DE1593518C3 - Process for the preparation of a 17 alpha-ester of the pregnane series - Google Patents

Description

The invention relates to a process for the direct acylation of the 17 α-hydroxyl group of 17 a-Hydroxysteroids of the Pregnan series to form a new class of steroid Trieste, the one Contain trihaloacetoxy group in the 11 /? Position, and from which mono- and diester compounds having valuable therapeutic properties are obtained can be.

So far, the direct acylation of the tertiary 17α-hydroxyl group in steroids of the pregnane series has been enforced by relatively high temperatures and powerful reagents, especially by the former. For example, it is known that, a 17-a-acylate is formed with an acylating agent consisting of trifluoroacetic anhydride and an aliphatic carboxylic acid, provided that the reaction temperature in the range of 80 to 100 ⁰ C is maintained. At these temperatures, the destruction of the valuable steroid substrate is often observed as a side effect of the acylation. At lower temperatures, e.g. B. at 6O ⁰ C, the 17 α-hydroxyl group remains essentially unaffected, while other, more reactive hydroxyl groups, which may be present, are esterified pike.

Furthermore, an acylating agent, which is an aliphatic carboxylic acid anhydride and a strong acid, such as p-toluenesulfonic acid, to form a 17 a-Acylate used. However, this reaction is temperature dependent and when carried out at room temperature the reaction kinetics are such that long times up to 48 hours are required to achieve the To lead the reaction to an acceptable level of completion. So far no procedure has been wrote that the direct acylation of the tertiary 17 α-hydroxyl group in steroids of the pregnane series in good yield, at moderate temperatures and with relatively short reaction times.

German patent specification 9 57 482 describes a process for the preparation of esters of 11-oxy derivatives of the pregnan, androstan and test series. The 11-hydroxysteroids are easily esterified with trifluoroacetoacetic acid and then hydrolyzed. The special esterification conditions and the process according to the present application are neither to be found in this German patent specification 9.57 482 ^! take still suggested in it.

It has now been found that the direct acylation of a 17 α-hydroxyl group in steroids of the pregnane series with formation of the corresponding ester in good yields with a relatively short reaction time, which is generally 1 to 3 hours, and at relatively low and easily controllable temperatures, for example at ambient temperature, if an acylating agent is used which is a trihaloacetic anhydride, a strong acid catalyst and a carboxylic acid contains.

The invention relates to a process for the preparation of a 17 α-ester of the pregnane series, which is characterized in that a 17 a-hydroxy compound of the pregnane series with a trihaloacetic anhydride, a strongly acidic catalyst and acylation medium containing a carboxylic acid treated and the 17 α-ester obtained, optionally a selective solvolysis of the 11/3-TrihaIoacetoxy-, preferably trifluoroacetoxy group to obtain a corresponding compound with a free OH group in the 11 / S position, the one in the 21 position as well may contain an ester group, is subjected or that in an aftertreatment a 11 /? - trihaloacetoxy, preferably a trifluoroacetoxy group together with a 9 α-bromine, chlorine or iodine substituent is eliminated by treating the obtained 17α-ester with a weak base and the 9 / 9,11 / 3-oxo derivative obtained in this way then with a hydrogen halide, preferably hydrogen fluoride, is reacted to form the corresponding 9 a-halo compound with free hydroxyl group in 11/5 position to obtain which can also contain an ester group in the 21-position or that the obtained 17 α-ester subjected to selective solvolysis of the ester group in the 21-position in the aftertreatment to convert a 17 a, 21-diester into the corresponding 17 a-monoester.

The corresponding 17 α-ester, which regardless of the The fact that the acylation process is usually at ambient temperature for its simplicity and effectiveness is carried out, is obtained in good yield, is then isolated in the usual manner.

The three components of the acylating agent or any two components of the acylating agent can be brought together prior to treatment of the 17α-hydroxy steroid, or each component can be added to the steroid separately. For example, the 17 a-hydroxysteroid is used in a possible embodiment of the acylation first brought together with a mixture that consists of the Carboxylic acid and the strong acid serving as a catalyst, whereupon the third component of the

_} Acylating agent, the trihaloacetic anhydride,

'is incorporated by adding the mixture to the anhydride or vice versa.

