KR850000969B1 - Androstane carbothioates - Google Patents

Abstract

Compds. of formula (I) are new wherein R1 represents a fluoro-, chloro- or bromo-methyl gp. or a 2'-fluoroethyl gp.; R2 represents a gp. COR6 where R6 is a C1-3 alkyl gp. or OR2 and R3 together form a 16 alpha, 17 alpha isopropylidenedioxy gp.; R3 represents a hydrogen atom, a methyl gp.(which may be in either the alpha- or beta- configuration) or a methylene gp.; R4 represents a hydrogen, chlorine or fluorine atom; R5 represents a hydrogen or fluorine atom and the dotted line represents a single or double bond. (I) are useful as topical antiflammatory agents.

Description

Process for preparing androstane carbothioate

The present invention relates to a process for the preparation of the novel androstane compounds of general formula (I) useful as anti-inflammatory agents.

In the above formula

R ¹ is a fluoro-, chloro- or bromo-methyl group or a 2'-fluoroethyl group,

R ² is a COR ⁶ group wherein R ⁶ is a C _1-3 alkyl group), or

OR ² and R ³ together form a 16α, 17α-isopropyldenoxydioxy group,

R ³ is a hydrogen atom, a methyl group (may be present in the α- or β-configuration) or a methylene group,

R ⁴ is hydrogen, chlorine or fluorine atom,

R ⁵ is hydrogen or a fluorine atom,

는 단일 또는 이중결합을 나타낸다. 본 발명은 소염제인 안드로스탄 계열 스테로이드에 관한 것이다.sign

Represents a single or double bond. The present invention relates to an androstane-based steroid which is an anti-inflammatory agent.

Anti-inflammatory steroids are the most representative of the corticoid type, namely pregnan derivatives. U.S. Pat.Nos.1384372,1438940 and 1514476 describe esters of androstane 17β-carboxylic acid with anti-inflammatory action. European Patent Application No. 79300500.0 (Publication 0004741) also describes esters of androstane 17β-carbothioic acid with anti-inflammatory action. The present invention reveals that certain androstane compounds having a haloalkyl carbothioate group at the 17β-position have a desirable anti-inflammatory action, as described below in detail.

The new compounds of formula (I) have a good anti-inflammatory effect during topical application, as measured by the Mckenzie patch test in humans and topical application of the compound to the skin of mice and rats to reduce edema caused by soybean oil. I have it.

Some of the compounds show superior local anti-inflammatory activity with minimal and hypothalamic-pituitary-adrenal-suppressive action after topical application in a papillary ear edema test in animals of the same species. These results indicate that systemic side effects of these compounds are undesirable and that the topical therapeutic agents in salts in humans and animals are minimal.

Preferred compounds of general formula (I) which exhibit good anti-inflammatory action are compounds of the following categories:

(a) a compound in which R ¹ is chloro- or fluoro-methyl

(b) R ² is acetyl or propionyl, preferably propionyl.

(c) a compound in which R ⁴ is fluorine;

(d) A compound wherein R ⁵ is fluorine.

(e) 1,4-diene compounds.

(f) R ⁴ is fluorine and R ³ is hydrogen, α- or β-methyl or methyllane 1, 4-diene compound When topical application, the hypothalamus-pituitary-adrenal-inhibition effect is minimal and the general anti-inflammatory effect is excellent ( The compounds of I) are 1, 4-dienes wherein R ¹ is chloro- or fluoro-methyl and R ⁴ and R ⁵ are fluorine and in particular R ³ is α-methyl.

Particularly preferred compounds according to the invention, which have a good local anti-inflammatory effect and have a good ratio of local anti-inflammatory action to systemic side effects, are as follows:

s-chloromethyl 9α-fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyl oxy-androstar-1, 4-diene-17β-carbothioate,

s-chloromethyl 9α-fluoro-11β-hydroxy-16-methyl-3-oxo-17α-propionyl oxyandrostar-1, 4-diene-17β-carbothioate,

s-fluoromethyl 6α, 9α-difluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxo-androsta-1, 4-diene-17β-carbothioate,

s-fluoromethyl 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyl-oxyandrostar-1, 4-diene-17β-carbothioate,

s-chloromethyl 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1, 4-diene-17β-carbothioate,

The last two compounds are particularly preferred in that their ratio of action is particularly advantageous. Compounds of formula (I) can be prepared according to a variety of different methods.

One method involves free 17β-carbothioic acid groups (or functionally equivalent groups) or free 17α-hydroxy groups (R ³ being a hydrogen atom, methyl or methylene group) and other reactive groups present in the molecule. As described above, a method of esterifying the androstane compound corresponding to the general formula that is appropriately protected.

For example, salts of parent 17β-carbothioic acid such as alkali metal salts such as lithium, sodium or calcium or alkyl ammonium salts such as triethyl-ammonium or tetrabutyl ammonium, preferably ketones such as acetone, dimethyl In polar solvents such as formamide, dimethylacetamide or amide such as hexamethylphosphoramide, it can be reacted with an appropriate alkylating agent, usually at a temperature of 15 to 100 ° C. Alkylating agents may include suitable dihalo compounds, ie compounds containing another halogen atom (preferably bromine or iodine atom) in addition to the halogen atom of the desired R 1 group. This method can be applied to the preparation of compounds wherein R 1 is a chloromethyl group, with bromochloromethane being preferred as the alkylating agent.

Alternatively, the parent 16-hydrogen, methyl or methylene-17α-hydroxy 17β-carbothioate corresponding to the compound of formula (I) can be esterified in the 17α-hydroxy group. This can be done by conventional techniques, for example by reacting the parent 17α-hydroxy compound with a mixed anhydride of the desired carboxylic acid. Mixed anhydrides can then be prepared in situ by reacting the carboxylic acid with a suitable anhydride such as trifluoroacetic anhydride, preferably in the presence of an acid catalyst such as p-toluene sulfonic acid or sulfosalicylic acid. Alternatively, mixed anhydrides can be prepared in situ by reacting the symmetric anhydride of the desired acid with another suitable acid, such as trifluoroacetic acid.

The reaction is usually carried out in a vessel solvent such as benzene, methylene chloride or excess carboxylic acid used and the reaction is usually carried out at a temperature of 20-100 ° C.

Alternatively, the 17α-hydroxy group preferably contains the parent 17α-hydroxy compound, optionally in the presence of a non-hydroxyl solvent such as chloroform, methylene chloride or benzene, preferably perchloric acid, p-toluene sulfonic acid or strong acid. It can be esterified by reacting with a suitable acid anhydride or acid chloride in the presence of a strong acid catalyst such as a cation exchange resin (Amberlite 1R 120) and this reaction is conveniently carried out at a temperature of 25 to 100 ° C.

Compounds of formula (I) also contain corresponding androstane compounds containing 17β-substituents of formula -COS (CH ₂ ) n Y (Y represents a substituent that can be substituted and n is 1 or 2). It may also be prepared by reacting a group Y with a compound which may be substituted with a halogen atom.

Therefore, the compound of general formula (I) can be substituted with a different halogen substituent when the group Y is halogen by an exchange reaction. The bromomethyl, fluoromethyl and fluoroethyl 17β-carbothioate compounds are thus derived from the corresponding iodomethyl or bromoethyl 17β-carbothioate compounds, in the case of bromomethyl 17β-carbothioate, such as lithium bromide The bromide salts can be used and in the case of fluoromethyl or fluoroethyl 17β-carbothioate compounds can be prepared using appropriate fluoro compounds such as silver fluoride (I) or silver fluoride (II). The iodomethyl 17-β carbothioate starting compound may be prepared from the corresponding chloromethyl 17β-carbothioate compound using quaternary ammonium iodide such as alkali metal, alkaline earth metal or sodium iodide.

The reaction is preferably carried out in a solvent medium such as acetone, acetonitrile, methyl ethyl ketone, dimethylformamide, dimethylacetamide or ethanol.

The reactions described above can also be carried out on the starting materials with various substituents or groups which are converted into substituents or groups present in the compounds of the invention as defined above.

The 11β-hydroxy compound of general formula (I) uses the corresponding 11-oxo compound as an alkali or alkaline earth metal borohydride such as sodium or calcium borohydride, usually an alcohol such as methanol or ethanol or It can be prepared by reducing in a water-soluble alcohol solvent.

Such 11-keto compounds can be prepared by oxidizing the corresponding 11α-hydroxy steroids using, for example, chromic acid reagents such as Jones reagent.

11β-Hydroxy compounds of formula (I) are also substituted at the 11β-position with a tri C _1-6 alkylsalyloxy group such as trimethylsilyloxy group or a perfluoro- or chloro-alkanoyloxy such as trifluoroacetoxy group It may also be prepared by deprotecting the corresponding compound having a protected hydroxyl group such as a group. The protecting group can be removed by hydrolysis and the trialkyl silyl group can be easily removed using weak acid or basic hydrolysis or especially fluorides, usually with hydrogen fluoride or ammonium fluoride. The perfluoro- or chloro-alkanoyl protecting group can also be removed by weak acid or basic hydrolysis or alcoholysis, preferably under acidic conditions when R ⁴ is a chlorine atom. Protected hydroxyl groups can be introduced, for example, by reacting the 11β-hydroxy steroid with a suitable reagent such as trialkylsalyl halide or anhydrous perfluoro- or chloro-alkanoic acid.

