CZ161994A3 - Process for preparing substituted steroids of diene type - 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

Technical field

The invention relates to a process for the manufacture of substituted diene-type steroids. It is an improved process for the preparation of the compounds described in U.S. Patent No. 5,017,568, issued May 21, 1991 to Holt et al., Which can be used to inhibit 5-alpha steroid reductase.

BACKGROUND OF THE INVENTION

Several processes for the production of substituted steroid diene derivatives are known. Use of oxalyl bromide to convert steroid alpha, beta-unsaturated 3-ketones to 3-bromo-3,5-diene intermediates in 40% yield followed by carboxylation in the presence of a catalyst or alkyllithium treatment (with 15% yield when N-butyllithium is used) the formation of steroid derivatives of 3,5-diene-3-carboxylic acids is described in U.S. Patent No. 5,017,568.

In addition to the overall low yield, another disadvantage of this process is that oxalyl bromide is a toxic and very expensive liquid, which is difficult to store and not readily available in the large quantities required for the industrial scale process.

The use of oxalyl chloride for the halogenation of steroid alpha, beta-unsaturated ketones to chlorinated steroid dienes achieves only low yields. In addition, the reactivity of the resulting substituent is low, so special procedures are required for subsequent transformations. It would therefore be desirable to provide a safe, economical and easy to perform method for halogenating steroid alpha, beta-unsaturated ketones to halogenated 1,3-dienes. Preferably, it should be possible to subject the bromination or iodination with steroid alpha .beta.-unsaturated ketones to the corresponding halogen-1,3-dienes.

SUMMARY OF THE INVENTION

The present invention provides a process for the production of substituted diene-type steroids by halogenation.

In particular, it is an improved process for converting steroid alpha, beta-unsaturated ketones to the corresponding halogen-1,3-diene derivatives.

The invention therefore relates to an improved process for the formation of a steroid carboxylic acid halide followed by nucleophilic conversion of the resulting halide.

In particular, the invention relates to an improved process for converting steroid carboxylic acids into steroid carboxamides in situ.

Specifically, the invention relates to a method for the simultaneous bromination and amidation of steroid 3-on-4-ene-17-carboxylic acids.

In particular, the invention relates to an improved process for the preparation of N-tert-butyllandrost-3,5-diene-17-beta-carboxamide-3-carboxylic acid.

By simultaneous is meant that the conversion of the steroid 3-one to the 3-halo-derivative and the conversion of the 17-carboxylic acid to 17-carboxamide are carried out in a single reaction without isolation of the intermediate.

, o

KU ivé

During the application and claims of the carbon, the number and number of nuclei are numbered and uniform. letters in the following way:

are and terny circles

The term reduced temperature is understood to mean a temperature below 25 ° C during the application, preferably a temperature in the range of -15 to 15 and especially 0 to 10 ° C.

The term binding agent is understood to mean, during the application, a compound and / or conditions in which the metal-containing group can form an acid, an ester, an alkylcarbonyl group having 1 to 5 carbon atoms in the alkyl moiety or an alkyl group having 1 to 20 carbon atoms. The metal-containing group is preferably a lithium-containing group prepared by reacting the corresponding halogenated group with an alkyllithium reagent. Compounds useful as said reagents are, for example, chloroformates, alkyl bromides and acid chlorides, preferably carbon dioxide is used as the reagent.

As used herein, the term "acid" refers to any group capable of acting as proton dc, such as -COOH, -P (O) (CH) ₂ , PH (O) OH -SO ₃ H, and - (€). H _{2) 1} _ ₃ -COOH.

The term ester means a group consisting of the above acid in which the cleavable protons have been replaced by alkyl substituents.

The term solvent or suitable solvent throughout the application refers to an organic solvent such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran THF, ethyl ether, toluene or ethyl acetate.

By halogenated Vilsmeier reagent is meant a halogenated disubstituted formamide derivative of the general formula wherein:

6

R and R are independently alkyl, aryl or arylalkyl groups, bromine or iodine, and

Y is a positive ion.

Said reagent may be prepared by:

a) reacting, at reduced temperature, a chloride ion source, for example oxalyl chloride or thionyl chloride, with a disubstituted formamide, for example dialkylformamide, preferably dimethylformamide, in a suitable solvent, preferably methylene chloride, to form a chlorinated Vilsmeier reagent which is reacted in situ; preferably at reduced temperature with a source of bromide or iodine, preferably with hydrogen bromide gas, or with a hydrogen bromide source

b) reacting, preferably at reduced temperature, a source of bromide or iodide, preferably oxalyl bromide, with a disubstituted formamide, preferably a dialkylformamide, and in particular with dimethylformamide in a suitable solvent, preferably methylene chloride.