It is generally advantageous to use the trihaloacetic anhydride in amounts of 1 to 5 ml and the strong acid serving as a catalyst in amounts of To use 50 to 150 mg / g of the 17 α-hydroxysteroids used.

In a typical embodiment of the acylation in the 17 α position is a 17 α-hydroxysteroid of the Pregnan series in a molar excess of the strong acid-containing carboxylic acid dissolved. Optionally, an inert solvent, e.g. B. a Chlorinated hydrocarbons, can be used as a diluent, but generally is not necessary. The mixture is then cooled to below room temperature, whereupon the trihaloacetic anhydride, preferably trifluoroacetic anhydride, is added in excess. The reaction mixture is then stirred for a period of up to 3 h at room temperature and then diluted with water. Then will the 17 α-ester present as a precipitate is removed from the mixture in good yield by conventional methods.

. divorced, for example by filtration with subsequent purification of the 17 α-ester by conversion

j crystallization from an inert organic solvent or solvent mixture, ζ. Β. Methanol, ethanol, acetone, ethyl acetate or ether-hexane, and / or by chromatography using an adsorbent such as silica gel or magnesium silicate.

The trihaloacetic anhydride serving as a component of the acylating agent is preferred Trifluoroacetic anhydride.

The expression "as a catalyst" used here

"Serving strong acid" includes acids that are in aqueous Solution are essentially completely ionized, and made using a strongly acidic color indicator can be titrated. Those suitable as catalysts for the process according to the invention strong acids are mainly non-oxidizing organic acids and inorganic mineral acids, that do not interfere with the reaction. Suitable acids are

_<4 for example p-toluene sulfonic acid, methanesulfonic acid

acid, benzenesulfonic acid, perchloric acid, hydrochloric acid

ao chemical acid and sulfuric acid. P-Toluene sulfonic acid is particularly suitable.

The choice of the carboxylic acid which forms one component of the acylating agent depends essentially on the type of 17α-ester group that is to be introduced into the steroid. The is elected desired ester group corresponding carboxylic acid. In general, any carboxylic acids are suitable, for example, straight and branched chain, saturated or unsaturated aliphatic carboxylic acids including saturated or unsaturated cycloaliphatic carboxylic acids, aromatic carboxylic acids and heterocyclic carboxylic acids. Since it is often the case that particularly important 17 α-esters of the pregnane series in the 17 a-ester group contain 1 to 9 carbon atoms, it can be concluded that carboxylic acids with a similar carbon number often form the carboxylic acid component of the acylating agent. Examples of such acids are acetic acid, propionic acid, butyric acid, valeric acid, benzoic acid, cyclopropylcarboxylic acid and octanoic acid.

The term "Pregnan series" used here is to be interpreted in a broad sense. All 17 α-hydroxysteroids including the unsaturated compounds, e.g. B. the Δ ¹ - and A ^ dehydroanalogues and the 19-nor derivatives of the pregnane series can be acylated to the corresponding 17 α-esters by the process according to the invention.

The starting compounds which can be acylated by the process according to the invention include monohydroxysteroids, e.g. B. 17 a-hydroxyprogesterone, 16-methylene-17 a-hydroxy-progesterone, 16-methal- (a or / S) -17 a-hydroxy-progesterone and 17 a-hydroxypregnenolone. If the Α ring of the starting compound contains a keto group and is otherwise saturated, or if it contains a 3-keto-A ⁴ mono system, the direct product can contain a small amount of the corresponding 3-enol ester. In these cases the 3-keto group is regenerated by treating the enol ester with a mild acid or base in a manner known for such conversions. Further suitable starting compounds are corticoids and intermediate compounds leading thereto, e.g. B. 2I-esters of prednisone, 16α-methylprednisone, 16/9-methylprednisone.

The foregoing clearly shows that the process is based on 17α-hydroxysteroids the Pregnan series is generally applicable, but that certain compounds are of particular importance as

