DE2360444A1 - Anti-inflammatory pregnan-21-carboxylic acids - are substd 16-alpa-17-alpa-isopropylidene-dioxy 3,20-dioxo-pregn-4-ene and 1,4-diene-21-acid derivs - Google Patents

Abstract

Title cpds. are of formula (I): (where A-B = CH2CH2-, CH=CH, or -CCl=CH-; X = H, Hal, or Me; Y-Z = -CHCH2-, -C=CH-; -CV.CHOU-, -CV.CO-, or -CW.WHW'-; U = H or acyl; V = H or hal; W and W' = hal; R' = alkyl; R2 = alkyl or aryl; or R' + R2 tog. = -(CH2)n- where n = 4 or 5; and R3 = H, alkali metal, or an opt. substd. hydrocarbon residue). I are prepd. e.g. (a) by oxidising a 21-al e.g. with PbO2/alkanol/CN-, (b) by oxidising a 20-ol e.G. with MnO2, (c) by halogenating of or halohydrin addn. to a 9 (11) ene, (d) by 1,2-dehydrogenation of a 4-ene-3-one.

Description

SCHERINGAG

Patent department

Berlin, November 30, 1973

New prenaiic acid derivatives

The invention "relates to new pregric acid derivatives of general IPorinel I

COOR-

C-O

(D,

wherein -AB- the groupings -CH ₀ -CHp-, -CH = CH- or -CCl = CH-,

X is hydrogen, a halogen atom or a methyl group, Y is a hydrogen or a halogen atom,

509823/0802

SCHERiNGAG

Patent Department - 2 -

2380444

E-, an alkyl group and Rp an alkyl group or aryl group or R-, and Eo together a tetramethylene group or pentamethylene group,

R ₇ . a hydrogen atom, an alkali metal atom or an optionally substituted carbon / hydrogen radical and E ^ represent an acyl group with 1-8 carbon atoms.

Among a halogen atom X and Y should preferably be one Fluorine, chlorine or bromine atom understood v / ground.

Alkyl groups R ^ and E ~ should preferably be lower Alkyl groups with 1 to 6 carbon atoms are understood to mean «.

Examples of alkyl groups that may be mentioned are: the methyl, ethyl, propyl, isopropyl and butyl groups.

An aryl radical E ₂ should preferably be a phenyl radical which can optionally be substituted. Examples of possible substituents of the phenyl radical are: lower alkyl with 1 to 4 carbon atoms, such as methyl, ethyl, isopropyl, or lower alkoxy groups 'ppen, like the methoxy group.

Under an optionally substituted hydrocarbon radical E, for example, should a group be understood, which has 1 to 18 carbon atoms.

509823/0802

SCHERiNGZ ⁵ G

_ X _ Patent Department

This group can be aliphatic or cycloaliphatic, saturated or unsaturated, substituted or unsubstituted.

Possible substituents on the group R ₅ include, for example:.

lower alkyl groups, such as the methyl, Ethyl-,. Propyl, isopropyl, butyl or tert-butyl group, ...'.... ■■ "■■.

Aryl groups, such as the phenyl group,

Cycloalkyl groups, such as the cyclopropyl, cyclopentyl or cyclohexyl group,

Hydroxyl groups,.

lower alkyloxy groups, such as the methoxy, Ethoxy, propyloxy, butyloxy or tert. -Butyloxy group,

a free or esterified carboxyl group and their. Sodium and potassium salts, amino groups and their salts, or mono- or di-lower-alkylamino groups such as, for example the methylamino, dimethylamino, ethylamino, diethylramino, Propylajnino or butylamino group and their salts.

509823/0802

SCHERING AG

". Ζμ "Patent Department

As salts of the amino, mono-lower-alkylamino or Di-lower-alkylamino groups are preferably the hydrochlorides, hydrobromides, sulfates, phosphates, oxalates, Maleates or tartrates of these groups can be considered.

