Field of the Invention

The present invention relates to an improved process for the preparation of substituted steroidal dienes. Such compounds are described in US Patent No. 5,017,568, issued on May 21, 1991 to Holt et al. , as being useful in inhibiting steroid 5-α-reductase.

Background nf the Inven ion

Processes for the preparation of substituted steroidal diene ^' derivatives, have previously been described. In particular the use of oxalyl bromide to convert steroidal α,β-unsaturated-3-ketones to 3-bromo- 3,5-diene intermediates (in 40% yield) followed by catalytic or alkyllithium mediated carboxylation (in 15% yield when N-butyl lithium was used) to yield steroidal- 3,5-diene-3-carboxylic acid derivatives is reported in US Patent No. 5,017,568.

in addition to a low overall yield, another shortcoming of this disclosure is that oxalyl bromide is a toxic, expensive liquid which is difficult to store and is not readily available in the bulk amounts needed for an industrial process.

The use of oxalyl chloride to halogenate steroidal α,β-unsaturated ketones to chloro-steroidal dienes proceeds with only marginal results. Furthermore, the relatively low reactivity of the resultant chloro substituent poses non-trivial synthetic considerations in subsequent transformations. Thus, there is a need in the art for a safe, economical and reliable method to halogenate steroidal α,β-unsaturated ketones to halc- 1,3-dienes. Preferably, said method will brominate cr iodinate steroidal α,β-unsaturated ketones to their corresponding halo-1, 3-dienes.

SUMMARY OF THE TNVENTTON

This invention relates to a process for the halogenation of a compound with multiple functional groups on the same molecule.

This invention relates to an improved process for converting steroidal α,β-unsaturated ketones to their corresponding halo-1,3 diene derivatives.

This invention relates to an improved process for the formation of acid-halide from a steroidal carboxylic acid substituent followed by nucleophilic displacement of said halide.

This invention specifically relates to an improved process for the in situ conversion of steroidal carboxylic acids to steroidal carboxa ides.

This invention specifically relates to a process for the simultaneous bromination and amidation of 3-one- 4-ene-17-carboxylic acid steroidal compounds.

This invention specifically relates to an improved process for the preparation of N-t-butyl-androst-3,5- diene-17β-carboxamide-3-carboxylic acid.

Detailed Description of the Inven inn

By the term "simultaneous" as used herein is meant that the transformation of the steroidal 3-one to 3-halo and 17-carboxylic acid to 17-carboxamide is performed in a single reaction without the isolation of an intermediate.

As used above and throughout the remainder of the specification and claims the carbons of the steroid

nucleus are numbered and the rings are lettered as follows:

By the term "reduced temperature" as used herein is meant below 25°C, preferably between -15 and 15°C, most preferably between 0 and 10°C.

By the term "coupling reagent" as used herein is meant a compound and/or conditions which are capable of reacting with a metalated moiety to form an acid, ester, Cχ_galkylcarbonyl or Ci-^O ³ ----^--- moiety. Preferably said metalated moiety is a lithium metalated moiety prepared by reacting the corresponding halogenated moiety with an alkyllithium reagent. Compounds useful as coupling reagents include chloro formates, alkyl bromides and acid chlorides. Preferably said coupling reagent will utilize carbon dioxide as the reacting compound.

By the term "acid" as used herein is meant any group which is capable of acting as a proton donor including but not limited to; -COOH, -P (0) (OH)2, PH(0)OH, -SO3H and - (CH ) 1-3-COOH.

By the term "ester" as used herein is meant a group consisting of an acid, as defined above, in which the donatable proton or protons are replaced by alkyl substituents.

By the term "solvent" or "appropriate solvent" as used herein is meant an organic solvent such as methylene chloride, ethylene chloride, chloroform.

carbon tetrachloride, tetrahydrofuran (THF) , ethyl ether carbon, toluene or ethyl acetate.

By the term "halogen-Vilsmeier reagent" as used herein is meant a halogenated disubstituted formamide reagent of the structure:

γ

wherein R^ and R^ are independently selected from an alkyl, aryl or arylalkyl group; and X is Br or I; and y is a counter ion, which is prepared by a) reacting, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably ethylene chloride, to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted in situ, preferably at reduced temperatures, with a bromide source or an iodine source, preferably hydrogen bromide gas or b) reacting, 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 an appropriate solvent, preferably methylene chloride.

