DK146017B - ANALOGY PROCEDURE FOR PREPARING 17ALFA-ACYLOXY-9ALFA, 21-DIHALOGEN-11BETA-HYDROXY-6ALFA-FLUOR-16BETA-METHYL-PREGNA-1,4-DIEN-3,20-DION COMPOUNDS - Google Patents

Description

in U6017

Patent No. 143,388 relates to an analogous process for the preparation of 17α-acyloxy-9α, 21-dihalogen-11β-hydroxy-6α-fluoro-16α-methyl-pregna-1,4-diene-3,20-dione compounds with the formula CHO-X2 CH, C = O HO 2 J 0 _ -O-R2 5 rI / y (A)

X J

oAAy i

F

1 2 1 wherein X is chlorine or fluorine, X is bromine or chlorine, R is hydrogen or chlorine and R is an alkanoyl group having a maximum of 7 C atoms, and the peculiarity of the main patent is that a) a compound of formula CH -X2 CEL C = 0 / \ ----- 0-R2 R1 CH3 y °

VyW '.

CEL

10 0Å / h <

F

Wherein R, R and X are as defined above with hydrogen chloride or hydrogen fluoride or with an agent giving off one of these hydrogen halides, or b) in a compound of the general formula 2 CHO-O-Ra I 2 CH C = 0 "V'nLJ ---- O-E2 E1 = ¾] i.

»>

F

Wherein R, RZ and Xx are as defined above and Ra is the residue of an organic sulfonic acid, replacing the sulfonyl-oxy group with bromine or chlorine, or c) for the preparation of compounds of formula A wherein X treats a 9 (11) unsaturated compound of formula CH - X2 I 2 CH3 c = o ------ O-R2

R1 CH3 I

oW

• (i

F

Wherein R, R and X are as defined above with chloro-10 acid or a chloro-acid acid release agent, or d) to prepare a compound of formula A wherein R 1 is hydrogen dehydrogenates a compound of formula 3 CEL-X2 CH3 9 = 0

H0 A O

------ O-R2 CH, oAÅ /

F

2 1 2 wherein R, X and X have the above meaning, in the 1,2-position, and, if desired, in a compound obtained according to the process of formula A wherein R 1 is hydrogen and the other symbols have the above meaning, chlorine adds to the 1,2-double bond and from the obtained compound of formula p-x2 CH, C = O

HO yw O.

----- O-R 2

Cl Kl 1..

T N / iYV CH3

F

In which R, x and X have the above meaning, 10 hydrogen chloride is decomposed, during which any of the two process steps can be worked under transient protection of the β-hydroxyl group by transfer into the trifluoroacetate.

The present invention relates to an analogous process according to Patent No. 143,708 for the preparation of novel 17α-acyloxy-9α, 21-dihalo-113-hydroxy-6α-fluoro-160-methyl-pregna-1,4-diene-3.20 -Dione Compounds of Formula 4 146017 CH - X2 I 2 CH- C = 0 H ° Λ -γΝ ------ O-R2 R1 CH3 (I) X °

OUCH

0:

F

1 2 1 wherein X is chlorine or fluorine, X bromine or chlorine, R

2 is hydrogen or chloro and R is an alkanoyl group having a maximum of 7 C atoms.

The process of the invention is characterized in that a) a compound of the formula CHO-X2 I 2 CH3 c = o -, ---- ο-R2 (II) s1 ° v ° 1. is treated.

\ ^ / Yv ^ CH3

ÖVV

l

F

Wherein R, R and X are as defined above with hydrogen chloride or hydrogen fluoride or with an agent which gives off one of these hydrogen halides, or b) in a compound of general formula 50101 CHO-O-Ra I 2 CH, C = 0 H0Y ^ _ | ---- O-R2 R1 CH31 J 1 (IV) οΛΑ /

F

wherein R 1, R 2 and X 1 have the above meaning and R a is the remainder of an organic sulfonic acid, replacing the sulfonyl oxy group with bromine or chlorine, or c) to prepare a compound of formula I wherein X a 9 (11) unsaturated compound of formula CHO-X2 I 2 CH, C = 0 ✓N-1 ---- O-R2 "1 CH, I (VII) γ ^ Ργ \ ΛοΗ3 oAv

F

Wherein R, R and X are as defined above with chloro-10 acid or a chloro-acid acid release agent, or d) for the preparation of a compound of formula I wherein R · represents hydrogen, dehydrogenates a compound of formula 6 CH2 -X2 I 2 CH- C = O HO2, v'N ------ O-R2 ^ H3l 1 1 (VIII) ΛΙΥ ^^ 0Ayv

J

in

F

Wherein R, X and X have the above meaning, at the 1,2-position, and, if desired, in a compound of formula I obtained according to the process wherein R 1 is hydrogen and the other symbols have of the above-mentioned meaning, chlorine adds to the 1,2-double bond and from the obtained compound of formula CH 2 -X 2 I 2 CH-. C = 0 ΓγΑ - »- * 2

Cl ΙψΙ I

T ^ ch3

oW

in

F

2 1 2 10 wherein R, X and X are as defined above, hydrogen chloride is cleaved, optionally, during both process steps, working under transient protection of the 11β-hydroxyl group upon transfer to the trifluoroacetate.

Carbonaceous compounds and groups hereinafter referred to as "low" contain at most 7 carbon atoms.

An alkanoyl group may be straight or branched and is e.g. acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, 2-ethyl-butyryl, 2,2- or 3,3- dimethyl-butyryl, hexanoyl or heptanoyl.

The compounds of formula I have valuable pharmacological properties. Thus, they are distinguished by an excellent anti-inflammatory effect with little systemic effect.

