiene-na ^ l-diol-S ^ O-dione ^ l-eth-60 oxy; and arylsulfonyloxy, e.g. B. Benzenesulfonyl

tixycarboxylate or a 9 <x-chloro-ll /? - tosyloxy- oxy, naphthalene-jJ-sulfonyloxy, p-toluenesulfonyloxy,

1.6 "'methyl-1,4-pregnadiene-17", 21-diol-3,20-dione- (= tosyloxy), o-toluene-oonyloxy, m-toluenesulfonyl-

21-acetate used as starting compounds. oxy, 3,4-xylenesulfonyloxy and dodecylbenzenesulfonyl-

10. The method according to any of the preceding oxy; further substituted hydrocarbon sulfonyl claims, characterized in that the 65 oxy groups with up to 20 carbon atoms, e.g. B. Treatment of the 9 * -halogen-II / 3-X-steroid with p-bromobenzenesulfonyloxy, p-chlorobenzenesulfonyloxy, the reagent YZ in the presence of a polar Lö- m-chlorobenzenesulfonyloxy, p-nitrobenzenesulfonyloxy, solvent, in particular a hydroxyl group p-methoxybenzenesulfonyloxy, o-dimethylaminoben-

zolsulfonyloxy, m- or p-cyanobenzenesulionyloxy is tosyloxy, preferably as a 21-lower alkanoate

and the like are any of the foregoing compounds

The used in the process of the invention reacts with water to form a 9 <x halogen Reagents YZ are ionizable compounds that ll / Miydroxy-pregnans with appropriately esterified

under the name nucleophiles (i.e. electron 5 corticoid side chain; such pregnans belong to a

Deficiency Centers Seeking Groups) are known and known class of compounds with adrenocorticoider

which consists of a nucleophilic Anton Y and an efficacy (e.g. such as hydrocortisone, prednisolone

Cation Z, which is preferably hydrogen, and the like, the well-known anti-inflammatory Ammonium or an alkali or alkaline earth metal ion are agents).

The ionizable reagents YZ close the «The inventive method is usually bonds that are self-ionized, and those that are not ionized in solution in a polar solvent, whereby it is not done for themselves, which preferably has a hydroxyl function ionized reagents is sufficient that it contains in the invention, such as water (which thus has a double role play according to the method as donors for the anion Y, namely both as a solvent and as can serve. The preferred reagents are 15 Reagent YZ can serve), lower alkanols (preferably those which have hydroxyl, azide and halide as anions, methanol), phenols and carboxylic acids, before to have. preferably lower alkanoic acids, e.g. B. acetic acid and

Equivalents of the foregoing preferred nucleo-propionic acid, and mixtures of the foregoing

Philic anions are other strongly nucleophilic anions, solvents.

such as cyanide, lower alkoxy, phosphate, amino, low- *> When carrying out the inventive method

rigalkylamino, arylamino, lower alkanoyloxy, aryl driving is preferably stirred a solution of the

carboxy, thio, Tbio-lower alkyl, thioaryl u. dgL Er- 9a-Halogen-II /? - X-steroids together with the nucleo-

according to the invention, each of the foregoing anphilic reagents YZ occurs at moderate temperatures, such as

ions Y in implementation, e.g. B. with a 9λ, 1 1 / J-Di- e.g. from about room temperature (i.e. about 18 ° C)

halogen steroid or a 9 «-halogen-II / 3-sulfonyl- 35 up to the boiling point of the solvent used,

oxysteroid, under the conditions of the present until the reaction has ended, what chromatographic

Procedure in place of the leaving group, analyzes (for the absence of the starting material), analysis

such as the halogen atom or the sulfonyloxy group, analyze for the presence of an equivalent of the

at C-II with formation of a 9ct-halogen-1 1 ^ -Y-standing group (e.g. if this is chlorine, analysis

roids. 30 on chloride ions) and other known methods

To the typical reagents YZ, which do not display themselves. You can then use the 9 «-halogen-

are ionized, include water (Y = hydroxy), isolate Nied- llß-Y-steroid according to known methods,

rigaü anic acids and especially acetic acid (Y = Al- Usually the process is carried out at temperatures in

kanoyloxy, e.g. B. acetoxy), aryl carboxylic acids, e.g. B. Range of about 30 to 75 ° C performed.

Benzoic acid (Y = benzoyloxy) and methylbenzoic acid are obtained according to the invention

acids (Y = methylbenzoyloxy), hydrogen sulfide substitution products with shorter reaction times,

(Y = hydrogen sulfide), alkyl mercaptans, e.g. B. Me- if you have a molar excess of nucleophilic

ethyl mercaptan (Y = methyl sulfide); Aryl mercaptans, reagent YZ used by best the

e.g. thicphenol (Y = phenyl sulfide), ammonia saturates the reaction solution with the nucleophilic reagent.

(Y = amino), alkyl and aryl amines, e.g. B. Methyl- 40 To avoid undesired competing side reactions

amine (Y = methylamino), dimethylamine (Y = di- to a low level, keep the

methylamine), phenylamine (Y = phenylamino) and the like. The pH of the reaction solution is preferably within

The typical self-ionized nucleophilic reagent ranges from about 4 to 8.5, especially im

Gentien include sodium azide (Y = azide), sodium range from about 6 to 7.5.

chloride (Y = chloride), sodium bromide (Y = bromide), 45 According to a preferred embodiment of this

Potassium cyanide (Y = cyanide), sodium methylate (Y invention stirs 9 ", 110-dichloro-16Ä-methyl-

= Methoxy), alkali metal hydrogen sulfides, e.g. B. Na- l, 4-pregnadiene-17 «, 21-diol-3,20-dione-21-disodium-

trium hydrogen sulfide (Y = hydrogen sulfide), alkali phosphate (X = chlorine) in water for about 6 hours

metaphosphate (Y = phosphate) u. like. about 6O ⁰ C, during which the pH is from 8.5 to

Unless otherwise defined, Ex 50 falls below 6 because the nucleophilic reagent (i.e.

press like »lower alkyl«, »lower alkoxy« and Y = hydroxyl) releasing chloride ion (X)

"Lower alkanoyloxy" in the present patent occurs at the C-11 site

registration to understand groups whose carbo-halohydrin (i.e. the 9a-chloro-II /? - hydroxy-deri-

hydrogen part preferably up to 8 carbon vat), by the reaction mixture up to one

contains atoms. 55 acidifies pH value less than 1 and then that

In a preferred embodiment of the inventively precipitated 9 "-chlorine-II /? - hydroxy-16" -methyl ·

The method according to the invention is the nucleophilic rea- 1,4-pregnadiene-17 <x, 21-diol-3,20-dione-21-phosphate (part

gens YZ water (i.e., the nucleophilic anion Y is a known anti-inflammatory agent)

Hydroxyl, and the cation Z is hydrogen), and the 21-phosphate can in turn be an enzymatic «

IIß-X group is either 11/3 halogen (preferred 60 dephosphoryliening according to known methods under

wise ll /? - chlorine) or 11 / f-tosyloxy, with 9 "-halo-throwing, which is based on the ester

gen-11 / S-hydroxy steroids can be obtained. On the underlying alcohol, 9 * -chloro-16 «-methylprednisolone

The most suitable for this preferred embodiment is also a potent anti-inflammatory agent

as 9 ", ll /? - dihalo- or 9ix-halo-ll ^ -tosyloxy- obtained.

