SK80094A3 - Method of preparation of halogenated stereoide dienes - 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

Process for the preparation of halogenated sreroid dienes

Technical field

The present invention relates to a process for the preparation of sub-secreted steroid dienes. Such compounds are described in U.S. Patent No. 5,017,568, issued May 21, 1991 (Ηοΐτ et al.), As useful for inhibiting seroid 5-α-reductase.

Current state of technology

Methods for the preparation of the sub-cross-linked sreroid diene derivatives have been described in the above-mentioned patent specification. Specifically, use of oxalyl bromide to convert steroid α, β-unsaturated-3-ketones to 3-bromo-3,5-diene intermediates (in 40% yield) followed by catalytic or alkyl lithium mediated carboxylation (with 15% yield when used). butyllithium) to form derivatives of the theroid 3,5-diene-3-carboxylic acid is described in U.S. Pat. No. 5,017,568.

In addition to the low overall yield and other drawbacks of this disclosure, it should be added that oxalyl bromide is a toxic, expensive liquid that is difficult to store and is not readily accessible in the large quantities required for industrial preparation.

The use of oxalyl chloride to halogenate the aero-, β-unsaturated clones to the chloro-steroid dienes continues with only marginal results. In addition, the relatively low reactivity of the resulting chlorine substituent causes no trivial synthetic issues in subsequent transformations. Therefore, there is a need in the art for a safe, economical and reliable method for halogenating steroidal α, β-unsaturated ketones to halogen-1,3-dienes. Preferably, the steroidal α, β-unsaturated ketones will be brominated or iodinated to their corresponding halogen-1,3-dienes.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention is directed to a process for halogenating compounds having multiple functional groups on the same molecule.

Another object of the invention is to convert steroid α, β-unsaturated ketones to their corresponding halogen-1,3-diene derivatives.

A further aspect of the invention is the formation of an acid halide from a steroid carboxylic acid substituent, followed by nucleophilic displacement of said halide.

A further aspect of the invention is the in situ conversion of steroid carboxylic acids to steroid carboxamides.

A further aspect of the invention is the simultaneous bromination and amidation of 3-on-4-ene-17-carboxylic acid steroid compounds.

Another object of the invention is the preparation of N-t-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid.

DETAILED DESCRIPTION OF THE INVENTION

The term simultaneous as used herein means that the transformation of the steroid 3-one to 3-halogen and 17-carboxylic acid to 17-carboxamide is carried out in a single reaction without isolation of the intermediate.

As described above and in the claims, the carbons of the steroid core are numbered and the circles are indicated by letters as follows:

The term reduced temperature, a temperature below 25 ° C, preferably between 0 ° C and 10 ° C, more preferably, as above

-15 ° C as used herein means

C, most preferably, a term coupling agent as used herein means a compound and / or reaction conditions in which reaction with a metal moiety is possible to form an acid, ester, C 1-6 alkylcarbonyl or C 1-6 alkyl moiety. Preferably said metal moiety is a lithium metal moiety prepared by reacting the corresponding halogenated moiety with an alkyllithium reagent. Compounds useful as coupling agents include chloroformates, alkyl bromides, and acid chlorides. Preferably said coupling agent will use carbon dioxide as the reaction compound.

The term acid as used herein means any group capable of reacting as a proton donor, including but not limited to -COOH,-, (O) (O) 2 · PH (O) OH, -SO ₃ H, and - _{(CH2) 1} _ ₃ -COOH.

The term ester as used herein means a group consisting of an acid as defined above in which the proton (s) to be provided are replaced by alkyl substituents.