For example, one can by topical use in crude cotton granuloma testing in rats, demonstrating an inhibition of inflammatory conditions in a dose range of ca. 0.001 to approx. 0.10 mg / pellet, the first signs of a systemic effect being first noticed at or even above the upper limit of this dose range, and thymus weight reduction first exceeding 0.03 mg / pellet, of adrenal glands above 0; 1 mg / pellet and of the total body weight above 1.0 mg / pellet. in topical administration (rat ear test after Tonelli), ED 10-30 mcg / ml. Because of these biological properties, compounds (I) are useful in all indications suitable for -glucocorticoid steroids with anti-inflammatory properties, especially as topically useful anti-inflammatory glucocorticoids, e.g. for the treatment of inflammatory dermatoses such as eczema, dermatides or partially corticoid resistant dermatoses, e.g. psoriasis.

It is known that 21-substituted 6α-fluoro-16-methylpreg-na-1,4-diene-3,20-dione, which is closely related to the compounds of formula (I), has anti-inflammatory action. Thus, Danish Patent Specification No. 129,835 discloses anti-inflammatory activity of 2-chloro-6-fluoro-16a-methylpregna-1,4-diene-3,20-dione of the general formula 8 146017 CH2r1 = 0

H0V XV

'γ ______OH

x 3 ολΛ /

F

is a free or one having a sulfuric acid, a phosphoric acid or a carboxylic acid having a maximum of 18 C atoms esterified or one having an α-tetrahydropyranol or α-tetrahydrofuranol etherified hydroxy group and X is a hydrogen The compounds of formula (I) have a surprisingly good anti-inflammatory effect over the known compounds, as shown in the comparative experiments below.

In the comparison experiment, the local anti-inflammatory effect of the compounds below and their systemic side effects are determined. The following test compounds are used:

St - 2-Chloro-6a, 9a-difluoro-118,17a, 21-trihydroxy-16a-methyl-pregna-1,4-diene-3,20-dione (known).

A - 21-Chloro-6a, 9a-difluoro-118,17a-dihydroxy-163-methyl-pregna-1,4-diene-3,20-dione-17-propionate.

B - 2,2i-Dichloro-6a, 9a-difluoro-113,17a-dihydroxy-163-methyl-pregna-1,4-diene-3,20-dione-17-propionate.

C-9a, 21-Dichloro-6a-fluoro-113,17a-dihydroxy-168-methyl-pregna-1,4-diene-3,20-dione-17-propionate.

The comparative compound St belongs to the powerfully known known corticoids and is known from Danish Patent Specification No. 129,835.

9 146017

Using the conventional raw cotton granuloma test, double-sided implantation of a cotton pellet is performed in normal male albino rats. One pellet is impregnated with a specific dose of the test compound, while the other 5 is untreated. To assess the anti-inflammatory effect, the weight of granulomas formed is determined after isolation. The weight difference between the untreated and the treated granuloma is expressed for each animal as the percentage reduction of the granuloma weight at the specific dose. One approx. 30% reduction in granuloma weight is considered significant for the anti-inflammatory effect and the corresponding dose is designated as ED20-30 *

In the same experiment, the undesirable side effects of the test compounds are also determined simultaneously, with a determination of the weight reduction of the adrenal glands and thymus in the treated animals compared to untreated control animals, ie. animals that have had double-sided implantation with impregnated raw cotton pellets. In this case too, an approx. 30% decrease in organ weight as significant for the effect of adrenal gland inhibition of the adrenal gland and for thymus the thymolytic effect. The corresponding doses are also referred to herein as ED 20

The results are shown in the table below.

Compound ED20-30 (λ osis in yg / pellet which produces a weight reduction of 30%)

Granuloma Thymus = T Adrenal 1 = - (G) (T) (N)

St 3 3 1 100 0.03 30 A 1 10 0.1 100 0.01 B 10 100 0.1> 100 <0.1 C 1-3> 1000 <0.003-> 1000 0.003- 0.001 -0.001 ίο 146017

It is evident from the results set forth above that with respect to the desired local anti-inflammatory effect, compounds A and C have a ca. three times the effect of the comparative compound St, and compound B has a third of the effect of the comparative compound.

With respect to the undesirable adrenal inhibition, Compound A has approx. one-third of the effect of Comparative Compound St, Compound C one-tenth to one-third of the effect of Comparative Compound St, wherein Compound B has a three-fold greater adrenal inhibition than Comparative Compound St. In terms of the undesirable thymolytic effect, compounds A and B have a ten times better effect than the comparison compound, and compound G has a thousand times better effect than the comparison compound, calculated on the desired anti-inflammatory effect.

According to the invention, it is particularly advantageous to prepare compounds of formula I wherein X 1 is fluorine or chlorine, 2 1 2 X chlorine, R hydrogen and R alkanoyl, especially propionyl, or

1 2 12 20 wherein X is fluorine or chlorine, X is chlorine, R is chlorine and R is

alkanoyl, especially propionyl.

In process a) the cleavage of the 9β, 11β oxido group is carried out in a starting material of formula II by treatment with hydrogen chloride or hydrogen fluoride in a manner known per se, suitably using an anhydrous hydrogen halide, optionally in the presence of an inert solvent such as chloroform, tetrahydrofuran or especially dimethylformamide, but hydrogen fluoride can also be used in aqueous solution.

Instead of hydrogen chloride or fluoride, one may also use a hydrogen fluoride or hydrogen chloride release agent such as the salt of such an acid with a tertiary organic base, e.g. pyridine or, especially in the case of hydrogen fluoride, a similar suitable addition compound. A particularly favorable process is disclosed in U.S. Patent No. 3,111,758, which uses hydrogen fluoride in the form of an adduct with a carbamic acid or thiocarbamic acid derivative, especially with urea.

