CZ188794A3 - Process for preparing 3-carbonylandrostadiene-17-carboxamides and novel intermediate - Google Patents

Abstract

Invented is an improved process for the preparation of substituted steroidal dienes. Also invented are novel intermediates used in said process.

Description

A process for the preparation of 3-carbonylandrostadiene-17-carboxamides and a novel intermediate

Technical field

The present invention relates to a novel process for converting substituted steroid 3-halo-3,5-diene derivatives into substituted steroid 3,5-diene-3-carboxylic acid derivatives.

No. 017,568 of May 21, 1991 (Holt et al.) As useful for inhibiting steroid 5-alpha-reductase.

BACKGROUND OF THE INVENTION

Numerous processes have been described for producing substituted steroid 3,5-diene-3-carboxylic acid derivatives from substituted intermediates, steroid 3-halo-3,5-diene derivatives. In particular, the carboxylation of steroid 3-bromo-3,5-diene intermediates is used catalytically or in the presence of alkyllithium to form steroid 3,5-diene-3-carboxylic acid derivatives. The products are obtained in a yield of 15% when N-butyllithium is used, the procedure described in U.S. Patent No. 5,017,568. It has been shown that using a basic medium for selective deprotonation of hydrogen acid atoms in the thickened intermediate in the above reaction before adding the dehalogenation The yield of the resulting steroid 3,5-diene-3-carboxylic acid derivative may be increased, as described in U.S. Patent Application Serial No. 07 / 817,179, filed Jan. 6, 1992, the yield being 63% for N-tertiary acid production. Butylandrost-3,5-diene-17β-carboxamide-3-carboxylic acid from N-tert-butlandrost-3,5-diene-3-bromo-17β-carboxamide. It is said to be a preferred base for formation

The 2-base medium is ethylmagnesium bromide and ethylmagnesium chloride.

In addition to the overall low yield, a major disadvantage of these processes is the fact that N-butyllithium, ethylmagnesium bromide and ethylmagnesium chloride are expensive reagents that make the process uneconomical. In addition, N-butyllithium is flammable and the carboxylation reaction must be carried out at dilute concentrations. Thus, there is a need for a safe, cost-effective and rapid process for converting substituted steroid 3-halo-3,5-diene derivatives to substituted steroid 3,5-diene-3-carboxylic acid derivatives.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention provides a novel process for preparing steroid derivatives of 3,5-diene-3-carboxylic acids by converting steroid 3-halo-3,5-diene derviates.

Specifically, the present invention provides an improved process for the preparation of N-tert-butyllandrost-3,5-diene-17β-carboxamide-3-carboxylic acid.

The invention also provides novel intermediates useful in carrying out this process.

During the application and claims, the carbon atoms of the steroid system will be numbered and at the same time the individual rings will be capitalized according to the following formula:

If desired, pharmaceutically acceptable salts, hydrates and solvates of the compounds of the invention can be prepared by known methods.

Unless expressly stated otherwise, the term halogen atom in the present application and in the claims refers to chlorine, bromine or iodine atoms, preferably bromine or iodine atoms.

Accordingly, the present invention provides a process for the preparation of 3-carbonylandrostadiene-17-carboxamides of the formula I

wherein R 6 is

3 2 3

i) a CONR R group wherein R and R are independently selected from hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, and phenyl, or form together with the nitrogen atom to which they are attached a five- to a six-membered saturated ring optionally containing an additional heteroatom, oxygen or nitrogen; or ii) groups which can be chemically converted to the groups of i) for example -C = M, -COOH or -COOC 4-6 -alkyl, or pharmaceutically acceptable salts, hydrates or solvates thereof, the process consisting in cyanating a compound of formula II

where r! has the above meaning; and

X is a halogen atom, in the presence of a cyanating reagent in a suitable solvent, preferably dimethylformamide, to form a compound of formula III

wherein R ¹ is as defined above, (III) followed by saponification of the compound of formula III to form a compound of formula I, which may then optionally be converted to a pharmaceutically acceptable salt, hydrase or solvate.

