DE1188592B - Method for the inversion of the epimeric forms of 20-keto-21-monosulfonyloxy-21-methyl steroids of the pregnane series - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int Cl .:

Number:
File number:
Registration date:
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C07c

German class: 12 ο -25/05

1188592
P30610IVb / 12o
November 20, 1962
March 11, 1965

The invention relates to a process for converting the epimeric forms of 21-methyl steroids among themselves.

A new group of therapeutically valuable steroids has only recently been described. These Pregnan derivatives are due to the presence of a side chain with 3 carbon atoms in the 17 ^ position marked, in contrast to the previously known active steroids, all of which are uniform carry a side chain with 2 carbon atoms in the 17/3 position. You can do the first group as 17 | 8- (a-hydroxy-propanoyl) -substituted steroids, refer to the second group as 17 ^ - (a-hydroxy-acetyl) -substituted steroids. Can be even easier the former are referred to as 21-methyl steroids.

An example of this new group of compounds is the compound 9a-fluoro-21-methyl-Mdi

Process for the inversion of the epimeric forms
of 20-keto-21-monosulfonyloxy-21-methyl steroids of the pregnane series

The formulas for the two epimers of this compound are shown below. The one with the asterisk designated carbon atom is asymmetric and leads to the formation of the two epimers To shape.

CH ₃
- ^ C- OAc

CH ₃
AcO-C-H

C = O

OH

B configuration

A configuration

The two epimers of the compounds of this type are active, but not necessarily in the same way Scope. The conversion of the less active epimer to the more active one is of value insofar as than it is a more effective therapeutic agent than it to the doctor or veterinarian despite the low dose Represent mixtures, supplies. The conversion of the more active epimer to the less active one also of great use to the chemical applicant:

Chas. Pfizer & Co., Inc., Brooklyn, NY
(V. St. A.)

Representative:

Dr. W. Beil, A. Hoeppener and Dr. H. J. Wolff, Lawyers, *

Frankfurt / M.-Höchst, Antoniterstr. 36

Named as inventor:

Hans Jürgen Ernst Hess, New London, Conn.

(V. St. A.)

and medical research, since it is then possible for the first time to use this epimer for study the physiological effects of the configuration changes in the steroid molecule. in the the rest is obtained in pure form by this process with the less active epimer Intermediate product for the manufacture of other steroids with the same configuration in the 21-position and more effective substituents elsewhere in the molecule, e.g. B. with a fluorine atom in 9 position.

The epimerization of 17,20,21-triols to invert the configuration in the 20-position is already done known for some time. Fukushima et al. (Journal of Biological Chemistry, 212, p. 449 [1955]) ζ. Β. show the inversion of a member of this group of compounds by making a 17,21-diacetate-20-tosylats and postulate a reaction mechanism that involves the participation of neighboring groups between 17 and 20 position. The mechanism is shown below in formulas,

509 518/484

in which only the C and D rings of the steroid are shown.

O 0

H ₂ C-O-C-CH ₃ H ₂ C-O-C-CH ₃

TsO - C - H

H — C — O

O-C-CH ₃

-TsO-

C-CH ₃

Ο ^κ

HCOC-CH ₃

+ H ₂ O

-Η® Ο
H ₂ C-O-C-CH ₃

CH ₃

The overall effect of this reaction is a saponification of the ester groups in the 17- and 20-position with a simultaneous shift of the acetyl group in the 17-position to the 20-position in connection with the inversion of the configuration in the 20-position. The importance of the participation of neighboring groups is emphasized by the fact that the treatment of Pregnan-3a, 17 <z, 20 / S, 21-tetrol-11-one-3,21-diacetate-20-tosylate with potassium acetate in glacial acetic acid under Conditions which - as one would expect - lead to inversion, instead of which leads to the production of a 3,20,21-triacetate in which the / 3-configuration is maintained in the 20-position. B ey 1 er et al. (Journal of Organic Chemistry, 24, p. 1386 [1959]) have J ^ -Pregnadiene- 17α, 20 & 21 -triol-3.11 -dione-21 - acetate by the following reactions in J! - ⁴ -Pregnadiene - 17α, 20α, 21 -triol-3,11 -dione-20.21 -diacetate converted, whereby - as one will find - exactly the same shift and inversion takes place.