The starting materials of formula II can be obtained in a manner known per se, e.g. by decomposing water from a 6a-fluoro-110-hydroxy-160-methyl-2-R1-17a-OR2-21-X2-pregna-1,4-diene-3,20-dione compound, e.g. by treatment with a suitable acid chloride such as phosphorus oxychloride or methanesulfonic acid chloride, in the presence of a base, e.g. pyridine, the addition of bromine sub-acid (as used, for example, in the form of N-bromoacetamide or N-bromosuccinimide) to the 9,11-double bond in the thus obtained 6a-fluoro-160-methyl-2-R1-17a-OR2 -21-X2-pregna-1,4,9 (11) -triene-3,20-dione compound and decomposition of hydrogen bromide from the corresponding 9a, 110-bromohydrin compound by treatment with a base, f. eg. an alkali metal carbonate or hydroxide, e.g. potassium carbonate or potassium hydroxide, to give the desired starting material of formula (II). In the above intermediates, R, R and X have the meanings given above.

Process b) replaces the sulfonyloxy group with bromine or chlorine in a manner known per se. In particular, the acyl residue Ra of an organic sulfonic acid is the acyl residue of an aliphatic or carbocyclic, optionally unsaturated or aromatic sulfonic acid. Such acids include optionally substituted, e.g. halogenated, lower alkanesulfonic acids, cycloalkanesulfonic acids wherein the cycloalkyl group may be mono or polycyclic, or optionally with lower alkyl, e.g.

Methyl, lower alkoxy, e.g. methoxy, halogen, e.g. chlorine or bromine, and / or nitro, substituted benzenesulfonic acids. As typical examples of such acids, mention is made of trifluoromethanesulfonic acid, (+) - campher-10-sulfonic acid, 4-bromo-benzenesulfonic acid and 3-nitrobenzenesulfonic acid, especially p-toluene sulfonic acid and, above all, methanesulfonic acid.

12 146017

The replacement reaction is usually carried out by treating the starting material of formula (IV) with an alkali metal halide of formula Μ - X2 (V) 5 wherein M represents an alkali metal, preferably lithium, in the presence of an aprotic organic solvent whose dielectric constant is 29 or higher.

As aprotic organic solvents, dilavalkyl sulfoxides, e.g. dimethylsulfoxide, N, N-10-dilavalkylamide-lavaliphatic carboxylic acids, e.g. Ν, Ν-dimethylformamide or Ν, Ν-dimethylacetamide, lower alkane or low alkene nitriles, e.g. acetonitrile, hexalavalkyl phosphoramides, e.g. hexamethylphosphoramide, or ketones, especially aliphatic or cycloaliphatic ketones having up to 10 carbon atoms, such as corresponding alkanones, e.g. acetone, 2-butanone, 2- or 3-pentanone, 2-hexanone or 4-decanone, or cycloalkanones with up to 8 ring carbon atoms, e.g. cyclopentanone or cyclohexanone, or mixtures of such solvents.

The reaction is conveniently carried out between room temperature and the boiling point of the reaction mixture, reacting with at least one equivalent of the alkali metal halide of formula (V).

The starting materials of formula (IV) are known or can be prepared in a manner known per se, e.g. by adding in a 6α-fluoro-11β, 21-dihydroxy-16β-methyl-2-R R-9a-X ^-17α-OR₂-pregna-1,4-diene-3,20-dione compound converting the 21-hydroxy group by treatment with a reactive derivative of an organic sulfonic acid of formula 30 Ra - OH (VI) especially with a corresponding sulfonic acid chloride of formula

Ra - Cl (Via) in the presence of a base, e.g. pyridine, to the desired 1A 6 017 13 organic sulfonyloxy group -0Ra.

In process c), the 9,11-double bond is prepared in the starting materials of formula (VII) by elements known in the art as chloro-undercutting. Including work 5, e.g. with aqueous chlorine undercutting, or a chlorine undercutting agent such as an N-chloro-carboxylic acid amide or imide can be used (cf. U.S. Patent No. 3,057,886). The reaction is carried out in an inert solvent such as a tertiary alcohol, e.g. tert-butanol, an ether, e.g. diethyl ether, methyl isopropyl ether, dioxane or tetrahydrofuran, or a ketone, e.g. acetone, in the presence of water and possibly a strong acid.

The addition of chlorine sub-acid to the 9,11-double bond in the starting material of formula (VII) can also take place in non-aqueous medium. A particularly advantageous embodiment of this modification is the use of low alkyl hypochlorites, primarily tert-butyl hypochlorite, in an inert, water-immiscible solvent such as e.g.

20 a nitrocarbon hydride, usually in the presence of perchloric acid (see German Patent No. 2,011,559).

The starting materials of formula (VII) can be prepared in a manner known per se, e.g. by cleavage of water from a 6α-fluoro-11b-hydroxy-16β-methyl-2-R ^-17α-OR ^-21-X ^ -25 pregna-1,4-diene-3,20-dione compound, eg. by treatment with a suitable acid chloride, such as phosphorus oxychloride or methanesulfonic acid chloride, in the presence of a base, e.g. pyridine.

In process d), the 1,2-double bond is introduced by dehydrogenation, e.g. by treatment with a suitable dehydrogenating quinone such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

1,2-Dehydrogenation of starting substances of formula (VIII) may also be effected by treatment with selenium dioxide or microbiologically, e.g. with suitable microorganisms such as Coryne bacterium simplex or Septomyxa affinis.

The starting materials of formula (VIII) can be obtained by transferring the 21-hydroxy group into a 6α-fluoro-113,21-dihydroxy-1,216β-methyl-9α-X-17α-OR-precipit-4-ene-3 , 20-dione compound, e.g. by treatment with a suitable sulfonic acid derivative, such as methanesulfonic acid chloride, to a 21-organic sulfonyl-oxy group and treating the intermediate with a lithium halide, e.g. lithium chloride.