The optionally substituted hydrocarbon radical E ^ should preferably be understood as meaning a group which has 1 to 12 carbon atoms.

Examples of groups R- include:

the methyl, carboxymethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl, 2-carboxyethyl, propyl, allyl, cyclopropylmethyl, Isopropyl-, 3-hydroxypropyl- * _ Px'opinyl-, 3-aminopropyl-, Butyl, sec-butyl, tert-butyl, butyl (2), cyclobutyl, Pentyl, isopentyl, tert-pentyl, 2-methylbutyl, cyclopentyl, Hexyl, cyclohexyl, cyclohex-2-enyl, cyclopentylmethyl, Heptyl, benzyl, 2-phenylethyl, octyl, bornyl, Isobornyl, menthyl, nonyl, decyl, 3-phenyl-propyl, 3-phenyl-prop-2-enyl-, dodecyl-, tetradecyl-, hexadecyl- and octadecyl group.

5 09823/0802

SCHERING Ä <

_ ς _ patent tailoring

An alkanoyl group is preferred among an acyl group R ^ to be understood as having 1 to 6 carbon atoms. As alkanoyl groups may be mentioned, for example: the i'ormyl, acetyl, Propionyl and the butyryl group.

The invention also relates to a process for the preparation of the pregnanic acid derivatives of the general formula I, which is characterized by

a) that a compound of the general formula II

(H)

wherein -AB-, X, Y, R- ,, Rp and R ^ ^ i ^{e have the} same meaning as in formula I, or the hydrates or hemiacetals of this compound are oxidized with oxidizing heavy metal oxides in the presence of alcohols, or

6 -

509 823/0 802

SCHERINGAG

- (5 _ Patent Department

b) that a compound of the general formula III

OOH,

(III)

wherein -AB-, X, Y, R-,, Rp, R ^ and Rv _{+ have} the same meaning as in formula I, oxidized in an inert solvent with oxidizing metal oxides or metal salts, or

c) that one has a connection to the general Formula IV

5098 2 3/0802

SCHERiNGAG

Security lead

device as in formula I, esterified in a manner known per se.

wherein -AB-, X, Y, ILp E ₂ and R _{7 have} the same meaning as

d) that for the production of Δ 'steroids the general formula I those saturated in the 1-, 2- position Compounds of the general formula I are dehydrated in a manner known per se

and, if desired, 21-esters of the general formula I. in the presence of basic catalysts .. reacts with the ultimately desired alcohol or that they are saponified and, if desired, re-esterified.

509823/0802

SCHERiNGAG

_ ο _ Patent Department

For the process according to variant a) can be used as oxidizing Heavy metal oxides "for example silver oxide, lead (IV) oxide, Red lead, vanadium (V) oxide, manganese (IV) oxide or Ohrom (VI) oxide used v / ground. The response is in the Way carried out that one preferably 0.5 g "to 50 g and in particular 1 g to 10 g heavy metal oxide per gram of compound II applies »

The alcohols used for this process variant preferably lower or medium, primary or secondary alcohols with 1 to 8 carbon atoms. As alcohols are named for example: methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, amyl alcohol, Isoamyl alcohol, hexanol, heptanol, or octanol. These Alcohols can also be used as solvents at the same time. Of course, it is also possible to use the Add further inert solvents to the reaction mixture in addition to the alcohols. Such inert solvents Examples of solvents are: hydrocarbons, such as Benzene, cyclohexane or toluene, chlorinated hydrocarbons, such as methylene chloride, chloroform or tetrachloroethane, ether,

509823/080 2

SCHERINGAG

Q patent department

such as diethyl ether, diisopropyl ether, dibutyl ether, Glycol dimethyl ether, dioxane or tetrahydrofuran, or dipolar, aprotic solvents such as dimethylformamide, N-methylacetamide or IT-methylpyrrolidpn.