5 6

Starting materials are, because they are particularly valuable in number, contained in the 21-position, give a special end product. In this context they form an important group of starting compounds for the 17 a-hydroxysteroids of the pregnane series, which are the acylation process. The meaning of this Ver-Trihalogenacetoxygruppe in the 11/3 position and a bonds, z. B. of 11/9 trifluoroacetoxy-3,20-diketo-hydroxyl, acyloxy or alkoxylate group with lower 5 l, 4-pregnadiene-17 ct, 21-diols and their 21-carbon number in the 21st -Position (and optionally an acid ester or alkyl carbonates, the alkyl group or several substituents of which has a lower carbon number at other positions, originates primarily from the molecule), a preferred group of the products that are obtained by using the acylic starting compounds . To be obtained from this group of electoral processes. These products, which include common compounds 11 / J-trifluoroacetate-21-10, represent a new class of steroid triesters, esters of betamethasone, dexamethasone, flumethasone, proved to be very valuable starting compounds for the production of paramethasone, prednisolone, 6 a-methyl-prednisolone of the corresponding 11/9 hydroxy and hydrocortisone, the 9 α-bromine and chlorine analogues 17 a, 21-diacyloxy esters and 11 / 3,21-dihydroxy-17 cider of the above 9 α-fluorine compounds and 11 ß- acyloxy esters.

Trifluoroacetate-21-ester and ll-trifluoroacetate-16,21-15 As pharmacological and clinical investigations

diester of triamcinolone. gen have shown many of these 17,21-diesters

Since the acylation process is not selective, musts and 17-monoesters of steroids of the pregnane series, any hydroxyl groups which may contain 1 to 9 carbon atoms at other points in the acyl groups in the steroid should first have exemplary therapeutic properties in this respect When wisely protected by ester groups, unless they are effective anti-inflammatory agents, these hydroxyl groups in the same ester, especially when applied topically. Of befunction as it appears in the 17α-position, of particular importance in this series are certain 17-to be converted. Since it is generally non-monoesters and 17,21-diesters of steroids that one desires that several or difficult-to-cleave ester-pregnane series, of which dexamethasone and beta groups are present, a selek- methasone prototype will preferably be. The new position produced after the acylation protection of the hydroxyl groups outside the 17 process according to the invention is carried out. If a hydroxyl group of steroid triesters can thus be used for preparation in the 21-position or elsewhere except for the aforementioned 17,21-diesters and 17-mono-11-position, it will preferably be used ester compounds
according to known esterification methods in a car- 30 The acyl group in the 21-position can be the same bonsäureester, z. B. a lower aliphatic acid such as the acyl group in the 17 α-position or ester, or in an alkyl carbonate whose alkyl group is different from it. If the starting compound has a low carbon number, converted. for the acylation process a free hydroxyl

For example, if the free hydroxyl group on the group contains in the 21-position, the 21-position obtained in betamethasone contains a lower acyloxy product, the same acyl group can be converted in both the 17 a group by using one as well as the 21-position . If so desired, lower aliphatic acid chloride or anhydride in it is preferably achieved in this manner. Appropriately pyridine is treated. For example, beta contains the acyl group in the 21-position 1 to 9 C-methasone acetate can be prepared by adding betametha atoms including straight-chain and branched but in pyridine with the acid chloride of acetic acid 4 ° acyl groups, such as those for the acyl group or with acetic anhydride are indicated at a temperature of in the 17 position. The alkyl carbonate treated about 0 to 30 ⁰ C about 1 to 24 hours group, the alkyl group of which has a lower carbon number. An alkyl carbonate group, the alkyl group of which may be present in the 21-position, has a lower carbon number, can be introduced in the 21-position, depending mainly on the availability of the material, by the betamethasone of 45 rials. Alkyl radicals with up to approximately free hydroxyl groups in the 21-position in pyridine 9 carbon atoms are possible, but alkyl carbonate groups with a lower alkyl chloroformate under similar alkyl groups will have 2 to 3 carbon atoms before conditions are treated as they for the introductions because of the relative simplicity with which they were described for the formation of the acyloxy group. That 21 can be.

Carbethoxylate of betamethasone can, for example, 5 °. The preferred trihaloacetoxy group is the

are made by placing betamethasone in pyridine trifluoroacetoxy group primarily because they are so light

removed with ethyl chloroformate at a temperature of about or under relatively mild conditions

0 to 30 ° C is treated for about 1 to 24 hours. gene can be hydrolyzed. This group can

However, if the 17 a-hydroxysteroid starting compound also contains a different trihaloacetoxy group,

also contains a 11 ^ hydroxyl group, this can be 55 z. B. be a trichloroacetoxy group.