A compound of formula (I) obtained in accordance with the process in which R 1 is hydrogen may in a manner known per se be converted to another compound of formula (I) wherein R 1 is chloro.

For this purpose, a molecule of chlorine can be added to the 1,2-double bond in such a compound and from the 1,2-dichloro-pregn-4-ene-3,20-dione intermediate a mole of hydrogen chloride is decomposed. The addition of chlorine to the 1,2-double bond 20 can be effected by treatment with elemental chlorine or with a mixture of two different chlorine-containing compounds, one of which gives off positive and the other negatively chlorine.

The treatment with elemental chlorine can be carried out in an inert organic solvent, e.g. an ether such as dioxane or tetrahydrofuran, a halogenated hydrocarbon, e.g. methylene chloride, or a carboxylic acid, especially a low-aliphatic carboxylic acid, such as acetic or propionic acid, or a derivative thereof, such as an acid amide, e.g. dimethylformamide, or a nitrile such as a lower alkanol nitrile, e.g. acetonitrile. Advantageously, mixtures of such solvents, in particular mixtures of an ether such as dioxane, may also be used with one of the mentioned lower alkane carboxylic acids. Chlorination is usually carried out with the stoichiometric amount of chlorine at a lower temperature, approx. between -50 ° C and + 30 ° C, e.g. between -20 and + 10 ° C, and excluding light.

According to a particularly preferred embodiment, the compound of formula (I) wherein R 1 stands for hydrogen is dissolved in one of said solvents, e.g. dioxane and a solution of chlorine in a low aliphatic carboxylic acid, e.g. propionic acid; this solution is then left e.g. at said temperature.

Mixtures of two different chlorinating agents are used as reagents which can release positive chlorine, i. chlorinated acid amides or acid imides such as chloro-succinimide or chloroacetamide, while as such, which delivers negative chlorine, e.g. hydrogen chloride and alkali metal chlorides are also added.

The decomposition of hydrogen chloride from the 1,2-dichloro-pregn-4-ene-3,20-dione intermediate is conveniently carried out by treatment with a basic agent. As basic agents 20, e.g. tertiary organic nitrogen bases such as low aliphatic amines, e.g. trilavalkylamine, such as triethylamine, heteroaromatic bases, e.g. pyridine or collidine, or mixed aliphatic-aromatic bases such as Ν, Ν-dilavalkyl-aniline, e.g. N, N-dimethyl-aniline.

25 Preferably, an excess of the base can be used, which can also serve as a solvent. However, inorganic bases can also be used, in particular the alkali metal or alkaline earth metal salts used for hydrolysis of the Ιΐβ-trifluoroacetate described below. potassium or sodium acetate or hydrogen carbonate, in aqueous-alcoholic solution, and the corresponding hydroxides. The dehydrochlorination is preferably carried out in a temperature range of from approx. 20 ° C to approx. 100 ° C. Conveniently, such agents and reaction conditions are chosen which leave the other functional groups, especially the functional groups in the 17 and / or 21 positions, unaffected.

Conveniently, prior to the chlorine addition to the 1,2-double bond, a compound of formula (I), wherein R 1 stands for hydrogen, is the β-hydroxyl group, e.g. by esterification, preferably as a trifluoroacetyloxy group, reacting a compound of formula (I) wherein R 1 is hydrogen, with a suitable reactive derivative of an acid, e.g. with trifluoroacetic acid chloride or anhydride, in a manner known per se. As is known, the trifluoroacetyl group can be readily decomposed solvolytically, e.g. hydrolytic or alcoholic, e.g. by the action of alkali metal or alkaline earth metal hydroxides, carbonates, hydrogen carbonates or acetates, in a suitable, e.g. alcoholic, such as methanolic, or aqueous-alcoholic medium. A particular embodiment of the solvolysis of the 11-trifluoroacetyloxy group is disclosed in German Patent No. 1,593,519, which is particularly important because an esterified hydroxyl group present in the 17a position thereby remaining intact; thereby proceeding by treating the Ιΐβ-trifluoroacetyloxy compound in a low alkanol with the salt of an acid whose pKa value is in the range of approx. 2.3 to approx. 7.3, such as with an alkali metal azide, e.g. sodium or potassium azide, or alkali metal formate, e.g. sodium or potassium formate, since this salt may also be used in clinical catalytic amounts. Furthermore, the Ιΐβ-trifluoroacetyl group may also be removed by treatment with other basic reagents, e.g. with amines, especially with heteroaromatic bases such as pyridine or collidine. Finally, consideration is also given to the cleavage of the trifluoroacetyloxy group by the action of silica gel according to the procedure described in German Publication No. 2.1441405.

The release of the β-hydroxyl group from the protected form 35 can occur immediately after the addition of chlorine to the 1,2-double bond or at the same time as the dehydrochlorination by a base, but possibly also separately in connection with this step.

The invention also relates to the embodiments of the process in which a starting material is formed under the reaction conditions.

Preferably, in the above steps of the process, the starting materials leading to the compounds previously described as particularly preferred are inserted.

Pharmaceutical compositions containing the compounds of formula (I) are preferably used for treating inflammatory conditions, especially in the form of topically applicable pharmaceutical compositions.

The process according to the invention is further illustrated in the following examples.

18 146017

Example 1

A solution of 228 mg of 21-chloro-6α, 9α-difluoro-113,17α-dihydroxy-16β-methyl-pregn-4-ene-3,20-dione-17-propionate in 11.4 ml of dioxane is heated after addition of 230 mg of 5 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) for 20 hours under refluxing nitrogen atmosphere. The reaction mixture is evaporated in water jet vacuum and the amorphous residue is chromatographed over the 10% double weight silica gel (step column). The fractions eluted with a mixture of methylene-10-chloride-methanol (99: 1) give the pure 21-chloro-6a, 9a-difluoro-1,1,17a-dihydroxy-16β-methyl-pregna-1,4-diene. 3,20-dione-17-propionate, which after recrystallization from methylene chloride / ether melts at 220-221 ° C.