Accordingly, the present invention provides a reaction carried out in situ using a brominated or iodinated Vilsmeier reagent prepared safely and economically from known and readily available reagents, preferably from the corresponding chlorinated Vilsmeier reagent. The invention will be applicable to all reactions involving the use of a brominated or iodinated Vilsmeier reagent.

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

Unless expressly stated otherwise, the term halogen during the application means bromine or iodine.

The pharmaceutically acceptable salts, hydrates and solvates of the compounds of formula (I) may be formed by known methods.

Accordingly, the present invention provides a process for the manufacture of substituted diene-type steroids of formula I

where

- 4 4.34

R is NR R, in which R and R are independently known to be hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or phenyl or together with the nitrogen atom to which they are attached form a saturated ring of 5 or 5 ring atoms, optionally containing an additional oxygen or nitrogen heteroatom; and

R represents an acid radical, an ester group, an alkylcarbonyl group having from 1 to 6 carbon atoms in the alkyl moiety or an alkyl residue having 1 to 20 carbon atoms, or a pharmaceutically acceptable salt, hydrate or solvate thereof, reacting a compound of formula II with an excess of a compound wherein R ¹ is as defined above, in the presence of a halogenated Vilsmeier reagent and in a solvent followed by interrupting the reaction to form a compound of formula III

where r! as defined above, then an alkyllithium reagent and then a coupling agent to form a compound of formula I are added in a suitable solvent and at a reduced temperature,

4

R @ 1 and / or R @ 2 is hydrogen, the compound of formula III is treated with a base suitable for selective deprotonation of the amide prior to addition of the alkyllithium reagent, optionally forming a pharmaceutically acceptable salt, hydrate or solvate of the resulting product.

The halogenated Vilsmeier reagent is preferably prepared by reacting, preferably under reduced pressure, a chloride source such as oxalyl chloride or thionyl chloride with a disubstituted formamide such as dialkylformamide, preferably dimethylformamide in a suitable solvent, preferably methylene chloride to form a chlorinated Vilsmeier agents which are then reacted in situ, preferably at reduced temperature, with a source of bromide or iodide, preferably hydrogen bromide gas.

Unless expressly stated otherwise, the hydrocarbon chain having the specified carbon atom range may have a straight or branched chain.

The term alkyl refers to a hydrocarbon chain, straight or branched. ·

The term aryl refers to an aromatic carbon or heterocyclic ring, unsubstituted or substituted with non-reactive substituents.

The halogenated Vilsmeier reagent used for the dihalogenation of the compounds of formula (II) is preferably prepared and utilized in situ.

The halogenated reagent in this sense is preferably a brominated Vilsmeier reagent.

The brominated Vilsmeier reagent is preferably (bromomethylene) dimethylammonium bromide.

Preferred organic acids for use in the meaning of R in Formula I are -COOH, -P (O) (OK) ₂ , -H (Q) OH,

-SO-H and - (CH3). CCOH. A particularly preferred group in this 6-L-meaning is -COOH.

A preferred base for use in the preparation of the basic deprotonation base amide III is, for example, metal hydride, alkyllithium reagents, Grignard reagent and metal alkoxide. Particularly preferred are ethylmagnesium bromide, butyllithium and ethylmagnesium chloride. A particularly preferred base is ethylmagnesium chloride. The selective amide deprotonation is preferably carried out at a temperature above 25, preferably 30 to 50 ° C.

The alkyllithium-type reagent for initiating the exchange of the halogen and metal atoms in Formula III is sec-butyllithium.

In a preferred embodiment of the invention, steroidal halogen-1,3-diene systems are prepared using alpha, beta-unsaturated ketones and halogenated Vilsmeier reagent prepared and used in situ.

A preferred embodiment of the invention is the halogenated Vilsmeier reagent induced formation of an acid halide type of steroid carboxylic acid, wherein said halide substituent is then exchanged by treatment with a nucleophilic reagent. A preferred nucleophilic reagent is a reagent HR type wherein R ¹ is as defined above, particularly preferred is tert-butylamine.

In a preferred embodiment of the process of the invention, a compound of formula (IIIA) may be prepared

and the compound is then converted to a compound of formula IA

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

The present invention will be illustrated by the following examples, which are not intended to limit the scope of the invention.

