CH651307A5 - Androsta-CARBOTHIOSAEUREN AND PROCESS FOR PRODUCING. - Google Patents

Description

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PATENT CLAIMS 1. Compounds of the general formula;

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wherein R "is a thiocarbamoyloxycarbonyl group -COOCSNRARB, in which RA and RB, which are the same or different, represent alkyl groups, or RA and RB together with the nitrogen atom to which they are attached form a 5- to 8-membered ring which optionally contains an additional heteroatom contains selected from oxygen, nitrogen and sulfur, and / or which is optionally substituted by one or two C1-3 alkyl groups or a group of the formula -COSR'A, wherein R1 A is a hydrogen atom or an R 'group, wherein R1 represents a fluorine, chlorine or bromomethyl group or a 2-fluoroethyl group, or a group - (CH2) n Y, where n represents 1 or 2 and Y represents a halogen atom, Rb represents an esterified hydroxyl group or Rb and Rc together form an iso-propylidenedioxy group; or if Ra represents a COSRIA group, Rb optionally represents a hydroxyl group; Rc represents a hydrogen atom, a methyl group which is in the a or β configuration gene, or represents a methylene group; Rd represents a hydroxy or protected hydroxy group in the a or β configuration or an oxo group; Re represents a hydrogen, bromine, chlorine or fluorine atom; or Rd and Re together represent an IC-carbon-carbon bond or an epoxy group in the β configuration; Rf represents a hydrogen or a fluorine atom and the symbol represents a single or double bond, and the salts of such compounds which contain a free carbothioic acid group; with the exception of the compounds of the formula:

COSR1

- OR

HO

where R1 and the symbol have the above meanings,

R2 represents a group -COR6, where R6 represents a Ci-3-alkyl group, or -OR2 and R3 together a 16a, 17a-

Form isopropylidenedioxy group, R3 represents a hydrogen atom, a methyl group which is in the a- or ß-configuration, or represents a methylene group, R4 represents a hydrogen *, chlorine or fluorine atom and R5 represents a hydrogen or fluorine atom.

2. Compounds according to claim 1, wherein Ra represents the group -COSH and Rb represents the hydroxyl group.

3. Compounds according to claim 1 or 2, wherein Rc represents an a-methyl group.

4. Compounds according to any one of claims 1 to 3, wherein Re and Rf each represent a fluorine atom.

5. Compounds according to any one of claims 1 to 3, wherein Re represents a hydrogen atom and Rf represents a fluorine atom.

6. Compounds according to any one of claims 1 to 3, wherein Rd and Re together represent an epoxy group.

7. Compounds according to one of claims 1 to 6,

which are 1,4-dienes.

8. Compounds according to claim 1, which are 1,4-dienes and wherein R 'represents a chlorine or fluoromethyl group and Re and Rf each represent a fluorine atom.

9. Compounds according to claim 8, wherein Re represents an a-methyl group.

10. Compounds according to claim 1, wherein Ra represents the group -COSH, Rb represents a hydroxyl group, Rc represents a hydrogen atom, an a- or β-methyl group or a methylene group, Re represents a hydrogen, chlorine or fluorine atom and Rd represents a hydroxyl group in the β configuration or represents an oxo group.

11. Compounds according to claim 1, wherein Rc represents a methyl group in the a or β configuration or a methylene group, Re represents a fluorine atom, Rd represents a hydroxyl group in the β configuration or an oxo group and the symbol in the 1,2- Position a coal

means carbon-carbon double bond.

12. Compounds according to claim 1, which are:

9a-fluoro-11β, 17a-dihydroxy-16ß-methyl-3-oxoandrosta-1,4-

dien-17ß-carbothioic acid and its salts;

9a-fluoro-17a-hydroxy-l 6ß-methyl-3,11 -dioxoandrosta-1,4-

dien-17ß-carbothioic acid and its salts;

9a-FIuor-l 1 ß, 17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-

dien-17ß-carbothioic acid and its salts;

9a-fluoro-17a-hydroxy-16a-methyl-3,11 -dioxoandrosta-1,4-

dien-17ß-carbothioic acid and its salts;

9a-fluoro-11ß, 17a-dihydroxy-16-methylene-3-oxoandrosta-

1,4-diene-17β-carbothioic acid and its salts, and

9a-fluoro-l 7a-hydroxy-16-methylene-3,11 -dioxoandrosta-1,4-

dien-17ß-carbothioic acid and its salts.

13. As compounds according to claim 1 the 6a, 9a-difluoro-11β, 17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17ß-carbothioic acid and its salts.

14. As compounds according to claim 1, 6a, 9a-difluoro-17 a-hydroxy-16a-methyl-3,11 -dioxoandrosta-1,4-diene-17β-carbothioic acid and its salts.

15. A process for the preparation of compounds according to claim 1 which carry a free -COSH group in the 17ß position, characterized in that a compound according to claim 1 which carries a thiocarbamoyloxycarbonyl group in the 17ß position, an aminolysis with rearrangement undergoes.

16. A process for the preparation of compounds according to claim 1, which carry a free -COSH group in the 17β-position, characterized in that a compound of the formula II according to claim 1, which has a 16a, 17a epoxy or 16a, 17a-isopropylidenedioxy group, but has a 17β-carboxyl group, or a salt thereof with a 2-halogen-aza-aromatic Ver2

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bond and then reacted with hydrogen sulfide.

17. A process for the preparation of compounds according to claim 1, which carry a free -COSH group in the 17β-position, characterized in that a corresponding compound of formula II, wherein Rb is a hydroxy group, but in the 17β-position carries a group -COR7, where R7 is a group of the formula:

in which X, Y and Z, which are the same or different, each represent CH or N, one or two of X, Y and ZN, the heterocyclic ring is optionally substituted on at least one carbon atom by a lower alkyl group and / or wherein the heterocyclic ring contains two adjacent carbon atoms, the ring optionally carrying a benzene ring fused to these two adjacent carbon atoms, reacted with hydrogen sulfide or a sulfide or hydrogen sulfide thereof.

18. A process for the preparation of compounds according to claim 1, which carry a -COSH group in the 17β-position, characterized in that a corresponding compound of formula II, which carries a carboxyl group in the 17ß-position, with a symmetrical or asymmetrical Connection of the formula:

R-W-R7 (III),

wherein W represents one of the groups -CO-, -CS-, SO or SO2 and R7 has the meaning given above, and the compound of the formula II obtained, which carries a group -COR7 in the 17β-position, without isolation thereof, in can react in situ with hydrogen sulfide or a sulfide or hydrogen sulfide salt thereof.

19. A process for the preparation of compounds according to claim 1, in which Rb is a hydroxyl group and Ra is the group -COSR1, in which R1 has the meaning given in claim 1, characterized in that a compound of the formula II in which Rb is a hydroxyl group and Ra represent the group -COSH, esterified.

20. A process for the preparation of compounds according to claim 1, in which Ra represents the group -COSH and Rb represents an esterified hydroxyl group, characterized in that a compound of formula II in which Rb represents the hydroxyl group and R "represents the group -COSH, esterified.

21. A process for the preparation of compounds according to claim 1, which carry a -COSH group in the 17β-position, characterized in that a compound of the formula II, which carries a carboxyl group in the 17ß-position, with a symmetrical or asymmetrical compound of the formula:

R7-W-R7 (III),

wherein W represents one of the groups -CO-, -CS-, -SO- or -SO2- and R7 has the meaning given in claim 17, to a compound of the formula II which bears a group -COR7 in the 17β-position, wherein R7 has the meaning given above, and the compound of formula II obtained can react with hydrogen sulfide or a sulfide or hydrogen sulfide thereof.

22. The method according to claim 21, characterized in that a compound of formula III, wherein W represents the group -CO-, -CS- or -SO-, is used.

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23. The method according to claim 22, characterized in that as the compound of formula III, the N, N'-carbonyldi (1,2,4-triazole), the N, N'-carbonyldibenzotriazole, the N, N'-carbonyldibenzimidazole , the N, N'-carbonyldi (3,5-dimethylpyrazole), the N, N'-thiocarbonyldiimidazole or the N, N'-thionyldiimidazole is used.

24. The method according to claim 22, characterized in that the N, N'-carbonyl diimidazole is used as the compound of formula III.

Certain androstane compounds which have a halo-alkyl carbothioate group in the 17β-position have particularly advantageous anti-inflammatory properties, as is explained in more detail in Swiss Patent No. 644,615.

The above-mentioned androstane compounds can be represented by the following formula I:

COSR1

--OR '

HO.

O

1

wherein R1 represents a fluorine, chlorine or bromomethyl group or a 2'-fluoroethyl group; R2 represents a group COR6, wherein R6 represents a C1-3 alkyl group, or OR2 and R3 together form a 16cc, 17oc-isopropylidenedioxy group; R3 represents a hydrogen atom, a methyl group (which may be in either the a or the β configuration) or a methylene group, R4 represents a hydrogen, chlorine or fluorine atom; R5 represents a hydrogen or fluorine atom and the symbol represents a single or double bond.

Compounds of formula I which are preferred for their good anti-inflammatory activity include the following categories, namely (a) those in which R1 is chloromethyl or fluoromethyl, (b) those in which R2 is acetyl or propionyl, preferably propionyl, (c) those in which R4 is fluorine, (d) those in which R5 is fluorine, (e) the 1,4-dienes and (f) those 1,4-dienes in which R4 is fluorine and RJ hydrogen, a- or β- Is methyl or methylene.

Compounds of formula I coupled with good anti-inflammatory activity coupled with minimal hypotha-lamus-pituitary-adrenaline suppressive activity in topical application include 1,4-dienes, wherein R1 is chloro or fluoromethyl, R4 and Rs are fluorine, and especially those in which R3 is a-methyl.

Particularly preferred compounds because of their good topical anti-inflammatory activity and the favorable ratio of topical anti-inflammatory activity to undesirable systemic activity include:

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S-chloromethyl-9a-fluoro-11β-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carbothioate; S-chloromethyl-9a-fluoro-11β-hydroxy-16-methylene-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carbothioate; S-fluoromethyl-6a, 9a-difluoro-11 β-hydroxy-16a, 17 a-isopro-pylidendioxy-3-oxoandrosta-1,4-diene-17ß-carbothioate; S-fluoromethyl-6a, 9a-difluoro-11β-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carbothioate; S-chloromethyl-6a, 9a-difluoro-11β-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carbothioate.

The latter connection is particularly preferred because of its particularly favorable ratio and additionally minimal skin atropy.

The compounds of formula I can be prepared by several different methods.