H ₃ CSOCH

OH

CH ₃ SO ₂ Cl

CH ₂ OC - CH ₃

HAc

PC ₆ H ₄ (CH ₃ ) (SO ₃ H)

continuation

H ₂ C - OC - CH ₃
H - C - O - C - CH ₃

Il ο

OH

KAc

HAcAc ₂ O

O-C-CH ₃

With this assumption, it is really surprising that it is possible to change the configuration on Reverse the 21-carbon atom of 21-methyl steroids in which the neighboring group is a carbonyl group instead of an acylated hydroxyl group.

Further, the hydroxyl group located on a carbon atom becomes that of the 20-position adjacent is not acylated.

The process according to the invention is characterized in that the 21-monosulfonic acid ester of the epimer to be invested is in dimethylformamide or a lower aliphatic oxygen-containing solvent which contains up to 5 carbon atoms, or mixtures thereof, for about 1 to 24 hours with an about 100 to 2000% igen molar excess of an alkali metal salt of a carboxylic acid at a temperature of about 20 to about 70 ⁰ C.

The carboxylic acid from which the alkali metal salt is derived is not critical. Indeed suitable any carboxylic acid, either as a free acid or modified e.g. B. as an acid halide or anhydride, a 21-carboxylic acid ester of a 21-hydroxysteroids forms. The acid can therefore be aliphatic or aromatic, substituted or unsubstituted, be monobasic or polybasic. Examples are vinegar, propion, valerian, lemon, Wine, maleic, fumaric, octadecane, cyclopentylpropion, butene, trichloroacetic, a-bromopropion, Cyclohexanoic, benzoic, phenylacetic, p-chlorobenzoic and p-nitrobenzoic acid are indicated. With the usual However, the alkali metal salts disclosed by Mono- and dicarboxylic acids with up to a total of 6 carbon atoms and which only contain carbon Contain hydrogen and oxygen. These compounds are mainly used because they are the most common esters of steroid compounds that enhance their therapeutic effectiveness due to be applied.

The selection of the sulfonic acid ester is not critical either. One can use the p-toluenesulfonic acid ester (Tosyl ester), the p-bromobenzenesulfonic acid ester (brosyl ester), the p-nitrobenzenesulfonic acid ester (nosyl ester) or various alkanesulfonic acid esters, such as. B. the methanesulfonic acid ester (mesyl ester) or Ethanesulfonic acid ester, use with equal ease. However, mesylates are generally used preferred because the source material is readily available and somewhat easier to work with.

The reaction takes place in a reaction-inert, lower aliphatic oxygen-containing solvent instead of containing up to 5 carbon atoms, esters, ketones and acids are particularly suitable. Dimethylformamide can also be used. Mixtures of solvents are often used. Examples of solvents which can be used in the process according to the invention are including acetic acid, propionic acid, valeric acid, ethyl acetate, methyl propionate, acetone and Methyl isopropyl ketone. Of these, acetone is preferred because it is readily available and in high yields results. It can be mixed with dimethylformamide, so that one has a higher boiling point Solvent receives. Mixtures containing about 10 to about 50 percent by volume of the latter compound included are valuable.

The reaction is carried out for about 1 hour to about 24 hours at a temperature of about 20 to about 70 ⁰ C. A temperature of about 50 are preferred to about 7O ⁰ C and a reaction time of about 1 to about 4 hours.

These conditions are preferred for practical reasons as they represent an acceptable compromise between the required heat and time conditions.
While equimolar amounts of the steroid substrate and the alkali metal salt can theoretically be used, a large excess of salt is generally used to ensure complete conversion of the more expensive steroid. An amount of salt in about 200% excess (molar) to about 2000% excess (molar) or even more is therefore used, with an excess (molar) of about 1000 to about 2000% being preferred.
The process according to the invention thus comprises a process for converting the epimeric forms of 21-methyl steroids by converting the 21-monosulfonic acid ester of the epimer to be inverted into dimethylformamide or a lower aliphatic oxygen-containing solvent which contains up to 5 carbon atoms with an excess (molar) of about 100 to about 2000% of an alkali metal salt of a carboxylic acid at a temperature of about 20 to about 70 ⁰ C during a

Duration of about 1 to 24 hours to obtain a 21-carboxylic acid ester with the opposite Configuration. In preferred embodiments, acetone, dimethylformamide, or mixtures used from these solvents.

It can be in an inert atmosphere, e.g. B. under nitrogen, work to avoid side reactions to keep a minimum; however, it is not absolutely necessary.