When carrying out the method according to variant a) surprisingly, a significant increase in the reaction rate and a significant increase are achieved the yield if this reaction step is carried out with the addition of cyanide ions as a catalyst. As cyanide ions supplying reagents are preferably alkali metal cyanides, such as sodium or potassium cyanide is used. Preference is given to using from 0.01 mol to 10 mol and in particular from 0.1 to 1.0 mole of cyanide per mole of compound II. If alkali metal cyanides are used as reagents which produce cyanide ions, the The reaction is conveniently carried out in such a way that the reaction mixture is additionally neutralized of the alkali cyanide required amount of mineral acids (such as: sulfuric acid, phosphoric acid or hydrogen chloride), Sulfonic acid (such as p-toluenesulfonic acid) or carboxylic acid (such as formic acid or acetic acid) added.

This preferred embodiment of process variant a)

-

50982 3/0802

SCHERiNGAG

"* ■ '-' ■ '~ Patent Department

is advantageously ⁰ C and carried out at a reaction temperature between -2O ⁰ C and + 100 preferably at a reaction temperature between 0 ° C and + 50 ⁰ C. The reaction time depends on the reaction temperature and the choice of reactants; in the preferred embodiment of process variant a) it is an average of 5 to 120 minutes.

It should be noted that the compounds of the general formula II can also be converted into the compounds of the general formula I using further oxidizing agents. _{For example, 5 tons of} 6-dichloro-2,3-dicyanobenzoquinone or triphenyltetrazolium chloride can be used as the oxidizing agent, but these oxidation methods are considerably more complex than the process according to variant a).

The starting substances for process variant a) can be obtained in a simple manner from the corresponding 21-hydroxysteroids can be produced by treating them with lower alcohols such as methanol, ethanol or butanol in the presence of copper (H ^ acetate reacts for 10 to 120 minutes at room temperature.

The compounds obtained after conventional work-up of the reaction mixture can be used directly as starting substances for the

-

509823/0802

SCHERING AG

Patent department

methods according to the invention are used.

The "compounds of general formula I can also according to the. Process according to variant b) are produced.

The inventive method according to variant b) can be carried out in those inert solvents which are in of steroid chemistry are commonly used in oxidations. Suitable solvents are, for example: hydrocarbons, such as cyclohexane, benzene, toluene or xylene, chlorinated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, tetrachlorethylene or chlorobenzene, ether, ie diethyl ether, Diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, Glycol dimethyl ether or anisole, ketones such as acetone, Methyl ethyl ketone, methyl isobutyl ketone or acetophenone or Alcohols such as methanol, ethanol, isopropanol or tert-butanol. The process according to the invention can also be carried out in mixtures of the abovementioned solvents.

The inventive method according to variant b) can under Use of manganese (IV) oxide or lead (IV) oxide carried out will. For this process variant, active manganese (IV) oxide is preferably used to achieve high yields, as is customary in steroid chemistry for oxidation reactions,. ,

609823/0802

-12-

SCHERING AG

"Ip _ patent department

B The implementation of the reaction according to Veriante) is preferably carried out at a reaction temperature between ⁰ C and 150 ⁰ C. It is thus possible, for example, the compounds of general formula III at room temperature or to oxidize the solvent used at the boiling point.

The starting substances of process variant b) can be derived from the corresponding 21-hydroxy-20-oxo-pregnane derivatives produce. To do this, this was dissolved in an alcohol, the solution was mixed with copper (II) acetate and stirred for several days long at room temperature. The mixture is then mixed with aqueous ammonia, extracted with, for example Methylene chloride, the organic phase is washed with water, dried and concentrated in vacuo. One obtains Crude product, x ^ elches from a mixture of the 20a and 20ß-hydroxysteroids consists. Without further purification, this mixture can be used as the starting substance for the inventive Process according to variant b) can be used.

Another possibility for the preparation of the new pregnanic acid derivatives of the general formula I exists in that the 11ß-hydroxy group of compounds of the general formula IV according to process variant c) in Esterified in a known manner. An example of an esterification method is esterification with carboxylic acid anhydrides called in the presence of basic esterification catalysts such as 4 ~ dimethylaminopyridine.

