CH618185A5 - Process for the preparation of pregnanoic acid derivatives. - Google Patents

Description

The invention relates to a process for the preparation of new pregianic acid derivatives of the formula

COOH

• R,

(I)

in which -A-B- the groupings -CH2-CH2-,

-CH = CH- or -CC1 = CH-,

X is hydrogen, a halogen atom or the methyl group, ^ Y-Z- the groups ^ CH — CH2—, ^ C = CH—,

^ CV-CHOU-, ^ CV-CO-, ^: CW-CHW'-

with U in the meaning of a hydrogen atom or an acyl group, V in the meaning of a hydrogen atom or halogen atom and W and W 'in the meaning of a halogen atom,

Ri is an alkyl group and R2 is an alkyl group or aryl group or Ri and R2 together are a tetramethylene group or pentamethylene group and the alkali metal salts. A halogen atom X, V, W and W 'should preferably be understood to mean a fluorine, chlorine and bromine atom, so an acyl group U should preferably be understood to mean an alkanoyl group having 1 to 6 carbon atoms. Examples of alkanoyl groups include: the formyl, acetyl, propionyl and butyryl groups.

Alkyl groups R 1 and R 2 should preferably be understood to mean lower alkyl groups with 1 to 6 carbon atoms. Examples of alkyl groups which may be mentioned are: the methyl, the ethyl, the propyl, the isopropyl and the butyl group. An aryl radical R2 should preferably be understood to mean a phenyl radical which may be substituted. Examples of possible substituents for the phenyl radical are: lower alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, isopropyl, or lower alkoxy groups, such as the methoxy group.

The process according to the invention for the preparation of the 6s compounds of the formula I is characterized in that a compound of the formula

618185

4th

CHO

■ B, E,

(II)

wherein-A-B-, X, J ^ Y-Z-,

Ri and R2 have the same meaning as in formula I,

or the hydrates or hemiacetals of this compound are oxidized with oxidizing heavy metal oxides and the acid obtained is optionally converted into an alkali metal salt.

Compounds of the formula I obtained which are saturated in the 1,2-position can be dehydrated to Al4 steroids.

Compounds obtained in accordance with the invention with an 11-hydroxy group can be esterified or also oxidized to the corresponding 11-keto compounds and compounds obtained as esters can also be saponified.

Halogen can be added to the A9 (1 ^ double bond of compounds of the formula I to give the corresponding 9a compounds, but HOC1 or HOBr can also be added, the corresponding 9 chlorine or 9-bromo-11β-hydroxy- Derivatives arise.

The compounds obtained according to the invention are in the form of free acids and can be used to form esters of the following formula

COOR-i

• B, B,

C = 0

(I A)

i

X

in which -A-B-, X, Z-,

Ri and R2 are defined above and R3 represents an optionally substituted hydrocarbon radical.

This esterification can then take place or even during the oxidation, in that the oxidation is carried out in the presence of an appropriate alcohol.

The optionally substituted hydrocarbon radicals R3 should be understood, for example, to mean a group which has 1 to 18 carbon atoms. This group can be aliphatic or cycloaliphatic, saturated or unsaturated, substituted or unsubstituted.

Examples of possible substituents on the group R3 are:

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, diethylamino, propylamino or butylamino group and their salts, such 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. The optionally substituted hydrocarbon radical R3 should preferably be understood to mean a group which has 1 to 12 carbon atoms.

Examples of groups R3 are:

the methyl, carboxymethyl, ethyl, 2-hydroxyethyl,

2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl, so 2-carboxyethyl, propyl, allyl, cyclopropyimethyl,

Isopropyl, 3-hydroxypropyl, propinyl, 3-aminopropyl, butyl, sec-butyl, tert-butyl, butyl (2), cyclobutyl, pentyl, isopentyl, tert. Pentyl, 2-methylbutyl, cyclopentyl, hexyl, cyclohexyl, cyclohex-2-enyI, cyclopentyl-65 methyl, heptyl, benzyl, 2-phenylethyl, octyl, bornyl, isobornyl, Menthyl, nonyl, decyl, 3-phenyl-propyl,

3-phenyl-prop-2-enyl, dodecyl, tetradecyl, hexadecyl and octadecyl group.

618185

As oxidizing heavy metal oxides, for example silver oxide, lead (IV) oxide, red lead, vanadium (V) oxide, manganese (IV) oxide or chromium (VI) oxide, can be used for the process according to the invention, but only the latter, if the compounds of general formula II no s

Possess 11-hydroxy group. The reaction is usually carried out in such a way that preferably 0.5 g to 50 g and in particular 1 g to 10 g of heavy metal oxide are used per gram of compound II.

This process can be carried out in the presence of alcohols, preferably lower or medium, primary or secondary alcohols having 1 to 8 carbon atoms. Examples of alcohols which may be mentioned are: methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, amyl alcohol, isoamyl alcohol, hexanol, heptanol or is

Octanol. These alcohols can also be used as solvents at the same time. Of course, it is also possible to add other inert solvents to the reaction mixture in addition to the alcohols.

Such inert solvents are, for example: hydrocarbons, such as benzene, cyclohexane or toluene, chlorinated hydrocarbons, such as methylene chloride, chloroform or tetrachloroethane, ethers, such as diethyl ether, diisopropyl ether, dibutyl ether, glycol dimethyl ether, dioxane or tetrahydrofuran, or dipolar, aprotic , 25 such as dimethylformamide, N-methylacetamide or N-methyl-pyrrolidone.