* 7

DETAILED DESCRIPTION OF THE INVENTION

From the compounds used in the Example section, dimethylformamide, oxalyl chloride, oxalyl bromide, tert-butylamine, 2.0M ethylmagnesium chloride in THP, 1.2M sec-butyllithium in cyclohexane and (+) - 4-cholesten-3-one from Aldrich Chemical can be obtained. Co., Milwaukee, Wl. Gaseous hydrogen bromide and gaseous carbon dioxide can be obtained from Msthesin, Ξ. Rutherford,

NJ. Androst-4-en-3-on-17-beta-carboxylic acid can be obtained from Berlichem, Inc., Wayne, NJ. 3-Bromoandrosta-3,5-diene-17-beta-carboxylic acid was prepared according to US Patent No. 5017568, Example 25B (ii).

Example 1

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

i) 3-bromo-N- (1,1-dimethylethyl) -androsta-3,5-diene-17-beta-carboxamide

To the flask was charged with 10 ml of methylene chloride and 6.12 ml, 2.5 molar equivalents of dimethylformamide under a nitrogen atmosphere. The solution is cooled to 0-5 ° C and then 6.9 ml (2.5 molar equivalents) of oxalyl chloride are added, maintaining the temperature between 0-10 ° C. A white precipitate formed. The mixture was stirred for an additional hour, and 50.1 g (19.6 molar equivalents) of hydrogen bromide gas was bubbled through the solution while maintaining the temperature at 0-10 ° C. The suspension becomes a clear colorless solution. This solution is degassed by reducing the volume of the solution to about half by distillation in vacuo, then making up to the original volume by adding methylene chloride. This procedure is repeated once more. To the resulting white suspension was added 10.0 g of androst-4-en-3-one-17-beta-carboxylic acid, one molar equivalent, and the mixture was warmed to room temperature and then stirred for two hours. The reaction was then quenched into a flask containing 100 mL of methylene chloride and 23.1 g, 10 molar equivalents of t-butylamine, maintaining the temperature at 0-10 ° C. The mixture is stirred for a further 30 minutes, then about 100 ml of water are added and the biphasic mixture is filtered through a pad of celite. The organic phase was separated and the volume reduced to approximately half by distillation in vacuo. Then the mixture is brought to its original volume by addition of acetone. This procedure is repeated two more times. About 300 mL of the resulting acetone solution was heated to 50 ° C and about 100 mL of water was added to precipitate the product. The suspension is cooled and the resulting product, 3-bromo-N- (1,1-dimethylethyl) anrostrost-3,5-diene-17-beta-carboxamide is collected by filtration and then dried. Yield 89%, mp 181-183 ° C.

ii) 17beta - [(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-17-beta-carboxamide in 250 mL of anhydrous THF was heated to 30 ° C under nitrogen.

29 ml of 2.0M ethylmagnesium chloride are added to the solution,

2.5 molar equivalents in THF and the temperature was allowed to rise to 40-50 ° C. The mixture is stirred for a further 20 minutes, then ironed at 0 to 5 ° C, and 82.5 ml of 1.2 M sec-butyllithium in cyclohexane, 2.5 molar equivalents are added. The mixture was stirred for an additional 5 minutes and excess anhydrous carbon dioxide was bubbled through the resulting solution. The gas was bubbled through the solution until it cooled to room temperature. The resulting suspension was then washed with 100 ml of a 3.3M aqueous hydrochloric acid solution and the aqueous phase separated. The organic phase is washed twice with 150 ml of water. X of the organic phase is added with 85 ml of water, then the organic phase is distilled under reduced pressure. The resulting aqueous product suspension was extracted with 100 mL of methyl ethyl ketone. The aqueous phase is separated and the organic phase is washed with 100 ml of water. Then 0.6 g of decolorizing charcoal is added to the organic phase and the mixture is filtered through a pad of celite. The filtrate was evaporated and the residue was triturated with ethyl acetate to give 6.4 g of 17beta - [(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-17-beta-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 0.85 g, 1.6 molar equivalents of oxalyl bromide was added. The reaction mixture was allowed to warm to room temperature and was stirred for 30 minutes. The solution is cooled to approximately 5 ° C and 0.95 g, 1 molar equivalent of 3-bromoandrosta-3,5-diene-17-beta-carboxylic acid in 20 ml of methylene chloride is added to the white suspension formed. The solution was allowed to warm to room temperature and was stirred for 1.5 hours. The reaction is then stopped at 2.2 ml, 8.4 molar equivalents of tert-butylamine and stirred for a further 5 minutes. The mixture was then poured into 100 ml of ethyl acetate and the organic phase was washed with 50 ml of 10% aqueous sodium hydroxide solution. The aqueous phase was separated and extracted with 50 ml of ethyl acetate. The organic phases were combined, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo to give a crude solid which was triturated with tert-butyl methyl ether: hexane (24: 50, 50: 50). The solids were collected by filtration and dried in vacuo. There was thus obtained 3-bromo-N- (1,1-dimethylethyl) andro-3,5-diene-17-beta-carboxamide (0.5 g). The filtrate was evaporated and worked up as above to give 0.25 g of product. The total yield of the product was 69%, mp 181-183 ° C.