509823/0802

SCHERING AG

Patent department

With the help of process variant d) it is possible 1,2-position saturated steroids of the general formula I.

1 4
to dehydrate to the corresponding Δ ⁵ steroids. This dehydration takes place by means of the known working methods. For example, chemical dehydrogenation using selenium dioxide or quinones, such as 2,3-dichloro-5,6-dicyanobenzoquinone, may be mentioned here.

When using selenium dioxide as a solvent, for example tert-butanol, tert-amyl alcohol or Acetic acid ester suitable. The reaction can be accelerated and succeeded by adding small amounts of glacial acetic acid by refluxing the reaction mixture The reaction is complete after about 10 to 50 stages.

When using 2,3-dichloro-5,6 - dicyano-benzoquinone works one expediently also at the boiling point of the solvent used. As solvents are for Suitable example: alcohols such as ethanol, butanol and tert-butanol, acetic acid ester, benzene, dioxane, tetrahydrofuran etc. To accelerate the reaction, small amounts of nitrobenzene or p-nitrophenol can be added. the Response times are between 5 and 50 hours. "

509823/0802

SCHERING AG

Patent department

If alcohols are used as solvents for the dehydrogenation, it is expedient to use alcohols of the formula E ₂ OH - in which R ^ has the same meaning as in formula I.

The subsequent saponification of the 21-esters, if desired, takes place according to working methods known per se.

Examples include the saponification of the esters in water or aqueous alcohols in the presence of acidic catalysts, such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or of basic catalysts such as potassium hydrogen carbonate, potassium carbonate, Sodium hydroxide or potassium hydroxide.

The subsequent esterification of the free Acids are also carried out according to working methods known per se. So you can, for example, the acids with diazomethane or Implement diazoethane and receive the corresponding methyl or ethyl esters. A generally applicable method is implementation the acids with the alcohols in the presence of carbonyldiimidazole, Dicyclohexylcarbodiimide or l'rifluoroacetic anhydride. It is also possible, for example, to react the acids in the presence of copper (I) oxide or silver oxide with alkyl halides,

509823/0802

SCHERING AG

Patent department

Another method is that the free acids with the corresponding Dimethylformamidalkylacetalen in the corresponding acid alkyl ester transferred. Furthermore, the acids can be used in the presence of strongly acidic catalysts, such as hydrogen chloride, sulfuric acid, perchloric acid, Trifluoromethylsulfonic acid or p-toluenesulfonic acid with convert the alcohols or the lower alkanecarboxylic acid esters of the alcohols «But it is also possible to convert the carboxylic acids to convert into the acid chlorides or acid anhydrides and to implement this in the presence of basic catalysts with the alcohols.

The salts of the carboxylic acids are formed, for example, in the saponification of the esters by means of basic catalysts or in the neutralization of acids by means of alkali carbonates or alkali hydroxides, such as sodium carbonate, sodium · hydrogen carbonate, sodium hydroxide, potassium carbonate, Potassium hydrogen carbonate or potassium hydroxide. It is also possible to use esters of the general formula I. to react in the presence of basic catalysts with the ultimately desired alcohol. Here one uses as basic catalysts, preferably alkali, alkaline earth or aluminum alcoholates.

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098 23/0802

SCHERING AG

. £. Patent department

This Eeaktion is preferably carried out at a reaction temperature between ⁰ C and 180 ⁰ C. In this reaction, the alcohol ultimately desired is used in excess, preferably 10 to 1000 moles of alcohol per mole of steroid are used. The alcohol can optionally with other solvents, such as ether, for example. Di-n-butyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether, or dipolar. aprotic solvents such as dimethylformamide, N-methylacetamide, dirnethylsulfoxide _? N-methylpyrrolidone or acetonitrile can be diluted. This reaction variant is carried out in such a way that preferably less than 1 mole of basic catalyst is used per mole of steroid. In particular, 0.0001 to 0.5 moles of basic catalyst are used per mole of steroid to carry out the reaction.