One such method involves the esterification of an androstane compound according to Formula I, but which contains either a free 17β-carbothioic acid group (or a functionally equivalent group) or a free 17a-hydroxy group (where R3 is a hydrogen atom or a methyl or methylene group), where any other reactive groups contained in the molecule are optionally suitably protected.

For example, a salt of starting 17β-carbothioic acid such as an alkali metal, e.g. Lithium, sodium or potassium salt or an alkylammonium e.g. Triethylammonium or tetrabutylammonium salt are reacted with a suitable alkylating agent, preferably in a polar solvent such as a ketone, e.g. Acetone, or an amide, such as dimethylformamide, dimethylacetamide or hexamethylphosphoramide, advantageously at a temperature of 15 to 100 ° C. The alkylating agent can comprise a suitable dihalogen compound, e.g. one containing another halogen atom (preferably a bromine or iodine atom) in addition to the halogen atom of the desired R 'group. This method is particularly applicable to the preparation of compounds in which R1 is a chloromethyl group, the alkylating agent advantageously being bromochloromethane.

Alternatively, the starting 16-hydrogen, methyl or methylene 17a-hydroxy-17β-carbothioates corresponding to the compounds of the formula I can be subjected to an esterification of the 17a-hydroxyl group. This can be done using conventional techniques, e.g. by reaction of the starting 17a-hydroxy compound with a mixed anhydride of the required carboxylic acid, which can be prepared, for example, in situ by reaction of the carboxylic acid with a suitable anhydride such as trifluoroacetic anhydride, preferably in the presence of an acid catalyst, e.g. p-toluenesulfonic acid or sulfosalicylic acid. Alternatively, the mixed anhydride can be generated in situ by reacting a symmetrical anhydride of the required acid with a suitable further acid e.g. Trifluoroacetic acid,

The reaction is advantageously carried out in an organic solvent medium such as benzene, methylene chloride or an excess of the carboxylic acid used, the reaction advantageously being carried out at a temperature of 20-100 ° C.

Alternatively, the 17a-hydroxy group can be esterified by reacting the starting 17a-hydroxy compound with the appropriate acid anhydride or acid chloride, optionally in the presence of non-hydroxylic solvents, e.g. Chloroform, methylene chloride or benzene and preferably in the presence of a strong acid catalyst e.g. Perchloric acid, p-toluenesulfonic acid or a strongly acidic cation exchange resin, e.g. Amberlite IR120,

the reaction is conveniently carried out at a temperature of 25 to 100 ° C.

The compounds of formula I can also be prepared by reacting a corresponding androstane compound containing a 17β-substituent of the formula -COS (CH2) nY (where Y is a replaceable substituent and n is 1 or 2) with a compound which serves to replace the group Y by a halogen atom.

Thus, the compounds of formula I can be subjected to a halogen exchange reaction which serves to replace the group Y, if it is halogen, with a different halogen substituent. Thus, the bromomethyl, fluoromethyl and fluoroethyl 17ß-carbothioate compounds can be prepared from the corresponding iodomethyl or bromoethyl-17ß-carbothioate compounds using a bromide such as lithium bromide, in the case of the bromomethyl-17ß-carbothioate compounds or a suitable fluoride, e.g. Silver monofluoride or silver-difluoride in the case of fluoromethyl or fluoroethyl-17ß-carbothioate compounds. The starting iodomethyl-17ß-car-bothioate compounds can be prepared from the corresponding chloromethyl-17ß-carbothioate compounds using, for example, an alkali metal, alkaline earth metal or quaternary ammonium iodide, e.g. Sodium iodide.

The reaction is preferably carried out in a solvent medium which contains, for example, acetone, acetonitrile, methyl ethyl ketone, dimethylformamide, dimethylacetamide or ethanol.

The above reactions can also be carried out on starting materials with different substituents or groupings which are subsequently converted into those substituents or groupings which are present in the compounds according to the invention as defined above.

The 1β-hydroxy compounds of formula I can thus be prepared by reducing a corresponding 11-oxo compound, e.g. using an alkali metal or alkaline earth metal borohydride, e.g. Sodium or calcium borohydride, suitably in an alcoholic or aqueous-alcoholic solvent such as methanol or ethanol.

Such an 11-keto compound can be prepared by oxidizing a corresponding 1 la hydroxysteroid, for example using a chromic acid reagent such as Jones' reagent.

A 1β-hydroxy compound of formula I can also be obtained by removing the protecting group of a corresponding compound having a protected hydroxyl group in the 11β position, for example a tri-C i -6-alkylsilyloxy group such as the trimethylsilyloxy group or a perfluoro or chloroalkanoyloxy group such as the tri-fluoroacetoxy group. The removal of the protecting group can be effected by hydrolysis, the trialkylsilyl group being conveniently removed by mild acidic or basic hydrolysis or particularly conveniently using fluoride, e.g. Hydrogen fluoride or an ammonium fluoride. The perfluoro or chloroalkanoyl protecting group can also be removed by mild acidic or basic hydrolysis or alcoholysis, but preferably under acidic conditions when R4 is a chlorine atom. Such a protected hydroxyl group can be introduced, for example, by reacting a 1β-hydroxy steroid with a suitable reagent such as a trialkylsilyl halide or a perfluoro or chloroalkanoic anhydride.

The compounds of formula I can also be prepared

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are by reacting a corresponding compound with a 9.11 double bond (and no substituent in the 11-position) with reagents which serve to introduce the required 9a-halogen-l 1 ß-hydroxy group. This can involve the initial formation of a bromohydrin by reaction with an N-bromamide or imide, such as N-bromosuccinimide, followed by the formation of the corresponding 9β, 11β-epoxide by treatment with a base and reaction of the epoxide with hydrogen fluoride or hydrogen chloride Introduction of the required fluorohydrin or. Chlorohydrin group. Alternatively, the 9,11-olefin compound can be reacted with an N-chloramide or imide to directly introduce the required 9a-chloro-11β-hydroxy group.

The A4 compounds can conveniently be prepared by partial reduction of the corresponding À1-4 compound, e.g. by hydrogenation using a palladium catalyst, conveniently in a solvent, e.g. Ethyl acetate or by homogeneous hydrogenation using e.g. tris (tri-phenylphosphine) rodium chloride, conveniently in a solvent such as benzene, or by exchange hydrogenation using e.g. cyclohexene in the presence of a palladium catalyst in a solvent e.g. Ethanol, preferably under reflux. This reduction can be carried out in a haloalkyl ester if it is sufficiently stable in such a reaction,

or can be accomplished at an earlier stage.

The abovementioned compounds which contain a free, -COSH group in the 17β-position can be prepared, for example, by aminolysis with rearrangement of a suitable 17ß-thiocarbamoyloxycarbonylandostane. The 17β-thiocarbamoyloxycarbonylandrostane is a mixed anhydride of the corresponding 17ß-carboxylic acid and a thiocarbamic acid and is conveniently prepared by reacting a 17ß-carboxylic acid 17a ester or 16a, 17cc acetonide with a thiocarbamoyl halide. The thiocarbamoyl group is N, N-disubstituted and can thus have the formula -COOCSNRARB, where RA and RB, which may be the same or different, are alkyl groups, e.g. Ci-4-alkyl groups, or RA and RB together with the nitrogen atom to which they are attached form a 5-8-membered ring which may optionally contain an additional heteroatom selected from oxygen, nitrogen and sulfur, and / or the optionally can be substituted by one or two Ci-3-alkyl, for example Methyl groups. RA and RB are preferably Ci-4-alkyl substituents, with the N, N-dimethylthiocarbamoyl group being preferred. The thiocarbamoyl halide is preferably the chloride. The reaction can be accelerated by adding an iodide salt, e.g. of sodium iodide.

The original androstane 17β-carboxylate salt can be, for example, an alkali metal, e.g. Sodium or potassium, alkaline earth metal, e.g. Calcium salt or a salt of a tertiary amine, e.g. Triethylamine.

Rearrangement aminolysis can be carried out, for example, by heating the mixed anhydride to an elevated temperature, e.g. in the presence of ammonia, a primary amine or particularly preferably a secondary amine such as dimethylamine or pyrrolidine. In the starting 17β-carboxylic acids, the 16 and 17cc positions are expediently substituted by the -R3 and -OR2 groups which are desired for the end product of the formula I.

17a-Hydroxyandrostane compounds in the 16-methylene series which carry the desired 17β-carbothioic acid group as described above can be prepared from the corresponding 16β-methyl-16a, 17a-epoxy-17ß-thio-

carboxylic acid, by causing rearrangement using a strong acid, e.g. a strong carboxylic acid such as trifluoroacetic acid. These 16a, 17a epoxides can be prepared from the corresponding 17β-carboxylic acids by treating with an onium salt of a 2-halogen aza-aromatic compound, followed by treating the resulting product with hydrogen sulfide or a salt thereof to form the free 17ß -Carbothioic acid, which can be alkylated as described above, preferably in situ, to form the desired 17β-carbothioate group.

16a, 17a-isopropylidenedioxy compounds of formula I can be prepared in the same manner by treating a corresponding 17β-carboxylic acid with an onium salt of a 2-halogen-aza-aromatic compound, followed by treating the resulting product with hydrogen sulfide to form the free 17β-carbothio- acid, which can then be esterified as described above.

Onium salts of the 2-halo-aza-aromatic compounds are suitable for causing carboxy activation. Such reagents include 2-halo-N-alkyl or 2-halo-N-phenylpyridium or pyrimidini salts bearing 1 to 2 other substituents selected from phenyl and lower (e.g. C1-4) alkyl groups such as methyl. The 2-halogen atoms can be fluorine, chlorine, bromine or iodine atoms. The salts are preferably sulfonates, e.g. Tosylates; Halides, e.g. Iodides; Fluoroborates or perfluoroalkyl sulfonates, a suitable salt being the 2-fluoro-N-methylpyridinium tosylate or the 2-chloro-N-methylbenzothiazolium trifluoromethanesulfonate.

The 16a, 17a-epoxy-16β-methyl-17ß-carboxylic acid compounds which can be used as starting materials in the above process can be prepared in a conventional manner, e.g. as described in GB 1,517,278.

The starting products used in these processes are new and form the subject of the present invention; they correspond to the general formula:

I.

I.

wherein the symbols Ra, Rb, Rc, Rd, Re and Rf have the meanings given in claim 1, with the exception of the compounds of the formula I as defined above.

If Rd represents a protected hydroxyl group, this can be, for example, a trialkylsilyloxy group or a perfluoro or perchloroalkanoyloxy group as defined above.