The 17-monopropionate used as a starting material is prepared as follows: a. To a suspension of 1.0 g of 21-chloro-9 | 3, β-epoxy-. 17α-hydroxy-160-methyl-pregn-4-ene-3,20-dione-17-propionate in 5.4 ml of dioxane and 1.4 ml of orthomyric acid triethyl ester are added 0.9 ml of a solution consisting of 277 mg of p-toluenesulfonic acid, 2.7 ml of dioxane and 0.55 ml of ethyl alcohol are stirred for 90 minutes at room temperature. After the addition of 3.8 ml pyridine, the reaction mixture is diluted with ethyl acetate, washed three times with saturated sodium chloride solution, dried and evaporated in water jet vacuum. The crude 3-ethyl-enol ether thus obtained (3-ethoxy-21-chloro-98,113-epoxy-17a-hydroxy-163-methyl-pregna-3,5-diene-20-one-17-propionate) is dissolved in a mixture of 30 50 ml of tetrahydrofuran and 10 ml of water and treated for 40 minutes at room temperature with gaseous perchloryl fluoride. After passing through nitrogen for 10 minutes, the reaction solution is diluted with ethyl acetate, washed successively with 10% 1 s potassium iodide solution, with 10% sodium thiosulphate solution and three times with saturated sodium chloride solution, dried and evaporated in water jet vacuum. The resulting crude product is chromatographed over the 100-fold by weight silica gel (step column). The fractions eluted with a mixture of toluene-ethyl acetate (90:10) give, recrystallized from methylene chloride / ether, 21-chloro-6a-fluoro-59 (3, 113-epoxy-17a-hydroxy-16 | 3-methyl) pregn-4-ene-3,20-dione-17-propionate, mp 174-177 ° C.

b, 720 mg of the latter compound is poured into a plastic container with 14.5 ml of a reagent prepared by mixing 10 g of urea with 13.25 g of 10 anhydrous liquid hydrogen fluoride and stirring for 3 hours under ice-cooling. The reaction mixture is poured into 55 ml of ice-cold saturated ammonia solution, acidified slightly with acetic acid and extracted twice with chloroform. The organic phases are combined, washed with ice-cold dilute sodium hydroxide solution, dried and evaporated in water jet vacuum. The crude product is chromatographed over the 100-fold weight silica gel (step column). The fractions eluted with a mixture of toluene-ethyl acetate (90:10) give, recrystallized from methylene chloride / ether, 21-chloro-6a, 9a-difluoro-113,17a-dihydroxy-163-methyl-pregn-4-ene. 3.20-dione-17-propionate, m.p. 212-213 ° C.

Example 2

To a solution of 3.70 g of 21-chloro-6α, 9α-difluoro-113,17α-2,5 dihydroxy-1ββ-methyl-pregna-1,4-diene-3,2-dione-17-propionate in 30 ml of dioxane is added 1.85 ml of a solution prepared by introducing 7.7 g of chlorine gas into 100 ml of propionic acid. The reaction mixture is left for 5 days at 3-4 ° C, then diluted with chloroform, washed successively with 30% potassium iodide solution, 10% sodium thiosulfate solution, dilute sodium hydroxide solution and water, dried and evaporated in water jet vacuum.

The crude 1,5,25,21-trichloro-6a, 9a-difluoro-113,17a-dihydroxy-163-methyl-pregn-4-ene-3,20-dione-17-35 propionate thus obtained is dissolved in methylene chloride to give HCl cleavage 20 146017 and filtered through a column of 37 g of basic alumina (activity 2). The eluted solution is evaporated and recrystallized from methylene chloride ether to give 2,21-dichloro-6α, 9α-difluoro-11β, 17α-dihydroxy-163-5 methyl-pregna-1,4-diene-3,20 dione-17-propionate, m.p.

202-204 ° C.

Example 3

A solution of 350 mg of 9α, 21-dichloro-6α-fluoro-lip, 17-dihydroxy-16β-methyl-pregn-4-ene-3,20-dione-17-propionate 10 and 525 mg of 2,3-dichloro 5,6-dicyan-1,4-benzoquinone in 17.5 ml of dioxane is refluxed for 20 hours in a nitrogen atmosphere. The cooled mixture is filtered, the filtrate is evaporated, and the residue is dissolved in methylene chloride and filtered through the 15-fold by weight neutral alumina (Activity II). The filtrate is evaporated and purified by preparative thin layer chromatography on silica gel using a mixture of toluene and methanol in the ratio 9: 1 as the eluent of the third pass. The desired zone is localized by UV light illumination with a wavelength of 254 nm, eluted from the column material with ethyl acetate and recrystallized from a mixture of methylene chloride and ether, thus obtaining the desired 9α, 21-dichloro-6α-fluorine. -Β, 17-dihydroxy-16β-methyl-pregna-1,4-diene-3,20-dione-17-propionate, m.p. 212-213 ° C (decomposition).

a. The steroid used as a starting material is prepared as follows:

To a solution of 400 mg of 21-chloro-6α-fluoro-93,11-30 epoxy-17-hydroxy-16β-methyl-pregn-4-ene-3,20-dione propionate in 20 ml of chloroform is added over 30 minutes gaseous hydrogen chloride at 0 ° C. The mixture is left for another 30 minutes at 0 ° C, diluted with chloroform, washed with an ice cold, saturated sodium hydrogen carbonate solution, dried and evaporated in vacuo. The crude 9a, 21-dichloro-formed 21ct-fluoro-ΙΙβ, 17β-γάΓθχγ · -16β-ιη0ΐ: 1ιγ1-ρΓθ9η-4-βη-3,20-dione-17-propionate can be used without purification by the dehydrogenation reaction.