Formula (I) compounds may also be prepared by reacting a corresponding compound having 9, 11-double bonds (or no substituent at the 11-position) with a reagent introducing the desired 9α-halo-11β-hydroxy group. This can be done by first reacting with N-bromo-amide or -imide such as N-bromosuccinimide to prepare bromohydrin and then treating with base to produce 9β, 11β-epoxide and the epoxide. Is reacted with hydrogen fluoride or hydrogen chloride to introduce the required fluorohydrin or chlorohydrin groups, or alternatively, a 9, 11-olefin compound is reacted with N-chloro-amide or imide. The 9α-chloro-11β-hydroxy group can be introduced directly.

The Δ ⁴ -compound according to the present invention is hydrogenated in a solvent such as ethyl acetate, usually using a corresponding Δ ^1,4- compound, or tris (triphenylphosphine) rhodium chloride, usually Can be prepared conventionally by partial reduction by homogeneous hydrogenation in a solvent such as benzene or by substitutional hydrogenation in the presence of a palladium catalyst using cyclohexene and in a solvent such as ethanol, preferably under reflux. Reduction can be carried out on halo alkyl esters which are very stable to this reaction or at an early stage. The above-mentioned compounds having the free -COSH group at the 17β-position can be prepared, for example, by amine decomposition of the appropriate 17β-thiocarbamoyloxycarbonyl astrostane. 17β-thiocarbamoyloxycarbonyl androstane can typically be prepared by reacting a 17β-carboxylic acid 17α-ester or a salt of 16α, 17α-acetonite with a thiocarbamoyl halide, such as chloride. The thiocarbamoyl group has the structural formula -COOCSNR ^A R ^{B where} R ^A and R ^B may be the same or different and are alkyl groups, such as C _1-4 alkyl groups, and are substituted by N, N-dimethyl thiocarbamoyl groups It is right. The reaction can be accelerated by the addition of an iodide salt such as sodium iodide.

Androstane 17β-carboxylate salts include, for example, alkali metals such as sodium or potassium, alkaline earth metal salts such as calcium or tertiary amine salts such as triethylamine.

Gaamine decomposition can be carried out by heating the mixed anhydride to a high temperature, for example in the presence of ammonia, primary amines or more preferably secondary amines such as diethylamine or philolidine. The 16- and 17α-positions in the starting 17β-carboxylic acids are usually substituted with the -R ³ and -OR ² groups preferred for the final product of formula (I).

As described above, the 17α-hydroxyandrostane compound in the 16-methylene series having the desired 17β-carbothioic acid group is a strong acid, eg, a corresponding 16β-methyl-16α, 17α-epoxy 17β-thiocarboxylic acid. It can be prepared by dislocations using strong carboxylic acids such as trifluoro acetic acid. These 16α, 17α-epoxides are treated with onium salts of the corresponding 17β-carboxylic acids with onium salts of 2-halo-aza-aromatic compounds followed by treatment of the product with hydrogen sulfide or salts thereof to produce free 17β-carbothioic acid, which As described above, it can preferably be prepared by alkylation in situ to give the desired 17β-carbothioate group.

The 16α, 17α-isopropylidenedioxy compounds of formula (I) are treated equally by treating the corresponding 17β-carboxylic acid with the onium salt of the 2-halo-aza-aromatic compound and then treating the product with hydrogen sulfide to 17β-carbothioic acid can be prepared and then esterified as described above.

Onium salts of 2-halo-aza-aromatic compounds can activate carboxyl. This reagent includes 2-halo-N-alkyl- or 2-halo-N-phenyl-pyridinium or pyridinium salts, and typical salts are 2-fluoro-N-methylpyridium tosylate or 2-chloro. -N-methyl benzothiazolium trifluoro methanesulfonate.

The 16α, 17α-epoxy-16β-methyl-17β-carboxylic acid compounds used as starting materials in this process can be prepared by conventional methods as described in British Patent No. 1,517,278.

17α-hydroxy 17β-carbothioic acid corresponding to formula (I) and salts thereof are prepared by the method described in the above-described compound preparation of formula (I) or 17α-hydroxy 17β-carbothioate or 17α. Carbothioate or 17α-carbothioic acid 17β-ester.

17α-hydroxy 17β-carbothioic acid can be prepared, for example, by reacting a reactive derivative of the corresponding 17α-hydroxy-17β-carboxylic acid with hydrogen sulfide or its sulfide or hydrosulfide salts. In general, examples of the cationic salt of sulfide or hydrosulfide include alkali metal salts such as sodium hydrogen sulfide or potassium hydrogen sulfide.

Reactive derivatives may be substituted with the corresponding 17α-hydroxy 17β-carboxylic acid with N, N'-carbonyldi (1, 2, 4-triazole), N, N'-carbonyldibenzotriazole, N, N'-carbonyldibenzi Midazole, N, N'-carbonyldi (3, 5-dimethylpyrazole), N, N'-thionyldiimidazole and especially N, N'-carbonyldiimidazole and N, N'-thiocarbonyl It can manufacture preferably by reacting with diimidazole. This reaction is usually carried out in an inert anhydrous solvent such as N, N-dimethylformamide or substituted amide solvents such as N, N'-dimethylacetamide, preferably in the absence of water, preferably below ambient temperature. For example, it is carried out at -30 to ℃ temperature. This reaction is usually carried out under approximately neutral conditions, advantageously in an inert atmosphere such as under nitrogen. The same solvents and conditions can also be applied to the reaction with H ₂ S or salts thereof. Hemicycle compounds such as imidazole or 1, 2, 4-triazole produced as by-products are easily removed by extraction with water.

The above reactions can also be carried out with compounds having several substituents or groups which are converted as described above in compounds of general formula (I).

The androstane 17β-carboxylic acid starting material used in the process may be prepared by conventional methods, for example by oxidizing the appropriate 21-hydroxy-20-ketopregnan with periodic acid in a solvent medium, preferably at room temperature. have. Alternatively, sodium bismuthate can be used to desirably oxidatively remove the 21-carbon atom of the 17α-acyloxy precnan compound. It is important to recognize that pregnane starting compounds carry substituents sensitive to the oxidation reaction and to protect this group appropriately.

The following examples illustrate the invention. Melting points were measured in degrees Celsius on Coppler blocks and were not corrected. Optical fluorescence was measured on a solution in dioxane at room temperature.

T.I.C (Thin Layer Chromatography), P.I.C (Preparative Chromatography) and h.p.J.c. (High Performance Liquid Chromatography) are performed on silica. Unless stated otherwise, the solution is dried over magnesium sulfate.

Preparation I

9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxy androstar-1, 4-diene-17β-carbodioic acid (I)

9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyl-oxy dissolved in dichloromethane (75 mL) with ethyl acetate (1/2 mol) and triethylamine (5.3 mL) Androstar-1, 4-diene-17β-carboxylic acid solution is stirred under nitrogen and treated with dimethylthiocarbamoyl chloride (0.571 g). After 24 hours, more reagent (5.320 g) is added. After 47 hours the mixture was diluted with ethyl acetate, washed with N-hydrochloric acid, 5% sodium bicarbonate solution and water and evaporated to dryness to give a viscous yellow oil (9.043 g). It is dissolved in diethylamine (50 ml) and stirred to heat to reflux for 5.75 h under nitrogen. The resulting brown solution is added to a mixture of concentrated hydrochloric acid (50 ml), water (250 ml) and ethyl acetate (50 ml). The product is extracted with ethyl acetate and the acid product is reextracted in 5% sodium carbonate solution. The aqueous phase is acidified with 6N hydrochloric acid (50 ml) and extracted with ethyl acetate. The extract was washed with N-hydrochloric acid and water, dried and evaporated to yield a pale yellow solid (3.440 g). Recrystallization with acetone affords a pale yellow crystal (1.980 g) of the title 17β-carbothioic acid having a melting point of 172-173 °.

Recrystallization of the analytical sample twice with acetone yields white crystals with a melting point of 177 to 179 ° C. and [α] _D + 110 ° (C 1.05).

Preparation II

S-Chloromethyl 9α-Fluoro-16β-methyl-3.11-dioxo-17α-propionyloxyandrostar-1.4-diene-17β-carbothioate (II)

To a stirred solution of the compound of Example 1 (described later) (998 mg) in acetone (2 ml) and dimethylformamide (2 ml) was added dropwise 8 N-johns reagent (1.5 ml) over 10 minutes. After 30 minutes the reaction mixture is slowly diluted with water (100 ml) with stirring and the resulting suspension is refrigerated for 1 hour. The precipitate was collected by filtration, washed with water and dried to give a cream solid (877 mg). PIC in chloroform-acetone (10: 1) gave white foam (755 mg), which was twice determined by acetone to have a melting point of 204 to 205 °. A title 11-ketone (523 mg) of [α] _D + 94 ° (C 1.04) is obtained as a white needle.

Preparation III

17β-N.N-dimethylthiocarbamoyloxycarbonyl-9α-fluoro-11β-hydroxy-16α-methyl-17α-propionyl-oxyandrostar-1.4-dien-3-one (III)

A solution of 9a-fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrostar-1.4-diene-17β-carboxylic acid (0.434 g) in dichloromethane (8 ml) was treated with triethylamine (0.14). ml), dimethylthiocarbamoylchloride (0.248 g) and sodium iodide (0.149 g) continue and the mixture is stirred at 20 ° C. under nitrogen for 6 hours. Ethyl acetate (30 ml) is added and the total volume is reduced in half in vacuo. Ethyl acetate (50 ml) is added again and the solution is washed with water, 2N hydrochloric acid, water, 3% sodium bicarbonate, water and saturated sodium chloride and dried. The solution is concentrated in vacuo to crystallize the product (0.329 g). Recrystallization with acetone (2X) gave the title anhydride with a melting point of 191 to 193 °. [Α] _D + 82 ° (C 0.57) as white needles.