17a-Hydroxy-17ß-carbothioic acids of Formula II and the salts thereof can be converted to the 17a-hydroxy-17ß-carbothioates of Formula II, wherein Ra represents the group COSR1 as defined in Formula I, or

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into the 17β-carbothioic acid 17a ester of formula II, by the method described above for the preparation of the compounds of formula I. The esterification of the 17a-hydroxy group is preferably effected with the corresponding carboxylic acid chloride in a solvent, such as a halogenated hydrocarbon, e.g. Methylene chloride, and advantageously in the presence of a base such as triethylamine, preferably at a low temperature, e.g. 0 ° C.

The 17a-hydroxy-17β-carbothioacids of the formula II and the salts thereof are particularly useful intermediates for the preparation of the androstane-17ß-carbothioates of the formula I; those in which Rc represents a hydrogen atom, an a- or β-methyl group or a methylene group, Re represents a hydrogen, chlorine or fluorine atom, Rd represents a hydroxyl group in the β configuration or an oxo group are preferred. More preferred compounds and salts thereof include those compounds wherein Rc represents a methyl group in the a or β configuration or a methylene group; Re represents a fluorine atom, Rd represents a hydroxyl group in the β configuration or an oxo group and the symbol in the 1,2 position represents a carbon atom.

lenstoff-carbon double bond means.

Particularly preferred compounds of the formula II include, for example, the following:

9o.-fluoro-11ß, 17ct-dihydroxy-16ß-methyl-3-oxo-androsta-1,4-diene-17ß-carbothioic acid;

9a-fluoro-11β, 17a-dihydroxy-16a-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid;

9a-fluoro-11β, 17 a-dihydroxy-16-methylene-3-oxo-androsta-1,4-diene-l 7ß-carbothioic acid;

6ct, 9a-difluoro-11β, 17a-dihydroxy-l 6a-methyl-3-oxo-

androsta-1,4-diene-17ß-carbothioic acid;

and the corresponding 11-ketones and salts thereof.

An advantage of the above intermediates is that they allow direct haloalkylation to form haloalkyl-17β-carbothioates when the corresponding R1 SH SH thiols are not available. The salts of these 17a-hydroxy-17β-carbothioic acids can, for example, alkali metal, e.g. Lithium, sodium or potassium salts; Alkaline earth metal, e.g. Calcium or magnesium salts; tertiary amine salts, e.g. Pyridinium or triethylammonium salts; or quaternary ammonium salts, e.g. Be tetra-butylammonium salts.

The 17a-hydroxy-17ß-carbothioic acids can be prepared, for example, by reacting a reactive derivative of a corresponding 17a-hydroxy-17ß-carboxylic acid with hydrogen sulfide or a sulfide or hydrogen sulfide thereof. In general, the cation of the sulfide or hydrosulfide can be, for example, an alkali metal salt such as sodium or potassium hydrogen sulfide. The reactive derivatives mentioned above correspond to compounds of the formula II in which Rb is a hydroxyl group and the group -COR7 is in the 17β-position, in which R7 represents a group of the formula in which X, Y and Z, which may be the same or different, each represents CH or N, one or two of X, Y and ZN, the heterocyclic ring optionally substituted on at least one carbon atom by a lower alkyl group (for example having 1 to 4 carbon atoms, such as a methyl group) and / or in which the heterocyclic ring is two contains adjacent carbon atoms, the ring optionally carrying a benzene ring fused to these two adjacent carbon atoms.

The reactive derivatives corresponding to the formula II mentioned above are preferably prepared by reacting corresponding 17a-hydroxy-17β-carboxylic acids of the formula II with a symmetrical or asymmetrical compound of the formula:

R7-W-R7 (III)

wherein W represents the groups CO, CS, SO or SO2 and the groups R7, which may be the same or different, have the above meanings.

The compounds of formula III are expediently symmetrical. In general, compounds of the formula III are used in which W has the meaning of CO, CS or SO. For example, particularly useful compounds include N, N'-carbonyldi (1,2,4-triazole), N, N'-carbonyldibenzotriazole, N, N'-carbonyldibenzimidazole, N, N'-carbonyldi (3.5 -dimethylpyrazole), N, N'-thionyldiimidazole and in particular N, N'-carbonyldiimidazole and N, N'-thiocarbonyldiimidazole.

The preparation of a 17a-hydroxy-17β-carbothioic acid with the formula II as defined above is conveniently effected by reacting a 17a-hydroxy-17ß-carboxylic acid with a compound of the formula III, followed by the reaction of the intermediate with the 17ß-COR7 group with hydrogen sulfide or a salt thereof, preferably in situ, without isolating the intermediate.

The 17cc-acyloxy-17ß-carbothioic acid of the formula II can be obtained in the same way directly from the corresponding 17a-acyloxy-17ß-carboxylic acid by reaction with a compound of the formula III. The 17a-acryloxy-17ß-carboxylic acids can be prepared by esterifying the corresponding 17a-hydroxy-17ß-carboxylic acids according to the methods described in GB Patent 1,384,372.

The reaction with the compound of formula III is conveniently carried out in the presence of an inert anhydrous solvent, e.g. a substituted amide solvent such as N, N-dimethylformamide or N, N-dime-thylacetamide, advantageously in the absence of water, advantageously at or below room temperature, e.g. at a temperature of -30 ° C to + 30 ° C. The reaction is conveniently effected under approximately neutral conditions, advantageously in an inert atmosphere, e.g. under nitrogen. The same solvents and conditions can also be applied to the subsequent reaction with H2S or a salt thereof. The heterocyclic compound, e.g. Imidazole or 1,2,4-triazole, which is formed as a by-product, can be easily removed, for example, by extraction with water.

The above reactions can also be carried out on compounds which have various substituents or groupings which are subsequently converted into compounds of the formula I as described above.

The andro-stan-17ß-carboxylic acid starting materials used in the above process can be prepared in a conventional manner, e.g. by oxidation of a corresponding 21-hydroxy-20-ketopregnane, for example with periodic acid, in a solvent medium and preferably at room temperature. Alternatively, sodium bismuthate can be used to effect the desired oxidative removal of the 21 carbon atom of a 17a acyloxypregnan compound. It can be seen that if the output pregnan connection

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Liehe should contain substituents that are sensitive to the oxidation desired above, such groups should be appropriately protected.

The following examples serve to illustrate the invention. Melting points were determined in ° C on a Kofler block and are not corrected. Optical rotations were determined at room temperature in solutions in dioxane.

Thin layer chromatography (T.l.c.), preparative layer chromatography (p.l.c.) and high-performance liquid chromatography (h.p.l.c.) were carried out over silicon dioxide.

Solutions were dried over magnesium sulfate unless otherwise stated.

a) Production of the starting products

Manufacturing V

11β-hydroxy-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carboxylic acid (V)

A solution of 13.5 g of 1 lß, 17a-dihydroxy-3-oxoan-drosta-l, 4-diene-17ß-carboxylic acid and 18 ml of triethylamine in 500 ml of methylene chloride was cooled to 4 ° C and then in portions over 15 min with 14 , 2 ml of propionyl chloride treated. It was further stirred at 4 ° C for a total of 1 h and the mixture was washed successively with 3% sodium hydrogen carbonate, water, 2N hydrochloric acid, water and saturated saline, then dried and evaporated under reduced pressure. The residue was dissolved in 300 ml of acetone and 14.3 ml of diethylamine was added with stirring. After 1 h at 20 ° C the solvent was removed under reduced pressure and the residue was dissolved in 150 ml of water. After acidifying to pH; with 2N hydrochloric acid, the product was extracted with ethyl acetate. The combined extracts were washed with water and saturated saline, dried and concentrated to a small volume. The solid product was collected by filtration, washed with ethyl acetate and dried in vacuo at 50 ° to give 13.309 g of the title 17a-propionate carboxylic acid in the form of crystals [a] d + 2 ° (c 1.10). A 389 mg portion was recrystallized twice from methanol to give a 256 mg analytical sample of mp 244-245 ° (dec.).

[a] d + 3 ° (c 0.83).

Production VI

6a, 9a-difluoro-11β-hydroxy-16a-methyl-3-oxo-17a-pro-pionyloxy-androsta-1,4-diene-17ß-carboxylic acid (VI)

A solution of 2.113 g of 6a, 9a-difluoro-11β, 17a-dihydroxy-16a-methyl-3-oxoandrosta-l, 4-diene-17ß-carboxylic acid and 2.5 ml of triethylamine in 60 ml of methylene chloride was stirred and treated at about 0 ° C with 1.85 ml propionyl chloride. After 1 h, the mixture was diluted with 50 ml of further solvent and washed successively with 3% sodium hydrogen carbonate, water, 2N hydrochloric acid, water, saturated saline, then dried and evaporated to a leather-colored solid. This was dissolved in 50 ml of acetone and 2.5 ml of dimethylamine were added. After 1 h at 22 ° C the solvent was removed in vacuo and the remaining gummy product was dissolved in 30 ml of water. Acidification to pH 1 with 2N hydrochloric acid precipitated a solid which was collected, washed with water and dried to give 2.230 g of the title carboxylic acid 17a-propionate, mp 220-225 °

[a] d + 4 ° (c 0.70).

Manufacturing X

6a-fluoro-11β, 17a-dihydroxy-3-oxoandrosta-1,4-diene-17ß-carboxylic acid (X)

A solution of 4,987 g of 6a-fluoro-prednisolone in 50 ml of tetrahydrofuran was stirred at 22 ° with a solution of 10.0 g of periodic acid in 24 ml of water. After 50 min the tetrahydrofuran was evaporated and the aqueous suspension was filtered. The solid product was washed with 300 ml of water and dried to give 4.80 g of a white solid. A 271 mg portion was crystallized from methanol to give 171 mg of the title acid of white needles, mp 241-248 °

[a] d + 54 ° (c 0.825).

Manufacturing XI

6a-fluoro-11β-hydroxy-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carboxylic acid (XI)

A solution of 4.491 g of X and 4.46 ml of triethylamine in 160 ml of dry methylene chloride at -5 ° was stirred and added dropwise with 2.80 ml (2.96 g) of propionyl chloride in about 5 ml of dry methylene chloride for 5 minutes at below 0 ° treated. After a further 20 min at 0 °, the reaction mixture was diluted with 160 ml of methylene chloride, washed with sodium bicarbonate solution and water, dried and evaporated to 5.701 g of a white solid. This was stirred with 4.60 ml (3.24 g) diethylamine in 30 ml acetone to give a clear yellow solution. After 30 minutes the solution was concentrated, 150 ml of water was added and the resulting solution was washed with twice 30 ml of ethyl acetate. The aqueous phase. was acidified to pH 2 using 50 ml of 2N hydrochloric acid with stirring and the product was extracted three times with ethyl acetate. The extracts were combined, washed with 50 ml of water, dried and evaporated to give 5.891 g of a white foam. A portion of 304 mg of the foam was crystallized from ethyl acetate to give 144 mg of the title 17a propionate in the form of small plates, mp 224-227 °

[a] d + 3 ° (c 0.861).