The end products are isolated according to the _ϊ0 known methods for isolating steroid esters.

Methods for making and isolating epimeric forms of 21-methyl steroids are already in place known. A g η e 11 ο describes a procedure under Reaction of diazomethane with a 21-aldehyde and subsequent enzymatic stereoselective Reduction of a Ca ^ i diketone, which is derived from the Aldehyde-diazomethane reaction product was made with fermentation yeast (A g η e 11 ο u. A., Abstract, 137. ACS Meeting, Cleveland, Ohio, April 1960, p. 20 N). This procedure results in an epimer of a 21-alcohol to which the 21/3 configuration is arbitrary was assigned.

F i g d o r has described a method that provides both the 21A and 21B epimers. In this process, etiocholenic acids were converted into the diazoketone via the acid chloride with diazoethane converted, this in turn into a chloroketone and the chlorine atom in the 21-position replaced by an acyloxy group, so that a 21-methyl-21-acyloxysteroid was obtained (F i g d ο r et al., Abstract, 137th ACS Meeting, Cleveland, Ohio, April 1960, p. 20 N).

It is interesting to note that in some cases the B-configuration 21-methyl steroid is more effective as an anti-inflammatory agent than the Α-configuration epimer. L1 aurad ο and Schneider have shown this with the epimers of 9a-fluoro-21-methyl-zl ¹ ' ⁴ -pregnadiene-llj3,17a, 21-triol-3,20-dione-21-acetate (44th Annual Meeting of the Federation of American Societies for Experimental Biology; Abstract in Fed. Proa, 19, p. 1959 [1960]. - In this publication the epimer with the B configuration is used as /? - ol and the epimer with the Α configuration as et-ol). It will then be found that the method of the present invention is useful in those cases where the physician or veterinarian prefers to use the more effective epimer.

In the examples, the epimers with the Α configuration are used as 21A compounds and those with of the B configuration are referred to as 21B connections. The optical rotation was in the dioxane determined at about 25 ° C. For the preparation of the starting compounds used according to the process Protection is not sought within the scope of the present invention.

Example I.
a) Preparation of the sulfonic acid esters

60

A total of l, 8g21-Methykd ⁴ -pregnen-17A, 21A-diol-3,20-dłoń were dissolved in 50 cc of pyridine and the solution to - 10 ⁰ C cooled. To this solution, 2.5 g of mesyl chloride was added dropwise over 20 minutes. After stirring for 4 hours at 0 ° C, the reaction mixture was recooled to - 10 ⁰ C cooled, and the Mesylchloridüberschuß was destroyed by dropwise addition of 10 cc of water in 20 minutes. The mixture was then poured into 200 ecm of water and extracted three times with 70 ecm of methylene chloride each time. The combined methylene chloride extracts were washed three times with 100 ecm each of ice-cold dilute hydrochloric acid (one part concentrated hydrochloric acid, 5 parts water) and brought to pH 1 to 2 and then washed with water until neutral. The organic solution was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo leaving the desired product as a residue.

The product obtained by this procedure was pure enough for inversion. By rubbing this residue with methanol, however, can be used to achieve an even purer compound.

This procedure has been applied to the preparation of mesylates, tosylates, brosylates, and nosylates Ethanesulfonates of steroid substrates in both the A and B configuration for use applied in the method according to the invention.

b) 21-methyl- / d ⁴ -pregnen-17a, 21B-diol-3, ll, 20-trione-21-acetate

A solution of 20 g of 21-methyl- <d ⁴ pregnen-17a, 21A-diol-3, ll, 20-trione-21-mesylate in 200 ecm of acetone was prepared and a molar excess of 2000% potassium acetate was added. The mixture was kept at 20 ° C for 24 hours. Most of the solvent was then evaporated in vacuo. Water was added and the mixture extracted three times with 80 ecm of methylene chloride. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the solvent evaporated to leave the desired product as a residue. It was cleaned by redissolving in 20 ecm hot acetone and cooling for 1 hour in an ice bath with stirring. The purified product precipitated; it was filtered off and washed with acetone. Mp 177-178 ° C; [a] _D = 191 ° C.