Preparation IV

9α-fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy androstar-1.4-diene-17β-carbodiic acid (IV)

A suspension of stirring (III) (2.467) in diethylamine (25 ml) is heated to reflux under nitrogen. After 3.5 hours, the reaction was poured into iced 3N hydrochloric acid (300 ml) and the mixture was extracted with ethyl acetate. The combined extracts are washed with water and extracted with 5% sodium carbonate solution. Combine the aqueous extracts, wash with ethyl acetate, pour ethyl acetate and acidify with hydrochloric acid to pH 1. The aqueous phase is extracted again with ethyl acetate, the extracts are combined, washed with water and saturated sodium chloride solution, dried and the solvent is removed in vacuo. The residue was crystallized twice with acetone to give the title carbodioic acid with a melting point of 141 to 143 ° [α] _D + 30 ° (C 0.51) as a white needle (1.309).

Recipe V

11β-hydroxy-3-oxo-17α-propionyloxyandrostar-1.4-diene-17β-carboxylic acid (V)

The 11β, 17α-dihydroxy-3-oxoandrostar-1.4-diene-17β-carboxylic acid (13.5 g) and triethylamine (18 ml) solution in dichloromethane (500 ml) was cooled to 4 ° C. and propionylchloride (14.2 ml) for 15 minutes in portions. Stirring is continued for a total of 1 hour at 4 ° C. and the mixture is continuously washed with 3% sodium bicarbonate, water, 2N-hydrochloric acid, water and saturated brine, dried and evaporated under reduced pressure. The residue is dissolved in acetone (30 ml) and diethylamine (14.3 ml) is added with stirring. After 1 hour at 20 ° C. the solvent is removed under reduced pressure and the residue is dissolved in water (150 ml). After acidifying to pH 1 with 2N hydrochloric acid, the product is extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried and concentrated to a small volume. The solid product was collected by filtration, washed with ethyl acetate and dried at 50 ° in vacuo to afford the title 17α-propionate carboxylic acid of [α] _D + 2 ° (C 1.10) as crystals (13.309 g). Recrystallization of a portion (389 mg) twice with methanol yields analytical specimens with melting points 244 to 245 ° (decomposition). [Α] _D + 3 ° (C 0.83).

Recipe VI

6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyl oxyandrostar-1, 4-diene-17β-carboxylic acid (VI)

6α, 9α-difluoro-11β, 17α-dihydroxy-16α-methyl-3-oxoandrostar-1, 4-diene-17β-carboxylic acid (2.113 g) and triethylamine in dichloromethane (60 ml) 2.5 ml) is stirred and treated with propionyl chloride (1.83 ml) at about 0 ° C. After 1 hour the mixture is again diluted with solvent (50 ml), washed continuously with 3% sodium bicarbonate, water, 2N hydrochloric acid, water, brine and evaporated to dryness to give a pale yellow solid. It is dissolved in acetone (50 ml) and diethylamine (2.5 ml) is added. After 1 hour at 22 ° the solvent is removed in vacuo and the gum residue is dissolved in water (30 ml). Acidified to pH 1 with 2N hydrochloric acid to precipitate a solid, which was collected, washed with water and dried to give the title carboxylic acid 17α-propionate (2.230 g) at melting point 220-225 °. [Α] _D + 4 ° (C 0.70). To obtain.

Preparation VII

17β-N, N-dimethylthiocarbamoyloxycarbonyl-6α, 9α-difluoro-11β-hydroxy-16α, 17α-isopropylidenedioxyandrostar-1,4-dien-3-one (VII )

6α, 9α-difluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrostar-1,4-diene in dichloromethane (170 mL) containing triethylamine (1.4 mL) Treat the -17β-carboxylic acid (4.354 g) solution with N, N-dimethylthiocarbamoyl chloride (2.519 g) and stir the reaction at 22 ° under nitrogen for 80 minutes. Ethyl acetate (500 ml) is added and the resulting solution is washed with 2N hydrochloric acid, water, sodium bicarbonate solution, water and sodium saline chloride solution, dried and the solution is concentrated. On cooling, crystallization occurs, and the solid is filtered and dried in vacuo, and the title anhydride (3.562 g) at melting point 283 to 287 ° (decomposition) and [α] _D + 156 ° (C 0.84, dimethylsulfoxide) is converted into a light yellow prism. Obtained.

Preparation VIII

6α, 9α-difluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrostar-1, 4-diene-17β-carbothioic acid (VIII)

VII (3.455 g) suspension in diethylamine (200 ml) is heated to reflux for 6 hours under nitrogen.

에 붓고 농염산(210ml)으로 pH 1로 산성화하여 에틸 아세테이트로 추출한다. 추출물을 합하여 물로 세척하고 5%탄산나트륨 용액과 물로 추출한후 수성추출물을 합한다. 합한 추출물을 6N-염산으로 산성화시키고 에틸아세테이트로 추출한다. 유기 추출물을 합하고 물과 포화염화나트륨 용액으로 세척한후 건조시키고 용매를 진공중에서 제거하면 연회색고체(2.31g)가 수득된다. 생성물중 일부(0.408g)를 에틸아세테이트로 결정화시키면 융점 191 내지 199℃, [α]_D+124°(C 1.04, 디메틸설폭시드)의 포제 카보티오산(0.149g)이 수득된다.At first the suspension dissolves quickly, but after 30 minutes it becomes a light brown suspension and remains unchanged. Cooled reaction mixture to water (1.0)

Pour into and acidify with concentrated hydrochloric acid (210ml) to pH 1 and extract with ethyl acetate. Combine the extracts and wash with water, extract with 5% sodium carbonate solution and water and combine the aqueous extracts. The combined extracts are acidified with 6N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with water and saturated sodium chloride solution, dried and the solvent was removed in vacuo to yield a pale gray solid (2.31 g). Crystallization of a portion of the product (0.408 g) with ethyl acetate gave a foamed carbothioic acid (0.149 g) with a melting point of 191-199 ° C., [α] _D + 124 ° (C 1.04, dimethylsulfoxide).

Recipe IX

6α-fluor-11β, 17β-dihydroxy-3-oxoandrostar-1, 4-diene-17β-carboxylic acid (IX)

A solution of 6α-fluoroprednisolone (4.987 g) in tetrahydrofuran (50 ml) is stirred 22 ° with a solution of periodic acid (10.0 g) in water (24 ml). After 50 minutes tetrahydrofuran is evaporated and the aqueous suspension is filtered. The solid product was washed with water (300 ml) and dried to give a white solid (4.80 g). Crystallization of a portion (217 mg) with methanol yields the title acid (171 mg) with melting point 241 to 248 °, [α] _D + 54 ° (C 0.825) as white needles.

Recipe X

6α-Fluoro-11β-hydroxy-3-oxo-17α-propionyl oxyandrostar-1, 4-diene-17β-carboxylic acid (X)

1 × (4.491 g) and triethylamine (4.46 ml) solution in anhydrous dichloromethane (160 ml) were stirred at −5 ° and propionyl chloride (2.80 ml, 2.96 g) in anhydrous dichloromethane (about 5 ml) was stirred at 0 °. It is added dropwise over 5 minutes and treated. After 20 minutes or less at 0 °, the reaction mixture was diluted with dichloromethane (160 ml), washed with sodium bicarbonate solution and water, dried and evaporated to give a white solid (5.701 g). This was stirred with diethylamine ((4.60ml, 3.24g) in acetone (30ml) to give a clear yellow solution.After 30 minutes the solution was concentrated and water (150ml) was added to give the resulting solution 2x30m of ethyl acetate. Wash with. The mixture is acidified to pH 2 with 2N hydrochloric acid (50 ml) with stirring and the product is extracted three times with ethyl acetate. The extracts were combined, washed with water (50 ml), dried and evaporated to yield white foam (5.819 g). Crystallization (340 mg) in foam was effected with ethyl acetate to give the title 17α-pyopionate (144 mg) with a melting point of 224 to 221 °, [α] _D + (C 0.861), in the form of small pins.

Preparation method XI to XXII

The following compounds are prepared according to the same general procedure as described in Preparation I but using 17β-carboxylic acid corresponding to the desired 17β-carbothioate as starting material (detailed methods are summarized in Table I below).

XI. 17α-acetoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrostar-1, 4-diene-17β-carbothioic acid, melting point 178.5 to 179 ° C, [α] _D + 98 ° (C 1.02).

XII. 17α-butylthioxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrostar-1, 4-diene-17β-carbothioic acid, melting point 175 to 176 ° C, [α] _D +107 ° C 0.96.

XIII. 9α-fluoro-11β-hydroxy-17α-isobutylyloxy-16β-methyl-3-oxoandrostar-1, 4-diene-17β-carbothioic acid, melting point 177 to 179 ° C., [α] _D + 119 ° (C 0.90).

XIV. 11β-hydroxy-3-oxo-17α-propionyloxy androstar-1, 4-diene-17β-carbothioic acid, melting point 134 to 138 ° [α] _D + 67 ° (C 0.66).

XV. 11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxy-androsta-1, 4-diene-17β-carbothioic acid, melting point 159-163 ° [α] _D + 113 ° (C 0.78) .

XVI. 9α-chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrostar-1, 4-diene-17β-carbothioic acid, melting point 167 to 171 ° [α] _D + 128 ° ( C 0.99).

XVII. 9α-fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrostar-1, 4-diene-17β-carbothioic acid, melting point 141 to 143 ° [α] _D + 30 ° (C 0.51).

XVIII. 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrostar-1, 4-diene-17β-carbothioic acid, melting point 236-239 ° [α] _D -71 ° (C 0.99).