If the starting compounds used for the process according to the invention are llß-acyloxy compounds of the general type Formulas II or III, they can be described in a simple way by saponifying the corresponding 11ß, 21-diacyloxy compounds under mild conditions (for example

by treatment with potassium carbonate in an aqueous-alcoholic solution and then the 11β-acyloxy-21-hydroxysteroids obtained in this way as described in the corresponding 21-aldehydes or 21 acids transferred.

509823/0802 -17-

SCHERiNGAG

Patsntabieiliiiig

The compounds of general formula I are four full pharmaceutical active ingredients or valuable intermediates for Manufacture of active pharmaceutical ingredients «,

The pharmacologically active compounds of the general Formula I have excellent anti-inflammatory activity when applied locally and also have the Advantage that they are practically ineffective when used systemically.

The new compounds are suitable for topical application in combination with the carriers customary in pharmaceutical pharmacy Treatment of contact dermatitis, eczema of the most diverse Type, neurodermatoses, erythroderma, burns, pruritis vulvae et ani, rosacea, erythematosus cutaneus, psoriasis, Liehen ruber planus et verrucosus and similar skin diseases.

The production of the drug specialties takes place in the usual way by converting the active ingredients with suitable additives into the desired application form, such as, for example: solutions, lotions, ointments, creams or plasters. In the pharmaceuticals formulated in this way, the concentration of the active substance depends on the form of application. In the case of lotions and ointments, an active ingredient concentration of 0.001% to 1% is preferably used.

The following examples serve to explain the inventive method.

509823/08 02 - ie

_ -ίο Patent Department

SCHERING AG

entdepartment

Example 1:

a) A solution of 1.06 g of 11ß, 21-diacetoxy-l, 4,16-pregnatriene-3,20-dione in 100 ml of acetone and 1.5 glacial acetic acid are mixed at ⁰ ° C. with a solution of 440 mg of potassium permariganate in 80 ml Treated acetone. The manganese dioxide formed is filtered off and the filtrate, after dilution with methylene chloride, is washed neutral with a sodium hydrogen carbonate solution. After the organic phase has been dried over sodium sulfate and concentrated, 1.03 g of 16a, 17a-dihydroxy-11ß, 21-diacetoxy-1,4-pregnadiene-3,20-dione are obtained.

b) The glycol obtained in this way is mixed with 140 ml of acetone and 1 ml of 7OpPOZ. Perchloric acid added and stirred for one hour at room temperature. The mixture is then diluted with water, methylene chloride is added, the organic phase is separated off, washed neutral, dried over sodium sulfate and concentrated to dryness. 1.15 g of 16a, 17a-isopropylidenedioxy-llß, 21-diacetoxy-1,4-pregnadiene-3,20-dione with a melting point of 252-253 ° G / q / p ⁵ = + 133 ° (chloroform) are obtained.

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509823/0802

SCHERINGAQ

- 19 - Patent Department

c) A solution of 1.0 g of 16a, 17a-isopropylidenedioxy-11ß, 21-diacetoxy-1,4-pregnadiene-3,20-dione in 120 ml of methanol is added for 20 minutes after adding 1 ml of a 10% aqueous potassium carbonate solution Room temperature stirred. After neutralization with dilute acetic acid, the mixture is concentrated and worked up as usual. Separation on preparative thin-layer plates in the chloroform / acetone system (8: 2) gives 4-50 mg of 21-hydroxy-16a, 17a-isopropylidenedioxy-11ß-acetoxy-1,4 -Pregnadien-3,20-dione of melting point 133-134- C ⁰ / a / Jp = + 91 ° (methanol). UV: E ₂₄₀ = 14-900 (methanol).

d) A solution of 500 mg of 21-hydroxy-16a, 17a-isopropylidene ~ dioxy-llß-acetoxy-1,4-pregnadiene-3j20-dione in 62.5 ml Methanol is mixed with 125 mg of Eupfer (II) acetate in 62.5 ml of methanol and stirred for 1.5 hours while passing through of air. The reaction mixture-is .with methylene chloride diluted, washed with ammonium chloride solution and water, dried over sodium sulfate, evaporated in vacuo and 596 mg of 16α, 17a-isopropylidenedioxy-llßacetoxy-3,20-dioxo-1,4-pregnadiene-21-al are obtained.