The starting steroid is a pregnan with one on the 21-Hy- 65 in the above reaction

Droxygruppe esterified corticoid side chain, where the 110-chlorine atom and the cation Z are chlorine

the 21-hydroxy group, when X is halogen, preferred hydrogen, the disodium phosphate ester in mono

wisely as a phosphate alkali metal salt, and when X converts sodium hydrogen phosphate ester. Further

5 6th

Acidification with strong acid sets the 21-phosphate-17 «, 21-diol-3,20-dione-21-ethoxyearboxylate can ester free. be isolated by distilling off the methanol,

9cü, ll / 3-Dihalogen-prcgnane with 21-position acidic the reaction mixture then with a Substance function are preferably extracted in the form of one of their water-immiscible solvents 21-phosphate alkali metal salts (e.g. mono- or di- 5 (e.g. with methyl chloride), then the sodium phosphate) of the treatment according to the invention restricts some extracts and so the aforementioned subject when one passes through the ll £ -halogen. 9 "-Chlor-II /? - hydroxy-pregnane obtained with special 110-hydroxy will replace The 21-phosphate-alkaline advantage is used in the invention metal salt is preferred as it is the steroid water- process then ll /? - tosyloxy as a leaving group, Solubilizes and also, like the rate of reaction, if one uses another at the C-II instead of hydroxyl Ability measurements show that the exit of the X group wants to introduce groups. You add, for example What seems to facilitate the complete um-9a-chloro-110-tosyloxy-16ar-methyl-1,4-pregnadiene conversion of the a9, llj9-dihalogenstero: ids into a 9 <x-Ha-17 ", 21-diol-3 , 20-dione-21-acetate (= 9a-chloro-16 <x-melogen-ll ^ -hydroxysteroid required 15 saturated solution of sodium azide in aqueous Me-reaction time for the exchange, of ll /? - chloro thanol (z. B. water to methanol = 1: 4), which Brought against a 110-hydroxyl function in a 9a, 110-di- with acetic acid to a pH of about 6 chlorine ^ -pregnen-na ^ l-diol-S ^ O-dion ^ l-disodium- and stirs this reaction solution about phosphate usually about 3 to 10 hours. 24 hours at about 60 ° C, the ll /? - tosyloxy

If the free steroid alcohol or a 21-lower group is replaced by the nucleophilic azide anion under the same alkanoate or a 21-alkoxycarbucylate thereof as the early formation of p-toluenesulfonic acid and the starting steroid used in the above reaction is 9 * -chloro-II /? - azido If -16a-methyl-1,4-pregnadiene is used, it is advantageous to use a low-17 ", 21-diol-3,20-dione, which for the new alkanol is preferably methanol, which is the solvent class of the 9" -halogen II / ? -azido-steroids the pre- or solvent ingredient. If you z. B. as gnanzeile belongs to a class with anti-inflammatory 9 ", ll /? - dichloro-16" -methyl-1,4-pregnadiene-3,20-dione-mender effectiveness which is solved by the 21-acetate according to the invention in 50% ig? m aqueous methanol process is accessible for the first time 24 hours at 6O ⁰ C, then one obtains a Mi. , 4-pregnadiene-17 «, 21-diol-3,20-dione-21-acetate with gelatinous reagents which form strongly basic solutions, compete with amounts of the corresponding compound with z. B. sodium azide, potassium cyanide and sodium methyl-free 21-hydroxy group. lat has been found to be beneficial to this

The latter compound is formed by hydrolysis solutions before the addition of 9 <x, 110-dihalogenous 21-lower alkanoate, brought about by chlorosteroids to a pH of about 4 to 7.5 buffer hydrogen from the exiting 11 / J-chlorine and 35 to avoid undesired side reactions, e.g. B. the the cation (hydrogen) is formed. The product reaction between halogen substituents and strong ones Mixing can easily be restricted to either the 21-ester alone bases, to a low level by reaction with acetic anhydride in pyridine. It was also found that the inventive

or to the 21-hydroxy compound alone by the Hy process, generally in the presence of water drolysc with acid or base by known methods 40 runs faster. B. advantageous to be converted into water. riges methanol instead of anhydrous methanol

Even if halogen atoms other than chlorine to be used as a solvent, if you are a C-9 of the 9,11-dihalogen starting steroid bonded 110-halogen atom or a ΙΙ / ί-tosyloxy group through, such as. B. in 9 "-Bromo-II ^ -chlor-16" -methyl- the azide group is replaced Replacement of 9a-fluoro-II / 3-chloro-1,4-pregnadiene-17a, 21-diol-3,20-di- of the 110-halogen or the II /? - tosyloxy group by on-21-disodium phosphate is obtained after which the azido group is also about 11/3 hydroxysteroid, which process according to the invention by its reaction, however, is easily separated from the resulting 110 azido derivative with water at, for example, 6O ⁰ C Jas corresponding easily by means of chromatographic methods. B. 9 "-Brom-II /? - hydroxy-16a-me- can be separated.

Ayl-l ^ pregnadien-na ^ l-diol-S.lO-dion ^ l-sodium- In a similar way, the inventive method is

Phosphate or 9 ”-fluoro-11/3-hydroxy-1,4-pregnadiene are best carried out in aqueous methanol 17ot, 21-diol-3,20-dione-21-sodium phosphate both of which if one has an 11/7 tosyloxy group by means of reaction have strong glucocorticoid effectiveness. with sodium chloride or sodium bromide by one

In the foregoing, a preferred embodiment was replaced. When stirring a solution of the embodiment of the process according to the invention, 9 "-chlorine-II /? - tosyloxy-16" -methyl-1,4-pregnadies were written, in which a 9 *, ll /? - Dihalogen-21-oxygenated 17a, 21-diol-3,20-dione-21-ethoxycarboxylate and Na-pregnane by treatment with water in the enttrium chloride (or sodium bromide) in an aqueous metal-speaking 9 "-halogen-II | The 9-hydroxy derivative converted by ethanol is used to convert the 110-tosyloxy group leaving the group. According to a further preferred embodiment, the nucleophilic halide ion is replaced and the process according to the invention is obtained. preferably a 110-tosyloxydiol-3,20-dione-21-ethoxycarboxylate (or 9 <x -chloro group, replaced by a hydroxyl group Diol leads, for example, to 9 "-chlorine-II / I-tosyloxy-16a-methyl-1,4-pre-3,20-dione-21-ethoxycarboxylate" gnadiene-17α _> 21-diol-3 ₎ 20-dione -21-äthoxycaΓboxylatge- 65 It should be noted that in the detachment according to the invention in 50% aqueous methanol for about 21 hours, the leaving group X is halogen and the same at 60 ° C. The 9,11-halohydrin formed, ie the nucleophilic anion, is introduced early Halogen anion can be 9a-chloro-II /? - hydroxy-16 <x-ynethyl-1,4-pregnadiene-, for example, obtained by reacting

jp

21-acetate with a saturated solution of sodium chloride in aqueous methanol (1: 4) according to the invention Method 9 "-Bromo-II /? - chloro-1,4-pregnadiene-17 <x, 21-diol-3,20-dione-21-acetate. By means of the process according to the invention, it is now possible to use the substituent X on the C-II of a 9'-halogen-11/8-X steroid by a nucleophilic anion Y while maintaining the respective configurations on C-9 and C-II to replace and on this Way to get a 9a-halo-II / 8-Y-steroid ·. The The method according to the invention therefore essentially represents a nucleophilic substitution reaction on one saturated carbon atom of a steroid structure, with the 110-X group as the "leaving group" and the 9 ”halogen atom act as a“ neighboring group ”and the nucleophilic anion Y to form the corresponding one 9 "-Halogen-II /? - Y-steroides occurs. It It is therefore particularly valuable that a 9'-halogen-11 / I-nucleophile-substituted by means of the process according to the invention Steroid product with the same configuration as that used as the starting material 9 «-halogensteroid is obtained as it is used in steroid chemistry and in particular in the series of Corticosteroids important for pharmacological efficacy are the 9a-halogen-II / J-Y configuration to have, especially if Y is hydroxy, since 9'-halogen-II / S-hydroxypregnane with a corticoid side chain are generally effective as corticoids at C-17, whereas their Ila isomers are generally effective not.