XX. 11β-hydroxy-3-oxo-17α-propionyloxy androsta-4-ene-17β-carbothioic acid, melting point 176 to 177 ° [α] _D + 101 ° (C 0.96).

XXI. 6α-fluoro-11β-hydroxy-3-oxo-17α-propionyloxyandrostar-1, 4-diene-17β-carbothioic acid, melting point 189-193 ° [α] _D -72 ° (C 0.74) .

TABLE I

Preparation of Mixed Anhydrides

Table I (continued)

Treating mixed anhydride intermediates with diethylamine

Note: EA = ethylacetate, A = acetone, P = petrol, boiling point 60-80 ° C.

1 Intermediate Some of (a) 500 mg, (b) 670 mg, (C) 424 mg and (D) 171 mg in anhydrous dimethylthiocarbamic acid are defined and characterized.

2. Characterization is carried out on specimens recrystallized twice with ethyl acetate. Recovery (a) 84%, (b) 69%.

3. Dissolve the product in ethyl acetate (about 0.2 moles).

4. Intermediate Crystalline dimethylthiocarbamic anhydride (1.435 g) with ethyl acetate. Part 95g is taken to define the characteristics.

5. Characterization is carried out on specimens recrystallized twice with acetone (recovery rate: 73%).

6. Crystallize the product with ethyl acetate.

7. Sodium iodide (1.46 g) may also be included during the reaction.

10. Sodium iodide (2.13 g) may also be included during the reaction.

XXII

9α-chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxy androstar-1,4-diene-17β-carbothioic acid and 9β, 11β-epoxy-16β-methyl-3-oxo -17α-propionyloxyandrostar-1, 4-diene-17βcarbothioic acid (XXII)

17β-N, N-dimethylthiocarbamoyloxycarbonyl-9α-chloro-11β-hydroxy-16β-methyl-17α-propionyloxy-androstar-1.4-dien-3-one in diethylamine (60 ml) (5.586 g) The solution is refluxed under nitrogen for 5 hours 40 minutes. The reaction is poured into water (450 ml), acidified to pH 10 with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 60 ml). The combined extracts were washed with water and extracted with an aqueous solution of sodium carbonate (4 × 50 ml). The aqueous extract is acidified to pH 1 with 6N hydrochloric acid and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with water and saturated sodium chloride solution, dried and the solvent was removed in vacuo to give a colorless foam (2.834 g).

Crystallization of the mixture twice with ethyl acetate resulted in 9α-chloro-11β-hydroxy 16β-methyl-17α-propionyloxyandrostar-1 having a melting point of 167 to 171 °, [α] _D + 128 ° (c 0.99). 4-diene-17β-carbothioic acid (0.527 g) is obtained as a white prism. When the mother liquor was crystallized, together with the above 9α-chloro-11β-hydroxy-cobothioic acid, 9β, 11β-epoxy-16β-methyl-3-oxo-17α-propionyl oxyandrostar-1, 4-diene-17β-carbo Thioic acid is further contained.

Preparation Method XXIII

S-ureomethyl 9α-fluoro-11β-hydroxy-16β-methyl-3-oxer-17α-propionyloxyandrostar-1. 4-diene-17β-carbothioate (XXIII)

A solution of Example 1 compound (described later) (500 mg) and sodium iodide (1.874 g) in acetone (15 ml) is stirred and heated to reflux for 6.5 hours. After addition of ethyl acetate (75 ml) the solution was washed with water, 10% sodium thiosulfate solution, 5% sodium hydrogen carbonate solution and water, washed, dried and evaporated to yield an off-white foam (525 mg). Plc in chloroform-acetone (6: 1) to give off-white foam (478 mg) and crystallization twice with acetone without heating above room temperature, melting point 196 to 197 °, [α] _D -32 ° (c 1.01) The title S-urethomethyl ester of (241 mg) is obtained as colorless crystals.

Preparation method XXIV to XXXV

Following the same general procedure as described in Preparation XXIII, but using S-chloromethyl 17β-carbothioate corresponding to the desired product as an extruder, the following compounds are prepared (detailed methods are summarized in Table II below): XXXIV . S-ureomethyl 9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrostar-1. 4-diene-17β-carbothioate, melting point 204 to 205 °, [α] _D + 29 ° (c 0.98).

XXV. S-Iodomethyl 11β-hydroxy-3-oxo-17α-propionyloxyandrostar-1.4-diene-17β-carbothioate, α _D + 26 ° (c 0.47).

XXVI. S-Iodomethyl 11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrostar-1. 4-diene-17β-carbothioate, [α] _D + 5 ° (c 0.74).

XXVII. S-Udomethyl 9α-chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrostar-1. 4-diene-17β-carbothioate, [α] _D + 7 ° (c

0.36).

XXVIII. S-ureomethyl 9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrostar-1. 4-diene-17β-carbothioate, [α] _D + 85 ° (c 0.55).

XXIX. S-ureomethyl 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrostar-1. 4-diene-17β-carbothioate.

XXX. S-Iodomethyl 9α-fluoro-11β-hydroxy-16-methylene-3-oxo-17α-propionyloxyandrosta-1.4-diene-17β-carbothioate, melting point 191-199 °, [α] _D + 31 ° (c 0.99).

XXXI. S-ureomethyl 9α-fluoro-11β-hydroxy-3-oxo-17α-propionyloxyandrostar-1. 4-diene-17β-carbothioate, melting point 175 to 178 °, [α] _D + 4 ° (c 0.50).

XXXII. S-ureomethyl 6α-fluoro-11β-hydroxy-3-oxo-17α-propionyloxyandrostar-1. 4-diene-17β-carbothioate, melting point 195-197 ° [α] _D + 18 ° (c 0.64).

XXXIII. S-ureomethyl 17α-acetoxy-6α, 9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrostar-1. 4-diene-17β-carbothioate, melting point 241 to 243 °, [α] _D + 78 ° (c 0.78).

XXXIV. S-ureomethyl 17α-butyryloxy-6α, 9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrostar-1. 4-diene-17β-carbothioate, melting point 210 to 212 °, [α] _D + 89 ° (c 0.90).

XXXV. S-ureomethyl 9α-fluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrostar-1. 4-diene-17β-carbothioate, melting point 261 to 270 ° (decomposition), [α] _D + 97 ° (c 0.48. Dimethyl sulfoxide).

TABLE II

Halogen exchange on S-haloalkyl 17α-acyloxy-androstan-17β-carbothioate

EA = ethyl acetate

A = acetone

M = methanol

P = petrol boiling point 60 to 80 °

week

1. Prepared in a portion (300 mg) in crude product (2.024 g).

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

3. The product is used directly in the preparation of the corresponding fluoromethyl 17β-carbothioate.

4. Use lithium chloride instead of sodium iodide.

5. Dissolve with 0.5 H ₂ O.

6. Dissolve with 0.1 EA.

7. Dissolve with 0.2EA + 0.5H ₂ O.

8. Prepared in part (300 mg) of crude crystal product (1.611 g).

Recipe XXXVI

S-ureomethyl 6α, 9α-difluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrostar-1. 4-diene-17β-carbothioate

A solution of Example 4 compound (described later) (0.795 g) in acetone (50 ml) was heated to reflux with sodium iodide (2.969 g) for 5.5 h. Ethyl acetate (75 ml) was added and the solution was washed continuously with water, sodium metasulfite solution and dried to remove the solvent in vacuo to yield an off white solid (0.893 g). Some of this (0.205 g) was crystallized twice with ethyl acetate, melting point 260 to 262 ° (decomposition). [Α] _D + 81 ° (c 0.6. Dimethylsulfoxide) of the title S-ureomethylthioester (0.105 g) is obtained as a white prism.

Preparation XXXVII

S-2′-Bromoethyl 9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrostar-1. 4-diene-17β-carbothioate (XXXVII)

I (0.5 g) was treated by the method described in S-chloro-methylester (Example 1 Method A described later) but using 1, 2-dibromoethane, melting point 174 to 175 °, [α] _D The title S-2'-bromoethyl ester (0.409 g) at + 120 ° (c 1.04) is obtained as colorless crystals.

Preparation XXXVIII

S-chloromethyl 16α, 17α-epoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrostar-1. 4-diene-17β-carbothioate (XXXVIII)

Method A

16α, 17α-epoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrostar-1 in dichloromethane (7 ml). A suspension of 4-diene-17β-carboxylic acid (753 mg) and 2-fluoro-1-methylpyridinium tosylate (680 mg) was treated dropwise with trimethylamine (1.39 ml) at 0 ° and then 1 hour at 0 °. Stir while. Hydrogen sulfide was passed through the mixture for 15 minutes and the resulting solution was stirred at 0 ° for 1 hour. Dilute with bromochloromethane (0.26 ml) and get 2N. The solid was taken up in chloroform-acetone (9: 1) p. l. c. (2 times).

Crystallization of the main band (515 mg) with acetone yields the title S-chloromethylester epoxide (447 mg) with a melting point of 246 to 251 °, [α] _D + 131 ° (c 0.67) as a white needle.