Hydroxyl function advantageous by conversion in addition to the special substituents mentioned above

an 11/3 trihaloacetate, preferably an 11/9 tri-tuent, the 11 / S-trihaloacetate-17 a, 21-di-

protect fluoroacetate group. One such ester group is ester compound substituents, e.g. B. hydroxyl,

labile and can be easily removed or hydrolyzed, keto, halogen, ether and alkyl groups, especially

to regenerate the 11-hydroxy function. It is sawn ^6o sondere lower alkyl groups (having up to 6 carbon atoms)

knows that a free 11/3-HydroxyIfunktion a wich in other places of the steroid nucleus, z. Tie

tiger substituent in many anti-inflammatory positions 1, 2, 4, 6, 7, 9, 16 and 20.

Pregnan range of steroids is. The starting materials for the manufacture of the

As already mentioned, 17 a-hydroxy steroids of the new-mentioned 11/3-trihaloacetate 17-α, pregnane series having a forward Trihalogenacetoxygruppe, ⁶ 5 21-diester compounds according to the Acylierungsverfahzugsweise a trifluoroacetoxy group in the 11 / 9- ren according to the invention are readily available. In the case of and a hydroxyl, acyloxy or alkyl, for example, the II-trifluoroacetate of a 1,4-precarbonate group, the alkyl group of which is a lower C-gnadiene-11 / Jn ^ l-trioI-S ^ O-dione compound

7 8

Process of British patent specification 9 43 632 the acetate is obtained; Yield 4.1 g; F 228-232 ° C;

Applicant are produced. For this purpose, the ent- [ajß ²⁵ -f- 151 ° (dioxane 1%).
speaking 1,4,9 (11) -Pregnadien-11 / 3,17 a, 21-triol-3,

20-dione-21 acetate, preferably in the presence of Example B
inert organic solvent, e.g. B. tetrahydro-5 To a mixture of 4 ml Trifluoressigsäureanfuran, carbon tetrachloride or chloroform, with hydride in 20 ml of dry pyridine kept at -2O ⁰ C a substance halonium ions under the reaction, 2 g of betamethasone are given. The tion conditions are able to form such. B. N-bromine mixture is stirred for 30 minutes and then reacted in 200 ml of succinimide and trifluoroacetic acid. This cold water is poured that contains 17.6 ml of concentrated salt special reagents act on the A ^^ - bond io acid. The mixture is stirred for 1 h, filtered and dried, the compound in a 9 a-bromine-11 ß-tn- the air at 40 ⁰ C. The dried precipitate is converted to fluoroacetoxy-analogs, which is a suitable in 10 % aqueous methanol is 0.1 part by weight of netes starting material for the acylation process p-toluenesulfonic acid monohydrate and the mixture is stirred for 2 hours. The 11 / J-trifluoroacetate can also from the ent- room temperature. It is diluted with 80 ml of water-speaking 9 a-halogen (e.g. 9 a-fluorine) - 11 ß- 15, filtered and air-dried at 40 ^° C. The crude hydroxy-1,4-pregnadiene-1 7 a, 21-diol-3,20-dione-21-acy-betamethasone-11 / J-trifluoroacetate is purified from acetone-hexane by recirculation by esterification of the free hydroxyl group; Yield of the 11-position, e.g. B. by treating the compound 620 mg; F 205 to 209 ^C C.

formation in pyridine with trifluoroacetic acid at lower. It is also possible to use the 11-trifluoroacetate monoester

Temperature. ao by acid hydrolysis of that obtained according to Example A.

The 11/3 trifluoroacetate-17a, 21-diester compounds correspond to 11 / J-trifluoroacetoxy-21-acetate diesters

are produced by selective solvolysis of the 11 / J-Trifluor-. To carry out this acid hydrolysis

1 g of betamethasone-II-trifluoroacetate-21-acetate is added to the corresponding 11 ß-hydroxy acetate group

17 a, converted to 21-diester. This can easily be done by, for example, a solution of 1.75 ml of 70% strength

Applying the method achieve the subject of 35 aqueous perchloric acid in 68.25 ml of methanol. Man

the German Offenlegungsschrift 15 93 519 forms and stirs the reaction mixture for 17 h at room temperature

take a solution of the 11-ester in a lower one and pour it into 700 ml of cold water. You separate that