In addition, 21-phosphate esters and their Prepare salts of 9 "-halogen-II /? - hydroxy-pregnanes with a corticoid side chain at C-17. this is of particular value when one uses the 21-phosphate of a 9'-chloro-11j8-hydroxy- or a 9a-bromine /? - hydroxy-pregnans, z. B. of 9a-chloro-16a-methyl-prednisolone or of 9 ″ -Bromo-16a-methyl-prednisolone, who wants to produce by known processes are difficult to manufacture.

Without affecting the course of the method according to the invention, the starting steroid, preferably a 9 ”-halogen-II /? -X-pregnan or -androstan (including the corresponding 19-nor analogs are understood), in general Double bonds in the steroid core, e.g. B. at the C-I and C-4, C-6, C-7, C-8, C-14, C-15 and C-16, and additional Substituents, e.g. B. methyl, methylene, hydroxyl, Ester and ether groups, e.g. B. at C-3, C-4, C-5, C-6, C-7, C-14, and C-16; Fluorine and chlorine, e.g. B. at C-6 and C-16; and keto groups, e.g. B. at C-3, C-17 and C-16; u. dgL have.

Instead of the preferred nucleophilic anions, can for example equivalents thereof, -as stated above, ' use / and adamit the appropriate 9i% -halogen-ll £ -Y-steroids are produced.

Thus, in the case of a solution of 9 "-chlorl ^ tosloxy ^ töäüiyll ^ pregnldiene17" 21diol 21-acetate, 9 <x-chloro-llj5-methoxy-16 "-methyl-1,4-pregnadiene-17a, 21-diol -3,20-dione-21-acetate, 9a-chloro-1 Iß - phosphoryloxy -16 "- methyl -1,4 - pregnadiene-17", 21-diol-3,20-dione-21-acetate, 9 " -Chlor-II / 3-amino-16a - methyl -1,4 - pregnadiene -17 ", 21 - diol - 3.20 - dione-21-acetate, 9" -Chlor-II / S-methylamino-16 "- methyl-1,4 - pregnadiene -17 ", 21 - diol - 3.20 - dione - 21 - acetate, 9" - chloro-llyi-phenylamino - 16 - methyl - 1,4-pregnadiene -17 ", 21 - diol - 3.20 - dione - 21 - acetate, 9 «- ChlorII / S-acetoxy-loa-methyl-l ^ -pregnadiene-Ua ^ l-diol- S ^ O-dione ^ l-acetate ^ a-chlorine-ll / J-benzoyloxy-loa-methyl-1,4-pregnadiene-17 ", 21-diol-3,20-dione-21-acetate, 9" -chlorine-II / 3-thiol-16 <x-methyl-l , 4-pregnadiene-17a, 21-diol-3,20-dione-21-acetate, 9 "-chlorine-II-thiomethyl ether -16" -methyl-1,4-pregnadiene -17 ", 21 -dtol-3 , 20-dione-21-acetate or 9 "-chloro-II / 3-thiophenyl ether-16a - methyl -1,4 - pregnadiene - 17a, 21 - diol - 3,20 - dione -21-acetate.

As a starting steroid for the inventive method

ao driving any 9a-halogen steroid with a ll /? - X group, as previously defined, can be used, provided that when an iodine atom is bonded to C-9, a halogen atom at C-II is fluorine, chlorine or Must be bromine. Usually 9a halogen

a5 11/3-X-substituted steroids of androstane and Pregnan series, including their 19-Nor-analoga, as Starting compounds used. Many of these connections are known and, if not, easily are available can be prepared from the corresponding 9 (11) -Dehydrosteroiden by known methods be made such. B. for the 9 ", ll /? - dihalosteroids in U.S. Patents 28 94963, 30 09 927 to 30 09 033.30 09 938.30 26 339.30 32 564, 30 49 554 and 31 31 200 described.

The parent 9a-halo-II /? -Sulfonyloxy steroids can e.g. B. be produced according to a known method explained below by way of example, by combining the corresponding 9 (11) -dehydrosteroid with, for example, p-toluenesulfonic acid in pyridine can react with N-bromosuccinimide or N-chlorosuccinimide, the corresponding 9a-halogen-110-tosyloxysteroid is obtained. Some typical examples of such compounds are 9a-ChlorllSlddi

35

40 jyyp

21-ethoxycarboxylate, 9a-chloro-ll ^ -tosyloxy-l, 4-androstadien-17/3-ol-3-one and 9a-chloro-ll /? - tosyloxy-19-nor-4-androsten-3,17 -dion. Treatment of the above 9-chloro-ll / S-tosyloxy-steroids with water in methanol, for example at 60 ⁰ C, the tosyloxy group at the C-Il is replaced by hydroxy, and one obtains the corresponding 9a-halo-llj9-hydroxy -Derivatives, ie 9a-chloro-II / 3-hydroxy-1,4-pregnadiene-17 ", 21-diol-3,20-dione (in a mixture with its 21-ethoxycarboxylate) _f 9a-chloro-II ^ -hydroxy -l, 4-an-

drostadien-17/3-oi-3 "-On ^v Szw. ' ^ a-Chlot-lljU ^ ya ^ oxy-19- «or-4-androsten-3,17-dione.

T ^> iscJie 9, il-Dihaldgen-AtisgangssJteroide ^ uid ^ & - drostanderivate, like ^ all ^ -Dichlor-l ^ ändröstädien-347HUOn 9U / SDichIoil7 ^ militfeS

50

S ^ O-dioa ^ r-acetate and a / aucleophilic reagent, 60 tat, e.g. lCaluincyam ^ l ^ atriummethylatiläiosphorsäure, 9 «-jod-

■ "* ·" · "v, -, i ..., iV. - _« .- ^ j.ik Esdgstöre, fa-CMö 17-Pföpionat ti and ti

_ -äol at 6O ⁰ C the äien-17 ^ ol-3-on- ^ ipi, _, ^

1 nucleophilic anion Y G & guest for 2 days -EriatieQ ÄitrWa LM-V .- ^. - faanA aaf ttomtä "" - = ^ ~ <- · «^ * - ^ - **"

«09« 24/52

diene-3,17-dione, 9 "-chlorine-II / 9-hydroxy-17" -methyltestosterone acetate, 9 "-Bromo-l /? - hydroxy-1,4-androstadiene-3,17-dione, 9 "-iodine-l / 3-hydroxy-1,4-androstadien-3,17-dione, 9" -chlorine-II / 9-hydroxy-1,4-androstadien-17 /? - ol-3-one -17-propionate or 9a-bromo-ll /? - hydroxy -1,4 - androstadiene - Πβ -Ο1-3-ΟΠ-17-propionate, including their 19-nor-androstane derivatives, such as 6a-fluoro-9a, ll ^ -dichlor-19-nor-4-androstene-3,17-dione and 9 "-Bromo-II) S-chloro-19-nor-4-androstene-3,17-clion, which when treated with water in Methanol at 60 ° C öa-fluorine ^ a-chloro-II / S-hydroxy - ^ - noM-androsten-3,17-dione or 9a-bromo-II / 3-hydroxy-19-nor-4-androsten- 3,17-dione yeasts which are valuable as anabolic and androgenic agents; also progesterone derivatives such as 9 ", ll ^ -dichloro-17" -hydroxy-progesterone, 9a, ll / i-dichloro-progesterone, 9a, ll /? - dichloro-17 * -acetoxy-progesterone, 9a-chloro-l l / S-fluoro-1,4-pregnadiene-3,20-dione, 9 ", 1 l / J-dichloro-19-norprogesterone land 9ft-bromo-l l /? - fluoro-l 7" -hydroxy-19-norprogesterone , on treatment with water in methanol at 60 ° C make the process according to the invention 9 "-ChlorII / S, 17" -dihydroxy-progesterone, 9 "-Chlor-II /? - hydroxy-progesterone, 9a-chlorine-l 1 / 3-hydroxy-l 7a-acetoxy-progesterone, 9 "-chlorine-l /? -Hydroxy-l, 4-pregnadiene-3,20-dione, 9" -chlorine-II / 3-hydroxy-19-norprogesteion or 9 "-Bromo-II / ?, 17" -dihydroxy-19-norprogesterone react, which are valuable agents with contraceptive and progesterone effectiveness.