Method B

16α, 17α-epoxy-9α-fluoro-11β-hydroxy-16-methylene-3-oxoandrostar-1 in dichloromethane. A suspension of 4-diene-17β-carboxylic acid (376 mg) and 2-chloro-N-methylbenzthiazolium trifluoromethane sulfonate (400 mg) is treated dropwise with triethylamine (0.7 ml) at 0 ° C. The resulting solution was stirred at 0 ° C. for 1.25 h and then the mixture was passed through hydrogen sulfide for 10 min. After 1 hour at 0 ° C. bromochloromethane (0.13 ml) is added and the mixture is stirred at room temperature. After 1.5 and 1.8 hours, bromochloromethane (0.13 ml) was added in two or more portions. 15 minutes after the last addition, the reaction mixture is diluted with ethyl acetate (200 ml) and washed continuously with 2N hydrochloric acid, 5% sodium hydrogen carbonate solution and water, dried and evaporated to give a red crystalline solid. The solid was taken up in chloroform-acetone (19: 1) p. l. c (3 times). In the narrower band, the title pink s-chloromethyl ester (134 ml) is obtained, which is t. l. It was confirmed on c.

Recipe XXXIX

S-chloromethyl 9α-fluoro-11β, 17α-dihydroxy-16-methylene-3-oxoandrostar-1. 4-diene-17β-carbothioate (XXXIX)

The XLI (400 mg) solution in trifluoroacetic acid (16 ml) is stirred at room temperature. After 5.5 hours the reaction mixture is evaporated to dryness and the residue is dissolved in ethyl acetate (100 ml). The solution is washed with 5% sodium hydrogen carbonate solution and water, dried and evaporated to yield yellow-green foam (466 mg). The foam is pl c in chloroform-acetone (9: 1) (3 times). Crystallization of a portion (80 mg) of the main band (315 mg) twice with acetone yields the title 16-methylene 17α-alcohol (48 mg) with melting points 242 to 243 ° and [α] _D + 36 ° (c 0.50) as white crystals. do.

Recipe XL

7α-fluoro-17α-hydroxy-16β-methyl-3. 11-dioxoandrostar-1. 4-diene-17β-carboxylic acid (XL).

9α-fluoro-17, 21-dihydroxy-16β-methylandrostar-1 in tetrahydrofuran. The stirred suspension of 4-diene-3, 11, 20-trione (4.842 g) is cooled on ice and treated dropwise over 5 minutes with a solution of flexible acid (4.255 g) in water (15 ml). Stir the reaction at 22 ° for 2.25 hours to dissolve most of the suspension. The solvent is removed in vacuo and water is sometimes added to maintain the original volume. The resulting precipitate was filtered off, washed with water and dried in air and in vacuo to yield the title carboxylic acid with a melting point of 279 to 272 ° (decomposition), [α] _D + 136 ° (c 1.04, dimethylsulfoxide) as a cream colored prism. .

Recipe XLI

9α-fluoro-11β, 17α-dihydroxy-16β-methyl-3-oxoandrostar-1, 4-diene-17β-carbothioic acid (XLI)

Stir 9α-fluoro-11β, 17α-dihydroxy-16β-methyl-3-oxoandrostar-1, 4-diene-17β-carboxylic acid (0.502 g) in anhydrous N, N-dimethylformamide (15 ml) The resulting solution was cooled to -5 ° under nitrogen, treated with N, N'-carbonyldiimidazole (0.435 g) and the reaction stirred at -5 ° for 18 hours. Hydrogen sulphide gas is passed through the reaction for 20 minutes and the solution is stirred for another 4 hours before gradually warming to 22 °. The reaction was poured into ethyl acetate and the resulting solution was washed with 2N hydrochloric acid and water and extracted with 2N-sodium carbonate solution (3 × 50 ml). The combined extracts were washed with ethyl acetate (60 ml) and then poured again with ethyl acetate (100 ml) and acidified to pH 1.0 with hydrochloric acid. The aqueous layer is extracted again with ethyl acetate, the extract is washed with water and saturated sodium chloride solution, dried and the solvent is removed in vacuo to give a white solid which is crystallized twice with ethyl acetate and has a melting point of 198 to 201 ° (decomposition). α] _D + 189 ° (c 0.71) of the title carbothioic acid (0.315 g) is obtained.

Recipe XLII

9α-fluoro-17α-hydroxy-16β-methyl-3, 11-oxoandrostar-1, 4-diene-17β-carbothioic acid (XLII).

A solution of XL (5.587 g) in anhydrous N, N-dimethylformamide (150 ml) was stirred at 20 ° for 4 hours. Hydrogen sulphide gas is passed through the reaction for 10 minutes and the solution is stirred for another hour. Pour the solution into ice (300 ml) and 2N hydrochloric acid (100 ml) to produce a pale yellow precipitate. After filtration and drying overnight (6.268 g) and crystallization with ethyl acetate, the title carbothioic acid (3.761 g) with a melting point of 215 to 218 °, [α] _D + 143 ° (c 0.88, dimethylformamide) was white prism. Obtained.

Preparation XLIII

S-chloromethyl 9α-fluoro-11β, 17α-dihydroxy-16β-methyl-3-oxoandrostar-1, 4-diene-17β-carbothioate (XLIII)

A solution of XLI (0.169 g) and sodium bicarbonate (0.040 g) in N, N-dimethylformamide (6 ml) was treated with bromochloromethane (0.1 ml) and stirring continued at 22 ° for 1 hour. The reaction mixture is diluted with ethyl acetate (100 ml) and the solution is continuously washed with 2N hydrochloric acid, water, 2N-sodium carbonate solution, water, and saturated sodium chloride solution, dried and the solvent is removed in vacuo. Crystallization of the residue with ethyl acetate affords the title S-chloromethylthioester (0.193 g) at melting point 126 to 130 °, [α] _D + 147.5 ° (c 0.64), dissolved in ethyl acetate. .

Recipe XLIV

9α-fluoro-16β-methyl-3, 11-dioxo-17α-propionyl-oxoandrostar-1, 4-diene-17β-carbothioic acid (XLIV)

A solution of XLV (0.485 g) and triethylamine (0.57 mL) in dichloromethane was cooled in ice salt and treated with propionyl chloride (0.43 mL) to stir the reaction at 0 ° for 1.5 h. The mixture was partitioned with ethyl acetate (75ml) in 2N-sodium carbonate solution (75ml) and the organic layer was washed with 2N-sodium carbonate solution, water, 2N-hydrochloric acid, water and saturated sodium chloride solution and dried to remove the solvent in vacuo. Crystalline solid (0.562 g) is obtained. It is dissolved in acetone (10 ml) and diethylamine (1.0 ml) is added and the reaction is stirred at 22 ° for 1.25 h. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate (30 ml) and 2N hydrochloric acid (30 ml). The ethyl acetate layer is washed with water and extracted with 2N-sodium carbonate solution (2 x 30 ml). The combined extracts are washed with ethyl acetate (30 ml), poured with ethyl acetate (60 ml) and acidified to pH 1.0 with hydrochloric acid. After washing the ethyl acetate layer with water and saturated sodium chloride solution and dried to remove the solvent in vacuo and to give a white solid crystallized twice with ethyl acetate, melting point 173 to 180 °, [α] _D + 148 ° (c 0.03) The title ester of (0.290 g) is obtained.

Manufacturing XLV

S-chloromethyl 9α-fluoro-17α-hydroxy-13β-methyl-3, 11-dioxoandrostar-1, 4-diene-17β-carbothioate (XLV)

The solution of XLII (5.006 g) and sodium bicarbonate (1.612 g) in N, N-dimethylacetamide (50 ml) was treated with bromochloromethane (1.24 ml) and the reaction stirred at 22 ° C. for 3.3 h. Dilute the solution with ethyl acetate (70 ml), continue washing with 2N hydrochloric acid, water, sodium metabisulfite solution, water and saturated sodium chloride solution, and dry to remove the solvent in vacuo to give a creamy solid (3.638 g). Analytical specimens were purified tlc (silica gel, chloroform: acetone = 9: 1) and crystallized with ethyl acetate to give the title ester of melting point 223 to 228 ° and [α] _D + 251 ° (≤1.2) as a colorless prism. Are manufactured.

Recipe XLVI

9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxoandrostar-1, 4-diene-17β-carbothioic acid (XLVI)

The stirred XLI (0.511 g) stirred solution in dichloromethane (20 ml) containing triethylamine (0.6 ml) was cooled to 2 °, treated with propionyl chloride (0.45 ml) and the reaction stirred at 2 ° for 2.5 hours. The reaction was partitioned between ethyl acetate and sodium hydrogen carbonate, the organic phase washed with water, 2N hydrochloric acid, water and saturated sodium chloride solution, dried and the solvent removed in vacuo to give a colorless solid (0.634 g). It is dissolved in acetone (30 ml), diethylamine (1.5 ml) is added, and the clear solution is stirred at 22 ° for 55 minutes. The reaction is diluted with ethyl acetate (50 ml), washed with 2N hydrochloric acid and water and extracted with 5% sodium carbonate solution. The extracts are combined, 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, dried and the solvent was removed to give a colorless foam (0.522 g) which was crystallized from ethyl acetate to give a melting point of 174 to 179 °, [α] _D + 107 ° (≤1.0). The title ester of is obtained as a colorless prism (0.307 g).

Preparation XLVII

9α-fluoro-11β, 17α-dihydroxy-16-methylene-3-oxoandrostar-1, 4-diene-17β-carbothioic acid (XLVII)

A solution of 9α-fluoro-11β, 17α-dihydroxy-16-methylene-3-oxoandrostar-1, 4-diene-17β-carboxylic acid in anhydrous N, N-dimethylformamide (10 ml) was 22 ° C., nitrogen Under N, N'-carbonyldiimidazole (0.254 g) and the reaction is stirred at 22 ° for 4 hours. Hydrogen sulfide gas is bubbled into the reaction for 5 minutes and the pale green mixture is stirred at 22 ° for 1 hour. The mixture was diluted with ethyl acetate (150 ml) to give the solution 2N hydrochloric acid. After washing with water and saturated sodium chloride solution and drying, the solvent was removed in vacuo to yield a yellow foam (0.222 g), which was crystallized twice with ethyl acetate and decomposed without dissolution at about 250 °. [Α] _D + The title carbothioic acid (0.078 g) at 117 ° (≦ 0.32) is obtained with a white prism.