Manufacturing XLIII

9a-fluoro-17a-hydroxy-16ß-methyl-3,11 -dioxoandrosta-l, 4-diene-17ß-carboxylic acid (XLIII)

A stirred suspension of 4.842 g of 9a-fluoro-17,21-dihydroxy-16β-methylpregna-l, 4-diene-3, l 1,20-trione in 50 ml of tetrahydrofuran was cooled in ice and added dropwise over 5 minutes with a solution of 4.255 g of periodic acid in 15 ml of water. The reaction was stirred at 22 ° for 2.25 h, with most of the suspension having dissolved. The solvent was removed in vacuo with periodic addition of water to maintain the original volume. The resulting precipitate was filtered off, washed with water and dried in air and in vacuo to give 4.55 g of the title carboxylic acid as cream-colored prisms of mp 270-272 ° (dec.)

[a] d + 136 ° (c 1.04, dimethyl sulfoxide).

Manufacturing LII

9a-fluoro-11ß, 17a-dihydroxy-3-oxoandrosta-1,4-diene-17ß-carboxylic acid (LH)

A suspension of 10 g of 9a-fluoroprednisolone in 55 ml of dry tetrahydrofuran was stirred and treated with a solution of 9.0 g of periodic acid in 90 ml of water, and the mixture was stirred at 22 ° C. for 2 hours. It was then poured into about 400 ml of iced water, and after stirring for 15 min, the solid product was collected, washed with water and dried to give s

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55

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651 307

8th

9.42 g of the title compound as a solid. A portion thereof, recrystallized from ethanol, had an mp of 289-293 ° to [a] d + 66 ° (c 0.73, methanol).

b) Examples according to the invention

Manufacturing I

9a-fluoro-11β-hydroxy-16ß-methyl-3-oxo-17a-propionyl-oxyandrosta-l, 4-diene-17ß-carbothioic acid (I)

A solution of 5.00 g of 9a-fluoro-11β-hydroxy-16ß-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carbonic acid, solvated with ethyl acetate (172 mol) and 5. 3 ml of triethylamine in 75 ml of methylene chloride was stirred under nitrogen and treated with 5.071 g of dimethylthiocarbamoylchloride. After 24 hours, another 5.320 g of reagent was added. After 47 hours the mixture was diluted with ethyl acetate and washed with n-hydrochloric acid, 5% sodium bicarbonate solution and water, dried and evaporated to give 9.043 g of a viscous yellow oil. This was dissolved in 50 ml of ethylamine, then stirred and stirred under reflux under nitrogen for 5.75 h. The resulting brown solution was added to a mixture of 50 ml of concentrated hydrochloric acid, 250 ml of water and 50 ml of ethyl acetate. The products were further extracted with ethyl acetate, then the acidic products were back extracted in 5% sodium carbonate solution. The aqueous phase was acidified with 50 ml of 6N hydrochloric acid and extracted with ethyl acetate. The extracts were washed with n-hydrochloric acid and water, dried and evaporated to 3.440 g of a leather-colored solid. This was recrystallized from acetone to give 1.980 g of pale leather-colored crystals of the title 17β-carbothioic acid, mp 172-173 °.

After two recrystallizations from acetone, the analytical sample was obtained as white crystals of mp 177-179 ° [a] D + 110 ° (c 1.05).

Production II

S-chloromethyl-9a-fluoro-16ß-methyl-3,11 -dioxo-17a-pro-pionyloxyandrosta-1,4-diene-17ß-carbothioate (II)

1.5 ml of 8n Jones reagent was added dropwise over 10 minutes to a stirred solution of 998 mg of the compound of Example 1 (described below) in 2 ml of acetone and 2 ml of dimethylformamide. After 30 minutes, the reaction mixture was slowly diluted with 100 ml of water with stirring and the resulting suspension was cooled for 1 hour. The precipitate was collected by filtration, washed with water and dried to give 877 mg of an off-white solid. P.l.c. in chloroform-acetone (10: 1) gave 755 g of a white foam which was crystallized twice from acetone to give 523 mg of white needles of the title 11-ketone, mp 204-205 ° [a] d + 94 ° ( c 1.04).

Production III

17β-N, N-dimethylthiocarbamoyloxycarbonyl-9a-fluoro-11β-hydroxy-16a-methyl-17a-propionyloxyandrosta-1,4-dien-3-one (III)

A solution of 0.434 g of 9a-fluoro-11β-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-l, 4-diene-17ß-carbonic acid in 8 ml of methylene chloride was treated successively with 0.14 ml of triethylamine, 0.248 g of dimethylthiocarbamoyl chloride and 0.149 g of sodium iodide were treated and the mixture was stirred under nitrogen at 20 ° C for 6 h. 30 ml of ethyl acetate was added and the total volume was reduced to half in vacuo. A further 50 ml of ethyl acetate was added, and the solution was washed with water, 2N hydrochloric acid, water, 3% sodium hydrogen carbonate, water and saturated sodium chloride solution and then dried. The solution was concentrated in vacuo when the product crystallized (0.329 g). This was recrystallized from acetone (twice) to form the title anhydride in the form of white needles, mp. 191-193 °

[a] d + 82 ° (c0.57).

Manufacturing IV

9a-fluoro-11β-hydroxy-16a-methyl-3-oxo-17a-propionyl-oxyandrosta-1,4-diene-17ß-carbothioic acid (IV)

A stirred suspension of 2.467 g III in 25 ml diethylamine was heated under reflux under nitrogen. After 2.5 h the reaction was poured into 300 ml of iced 3N hydrochloric acid and the mixture was extracted with ethyl acetate. The combined extracts were washed with water and extracted with 5% sodium carbonate solution. The combined aqueous extracts were washed with ethyl acetate, then covered with ethyl acetate and acidified to pH 1 with hydrochloric acid. The aqueous phase was extracted with further ethyl acetate, and the combined extracts were washed with water, saturated sodium chloride solution, dried and the solvent was removed in vacuo. The residue was crystallized twice from acetone to give 1.309 g of the title carbothioic acid in the form of white needles, mp 141-143 °

[a] D + 30 ° (c0.51).

Production VII

17ß-N, N-dimethylthiocarbamoyloxycarbonyl-9a-fluoro-11 ß-hydroxy-16a, 17 a-isopropy lidendioxy andrò sta-1,4-dien -3-one (VII)

A solution of 1,000 g of 9a-fluoro-l 1β-hydroxy-16a, 17a-iso-propylidendioxy-3-oxoandrosta-1,4-diene-17ß-carboxylic acid in 15 ml of methylene chloride and 0.33 ml of triethylamine was reacted with 588 under nitrogen mg of N, N-dimethylthiocarbamoyl chloride was treated and the mixture was stirred at room temperature. After 68 hours the mixture was diluted with 50 ml of ethyl acetate and washed with 2.10 ml of n-hydrochloric acid, 5% sodium hydrogen carbonate solution and water, dried and evaporated to give 1.123 g of a pale yellow crystalline solid. P.l.c. A portion of 200 mg in chloroform-acetone (9: 1) gave an almost white solid of 161 mg, which crystallized from ethyl acetate in the form of 131 mg of white needles of the title mixed anhydride, mp. 279-281 °

[a] d + 174 ° (c 0.61, dimethyl sulfoxide).

Production VIII

17ß-N, N-dimethylthiocarbamoyloxycarbonyl-6a, 9a-difluoro-11 ß-hydroxy-16a, 17 a-isopropylidendioxyandrosta-l, 4-dien-3-one (VIII)

A solution of 4.354 g of 6a, 9a-difluoro-1 1 ß-hydroxy-16a, 17a-isopropylidendioxy-3-oxoandrosta-1,4-diene-17ß-carboxylic acid in 150 ml of methylene chloride, containing 1.4 ml of triethylamine, was treated with 2.519 g of N, N-dimethylthiocarbamoyl chloride and the reaction was stirred under nitrogen at 22 ° for 80 min. 500 ml of ethyl acetate was added, and the resulting solution was washed successively with 2N hydrochloric acid, water, sodium hydrogen carbonate solution, water and saturated sodium chloride solution and dried, and the solution was concentrated. Crystallization occurred on cooling and the solid was filtered and dried in vacuo to give 3.562 g of the title anhydride as pale yellow prisms, mp 283-287 ° (dec.)

[a] d + 156 ° (c 0.84, dimethyl sulfoxide).

s

10th

IS

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35

40

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50

55

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651 307

Production IX

6a, 9a-difluoro-11β-hydroxy-16a, 17a-isopropylidenedioxy-3-oxoandrosta-1,4-diene-17ß-carbothioic acid (IX)

A suspension of 3.455 g VIII in 200 ml diethylamine was heated under reflux under nitrogen for 6 hours. The original suspension dissolved quickly, but a brown suspension formed after 30 minutes and remained unchanged. The cooled reaction mixture was poured into 1.01 water, acidified to pH 1 with 210 ml concentrated hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water and extracted with 5% sodium carbonate solution and water, and the aqueous extracts were combined. The combined extracts were acidified with 6N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with water and saturated sodium chloride solution, then dried and the solvent was removed in vacuo to give 2.31 g of a pale gray solid.

A portion of the product, 0.408 g, was crystallized from ethyl acetate to give 0.149 g of the title carbothioic acid, mp 191-199 °

[a] d + 124 ° (c 1.04, dimethyl sulfoxide).

Preparations XII - XXIII

Following the general procedure as described in Preparation I, but using the starting material from the 17β-carboxylic acid corresponding to the desired 17β-carbothioate, the following compounds were prepared (process details are given in Table I below):

XII. 17 <x-acetoxy-9a-fluoro-1 1β-hydroxy-16ß-methyl-3-oxoandrosta-l, 4-diene-17ß-carbothioic acid, mp 178.5-179 °, [a] d + 98 ° (c 1.02).

XIII. 17a-butyryloxy-9a-fluoro-l 1ß-hydroxy-16ß-methyl-3-oxoandrosta-l, 4-diene-17ß-carbothioic acid, mp 175-176 °, [a] D + 107 ° (c 0, 96).

