SI9300006A - Process for the preparation of substituted steroidal derivatives - Google Patents

Abstract

The invention provides an improved process for the preparation of a halogenated steroidal diene. The process involves the simultaneous transformation of the steroidal 3-one to 3-halo and 17-carboxylic acid to 17-carboxamide in a single reaction without the isolation of an intermediate. The process takes place by reacting the steroidal starting material with a halogen-Vilsmeier reagent.

Description

SMITHKLINE BEECHAM CORPORATION

A process for the preparation of substituted steroid derivatives

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of substituted steroid dienes. Such compounds have been described in U.S. Pat. No. 5,017,568, issued May 21, 1991, by Holt et al., As useful in inhibiting 5-α-reductase steroid.

BACKGROUND OF THE INVENTION

Methods for the preparation of substituted steroidal diene derivatives have already been described. In U.S. Pat. 5,017,568 specifically reported the use of oxalyl bromide for the conversion of steroidal α, 3-unsaturated-3-ketones into 3-bromo-3,5-diene intermediates (in 40% yield), followed by catalytic or alkylityl-mediated carboxylation (in 15% yield when using N-butyl lithium) to give the steroid derivatives of 3,5-diene-3-carboxylic acid.

Aside from the low overall yield, an additional disadvantage of this publication is that oxalyl bromide is a toxic, expensive liquid that is difficult to store and is not readily available in large quantities required for the industrial process.

The use of oxalyl chloride to halogenate steroidal α, β-unsaturated ketones into chloro-steroidal dienes succeeds with only limited results. Furthermore, the relatively low reactivity of the resulting chloro substituent possesses non-trivial synthesis tendencies in later transformations. Thus, there is a need in the art for a safe, economical and reliable process for halogenating steroid aiS-unsaturated ketones into halo 1,3-dienes. Preferably, by said method, the brominated or iodinated α-unsaturated ketones are brominated or iodinated into their corresponding halo-1,3-dienes.

Summary of the Invention

The present invention relates to a process for halogenating a compound with multiple functional groups on the same molecule.

The present invention relates to an improved process for the conversion of steroidal αβ-unsaturated ketones into their corresponding halo-1,3-diene derivatives.

The present invention relates to an improved process for the formation of an acid halide from a steroid carboxylic acid substituent followed by nucleophilic replacement of said halide.

The present invention more specifically relates to an improved process for the in situ conversion of steroid carboxylic acids into steroid carboxamides.

The present invention relates more specifically to a process for the simultaneous bromination and amidation of 3-on-4-en-17-carboxylic acid steroid compounds.

The present invention more specifically relates to an improved process for the preparation of N-t-butylandrost-3,5-diene-17/3-carboxamide-3-carboxylic acid.

A more similar description of the invention

The term simultaneous, as used herein, means the transformation of steroid 3-one into 3-halo and 17-carboxylic acids into 17-carboxamide in a single reaction without isolation of the intermediate.

As used above and after all the further descriptions and claims, the carbon of the steroid core is numbered and the rings are numbered as follows:

The term "reduced temperature" as used herein means below 25 ° C, preferably between -15 and 15 ° C, most preferably between 0 and 10 ° C.

The term coupling reagent as used herein means a compound and / or conditions that are capable of being metabolised by a metallic moiety to form an acidic, ester, alkylcarbonyl or C ₁₂₀ alkyl moiety. Preferably, said metallic moiety, a lithium metal moiety, is prepared by metabolizing the corresponding halogenated moiety with an alkylity reagent. Compounds useful as coupling reagents include chloro formates, alkyl bromides, and acid chlorides. Preferably carbon dioxide is used as the reaction compound in said coupling reagent.

The term acid as used herein means any group capable of reacting as a proton donor, including but not limited to; -COOH, -P (O) (0H) ₂ , PH ((O) OH, -SO ₃ H and - (CH 2 -COOH.

The term ester as used herein means a group consisting of an acid, as defined above, in which the donor proton or protons are replaced by alkyl substituents.