Preparation XLVIII

9α-fluoro-11β, 17α-dihydroxy-3-oxoandrostar-1, 4-diene-17β-carboxylic acid (XLVIII)

Suspension of 9α-fluoroprednisolone (10 g) in anhydrous tetrahydrofuran (55 ml) is stirred and treated with a solution of the periodic acid (9.0 g) in water (90 ml) and the mixture is stirred at 22 ° for 2 hours. It is poured into ice water (about 400 ml), stirred for 15 minutes, the solid product is collected, washed with water and dried to give the title acid as a solid (9.42 g). Recrystallization with ethanol has a melting point of 289 to 293 °, [α] _D + 66 ° (≦ 0.73, methanol).

Recipe XLIX

6α, 9α-difluoro-11β, 17α-dihydroxy-16α-methyl-3-oxoandrostar-1,4-diene-17β-carbothioic acid (XLIX)

Stir solution of 6α, 9α-difluoro-11β, 17α-dihydroxy-16α-methyl-3-oxoandrostar-1,4-diene-17β-carboxylic acid (12.0 g) in anhydrous dimethylformamide (250 ml) Treated with N, N′-carbonylamidazole (9.94 g) at room temperature under nitrogen. After 4 hours hydrogen sulfide is passed through the solution for 0.5 hours and the mixture is left for 0.5 hours. The reaction mixture is poured into 2N hydrochloric acid (500 ml) containing ice (about 250 g). The resulting precipitate was collected, washed with water and dried in vacuo to yield the title thioacid as a white solid (11.47 g) with a melting point of 230 to 232 °, [α] _D + 94 ° (≦ 0.91).

Recipe L

17α-acetoxy-6α, 9α-difluoro-13β-hydroxy-16α-methyl-3-oxo-androstar-1, 4-diene-17β-carbothioic acid (L)

A solution of XLIX (1.625 g) and triethylamine (2.0 ml) in dichloromethane (75 ml) is stirred at about 0 °, treated dropwise with acetylchloride (1.275 ml) and stirred at this temperature for 1.25 h. The mixture was washed with 2N-sodium carbonate (50 ml), water, 2N-hydrochloric acid (50 ml), water (3 x 50 ml), brine (50 ml), dried and evaporated to give a white solid (1.91 g). It is dissolved in acetone (40 ml) and stirred with diethylamine (4 ml) at 27 ° for 45 minutes. Concentrate to about 25 ml of the mixture and pour into 2N hydrochloric acid (100 ml) containing ice (about 100 g). After stirring, the resulting precipitates were collected, washed with water and dried to give a solid (1.685 g). Recrystallization of a portion (400 mg) with ethyl acetate yields the title 17α-acetate (280 mg) with a melting point of 175 to 177 °.

Recipe LI

17α-butylyloxy-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrostar-1, 4-diene-17β-carbothioic acid (LI)

Use the same method as described in Preparation L and convert XLIX (2.0 g) to title 17α-butyrate (2.08 g) with butyryl chloride (1.5 ml) instead of acetylchloride. Recrystallization with ethyl acetate has a melting point of 155 to 157 °.

Recipe LII

6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy androstar-1, 4-diene-17β-carbathioic acid (L II)

XLIX (5.0 g) and triethylamine (6.15 ml) solution in dichloromethane (140 ml) were cooled with ice salt and treated dropwise with propionyl chloride (4.7 ml). The reaction mixture is stirred at about 0 ° for 0.75 hours and then washed continuously with 2N-sodium carbonate, water, 2N-hydrochloric acid, water and brine. The solvent is removed after drying to give a white solid (6.34 g). It is redissolved in acetone (120 ml) and diethylamine (12.5 ml) and stirred at room temperature for 1 hour before the volume is reduced to about 75 ml. The solution is poured into 2N hydrochloric acid (200 ml) containing ice (about 300 g), the resulting precipitates are collected, washed with water and dried in the air to yield a white solid (5.17 g) with a melting point of 152 to 155 °. Recrystallization of some (400 mg) with ethyl acetate gave analytical pure titlethioic acid 17α-propionate as colorless crystals (290 mg) having a melting point of 161 to 164 °, [α] _D -27 ° (≤0.95). -Infrared spectrum (in nusol) revealed a different crystalline form than the sample prepared in Preparation XIX.

Preparation L III

S-Chloromethyl-9α-fluoro-16β-methyl-3, 11-dioxo-17α-propionyloxyandrostar-1, 4-diene-17β-carbothioate (L III)

XLV (409 mg) in propionic acid (5 ml), trifluoro acetic anhydride (2 ml) and toluene p-sulfonic acid (0.1 ml of anhydrous chloroform solution, 80 mg / ml), the solution is stirred at 22 ° for 2.75 days. Pour into saturated sodium hydrogen carbonate and extract with ethyl acetate to separate the non-acidic product. The crude material was chromatographed on silica in chloroform-acetone (14: 1) and crystallized with ethyl acetate-petrol (boiling point 60-80 ° C.) to give a title of melting point 205-206 °, [α] _D + 95 ° (≦ 1.15). 17α-propionate is obtained as colorless crystals.

Recipe L IV

S-chloromethyl-9α-fluoro-11β, 17α-dihydroxy-16β-methyl-3-oxoandrostar-1, 4-diene-17β-carbothioate (L IV)

XLV (102 mg) suspension in ethanol (2.5 ml) is stirred with sodium borohydride (10 mg) at 22 ° for 1 hour. The reaction mixture is treated with acetone (5 ml) and then concentrated to dryness. The residue is dissolved in ethyl acetate (25 ml) and washed with N-hydrochloric acid, water and brine. The organic solvent was removed after drying to give the title 11β-alcohol-free colorless foam (103 mg), the main component of which was t. l. Comparison on c (silica: chloroform, 9: 1) showed the same polarity as the sample material.

Manufacturing method LV

S-Chloromethyl-6α, 9α-difluoro-16β-methyl-3-oxo-17α-propionyloxy-11β-trifluoroacetoxyandrostar-1,4-diene-17β-carbothioate (LV )

A solution of Example 5 compound (described later) (100 mg) in anhydrous tetrahydrofuran (2 ml) and pyridine (0.1 ml) was treated with anhydrous trifluoroacetic acid (0.05 ml) and the mixture was stored at room temperature for 0.5 h. . The reaction mixture is poured into water and the product is extracted with ethyl acetate (3X). The organic extracts were washed with water, dried and evaporated to give ¹ Hnmr spectroscopy (single line at 19.9, quantum, deuterium chloroform) and tl c (acetone-petrol, boiling point 40-60 °, 1: 3) on silica gel. A homogeneous title or trifluoroacetate (116 mg) is obtained. Analytical specimens from ether-pentane have melting points 158 to 162 °, [α] _D + 56 ° (≦ 0.23).

Example 1

S-Chloromethyl 9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-flopionyloxyandrostar-1, 4-diene-17β-carbothioate

Method A

The solution of I (2.115 g) in dimethylacetamide (7 ml) is treated with sodium bicarbonate (592 mg) and bromochloromethane (0.46 ml) and the mixture is stirred at room temperature. After 2 hours, the reaction mixture was diluted with ethyl acetate (500 ml), washed with 5% sodium bicarbonate solution and water, dried and evaporated to give an orange foam (1.560 g). P. In chloroform-acetone (19: 1). l. When c, an off-white foam (803 mg) was obtained, it was determined twice with methanol to give the title S-chloromethyl ester (688 mg) having a melting point of 212 to 214 °, [α] D + 44 ° (≤ 1.06) as an off-white needle.

Method B

The title compound is prepared in the same manner using chloroyodomethane instead of bromo chlorometha.

Method C

Sodium brohydride (19 mg) is added to a solution of II (230 mg) in ethanol (3.5 ml) and the solution is stirred at room temperature. After 20 minutes acetone (1 ml) is added and the solution is concentrated to about 1/4 volume. Ethyl acetate (30 ml) was added, the solution was washed with N-hydrochloric acid and water, dried and evaporated to give a white foam (239 mg). In chloroform-acetone (19: 1) p. l. c to give white foam (188 mg) which was determined twice with methanol to give the title S-chloromethyl ester (158 mg) having a melting point of 210 to 212 °, [α] D + 44 ° (C, ≤ 1.07) as a white needle. Obtained.

Example 2

2-Chloromethyl 9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-flopionyloxyandrostar-1, 4-diene-17β-carbothioate

The IV (0.927 g) solution in dimethylacetamide (4 ml) is treated with sodium bicarbonate (0.256 g) and bromochloromethane (0.20 ml) and the mixture is stirred at 22 ° for 2 hours. The reaction mixture is partitioned between ethyl acetate (100 ml) and 2N hydrochloric acid (20 ml) and the aqueous layer is extracted with ethyl acetate. Combine extracts and continue to wash with 2N hydrochloric acid, water, 3% sodium bicarbonate, water and saturated brine. After drying, the solvent is removed and the crude product (757 mg) is crystallized twice with acetone to give the title chloromethyl thiol ester (0.367 g) having a melting point of 247 to 250 ° C., [α] D + 50.5 ° (≦ 0.63).