XIV. 9a-fluoro-l 1β-hydroxy-17a-isobutyryloxy-16ß-methyl-3-oxoandrosta-l, 4-diene-17ß-carbothioic acid of mp 177-179, [<x] d + 1 19 ° ( c 0.90).

XV. 11β-Hydroxy-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-carbothioic acid, mp 134-138 °, [a] d + 67 °

(c 0.66).

XVI. 11β-Hydroxy-16ß-methyl-3-oxo-17a-propionyloxy-androsta-l, 4-diene-17ß-carbothioic acid, mp 159-163 °, [<X] d + 113 ° (C0.78).

XVII. 9cc-chloro-lß-hydroxy-16ß-methyl-3-oxo-17a-pro-pionyloxyandrosta-l, 4-diene-17ß-carbothioic acid, mp 167-171, [a] D + 128 ° (cO, 99 ).

XVIII. 9a-fluoro-lß-hydroxy-16a-methyl-3-oxo-17a-propionyIoxyandrosta-l, 4-diene-17ß-carbothioic acid, mp 141-143 °, [<x] d + 30 ° (c 0, 51).

XIX. 6a, 9a-difluoro-l 1 ß-hydroxy-16a-methyl 1-3-oxo-17a-propionyloxyandrosta-l, 4-diene-17ß-carbothioic acid, mp 136-139 °, [a] d-30 ° ( c0.56).

XX. 9a-fluoro-11β-hydroxy-16-methylene-3-oxo-17a-pro-pionyloxyandrosta-l, 4-diene-17ß-carbothioic acid, mp 236-239 °, [a] d -7 l ° (c 0.99).

XXI. 1 lß-Hydroxy-3-oxo-17a-propionyloxyandrosta-4-en-17ß-carbothioic acid, mp 176-177 °, [a] d +101 °

(c 0.96).

XXII. 9a-fluoro-l 1 ß-hydroxy-16a, 17a-isopropylidene-dioxy-3-oxoandrosta-l, 4-diene-17ß-carbothioic acid of mp 274-304 ° (dee.), [A] d +121 ° ( c 0.51, dimethyl sulfoxide).

XXIII. 6a-Fluoro-11ß-hydroxy-3-oxo-17a-propionyloxy-androsta-l, 4-diene-17ß-carbothioic acid, mp 189-193 °, [a] d + 72 ° (c 0.74).

Table I

Formation of the mixed anhydrides

Manufacturing

17ß-carbon

Cl-CSNMei

NEtJ

Solution

Reaction

acid-

(G)

(ml)

medium time (days)

Insert (g)

(CHiCh) (ml)

at

Room temperature

XII

5,000

2,940

1.66

75

5Ia

XIII

15,354

8,809

4.8

250

6

XIV

4,182

2,399

1.3

80

4th

XV

7,148

4.40

2.6

150

6ib

XVI

6,137

3.77

2.05

140

6lc

XVII

5,973

3,350

1.34

100

7

XVIII

4,207

2.39

1.35

80

0.677'ld

XIX

2,130

1.80

0.66

50

64

XX

5,000

2,507

1.41

75

3rd

XXI

1,000

2,442

1.22

15

2.7

XXII

1,000

0.588

0.33

15

2.88

XXIII

6,000

3.55

2.0

120

1.2510

Table 1 (continued)

Treatment of mixed anhydride intermediates with diethylamine

Manufacturing

NHEtz (ml)

Response time (h) under reflux

Product (g)

Crystallization solvent

XII

50

5.5

2,104

EA2a

XIII

250

4th

5,244

EA3

XIV

60

4.5

1.00

EA

XV

60

4th

3.29

EA

XVI

50

3.5

1,382

EA

XVII

60

5.7

0.527

EA

XVIII

25th

4.75

1,309

A

XIX

12

6

0.418

EA

XX

50

3.75

1,296

EA2b

XXI

15

4th

0.3976

. A5

XXII

(a) 8

(a) 3

0.4649

A

(b) 16

(b) 2.5

XXIII

60

4.5

2.88

EA-P

EA = ethyl acetate. A = acetone. P = petroleum ether Kp 60 - 80 °.

Remarks:

1. Portions (a) 500 mg, (b) 670 mg, (c) 424 mg, (d) 171 mg of the intermediate dimethylthiocarbamic anhydride were removed for characterization.

2. The characterization was carried out on a sample which was recrystallized twice from ethyl acetate. Yields (a) 84%, (b) 69%.

3. The product was solvated with ethyl acetate (about 0.2 mol).

4. The intermediate dimethylthiocarbamic anhydride (1.435 g) crystallized from ethyl acetate. A portion of 95 mg removed for characterization.

5. The characterization was carried out on a sample, recrystallized twice from acetone (yield 73%).

6. The product crystallized from ethyl acetate.

7. 1.46 g of sodium iodide was also present in the reaction.

8. The intermediate dimethylthiocarbamic anhydride (1.123 g) crystallized from ethyl acetate. A 200 mg portion was chromatographed (p.l.c., chloroform-acetone, 9: 1) and recrystallized from ethyl acetate (yield 65%).

9. The reaction was carried out on 781 mg of anhydride.

10. 2.13g sodium iodide was also present in the reaction.

Manufacturing XXIV

9a-chloro-11β-hydroxy-16ß-methyl-3-oxo Î7 a-propionyl-oxyandrosta-1,4-diene-17ß-carbothioic acid and

9ß, 11 ß-epoxy-16ß-methyl-3-oxo-17a-propionyloxyan-drosta-1,4-diene-17ß-carbothioic acid (XXIV)

A suspension of 5.586 g 17ß-N, N-dimethyIthiocarba-

5

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15

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25th

30th

35

40

45

50

55

60

65

651307

10th

moyloxycarbonyï-9a-chloro-11β-hydroxy-16ß-methyl-17a-propionyloxyandrosta-l, 4-dien-3-one in 16 ml of diethylamine was kept under reflux under nitrogen for 5 h 40 min. The reaction was poured into 450 ml of water, acidified to pH 10 with concentrated hydrochloric acid and extracted with three times 60 ml of ethyl acetate. The combined extracts were washed with water and then extracted four times with 50 ml of aqueous sodium carbonate solution. The aqueous extracts were acidified to pH 1 with 6N hydrochloric acid and extracted three times with 50 ml of ethyl acetate. The combined extracts were washed with water and saturated sodium chloride solution and dried, and the solvent was removed in vacuo to give 2.834 g of a colorless foam.

Two crystallizations of the mixture from ethyl acetate gave 0.527 g of 9a-chloro-l 1β-hydroxy-16ß-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carbothioic acid in the form of white prisms, mp. 167- 171 °

[a] d + 128 ° (c 0.99).

The mother liquors from the crystallizations contained a further amount of the above 9a-chloro-1β-hydroxycarbothioic acid together with 9β, 11β-epoxy-16β-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-1 7ß- carbothioic acid.

Manufacturing XXV

S-J odmethyl-9a-fluorine-11β-hydroxy-16ß-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carbothioate (XXV)

A solution of 500 mg of the compound of Example 1 (described below) and 1.874 g of sodium iodide in 15 ml of acetone was stirred and heated under reflux for 6.5 h. 75 ml of ethyl acetate was then added and the solution was washed successively with water, 10% sodium thiosulfate solution, 5% sodium hydrogen carbonate solution and water, dried and evaporated to give 525 mg of an almost white foam. P.l.c. in chloroform-acetone (6: 1) gave 478 mg of an almost white foam, which was crystallized twice from acetone, without heating above room temperature, to give 241 mg of colorless crystals of the title S-iodomethyl ester, mp 196-197 °, [a] d -32 ° (c 1.01).

Manufacturing XXVI-XXXVII

Following the same general procedure as in the

Preparation XXV described, but using S-chloromethyl-17ß-carbothioate corresponding to the desired product as the starting material (the process details are listed in Table II below), the following compounds were prepared:

XXVI. S-iodomethyl-17a-acetoxy-9a-fluoro-lß-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carbothioate, mp.

io 204-205 °, [a] d -29 ° (c 0.98).

XXVII. S-iodomethyl-1ß-hydroxy-3-oxo-17a-propionyI-oxyandrosta-l, 4-diene-17ß-carbothioate, [a] d + 26 ° (c0.47).

XXVIII. S-iodomethyl-1ß-hydroxy-16ß-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carbothioate,

15 [a] d + 5 ° (c0.47).

XXIX. S-iodomethyl-9a-chloro-11ß-hydroxy-16ß-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-l 7ß-carbothioate, [a] d + 7 ° (c0.36).

XXX. S-iodomethyl-9a-fluoro-lß-hydroxy-16a-methyl-3-

20 oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carbothioate,

[a] D + 85 ° (cO, 55).

XXXI. S-iodomethyl-6a, 9a-difluoro-11β-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-car-bothioate.

25 XXXII. S-iodomethyl-9a-fluoro-11β-hydroxy-16-methylene-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carbothioate, mp. 191 -199 °, [a] d -31 ° ( c 0.99).

XXXIII. S-iodomethyl-9a-fluoro-lß-hydroxy-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carbothioate, m.p.

so 175-178 °, [a] D + 4 ° (c 0.50).

XXXIV. S-iodomethyl-6a-fluoro-lß-hydroxy-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carbothioate, mp 195-197 °, [a] o + 18 ° (co, 64) .

XXXV. S-iodomethyl-17a-acetoxy-6a, 9a-difluoro-11 ß-

35 hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17ß-carbo-

thioate, mp 241-243 °, [a] d + 78 ° (c0.78).

XXXVI. S-iodomethyl-17a-butyryloxy-6a, 9a-difluoro-l lß-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17ß-carbothioate, mp. 210-212 °, [a] d + 89 ° (c 0.90).

40 XXXVII. S-iodomethyl-9a-fluoro-11ß-hydroxy-16a, 17a-isopropylidenedioxy-3-oxoandrosta-l, 4-diene-17ß-carbothioate, mp. 261-270 ° (dec.),

[a] d + 97 ° (c0.48, dimethyl sulfoxide).

Table II

Halogen exchange on S-haloalkyl-17a-acyloxyandrostane-17ß-carbothioates

Manufacturing No.