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82 3 / 08-02

SCHERING AG

- 2G - patent department

e) 596 mg of the aldehyde thus obtained are dissolved in 5.5 methylene chloride and 30 ml of n-butanol and the solution is stirred for 50 minutes after adding 90 mg of potassium canide, 0.55 ml of acetic acid and 1.1 g of manganese (IV) oxide . The manganese (IV) oxide is filtered off, the filtrate is diluted with methylene chloride and washed with water, dried and evaporated in vacuo. The residue is chromatographed on silica gel with a methylene chloride-acetone gradient and 208 mg of 16a, 17a-isopropylidenedioxy-11-acetoxy-3,20-dioxo-1,4-pregnadiene-21-acid butyl ester with a melting point of 210-211 are obtained ⁰ C / q / jjp >> + 70 ° (chloroform).

Example_2:

a) A solution of 500 mg of 21-hydroxy ~ 16a, 17a-isopropylidene ~ Dioxy-llß-acetoxy-1,4-pregnadiene-3,20-dione is analogous the example Id to 16a, 17ct-Isopropylidenendioxy-llß ~ acetoxy-3,20-dioxo-1,4-pregnadien-21-al implemented.

b) The aldehyde thus obtained is reacted under the conditions described in Example Ie, but in ethanol, and 213 mg of 16a, 17a-isopropylidenedioxy-llßacetoxy-3,20-dioxo-1,4-pregnadiene-21-acid are obtained acid ethyl ester of melting point 110-111.5 ⁰ C / VJP = ⁺⁶⁹ ° (chloroform).

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509823/0802

SCHERING AG

~ ^ iJ- "" 'Patent Department

400 mg of hydroxy-16a, 17a-isopropylidenedioxy-3.20-dioxo-1,4-pregnadiene-21-acid butyl ester are dissolved in 8 ml of pyridine and 2.4 ml of propionic anhydride. 24 mg of 4-dimethylaminopyridine are added and the mixture is stirred overnight at room temperature. With ice-water precipitation and customary work-up, the separation is carried out on preparative thin-layer plates in the chloroform / acetone (8: 2) system and 355 mg of 16a, 17a-isopropylidenedioxy-llßpropionyloxy-3,20-dioxo-1,4-pi-egnadiene-2l are obtained acid - butyl ester as foam / cc / jjp = ₊ q2 ° (chloroform).

a) 3g llß, 21-Diformyloxy-l, 4,16-pregnatrien-3,20-dione become reacted under the conditions described in Example 1a and 3.15 S 16a, 17 & -dihydroxy- ~ llß, 21 ~ is obtained diformyloxy-1,4-pregnadiene ~ 3.20 ~ dione.

b) The glycol thus obtained is under the in Example Ib described conditions for 16a, 17a-I-sopropyridendioxy ~ llß, 21-diforiüyloxy-1,4-pregnadiene ~ 3} 20 "dione implemented. Yield 3.4g.

c) 3.4 g of 16a, 17a-isopropylidenedioxy-IIß, 21-diformyloxyl, 4-pregnadiene-3,2O-dione are under the example Ic

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509823/0802

SCHERING AG

- CC- ~~ Patent Department

The described condition for _m 21-H _y dr _OXy -16a, l ^ - ^{6 Ο 4 U}

isopropylidenedioxy-11β-formyloxy-1,4-pregnadiene-3,20-dione saponified. Yield 2.3 g. Melting point 215-218 ° C = + 136 ° (chloroform).

d) 500 mg of 21-hydroxy-16a, 17a-isopropylidenedioxy-llßf orinyloxy-1,4-pregnadiene-3,20-dione are oxidized to 21-aldehyde under the conditions described in Example Id "and this, under the im The conditions described in Example Ie, converted with butanol into 16a, 17a-isopropylidenedioxyl-β-f oriayloxy-3,20-dioxo-1,4-p: regnadiene-2l-acid butyl ester, yield 14-6 mg, melting point 156-157 ° C / α / ρ ⁵ ^ - + 79 ° (chloroform).