Alkanol with a salt of an acid, whose pKa value precipitated betamethasone-11/5-trifluoroacetate by

in the range from about 2.3 to 7.3, for room filtration and air-drying at 40 ° C. Man

temperature is stirred. Alkali and alkaline earth salts 3 <> purifies by recrystallization from acetone-hexane.

of acids, e.g. B. sodium or potassium azide or. . . _c

-formate are particularly suitable, and as a low egg spie

Alkanol, methanol is preferred. In cases where In the manner described in Example A, 16 a-

the 11 / J-triiluoroacetate-17 a, 21-diester compound au- hydroxy-9 a-fluorprednisolone-lo ^ l-diacetate with tri-

ßerdem treated a bromine, chlorine or iodine substituent in 35 fluoroacetic anhydride in pyridine, with

contains the 9 α-position, causes a treatment of a 16 a-hydroxy-9 a-fluorprednisolone-11 / J-trifluoroacetate-

such compound with a weak base, e.g. B. 16,21-diacetate in excellent yield and only

Potassium or sodium acetate in acetone, removing a small amount of by-products of the reaction

the acyl component can be obtained together with the halogen,
atom forming a 9 / 3.11 β-Οχιάο-Π cc, 21-di- 4 °

esters. The latter substance leads when implemented example

with hydrogen halide, preferably hydrofluoric acid To a cooled solution containing 1 g of the according to

substance, in a known manner for the regression of the 9 α- Example A obtained betamethasone-11 /? - trifluorace-

Halogen (fluoro) -l 1 / I-hydroxy function. tat-21-acetate (16 /? - methyl-9 a-fluorprednisolone-ll ß-

The in this way according to the above 45 trifluoroacetate-21-acetate) and 100 mg p-toluene sulfone

drive obtained 17 a, 21-diesters are contained by selek- acid monohydrate in 10 ml valeric acid, are

tive hydrolysis of the ester group in the 21-position in the 4 ml of trifluoroacetic anhydride. To

known way, e.g. B. by using an alcohol 5 minutes is removed from the ice bath and 3 h at

lischen acid solution, z. B. perchloric acid in methanol, left to stand at room temperature. One pours in water

converted into the 17 a monoester. 5 ° stirs for 15 min and then takes in 100 ml of methylene

The invention is based on chloride in the following examples. Wash the methylene chloride once

explained in more detail. The first three examples describe with 5% sodium hydroxide, three times with water,

the preparation of representative 11 / J-trihalogen- dries over magnesium sulfate and filtered. One gives

acetoxy starting compounds from which new steroid 100 ml of methanol to the filtrate and distilled with

de Trieste produced according to the invention 55 water vapor to remove residual Valerian-

be able. acid. One cools to room temperature, solves the pro

-IA duct in a small amount of methylene chloride, dries

B e 1 s ρ 1 e 1 A _over magnesium sulfate, filtered and chromatographed

While the temperature is kept at -20 ° C, on 100 g of silica gel, Betamethason-11 /? - trifluor-

5 ml of trifluoroacetic anhydride and then ^6o acetate-17a-valerate-21 acetate are obtained; Yield:

ßend 5 g betamethasone acetate to 50 ml dry 1.21 g; IR spectrum shows no hydroxyl absorption.

Given pyridine. The mixture is half an hour. .

touched. The reaction mixture is poured into 500 ml of Example 2

Ice water containing 44 ml of dry hydrochloric acid is stirred. Treated in the manner described in Example 1

30 minutes, the precipitate is filtered off and washed with ⁶ 5 one 8 g of 16 / J-methyl-9 a-bromo-prednisolone-11 / J-tri-

Water until the draining wash water is neutral. fluoroacetate-21-carbethoxylate with 80 ml valeric acid,

It is dried at 50X and crystallized from aqueous 800 mg of p-toluenesulfonic acid monohydrate and 32 ml

Methanol, where betamethasone-11 ^ -trifluoroacetate-21-trifluoroacetic anhydride, where 16 / J-methylone-

bromo-prednisolone-II / f-trifluoroacetate-17a-valerate-21-carbethoxylate is obtained in good yield. The product is recrystallized from ether-hexane. Yield: 89% of theory; F 120 to 180 ^° C (cens.); [ah ²⁵ + 106 ° (dioxane 1%).