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

The term halogen-Vilsmeier reagent, as used herein, means a halogenated disubstituted formamide reagent of the structure:

wherein and r 6 are independently selected from alkyl, aryl or arylalkyl;

X is bromine or iodine; and

Y is the proxion that is being prepared

a) reaction, preferably at reduced temperatures, of a chloride source, for example oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, for example a dialkyl substituted formamide reagent, preferably dimethylformamide, in a suitable solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent reacts in situ. preferably at reduced temperatures, with a bromide source or iodide source, preferably hydrogen bromide gas, or

b) reacting, preferably at reduced temperatures, a bromide source or iodide source, preferably oxalyl bromide with a disubstituted formamide reagent, for example 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 bromo-Vilsmeier reagent or iodo-Vilsmeier reagent, wherein said reagents are prepared safely and economically from known and readily available reagents, preferably from the corresponding chloro-Vilsmeier reagent. As such, the present invention will have utility in all reactions where bromine-Vilsmeier reagents or iodine-Vilsmeier reagents are utilized.

Preferred alkyl lithium reagents used herein include n-butyllithium, sec-butyllithium and tert-butyllithium.

is not specified and its derivatives as used herein,

Unless otherwise, halogen means bromine or iodine.

Pharmaceutically acceptable salts of the nin hydrates of formula (I) are prepared by methods well com.

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

in which:

R it is NR R, and wherein R ³ is independently selected from hydrogen, C ₁ _galkylu, C ^ _gcykloalkylu, phenyl; or R ³ and R 6 together with the nitrogen to which they are attached represent a 5 to 6-membered saturated ring containing at most one other heteroatom selected from oxygen and nitrogen; an

R is an acid, ester, C1-4 alkylcarbonyl or C2Q ^and alkyl;

or a pharmaceutically acceptable salt, solvate or hydrate thereof, which comprises a reduced temperature reaction of a compound of formula (II)

) in the presence of halogen-Vilsmeier rapid cooling with an excess of HR ¹ , reagent and solvent, where _n 1 .....

R is as described above to give a compound of formula (III)

and

(III) in which

R ¹ is as defined above in a solvent and at a reduced coupling of β 3 followed by reaction, at a suitable temperature, by adding an alkyllithium reagent and a reagent to form a compound of formula (I), provided that R and / or R 6 is H, ) is subjected to a basic medium suitable for the selective deprotonation of the amide prior to addition of the alkyllithium reagent followed by optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.

Preferably, said halogen-Vilsmeier reagent is prepared by reaction, preferably at reduced temperatures, of a chloride source, for example oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, for example a dialkyl substituted formamide reagent, preferably dimethylformamide, in a suitable solvent, preferably methylene chloride. A Vilsmeier reagent, wherein said chlorine-Vilsmeier reagent reacts in situ, preferably at reduced temperatures, with a bromine source or an iodine source, preferably hydrogen bromide gas.

Unless otherwise specified, C ^ .j alkyl is a straight or branched hydrocarbon chain having C ^ _ _n carbons.

Unless otherwise stated, alkyl means a straight or branched hydrocarbon chain.

Unless otherwise indicated, 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 compounds of formula (II) are prepared and used in situ.

Said halogen-Vilsmeier reagent is preferably bromine Vilsmeier reagent.

Said bromo-Vilsmeier reagent is: preferably (bromomethylene) -dimethylammonium bromide.

The preferred organic acids used as R in formula (I) include: -COOH, -P (O) (OH) _2, -PH (O) (OH), -SO ₃ H and - _{(CH2) 1} _ ₃ COOH. Most preferred is -COOH.

Preferred bases used to prepare the basic medium used to selectively deprotonate the amide of formula (III) include metal hydrides, alkyl lithium reagents, Grignard reagents and metal alkoxides. Ethylmagnesium bromide, butyllithium and ethylmagnesium chloride are preferred. Most preferred is ethylmagnesium chloride. Preferably, the selective deprotonation of said amide is carried out at a temperature above 25 ° C, most preferably between 30 ° C and 50 ° C.

The alkyllithium reagent used to initiate the halogen-metal exchange in the compounds of formula (III) is preferably sec-butyllithium.