Example II

2a, 21-dimethyl-zl ¹ ' ⁴ -pregnadiene-II / 3.17a, 21B-triol-3,20-dione-21-propionate

A solution of 10 g of 2a, 21-dimethyl-/ J ^1-4 -Pregnadien-11 SS, 17a, 21a-triol-3,20-dione 21-tosylate in 200 cc of dimethylformamide, and a 200% strength Excess of sodium propionate added. The mixture was ^{kept at 70 °} C. for 1 hour and the solvent was completely removed in vacuo. The residue was taken up in 100 ecm of chloroform, dried over anhydrous sodium sulfate and filtered, and the desired product was obtained by removing the solvent in vacuo.

Example III

6a-fluoro-21-methyl- ^ ⁴ -pregnen-llßl7a, 21A-triol-3, -20-dione-21-benzoate

A solution of 15 g of 6a-fluoro-21-methyl-zl ⁴ -pregnen-1 l / 5,17a, 21B-triol-3,20-dione-21-brosylate was taken up in 200 ecm of acetone which contained 10 percent by volume of dimethylformamide , then became

a 1000% molar excess of sodium benzoate was added. The mixture was ^{kept at 60 °} C. for 10 hours and most of the solvent was removed in vacuo. Then water was added and the mixture was extracted three times with 75 ecm of ethylene chloride each time. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to leave the desired product as a residue. ro

Example IV

6a-chloro-21-methyl- ^ I ⁴ -pregnen-ll _J 8,17a, 21A-triol-

3,20-dione-21-crotonate '5

A solution of 15 g of 6a-chloro-21-methyl-zl ⁴ -pregnen-II / S, 17a, 21B-triol-3,20-dione-21-nosylate was dissolved in 200 ecm of a mixture of acetone and dimethylformamide (1 r 1) and added a 1000 ⁰ / o molar excess of lithium crotonate. The mixture was kept at 60 ° C. for 10 hours and most of the solvent was removed in vacuo. Then water was added and the mixture extracted three times with 75 ecm of ethylene chloride each time. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to leave the desired product as a residue.

Example V

21-methyl- / l ⁴ ' ⁶ -pregnadiene-ll / S, 14a, 17a, 21A-tetrol-

3,20-dione-21-trimethyl acetate

35

A solution of 3 g of 21-methyl- ^{I 4} ' ⁶ -pregnadiene-II ^, 14a, 17a, 21B-tetrol-3,20-dione-21-ethanesulfonate in 100 ecm acetic acid was prepared and a 2000% molar excess of cesium trimethyl acetate added. The mixture was kept under nitrogen ^{at 70 ° C. for 2 hours.} An equal volume of methylene chloride was added and the mixture was washed several times with 100 ecm of 5% sodium hydroxide each time. The organic layer was separated and evaporated in vacuo. The residue was taken up in 50 ecm of methylene chloride, washed three times with equal volumes of water, dried over anhydrous magnesium sulfate, filtered and evaporated, so that the desired product remained as a residue.

Example VI

⁵⁵

y ^
3.1 l, 20-trione-21-decanoic acid ester

An excess of potassium decanoate was added to a solution of 5 g of 16a, 21-dimethyl / l ¹ ' ⁴ ' ⁶ -pregnatriene-17a, 21 B-diol-3.1 l, 20-trione-21 mesylate in 100 ecm of ethyl acetate of 100 mole percent added. The mixture was kept under nitrogen ^{at 20 ° C. for 24 hours.} Most of the solvent was then evaporated in vacuo. Then water was added and the mixture was extracted three times with 80 ecm of methylene chloride each time. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the solvent evaporated to leave the desired product as a residue. It was purified by redissolving in 20 ecm hot acetone and cooling for 1 hour on an ice bath with stirring. The purified product precipitated; it was filtered off and washed with acetone.

Example VII

16 / 5.21 -Dimethyl- J ¹ x ⁴ x ⁶ -pregnatriene-17α, 21 A-dioI-3.1 l, 20-trione-21-decanoic acid ester

A solution of 5 g / yp
Sodium 17cc, 21 B-diol-3, II, 20-trione-21 mesylate in 100 ecm of methyl isopropyl ketone was added to an excess of 100 mol percent of potassium decanoate. The mixture was ^{kept at 20 °} C. for 24 hours. Most of the solvent was then evaporated in vacuo. Water was added and the mixture was extracted three times with 80 ecm of methylene chloride each time. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the solvent evaporated to leave the desired product as a residue. It was purified by redissolving in 20 ecm hot acetone and cooling for 1 hour on an ice bath with stirring. The purified product precipitated; it was filtered and washed with acetone.