When carrying out the process according to the invention, a significant increase in the reaction rate and a significant increase in the yield are surprisingly achieved if this reaction step is preferably carried out with the addition of cyanide ions as catalyst. In particular, alkali metal cyanides such as sodium or potassium cyanide are used as reagents which supply cyanide ions. Preferably 0.01 mol to 10 mol of 35 and in particular 0.1 to 1.0 mol of cyanide are used per mol of compound II. B. As reagents which supply cyanide ions, alkali metal cyanides, the reaction is expediently carried out in such a way that the reaction mixture is additionally subjected to the amount of mineral acids required for neutralizing the alkali metal cyanide (such as: sulfuric acid, phosphoric acid or hydrogen chloride),

Add sulfonic acid (such as p-toluenesulfonic acid) or carboxylic acid (such as formic acid or acetic acid).

45

This preferred embodiment of the process is expediently carried out at a reaction temperature between −200 ° C. and +1000 ° C. and preferably at a reaction temperature between 0 ° C. and + 50 ° C. The reaction time depends on the reaction temperature and the choice of the reactants; it averages 5 to 120 minutes.

It should be noted that the compounds of the formula II can also be converted into the compounds of the formula I using other oxidizing agents. For example, 5,6-dichloro-2,3-dicyano-benzoquinone or triphenyltetrazolium chloride can be used as the oxidizing agent,

however, these oxidation methods are considerably more complex than the process mentioned.

The starting substances for the process according to the invention can be prepared in a simple manner from the corresponding 21-hydroxysteroids by adding them with lower alcohols, such as methanol, ethanol or butanol, in the presence of copper (II) acetate for 10 to 120 minutes Room temperature. The compounds obtained after customary processing 65 of the reaction mixture can be used directly as starting substances for the process according to the invention.

There are a number of options for the preferred attachment of halogen to the A9 (11) double bond. For example, halogens, such as chlorine or bromine, or compounds of the halogens with one another, for example chloromonomofluoride or bromine monochloride, or halogen from polyhalides, such as, for example, potassium tri-iodide or iodobenzodichloride, can be added directly to the double bond.

Halogen addition is particularly successful when a positive and a negative halogen are simultaneously acted on the A9 ('11) steroids. Possible reagents which contain positive halogen are, for example: halosuccinimides, haloacetamides or the halogens themselves; Possible reagents that supply negative halogen are, for example, hydrogen halides and alkali metal halides, in particular lithium halides, such as lithium chloride and lithium bromide.

The addition of halogens to the A9 (1 ^ double bond of the steroid generally always takes place in such a way that the positively charged halogen attaches to the 9-position and the negatively charged halogen to the 11-position of the molecule. The atomic weight of the halogen in Because of the known different electronegativity of the halogens, the 9-position can never be smaller than that of the halogen in the 11. The halogen addition to the A9 <1 ^ double bond is preferably carried out at temperatures between -75 ° C and + 50 ° C.

The preferred addition of hypochlorous or bromine acid to the A9 ^^ - double bond of the compounds can be carried out according to the generally known working methods sr von

Release water and acidic medium in the course of the reaction hypochlorous or bromine acids,

thus in particular reagents which form halogen cations, such as, for example, dibromomethylhydantoin, N-haloacylamides, in particular N-chloro- or N-bromoacetamide, or N-haloacylimides, in particular N-bromo- or N-chlorosuccinimide.

It is also possible to dehydrate the steroids of the formula I saturated in the 1,2-position to the corresponding A1,4 steroids. This dehydration is usually carried out using known working methods. Chemical dehydrogenation using selenium dioxide or quinones, such as 2,3-dichloro-5,6-dicyanobenzoquinone, may be mentioned here, for example.

When using selenium dioxide, for example, tert-butanol, tert-amyl alcohol or acetic acid esters are suitable as solvents. The reaction can be accelerated by adding small amounts of glacial acetic acid and can be achieved by heating the reaction mixture under reflux. The reaction is complete after about 10 to 50 hours.

When 2,3-dichloro-5,6-dicyanobenzoquinone is used, it is also expedient to also work at the boiling point of the solvent used. Examples of suitable solvents are: alcohols, such as ethanol, butanol and tert-butanol, acetic acid esters, 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.

If you use e.g. B. for the dehydrogenation as solvent alcohols, it is expedient to use alcohols of the formula R2OH — in which R2 has the same meaning as in formula I.

Any subsequent oxidation of the IIβ-hydroxy-steroids of the formula I to the corresponding 11-ketones is generally carried out using known working methods, for example using chromic acid.

618185

6

Subsequent saponification of esters is usually carried out according to known working methods. 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 bicarbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.

The subsequent subsequent esterification of the free acids can also be carried out according to known working methods. For example, the acids can be reacted with diazomethane or diazoethane and the corresponding methyl or ethyl esters are obtained. A generally applicable method is the reaction of the acids with the alcohols in the presence of carbonyldiimidazole, dicyclo-hexylcarbodiimide or trifluoroacetic anhydride. It is also possible, for example, to react the acids with alkyl halides in the presence of copper (I) oxide or silver oxide.

Another preferred method consists in converting the free acids with the corresponding dimethylformamide alkyl acetals into the corresponding acid alkyl esters. Furthermore, the acids can be reacted with the alcohols or the lower alkane carboxylic acid esters of the alcohols in the presence of strongly acidic catalysts, such as hydrogen chloride, sulfuric acid, perchloric acid, trifluoromethylsulfonic acid or p-toluenesulfonic acid. However, it is also possible to convert the carboxylic acids into the acid chloride or acid anhydrides and to react them with the alcohols in the presence of basic catalysts.

The salts of the carboxylic acids are formed, for example, when the esters are saponified by means of basic catalysts or when the acids are neutralized by means of alkali metal carbonates or alkali metal hydroxides, such as, for example, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium carbonate, potassium hydrogen carbonate or potassium hydroxide.