The term solvent or suitable solvent as used herein means an organic solvent such as measuring chloride, ethylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran (THF), ethyl ether carbon, toluene or ethyl acetate.

The term halogen-Wilsmeier reagent as used herein means a halogenated disubstituted formamide reagent having the structure:

χθγ

N = C in which R ⁵ and R ^{6 are} independently selected from an alkyl, aryl or arylalkyl group; and X is Br or J; and Y is the counter ion prepared by:

a) metabolism, preferably at reduced temperatures, of a chloride source, such as oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent such as dialkyl substituted formamide reagent, preferably dimethylformamide, in a suitable solvent, preferably methylene chloride, to obtain chloro chloride, said chloroVilsmeier reagent is reacted in situ, preferably at reduced temperatures, with a bromine source or iodine source, preferably a gas hydrobromide, or

b) metabolizing, preferably at reduced temperatures, a bromide source or an iodide source, preferably oxalyl bromide, with a disubstituted formamide reagent such as a dialkyl substituted formamide reagent, preferably dimethylformamide in a suitable solvent, preferably methylene chloride.

The present invention therefore relates to the in situ preparation and use of a bromoVilsmeier reagent or an iodo-Vilsmeier reagent, wherein the reagent is prepared safely and economically from known and readily available reagents, preferably a suitable chloro-Vilsemier reagent. As such, the present invention has utility in all reactions where bromo-Vilsmeier reagents or iodo-Vilsmeier reagents are used.

Preferred alkyllithium reagents for use herein include n-butyllithium, sec-butyllithium and tert-butyllithium.

Unless otherwise specified, the term halogen and its derivatives as used herein means bromine or iodine.

Pharmaceutically acceptable salts, hydrates and solvates of the compounds of formula (I) are prepared, where appropriate, by methods well known in the art.

The present invention relates to a process for the production of a compound of formula (I):

in which:

R ^{1 is} NR ³ R ⁴ wherein R ³ and R ^{4 are} each independently selected from hydrogen, C 1-6 alkyl, C 1-4 cycloalkyl, phenyl; or R ³ and R ⁴ together with the nitrogen to which they are attached represent a 5-6 membered saturated ring containing up to one different heteroatom selected from oxygen and nitrogen; and R ^{2 is an} acid, ester, C 1-6 alkylcarbonyl or C _1-2 alkyl;

or a pharmaceutically acceptable salt, hydrate or solvate thereof, including reduced-metabolism, compounds of formula (II)

(II) in the presence of a halogen-Vilsmeier reagent and a solvent, the reaction is then stopped with excess HR ¹ where R ¹ is as described above to give the compound of formula (III):

halogen (III) in which R ¹ is as defined above and then in a suitable solvent and at reduced temperature an alkylityl reagent is added followed by a coupling reagent to give the compound of formula (I) if R ³ and / or R ⁴ H, the compound of formula (III) is subjected to a basic medium suitable for the selective deprotonation of the amide before the alkylityl reagent is added, and then a pharmaceutically acceptable salt, hydrate or solvate thereof is obtained.

Preferably, said halogen-Wilsmeier reagent is prepared by, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent such as dialkyl substituted formamide reagent, preferably dimethylformamide, in a suitable topidyl, preferably a chloro-Vilsmeier reagent is obtained, whereby the chloro-Vilsmeier reagent is reacted in situ, preferably at reduced temperatures, with a bromide source or an iodide source, preferably with a gas bromine hydrogen.

As used herein, unless otherwise specified, it means a C _n alkyl, straight or branched hydrocarbon chain with the carbons.

As used herein, unless otherwise specified, alkyl means a straight or branched hydrocarbon chain.

As used herein, unless otherwise specified, an aryl is an aromatic carbocyclic or heterocyclic ring which is unsubstituted or substituted by non-reactive substituents.

Preferably, the halogen-Vilsmeier reagents used in the dihalogenation of the compounds of formula (II) are prepared and used in situ.