Example 3

In the manner described in Example 1, 8 g of 16 /? - methyl-9 a-bromo-prednisolone-11 / I-trifluoroacetate-21-acetate are treated with 80 ml of valeric acid, 800 mg of p-toluenesulfonic acid monohydrate and 32 ml of trifluoroacetic anhydride, with 16 /? - Methyl-9 a-bromoprednisolone-11 / J-trifluoroacetate-17 a-vaIerat-21-acetate is obtained, which is recrystallized from acetone-isopropyl ether; Yield: 75% of theory; F 202-203 ⁰ C (Zen.); [ajo ²⁵ + 10.9 ° (dioxane 1%).

Example 4

In the manner described in Example 1, 4.27 g of 16 a-methyl dichlorisone (16 a-methyl-9 a, ll ß dichloro-1,4-pregnadiene-17 a, 21-diol-3,20-dione) treated with 42.7 ml of butyric acid, 427 mg of p-toluenesulfonic acid monohydrate and 17.1 ml of trifluoroacetic anhydride to give 16α-methyl dichloroisone-17α, 21-dibutyrate, which is recrystallized from aqueous methanol; Yield: 4.55 g (83% of theory); F 176-180 ° C; [α] ²⁵ + 86 ° (dioxane 1%).

Example 5 .-

16 a- methyl-dichlorisone with propionic acid, p-toluenesulfonic acid and trifluoroacetic anhydride is treated in the manner described in Example 1, with 16 21-dipropionate is obtained a-methyl-dichlorisone-17 a, which is recrystallized from aqueous methanol; Yield: 80% of theory; F 200 to 207 ⁰ C; [α] /, ²⁵ + 92.9 ° (dioxane 1%).

Example 6

In the manner described in Example 1, 500 mg of 16 a-methyl-dichloroisone-21-acetate are treated with 5 ml of butyric acid, 50 mg of p-toluene-sulfonic anhydride and 2 ml of trifluoroacetic anhydride, 16 a- methyl-dichlorisone-na-butyrate ^ l- acetate in good yield is obtained. The product is recrystallized from aqueous methanol; Yield: 412 mg (73% of theory); 196-199 ° C; [α] /, ²⁵ + 85 ° (dioxane

50

Example 7

In the manner described in Example 1, 16β- methyl-dichlorisone is treated with propionic acid, p-toluene-sulfonic acid monohydrate and trifluoroacetic anhydride, 16 / S-methyl-dichloroisone-17a, 21-dipropionate being obtained, which is recrystallized from aqueous methanol; Yield: 78% of theory; F 165 to 170 ° C; [a] _D ^ + 114 ° (dioxane 1%).

60 Example 8

In the manner described in Example 1, 4.09 g of dichlorisone are treated with 41 ml of butyric acid, 409 mg of p-toluenesulfonic acid and 16.3 ml of trifluoroacetic anhydride, dichlorisone-17a, 21-dibutyrate being obtained, which is recrystallized from methanol; Yield: 4.52 g (82% of theory); F 198 to 200 ⁰ C; Mo ²⁵ -I- 106 = (dioxane 1%).

Example 9

In the manner described in Example 1, 1.0 g of 16 a-methyl-dichlorisone-22-acetate with 10 ml of 2-methylvaleric acid, 100 mg p-toluene sulfonic acid monohydrate and 4 ml of trifluoroacetic anhydride treated, wherein

16 a-methyl-dichlorisone-17 a- (2'-methylvalerate) -21-acetate is obtained, which is recrystallized from methanol; F 165 to 170 ° C; [0J ₀ ²⁵ + 79.2 ° (dioxane 1%).

Example 10

In the manner described in Example 1, prednisone is made with butyric acid, p-toluenesulfonic acid and trifluoroacetic anhydride treated, whereby prednisone-17 α, 21-dibutyrate is obtained, which is obtained from acetone-hexane is recrystallized.