It is also possible to obtain esters of the formula IA in the presence of basic catalysts and reaction of the free acids with the ultimately desired alcohol. Alkali, alkaline earth or aluminum alcoholates are preferably used as basic catalysts. This reaction is preferably carried out at a reaction temperature between 0 ° C and 180 ° C. In this reaction the ultimately desired alcohol is usually 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, such as di-n-butyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether, or dipolar aprotic solvents such as dimethyl formamide, N-methylacetamide, dimethyl sulfoxide, N-methyl-pyrrolidone or Acetonitrile can be diluted. This reaction variant is e.g. B. performed so that preferably less than 1 mole of basic catalyst is used per mole of steroid. In particular, 0.0001 to 0.5 mole of basic catalyst per mole of steroid is used to carry out the reaction.

Is used as starting compounds for the inventive method z. B. 11 ß-acyloxy compounds of formula II, they can be prepared in a simple manner by saponifying the corresponding llß, 21-diacyloxy compounds under mild conditions (for example by treatment with calcium carbonate in alcoholic solution) and then the llß thus obtained -Acyloxy-21-hydroxy-steroids as described in the corresponding 21-aldehydes or 21 acids.

The compounds of the general formulas I and IA are valuable active pharmaceutical ingredients or valuable intermediates for the preparation of active pharmaceutical ingredients.

When used locally, the pharmacologically active compounds of the formula I and the formula IA have an excellent anti-inflammatory activity and, moreover, have the advantage that they are virtually ineffective when used systemically.

The new compounds mentioned are suitable in combination with the carrier agents customary in galenical pharmacy for the local treatment of contact dermatitis, various types of eczema, neurodermatoses, erythro-dermine, burns, pruritis vulvae et ani, rosacea, erythematosus cutaneus, psoriasis, and Lieber ruber planus et verrucosus and similar skin diseases.

The pharmaceutical specialties are usually produced in a customary manner by converting the active ingredients into the desired application form, for example: solutions, lotions, ointments, creams or plasters, with suitable additives. In the pharmaceuticals formulated in this way, the active substance concentration depends on the form of administration. For lotions and ointments, an active ingredient concentration of 0.001% to 1% is preferably used.

The following examples serve to explain the method according to the invention.

example 1

a) A solution of 2.0 g of 9a-fluoro-IIß, 21-dihydroxy-16a, 17a-isopropylidendioxy-l, 4-pregnadien-3,20-dione in 250 ml of methanol is mixed with 500 mg of copper (II) - acetate in 250 ml of methanol and stirred for 30 minutes while passing air. The reaction mixture is diluted with dichloromethane, washed with dilute ammonium chloride solution and water, dried with sodium sulfate and evaporated in vacuo. The yield is 2.1 g of 9a-fluoro-11ß-hydroxy-16a, 17a-isopropylidendioxy-3.20-dioxo-l, 4-pregna-dien-21-al as a crude product.

b) 1.0 g of the aldehyde thus obtained is dissolved in 50 ml of methanol and 10 ml of dichloromethane and the solution is stirred for 5 minutes after adding 160 mg of potassium cyanide, 1.0 ml of acetic acid and 2.0 g of manganese (IV) oxide. The manganese (IV) oxide is filtered off, the filtrate is diluted with dichloromethane, washed with water, dried and evaporated in vacuo. The residue is chromatographed on silica gel with a methylene chloride-acetone gradient (0-30% acetone). Yield 578 mg of 9a-fluoro-11ß-hydroxy-16a, 17a-iso-propylidendioxy-3.20-dioxo-1,4-pregnadiene-21-acidic acid methyl ester. Melting point 325 ° C (with decomposition), [o.] ^ 5: + 55 ° (chloroform). UV: £ 238 = 15,600 (methanol).

Example 2

2.1 g of 9a-fluoro-11ß-hydroxy-16a, 17 <x-isopropylidene-dioxy-3,20-dioxo-l, 4-pregnadien-21-al are, under the conditions described in Example lb, but in butanol , implemented. Yield 585 mg of 9a-fluoro-11β-hydroxy-16a, 17a-isopropylidenedioxy-3.20-dioxo-l, 4-pregnadiene-21-acid-butyl ester. Melting point 281 ° (with decomposition), [a] ": + 47 ° (chloroform). UV: e238 = 16,000 (methanol).

Example 3

5.0 g of 9a-fluoro-11β-hydroxy-16a, 17a-isopropylidene-dioxy-3,20-dioxo-l, 4-pregnadien-21-al are, under the conditions described in Example lb, but reacted in pentanol. Yield 2.58 g of 9 <x-fluoro-11β-fluoro-11ß-hydroxy-16a, 17a-isopropylidenedioxy-3.20-dioxo-l, 4-pregnadiene-21-acidic acid pentyl ester. Melting point 247 ° C. [a] ^ 5: + 45 ° (chloroform). UV: £ 238 = 15,900 (methanol).

Example 4

The solution of 500 mg of 9a-fluoro-11ß-hydroxy-16a, 17a-isopropylidendioxy-3.20-dioxo-l, 4-pregnadien-21-acid-

s

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

7

618185

100 mg of potassium tert-butoxide are added to pentyl ester in 80 ml of propanol and the mixture is stirred at room temperature under nitrogen for 5 hours. The solution is diluted with dichloromethane, washed with dilute acetic acid, sodium hydrogen carbonate solution and water, dried over sodium sulfate and evaporated in vacuo. The crude product is recrystallized from acetone-hexane. Yield 230 mg of 9a-fluoro-11β-hydroxy-16a, 17a-isopropylidenedioxy-3.20-dioxo-l, 4-pregnadiene-21-acid-propyl ester. Melting point 285 ° C (with decomposition), [a] ^ 5: + 49 ° (chloroform). UV: E238 = 15,900 (methanol).