Preferably said halogen-Vilsmeier reagent is a bromo-Vilsmeier reagent.

Preferably said bromo-Wilsmeier reagent is (bromomethylene) dimethyl ammonium bromide.

Preferred organic acids used to describe R ² in formula (I) include: -COOH, -P (O) (OH) ₂ , -PH (O) (OH), -SO ₃ H, and - (CH ^ COOH Particularly preferred of the above acids is -COOH.

Preferred bases used in the preparation of the basic medium used for the selective deprotonation of the amide of compounds of formula (II) include metal hydrides, alkyllithium reagents, Grignard reagents and metal alkoxides. Preferred bases described above are ethylmagnesium bromide, butyllithium and ethylmagnesium chloride. Particularly preferred of the bases described above is ethylmagnesium chloride. Preferably, the selective deprotonation of said amide is conducted at a temperature above 25 ° C, most preferably between 30 and 50 ° C.

Preferably, an allyl lithium reagent is used to initiate halogen-metal exchange on the compounds of formula (III), sec-butyllithium.

An advantageous aspect of the present invention is the preparation of sterodine halo-1,3-diene systems from sterodine α, β-unsaturated ketones using a halogen-Vilsmeier reagent, which is prepared and used in situ.

An advantageous aspect of the present invention is the formation of an acid halide moiety from the sterodine carboxylic acid moiety by the halogen-Vilsmeier reagent, wherein said acid halide substituent is displaced by the nucleophilic reagent. Preferred nucleophilic reagents as used herein include HR ¹ where R ¹ is as defined above. Particularly preferred among the above nucleophilic reagents is tert-butylamine.

Preferably, therefore, the process of the present invention is particularly useful for the preparation of a compound of structure (ΙΙΙΑ):

Ο

(ΙΙΙΑ) and its conversion to the following compound of structure (IA)

Oh

II

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Without further elaboration, it is believed that the skilled person, using the foregoing description, can use the present invention to its fullest extent. The following examples are therefore to be construed as predominantly illustrative rather than limiting the scope of the present invention in any sense.

I. Examples of synthesis

Dimethylformamide, oxalyl chloride, oxalyl bromide, tert-butylamines, 2.0 M ethylmagnesium chloride in THF, 1.2 M sec-butyllithium in cyclohexane and (+) - 4-cholesten-3-one are available from Aldrich Chemical Co. (Mihvaukee, WI). Hydrogen bromide gas and carbon dioxide gas are available from Matheson (E. Rutherford, NJ). Androst-4-en-3one-17/3-carboxylic acid is available from Berlichem, Inc. (Wayne, NJ).

3-Bromo-androsta-3,5-diene-17/3-carboxylic acid was prepared as described in U.S. Pat. 5,017,568 (Example 25B (ii)).

Example 1

17g-i [(1,1-dimethylethyl) amino] carbonyl-sulphon-3,5-diene-3-carboxylic acid (i) 3-Bromo-N- (1,1-dimethylethyl) -androsta-3,5-diene 17/3-carboxamide

Fill the flask under a nitrogen atmosphere with 100 ml of methylene chloride and 6.12 ml (2.5 molar equivalents) of dimethylformamide. The solution was cooled to 0-5 ° C and treated with 6.9 ml (2.5 molar equivalents) of oxalyl chloride while maintaining the temperature between 0-10 ° C. A white precipitate forms. After stirring for one hour,