Example 3

3-bromocholesta-3,5-diene

10 ml methylene chloride solution containing 0,24 ml,

1.2 molar equivalents of dimethylformamide are cooled to 0 ° C and 0.62 g, 1.1 molar equivalents of oxalyl bromide are added. The resulting white suspension was stirred at -5 ° C for 45 minutes and then 1.0 g, 1 molar equivalent of (+) - 4-cholesten-3-one in 6 mL of methylene chloride was added. The solution was allowed to warm to room temperature and was stirred for 30 minutes. The reaction mixture was then 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 organic phases were combined and washed with 10 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to a solid which was purified by silica gel chromatography using hexane to give 1.1 g of 3-bromo-cholestha-3,5-diene (93% yield). A sample recrystallized from a mixture of methanol and diethyl ether had a melting point of 64-67 ° C.

AND

- 15 - g

Example 4

3-bromo-N- (1,1-dimethylethyl) andrcsta-3,5-diene-17-beta-carboxamide

0.5 g, 2.5 molar equivalents of dimethylformamide in 20 ml of methylene chloride are charged to the flask under a nitrogen atmosphere. The solution was cooled to 0-5 ° C and 1.71 g (2.5 molar equivalents) of oxalyl bromide was added, maintaining the temperature in the range of 0-10 ° C. A white precipitate is formed. 1 g, 1 molar equivalent of androst-4-en-3-one-17-beta-carboxylic acid is added and the mixture is warmed to about room temperature and stirred for a further 30 minutes. Then 2.2 ml, 8 molar equivalents of t-butylamine in 2 ml of methylene chloride are added to the reaction mixture, maintaining the temperature in the range of 0 to 10 ° C. The reaction mixture was stirred for a further 10 minutes and then poured into a mixture of 150 ml of ethyl acetate and 50 ml of 10% sodium hydroxide. The organic phase was separated, washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to a solid which was triturated with a mixture of 4 ml of tert-butyl methyl ether and 4 ml of hexanes, collected by filtration and dried to give 3-b. rom-N -, (1,1-dimethylethyl) androsta-3,5-diene-17-beta-carboxamide. Yield 58%, mp 177-179 ° C.

Claims (25)