Of particular value as starting compounds for the preferred embodiment of the invention; according to the method are the 21-oxygenated 9,11-dihalo-pregnanes as described in U.S. Patents 2,894,963 and 3,049,554, including 9 », \\ ß- dichloro-1,4-pregnadiene-17λ , 21-diol-3,20-dione, its 16 "-methyl and its 16 ^ -methyl-a homologues and 21-lower alkanoates and 21-disodium phosphate esters thereof; Each of these starting compounds reacts on treatment with water by the process according to the invention to form the corresponding 9 "-chloro-11 ^ -hydroxy-pregnane, namely z) i 9" -chloro-prednisolone, its 16 "- and 16 / ff-methyl homologues and 21-lower alkanoates and 21-disodium phosphate esters thereof, respectively, all of which are known to be valuable anti-inflammatory agents.

The process according to the invention is illustrated by way of example by means of the following examples.

2.16 * -Methyl-1,4,9 (ll) -pregnatriene-17 «, 21-diol- = ' 3,20-dione-21-methanesulfonate

A solution of 16 g of 16a-methyl-1,4,9 (11> pre * S gnatnen-17 «, 21-diol-3,20-dione in 160 ml of pyridine is added dropwise for 30 minutes with stirring at 0 ^° C 16 »J methanesulfonyl chloride, stirred for a further 30 minutes beil 0 C and then poured into dilute aqueous Salzsäiar $ hltnert from the resulting precipitate, ^{wäschtihö;"} ο nut water and dried in the air and gets ^ Löa-methyl-l ^^ il ^ -pregnatriene-nƒ ^ l-DLOL-S ^ äiti on-21-methanesulfonate is purified from acetone-hexane which tion by UmkristaUisfeΐ.%% φ

.. 3.16 3,20-dione

, I ² I- ^16a - ^meth y ¹ - ¹ A9 (II) -pregnatriene-17 «, 21-diol. J, 20-dione-21-methansuhOnat in 180 ml of acetone are mixed with 12 g of sodium iodide, the reaction mixture is refluxed for 15 minutes, then ^m ); ^Poured water and removed the resulting precipitate, washed with water and dried and

fön α · ¹⁶ * " ^K i ^et , ^h y ¹ - ²¹ -J ° ^d - ^{1. 4. 9} (II) -pregnatriene-17« -ol-3,20-dione.

40 -21-phosphate
In 43.03 ml of methanol is added dropwise at room temperature

S ° ^Per r ^{Ur Unter Röhren 24} · ^{05 ml of} 85% phosphorus ^UI ?, Carefully add 75.40 ml of triethylamine, followed by 2.7 g of 16 “-methyl-21-iodine-1,4.9 (ll) ^ regnatnen-17 <x-ol-3,20-dione, heated the reaction mixture on a steam bath for 30 minutes, pour it S3? "R ^ ^{611 in a} mixture of water f ^^ ⁰ ^ ^{d concentrated} hydrochloric acid (72.54 ml) and the precipitated 16" -Methyl-1A W i ) -pregnatnen-17 ", 21-diol-3.20 -dione-21-phosphate, which is purified by recrystallization from aqueous acetone.

Preparation method A

Production of 9 "-Brom-II _/ 9-chloΓ-16Ä-methyl-

l ^ pregnadien-na ^ l-diolO ^ O-dione-

21-disodium phosphate f. _Ft ⁶ * ^meth J ^I1 ' ⁴

-3,20-dione-21-phosphate

an? ä ^L i ° ^? Y ^{On 3 '27} 8 16 "-Methyl-1,4,9 (II) -pregnatnen-17 _Ä 21-d, ol-3,2 (Wion-21-phosphate üi 120 ml glacial acetic acid wu-d with 13.05 g of lithium chloride and 1.13 g of N-bromo-acetamide and then immediately treated with 315 mg m Lrtbumchlond tetrahydrofuran (1.35 ml), Nachdem_ sxch the solution back to room Tempe-S ^ e * ^h ^ ^ to 1 hour and they 15 Mi- ^{water 1} ^ ***** ™ with concea-

% Pexaa r-16a-i

■ 21-phos ^. .— «. .. "*,".

Umk ^ iaiisjgfea ajfc

Z .-: .-. - .. i: - ^; .-: _v i .'- ■ · ■, ■: Z '■ - *. & $ ^ ψ ·} Φ, ν - ^ <&ζ> ^ setzanrt · LvIJS - "'t" tVif ^ S ^^ © 5 "-" "*' '^' sKv ^ fsra

IMS ^ tubes m IQ ©,

jyTMian, 'leads further

^ i ^^^ P ^ aster and & i6fenet

* £ & ϊχβί? 0 & 3

example 1

9 "-Chlor-II) S-hydroxy-16" -methyl-1,4-pregnadiene-

17a, 21-diol-3,20-dione (= 9a-chloro-16a-methyl-prednisolone)

A. Production of Qa-Chlor-II / S-hydroxy-löoc-me-

phate from 9a, 11ß-dichloro-16a-methyl-1,4-pregnadiene-17a, 21-diol-3,20-dione-21-disodium phosphate by treatment with water

1. A solution of 9a, ll /? - dichloro-16 "-methyl-1,4-pregnadiene-17", 21-diol-3 ^ 0-dione-21-disodium phosphate (800 mg) is heated for 6 hours in 40 ml distilled water at 6O ⁰ C (pH 5.6), the reaction mixture is acidified to a pH less than 1 by adding hydrochloric acid, filtered, the precipitated 9 '- chloro -11/3 - hydroxy - 16α - methyl-1 , 4 - pregnadiene - 17 <x, 21 - diol - 3.20 - dione - 21 - phosphate (400 mg) and purifies it by recrystallization from acetone-water, melting point 173 to 175.1 ° C; [α]? = + 106 ° (in dioxane).

2. The treatment is similar to that described above

thyl-l, 4-pregnadiene-17 ", 21-diol-3,20-dione-21-disodium phosphate in 40 ml of methanol-water mixture (50: 50) for 24 hours at 60 ⁰ C, the reaction mixture is acidified to a pH -Value less than 1 by adding hydrochloric acid, the precipitated 9a - chlorine -11 /? - hydroxy - 16α - methyll, 4-pregnadiene-17a, 21-diol-3,20-dione-21-phosphate and purifies it by recrystallization from acetone-hexane, melting point = 173 to 175 ° C.