50.1 g (19.6 molar equivalents) of the bromine gas are bubbled through the solution while maintaining the temperature between 0-10 ° C. The suspension becomes a clear colorless solution. The solution is degassed by reducing the volume of the solution by about one half by vacuum distillation and returning to its original volume with methylene chloride. We repeat this concentration / replenishment process. Androst-4-en-3-one17 / 3-carboxylic acid, 10.0 g (1 molar equivalent), was added to the resulting white suspension and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into a container containing 100 ml of methylene chloride and 23.1 g (10 molar equivalents) of tert-butylamine while maintaining the temperature between 0-10 ° C. The mixture was stirred for 30 minutes. About 100 ml of water is added and the biphasic mixture is filtered through a Celite pad. The organic phase is separated and reduced to about half its volume by vacuum distillation. Return the solution to its original volume with acetone. Repeat this concentration / replenishment procedure twice more. The resulting acetone solution (about 300 ml) is heated to about 50 ° C and treated with about 100 ml of water to precipitate the product. The suspension was cooled and the product, 3-bromo-N (1,1-dimethylethyl) -androsta-3,5-diene-17/3-carboxamide, was isolated by filtration and dried. Yield 89%, m.p. 181-183 ° C.

(ii) 17 / 3- ([(1,1, dimethylethyl) amino] carbonyl] androsta-3,5-diene-3-carboxylic acid

A solution of 10.0 g (1 molar equivalent) of 3-bromo-N- (1,1-dimethylethyl) -androst-3,5diene-17/3-carboxamide in 250 ml of dry THF was heated to 30 ° C under a nitrogen atmosphere. The solution was treated with 29 ml of 2.0 M ethyl magnesium chloride (2.5 molar equivalents) in THF and allowed to rise to about 40-50 ° C. After stirring for 20 minutes, the reaction was cooled to 0-5 ° C and treated with 82.5 ml of 1.2 M secbutyllithium in cyclohexane (2.5 mole equivalents). After stirring for 5 minutes, excess dry carbon dioxide is bubbled through the solution. Continue pouring while allowing the solution to warm to room temperature. The resulting suspension was then washed with 100 ml of 3.3 M aqueous hydrochloric acid and the aqueous phase was removed. The organic phase is washed twice with about 150 ml of water. About 85 ml of water was added to the organic phase, and the organic phase was then removed by distillation under reduced pressure. The resulting aqueous suspension of the product was extracted into 100 ml of methyl ethyl ketone. The aqueous phase was separated and the organic phase was washed with 100 ml of water. The organic phase is treated with 0.6 g of decolourising charcoal and filtered through Celite. Evaporation of the filtrate was followed by trituration in ethyl acetate to give 6.4 g of 17/3 - [[(1,1-dimethylethyl) amino] carbonyl] androsta-3,5-diene-3-carboxylic acid. Yield 63%, m.p. 248-249 ° C.

Example 2

3-Bromo-N- (1,1-dimethylethyl) -androsta-3,5-diene-17/3-carboxamide

A solution of 10 ml of methylene chloride containing 5 mg of p-quinone and 0.328 g (1.8 molar equivalent) of dimethylformamide were cooled to 0 ° C and treated with 0.85 g (1.6 molar equivalent) of oxalyl bromide. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The solution was cooled to about 5 ° C and 0.95 g (1 molar equivalent) of 3-bromo-androst-3,5-diene-17/3-carboxylic acid in 20 ml of methylene chloride was added to the white suspension. Allow the ratopa to warm to room temperature and stir for 1.5 hours. Pour the reaction mixture with 2.2 ml (8.4 molar equivalents) of t-butylamine and stir for 5 minutes. The mixture was poured into 100 ml of ethyl acetate and the organic phase was washed with 50 ml of 10% aqueous sodium hydroxide. The aqueous phase was separated and extracted with 50 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude solid, which was triturated with 24 ml of 50/50 t-butylmethyl ether / hexane. The solid was isolated by filtration and dried under vacuum to give 0.5 gram

3-bromo-N- (1,1-dimethylethyl) -androsta-3,5-diene-17/3-carboxamide. The filtrate was concentrated and triturated as above to give a further 0.25 g of product. The overall product yield is 69%, m.p. 181-183 ° C.