This invention, therefore, relates to the in situ prepartation and use of a bromo-Vilsmeier reagent or an iodo-Vilsmeier reagent, said reagents being prepared safely and economically from known and readily available

reagents preferably the corresponding chloro-Vilsmeier reagent. As such, this invention will have utility in all reactions wherein bromo-Vilsmeier reagents or iodo- Vilsmeier reagents are utilized.

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 Formula (I) compounds are formed where appropriate by methods well known to those of skill in the art.

The present invention provides a process for the production of a compound of formula (I)

in which:

R ^1' is R3R ⁴ , where R^ and R ⁴ are each independently selected from hydrogen, Ci-galkyl, C3_gcycloalkyl, phenyl; or R~- and R ⁴ taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring containing up to one other heteroatom selected from oxygen and nitrogen; and R2 is an acid, ester, C-]__galkylcarbonyl or C-]__2o alkyl; or .a pharmaceutically acceptable salt, hydrate or

solvate thereof, which comprises reacting, at a reduced temperature, a compound of formula (II)

in the presence of a halogen-vilsmeier reagent and a solvent then quenching with excess H-R ¹ , where R-- is as described above, to form a compound of formula (III)

in which R*-- is as defined above and subsequently, in an appropriate solvent and at a reduced temperature, adding an alkyllithium reagent followed by a coupling reagent to form a compound of formula (I) , provided that when R3 and/or R ⁴ is H the compound of formula (III) is subjected to a basic medium suitable for the selective deprotination of the amide prior to the addition of the alkyllithium reagent, and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.

Preferably said halogen-vilsmeier reagent is prepared by reacting, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride, with a disubstituted formamide

reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride, to form a chloro- Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted in situ, preferably at reduced temperatures, with a bromide source or an iodide source, preferably hydrogen bromide gas.

As used herein, unless otherwise specified, C]__ _n alkyl means a straight or branched hydrocarbon chain having Cι_ _n carbons.

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

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

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

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

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

Preferred organic acids used to describe R-- in formula (I) include; -COOH, -P(0) (OH)2, -PH(0) (OH), -SO3H and - (CH2) 1-3COOH. Particularly preferred among the above acids is -COOH.

Preferred bases utilized in preparing the basic medium used to selectively deprotonate the amide of

formula (III) compounds include metal hydrides, alkyllithium reagents, Grignard reagents and metal alkoxides. Preferred amori'g the above disclosed bases are ethylmagnesium bromide, butyllithium and ethylmagnesium chloride. Particularly preferred among the above disclosed bases is ethylmagensium chloride. Preferably the selective deprotonation of said amide is conducted at a temperature above 25°C, most preferably between 30 and 50°C.

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

A preferred aspect of the invention is the preparation of steroidal halo-1,3-diene systems from steroidal α,β-unsaturated ketones utilizing a halogen- vilsmeier reagent prepared and utilized in ____i____.il.

A preferred aspect of the invention is the halogen- vilsmeier induced formation of an acid halide moiety from a steroidal carboxylic acid moiety, said acid- halide substituent being subject to displacement by a nucleophilic reagent. Preferred nucleophilic reagents as used herein include H-R ¹ where R*-- is as defined above. Especially preferred among the above nucleophilic reagents is tert-butyla ine.

Preferably, therefore, the process of the present invention is particularly useful for preparing a compound of structure (IIIA)

and converting the same into the following compound of structure (IA)

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

I. SYNTHETIC EXAMPLES '

Dimethylformamide, oxalyl chloride, oxalyl bromide, tert-butylamine, 2.0M ethylmagnesium chloride in THF, 1.2M sec-butyllithium in cyclohexane, and (+)-4- cholesten-3-one are available from Aldrich Chemical Co. (Milwaukee, WI) . Hydrogen bromide gas and carbon dioxide gas are available from Matheson (E. Rutherford, NJ) .

Androst-4-en-3-one-17β-carboxylic acid is available from Berliche , Inc. (Wayne, NJ) . 3-Bromo-androsta-3,5-diene- 17β-carboxylic acid was prepared as described in U.S. Patent 5,017,568 (Example 25B(ii)).