Nal

Parent steroid

Solution

Response time (h)

PLC

Crystallization

product

(mg)

Halogen insert medium and reflux

(Silicon dioxide)

solvent

(mg)

(mg)

(ml)

CHCb-MeaCO

XXVI

6632

Cl1715

20th

"3.5

-

EA

2161

XXVII

3800

Cl 925

10th

4th

-

-

1084

XXXVIII

3260

Cl 840

10th

3rd

-

-

969

XXIX

1995

Cl 536

20th

6.5

-

-

591

XXX

2160

Cl 580

10th

3rd

-

-

685

XXXI

1200

Cl 303

30th

5

-

-

3173

XXXII

7361

Cl1953

23

6

19: 1

A

2962

XXXIII

5500

Cl1300

35

4th

-

M

12506

XXXIV

8400

Cl 2000

54

4.5

-

EA-P

1800

XXXV

19000

Cl4750

200

5

-

EA

46205

XXXVI

6500

Cl1620

70

5.5

-

EA

16104

XXXVII

5491

Cl 1419

20th

24th

9: 1

A

2247

EA = ethyl acetate; A = acetone; M = methanol; P = petroleum ether bp 60-80 °.

Remarks:

1. Obtained from a portion of 300 mg of the crude product (2.024 g)

2. Obtained from a portion of 400 mg of the crude product (2.058 g).

3. The product was used directly to prepare the corresponding fluoromethyl-17β-carbothioate.

4. Solvated with 0.5 h2o.

5. Solvated with 0.1 EA.

6. Solvated with 0.2 EA + 0.5 HiO.

7. Obtained from a portion of 300 mg of the crude crystalline product (1.611 j

11

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Production XXXVIII

S-J odmethyl-6a, 9a-difluoro-11β-hydroxy-16a, 17a-isopro-pylidendioxy-3-oxoandrosta-1,4-diene-17ß-carbothioate

(XXXVIII)

A solution of 0.795 g of the compound of Example 4 described below in 50 ml of acetone was heated under reflux with 2.969 g of sodium iodide for 5.5 hours. 75 ml of ethyl acetate was added and the solution was washed successively with water, sodium metabisulfite solution, then dried and the solvent was removed in vacuo to give 0.893 g of an almost white solid. A portion of 0.205 g thereof was crystallized twice from ethyl acetate to give 0.105 g of the title S-iodomethylthioester in the form of white prisms, mp. 260-262 ° (dec.)

[a] d + 81 ° (c 0.6, dimethyl sulfoxide).

Manufacture XXXIX

S-2 '-Bromethyl-9a-fluoro-11β-hydroxy-16ß-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carbothioate

(XXXIX)

0.5 g of I was treated as for the S-chloromethyl ester (Example 1, Method A as described below), but using 1,2-dibromoethane to form 0.409 g of colorless crystals of the title S-2'-bromoethyl ester m.p. 174-145 °

[a] d + 120 ° (c 1.04).

Manufacturing XL

16a, 17a-epoxy-9a-fluoro-11β-hydroxy-16ß-methyl-3-oxoandrosta-l, 4-diene-17ß-carbothioic acid (XL)

A mixture of 377 mg of 16a, 17a-epoxy-9a-fluoro-1ß-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylic acid and 340 mg of 2-fluoro-1-methylpyridinium tosylate in 7 ml of dry methylene chloride was stirred, cooled in ice and treated with 0.42 ml of triethylamine for 1 min. After 1 hour, hydrogen sulfide was bubbled through the mixture for 30 minutes to form a yellow solution. T.l.c. (Chloroform-acetone-acetic acid, 30: 8: 1) showed that a less polar major product had formed. After warming to room temperature for 1 h, the mixture was treated with 30 ml of 2N hydrochloric acid and the product was extracted with ethyl acetate (3 times 20 ml). The acidic product was extracted from the organic phase with 5% sodium carbonate, the aqueous extracts were combined, acidified with 6N hydrochloric acid and then extracted with ethyl acetate. The combined acidic extracts were washed with water, dried, concentrated under reduced pressure to form after filtering 274 mg of almost white crystals, probably largely the unstable 16a, 17a-epoxy-9a-fluoro-11β-hydroxy-16ß-methyl- 3-oxoandrosta-1,4-diene-17ß-car-bonthioic acid (no starting oxyacid was present) as indicated by the tlc rated (chloroform-acetone-acetic acid, 30: 8: 1, Rr about 0.7).

Manufacturing XLI

S-chloromethyl-16a, 17a-epoxy-9a-fluoro-11β-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carbothioate (XLI)

Method A

A suspension of 753 mg 16a, 17a-epoxy-9a-fluoro-1 lß-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylic acid and 680 mg 2-fluoro-1-methylpyridinium tosylate in 7 ml of methylene chloride was treated dropwise at 0 ° C with 1.39 ml of triethylamine and then stirred at 0 ° C for 1 h. Hydrogen sulfide was then passed through the mixture for 15 min, and finally the resulting solution was stirred at 0 ° C for another hour. 0.26 ml bromochloromethane was then added and the mixture was stirred and allowed to warm to room temperature. After a further 1.5 h, the reaction mixture was diluted with 250 ml of ethyl acetate and washed successively with 2N hydrochloric acid, 5% sodium hydrogen carbonate solution and water, dried and evaporated to 818 mg of a pale yellow solid. The solid was a p.l.c. in chloroform-acetone (9: 1) (two runs). The main band (515 mg) was crystallized from acetone to give 447 mg of white needles of the title S-chloromethyl ester epoxide, mp 246-251 °

[a] d + 131 ° (c 0.67).

Method B

A suspension of 376 mg 16a, 17a-epoxy-9a-fluoro-1 lß-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylic acid and 400 mg 2-chloro-N-methylbenzothiazolium trifluoro- methanesulfonate in methylene chloride was treated dropwise at 0 ° C with 0.7 ml of triethylamine. The resulting solution was stirred at 0 ° C for 1.25 h and then hydrogen sulfide was passed through the mixture for 10 min. After another hour at 0 ° C, 0.13 ml of bromochloromethane was added and the mixture was stirred at room temperature. Two further portions of bromochloromethane (0.13 ml) were then added after a further 1.5 h and 1.8 h. 15 min after the last addition, the reaction mixture was diluted with 200 ml of ethyl acetate and washed successively with 2N hydrochloric acid, 5% sodium hydrogen carbonate solution and water, dried and evaporated to a red crystalline solid. The solid was a p.l.c. in chloroform-acetone (19: 1) (three runs). The more polar band gave a pale pink solid of 134 mg of the title S-chloromethyl ester, identical to an authentic sample in the t.l.c.

Manufacturing XLII

S-chloromethyl-9a-fluorine-11β-, 17a-dihydroxy-16-methylene-3-oxoandrosta-1,4-diene-17ß-carbothioate (XLII)

A solution of 400 mg XLI in 16 ml trifluoroacetic acid was stirred at room temperature. After 5.5 h, the reaction mixture was evaporated almost to dryness and the residue was dissolved in 100 ml of ethyl acetate. The solution was washed with 5% sodium hydrogen carbonate solution and water, dried and evaporated to 466 mg of a yellowish green foam. The foam became a p.l.c. in chloroform-acetone (9: 1) (three runs). A portion of 80 mg of the main band (315 mg) was crystallized twice from acetone to form 48 mg of white crystals of the title 16-methylene-17a alcohol, mp 242-243 ° [a] D + 36 ° (c 0 , 50).

Manufacturing XLIV

9a-fluoro-11ß, 17a-dihydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carbothioic acid (XLIV)

A stirred solution of 0.502 g of 9a-fluoro-lß, 17a-dihydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylic acid in 15 ml of dry N, N-dimethylformamide was at -5 ° Cooled under nitrogen and treated with 0.435 g of N, N'-carbonyldiimidazole, and the reaction was stirred at -5 ° for 18 h. Hydrogen sulfide gas was bubbled into the reaction over 20 minutes and the solution was stirred for an additional 4 hours and allowed to gradually warm to 22 °. The reaction was poured into ethyl acetate, and the resulting solution was washed with 2N hydrochloric acid and water, and then with 2N sodium carbo-

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nat solution (three times 50 ml) extracted. The combined extracts were washed with 60 ml of ethyl acetate and then covered with a further 100 ml of ethyl acetate and acidified to pH 1.0 with hydrochloric acid. The aqueous layer was extracted with more ethyl acetate, and the extracts were washed with water and saturated sodium chloride solution, then dried, and the solvent was removed in vacuo to give a white solid which was crystallized twice from ethyl acetate to give 0.315 g of the title -Carbothioic acid, mp. 198-201 ° (dec.)

[<x] d + 189 ° (c 0.71).

Manufacturing XLV

9a-fluoro-17 a-hydroxy-16ß-methyl-3,11 -dioxoandrosta-1,4-diene-17ß-carbothioic acid (XLV)

A stirred solution of 5.587 g XLIII in 150 ml dry N, N-dimethylformamide was treated with 4.847 g N, N'-carbonyldiimidazole at 20 ° under nitrogen and the reaction was stirred at 20 ° for 4 h. Hydrogen sulfide gas was bubbled into the reaction for 10 minutes and the solution was stirred for an additional hour. The solution was poured into 300 ml of ice and 100 ml of 2N hydrochloric acid to form a leather-colored precipitate. This was filtered off, dried overnight (6.268 g) and crystallized from ethyl acetate to give 3.761 g of the title carbothioic acid in the form of white prisms, mp. 215-218 °

[a] d + 143 ° (c 0.88, dimethylformamide).

Manufacturing XLVI

9a-fluoro-17a-hydroxy-16ß-methyl-3,11 -dioxoandrosta-1,4-diene-17ß-carbothioic acid (XLVI)

A stirred solution of 1.059 g XLIII in 50 ml dry N, N-dimethylformamide was treated with 1.368 g N, N'-thiocarbonyldiimidazole at 20 ° under nitrogen and the reaction was stirred at 20 ° for 4 hours. Hydrogen sulfide gas was bubbled into the reaction for 5 minutes and the solution was stirred for an additional hour. The reaction was partitioned between 100 ml of ethyl acetate and 100 ml of 2N hydrochloric acid, and the organic phase was washed with 100 ml of 2N hydrochloric acid and twice 100 ml of water and extracted with twice 75 ml of 2N sodium carbonate solution. The combined extracts were washed with 50 ml of ethyl acetate, then covered with 100 ml of ethyl acetate and acidified to pH 1 with hydrochloric acid. The aqueous layer was extracted with an additional 50 ml of ethyl acetate and the extracts were washed with water, saturated sodium chloride solution, dried and the solvent was removed in vacuo. The residue was crystallized from ethyl acetate to give 0.559 g of the title carbothioic acid, mp 212-219 ° [a] d + 145 ° (c0.81, dimethylformamide).