Example 4 To a solution of 2.8 g of 21-chloro-6a-fluoro-9β, 11-epoxy-17-hydroxy-168-methyl-pregna-1,4-diene-3,20-dione propionate in 140 In chloroform, gaseous hydrogen chloride is passed over 30 minutes at 0 ° C. The mixture is allowed to stand for another 30 minutes at 0 ° C, diluted with 10 chloroform, washed with an ice-cooled saturated sodium hydrogen and carbonate solution, dried and evaporated in vacuo.

The crude product obtained is chromatographed on a 100-fold by weight silica gel (step column). The desired product is eluted with a mixture of toluene and methanol in the ratio 99: 1. After crystallization from a mixture of methylene chloride and ether, 9α, 21-dichloro-6α-fluoro-β, 17-dihydroxy-16β-methyl-pregna-1/4-diene-3,20-dione-17-propionate were obtained, m.p. 212-213 ° C (decomposition), which is identical to the product of Example 3.

a 20 The steroid compound used as a starting material is prepared as follows:

A mixture of 3g of 21-chloro-6a-fluoro-9B, 11-epoxy-17-hydroxy-16β-methyl-pregn-4-ene-3,20-dione propionate and 3g of 2,3-dichloro-5, 6-dicyan-1,4-benzoquinone in 150 ml of dioxane is refluxed for 20 hours in a nitrogen atom. The cooled mixture is filtered, the filtrate is evaporated, the residue is dissolved in methylene chloride and filtered through the 15-fold by weight of neutral alumina (Activity II). The filtrate is evaporated to give crude 21-ο1ι1θΓ-6α-ί1ηοΓ-9β, 11-βροχγ-17 -] - 1β: οχγ-16β-ιηβ propionate, which is used for the reaction with hydrogen chloride without further purification.

22 146017

Example 5

Using the procedure described in Example 1b, is prepared from 21-chloro-6α-fluoro-93,11-epoxy-17-hydroxy-16β-methyl-pregna-1,4-diene-3,20-dione-5 propionate (prepared according to Example 4a) 21-chloro-6a, 9a-difluoro-ΙΙβ, 17a-dihydroxy-16f} -methyl-pregna-1,4-diene ~ 3,20-dione-17-propionate, m.p. -221 ° C (from a mixture of methylene chloride and ether).

Example 6 To a solution of 2.97 g of 2-chloro-6α, 9α-difluoro-β, 17α, 21-trihydroxy-16β-methyl-pregna-1,4-diene-3,20-dione-17-propionate in 60 ml of pyridine is added dropwise at approx.

-10 ° C with stirring 2.23 ml of methanesulfonic acid chloride, after which the mixture is left to stand at ca. 5 ° C for an additional 21 hours. Then, the reaction mixture is poured into 1.5 L of ice water and stirred for 20 minutes. The precipitated precipitate is filtered off, washed with water, taken up in chloroform, the solution dried and evaporated under water-jet vacuum. The 21-mesylate thus prepared behaves by thin layer chromatography as a practically pure substance. It is dissolved directly in 75 ml of dimethylformamide without further purification, and after addition of 11.25 g of lithium chloride, it is stirred for 16 hours under nitrogen at 100 ° C, then cooled and the mixture is poured into ca. 1.5 l of ice water. The precipitate is filtered off, washed with water and dissolved in chloroform, the solution washed with water, dried and evaporated in vacuo. The crude product obtained is chromatographed on the 40-fold by weight silica gel (step column). From the fractions eluted with a mixture of toluene and ethyl acetate (95: 5), after recrystallization is obtained from a mixture of methylene chloride, methanol and ether pure 2,21-dichloro-6a, 9a-di-fluoro-ΙΙβ, 17α- · dihydroxy -16β-methyl-pregna-1,4-diene-3,20-dione-17-propionate, m.p. 202-204 ° C.

From the subsequent fractions eluted with a mixture of toluene and ethyl acetate (92: 8), ca.

1.3 g of unreacted 21-mesylate (2-chloro-6a, 9 <x -difluoro-11,17,17a, 21-trihydroxy-163-methyl-pregna-1,4-diene-3,20-dione-17-propionate 21-mesylate).

The 17-monopropionate used as starting material is prepared as follows: a. A solution of 3.0 g of 2-chloro-6a, 9a-difluoro-113, 17a, 21-trihydroxy-163-methyl-pregna-1,4 diene-3,20-dione in 15 ml of absolute tetrahydrofuran is added 3.6 ml of orthopropionic acid triethyl ester and 100 mg of p-toluenesulfonic acid, and the mixture is stirred for 1.5 hours at room temperature. Then, 1.2 ml of pyridine is added dropwise to the reaction solution, which is poured into ice water, extracted with 400 ml of ethyl acetate twice, after which the organic solutions are washed with 5 times 100 ml of saturated sodium chloride solution, dried and evaporated under water jet vacuum. The resulting crude 17.21 ethyl orthopropionate is dissolved in 150 ml of ethanol.

The solution is stirred after adding 1.1 g of oxalic acid in 9 ml of water for 1 hour at 55 ° C, adding 100 ml of water and evaporating under water jet vacuum.

The precipitated precipitate is filtered off, washed with water and dissolved in chloroform. The solution is dried over sodium sulfate and evaporated in vacuo. The thus-obtained crude 2-chloro-6a, 9a-difluoro-113,17a, 21-trihydroxy-163-methyl-pregna-1,4-diene-3,20-dione-17-propionate behaves by thin layer chromatography. as a virtually uniform substance and can be used directly without further purification in the reaction described above to the corresponding 21-chloro compound.