B e i s ρ i e 1 3

^ ßypg ol-3,20-dione-21-disodium phosphate and 9 <x, ll / f-dichloro-1,4-pregnadiene-17a, 21-diol - 3,20-dione-21-disodium phosphate with water for 6 hours 6O ⁰ C, isolates and purifies the resulting product as described and thus obtains 9a-chloro-II / hydroxy-16 / I-methyl-1,4-pregnadiene-17 «, 21-diol-3,20-dione-21 phosphate or 9a-chloro-II /? - hydroxy-1,4-pregnadiene-17 «, 21-diol-3,20-dione-21-phosphaL

3. Similarly, when using 9 *, 11 β- dichloro-4-pregnen-17 ", 21-diol-3.20-dione-21-disodium phosphate as the starting compound in the above process, 9" -chloro-ll ^ -hydroxy -4-pregnen-17a, 21-diol-3,20-dione-21-phosphate (= 9 «-chlorohydrocortisone-21-phosphate), an anti-inflammatory agent.

B. The 21-phosphates thus obtained can be converted into the analogous 21-hydroxy compounds, for example by means of Baketerienalkaliphosphatase (Worthmgton Biochemical Corporation, Freehold, NJ) in aqueous trishydroxymethylaminomethane solution. For example, 9 <x-ChlorII ^ -hydroxy-16 "-methyl-1,4-pregnadiene-17", 21-diol-3,20-dkn, melting point = 237 to 238 ° C (decomposition \ [«] ? = + 106.9 ° (in dimethylformamide), λ £ 2 "= 2.81; 2.88; 5.82; 6.00; 6.12; 6.20; 113 μ 9« -chlorine-II / ! -hydroxy-16 ^ -methyl-1,4-pregnadiene-17 ", 21-diol-3,20-dione (= 9" -chloro-16 / S-methylprednisolone), 9 "-Chkr-hydrocortisone and 9" -Chlor-II ^ -hydroxy - 1,4 - pregnadiene - 17a, 21 - diol - 3.20 - dione (= 9 "-Chlorpredniüolon). The 9" -Chlorptednisclone. One can, for example, in the corresponding 21- acetate, melting point = 229 to 235 ° C (ZeEseJtomg) » fcW = Ht-141 ° 0n Äthane ^ Ä =" 239 / jBft (ε = 14 700) Oberfühfeit.

1a 9a-chlorine-l l / miydroxy-loa-methyl-l ^ pregnadiene-

17a, 21-diol-3,20-dione (= 9 "-chloro-16" -methylprednisolone)

Production of 9a-chloro-II / 3-hydroxy-16a-methyl-

1,4-pregnadiene-17a, 21-diol-3,20-dione-21-phosphate from 9a, ll ^ -Dichlor-16a-methyl-1,4-pregnadiene-

^ao 17a, 21-diol-3,20-dione-21-disodium phosphate

Handling with human serum

800 ml of 9a, ll /? - dichloro-16a-methyl-1,4-pregnadiene-17a, 21-diol-3,20-dione-21-disodium phosphate are dissolved in 40 ml of human serum (whole human blood without red blood cells) at pH 7, stir the reaction mixture 5 days at 38 ° C, then add water, then concentrated hydrochloric acid until the pH of the reaction mixture is less than 1, then extracted with ethyl acetate (approximately with one liter), washes the combined ethyl acetate 'extracts with water, then dried them over sodium sulfate and evaporated them in vacuo to form one A residue consisting of 9a-chloro-II / 3-hydroxy-16a-me ethyl 1,4-pregnadiene-17 «, 21-diol-3,20-dione-21-phosphate (460 mg) This product is used without purification in Procedure 3B below.

If the above reaction is only carried out for 24 hours at 38 ° C (instead of 5 days, as explained above) and the product obtained is isolated and purified in a manner similar to that described above, giving 9a-chloroII /? - hydroxy-16 "-methyl-1,4-pregnadiene-17a, 21-diol-3,20-dione-21-phosphate.

Example 4 Production of 9a-chlorine-II / ?, 17a-dihydroxypro-

gesterone from 9 ", ll /? - dichloro-17" -hydroxy-progesterone by handling with water-methanol (1: 1)

115 mg of 9 <x, 110-dichloro-17a-hydroxy-pro ^ gesterone are dissolved in methanol (400 ml) and water (400 ml), the solution is heated to 60 ^° C. with stirring for 24 hours, and the reaction mixture is concentrated by distillation a smaller volume en ^ adds ^ aanirWiBBeKBmz ^ and exfeamert nfit MfefliylencnlbriaS ^ - ~~ * ~ * ~ -

fonn acetic acid a ^ y preparative

man e | ne> Lösurjgr

Example p

Pa-brom-llyJ-hydroxy-loa-methyl-M-pregnadiene-

17 «, 21-diol-3,20-dione (= 9a-bromo-16a-methylprednisolone)

Production of 9a-bromo-II /? - hydroxy-16 "-methyl-.

1,4-pregnadiene-17 «, 21-diol-3,20-dione-21-phosphate from 9 "-Bromo-II /? - chloro-16" -methyl-1,4-pregnadiene-

17a, 21-diol-3,20-dione-21-disodium phosphate by treating with water

Dissolve 9a-bromo-lljff-chloro-16'-methyl-1,4-pregnadiene-17 (X, 21-diol-3,20-dione-21-disodium phosphate (800 mg) in distilled water (40 ml), the reaction mixture is stirred for 3 hours at 60 ° C. and cooled and brings it to a pH value by adding hydrochloric acid, starting from a pH value of 2 less than 1. The reaction mixture is extracted with ethyl acetate, the combined extracts dried over sodium sulfate and concentrated in vacuo to a residue (560 mg), which consists of 9 «-Bromo-

21-acetate (200 mg) in methanol (40 ml) and distilled Water (20 ml) for 4 days at 60 ° C. A large volume of water is then added, the mixture is filtered and washed the resulting precipitate with water, dries it and thus receives a mixture of 9 "-chlorine-II / 3-hy-

di

/ p

Consists of 3,20-dione-21-phosphate; this product will converted into the above-mentioned 21-hydroxy compound without further purification

Example 6

Production of 9a-chloro-II /? - hydroxy-16 * -methyll, 4-pregnadiene-17 *, 21-diol-3,20-dione-21-acetate (= SrOt-Chlor-Löot-Methyl-PrednisoIon ^ l-Acetate) from Pl ^ ili

17 «, 21-diol-3,20-dione-21-acetate by treating with water-methanol

A. Dissolve 9a, ll /? - dichloro-16'-methyl-1,4-pregnaden-17A, 21-diol-3,20-dione-21-acetate (115 mg) in metal anol (400 ml) and Water (400 ml) and stir the solution for 24 hours at 60 ^° C. The reaction mixture is concentrated in vacuo to a third of its volume, filtered and the aqueous filtrate extracted with methylene chloride. The combined methylene chloride extracts are dried over sodium sulphate and concentrated to a residue , which consists of a mixture of 9 "-chlorine-II /? -hydroxy-16" -methyll, 4-pregnadiene-17a, 21-diol-3,20-dione and its 21-acetate

The above mixture is dissolved in pyridine (0.4 ml), acetic anhydride (0.04 ml) added and the The reaction mixture was allowed to stand at room temperature for approximately 18 hours. It is poured in water extracted with ethyl acetate, combined the ethyl acetate extracts, washes them with water, dries them over sodium sulfate, filters them and concentrates them a residue consisting of 9 "-chlorine-II /? - hydroxyi6" -methyl-1,4-pregnadiene-17a, 21-diol-3,20-dione