Example 3

S-Chloromethyl-11β-hydroxy-3-oxo-17α-flopionyl-oxyandrostar-1, 4-diene-17β-carbothioate

The title compound is prepared by the same method as Preparation XIV. Melting point 117 to 120 °, [α] D + 56 ° (≦ 1.3)

Example 4

S-chloromethyl 6α, 9α-difluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrostar-1, 4-diene-17β-carbothioate

0.96, 디메틸설폭시드)의 표제 S-클로로메틸 티오에스테르(0.475g)를 백색 프리즘으로써 수득한다.The stirred solution of VIII (1.360 g) in N, N-dimentylacetamide (10 ml) was treated with sodium carbonate (0.377 g) and bromochloromethane (0.3 ml) and stirring continued for 1.5 hours Ethyl acetate (100 ml) was added The resulting solution is continuously washed with 2N hydrochloric acid, water, sodium metabisulfide solution, water, sodium bicarbonate solution, water and saturated sodium chloride solution, dried and the solution is concentrated until crystallization. The crystallized product (0.765 g) was purified on silica gel by developing with chloroform: acetone (9: 1), plc. The main band was eluted with ethyl acetate and crystallized with ethyl acetate to give a melting point of 271 to 278 °, [α] _D + 116 °, (

0.96, dimethylsulfoxide), is titled S-chloromethyl thioester (0.475 g) as a white prism.

Example 5

S-chloromethyl 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrostar-1, 4-diene-17β-carbothioate

0.35)의 표제 클로로메틸 티올에스테르 (0.404g)가 수득된다.A solution of XVIII (0.546 g) in dimethylacetamide (3 ml) was treated with sodium bicarbonate (202 mg) and bromochloromethane (0.16 ml) at 22 ° for 3 hours. The mixture is treated with 2N hydrochloric acid (50 ml) and the product is extracted with ethyl acetate. The combined extracts were washed continuously with 2N hydrochloric acid, water and saturated brine and dried to remove solvent. Crystallization twice with ethyl acetate results in melting point 272 to 275 ° and [α] _D + 49 ° (

0.35) of the title chloromethyl thiol ester (0.404 g) are obtained.

[Examples 6 to 15]

Following the same general procedure as in Example 1 (Method A), but using 17β-carbothioic acid corresponding to the desired 17β-carbothioate as a starting material (the detailed method is summarized in Table III below), the following compounds were prepared: :

1.05).6. S-Chloromethyl 11β-hydroxy-16β-methyl-3-oxo 17α-propionyloxyandrostar-1, 4-diene-17β-carbothioate, melting point 192-193 °, [α] _D +65 ° (

1.05).

0.99).7. S-chloromethyl 9α-fluoro-11β-hydroxy-16-methylene-3-oxy-17α-propionyloxyandrostar-1, 4-diene-17β-carbothioate, melting point 212 to 221 °, [α] _D -56 ° (

0.99).

1.06).8. S-Chloromethyl 17α-acetoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrostar-1, 4-diene-17β-carbothioate, melting point 220-223 °, [ α] _D + 39.5 ° (

1.06).

1.10).9. S-Chloromethyl 17α-butyryloxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrostar-1,4-diene-17β-carbothioate, melting point 172 to 175 °, [α] _D + 46 ° (

1.10).

1.00).10. S-Chloromethyl 9α-fluoro-11β-hydroxy-17α-isobutyryloxy-16β-kenyl-3-oxoandrostar-1,4-diene-17β-carbothioate, melting point 234-239 ° C. , [α] _D + 43 ° (

1.00).

1.97).11. S-Chloromethyl 9α-fluoro-11β-hydroxy-3-oxo-17α-propionyloxyandrostar-1,4-diene-18β-carbothioate, melting point 196-196 °, [α] _D + 38 ° (

1.97).

0.91).12. S-Chloromethyl 6α-fluoro-11β-hydroxy-3-oxo-17α-propionyloxyandrostar-1,4-diene-18β-carbothioate, melting point 188-191 °, [α] _D + 48 ° (

0.91).

0.80).13. S-chloromethyl 17α-acetoxy-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrostar-1, 4-diene 17β-carbothioate, melting point 280 to 283 ° , [α] _D + 45 ° (

0.80).

0.65).14.S-Chloromethyl 17α-butyryloxy-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrostar-1, 4-diene 17β-carbothioate, melting point 235 to 238 °, [α] _D + 49 ° (

0.65).

0.51, 디메틸설폭시드).15. S-Chloromethyl 9α-fluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrostar-1, 4-diene-17β-carbothioate, melting point 276 to 280 ° ( Resolution), [α] _D + 127 ° (

0.51, dimethyl sulfoxide).

TABLE III

Note: EA = ethyl acetate M = methanol

A = acetone P = petroleum boiling point 60 to 80 °

* Manufactured from a portion of the crude product (2.35g) (400mg)

* Manufactured from a portion of crude product (1.72g) (300mg)

Example 16

S-Chloromethyl 9α-chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1, 4-diene-17β-carbothioate and S-chloromethyl 9β, 11β-epoxy -16β-methyl-3-oxo-17α-propionyloxyandrostar-1, 4-diene-17β-carbothioate

Treatment of a solution of mixture XXII (1.032 g) in dimethylacetamide (5 ml) with bromo chloromethane (0.2 ml), followed by sodium bicarbonate (0.203 g) and the reaction stirred at 22 ° for 1.5 h, ethyl acetate (50 ml) and 2N hydrochloric acid (35 ml). The aqueous phase was extracted again with ethyl acetate (2 × 30 ml), the extracts were combined, washed with 2N hydrochloric acid, water, saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried and the solvent was removed in vacuo to give the title S-chloromethyl ( Creamy foam (0.856 g) containing a mixture of esters is obtained.

1.23)의 S-클로로메틸 9α-클로로-11β-하이드록시-16β-메틸-3-옥소-17α-프로피오닐옥시-안드로스타-1,4-디엔-17β--카보티오에이트(0.232g)가 백색 판상으로 수득된다.It was developed by chloroform: acetone (19: 1) on silica and separated by plc. Crystallization of the larger polar component (0.306 g) twice with ethyl acetate results in a melting point of 222-229 °, [α] _D + 70 ° (

1.23) of S-chloromethyl 9α-chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β--carbothioate (0.232 g) Obtained in white plates.

1.23)의 S-클로로메틸 9α-클로로-11β-하이드록시-16β-메틸-3-옥소-17α-프로피오닐옥시-안드로스타-1, 4-디엔-17β-카보티오에이트(0.065g)가 수득된다.The more polar component (0.210 g) is crystallized with acetone-petrol to give a melting point of 169 to 173 ° (

1.23) S-chloromethyl 9α-chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxy-androsta-1, 4-diene-17β-carbothioate (0.065 g) is obtained do.

Example 17

S-fluoromethyl 9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrostar-1, 4-diene-17β-carbothioate

0.98).의 표제 S-플루오로메틸 에스테르(176mg)가 수득된다.XXIII (660 mg) is stirred at room temperature in the dark with a suspension of fluoride (1.42 g) in acetonitrile (8.5 ml). After 72 hours, the reaction mixture is diluted with ethyl acetate (200 ml) and passed through a pad of diatomaceous earth and filtered. The filtrate was washed with water, dried and evaporated to yield white foam (517 mg). Plc in chloroform-cyclohexane (19: 1) and chloroform to give an off-white foam (270 mg) which was crystallized with methanol and then crystallized with methanol-diethyl ether to give a melting point of 241 to 242 °, [α] _D + 97.5 ° (

0.98)., The title S-fluoromethyl ester (176 mg) are obtained.

Example 18

S-fluoromethyl 9α-fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrostar-1, 4-diene-17β-carbothioate

0.75)의 표제 플루오로메틸티오에스테르(0.244g)가 수득된다.A solution of XXVIII (0.640 g) in acetonitrile (8 ml) is treated with anhydrous silver fluoride (1.511 g) and stirred for 46.5 h at 22 ° in the dark. The mixture is diluted with ethyl acetate (200 ml) and filtered through diatomaceous earth. The solution was washed with 2N hydrochloric acid, water and saturated sodium chloride solution to remove the solvent in vacuo to yield a pale yellow foam (0.504 g). It is chromatographed (plc) on silica gel with 5% acetone in chloroform. Elution of the main band with ethyl acetate and crystallization twice with acetone resulted in melting points of 242 ° to 243 ° (decomposition) and [α] _D + 37 ° (

0.75) title fluoromethylthioester (0.244 g) is obtained.

Example 19

S-fluoromethyl 6α, 9α-difluoro-11β-hydroxy-16α-methyl-17β-propionyloxy-3-oxoandrostar-1, 4-diene-17β-carbothioate

0.35)의 표제플루오로메틸 티올에스테르(0.075g)가 수득된다.A solution of XXIX (310 mg) in acetonitrile (10 ml) is stirred with silver fluoride (947 mg) for 3 days at room temperature in the dark. Ethyl acetate (100 ml) is added and the mixture is filtered through diatomaceous earth. The filtrate is continuously washed with 2N hydrochloric acid, water and saturated brine and then dried. The solvent is removed and the residue is plc in chloroform and then in chloroform-acetone (19: 1). Elution of the product with ethyl acetate and crystallization of the concentrate of the solution gave a melting point of 272 to 273 ° (decomposition), [α] _D + 30 ° (

0.35) of the title fluoromethyl thiol ester (0.075 g) are obtained.