Example 7

Using the procedure described in Example 6, 1.0 g of 9α-chloro-6α-fluoro-113,17α, 21-tri-hydroxy-16β-methyl-pregn-4-ene-3,20 dione-17-propionate with methanesulfonic acid chloride in pyridine. The resulting 21-mesylate is dissolved in 30 ml of acetone and 20 ml of dimethylformamide, and after addition of 3.9 g of lithium chloride 5 is stirred for 16 hours in a molten pressure tube at 80 ° C. The cooled mixture is poured into ice water, the precipitate is washed with water, taken up in methylene chloride, dried, and evaporated under water jet vacuum. The crude product obtained is dissolved in toluene and chromatographed on a 50-10 double weight silica gel. The fractions eluted with a mixture of toluene and ethyl acetate (95: 5) give, after conversion from a mixture of methylene chloride and ether 9α, 21-dichloro-6α-fluoro-ΙΙβ, 17α-dihydroxy-Ιββ-methyl-yl. pregn-4-ene-3,20-dione-17-propionate, which melts at 15 198 ° C (dec.).

The starting material can be prepared as follows: a. A solution of 20 g of 6α-fluoro-β, 17α, 21-trihydroxy-16B-methyl-pregn-4-ene-3,20-dione-21-acetate in 120 ml dimethylformamide and 40 ml of 2,4,6-trimethylpyridine 20 are added dropwise at 10 ° C with stirring 30 ml of a solution made of 2 g of sulfur dioxide and 40 ml of methanesulfochloride (mesyl chloride). After heating to 30 ° C, the temperature increases spontaneously with continued stirring for 20 minutes to 55 ° C. The mixture is poured into 1500 ml of water and the precipitate formed is filtered off, washed with water and dissolved in chloroform. The solution is dried with sodium sulfate and evaporated in water jet vacuum. The dark residual oil is dissolved in methylene chloride and filtered through a 30-fold by weight alumina (neutral, activity 2). Evaporation of the solvent from the filtrate gives colorless 6a-fluoro-17a, 21-dihydroxy-16β-methyl-pregna-4,9 (11) -diene-3,20-dione-21-acetate, which behaves as thin layer chromatography as 35 a uniform substance.

B. 5.0 g of the compound prepared above under a is poured with 100 ml of t-butanol and added with nitrogen and stirring 6.5 ml of 10% perchloric acid solution and finally 2 ml of t-butyl hypochlorite.

After 3.5 hours of further stirring at room temperature, the yellow solution is poured into ice water and the product is taken up in chloroform. The organic solution is washed with 10% potassium iodide solution, 10% sodium thiosulfate solution and finally with ice-10 cold diluted sodium hydroxide solution, then dried and evaporated in water jet vacuum. The crude 9α-chloro-6α-fluoro-113.17a, 21-trihydroxy-16β-methyl-pregn-4-ene-3,20-dione-21-acetate is purified by reaction from a mixture of methylene chloride, methanol and ether. .

c. A solution of 4.5 g of the above 21-acetate in 300 ml of methanol is added under nitrogen to 22.5 ml of a solution of 2.76 g of sodium hydrogen carbonate in 32.4 ml of water and stirred for 3 hours. , 5 hours 20 at room temperature. The mixture is added with 1.35 ml glacial acetic acid and 225 ml water, the methanol is completely removed in vacuo. The separated precipitate is suction filtered, washed with water and again suction filtered. The residue is dissolved in chloroform, the solution is dried over sodium sulfate and evaporated to give crystalline 9α-chloro-6α-fluoro-11β, 17α, 21-trihydroxy-16β-methyl-pregn-4-ene-3.20 -dione.

d. A solution of 3.12 g of the above compound in 31.2 ml of tetrahydrofuran is stirred for 1.5 30 hours at 20 ° C with 3.9 ml of orthopropionic acid triethyl ester and 156 mg of p-toluenesulfonic acid, then 4 The mixture is then evaporated in vacuo and taken up in ethyl acetate. The extract is washed twice with a saturated sodium chloride solution, dried and evaporated. As the residue, crude ethyl, 17α, 21-orthopropionate of 2,9a-dichloro-6a-fluoro-11β, 17α, 21-trihydroxy-16b-methyl-pregn-4-ene-3,20-dione is obtained, which is used. without purification in the subsequent step.

e. A solution of 3.10 g of the above-prepared ortho ester in 155 ml of ethyl alcohol is added to a solution of 0.96 g of oxalic acid dihydrate in 8.3 ml of water and stirred at 50 ° C, after which diluted with 96 ml of water, evaporated in vacuo and extracted with ethyl acetate. The organic extract is washed twice with an ice-cooled 2N solution of potassium hydrogen carbonate and three times with water, then dried and evaporated. The residue consists of the crude 9α-chloro-6α-fluoro-ββ, 17α, 21-trihydroxy-16β-methyl-pregn-4-ene-3,20-dione-17-propionate which is purified by crystallization from a mixture of methylene chloride, methanol and ether.

Example 8

Using the procedure described in Example 7, however, using as starting material, 20α-chloro-6α-fluoro-β, 17α, 21-trihydroxy-16β-methyl-pregna-1,4-diene-3.20 -dione-17-propionate (which can be prepared from the starting material of Example 7 by dehydrogenation), 9a, 21-dichloro-6a-fluoro-ΙΙβ, 17a-dihydroxy-16β-methyl-pregna-1,4-diene-3 are prepared. , 20-dione-17-propionate with 25 m.p. 212-213 ° C (dec.).