Example 1 17ft- r Γ fl.l-dimethylethyl. aminolcarbonyl1andro<■^ a-3.5- ^ ■n - -ca boxy■li(-. acid

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

A flask under nitrogen atmosphere was charged 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 was treated with 6.9 mL (2.5 molar equivalents) of oxalyl chloride while maintaining the temperature between 0-10°C. A white precipitate formed. After stirring for one hour, 50.1 grams (19.6 molar equivalents) of hydrogen bromide gas were bubbled through the solution while maintaining the temperature between 0-10°C. The suspension became a clear colorless solution. The solution was degassed by reducing the solution volume by about one-half by vacuum distillation and restoring to its original volume with methylene chloride. This concentration/refill procedure was repeated. Androst-4-en-3-one-17β-carboxylic acid, 10.0 grams (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 quenched into a vessel containing 100 mL of methylene chloride and 23.1 grams (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 were added and the biphase mixture was filtered through a pad of Celite. The organic phase was separated and reduced to about half its volume by vacuum distillation. The solution was restored to its

original volume with acetone. This concentration/fill procedure was repeated twice more. The resulting acetone solution (about 300 mL) was warmed to about 50°C and was 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-17β- carboxamide, was isolated by filtration and dried. Yield 89%, mp 181-183°C.

(ii) 17β-[[ (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)-androsta-3,5-diene-17β- carboxamide in 250 mL of dry THF was warmed to 30°C under a nitrogen atmosphere. The solution was treated with 29 mL of 2.0M ethylmagnesium chloride (2.5 molar equivalents) in THF, and the temperature was 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 1.2M sec-butyllithium in cyclohexane (2.5 molar equivalents) . After stirring for 5 minutes, excess dry carbon dioxide was bubbled through the solution. The gassing was continued as the solution was allowed to warm to room temperature. The resulting suspension was then washed with 100 mL of 3.3M aq. hydrochloric acid and the aqueous phase was removed. The organic phase was 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 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 was treated with 0.6 g of decolorizing carbon and was filtered through celite. Evaporation of the filtrate followed by trituration in ethyl acetate to afford 6.4 g

of 17β-[ [(1,1-dimethylethyl)amino]-carbonyl]androsta- 3,5-diene-3-carboxylic acid. Yield 63%, mp 248-249°C.

Examplf. -Bromo-N-π .1-dimethylethy . -androst.a-3.5-diene-17ft- carboxamide

A solution of 10 mL of methylene chloride containing 5 mg of p-quinone, and 0.328 g (1.8 molar equivalents) of dimethylformamide was cooled to 0°C and treated with 0.85 g (1.6 molar equivalents) of oxalyl bromide. The reaction mixture was allowed to warm to room temperature and was stirred for 30 minutes. The solution was cooled to about 5°C and 0.95 g (1 molar equivalent) of 3-bromo-androsta-3,5-diene-17β-carboxylic acid in 20 mL of methylene chloride was added to the white suspension. The solution was allowed to warm to room temperature and was stirred for 1.5 hours. The reaction mixture was quenched with 2.2 mL (8.4 molar equivalents) of t-butylamine and stirred for 5 minutes. The mixture was poured into 100 mL of ethyl acetate and the organic phase was washed with 50 mL of 10% aq 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 under vacuum to afford a crude solid which was triturated with 24 mL of 50/50 t- butylmethyl ether/hexane. The solid product was isolated by filtration and dried under vacuum to afford 0.5 gram of 3-bromo-N-(1,1-dimethylethyl)-androsta-3,5-diene-17β- carboxamide. The filtrate was concentrated and triturated as above to yield another 0.25 g of product. The total yield of product was 69%. mp 181-183°C.

Example 3

3-Brnmocholftfit.a-3.5-diene

A solution of 10 mL of methylene chloride containing 0.24 mL (1.2 molar equivalents) of dimethylformamide was cooled to 0°C and treated with 0.62 gram (1.1 molar equivalents) of oxalyl bromide. The resulting white suspension was stirred at -5°C for 45 minutes, and 1.0 gram (1 molar equivalent) of (+)-4- cholesten-3-one in 6 mL of methylene chloride was added to the white suspension. The solution was allowed to warm to room temperature and was stirred 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 under vacuum to afford a crude solid which was purified by silica gel chromatography using hexane to afford 1.1 g of 3-bromocholesta-3,5- diene. Yield 93%. A sample was recrystallized from methanol-diethyl ether which had mp 64-67°C.

Example 4 3-Bromo-N- .1.1-dimethylethy1. -androfit.a-3.5-driene-

17β,-carboxaττn e A flask under nitrogen atmosphere was charged 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 formed. Androst-4-en-3- one-17β-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 afford a solid. The solid was triturated in a solution of t-Butyl methyl ether (4 ml) /hexanes (4 ml), isolated by filtration and dried to yield 3-Bromo-N-(1,1-diemthylethyl)-androsta-3,5-diene- 17β-carboxamide. yield 58%. MP 177-179°C.