Manufacturing XLVII

S-chloromethyl-9a-fluoro-11ß, 17a-dihydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carbothioate (XLVII)

A stirred solution of 0.160 g XLIV and 0.040 g sodium hydrogen carbonate in 6 ml N, N-dimethylformamide was treated with 0.1 ml bromochloromethane and stirring was continued at 22 ° for an additional hour. The reaction mixture was diluted with 100 ml of ethyl acetate and the solution was washed successively with 2N hydrochloric acid, water, 2N sodium carbonate solution, water and saturated sodium chloride solution, then dried, and the solvent was removed in vacuo. The residue was crystallized twice from ethyl acetate to give 0.193 g of the title S-chloromethylthiol ester in the form of white plates, solvated with ethyl acetate (1 mol), mp 126-130 °

[a] d + 147.5 ° (c 0.64).

Manufacturing XLVIII

9a-fluoro-16ß-methyl-3,11 -dioxo-17a-propionyloxyan-drosta-1,4-diene-17ß-carbothioic acid (XLVIII)

A stirred solution of 0.485 g XLV and 0.57 ml triethylamine in methylene chloride was cooled in ice salt, treated with 0.43 ml propionyl chloride and the reaction was stirred at 0 ° for 1.5 h. The mixture was partitioned between 75 ml of ethyl acetate and 75 ml of 2N sodium carbonate solution, and the organic layer was washed successively with further 2N sodium carbonate solution, water, 2N hydrochloric acid, water and saturated sodium chloride solution, then dried, and the solvent was evaporated in Vacuum removed to give 0.562 g of a yellow crystalline solid. This was dissolved in 10 ml of acetone, 1.0 ml of diethylamine was added, and the reaction was stirred at 22 ° for 1.25 h. The solvents were removed in vacuo and the residue was partitioned between 30 ml of ethyl acetate and 30 ml of 2N hydrochloric acid. The ethyl acetate layer was washed with water and extracted with twice 30 ml of 2N sodium carbonate solution. The combined extracts were washed with 30 ml of ethyl acetate and covered with 60 ml of ethyl acetate and acidified to pH 1 with hydrochloric acid. The ethyl acetate layer was washed with water and saturated sodium chloride solution, then dried, and the solvent was removed in vacuo to give a white solid which was crystallized twice from ethyl acetate to give 0.290 g of the title ester, mp 173-180 °

[a] d + 148 ° (c 1.03).

Manufacturing XLIX

S-chloromethyl-9a-fluoro-17ß-hydroxy-16ß-methyl-3,11-dioxoandrosta-l, 4-diene-17ß-carbothioate (XLIX)

A solution of 5.006 g XLV and 1.612 g sodium bicarbonate in 50 ml N, N-dimethylacetamide was treated with 1.24 ml bromochloromethane and the reaction was stirred at 22 ° for 3.3 hours. The solution was diluted with 70 ml of ethyl acetate and washed successively with 2N hydrochloric acid, water, sodium etabisulfite solution, water and saturated sodium chloride solution, then dried, and the solvent was removed in vacuo to give 3.638 g of an off-white solid. The analytical sample was obtained after preparative t.l.c. (Silicon dioxide gel, developed with chloroform: acetone = 9.1) and crystallized from ethyl acetate in the form of 0.262 g of colorless prisms of the title ester of mp 223-228 °

[a] d + 251 ° (cl, 2).

Manufacturing L

9a-fluoro-11β-hydroxy-16ß-methyl-3-oxo-17a-propionyl-oxy androsta-1,4-diene-17ß-carbothioic acid (L)

A stirred solution of 0.511 g XLIV in 20 ml methylene chloride containing 0.6 ml triethylamine was cooled to 2 ° and treated with 0.45 ml propionyl chloride, and the reaction was stirred at 2 ° for 2.5 h. The reaction was partitioned between ethyl acetate and sodium hydrogen carbonate and the organic phase was washed with water, 2N hydrochloric acid, water and saturated sodium chloride solution, dried and the solvent was removed in vacuo to give 0.634 g of a colorless solid. This was dissolved in 30 ml of acetone, 1.5 ml of diethylamine were added and the clear solution was stirred at 22 ° for 55 min. The reaction was carried out with 50 ml of ethyl

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diluted acetate and was washed with 2N hydrochloric acid and water and then extracted with 5% sodium carbonate solution. The combined extracts were acidified to pH 1 with 2N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water and saturated sodium chloride solution and dried and the solvent was removed to give 0.522 g of a colorless foam which was crystallized from ethyl acetate to give the title ester as 0.307 g of colorless prisms, mp 174- 179 ° i «

[cc] d + 107 ° (c 1.0).

Manufacturing LI

9a-fluoro-11β, 17a-dihydroxy-16-methylene-3-oxoandrosta-1,4-diene-17ß-carbothioic acid (LI) 15

A solution of 0.218 g of 9a-fluoro-11β, 17a-dihydroxy-16-methylene-3-oxoandrosta-l, 4-diene-17ß-carboxylic acid in 10 ml of dry N, N-dimethylformamide was made at 22 ° under nitrogen with 0.254 g of N, N'-carbonyldiimidazole was treated and the reaction was stirred at 22 ° for 4 h. Hydrogen sulfide gas was bubbled into the reaction for 5 minutes and the mixture, which was now pale green, was stirred at 22 ° for 1 hour. The mixture was diluted with 150 ml of ethyl acetate and the solution was washed with 2N hydrochloric acid, water and saturated sodium chloride solution, dried, and the solvent was removed in vacuo to give 0.222 g of a yellow foam which was crystallized twice from ethyl acetate to form 0.078 g of the title carbothioic acid in the form of white prisms, which decomposed at about 250 ° without melting 30 [a] d + 117 ° (cO, 32).

Production LIII

9a-Fior-lß, 17a-dihydroxy-3-oxoandrosta-l, 4-diene-17ß- 35 carbothioic acid (LIII)

A solution of 4.5 g9a-fluoro-lß, 17a-dihydroxy-3-oxoandrosta-l, 4-diene-17ß-carboxylic acid in 100 ml dry dimethylformamide was added under nitrogen with 4.04 g N, N'-carbonyldiimidazole 4 h at 22 ° C stirred. Hydrogen sulfide was then blown through the solution for 30 min and then left for a further 15 min. The mixture was poured into a mixture of 250 ml of 2N hydrochloric acid and about 100 g of ice, and the resulting precipitate was collected, washed with water and dried to give 4.56 g of a white solid. A portion of 120 mg was recrystallized from ethanol to form the title thioic acid in the form of 70 mg of colorless crystals, mp. 222-225 °

[a] d + 116 ° (c0.57). so

Manufacturing LIV

6a, 9a-difluoro-11β, 17a-dihydroxy-16a-methyl-3-oxoan-drosta-1,4-diene-17ß-carbothioic acid (LIV) 55

A solution of 12.0 g of 6a, 9a-difluoro-lß, 17a-dihydroxy-16a-methyl-3-oxoandrosta-l, 4-diene-17ß-carboxylic acid in 250 ml of dry dimethylformamide was stirred and with 9.94 g Treated N, N'-carbonyldiimidazole under nitrogen at room temperature. After 4 hours, hydrogen sulfide 60 was bubbled through the solution for 0.5 hours and the mixture was left for an additional 0.5 hours. The reaction mixture was poured into 500 ml of 2N hydrochloric acid containing about 250 g of ice. The resulting precipitate was collected, washed with water and dried in vacuo to give the title thioic acid in the form of 11.47 g of a white solid, mp 230-232 °

[a] d + 94 ° (c 0.91).

Manufacturing LV

17a-acetoxy-6a, 9a-difluoro-11β-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17ß-carbothioic acid (LV)

A solution of 1.625 g of LIV and 2.0 ml of triethylamine in 75 ml of methylene chloride was stirred at about 0 ° C. and treated dropwise with 1.275 ml of acetyl chloride and stirred at this temperature for 1.25 h. The mixture was washed with 50 ml of 2N sodium carbonate, water, 50 ml of 2N hydrochloric acid, three times 50 ml of water, 50 ml of brine, then dried and evaporated to 1.91 g of a white solid. This was dissolved in 40 ml of acetone and stirred with 4 ml of diethylamine at 27 ° C. for 45 min. The mixture was concentrated to about 25 ml and poured into 100 ml of 2N hydrochloric acid containing about 100 g of ice. After stirring, the resulting precipitate was collected, washed with water and dried to give 1.685 g of a solid. A portion of 400 mg was recrystallized from ethyl acetate to give 280 mg of the title 17a acetate, mp 175-177 °.

Manufacturing LVI

17a-butyryloxy-6a, 9a-difluoro-11β-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17ß-carbothioic acid (LVI)

Using the same procedure as that described in Preparation LV, 2.0 g of LIV with 1.5 ml of butyryl chloride instead of the acetyl chloride was converted to 2.08 g of the title 17a butyrate. A portion that was recrystallized from ethyl acetate had an mp of 155-157 °.

Manufacturing LVII

9a-fluoro-11β-hydroxy-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carbothioic acid (LVII)

Using the same procedure as described in Preparation LV, 3.8 g of LIII was used using 3.9 ml of propionyl chloride instead of acetyl chloride and after aminolysis of the intermediate with 10.35 ml of diethylamine in 4.17 g of title 17a- Propionate converted. A portion of 350 mg, recrystallized from ethyl acetate, gave 165 mg of colorless needles, mp. 135-138 °

[a] D + 72 ° (c 0.92).

Manufacturing LVIII

6a, 9a-difluoro-l 1β-hydroxy-16a-methyl-3-oxo-17a-pro-7ß-carbothioic acid (LVIII)

A solution of 5.0 g LIV and 6.15 ml triethylamine in 140 ml methylene chloride was cooled with ice salt and treated dropwise with 4.74 ml propionyl chloride. The reaction mixture was stirred for a further 0.75 h at about 0 ° C. and then washed successively with 2 n sodium carbonate, water, 2 n hydrochloric acid, water and brine. After drying, the solvent was removed to give 6.35 g of a white solid. This was redissolved in 120 ml of acetone and 12.5 ml of diethylamine, and after stirring at room temperature for 1 hour, the volume was reduced to about 75 ml. The solution was poured into 200 ml of 2N hydrochloric acid containing about 300 g of ice and the resulting precipitate was collected, washed with water and dried in vacuo to give 5.17 g of a white solid, mp 152-155 °. By recrystallizing a portion of 400 mg from ethyl acetate, 290 mg of the analytically pure title thioic acid 17a-propionate was obtained as colorless crystals of mp. 161-164 °

[a] d -27 ° (c 0.95), whose infrared spectrum in the solid state (in nujol) showed a different crystalline form from that obtained in preparation XIX.