Example 3

3-Bromocholesta-3,5-diene

A solution of 10 ml of methylene chloride containing 0.24 ml (1.2 molar equivalent) of dimethylformamide was cooled to 0 ° C and treated with 0.62 g (1.1 molar equivalent) of oxalyl bromide. The resulting white suspension was stirred at -5 ° C for 45 minutes and 1.0 g (1 molar equivalent) of (+) - 4-cholesten-3-one in 6 ml of methylene chloride was added to the white suspension. Allow the solution to warm to room temperature and stir for 30 minutes. The reaction mixture was poured into a mixture of 100 ml of ethyl acetate and 40 ml of water. The organic phase was separated and extracted with 50 ml of ethyl acetate. The combined organic phases were washed with 10 ml of brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude solid which was purified by silica gel chromatography using hexane to give 1.1 g of 3-bromocholesterol-3,5diene. Yield 93%. The sample was recrystallized from methanol-diethyl ether having a melting point at 64-67 ° C.

Example 4

3-Bromo-N- (1,1-dimethylethyl) -androsta-3,5-diene-17/3-carboxamide

Fill the flask under a nitrogen atmosphere with dimethylformamide 0.6 g (2.6 molar equivalents) in methylene chloride (20 ml). The solution was cooled to 0-5 ° C and treated with oxalyl bromide 1.71 g (2.5 molar equivalents) while maintaining the temperature between 0-10 ° C. A white precipitate forms. Androst-4-en-3-one-17/3-carboxylic acid, 1 g (1 molar equivalent) was added to the resulting white suspension and the mixture was warmed to near room temperature and stirred for 30 minutes. The reaction was treated with tert-butylamine, 2.2 ml (8 molar equivalents), in methylene chloride (2 ml), while maintaining the temperature between 0-10 ° C. The reaction was stirred for 10 minutes, then poured into a mixture of ethyl acetate (150 ml) and 10% sodium hydroxide (50 ml). The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated to give a solid product. The solid was triturated in a solution of t-butyl methyl ether (4 ml) / hexanes (4 ml), isolated by filtration and dried to give

3-Bromo-N- (1,1-dimethylethyl) -androsta-3,5-diene-17 H -carboxamide. The yield is 58%. Tal. 177-179 ° C.

Claims (24)