Example 11

To a cooled solution containing 1.0 g of 16-methylene

17 contains α-hydroxyprogesterone and 100 mg of p-toluenesulfonic acid in 10 ml of caproic acid, 4 ml of trifluoroacetic anhydride are added. After 5 minutes, it is removed from the ice bath and left to stand at room temperature for 30 minutes. It is poured into water, stirred for 15 minutes and taken up in 100 ml of methylene chloride. It is washed once with 5% sodium hydroxide, three times with water, dried over magnesium sulfate and filtered. 100 ml of methanol are added to the filtrate and the mixture is distilled with steam to remove residual caproic acid. It is cooled to room temperature, dissolved in a small amount of methylene chloride, dried over magnesium sulfate, filtered and chromatographs on 100 g of the product with the trade name "Florisil" with hexane ether as the eluent. The product is recrystallized from ether-hexane, the 17 a-caproate of 16-methylene-17 a-hydroxy-progesterone being obtained in good yield; 124-127 ° C; [ajo ²⁵ - 45 ° (dioxane

Example 12

In the manner described in Example 1, 16 a- hydroxy-9 a-fluoro-prednisolone-11 / S-trifluoroacetate-16, 21-acetate is treated with valeric acid, p-toluenesulfonic acid and trifluoroacetic anhydride, with 16 a- hydroxy-9 a- fluoro-prednisolone-11 / J-trifluoroacetate-16, 21-diacetate-17 a-valerate is obtained, which is recrystallized from acetone-hexane.

Example 13

In the manner described in Example 1, 8 g of 16 / J-methyl-9 a-fluoro-prednisolone-11/5-trifluoroacetate-21-carbethoxylate are obtained with 80 ml of valeric acid, 800 mg of p-toluenesulfonic acid monohydrate and 32 ml of trifluoroacetic anhydride treated, whereby betamethasone-11 /? - trifluoroacetate-17 a-valerate-21-carbethoxylate in good yield is obtained.

Example 14

In the manner described in Example 1, 8 g of 16 / S-methyl-9 a-fluoro-prednisolone-11/9-trifluoroacetate-21-propionate are obtained with 80 ml of propionic acid, 800 mg of p-toluenesulfonic acid monohydrate and 32 ml of trifluoroacetic anhydride treated, whereby betamethasone-11/3-trifluoroacetate-17 a, 21-dipropionate is obtained in good yield.

As already mentioned, the new 11/3 trifluoroacetate-17 a, 21- prepared according to the invention

diester easily into the corresponding 11 ß-hydroxy-17 α, 21-diester and II / ?, 21-dihydroxy-17α-monoester are converted and thus as valuable starting products for the production of these steroids, from many of which have powerful anti-inflammatory effects, use a new method. This Conversions are described in the following three examples.

Example 15

10 g of sodium azide are added to a solution of 1 g of betamethasone 11/5 trifluoroacetate 17α-valerate 21-acetate (prepared in the manner described in Example 4) in 45 ml of methanol. The mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into 450 ml of cold water, filtered and ^{dried at 60 °} C. in the air. The crude betamethasone-17α-valerate-21-acetate is purified by recrystallization from acetone-hexane.

ok

^15th

³ °

Example 16

Add 1 g of betamethasone 17-valerate a 21-acetate corresponds to a maintained at about O'C solution containing 7 ml of 70% aqueous perchloric acid in 68 ml of methanol holds ^a5. The reaction mixture is stirred for about 48 hours, poured into 700 ml of cold water, the precipitate is filtered off, dried in air at 40 ° C. and the crude betamethasone-17α-valerate is purified by recrystallization from acetone-hexane.

Example 17

To a suspension of 10 g of potassium formate in 40 M ethanol is added 1 g of betamethasone-11 / I-tnfluoroacetate-17a, 21-dipropionate (prepared in the manner described in Example 17). The mixture is stirred for 1 h at room temperature, the reaction mixture is poured. sch in cold water, filtered off the precipitate and dried at 60 ⁰ C in the air. The crude betamethasone-17 a, 21-dipropionate is purified by recrystallization from acetone-hexane.

The following examples describe procedures necessary for the conversion of the new 11β-trifluoroacetate-17 a, 21-diester compounds which contain a 9 α-bromine, chlorine or iodine substituent into the corresponding 9 α-fluorine compounds are used be able.

. .
for example 18

6 g of 16 / J-methyl-9 a-bromo-prednisolone-11 /? - trifluoroacetate-17 a-valerate-21-cathyIat, prepared according to Example 5, are refluxed in 600 ml of acetone for 17 h in the presence of 18 g of potassium acetate heated. After cooling the reaction mixture to room temperature, the insoluble constituents are filtered off. The reaction mixture is concentrated ml to 60 and ass with ³ J ?. ^"1! Distilled W he offset Fa Jung is ^from f J ^{et 1} ™ ^{1} and} g? ^Ckn f wherein 16 £ methylene-9 beta, l 1 ß oxido-, 4-pregnadiene-17a, 21-diol-3,20-dione-17a-valerate-21-cathylate.