Example 20

S-fluoromethyl 6α, 9α-difluoro-113β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrostar-1, 4-diene-17β-carbothioate

0.73디메틸설폭시드)의 표제 S-플루오로메틸티오에스테르(0.118g)를 백색 프리즘으로 수득한다.A solution of XXXVI (0.804 g) in acetonitrile (60 ml) was treated with silver fluoride (1.821 g) and the reaction stirred for 18 h in the dark. The reaction is diluted with ethyl acetate and filtered through diatomaceous earth. The filtrate was washed with water and saturated sodium chloride solution, dried and the solvent was removed in vacuo to yield a light cream solid (0.636 g). This was purified by silica by developing twice with chloroform: acetone (14: 1) on silica gel. The main band was eluted with ethyl acetate and crystallized five times with ethyl acetate to give a melting point of 305 to 311 °, [α] _D + 125 ° (

0.73 dimethyl sulfoxide) is titled S-fluoromethylthioester (0.118 g) as a white prism.

[Examples 21 to 29]

The same general procedure as in Example 17 was followed, but using the S-dodomethyl 17β-carbothioate corresponding to the desired product as a starting material (detailed methods are summarized in Table IV below) to prepare the following compounds:

1.08).21. S-fluoromethyl 17α-acetoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrostar-1, 4-diene-17β-carbothioate, melting point 248-249 °, [α] _D + 101 °

1.08).

22. S-fluoromethyl 11β-hydroxy-3-oxo-17α-propionyloxy-androsta-1, 4-diene-17β-carbothioate, melting point 112-117 °, [α] _D + 67 ° ( C 0.76).

0.38).23. S-fluoromethyl 11β-hydroxy-16β-methyl-3-17α-oxopropionyloxyandrosta-1, 4-diene-17β-carbothioate, melting point 223 to 225 °, [α] _D + 103 ° (

0.38).

0.75).24. S-Fluoromethyl 9α-chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxy-androsta-1, 4-diene-17β-carbothioate, melting point 182-193 ° , [α] _D + 116 ° (

0.75).

1.00).25. S-fluoro methyl 9α-fluoro-11β-hydroxy-16-methylene-3-oxo-17α-propionyl-oxyandrostar-1, 4-diene-17β-carbothioate, melting point 205 ° to 215 °, [α] _D + 58 ° (

1.00).

0.88).26. S-fluoromethyl 9α-fluoro-11β-hydroxy-3-oxo-17β-propionyloxyandrostar-1, 4-diene-17β-carbothioate, melting point 207-211 °, [α] _D + 70 ° (

0.88).

0.79).27. S-fluoromethyl 6α-fluoro-11β-hydroxy-3-oxo-17α-propionyloxyandrosta-1, 4-diene-17β-carbothioate, melting point 224 to 225 °, [α] _D + 70 ° (

0.79).

0.80).28. S-fluoromethyl 17β-acetoxy-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrostar-1, 4-diene-17β-carbothioate, solution 308 to 310 °, [α] _D + 29 ° (

0.80).

1.05).29. S-fluoromethyl 17α-butyryloxy-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrostar-1,4-diene-17β-carbothioate, melting point 249 To 252 °, [α] _D + 32 ° (

1.05).

TABLE IV

Halogen-exchanged S-fluoromethyl 17α-acyloxyandrostane-17β-carbothioate

EA = Ethyl Acetate A = Acetone M = Methanol P = Petrol Boiling Point 60-80 ° * Purity about 95%

Example 30

S-Bromomethyl 9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxy androstar-1, 4-diene-17β-carbothioate

A solution of XXIII (660 mg) in acetone (20 ml) is stirred with lithium bromide (972 mg) for 5 days at room temperature. Dilution of the reaction mixture with ethyl acetate (150 ml) followed by continued washing with 10% sodium thiosulfate solution, water and brine followed by drying and evaporation yielded off-white foam (9624 mg).

0.99)의 표제 S-브로모메틸 에스테르(499mg)가 무색 결정으로 스득된다.This was crystallized twice with acetone-petroleum ether (solution 40-60 °) to give solutions 186.5-187 °, [α] _D + 2 ° (

0.99) titled S-bromomethyl ester (499 mg) is obtained as colorless crystals.

Example 31

S-2'-fluoroethyl 9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrostar-1, 4-diene-17β-carbothioate

A solution of XXXVII (910 mg) in acetonitrile (20 ml) is stirred with silver fluoride (I) (2.071 g) in the dark at room temperature. After 6 days the reaction mixture is diluted with ethyl acetate (150 ml) and filtered through diatomaceous earth. The filtrate was further diluted with ethyl acetate (150 ml), washed with water, dried and evaporated to yield white foam (704 mg).

0.98)의 표제 S-2'-플루오로에틸 에스테르(253mg)가 수득된다.Chloroform: PIC in acetone (9: 1) gives a more polar product as a yellow foam (431 mg), which is crystallized twice with methanol and has a melting point of 133 to 134 °, [α] _D + 104.5 ° (

0.98) to give the title S-2'-fluoroethyl ester (253 mg).

[Example 32]

S-chloromethyl 9α-fluoro-11β-hydroxy-16-methylene-3-oxo-17α-propionyloxy androstar-1, 4-diene-17β-carbothioate

XXXIX (227 mg) suspension in propionic acid (2.2 ml) and trifluoroacetic anhydride (0.7 ml) was treated with anhydrous chloroform solution of toluene-P-sulfonic acid (0.044 ml, about 80 mg / ml) followed by 6 hours at room temperature. After stirring for 16.5 hours at 3 °. The reaction mixture is diluted with 5% sodium hydrocarbon solution (75 ml) and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried and evaporated to afford brown gum (254 mg). The gum is PIC in chloroform-acetone (19: 1) (3 times). Crystallization of the main band (152 mg) twice with ethanol gave S-chloromethyl 9α-fluoro-17α-hydroxy-16-methylene-3-oxo-11β-propionyloxyandrostar- as shown in ¹ Hnmr spectroscopy. White crystals (30 mg) of the title S-chloromethylester 17α-propionate mixed with 1,4-diene-17β-carbothioate are obtained.

Example 33

S-chloromethyl 9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrost-4-ene-17β-carbothioate

0.83)의 표제 클로롤 메틸 티올에스테르(0.142g)가 백색 침상으로 수득된다.Example 1 Compound (0.646 g) was catalytically reduced with tris (triphenyl phosphine) chlorodium (I) (800 mg) in benzene (100 ml) and chromatographed on silica in chloroform-acetone (9: 1) Crystallized twice with acetone, solution 217-225 °, [α] _D + 54 ° (

0.83) of the title chloromethyl thiol ester (0.142 g) are obtained as white needles.

Example 34

S-fluoromethyl 11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrost-4-ene-17β-carbothioate

0.55)의 표제 Δ^Δ-3-케톤(0.106g)을 수득한다.Example 23 compound of benzene (60 ml) was catalytically reduced at 22 ° for 24 hours and chromatographed several times on silica before solution 174-177 °, [α] _D + 123 ° (

0.55) to give the title ketone Δ ^Δ -3- (0.106g).

Example 35

S-Chloromethyl 9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrostar-1, 4-diene-17β-carbothioate

S-chloromethyl 9β, 11β-epoxy-16β-methyl-3-oxo-17α-propionyl-oxyandrostar-1, 4-diene-17β-carbothioate (about 0.9 mg) in Example 16 Treat with hydrogen-urea complex (about 1 ml) and stir for 24 hours in Silyon.

The mixture is treated with sodium bicarbonate to extract the product twice with ethyl acetate, washed twice with water, dried and evaporated. Real sample on silica in three different solvent systems (acetone-petrol boiling point 40 to 60 °, 1: 2: chloroform-acetone 9: 1: 1 ethyl acetate-petroleum boiling point 40 to 60 °, 1: 2, twice) It was found by tlc in comparison to that the title contains fluorohydrin.

Example 36

S-chloromethyl 6α, 9α, -fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy androstar-1, 4-diene-17β-carbothioate

LV (29 mg) solution in methanol (2 ml) is stored at room temperature for 3 hours. The mixture was evaporated to dryness to give the title 11β - alcohol (25 mg) identified by ¹ Hnmr spectrum (in deuterium dimethyl sulfoxide) and tlc (silica, acetone-petrol boiling point 40-60 °, 1: 3) compared to the real sample. do.

The active androstane compound can be formulated into a formulation suitable for topical administration by conventional methods using topical vehicles. Topical administration as used herein includes blowing and aspiration administration.

Skin topical administration-formulations can be used for the treatment of inflammatory dermatitis in humans and animals, such as eczema, which typically responds to corticosteroid therapy, and also for the treatment of weakly reactive conditions such as pruritus in the human body.

Upon medical administration, the novel compounds according to the invention can be formulated for oral, parenteral or rectal administration in a conventional manner.

Claims (1)

Esterifying a compound of formula (II), a salt thereof, or a compound of formula (II a), or reacting a compound of formula (III) with a compound capable of reducing group Y to a halogen atom, or IV) reducing the compound, deprotecting the compound of formula (V), or reacting with a reagent capable of introducing the desired 9α-halo 11β-hydroxy group to the compound of formula (VI), or (VII) A process for preparing the following compound of formula (I), characterized in part by reducing the compound.

Wherein R ¹ is a fluoro-, chloro- or bromo-kenyl group or 2'-fluoroethyl group, R ² is a COR ⁶ group (wherein R ⁶ is a C _1-3 alkyl group) or OR ² And R ³ together form a 16α, 17α-isopropylidenedioxy group, R ³ may be present as a hydrogen atom, a methyl group (α- or β-coordination) or a methylene group, and R ⁴ is hydrogen, chlorine Or a fluorine atom, R ⁵ is hydrogen or a fluorine atom, and a symbol

Represents a single bond or a double bond, Y is a substitutable substituent, n is 1 or 2, and M is a protecting group.