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Manufacturing LIX

S-chloromethyl-9a-fluoro-16ß-methyl-3.11-dioxo-17cc-pro-pionyloxyandrosta-1,4-diene-17ß-carbothioate (LIX)

A solution of 409 mg XLIX in 5 ml propionic acid, 2 ml trifluoroacetic anhydride and toluene-p-sulfonic acid (0.1 ml dry chloroform solution, 80 mg / ml) was stirred at 22 ° C. for 2.75 days. The non-acidic product was isolated by extracting with ethyl acetate after pouring it into saturated sodium hydrogen carbonate. The crude material was chromatographed on silica in chloroform-acetone (14: 1) and crystallized from ethyl acetate-petroleum ether (bp. 60-80 ° C) to give the title 17a-propionate as colorless crystals of mp. 205-206 ° [a] n> + 95 ° (c 1.15).

Manufacturing LX

S-chloromethyl-9a-fluoro-11ß, 17 a-dihydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carbothioate (LX)

A suspension of 102 mg XLIX in 2.5 ml ethanol was stirred with 10 mg sodium borohydride at 22 ° C for 1 h. The reaction mixture was treated with 5 ml of acetone and then concentrated almost to dryness. The residue was dissolved in 25 ml of ethyl acetate, washed with n-hydrochloric acid, water and brine. After drying, the organic solvent was removed to give the title 1ß alcohol as 103 mg of a colorless foam, the only major component of which was equipolar with an authentic sample by tlc comparison (silica, chloroform-acetone, 9: 1) .

Manufacturing LXI

9a-fluoro-l 1β-hydroxy-16ß-methyl-3-oxo-17a-propionyl-oxyandrosta-1,4-diene-17ß-carbothioic acid (LXI)

Method A

A solution of 603 mg (0.75 mol of ethyl acetate solvate) 9a-fluoro-11β-hydroxy-16ß-methyl-3-oxo-17a-propionyloxy-androsta-l, 4-diene-17ß-carboxylic acid and 0.997 mg N , N'-Car-bonyldi (1,2,4-triazole) in 45 ml of dry dimethylformamide was stirred under nitrogen at about 22 ° C. for 18.5 h. 15 ml of a solution prepared from 305 mg of sodium hydride in dimethylformamide by saturation with hydrogen sulfide was added, and it was stirred at room temperature for 3 days. The reaction mixture was poured into 200 ml of 2N hydrochloric acid and the product was extracted three times with ethyl acetate. The organic extracts were combined, washed with water and back extracted with 5% sodium carbonate solution: the alkaline extracts were acidified with hydrochloric acid and extracted three times with ethyl acetate. After washing with water and brine, the organic extracts were dried and concentrated to a small volume. The title thioic acid separated out in the form of 101 mg of cream-colored crystals, the only main component of which was compared with an authentic sample in 'H NMR and by t.l.c. (Silica, chloroform-acetone, 4: 1) was identified.

Method B

A solution of 701 mg (0.75 mol ethyl acetate solvate) 9a-fluoro-1 1β-hydroxy-16ß-methyl-3-oxo-17a-propionyloxy-androsta-l, 4-diene-17ß-carboxylic acid and 473 mg N , N'-carbonyldiimidazole in 26 mg of dry dimethylformamide was stirred under nitrogen for 19.5 hours at about 22 ° C. and then with 10 ml of a solution of sodium hydride (60% dispersion in oil, 233 mg) in 10 ml of dimethylformamide, saturated with hydrogen sulfide, treated. The resulting mixture was then stirred at room temperature for 5.5 hours. The reaction mixture was diluted with 100 ml of ethyl acetate and washed with 2N hydrochloric acid, water and brine, then dried and evaporated to 186 mg of a foam. The title thioacid appeared as the main component in the product by 'H NMR and by t.l.c. (Silica, chloroform-acetone, 4: 1, and chloroform-acetone-acetic acid, 30: 8: 1) compared to an authentic sample.

Method C

In an almost identical reaction to that described in Method A, the carboxylic acid was treated with 1.587 g of 1,1'-carbonyldibenzotriazole instead of N, N'-carbonyl-di (1,2,4-triazole) at room temperature for 6 hours. After the addition of the solution, obtained from hydrogen sulfide and sodium hydride in dimethylformamide, the reaction was continued for 41.5 h. The crude product was obtained as a foam; t.l.c. (Silicon dioxide, chloroform-acetone, 4: 1, and chloroform-acetone-acetic acid, 30: 8: 1) showed that the title thioic acid was present as the main component, using a comparison with an authentic sample.

Manufacturing LXII

S-chloromethyl-6a, 9a-difluoro-16a-methyl-3-oxo-17a-pro-pionyloxy-11β-trifluoroacetoxyandrosta-1,4-diene-17ß-carbothioate (LXII)

A solution of 100 mg of the compound of Example 5 (listed below) in 2 ml of dry tetrahydrofuran and 0.1 ml of pyridine was treated with 0.05 ml of trifluoroacetic anhydride and the mixture was kept at room temperature for 0.5 h. The reaction mixture was poured into water and the product was extracted three times with ethyl acetate. The organic extracts were washed with water, dried and evaporated to give 116 mg of the homogeneous title trifluoroacetate according to 1 H NMR spectroscopy (singlet at 8.59 t, 19 protons in deuterochloroform) and t.l.c. on silica (acetone-petroleum ether, bp 40-60 ° C, 1: 3). An analytical sample of ether-pentane showed mp 158-162 °

[a] d + 56 ° (c0.23).

Examples of esterification

example 1

S-chloromethyl-9a-fluoro-11β-hydroxy-16ß-methyl-3-oxo-17a-propionyloxyandrosta-l, 4-diene-17ß-carbothioate

Method A

A solution of 2.115 g I in 7 ml dimethylacetamide was treated with 592 mg sodium hydrogen carbonate and 0.46 ml bromochloromethane and the mixture was stirred at room temperature. After 2 hours, the reaction mixture was diluted with 500 ml of ethyl acetate and washed with 5% sodium hydrogen carbonate solution and water, dried and evaporated to give 1.560 g of an orange foam. P.l.c. in chloroform-acetone (19: 1) gave 803 mg of an almost white foam which was crystallized twice from methanol to give 668 mg of almost white needles of the title S-chloromethyl ester, mp 212-214 ° C [a] d + 44 ° (c 1.06).

Method B

The title compound was prepared in the same way using chloroiodomethane instead of bromochloromethane.

Method C

19 mg sodium borohydride became a solution of 230

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mg II in 3.5 ml of ethanol was added and the solution was stirred at room temperature. After 20 minutes, 1 ml of acetone was added and the solution was concentrated to about a quarter volume. 30 ml of ethyl acetate was then added and the solution was washed with n-hydrochloric acid and water, dried and evaporated to give 239 mg of a white foam. P.l.c. in chloroform-acetone (19: 1) gave 188 mg of a white foam, which was crystallized twice from methanol to give 158 mg of white needles of the title S-chloromethyl ester of mp 210-212 °

[a] d + 44 ° (c 1.07).

Example 2

S-chloromethyl-9a-fluoro-11β-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carbothioate

A solution of 0.927 g IV in 4 ml dimethylacetamide was treated with 0.256 g sodium hydrogen carbonate and 0.20 ml bromochloromethane and the mixture was stirred at 22 ° C for 2 h. The reaction mixture was partitioned between 100 ml of 20 ethyl acetate and 20 ml of 2N hydrochloric acid, and the aqueous layer was further extracted with ethyl acetate. The combined extracts were washed successively with 2N hydrochloric acid, water, 3% sodium hydrogen carbonate, water and saturated saline. 25 After drying, the solvent was removed and the crude product (757 mg) was crystallized twice from acetone to give 0.367 g of the title chloromethylthiol ester, mp 247-250 °

[<x] d + 50.5 ° (c 0.63). 30th

Example 3

S-chloromethyl-11β-hydroxy-3-oxo-17a-propionyloxyan-drosta-1,4-diene-17ß-carbothioate

A solution of 2.366 g of crude XV in 10 ml of dimethylacet 35 amide was treated with 756 mg of sodium hydrogen carbonate and 0.59 ml of bromochloromethane at 22 ° C. for 16 h. It was partitioned between ethyl acetate and 2N hydrochloric acid, and the aqueous layer was further extracted with ethyl acetate. The combined organic phases were washed successively with 2N hydrochloric acid, water, sodium hydrogen carbonate, water and saturated saline and then dried, and the solvent was removed to give a yellow foam. The neutral product was cleaned by h.p.l.c. on silica (15p. or (im) in 7% acetone in chloroform, and the main product crystallized from acetone to give 0.511 g of the title chloromethylthiol ester of mp 117-120 °

[ex] d + 56 ° (c 1.3).

Example 4

S-chloromethyl-6a, 9a-difluoro-11β-hydroxy-16a, 17a-iso-propylidene-dioxy-3-oxoandrosta-1,4-diene-17ß-carbothioate A stirred solution of 1.360 g IX in 10 ml N, N-Dime-thylacetamide was treated with 0.377 g of sodium hydrogen carbonate and 0.3 ml of bromochloromethane and stirring was continued for 1.5 hours. 100 ml of ethyl acetate was added, and the resulting solution was washed successively with 2N hydrochloric acid, water, sodium metabisulfite solution, water, sodium bicarbonate solution, water and saturated sodium chloride solution, then dried, and the solution was concentrated, followed by crystallization. The crystallized product (0.765 g) was purified by p.l.c. purified on silica gel, developed with chloroform: acetone (9: 1). The main band was eluted with ethyl acetate and crystallized from ethyl acetate to give 0.475 g of the title S-chloromethylthioester in the form of white prisms, mp 271-278 °

[a] d + 116 ° (c 0.96, dimethyl sulfoxide).

Example 5

S-chloromethyl-6a, 9a-difluoro-11β-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ß-carbothioate A solution of 0.546 g XIX in 3 ml dimethylacetamide was added with 202 mg Sodium bicarbonate and 0.16 ml bromochloromethane treated at 22 ° for 3 h. The mixture was treated with 50 ml of 2N hydrochloric acid and the product was extracted with ethyl acetate. The extracts were combined and washed successively with 2N hydrochloric acid, water, saturated brine, dried and the solvent was removed. Crystallization from ethyl acetate gave 0.404 g of the title chloromethylthiol ester, mp 272-275 °

[a] D + 49 ° (c 0.35).

b