Example 5

Under the conditions given in Example 4, 500 mg of 9a-fluoro-11β-hydroxy-16a, 17a-isopropylidenedioxy-3,20-dioxo-l, p-4-pregnadiene-21-acid with isopropyl alcohol in 9a-fluorine -llß-hydroxy-16a, 17a-isopropyl-idendioxy-3,20-dioxo-l, 4-pregnadiene-21-acid-isopropyl ester. Yield 291 mg. Melting point 286 ° C (with decomposition). [a] £ f: + 51 ° C (chloroform). UV: e238 -15 900 (methanol).

Example 6

Under the conditions given in Example 4, 350 mg of 9a-fluoro-11β-hydroxy-16 a, 17 a-isopropylidenedioxy-3,20-dioxo-l, 4-pregnadiene-21-acidic acid pentyl ester with ethanol in9a-fluorine IIß-hydroxy-16a, 17a-isopropylidenedioxy-3,20-dioxo-l, 4-pregnadien-21-acidic acid ethyl ester. Yield 119 mg. Melting point 288 ° C (with decomposition), [a] ^ 5: + 46 ° (chloroform). UV: 8238 = 15,700 (methanol).

Example 7

100 mg methyl 9a-fluoro-11ß-hydroxy-16a, 17a-isopropylenedioxy-3,20-dioxo-l, 4-pregnadiene-21-acid,

under the conditions given in Example 4, with decanol in 9a-fluoro-1-lß-hydroxy-16a, 17a-isopropylidenedioxy-3,20-dioxo-1, 4-pregnadiene-21-acidic acid decyl ester. Yield 110 mg of a non-crystallizing oil.

Example 8

250 mg of 9a-fluoro-11β-hydroxy-16a, 17a-isopropylidene-dioxo-3.20-dioxo-l, 4-pregnadiene-21-acidic acid methyl ester, under the conditions given in Example 4, with 2-propene l-ol converted to 9a-fluoro-11ß-hydroxy-16a, 17a-isopropyl-idendioxy-3,20-dioxo-l, 4-pregnadien-21-acid-2-propenyl ester. Yield 183 mg.

Example 9

250 mg pentyl 9a-fluoro-11ß-hydroxy-16a, 17a-isopropylidene-dioxy-3,20-dioxo-l, 4-pregnadiene-21-acid are, under the conditions given in Example 4, with 2-propyne 1 -ol converted into 9a-fluoro-1 1 ß-hydroxy-16a, 17a-isopropyl-idendioxy-3,20-dioxo-l, 4-pregnadiene-21-acid-2-propynyl ester. Yield 120 mg.

Example 10

A solution of 810 mg of 9a-fluoro-11β-hydroxy-16a, 17a-isopropylidenedioxy-3.20-dioxo-l, pentyl 4-pregnadiene-21-acid in 50 ml of dichloromethane and 60 ml of methanol is mixed with the solution of 960 mg of potassium hydroxide in 5 ml of water and stirred for 30 minutes under nitrogen at room temperature. The alkaline reaction solution is then mixed with water and extracted with dichloromethane. The aqueous phase is acidified with 2N hydrochloric acid and also extracted with dichloromethane. The second dichloromethane phase is washed with water, dried and evaporated in vacuo at 30 °. The residue is taken up in a little tetrahydrofuran and ethyl acetate is added until crystallization begins. 490 mg of 9a-fluoro-11β-hydroxy-16a, 17a-isopropylidenedioxy-3.20-dioxo-l, 4-pregnadien-21-acid of melting point 293 ° C. (with decomposition) are obtained. [a] j * s: + 57 ° (pyridine). UV: E238 = 15,300 (methanol).

Example 11

100 mg of 9a-fluoro-11β-hydroxy-16a, 17a-isopropylidene-dioxy-3.20-dioxo-l, 4-pregnadien-21-acid is dissolved in 15 ml of methanol and mixed with 2.23 ml of an n / 10 -Solution of potassium hydroxide in methanol. The solvent is largely evaporated off in vacuo and 25 ml of ether are added to the residue. The precipitated sodium salt of 9a-fluoro-11ß-hydroxy-16a, 17a-isopropylidendioxy-3.20-dioxo-l, 4-pregnadien-21-acid is suction filtered and dried in vacuo. Yield 93 mg.

Example 12

1.0 g of 6a, 9a-difluoro-11ß, 21-dihydroxy-16a, 17a-iso-propylidendioxy-l, 4-pregnadien-3,20-dione becomes 6a, 9a- under the conditions given in example la Difluoro-11 ß-hydroxy-16a, 17a-isopropylidendioxy-3,20-dioxo-1,4-pregnadien-21-al oxidized. 500 mg of the product obtained in this way, under the conditions described in Example 1b, in 6a, 9a-difluoro-11β-hydroxy-16a, 17a-isopropylidenedioxy-3,20-dioxo-l, 4-pregnadiene-21-acidic acid transferred methyl ester. Yield 277 mg. Melting point 314 ° C (with decomposition). [a] £ 5: + 43 ° (chloroform). UV: E238 = 16,500 (methanol).

Example 13

500 mg of 6a, 9a-difluoro-11ß-hydroxy-16a, 17a-isopropylidene-dioxy-3,20-dioxo-l, 4-pregnadien-21-al are, under the conditions described in Example 1b, but in butanol, with Vanadium (V) oxide, converted to 6a, 9a-difluoro-11ß-hydroxy-16a, 17a-isopropylidenedioxy-3,20-dioxo-l, 4-pregnadiene-21-acid-butyl ester. Yield 364 mg. Melting point 248 ° C (with decomposition), [a] ^, 5: + 55 ° (pyridine). UV: 8238 = 16,400 (methanol).