Example 9

To a solution of 6.0 g of 6α, 9α-difluoro-1,7,17α, 21-tri-hydroxy-16β-methyl-pregna-1,4-diene-3,20-dione-17-propionate-21 -Methanesulfonate in 150 ml of dimethylformamide 30 is added 18 g of dry lithium chloride and stirred for 16 hours at 100 ° C under a nitrogen atmosphere. The cooled mixture is poured into ice water, the precipitate formed is filtered off, washed thoroughly with water and dissolved in chloroform. The organic solution is evaporated after drying under water jet vacuum and the residue is separated by preparative thin layer chromatography on silica gel with a 50:50 mixture of toluene and ethyl acetate as liquid phase. Leaching the main zone with 5 ethyl acetate gives 21-chloro-6a, 9a-difluoro-lip, 17a-dihydroxy-1ββ-methyl-pregna-1,4-diene-3,20-dione-17-propionate, which after recrystallization from a mixture of chloroform, methanol and diethyl ether melts at 220-221 ° C.

Using the procedure described above, however, starting from the corresponding 1,2-saturated 17-propionate-21-methanesulfonate, 21-chloro-6a, 9a-difluoro-lip, 17a-dihydroxy-163-methyl pregn-4-ene-3,20-dione-17-propionate, m.p. 212-213 ° C.

The starting material used was 21-methanesulfonate of 6α, 9α-difluoro-ββ, 17α, 21-trihydroxy-163-methyl-pregna-1,4-diene-3,20-dione-17-propionate or the corresponding 1,2 -saturated compound is prepared by esterification of the 21-hydroxy group of the corresponding 6a, 9a-difluoro-113, 17a, 21-trihydroxy-17-propionate by treatment with 20 methanesulfonic acid chloride in the presence of pyridine at 5 ° C.

Example 10

A stirred suspension of 7.45 g of 21-chloro-6α-fluoro-17α-hydroxy-16β-methyl-pregna-4,9 (11) -diene-3,20-dione-17-25 propionate in 150 ml of t butyl alcohol is added under nitrogen 7.55 ml of 10% perchloric acid solution and then 2.15 ml of t-butyl hypochlorite, then stirred for an additional 3.5 hours at room temperature, then the mixture is poured into ice-water. The precipitate is aspirated, washed thoroughly with water 3q and dissolved in chloroform and a little methanol. The solution is dried with a sodium sulfate and evaporated in water-jet vacuum. After reaction of the residue obtained from a mixture of methylene chloride, methanol and ether, 9a, 21-dichloro-6a-fluoro-113,17a-dihydroxy-353-methyl-pregn-4-ene-3,20-dione-17 are obtained. propionate, which melts at 146 ° C during decomposition.

Example 11

Using the procedure described in Example 10, a suspension of 2.95 g of 21-chloro-5,6 <xfluoro-17α-hydroxy-163-methyl-pregna-1,4,9 (11) -tri-3 is prepared. 20-dione-17-propionate in 60 ml of t-butyl alcohol added to 2.95 ml of 10% perchloric acid solution and 0.85 ml of t-butyl hypochlorite. After working up, 9a, 21-dichloro-6a-fluoro-lip, 17a-dihydroxy-163-methyl-pregna-1,4-diene-10,20-dione-17-propionate are obtained with m.p. 212-213 ° C (dec.).

Claims (3)

146017 An analogous process according to patent No. 143,708 for the preparation of 17α-acyloxy-9α, 21-dihalogen-11β-hydroxy-6α-fluoro-163-methylpregna-1,4-diene-3,20-dione compounds 5 with the formula CHO-X2 I 2 CH C = 0 \ /> ----- O-R2 R1 ch3 (I) F 1 2 1 wherein X is chlorine or fluorine, X is bromine or chlorine, R2 is hydrogen or chlorine and R is alkanoyl group having a maximum of 7 C atoms, characterized in that a) treating a compound of formula CEL-X2 I 2 CH, C = 0 W_ | ---- 0-R2 R1 CH3 / ° 10 γγγ \ ΛθΗ3 111> 0A Wherein R, R and X are as defined above with hydrogen chloride or hydrogen fluoride or with an agent which gives off one of these hydrogen halides, or b) in a compound of general formula 148017 CHO-0 -Ra in 2 ch3 c = o HO. J? X / x ------ O-R2 R1 CH3I I (IV) οΚίΚ / F wherein r \ R2 and X1 have the above meaning and Ra is the remainder of an organic sulfonic acid, replacing the sulfonyl oxy group with bromine or chlorine, or c) for the preparation of a compound of formula I wherein X * = chlorine, a 9 (11) unsaturated compound of formula ch9-x2 is treated with 2 CH3 c = o ----- O-R2 'y Wherein R, R and X have the above meaning, with chloro-10 subcirculation or a chloro-subcooler, or d) to prepare a compound of formula I wherein R4 hydrogen, dehydrogenates a compound of formula 146017 <jH2 - X2 CH, C = 0 R ° y \ 9 X / ^ ----- O-R2 (wine) oA ^ V in F 2 1 2 wherein R, X and X has the above meaning, in the 1,2-position, and, if desired, in a compound of formula I obtained in accordance with the process wherein R "*" means hydrogen and the other symbols having the above meaning, chlorine The 1,2-double bond and from the obtained lining compound of the formula CEL-X2 I 2 CH, C = 0 H0 yv o Cl ----- ° -R CyA> / \ AcH3 x1 J oAA / t F 2 1 2 wherein R, X and X have the above meaning, decomposes 10 hydrochloric acid, optionally during both process steps under the temporary protection of the 11β-hydroxyl group upon transfer to the trifluoroacetate. Process according to claim 1, characterized in that 2,2-dichloro-6a, 9a-difluoro-113,17a-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-17-propionate are prepared. . Process according to claim 1, characterized in that 9a, 21-dichloro-6a-fluoro-113,17a-dihydroxy-163-methylpregna-1,4-diene-3,20-dione-17-propionate are prepared.