Preferred is the preparation of steroidal halogen-1,3-diene systems from steroidal α, β-unsaturated ketones using a halogen-Vilsmeier reagent prepared and used in situ.

A preferred aspect of the invention is the halogen-Vilsmeier-induced formation of a halide-acid moiety from a steroid carboxylic acid moiety, wherein said acid halide substituent is replaced by a nucleophilic reagent. Preferred nucleophilic agents used herein include HR ¹ , wherein R ¹ is as defined above. Among the above-mentioned nucleophilic agents, tertiary butylamine is particularly preferred.

Preferably, the present invention is used to prepare a compound of structure (IIIA)

ABOUT

and converting the compound to the following compound of structure (IA)

- 9

II

CN (H) C _(CH3)

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

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

DETAILED DESCRIPTION OF THE INVENTION

Dimethylformamide, oxalyl chloride, oxalyl bromide, tert-butylamine, 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. (Milwaukee, VI). 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 Berlichem, Inc. (Vayne, NJ) 3-Bromo-androsta-3,5-diene-17β-carboxylic acid was prepared as described in US Patent No. 5,017,568 (Example 25b (iii)).

Example 1

17β - [[(1,1-dimethylethyl) amino] carbonyl] androsta-3,5-diene-3-carboxylic acid (i) 3-bromo-N- (1,1-dimethylethyl) androsta-3,5-diene-17β -carboxam id

The flask was charged with 100 mL of methylene chloride and 6.12 mL (2.5 mol) of dimethylformamide under a nitrogen atmosphere. The solution was cooled to 0-5 ° C and reacted with 6.9 mL (2.5 mol) of oxalyl chloride, maintaining the temperature between 0-10 ° C. A white precipitate formed. After stirring for one hour, 50.1 grams (16.6 moles) of hydrogen bromide gas was bubbled through the solution, maintaining the temperature between 0-10 ° C. The suspension became a clear colorless solution. The solution was degassed by reducing the volume of the solution by about one-half by vacuum distilling off and making up to its original volume with methylene chloride. This concentration and replenishment procedure was repeated. 10.0 grams (1 mol) of androst-4-en-3-one-17β-carboxylic acid was added to the resulting white suspension and the mixture was warmed to room temperature and stirred for two hours. The reaction mixture was stirred into a vessel containing 100 mL of methylene chloride and 23.1 grams (10 mol) of tertiary butylamine, maintaining the temperature between 0-10 ° C. The mixture was stirred for 30 minutes. About 100 mL of water was added and the biphasic 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 recovered to its original volume with acetone. This concentration / replenishment procedure was repeated two more times. The resulting acetone solution (about 300 mL) was warmed to about 50 ° C and treated with about 10 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 mol) of 3-bromo-N- (1,1-dimethylethyl) -androsta-3,5-diene-17β-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 ethylmagnesium chloride (2.5 mol) in THF and allowed to rise to approximately 40-50 ° C. After stirring for 20 minutes, the reaction mixture was cooled to 0-5 ° C and treated with 82.5 mL of 1.2 M sec-butyllithium in cyclohexane (2.5 mol). After stirring for 5 minutes, excess dry carbon dioxide was bubbled through the solution. Gas bubbling was continued as the solution was allowed 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 discarded. The organic phase was washed twice with approximately 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 product suspension 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 filtered through celite. Evaporation of the filtrate followed by trituration in ethyl acetate gave 6.4 g of 17β - [[(1,1-dimethylethyl) amino] carbonyl] androsta-3,5-diene-3-carboxylic acid. Yield 63%, mp 248-249 ° C.