Example 5j__

500 rag Sa-chloro-llß-hydroxy-IgoCilVcc-isopropylidenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid-butyl ester vjerden, under the conditions described in Example 3, however with acetic anhydride, in 9a ~ chlorine ~ 16a, 17a-isopropylidenedioxy ~ llß ~ acetoxy-3.20 ~ dioxo ~ l, 4 ~ pregnadiene-21-acid-butyl ester? convicted. Separation on preparative thin-layer plates in the chloroform / acetone (8: 2) system yields 440 mg Pure product with a melting point of 207.5 - 208.5 ° C / o / Jp = + 82 ° (Chloroform).

509823/0802

INSPECTED

SCHERiNG AG

Patent department

_{For example E} iel_6: * & 2360444

A solution of 700 mg of 9a-fluoro-11ß-hydroxy-16a, 17α-isopropylidenedioxy-3? 20-dioxo-1,4-pregnadiene-21-acid butyl ester in 10.5 ml of pyridine and 1.75 ml of acetic anhydride is mixed with 35 mg of 4-dimethylaminopyridine. The mixture is stirred for 3 hours at room temperature and the reaction product is precipitated with ice water. The precipitate is filtered off, recrystallized from acetone-hexane, while treating with activated charcoal, and 586 mg of 9a-1 ⁿ luor-16a, 17a-isopropylidenedioxy-11ß-acetoxy-3,20-dioxo-1,4-pregnadiene-21 are obtained -butyl ester of melting point 228 ⁰ C = + 65 ° (chloroform).

560 mg of 9oc-luoro-11ß-hydroxy-16a, 17a- (14-phenylethylidenedioxy) -3,20-dioxo-1,4-pregnadiene-21-acid butyl ester are, under the conditions described in Example 3, but with acetic anhydride, reacted. After ice water precipitation and the usual work-up, separation is carried out using preparative thin-layer plates in the chloroform / acetoa system. (8: 2) and 495 mg of ^ cc-FB-Uor-loa, 17 «- (1-phenyl ™ ethylidendioxy) -llß-acetoxy-3,20-dioxo-1,4-pregnadiene-21-acid butyl ester of melting point 177 ° C jp (chloroform).

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SCHERING AG

Patent department

610 mg of 21-hydroxy ~ 16a, 17 <x- (1'-phenylethylidenedioxy) -113-acetoxy-1, ^z ! 21-aldehyde oxidized. The aldehyde obtained in this way is, under the conditions described in Example Ie, converted to Uß-acetoxy-16a, 17a- (1'-phenylethylidenedioxy) -3 _5, 20-dioxo-1,4-pregnadiene-21-acid butyl ester » Yield 168 mg. Melting point 163 ° C / a / jp = -18 ° (chloroform).

Example 9:

550 mg of ILß-Hydroxy-16a, 17a- (1'-phenylethylidenedioxy) -3,20-dioxo-1,4-pregnadiene-21-methyl ester are reacted with acetic anhydride under the conditions described in Example $ and 500 mg are obtained 11β-acetoxy-16a, 17cc- (1 ^l -phenylethylidenedioxy) -3,20-dioxo-1,4-pregnadiene-21-acid methyl ester, melting point 184 ° C fa / ψ = -6 ° (chloroform).