Example VIII

9a-fluoro-21-methykd ^I ' ⁴ -pregnadien-II / 3,17a, 21B-trioI-3,20-dione-21- (a-phenyl acetate)

A solution of 5 g of 9a-fluoro-21-methyl / d ¹ - ⁴ -pregnadiene-11 ß, 17 <z, 21 A-triol-3,20-dione-21 tosylate in 100 ecm methyl isopropyl ketone was a 100% iger molar excess of sodium a-phenyl acetate was added. The mixture was ^{kept at 20 °} C. for 24 hours. Most of the solvent was then evaporated in vacuo. Then water was added and the mixture was extracted three times with 80 ecm of methylene chloride each time. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the solvent evaporated to leave the desired product as a residue. It was purified by redissolving in 20 ecm hot acetone and cooling on an ice bath for 1 hour. The purified product precipitated; it was filtered off and washed with acetone.

Example IX

9a-Bromo-21-methyl-4 ⁴ ' ⁶ -pregnadiene-17a, 21A-diol-3,11,20-trione-21 -valeric acid ester

A solution of 10 g of 9a-bromo-21-methyl- d ⁴ · ⁶ -pregnadiene-17a, 21 B-diol-3,11,20-trione-21 tosylate in 200 ecm of dimethylformamide was a 200% excess of valeric acid Sodium added. The mixture was kept for 1 hour at 7O ⁰ C and the solvent completely removed in vacuo. The residue was taken up in 100 ecm of chloroform, dried over anhydrous sodium sulfate and filtered, and the desired product was obtained by removing the solvent in vacuo.

509 518/484

Example X

21-methyl <d ^{4 'e} -Pregnadien-17a, 21A-diol-3,11,20-trione-21 -toluat

A 200% excess of sodium toluic acid was added to a solution of 10 g of 21-methyl- / l ⁴ ' ⁶ -pregnadiene-17a, 21B-diol-3, l, 20-trione-21-brosylate in 200 ecm of dimethylformamide. The mixture was ^{kept at 50 °} C. for 10 hours and the solvent was completely removed in vacuo. The residue was taken up in 100 ecm of chloroform, dried over anhydrous sodium sulfate and filtered, and the desired product was obtained by removing the solvent in vacuo.

Example XI

21 -Methyl- ^ ⁴ - ^e -pregnadiene-17a, 21 A-diol-3,20-dione-21-p-nitrobenzoate

A solution of 10 g 21-Methykd ⁴ - ⁶ -Pregnadien-17a, 21B-diol-3,20-dione 21-tosylate in 200 cc of dimethylformamide, a 200% excess of sodium-p-nitrobenzoate was added. The mixture was ^{kept at 50 °} C. for 10 hours and the solvent was completely removed in vacuo. The residue was taken up in 100 ecm of chloroform, dried over anhydrous sodium sulfate and filtered, and the desired product was obtained by removing the solvent in vacuo.

30 Example XII

6a, 9a-Difluoro-21-methyl-zl ¹ ' ⁴ -pregnadienlljS, 17a, 21B-triol-3,20-dione-21-acetate

A solution of 20 g of 6a, 9a-difluoro-21-methyl-

sylate in 200 ecm acetone, a 2000% molar excess of potassium acetate was added. The mixture was ^{kept at 20 °} C. for 24 hours. Most of the solvent was evaporated in vacuo. Water was added and the mixture was extracted three times with 50 ecm of methylene chloride each time. The organic layer was separated off, dried over anhydrous sodium sulfate, filtered and the solvent evaporated so that the desired product remained as a residue. It was purified by redissolving in 20 ecm hot acetone and cooling for 1 hour on an ice bath with stirring. The purified product precipitated; it was filtered and washed with acetone. M.p. 244.5 to 245 ° C; [a] _D = 86 °.

Example XIII
9a-fluoro-21-methyl-J * ^ -pregnadiene-

60

A solution of 20 g of 9a-fluoro-21-methyl- ^ • "-pregnadiene-l Iß, 17α, 21 A-triol-3,20-dione-21-mesylate in 200 ecm acetone was a 2000% molar excess of potassium acetate was added. the mixture was kept for 24 hours at 2O ⁰ C. most of the solvent was then evaporated under vacuum. then water was added and extracted the mixture three times with 80 cc of methylene chloride. the organic layer was separated, dried over anhydrous sodium sulfate, filtered and the solvent evaporated, leaving the desired product as a residue. It was purified by redissolving in 20 ecm hot acetone and 1 hour cooling on an ice bath with stirring. The purified product precipitated; it was filtered off and washed with acetone. F.234bis238 ⁰ C (decomposition); [a] _o = 127 °.