Example iy

A solution of 660 one gives the oxido compound prepared according to Example 18 in 7 ml tetrahydrofuran at 0 mg ⁰ C to 13 ml of 70% aqueous hydrogen fluoride. The reaction mixture is ^{kept at 0 °} C. for 29 h and then slowly poured into 500 ml of water which contains 30 g of sodium carbonate. It is extracted with methylene chloride and the organic phase is washed with water. The organic phase is concentrated to a residue. The residue is recrystallized from ether, betamethasone 17α-valerate-21-cathylate being obtained.

Example 20

In the manner described in Example 18, 3 g

16 / S-methyl-9 a-bromoprednisolone-11 / J-trifluoroacetate-

17 a-valerate 21-acetate, the _Wurd prepared according to Example 3 _{in m m, acetone 9 K} aliumacetat be _hande i _t, where 16 / - 4-methyl-9 / J ₁ Il / 3-oxido-l,? pregna _dien . ₁₇ ^ i-diol- ^ O-dione-l? a-valerate 21-acetate he _{ha, is th The product is} recrystallized _from methylene chloride _{isopropyl ether.}

Example 21

In the manner described in Example 19, 500 g of the oxido compound prepared according to Example 20 are obtained treated in 5 ml of tetrahydrofuran with 12 ml of 70% aqueous hydrogen fluoride, whereby betamethasone-17 a-valerate-21-acetate is obtained.

Claims (10)

Patent claims: 1. A process for the preparation of a 17 α-ester of the Pregnan series, characterized in that a 17 α-Hydroxy compound of the Pregnan series is treated with an acylation medium containing a trihaloacetic anhydride, a strongly acidic catalyst and a carboxylic acid and the 17 α-ester obtained is optionally treated with a selective solvolysis the 11/7-trihaloacetoxy, preferably trifluoroacetoxy group to obtain a corresponding compound with a free OH group in the 11 y? -position, which can also contain an ester group in the 21-position, or that an 11 / I-Trihaloacetoxy, preferably a trifluoroacetoxy group together with a 9 α-bromine, chlorine or iodine substituent is eliminated by treating the 17 α-ester obtained with a weak base and the 9 / 5,11 /? - Oxide derivative is then reacted with a hydrogen halide, preferably hydrogen fluoride, to produce the corresponding 9 a-halo compound free hydroxyl group in the 11 ß -position which can also contain an ester group in the 21-position or that the 17 α-ester obtained is subjected to a selective solvolysis of the ester group in the 21-position in the aftertreatment to obtain a 17 α, Converting 21-diester into the corresponding 17 a-monoester. 2. The method according to claim 1, characterized in that the acylation at room temperature is carried out for a period of 1 to 3 hours. 3. The method according to claim 1 or 2, characterized in that the trihaloacetic anhydride in amounts of 1 to 5 ml / g and the strongly acidic catalyst in amounts of 5 to 150 mg / g of des 17 a-hydroxysteroids can be used. 4. The method according to any one of claims 1 to 3, characterized in that at least 2 components of the acylation medium even before the treatment of the 17α-hydroxysteroids with one another be brought together. 5. The method according to claim 4, characterized in that first the strongly acidic catalyst and the carboxylic acid are mixed together to form the 17α-hydroxysteroid in this mixture dissolved and only then the trihaloacetic anhydride is added. 6. The method according to claim 5, characterized in that the 17 a-hydroxysteroid already containing mixture prior to the addition of the trihaloacetic anhydride cooled below room temperature. 7. The method according to any one of claims 1 to 3, characterized in that each of the components of the acylation medium separated with the 17 a-hydroxysteroid is brought into contact. 8. The method according to any one of the preceding claims, characterized in that the trihaloacetic anhydride trifluoroacetic anhydride is used in the acylation medium. 9. The method according to any one of the preceding ⁶ S claims, characterized in that a non-oxidizing organic or inorganic acid is used as the strongly acidic catalyst. 10. The method according to claim 9, characterized in that the strongly acidic catalyst is para-toluenesulfonic acid, Methanesulfonic acid, benzenesulfonic acid, perchloric acid, hydrochloric acid or sulfuric acid is used.