Example 14

Under the conditions described in Example la, 500 mg of 6a-fluoro-9a-chloro-11ß, 21-dihydroxy-16a, 17 a-isopropylidenedioxy-l, 4-pregnadiene-3,20-dione are oxidized to the 21-aldehyde and this, under the conditions described in Example 1b, with butanol converted to 6-fluoro-9a-chloro-11β-hydroxy-16a, 17a-isopropylidenedioxy-3,20-dioxo-l, 4-pregnadiene-21-acid-butyl ester. Yield: 336 mg. Melting point: 296 ° C (with decomposition), [a] ^ 5: + 68 ° (chloroform). UV: 8238 = 16 100 (methanol).

Example 15

150 mg of 6a-fluoro-9a-chloro-11ß-hydroxy-16a, 17a-iso-propylidendioxy-3.20-dioxo-l, 4-pregnadiene-21-acidic acid butyl ester under the conditions given in Example 4 , converted into methanol in 6a-fluoro-9a-chloro-11ß-hydroxy-16a, 17a-isopropylidendioxy ~ 3.20-dioxo-l, 4-pregnadien-21-acidic acid methyl ester.

Yield: 98 mg. Melting point: 329 ° C (with decomposition). [a] £ s: + 74 ° (chloroform). UV: 8238 = 16,200 (methanol).

Example 16

Under the conditions given in Example 1, 3.0 mg of 6a-fluoro-11ß, 21-dihydroxy-16a, 17a ~ isopropylidene-dioxy-1, 4-pregnadiene-3,20-dione are oxidized to the aldehyde and this with ethanol in 6a -Fluoro-llß-hydroxy-16a, 17a-iso-propylidendioxy-3,20-dioxo-1,4-pregnadiene-21-acid-ethyl ester transferred. Yield: 1.56 g. Melting point: 279 ° C (with decomposition), [a] ^, 5: + 51 ° (chloroform). UV: 8242 = 16,300 (methanol).

5

19th

15

20th

25th

30th

35

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618185

Example 17

Under the conditions given in Example 4, 750 mg of 6a-fluoro-11ß-hydroxy-16a, 17a-isopropylidene-dioxy-3,20-dioxo-l, 4-pregnadiene-21-acidic acid ethyl ester with butanol in 6a-fluorine IIß-hydroxy-16a, 17a-isopropylidene-dioxy-3,20-dioxo-l, 4-pregnadiene-21-acid-butyl ester. Yield: 451 mg. Melting point: 294 ° C (with decomposition). [a] ^ 5: + 54 ° (chloroform).

UV: 6242 = 16,600 (methanol).

Example 18

150 mg of 6a-fluoro-9a, 11ß-dichloro-16a, 17a-isopropyl-idendioxy-l, 4-pregnadien-3,20-dione, under the conditions described in Example 1, via the corresponding 21-aldehydin 6a-fluorine 9a, llß-dichloro-16a, 17a-isopropylidenedioxy-3,20-dioxo-l, 4-pregnadiene-21-acidic acid methyl ester. Yield 86 mg. Melting point 330 ° C (with decomposition), [a] ^ 5: + 86 ° (chloroform). UV: 8237 = 15,900 (methanol).

Example 19

Under the conditions described in Example la, 75 mg of 6a-fluoro-9a, 11ß-dichloro-16a, 17a-isopropylidene-dioxy-l, 4-pregnadiene-3,20-dione are oxidized to the 21-aldehyde and this, under the conditions in Example lb conditions described, with butanol converted to 6a-fluoro-9a, lß-dichloro-16a, 17a-iso-propylidendioxy-3,20-dioxo-l, 4-pregnadiene-21-acid-butyl ester. Yield 37 mg. Melting point 246 ° C. [a] ~ 5: + 84 ° (chloroform). UV: 8237 = 16 100 (methanol).

Example 20

Under the conditions described in Example la, 500 mg of 6a, 11ß-difluoro-16a, 17a-isopropylidenedioxy-l, 4-pregnadiene-3,20-dione are oxidized to 21-aldehyde and this is treated with butanol in under the conditions described in Example lb. 6a, 1 Lß-difluoro-9a-chloro-16a, 17a-isopropylidene-dioxy-3,20-dioxo-l, 4-pregnadiene-21-acidic acid butyl ester. Yield 416 mg. Melting point above 330 ° C. [a] * s: + 55 ° (chloroform). UV: 8236 = 15,800 (methanol).

Example 21

Under the conditions described in Example la, 300 mg of 6a-fluoro-IIß, 21-dihydroxy-16a, 17a-iso-propylidendioxy-4-pregnen-3,20-dione are oxidized to the 21-aldehyde and this is oxidized under those described in Example Ib Conversion conditions with butanol to 6-fluoro-1-beta-hydroxy-16a, 17a-isopropylidenedioxy-3,20-dioxo-4-pregnene-21-acid ester. Yield 129 mg. Melting point 262 ° C (with decomposition).

[a] 2S: + 86 ° (chloroform). UV: 8236 = 16 100 (methanol).

Example 22

Under the conditions described in Example 1, 5.0 g of 11β, 21-dihydroxy-16a, 17a-isopropylidene-dioxy-1, 4-pregnadien-3,20-dione are converted into 11β-hydroxy-16a via the 21-aldehyde, 17 a-Isopropylidendioxy-3,20-dioxo-l, 4-pregnadien-21-acidic acid methyl ester transferred. Yield 3.8 g.