609823/0802

Claims (11)

Patent claims: 1. Jl pregnanic acid derivatives of the general formula I. COOK, Ti (D, wherein -A-B- the groupings -CHo-CHp-, -CH = CH- or -CCl = CH-, X is hydrogen, a halogen atom or a methyl group, Y is a hydrogen or a halogen atom, E-, an alkyl group and Ep an alkyl group or aryl group or E-, and Ep together represent a tetramethylene group or Pentamethylene group, Εν a water atom, an alkali metal atom or a optionally substituted hydrocarbon radical, and E ^ represent an acyl group having 1-8 carbon atoms. 509823/0802 - 26 - SCHERING AG Patent department 2) 16a, 17a-Isopropylidenedioxy ~ llß ~ acetoxy-3,20-dioxo- ■ 1,4-pregnadiene ~ 21 ~ acid ~ butyl ester 3) 16a, 17a-Isopropylidenedioxy-11ß-acetoxy-3 »20-dioxo-1 ^ -pregnadien- ^ l-acid- .thylestei "" 4) 16a, 17a-Isopropylidenedii3xy-11ß-propionyloxy-3> 20 ~ dioxole, 4 ~ pregnadiene-2l-acid-butyl ester 5) 16a, 17a-Isopropylidenedioxy-11ß-formyloxy-3,20-dioxole, 4-pregnadiene-21-acid-butyl ester 6) 9a-Clilor-16a, 17a-isopropylidenedioxy-11ß-acetoxy-3 _5, 20-dioxole, 4-pregnadiene-21-acid butyl ester 7) 9a-Pluor-16a, 17a-isopropylidenedioxy-11ß-acetoxy-3,20-dioxole, 4-pregnadiene-21-acid-butyl ester 8) 9a-fluoro-16a, 17a> - (1 '-plienylethylidendioxy) -llß ~ acetoxy-3,20-dioxo-1,4-pregnadiene-21-acid-butyl-over 9) 16a, 17a- (1'-phenylethylidenedioxy) -113-acetoxy-3,20-dioxole, 4-pregnadiene-21-acid butyl ester 10) 16a, 17a- (1'-Hienyläthylidendioxy) -llß-acetoxy-3,20-dioxole, 4-pregnadiene-21-acid methyl ester 509823/0802 SCHERING AG Patent department 11) Process for the preparation of pregnanic acid derivatives of the general formula I. COOE, 509823/0802 -: 28- SCHERING AG Patent department wherein -A-B the groupings -CHp-CHo-, -CH = CH- or -CCl = CH-, X is hydrogen, a halogen atom or a methyl group, X is a water or a halogen atom, R-, an alkyl group and R- an alkyl group or aryl group or R-j and Rp together represent a tetramethylene group or Pentamethylene group, R ^ a water atom, an alkali metal atom or a optionally substituted hydrocarbon radical and R ^ represent an acyl group with 1 to 8 carbon atoms, characterized, a) that a compound of the general formula II R-, wherein -AB-, X, Y, R-,, R ₂ and R ^ have the same meaning as in -29- 509823/08 02 SCHERING AG Patent department -29- Formula I own, or the hydrates or hemiacetals this compound with oxidizing heavy rivet oxides oxidized in the presence of alcohols, or b) that a compound of the general formula III COOE, I ■ * CH OH (III), where -AB-, X, Y, E- ,, Ep, E ₇ and E ^ have the same meaning as in formula I _? in an inert solvent with oxidizing metal oxides or metal salts oxidized, or c) that a compound of the general formula IV COOE, C = O 0- (IV), 509823/080 2 SCHERING AG Patent department where -A-B-, X, Y, IL · and E ^ have the same meaning as in formula I, esterified or in a manner known per se d) that for the production of Δ 'steroids the general formula I those saturated in the 1,2-position Compounds of the general formula I are dehydrated in a manner known per se and, if desired, 21-esters of the general formula I in the presence of basic catalysts with the ifebztlich converts the desired alcohol or that they are saponified and, if desired, re-esterified. 509823/0802