Thin-layer chrome

: ^ untCT ^ Vejw ^ adung. of the solvent "~" "" TarealhylesterXS: 2) purified

~ "~ aa ^ polar product from the ymd MethyJenchlorid. xl.zn cmem ^ ückstaud evaporated ^ ^r * - ^i3E -affisiert DasLifiarot-XauUientischen sample yypg
on, its 21-acetate and some starting material (158 mg). The desired product is determined by thin layer chromatography using the Lör

to solvent choroform-ethyl acetate (3: 2) isolated. The more polar products are extracted from the preparative plate with acetone-methylene chloride and concentrates this extract to a residue that consists of a mixture of 9 "-Ghlbr-II / J-hydroxy-16 * -methyl-1,4-pregnadiene-17", 21-diol-3,20-di- on and its 21 acetate. This product mix dissolve in pyridine (1.6 ml), add acetic anhydride (0.6 ml) and leave the reaction mixture at room temperature for about 18 hours

so stand. Then you pour it into water and filter the resulting precipitate, washes it with water and dries the product obtained, which from 9 "- chloro-11 / I-hydroxy-16" -methyl-1,4-pregnadiene-17a, 21-diol-3,20-dione-21-acetate consists. It is carried out by means of thin-layer chromatography using the solvent chloroform-ethyl acetate (3: 2) purified, the more polar product with Acetone-methylene chloride extracted and so 9 "-ChlorII / J-hydroxy-loa-methyl-M-pregnadiene-na ^ l-diol-

3,20-dione-21-acetate was obtained.

C. Use 6A and 6B in place of 9a in procedures 6a, 110-dichloro-16 "-methyll ^ pregnadiene-na ^ l-diol-S ^ O-dione ^ l-acetate other 9a, II / S dihalosteroids, e.g. B. 9a, ll / i-dichloro

4-pregnen-16a, 17a, 21-triol-3,20-dione-16,21-diacetate or 2a-methyl-9 ", l l £ -dichlor-4-pregnen-17", 21-diol-3,20-dione-21-acetate, the corresponding 9 "-halogen-II / 5-hydroxy compounds are obtained, such as 9 * -ChlorII /? - hydroxy-4-pregnen-16", 17 ", 21-triol-3,20-dione-

16,21-diacetate mixed with its 16-M:> noacetat,

or 2α-methyl-9α-chloΓ-ll £ -nydΓOxy-4-pΓegnen-

17 ", 21-diol-3,20-dione mixed with its 21-acetate

Bring the above connections

each with acetic anhydride in pyridine to react

tion, the corresponding fully esterified products are obtained.

D. In the above processes 6 A and 6 B, other 21-low alkanoic acid esters of 9a, 11j8-dichloro-16 "-methyl-1,4-pregnadiene-17", 21-diol-3,20-dione-

turn, e.g. B. 21-t-butyrate, 21-heptanoate, 21-caproate, 21-caprylate and 21-decanoate, and thus constitutes 9 "-Chlorllffhdieil 3,20-dione mixed with the corresponding 21-alkanoate here.

, Example 7 * - '· «·'

■ · -

icTöform-E

9a-chloro-16 «-methyl-pTednisolon-21-aaoxybari> ox9k) _t

IN THE?;

diol-3 ^ Ö-diöä-

Chloramic acid ethyl ester obtained in pyridine at room temperature as follows.

Dissolve 100 g of p-toluenesulfonic acid monohydrate and 27.33 g of sodium-p-toluolsu3onat in one liter of pyridine and concentrated in vacuo to approximately this Lösuag SOU ml, where the temperature is maintained at about 40 ⁰ C. The mixture is then cooled to room temperature, 13.17 g of crystallized N-chlorosuccinimide and immediately thereafter 20 g of 16a-methyl-1,4,9 (ll) -pregnatriene-na ^ l-diol-S ^ O-dione ^ ethoxycarboxylate

³ °

^3S

added, the reaction mixture is stirred for 20 hours at room temperature, then poured into 10 liters of ice / water mixture containing one liter of concentrated sulfuric acid, the resulting precipitate is abfihnert, air dried with water until washed to neutrality and at 6O ⁰ C and so 9a- ChlorII /? - tojsyloxy-16a-methyl-1,4-pregnadiene-17a, 21-diol-3,20-dione-21-ethoxycarboxylate. It is purified by chromatography on silica gel, which is eluted with chloroform which contains 10 to 15% acetic acid ao ether. The first similar fractions are combined and concentrated to a residue. This residue is crystallized from acetone-hexane, and 9Ä-chloro-110-tosyloxy-16a-methyl-1,4-pregnadiene-17a, 21-diolO ^ O-dione-as 21-ethoxycarboxylate, melting point = 201 to 203 ^° C; W? = + 65 ° (in dioxane); A ^ ™ "= 231 with (c = 26600).

B. Production of 9 "-chlorine-II / 9-hydroxy-

16a-methYl-1,4-pregnadiene-17a, 21-diol-3,20-dione-21-ethoxycarboxylate (= 9 "-chloro-16" -methylprednisolone-21-ethoxycarboxylate) from 9 "-chlorIII / I-tosytoxy -l & x-methyl-l ^ pregnadiene-17 «, 21-diol-3,20-dione-21-ethoxycarboxylate Treatment with methanol-water (1: 1)

A solution of 9 "-chlorine-l 1 / I-tosyloxy-16a-methyl-1,4-pregnadiene-17", 21 ■ diol-3.20-dione-21-ethoxycarboxylate (100 mg) in methanol ( 400 ml) and distilled water (400 ml) at 6O ⁰ C for 24 hours. The reaction mixture is concentrated to a volume of approximately 20 ml, cooled and the precipitated product is filtered off, which consists of 9 "-Chlorll ^ -hydroxy-16" -methyl- 1,4-pregnadiene-17 «, 21-diol-3,20-dione-21-ethoxycarboxylate consists of thin-layer chromatography on a preparative thin-layer plate (silica gel) using ethyl acetate-chloroform (1: 3) as the solvent system, and subsequent crystallization from acetone-hexane purified, melting point = 214 to 219 ^° C., yield 55 mg.

B e i s ρ i e 1 8

Production of 9 "-chlorine-II /? - azido-16" -methyl-

1,4-pregnadiene-17 «, 21-diol-3,20-dione-21-ethboxy-

carboxylate from Fe-Chlor-II / I-tosyloxy-löa-methyl 1,4-pregnadiene-17 «, 21-diol-3,20-dione-21-ethoxy- carboxylate by treatment with sodium azide in

Methanol-water (1: 1)

Acetic acid is added to a solution of 150 g of sodium azide in 1.5 liters of water and 1.5 liters of methanol until the pH of the solution is 6.6 -methyli, 4-jpΓegnadieή-17ά, 2i-dίol-3,20-dione-21-äthoxycaΓb- added oxylate und'rührt 48 hours at 6O ⁰ C. This adds 2 liters of water and extracted methylene chloride nut, Wash the combined methylene chloride -

55 extracts with water and dries over magnesium sulfate, concentrates them in vacuo to a residue which is composed of 9 <x -chloro-II / J-azido-.16a-ynethyl-1,4-pregnadiene-17a, 21-diol-3, It is purified by means of preparative thin-layer chromatography on silica gel using ethyl acetate-cyclohexane (2: 3) as the solvent system and subsequent crystallization from acetone-hexane and so 9 "-chlorine-II # -azido-16" obtained methyl 1,4-pregnadiene-17 «, 21-diol-3,20-dione-21-ethoxycarboxylate; Melting point = 220 to 223 ° C; [*]? = + 168.4 ° (in dioxane); X% T ° * = 238ΐημ.