Example 23

1.0 g of 11β-hydroxy-16a, 17a-isopropylidenedioxy-3,20-dioxo-l, 4-pregnadiene-21-acidic acid methyl ester are transesterified in butanol under the conditions described in Example 4. Yield 633 mg llß-hydroxy-16a, 17a-iso-propylidendioxy-3,20-dioxo-l, 4-pregnadiene-21-acid-butyl ester. Melting point 253 ° C. [a] ^ 5 = + 53 ° (chloroform).

Example 24

500 mg llß-hydroxy-16a, 17a- (l-phenylethylidendioxy) -l, 4-pregnadiene-3,20-dione, under the conditions given in Example 1, over the 21-aldehyde in 11ß-hydroxy-16a, 17a - (l-phenylethylenedioxy) -3,20-dioxo-l, 4-pregnadien-21-acidic acid methyl ester. Yield 210 mg. Melting point 228 ° C. [a] ^ 5 = -19 ° (chloroform).

Example 25

2.0 g of 6a-fluoro-21-hydroxy-16a, 17a-isopropylidenedioxy-4-pregnen-3,20-dione are, under the conditions given in Example 1, over the 21-aldehyde in 6a-fluoro-16a, 17a -Isopropylidendioxy-3,20-dioxo-4-pregnen-21-acidic acid methyl ester transferred. Yield 940 mg. Melting point 149 ° C. [a] D = + 58 ° (chloroform).

Example 26

1.0 g of 21-hydroxy-16 a, 17 a-isopropylidenedioxy-4-pregnen-3,20-dione are oxidized to 21-aldehyde under the conditions given in example la and this under the conditions given in example lb , with butanol in 16a, 17a-isopropylidenedioxy-3,20-dioxo-4-pregnen-21-acidic acid butyl ester. Yield 435 mg.

Example 27

750 mg llß, 21-dihydroxy-16a, 17a-isopropylidendioxy-6a-methyl-l, 4-pregnadiene-3,20-dione are, under the conditions given in Example la, oxidized to 21-aldehyde and this, under the conditions in Example Ib specified conditions with butanol in 11ß-Hydroxy-16a, 17a-iso-propylidendioxy-3.20-dioxo-6a-methyl-1,4-pregnadiene-21-acidic acid-butyl ester converted. Yield 320 mg.

Example 28

a) A solution of 560 mg of 21-hydroxy-16a, 17a-iso-propylidendioxy-l, 4-pregnadiene-3,20-dione in methanol is reacted analogously to example la. The yield is 729 mg of 16a, 17a-isopropylidenedioxy-3,20-dioxo-l, 4-pregna-dien-21-al as the crude product.

b) 729 mg of the aldehyde thus obtained are reacted under the conditions described in Example 1b, but in ethanol. Yield 284 mg 16a, 17a-isopropylidenedioxy-3,20-dioxo-l, 4-pregnadien-21-acidic acid ethyl ester. Melting point 207-208 ° C. [a5 = + 33 ° (chloroform). UV: 8243 = 16 100 (methanol).

Example 29

a) A solution of 700 mg of 21-hydroxy-16a, 17a-iso-propylidendioxy-l, 4-pregnadien-3,20-dione in methanol is converted to 16a, 17a-isopropylidendioxy-

3,20-dioxo-l, 4-pregnadien-21-al implemented.

b) The crude aldehyde thus obtained is reacted under the conditions described in Example 1b, but in butanol. Yield 318 mg 16a, 17a-xsopropylidenedioxy-3,20-dioxo-l, 4-pregnadien-21-acid-butyl ester. Melting point 145-146 ° C. [A] 2j = = + 34 ° (chloroform). UV: 8243-16 300 (methanol).

Example 30

Under the conditions described in Example la, 700 mg of 11β, 21-dihydroxy-16a, 17a-isopropylidene-dioxy-l, 4-pregnadiene-3,20-dione are oxidized to the 21-aldehyde. This is, under the conditions described in Example 1b, converted with ethanol into 11β-hydroxy-16a, 17a-isopropylidene-dioxy-3,20-dioxo-l, 4-pregnadiene-21-acidic acid ethyl ester. Yield 331 mg. Melting point 260-261 ° C. [a] £ 5 = + 53 ° (chloroform). UV: 8242 = 15,300 (methanol).

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Example 31

Under the conditions described in Example 1a, 560 mg 11β, 21-dihydroxy-16a, 17a-isopropylidene-dioxy-1,4-4-pregnadiene-3,20-dione are oxidized to the 21-aldehyde and this under the conditions described in Example Ib , with cyclohexanol in 11ß-hydroxy-16a, 17a-iso-propylidendioxy-3,20-dioxo-l, 4-pregnadiene-21-acid-cyclohexyl ester. Yield 141 mg. Melting point 274-275 ° C. [a5 = + 58 ° (chloroform). UV: 8242 = 15,400 (methanol).

Example 32

Under the conditions described in Example la, 500 mg of 9cx-chloro-11ß, 21-dihydroxy-16 <x, 17a-isopropylidendioxy-l, 4-pregnadiene-3,20-dione are oxidized to the 21-aldehyde and this, under the im Example 1b conditions described with butanol in 9 <x-chloro-1 lß-hydroxy-16a, 17a-isopropylidendioxy-3,20-dioxo-1, 4-pregnadiene-21-acidic acid butyl ester. Yield 185 mg. Mp 247.5-248.5 ° C (with decomposition). [a5 = + 75 ° (pyridine). UV: 8239 = 15300 (methanol).

Example 33

Under the conditions described in Example la, 500 mg of 21-hydroxy-16a, 17a-isopropylidenedioxy-l, 4-pregnadiene-3, ll, 20-trione are oxidized to 21-aldehyde and this, under the conditions described in example lb, with Ethanol in 16a, 17a-isopropylidenedioxy-3,11,20-trioxo-1,4-pregnadien-21-acidic acid ethyl ester. Yield 161 mg. Mp 184-185 ° C. [a5 = + 105 ° (chloroform).