Example 2

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

A solution of 10 ml of methylene chloride containing 5 mg of p-quinone and 0.328 g (1.8 mol) of methylformamide was cooled to 0 ° C and treated with 0.85 g (1.6 mol) 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 mol) 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 stirred for 1.5 hours. The reaction mixture was quenched with 2.2 mL (8.4 mol) 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% 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-butyl methyl ether / hexane. The solid product was isolated by filtration and dried under vacuum to give 0.5 grams of 3-bromo-N- (1,1-dimethylethyl) -androsta-3,5-diene-17β-carboxamide. The filtrate was concentrated triturated as above to give an additional 0.25 g of product. The total yield of the product was 69%, m.p.

183 ’C.

Example 3

3-bromocholesta-3,5-diene

A solution of 10 ml of methylene chloride containing 0.24 ml (1.2 mol) of dimethylformamide was cooled to 0 ° C and treated with 0.62 g (1.1 mol) of oxalyl bromide. The resulting white suspension was stirred at -5 ° C for 45 minutes and 1.0 g (1 mol) 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 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 in vacuo to give a crude solid, which was purified by silica gel chromatography using hexane to give 1.1 g of 3-bromo-chloro-3,5-diene. The yield was 93%. The sample was recrystallized from methanol-diethyl ether, mp 64-67 ° C.

Example 4

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

A flask under nitrogen was charged with 0.6 g (2.6 mol) of dimethylformamide in methylene chloride (20 mL). The solution was cooled to 0-5 ° C and reacted with 1.71 g (2.5 mol) of oxalyl bromide, maintaining the temperature between 0-10 ° C. A white precipitate formed. 1 g (1 mol) of androsr-4-en-3-one-17β-carboxylic acid was added to the resulting white sus pension and the mixture was warmed to near room temperature and stirred for 30 minutes. The reaction mixture was treated with 2.2 mL (8 mol) of tert-butylamine in methylene chloride (2 mL), maintaining the temperature between 0-10 ° C. The reaction mixture was stirred for 10 minutes and then poured into ethyl acetate (15 mL). 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. The solid was triturated in t-butyl methyl ether (4 mL) / hexane (4 mL). It was isolated by filtration and dried to give 3-bromo-N- (1,1-dimethylethyl) -androsta-3,5-diene-17β-carboxamide. Yield 58%. Melting point: 177-179 ° C.

Claims (20)