A process for the manufacture of substituted diene-type steroids of the general formula I wherein R @ ³ represents a group NR ^{@ 3} R ^{@ 4} in which R @ ³ and R @ ⁴ independently represent hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl or together with the nitrogen atom to which they are attached to form a saturated ring of 5 or 6 ring atoms, optionally containing an additional heteroatom selected from oxygen or nitrogen; and R ² represents an acid radical, an ester group, an alkylcarbonyl group having 1-6 carbon atoms in the alkyl moiety or an alkyl radical having 1 to 20 carbon atoms, nebo'farmaceuticky acceptable salts, hydrates or solvates thereof, characterized in that a) reacting the compound of formula II with an excess of the compound at reduced temperature H - R ¹ wherein R ¹ is as defined above, in the presence of a halogenated Vilsmeier reagent and in a solvent followed by reaction to form a compound of formula III wherein R ¹ is as defined above, and halogen is bromine or iodine, b) adding an alkyllithium reagent in a suitable solvent at reduced temperature followed by a coupling agent to form a compound of formula I, Process according to claim 1, characterized in that the reaction is carried out in the presence of a halogenated Vilsmeier reagent prepared by reaction of a chloride source, for example oxalyl chloride or thionyl chloride at reduced temperature with a disubstituted formamide, for example dialkyl formamide, preferably dimethylformamide in a suitable form. a solvent, preferably methylene chloride, and the chlorinated Vils Meier reagent obtained are reacted in situ, preferably at reduced temperature, with a source of bromide or iodide, preferably hydrogen bromide gas. 3 4 R and R independently represent hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl, or together with the nitrogen atom to which they are attached a saturated ring of 5 or 6 carbon atoms in the ring containing to one of the other heteroatoms selected from oxygen or nitrogen. 3. A process according to claim 2, wherein the reaction is carried out in the presence of a thickened Vils meier reagent. ·. Wherein when R and / or R 'is hydrogen, the compound of formula III is treated with a basic amide selective deprotonation medium prior to addition of the alkyllithium reagent, optionally forming a pharmaceutically acceptable salt, hydrate or solvate. 4. A process according to claim 2 wherein the reaction is carried out in the presence of an iodinated Vilsmeier reagent. 5. The process of claim 3, wherein the reaction is carried out in the presence of (bromomethylene) dimethylammonium bromide as the Vilsmeier reagent to be accumulated. 6. The method according to claim 2 for the manufacture of substituted steroid in which R is -SO ^ H, -Ρ (0) (ΌΗ) _2> -Ph (O) OH or - (CH _{2) 1} -COOH _G. A process according to claim 2, for the manufacture of a substituted -2-steroid, in which R is -COOH. 8. The process of claim 2, wherein hydrides, alkyllithium, Grigranrd reagent or metal alkoxides are used to form the basic amide selective deprotonation medium. 9. The process according to claim 8, wherein ethylmagnesium bromide or ethylmagnesium chloride is used to form the basic medium. 10. The process of claim 9 wherein ethylmagnesium chloride is used to form the basic medium. 11. The process of claim 2 wherein the alkyl lithium is sec-butyl lithium. 12. The method of claim 2, wherein r ' is -N (H) C (CH3) 2. 13. The method of claim 2, wherein the compound to be prepared is a compound of formula IA or pharmaceutically acceptable salts, solvates or hydrates. A process for the preparation of a steroidal carboxamide substituent, characterized in that the corresponding carboxylic acid is halogenated with a halogenated Vilsmeier reagent, the reaction is stopped using an excess of H-R, where R is NR R, in which 15. The process according to claim 14, wherein the halogenation is a halogenated Vilsmeier reagent prepared by reacting a chloride source such as oxalyl chloride or thionyl chloride at reduced temperature with a disubstituted formamide such as dialkylformamide, preferably dimethylformamide in a suitable solvent. , preferably methylene chloride and obtained chlorinated 2L The Vilsmeier reagent is reacted in situ, preferably at reduced temperature, with a bromide or iodide source, preferably hydrogen bromide gas. ’ 16. The process of claim 16 wherein the halogenation is a brominated reagent. 17. The process of claim 16, wherein the brominated Vilsmeier reagent is prepared and used in situ. 18. The process of claim 17 wherein the brominated Vilsmeier reagent is (bromomethylene) dimethylammonium bromide. 19. A process for the production of steroidal halogenated 1,3-dienes, characterized in that the corresponding alpha, beta-unsaturated ketone is halogenated with a halogenated Vilsmeier reagent. 20. The process according to claim 19, wherein the halogenation is carried out using a halogenated Vilsmeier reagent prepared by reacting a chloride source such as oxalyl chloride or thionyl chloride at reduced temperature with a disubstituted formamide such as dialkyl ¹ formamide, preferably dimethylformamide. a suitable solvent, preferably methylene chloride, and the chlorinated Vilsmeier reagent obtained are reacted in situ, preferably at a reduced temperature, with a source of bromide or iodide, preferably hydrogen chloride gas. 21. The method of claim 20 wherein the compound is steroid bromo-1,3-diene. IF - 22. The method of claim 20, wherein the compound is a steroid 3-bromo-3,5-chien. 23. The method of claim 22, wherein the halogenated Vilsmeier reagent is (bromomethylene) dimethylammonium bromide. 24. A process for halogenating a plurality of functional groups in one molecule, characterized in that the molecule is halogenated by treatment with a halogenated Vilsmeier reagent. • - 25. A method according to claim 24 _| define _the tear T in that the halogenation employing halogenated Vilsmeier reagent prepared by reaction of a chloride source such as oxalyl chloride or thionyl chloride at reduced temperature with a disubstituted formamide, such dialkylformamideto, preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride and the chlorinated Vilsmeier reagent obtained are reacted in situ, preferably at a reduced temperature, with a source of bromide or iodide, preferably hydrogen bromide gas.