UV: 8238 = 15 9 00 (methanol).

Example 34

Under the conditions described in Example la, 600 mg of 21-hydroxy-16a, 17a-isopropylidenedioxy-l, 4-pregna-diene-3, 11, 20-trione are oxidized to 21-aldehyde. This one will

under the conditions described in Example 1b, with butanol in 16a, 17-isopropylidenedioxy-3, 11, 20-trioxo-l, 4-pregnadiene-21-acidic acid butyl ester. Yield 301 mg. Mp 131-133 ° C. [a5 = + 96 ° (chloroform). UV: 8239 = 15700 (methanol.).

Example 3 5

500 mg of 9a-chloro-11ß-hydroxy-16a, 17a-isopropyl-idendioxy-3,20-dioxo-l, 4-pregnadiene-21-acidic acid butyl ester in methylene chloride are treated with Collins reagent for 90 minutes. It is then precipitated with water, the precipitate is isolated and recrystallized from acetone-hexane.

Yield 420 mg of 9a-chloro-16ot, 17a-isopropylidenedioxy-3,11,20-trioxo-1,4-pregnadiene-21-acid acid butyl ester.

Mp 198-200 ° C. [a5 = + 153 ° (chloroform).

UV: 8237 = 15900 (methanol).

Example 36

750 mg of 9a, 11ß-dichloro-21-hydroxy-16a, 17a-isopropyl-idendioxy-l, 4-pregnadiene-3,20-dione are oxidized to 21-aldehyde under the conditions described in Example la. This is, under the conditions described in Example 1b, converted with butanolin 9a, 11ß-dichloro-16a, 17a-iso-propylidendioxy-3,20-dioxo-l, 4-pregnadiene-21-acidic acid ester. Yield 300 mg. Mp 242-243 ° C (with decomposition), [aß5 = + 101 ° (chloroform).

UV: 8237 = 15500 (methanol).

Example 37

1.9 g of 9a-fluoro-11ß-hydroxy-16a, 17a-isopropylidene-dioxy-3,20-dioxo-l, 4-pregnadien-21-al are reacted under the conditions described in Example 1b, but in cyclohexanol. Yield 451 mg of 9a-fluoro-11β-hydroxy-16a, 17a-isopropylidendioxy-3.20-dioxo-l, 4-pregnadiene-21-acid-cyclohexyl ester. Mp 274 ° C (with decomposition). [aß5 = + 64 ° (pyridine). UV: 8238 = 15700 (methanol).

Example 38

3.4 g of 6cc-fluoro-21-hydroxy-16a, 17a-isopropyl-idendioxy-4-pregnen-3.20-dione are oxidized to the 21-aldehyde under the conditions described in Example 1a. This is then, under the conditions described in Example 1b, converted with butanol to the 6a-fluoro-16a, 17a-isopropylidenedioxy-3,20-dioxo-4-pregnen-21-acid-butyl ester. Yield 1.63 g. Mp 185 ° C.

[a5 = + 56 ° (chloroform). UV: E235 = 17000 (methanol).

Example 39

Under the conditions described in Example 1, 1.5 g of 21-hydroxy-16a, 17a-isopropylidenedioxy-1,4-pregnadiene-3,20-dione are converted into 16a, 17a-isopropylidenedioxy-3,20-dioxo via the corresponding 21-aldehyde -l, 4-pregnadiene-21-acid methyl ester transferred. Yield 800 mg. Mp 216 ° C. [a5 = + 39 ° C (chloroform).

Example 40

500 mg of 16a, 17a-isopropylidenedioxy-3,20-dioxo-l, 4-pregnadiene-21-acidic acid methyl ester are saponified under the conditions described in Example 10. 450 mg of 16a, 17a-isopropylidenedioxy-3,20-dioxo-l, 4-pregnadien-21-acid are obtained. Mp 234 ° C (dec.). [a5 = + 44 ° (methanol).

Example 41

Under the conditions described in Example 11, 200 mg of 16a, 17a-isopropylidenedioxy-3,20-dioxo-21-acid are converted into the sodium salt. Yield 181 mg. Mp> 300 ° C. [aß5 = + 20 ° (methanol).

Example 42

Under the conditions described in Example la, 800 mg of 21-hydroxy-16a, 17a-isopropylidenedioxy-l, 4-pregnadiene-3,20-dione are oxidized to the 21-aldehyde. Under the conditions described in Example 1b, however, this is converted into cyclohexanol in the 16a, 17a-isopropylidene-dioxy-3,20-dioxo-l, 4-pregnadiene-21-acid-cyclohexyl ester. Yield 344 mg.

Example 43

1.0 g of 9a-fluoro-IIß-21-dihydroxy-16a, 17a- (l-phenyl-ethylidene-dioxy) -l, 4-pregnadiene-3,20-dione are oxidized to the aldehyde under the conditions described in Example la . This is, as described in the presentation of lb, but with butanol, in 9a-fluoro-lß-hydroxy-16a, 17a- (l-phenylethylenedioxy) -3,20-dioxo-1,4-pregnadiene-21-acid -butyl ester. Yield 570 mg. Mp 217 ° C. [a5 = -32 ° (chloroform); UV: 8239 = 15300 (methanol)

Example 44

590 mg llß, 21-dihydroxy-16a, 17a- (r-phenylethyl-idendioxy) -l, 4-pregnadiene-3,20-dione are oxidized to the 21-aldehyde under the conditions described in Example la. The aldehyde thus obtained is converted to 11β-hydroxy-16a, 17a- (l'-phenylethylidendioxy) -3,20-dioxo-l, 4-pregnadiene-21-acid-butyl ester under the conditions described in Example 1b, but in butanol implemented. Yield 261 mg. 211 ° C. [aß5 = -26 ° (chloroform)

UV: 8239 = 15700 (methanol).