PATENT CLAIMS A process for the preparation of a compound of formula (I) -i in which: R ¹ is NR 4 R ⁴ , wherein R 4 and R 4 are each independently selected from hydrogen, C 1-6 alkyl, C 8-6 cycloalkyl, phenyl or R 4 and R ⁴ together with the nitrogen to which they are attached form a 5-6 membered saturated ring containing at most one additional heteroatom selected from oxygen and nitrogen; and R 'is an acid or an ester; or a pharmaceutically acceptable salt, hydrate or solvate thereof, comprising (a) (II) in the presence of a halogen-Vilsmeier reagent and solvent, followed by quenching with an excess of H-rI as defined above, L5 formation compound pattern ca (III) C in which halo (III) halogen is bromine or iodine, R ¹ is as defined above; and (b) subsequently, in a suitable solvent and at a reduced replicate, treated with an alkyllithium reagent, then a coupling reagent, to form a compound of formula (I), provided that R ³ and / or R 6 is H, the compound of formula (III) is exposed to a basic medium suitable for selectively deprotonating the amide prior to addition of the alkyllithium reagent, followed by optionally forming a pharmaceutically acceptable salt, hydrate or solvate. Process according to claim 1, characterized in that the halogen-Vilsmeier reagent used is prepared by reaction, preferably at reduced temperatures, of a chloride source, for example oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, for example a dialkyl substituted formamide reagent, preferably dimethylformamide, in a suitable solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent, wherein said chloro-Vilsmeier reagent reacts in situ, preferably at reduced temperatures, with a bromine source or iodine source, preferably hydrogen bromide gas. A method according to claim 2, characterized in that: characterized in that the halogen-Vilsmeier reagent is a bromo-Vilsmeier reagent. 4. A process according to claim 2, wherein the halogen-Vilsmeier reagent is an iodine-Vilsmeier reagent. 5. A process according to claim 3, wherein the bromo-Vilsmeier reagent is (bromomethylene) dimethylammonium bromide: 6. A process according to claim 2, wherein R &lt; 1 &gt; is -SO4H, -P (O) (OH) 2-OH _. , -PH (O) OH, or (CH _{2) 1-3} -COOH. A process according to claim 2, characterized in that R 1 is - COOH. 8. A process according to claim 2 wherein the base used to prepare said basic medium is selected from the group consisting of hydrides, alkyl lithium, Grignard reagents or metal alkoxides. 9. A process according to claim 8, wherein the base is ethylmagnesium bromide or ethylmagnesium chloride. 10. process the preparation of claim 9, v y z n a č u j ú - c i s a by that the base is ethylmagnesium bromide. 11. process the preparation of claim 2, v y z n a č u j ú - c í S <1 by that the alkyl lithium reagent is sec-butylli- t.i um. 12. process the preparation of claim 2, v y z n a č u j ú - c i s a by R ¹ is -N (H) C (CH ₃ ) ₃ . 13. process the preparation of claim 2, v y z n a č u j ú - c i s a by that the compound prepared is a Ο II Or a pharmaceutically acceptable salt, hydrate or solvate thereof. A process for preparing a steroidal carboxamide substituent comprising halogenating the corresponding carboxylic acid with a halogen-Vilsmeier reagent, followed by quenching with an excess of H-r ¹ , wherein R ¹ is NR ³ R ⁴ , wherein R ³ and R ⁴ are each independently selected from hydrogen, C - ^ _ alkyl, C ^ _ gcykloalkyl, phenyl, or R ³ and R ⁴ together with the nitrogen to which they are linked, form a 5-6 membered saturated ring comprising up to one other heteroatom selected from: O and nitrogen. Process according to claim 14, characterized in that the halogen-Vilsmeier reagent is prepared by reacting, preferably at reduced temperatures, a chloride source, for example oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, for example a dialkyl substituted formamide reagent, preferably dimethylformamide. a suitable solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent, wherein said chloro-Vilsmeier reagent reacts in situ, preferably at reduced temperatures, with a bromide source or iodide source, preferably hydrogen bromide gas. 16. A process according to claim 15 wherein the halogen is bromine. 17. A method according to claim 16, wherein the bromine-V -meier reagent is prepared and used in situ. 18. A process according to claim 17, wherein the bromo-Vilsmeier reagent is (bromomethylene) dimethylammonium bromide. A process for the preparation of steroidal halo-1,3-dienes, characterized in that it comprises halogenating the corresponding α, β-unsaturated ketone with a halogen-Vilsmeier reagent. Process according to claim 18, characterized in that the halogen-Vilsmeier reagent is prepared by reacting, preferably at reduced temperatures, a chloride source, for example oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, for example a dialkyl substituted formamide reagent, preferably dimethylformamide. , in a suitable solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent, wherein said chloro-Vilsmeier reagent reacts in situ, preferably at reduced temperatures, with a bromide source or iodide source, preferably hydrogen bromide gas. The method of claim 19, wherein the compound is steroid bromo-1,3-diene. 21. The method of claim 19, wherein the compound is a steroidal 3-bromo-3,5-diene. 22. A process according to claim 21, wherein the halogen-Vmmeier reagent is (bromomethylene) dimethylammonium bromide. A method of halogenating multiple functional groups on a single molecule, which comprises halogenating a multi-functional molecule with a halogen-Vilsmeier reagent. The method of claim 23, wherein the halogen-Vilsmeier reagent is prepared by reacting, preferably at reduced temperatures, a chloride source, for example oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, for example a dialkyl substituted formamide reagent, preferably dimethylformamide, in a suitable a solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent, wherein said chloro-Vilsmeier reagent reacts in situ, preferably at reduced temperatures, with a bromide source or iodide source.