Example XIV

oa ^ a-Difluor ^ l-methyl-zl ^ -pregnadienlIß, 17a, 21A-triol-3,20-dione-21-acetate

A solution of 20 g of 6a, 9a-difluoro-21-methylzl ^ -pregnadiene-11β , 17a, 21 B-triol-3,20-dione-21 mesylate in 200 ecm acetone was a 2000% molar excess of Potassium acetate added. The mixture was ^{kept at 20 °} C. for 24 hours. Most of the solvent was then evaporated in vacuo. Water was added and the mixture was extracted three times with 80 ecm of methylene chloride each time. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the solvent evaporated to leave the desired product as a residue. It was purified by redissolving in 20 ecm hot acetone and cooling for 1 hour on an ice bath with stirring. The purified product precipitated; it was filtered off and washed with acetone. F. 241 to 243 ° (decomposition).

Example XV

9 <z-fluoro-21-methyl- / l ¹ ' ⁴ -pregnadiene-11 ß, Yla, 2 1 A-triol-3,20-dione-21-acetate

A solution of 20 g of 9a-fluoro-21-methyl-zl ^ -pregnadiene-11 ß, 17a, 21 B-triol-3,20-dione-21-mesylate in 200 ecm acetone was a 2000% molar excess of potassium acetate added. The mixture was ^{kept at 20 °} C. for 24 hours. Most of the solvent was then evaporated in vacuo. Water was added and the mixture was extracted three times with 80 ecm of methylene chloride each time. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the solvent evaporated to leave the desired product as a residue. It was purified by redissolving in 20 ecm hot acetone and cooling for 1 hour on an ice bath with stirring. The purified product precipitated; it was filtered and washed with acetone. M.p. 247 to 248 ° C; [a] _D = 60.2 °.

Example XVI

21-methyl-J ⁴ -pregnen-17a, 21A-diol-3,11,20-trione-21-acetate

A 2000% molar excess of potassium acetate was added to a solution of 20 g of 21-methyl- ^{I 4} -pregnen-17a, 21B-diol-3, 11, 20-trione-21-mesylate in 200 ecm of acetone. The mixture was ^{kept at 50 °} C. for 4 hours. Most of the solvent was then evaporated in vacuo. Water was added and the mixture was extracted three times with 80 ecm of methylene chloride each time. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the solvent evaporated to leave the desired product as a residue. It was through again

Dissolve in 20 ecm hot acetone and cool for 1 hour on an ice bath with stirring. The purified product precipitated; it was filtered off and washed with acetone. M.p. 179 to 180 ^° C; [a] o = 169 °.

Claims (4)

Patent claims: 1. Procedure for the inversion of the epimers Forms of lO-keto ^ l-monosulfonyloxy ^ l-methyl steroids the Pregnan series, with binding of a corresponding 21-carboxylic acid ester with the opposite configuration, thereby characterized in that the 21-monosulfonic acid ester of the epimer to be invested in dimethylformamide or a lower aliphatic oxygenated solvent containing up to 5 carbon atoms or mixtures thereof, about 1 to 24 hours with about a 100 to 2000% molar excess of one 14th Alkali metal salt of a carboxylic acid at a temperature of about 20 to about 70 ⁰ C converts. 2. The method according to claim 1, characterized in that the solvent used is acetone or acetone with about 10 to about 50 volume percent dimethylformamide is used. 3. The method according to claim 1 or 2, characterized in that one has a corresponding 21-mesyloxy or 21-tosyloxy compound des Used as the starting material. 4. The method according to claim 1 to 3, characterized in that one 6a, 9 <z-difluoro-21-methylol ¹ ^ -pregnadiene 11 ß, 17 α, 21 A-triol-3,20-dione-21 mesylate , 9a-fluoro-21-methyl-zl ^ -pregnadiene-1 liS, 17a, 21A-triol-3,20-dione-21-mesylate, 6a, 9a-difluoro ^ l-methyl-zl ^ -pregnadiene-l l ^, 17a, 21B-triol-3,20-dione-21-mesylate or 9a-fluoro-21-methyl-JW-pregnadiene-lljö, 17a, 21B-triol-3,20-dione-21-mesylate used as starting compounds . 509 518/484 p. 65 © Bundesdruckerei Berlin