Example 9 Production of 9 ", ll /? - dichloro-16" -methyl-1,4-pre-

Gnadien-17a, 21-diol-3,20-dione-21-ethoxy carboxylate from 9 "-Chior-II ^ -tosyloxy-16" -methyl-1,4-pregna-

diene-17 ", 21-diol-3,20-dione-21-ethoxycarboxylate

by treatment with sodium chloride in

Methanol-water (1: 1)

A solution of 40 g of sodium chloride in 200 ml of methanol and 200 ml of water is mixed with 50 mg of 9 "chlorine / I-tosyloxy-16 (xn ⁱ ethyl-1,4-pregnadiene-17", 21-diol-3.20- dione-21-ätLoxycarboxylat offset (the compound of example 8A) and heated 70 hours at 6O ⁰ C the reaction mixture is almost evaporated to dryness, then treated with methylene chloride and filtered Dry the methylene chloride solution over magnesium sulfate and concentrated to a residue, which consists of 9 ", ll /? - dichlar-16" -methyl-1,4-pregnadiene-17 ", 21-diol-3,20-dione-21-ethoxycarboxylate

Example 10

9 <x-chloro-II /! - azido-16 "-methyl-1,4-pregnadiene-17a, 21-diol-3 ^ 0-dione-21-ethoxycarboxylate

A. 9jt-Chlor * II / J-tosyloxy-16a-methyl-1,4-pregnadiene-17 <x, 21-diol-3,20-dione-21-acetate

A solution of 16'-methyl-1,4,9 (II) -pregnatriene · 17a, 21-diol-3,20-dione-21-acetate (6.0 g) in 600 ml of pyridine is mixed with 8 g of sodium tosylate and 30 g of p-toluenesulfonic acid monohydrate are added. The solution is concentrated to a volume of 300 ml, then 4 g of N-chlorosuccinimide are added and the mixture is stirred for 24 hours at room temperature. The reaction mixture is then poured into 3 liters of cold 10% strength aqueous sulfuric acid, the precipitated 9 "-chlorine-II /? -Tosyloxy-16" -methyl-1,4-pregnadiene-17 (x, 21-diol-3.20 Dione-21-acetate is filtered off, air-dried and purified by chromatography on silica gel, eluting with chloroform which contains 15% ethyl acetate. The combined eluates are concentrated to a residue which is then crystallized from acetone-hexane; melting point = 203 to 206 ⁰ C; [ä] F = + 71.2 ° (in dioxane); ASS? - ⁰¹ - 230πιμ (e = 19 500).

B. Preparation of 9 "-chloro-llj9-azido-16" -methyll, 4-pregnadiene-17 ", 21-diol-3,20 * dione-21-acetate from 9 "-Chlor-II / i-tosyloxy-16a-methyl-1,4-pregnadiene-17", 21-diol-3,20-dione-21-acetate by treatment with methanol-water

A solution of 100 g of sodium azide in one liter of water and 2.5 liters of methanol is mixed with acetic acid added until the solution has a pH of 6.0.

100 mg of 9 ", 110-DicMör-19-nor-4-pre- A solution of 100 mg of $ Ä-Chjor- is heated.

gnen-3,20-dione in 400 ml of distilled water Udd II / 5-tosyloxy-19-nor-4 ^ androstenT3 _# 17-dipn in 400 ml of 400 ml of methanol for 48 hours at 6O ⁰ C, isolated and 65 methanol and 400 ml water for 24 hours at 6O ⁰ C, the product obtained rebigt similarly as in the examples, the product obtained is isolated similarly as in the case of game · 11 described and obtained so 9A-ouor-IIjS-IJy- game described 11 and thus obtains 9 "-Chlof41 ^ h> diOxy * 19-nor-4-pregnen'3,20-dione. droxy-W-noM-androsten-an-clion.

17 _ ^lo ■■%

Add 2 g of ga-chlorine-ll ^ -tosyloxy-löa-methyl-bis ρ ι e 1 14 ^

1,4-pregnadiene'17! x, 21-diol-3,20-dione-21-acetate added " _{OUA 1 / t} α t λ- πλ ι, Ä

and stir at 60 ° C for 24 hours. Then 9 "-chlorine-II ^ hydroxy-1,4-androstadien-17 ^ -ol-3-one ..; J |

Add 3 liters of water to the reaction mixture and extract. o _a <: hlor-ll / S-tosyIoxy-1,4-androstadien-

them with methylene chloride. The methyl chloride extracts 5 ₁₇ e ^ 3 ^ _n Ä

weirdsn washed with water, over magnesium sulfate ^H , "_. ,, -. . 5Äi

dried and concentrated to a residue which is dissolved from 40 g of p-loluenesulfonic acid monohydrate and , ^ SQ

9 «- chlorine -115 - azide -16- * - methyl -1,4 - pregnadiene- 7 g sodium p-toluenesulfonate in 600 ml Pyndm, narrow>: /! P

17 «^ 1-diol-3,20-dione-21-acetate consists. It is then with- then the solution in vacuo to about 300 ml Jg;

telii preparative thin-layer chromatography on io, adds 3 gl, 4.9 (ll) -andro- at room temperature . _: ^ JSS

Siticagel using the solvent system statrien-17 / J-ol-3-one and immediately afterwards 2.8 g ^ Ethyl ethyl ester cyclohexane (2: 3) purified. Recrystallized N-chlorosuccinimide is added and the mixture is stirred

extract the desired product with chloroform reaction mixture for 20 hours at room temperature "*

corresponding to the infrared and ultraviolet spectra and then pour them into 4 liters of ice water, which

and crystallizes the residue of the chloroform 15 400 ml of concentrated sulfuric acid contains the

extracts from ethyl acetate to; Melting point precipitated gac-chlorine-ll ^ -tosyloxy-l ^ andro-

= 246 to 247 ^° C; [«]? = + 177.8 ° (in dioxane); stages-17 /? - ol-3-one is filtered and washed with water

^ Mwuaoi = 238 πιμ (e = 15 600). until neutral and dries it at 60 ° C on the

"" Air It is chromatographed on silica gel

Beispielll 20 cleaned, with chloroform, which 10 to Treatment with water-methanol ^ _{ß Production of} ^ -Chlor-ll / i-hydroxy-l ^ andro-

] Wan heats a solution of 100 mg.

ch] or-17 «-methyl-4-androsten-17 ^ -ol-3-one in 400 ml 1,4-androstadien-17 /? - ol-3-one by treatment

Methanol and 400 ml of distilled water for 48 hours with water-methanol

to 6O ⁰ C. The reaction mixture is then im

Reduced vacuum to about 20 ml, then the 30 Man heated a solution of 100 mg of 9a-chloro-Rickstartd extracted with methylene chloride, the Me- ll /? - tosyloxy-1,4-androstadien-17 (0-ol-3-one dried sulfate in 400 ml of ethylene chloride extract with anhydrous magnesium distilled water and 400 ml of methanol for 24 hours and the extract in vacuo to 6O ⁰ C, isolates and purifies the product obtained concentrated to a residue of 9 * chlorine similar to example 12 described and thus obtained ll /? - hydroxy-17a-methyl-4-androstene-17 ^ -ol-3-one 35 9 "-Chlor-ll ^ -hydroxy-1,4-androstadien-17 / i-ol-3 -on. (= 9A-ChIOr-I l / f-hydroxy-nÄ-methyl-testosterone) be...,

If it is by means of preparative thin-film example 13

Purified chromatography on silica gel, eluting with 9a-chloro-il /? - hydroxy-19-nor-4-androstene-3,17-dione OJorofonn-ethyl acetate (9: 1). . "", ,,. . _in . . It is crystallized from acetone-HexW 40 ^A ^ -CWor-ll ^ -tosyloxy-ig-nor- ^ androsten-

3,17-dione

EXAMPLE 12 70 g of p-toluenesulfonic acid monohydrate and Production of δ-fluorine-chloro-II / i-hydroxy- «g sodium p-toluenesulfonate in 1 liter of pyridine, concentrated

19-nor-4 ^ ndrosten-3,17-dionaus6 «-Fluor- ^ ° Τ &, Τ Ύ ³ ™ *? ·" ^{Ί,? Ί Μ} "5 * ϊ * ^5g

9 _Ä , llß-dichlor-19-nor ^ -androsten-3,17-dione «19-Nor-4 9 (ll> androstadien-3,17-dione and immediately an-

by treatment with water-methanol then 5 g of recrystallized N-chlorosuccimide

added and stirred for 18 hours at room temperature.