Patent claims A process for the preparation of a compound of formula (I) Oh G in which: R ^{1 is} NR ³ R ⁴ , wherein R ³ and R ^{4 are} each independently selected from hydrogen, alkyl, C _3-5 cycloalkyl, phenyl; or R ³ and R ⁴ together with the nitrogen to which they are attached represent a 5-6 membered saturated ring containing up to one heteroatom selected from oxygen and nitrogen; and R ^{2 is an} acid or ester; or a pharmaceutically acceptable salt, hydrate or solvate thereof, characterized in that a) at reduced temperature, the compound of formula (II) is reacted O (II) in the presence of a halogen-Vilsmeier reagent and solvent, is then terminated by reaction with excess HR ¹ , wherein R ¹ is as previously defined to give a compound of formula (III) wherein halogen is bromine or iodine; and R ¹ is as defined above and b) subsequently, in a suitable solvent and at reduced temperature, an allycyl lithium reagent, followed by a coupling reagent, is added to give the compound of formula (I) to subject the compound of formula (III) when R ³ and / or R ⁴ H. to a basic medium suitable for the selective deprotonation of the amide, prior to the addition of an allycyl lithium reagent and then optionally preparing a pharmaceutically acceptable salt, hydrate or solvate. Process according to claim 1, characterized in that the halogen-Wilsmeier reagent is prepared by metabolizing, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride with a disubstituted formamide reagent such as dialkyl substituted formamide reagent, preferably dimethyl formamide, in a suitable solvent, preferably methylene chloride, to give the chloroVilsmeier reagent, said chloro-Wilsmeire reagent being reacted, preferably at reduced temperatures, with a bromide source or an iodide source, preferably with a gas bromide hydrogen gas. Process according to claim 2, characterized in that the halogen-Vilsmeier reagent is a bromo-Vilsmeier reagent. Process according to claim 2, characterized in that the halogen-Vilsmeier reagent is an iodo-Vilsmeier reagent. Process according to claim 3, characterized in that the bromo-Wilsmeier reagent is (bromomethylene) dimethyl ammonium bromide. A process according to claim 2, characterized in that R ^{2 is} : -SO ₃ H, -P (O) (OH) ₂ , -PH (O) (OH) or - (CH 2 COOH. The process of claim 2, wherein R ^{2 is} -COOH. Process according to claim 2, characterized in that the base used for the preparation of the basic medium is selected from the group consisting mainly of: hydrides, alkyl lithium, gringnard reagents and metal alkoxides. A process according to claim 8, characterized in that the base is ethylmagnesium bromide or ethylmagnesium chloride. A process according to claim 9, characterized in that the base is ethylmagnesium chloride. 11. The process of claim 2, wherein the alkyllithium reagent is sec-butyllithium. A process according to claim 2, wherein R ^{1 is} -N (H) C (CH ₃ ) ₃ . Process according to claim 2, characterized in that a compound is prepared Oh II or a pharmaceutically acceptable salt, hydrate or solvate thereof. 14. A process for the preparation of a steroid carboxamide substituent, characterized in that the corresponding carboxylic acid is halogenated with a halogen-Vilsmeier reagent and then terminated with excess HR ¹ , wherein R ^{1 is} NR ³ R ⁴ , wherein R ³ and R ^{4 are} each independently selected from hydrogen, _g alkyl, C ₃ ^ cycloalkyl, phenyl; or R ³ and R ⁴ together with the nitrogen to which they are attached represent a 5-6 membered saturated ring which includes up to one heteroatom selected from oxygen and nitrogen. Process according to claim 14, characterized in that the halogen-Wilsmeier reagent is prepared by metabolizing, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride with a disubstituted formamide reagent, such as dialkyl substituted formamide reagent, preferably dimethylformyl , in a suitable solvent, preferably methylene chloride, to give the chloroVilsmeier reagent, said chloro-Wilsemier reagent being reacted in situ, preferably at reduced temperatures, with a bromide source or an iodide source, preferably with a gas bromine hydrogen gas. A process according to claim 15, characterized in that it is halogen bromine. Process according to claim 16, characterized in that the bromo-Wilsmeier reagent is prepared and used in situ. 18. The process according to claim 17, wherein the bromo-Wilsmeier reagent is (bromomethylene) dimethyl ammonium bromide. 19. A process for the preparation of steroidal halo-1,3-dienes, characterized in that the corresponding α, / 3-unsaturated ketone is halogenated with a halogen-Vilsmeier reagent. Process according to claim 19, characterized in that the halogen-Wilsmeier reagent is prepared by metabolizing, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride with a disubstituted formamide reagent such as dialkyl substituted formamide reagent, preferably dimethylformamide , in a suitable solvent, preferably methylene chloride, to obtain the chloroVilsmeier reagent, said chloro-Wilsmeier reagent being reacted in situ, preferably at reduced temperatures, with a bromide source or an iodide source, preferably a gas bromine hydrogen gas. 21. The method of claim 20, wherein the compound is steroid bromo-1,3-diene. The process of claim 21, wherein the compound is 3-bromo-3,5diene. A process according to claim 22, characterized in that the halogen-Wilsmeier reagent is (bromomethylene) dimethyl ammonium bromide. 23. A process for halogenating multiple functional groups on a single molecule, characterized in that the molecule is halogenated with multiple functional groups with a halogen-Vilsmeier reagent. Process according to claim 24, characterized in that the halogen-Wilsmeier reagent is prepared by metabolizing, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride with a disubstituted formamide reagent such as dialkyl substituted formamide reagent, preferably dimethylformamide , in a suitable solvent, preferably methylene chloride, to obtain the chloroVilsmeier reagent, said chloro-Vilsmeie reagent is reacted in situ, preferably at reduced temperatures, with a bromide source or an iodide source, preferably a gas bromine hydrogen chloride.