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Example 45

a) A solution of 1.06 g llß, 21-diacetoxy-l, 4,16-pregnatrien-3,20-dione in 100 ml acetone and 1.5 ml glacial acetic acid at 0 ° C with a solution of 440 mg potassium permanganate treated in 80 ml acetone. The resulting manganese dioxide is filtered off and, after dilution with methylene chloride, the filtrate is washed neutral with a sodium hydrogen carbonate solution. After drying the organic phase over sodium sulfate and concentrating, 1.03 g of 16a, 17a-dihydroxy-11ß, 21-diacetoxy-l, 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 70 percent. Perchloric acid was added and the mixture was stirred at room temperature for one hour. The mixture is then diluted with water, methylene chloride is added, the organic phase is separated off, washed neutral, dried over sodium sulfate and evaporated to dryness. 1.15 g of 16a, 17a-isopropylidene-dioxy-11ß, 21-diacetoxy-l, 4-pregnadien-3,20-dione with a melting point of 252-253 ° C [aß5 = + 133 ° (chloroform) are obtained.

c) A solution of 1.0 g Ì6a, 17a-isopropylidendioxy-11ß, 21-diacetoxy-l, 4-pregnadien-3,20-dionine in 120 ml of methanol is added after the addition of 1 ml of an 10% proc. aqueous potassium carbonate solution stirred for 20 minutes at room temperature. After neutralization with dilute acetic acid, the mixture is concentrated and worked up as usual. Separation using preparative thin-layer plates in the chloroform / system

Acetone (8: 2) provides 450 mg of 21-hydroxy-16a, 17a-isopropylidendioxy-11ß-acetoxy-l, 4-pregnadiene-3,20-dione, melting point 133-134 ° C. [aß5 = + 91 ° (methanol). UV: £ 240 = 14900 (methanol).

sd) A solution of 500 mg of 21-hydroxy-16a, 17a-iso-propylidene-dioxy-llß-acetoxy-l, 4-pregnadiene-3,20-dione in 6.25 ml of methanol is mixed with 125 mg of copper (ll ) acetate in 62.5 ml of methanol and stirred for 1.5 hours while passing air. The reaction mixture is diluted with methylene chloride, washed with ammonium chloride solution and water, dried over sodium sulfate, evaporated in vacuo and 596 mg of 16a, 17a-isopropylidenedioxy-11β-acetoxy-3,20-dioxo-l, 4-pregnadien-21-al are obtained .

e) 596 mg of the aldehyde thus obtained are dissolved in 5.5 ml of methylene chloride and 30 ml of n-butanol and the solution after adding 90 mg of potassium cyanide, 0.55 ml of acetic acid and 1.1 g of manganese (IV) oxide for 30 minutes touched. The manganese (IV) oxide is filtered off, the filtrate mixed with methylene chloride

20 thins 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-isopropylidendioxy-11β-acetoxy-3.20-dioxo-l, 4-pregnadiene-21-acid-butyl-

• 25 esters with a melting point of 210-211 ° C.

Mrf = + 70 ° (chloroform).

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Claims (3)

618185 2. The method according to claim 1, characterized in that that dehydrated compounds of the formula I which are saturated in the 1,2-position are dehydrogenated to give the A1.4 steroids. 3. The method according to claim 1, characterized in that esterified compounds of the formula I which have an 11-hydroxy group are esterified. 4. The method according to claim 1, characterized in that compounds of formula I obtained which have an 11-hydroxy group are oxidized to the corresponding 11-keto compounds. 5. The method according to claim 1, characterized in that saponified compounds of formula I which are present as esters are saponified. 6. The method according to claim 1, characterized in that compounds of the formula I obtained which have such an A9 (1 ^ double bond) are converted into the corresponding 9a compounds by addition of halogen onto the double bond. 7. The method according to claim 1, characterized in that 9-chloro or 9-bromo- from the compounds of formula I obtained, which have a SS A9 (11) double bond, by addition of hypochlorous or bromonic acid to the double bond llß-hydroxy compounds. 8. Use of the method according to claim 1 60 compounds of the formula I obtained, which are present as free acid, for the preparation of esters of the formula 2 CID where -A-B, Z-, Ri and R2 have the same meaning as in formula I, or the hydrates or hemiacetals of this compound are oxidized with oxidizing heavy metal oxides and the acid obtained is optionally converted into an alkali metal salt. 2nd PATENT CLAIMS 1. Process for the preparation of new pregnanic acids of the formula COOH CI) where — A-B- is the groupings-CH2-CH2-, -CH = CH- or-CCl = CH-, X is hydrogen, a halogen atom or the methyl group, ^ Y — Z- the groups ^ CH-Œfc—, ^ C = CH-, pcv-cHou-, ^ CV-CO-, ^ ICW-CHW'- with U in the meaning of a hydrogen atom or a 20 acyl group, V in the meaning of a hydrogen atom or halogen atom and W and W 'in the meaning of a halogen atom, Ri is an alkyl group and R2 is an alkyl group or aryl group or Ri and R2 together are a tetramethylene group. 25 or pentamethylene group and the alkali metal salts, characterized in that a compound of the formula CHO 0 = 0 • R, B 3rd COOR- C = 0 0 .0- • R, 618185 (I A) wherein R3 is an optionally substituted hydrocarbon radical, characterized in that the free acid is esterified accordingly.