Similar to that described in Example 11, the reaction mixture is heated in 4 liters of ice-water 100 mg öa-fluorine ^ a.ll ^ -dichlor- ^ - nor- ^ androsten- poured, which 400 ml of concentrated sulfuric acid 3.17-aeon in 400 ml of water and 400 ml of methanol 50 contains the precipitated 9a-chloro-II /? - tosyloxy-72 hours at 6O ⁰ C, isolated and purified the 19-nor-4-androstene-3,17-dione obtained is filtered off, Use a product similar to that described in Example 11 and wash water until neutral and air dry aa-fluorine-ga-chlorine-II / S-hydroxy-l ^ nor ^ an- It is chromatographed on SUidii3 $ th-3.17 -dion. cagel purified, eluting with chloroform,

, 55 which contains 10 to 15% ethyl acetate

Example 13 combined eluates are concentrated and the resulting Production of 9 "-chlorine-II / I-hydroxy-19-nor residue from acetone-hexane crystallized Example 16 deals with p-toluenesulfonic acid and its Na-

trium salt similar to that described in Example 7A. the Products obtained from 9ix-chloro-llA17a-dihydroxy-19-nor-progesterone are isoherted as described

A. 9a-chloro-lie-tosyloxy-17e-hvdroxv-19-nor " ¹ ^ S« «™« ¹ namely 21-carbomethoxylate, progesterone hydroxy-19-nor- ₅ 21-carbopropoxylate, 21-carbobutoxylate, 21 -Carboct-

oxylate or the 21-carbodecoxyate of 9 «-chlorine-

As described in Example 14A, 11 ^ -tosyloxy-16a-methyl-1,4-pregnadiene-17 «, 21-diol-48 g of p-toluenesulfonic acid monohydrate and 9.7 g of Na-3,20-dione are dissolved.

trium p-toluenesulfonate in 600 ml of pyridine and dance B. Treat each of the above

trates the solution in a vacuum to a volume of 9 "- <Mor-ll /? - tosylc" y-pregnadien-40OmL adds 4 g of 17 "-hydroxy-19-nor-4,9 (ll) -pregna- 21-carbalkxylate with aqueous methanol at 60 ⁰ C diene-3,20-dione and immediately thereafter 3.4 g um- similar to that described in Example 7B, isohert and crystallized N-chlorosuccinimide is added, which stirs the products obtained in a similar way described reaction mixture 18 Stand at Zhnmertempe- and thus receives the 21-carbometboxylate, 21-carboproprature, isolates and purifies the product obtained ahn- 15 oxylate, 21-carbobutoxylate, 21-carbobutoxylate or Hch as described in Example 15 A and thus receives the 21-carbodecoxylate of 9 "-chloro-114-hydroxy-9α-CbloΓ-110-tosyloxy-17α-hydΓOxy-19-noΓ-pΓoge-16" -methyl-1,4-pregnadiene-17a ^ l-diol-3 ^ 0-dione. sterone.

B. Production of 9a-CMor-llftl7 «-difeydroxy- B e 1 s ρ 1 e 1 18 19-nor-progesterone from ffa-chloro-ll ^ -tosyloxy- * ° production of 9 "-chloro-ll ^ -azido-16" -methyl-17 "-hydroxy-19-nor-progesterone 1,4-pregnadiene- 17 «^ l-diol-3 ^ 0-dione-21-acetate from

A solution of 100mg 9, X-ChIOrll / J-tosyloxy-na-hydroxy-W-nor-progeWrott ia 400ml methanol and 400ml Wassef 24Stnnden at a ₅ 6O ⁰ C is stirred, isolating and purifying the resulting product are added to a solution of 100 g of sodium azide

similar to that described in Example 11 and obtained se m one liter of water and 2.5 liters of methanol, vinegar-9 "-chlorine-II) 3.17" -dihydroxy-19-nor-progesterone. acid, bfe a pH of 6 is seen

1.75 ς 9a-CMor-ll ^ -mesyloxy-16 "-methyl-1,4-pregna-B e 1 s ρ ι e 1 17 _3O αίβη-17" ^ 1- <ϋο1-3,20-Λοη- 21-3θβΐΗΐ with and stirs with

go-chlorine-ll ^ hydroxy-ieÄ-methyl-l. ^ regnadien- ^ω °° ^{vßiaeBd 24} hours. Is added 3 liters of water 17 «^ l-diol-3 ^ 0-dione 21-alkoxycarboxylates ^m *** Reaktionsmischuag and extracted with Me

ethylene chloride. The methylene chloride is washed

A. Similar to that described in Example 7 A, extracts are prepared with water, dried over magnesium and other 21-alkoxycarboxylic acid esters of 1 & x-Mc-35 sulfate and concentrated to a residue, the ethyl-1,4 ^ (ll) -pregnatriene -17oai-diol-3 ^ 0-dione by 9 "- chlorine - Uß - azide -16" - methyl -1,4 - pregnadien your treatment with other chloroformic acid alkyl-17a, 21-diol-3,20-dione-21-acetate If you clean esters, z. B. with ethyl chloroformate, by means of preparative thin-layer chromatography on propyl chloroformate, sulfuric chloroformate using the solvent system n-butyl ester, n-octyl chloroformate and ethyl acetate-cyclohexane (2: 3). Extra-Chlorameisensäore-n-decykster is obtained, and this gives the desired product with chloroform, iden-21-carbomethoxylate, 21-carbopropoxylate, 21-carbotified by means of infrared and ultraviolet spectra and butoxylate, 21-carbocarbonate or 21-carbodecoxy The residue of the chloroform extracts crystallized from 16 "-Methyl-1,4 ^ (ll> pregnatrien-17fls21-diol- from ethyl acetate, melting point = 246 to 3.20-dione. 45 247 ^° C, [«]? = + 177.8 ° fm dioxane); AJ £

Each of the preceding 21-carbalkoxylates be = 238 πψ. (e = 15,600).

Claims (1)

containing solvent, in particular water and / claims: or methanol executes. 11. Method according to one of the preceding 1. A method for modifying the 11-SteÜung claims, characterized in that the 9 "-halogensteroids of the Pregnan- or treatment of the 9 * -halogen-110-X-steroid with the Drostan series, indicated by this, reagent YZ in the temperature range of about 30 that up to 75 ° C is carried out in a corresponding 9 "-halogen. U: O-X-steroid, in which X is a group, the 12. Method according to any of the preceding in the presence of a strongly micophilic anion from claims, characterized in that the the position to which it is bound, in terms of reagent YZ in molar excess with respect to An anion emerges and preferably a hat 9 <x -halogen-II /? - X-steroid is used, logen atom or a sulfonyloxy group, but 13. The method according to any of the preceding damn is not an iodine atom if the halogen- claims, characterized in that the atom in the 9 position is iodine, the substituent action of the 9 * -halogen-110-X-steroid with the by treatment with a reagent of General Reagent YZ in the pH range from about 4 to 8.5 mean formula YZ, where Y is a strongly nucleophile. Anion and Z is a cation, exchanged for Y will.