R ¹ preferably represents

3 2 3

i) a CONR R group wherein R and R are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or phenyl; or ii) -C 5 N, -COOH, or -COOC 1-4 alkyl.

The most preferred value for R ¹ when performing the above 2 3 2 3 group of said process is a beta-CONR R, wherein R and R are independently hydrogen, alkyl of 1-8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl.

The compounds of formula I contain R @ ¹ or groups which can be chemically converted to R @ 1 ^by known reactions, for example those described in Derek Barton and UD Ollis, Comprehensive Organic Chemistry: The Synthesis and Reactions of Organic Compounds, Pergamon Press. 1979, provided that R ¹ does not include groups that would impede the implementation of the method according to the invention. Reactions to convert some of the groups to the R group can be carried out on the resulting products or on some of the intermediates during the process. For example, carboxylic acid substituents can be converted to carboxamides by conversion to an acid halide, which is then reacted with an amine. The esters can be converted to the acid and worked up as described above. Nitriles can be converted to carboxamides by reaction with an alkylating agent, for example tert-butyl acetate or tert-butanol, catalyzed using an acidic medium.

In the process according to the invention for the preparation of the compounds of formula (I), new intermediates of formula (IV) are produced

where r! means

3 2 3

i) a CONR R group in which R and R are independently selected from hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms and phenyl, or together form, with the nitrogen atom to which they are attached, five or a six-membered saturated ring, optionally containing an additional heteroatom, oxygen or nitrogen, or ii) groups which can be chemically converted to the groups of i), for example -C NN, -COOH or -0000-4-alkyl.

A preferred value for R ^ in a compound of formula

IV are the following groups:

3 2 3

i) a CONR R group wherein R and R are independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl or phenyl; or ii) -C = N, -COOH or -COOC 3; g-alkyl.

Most preferably, R in R 2 is the beta-CONR R group wherein R and R are not independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl and phenyl .

The process according to the invention has several advantages over known methods. The reagents and conditions used to convert the steroid 3-halo-3,5-dienes to the steroid 3,5-diene-3-carboxylic acid are safe, inexpensive, the reaction can be carried out at high concentrations while achieving high yields of the resulting products, so the process is suitable for industrial scale implementation.

Throughout the application and claims, the alkyl radicals may be straight or branched, unless expressly stated otherwise.

The term cyanating reagent throughout the specification refers to a reagent capable of reacting with a halogenated group under certain conditions to form a cyanated group. Preferably, the corresponding halogenated group is reacted with a cyanating reagent in a suitable solvent such as N, N-dimethyl-N, N-propylene urea DMPU, N, N-dimethylformamide DMF, or N-methyl-2-pyrrolidinone NMP, with preferably DMF at a higher temperature.

The term saponification refers to the use of a compound or reagent or group of reagents that is capable of reacting with a nitrile under appropriate conditions to form a substituted carboxylic acid throughout the application. The substituted carboxyl group is preferably prepared by reacting the corresponding cyanated group with a hydroxide, preferably an aqueous solution of sodium hydroxide in a suitable solvent such as ethylene glycol, isopropyl alcohol or ethanol, preferably ethanol at elevated temperature followed by acidification of the reaction mixture.

The term elevated temperature during the application means a temperature higher than 25 ° C, preferably reflux.

Cyanide complexes as described in Richard C. Larock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, VCH Publishers, Inc., may be used as a cyanating reagent for use in the present invention. 1989, p. 861. An example of a useful cyanide complex for use herein is a mixture of KCN, NiBr ₂ (PPh ₂ ) ₂ , Zn, PPh 2 formed in the reaction mixture. A diaphragm example would be: Co (CN) ³ 7 K4Ni2 (CH) g KCN further KCN, cat Pd (PPho)., Co (Cr) ³ "CuCN and NaCu (CN) o. As for the NaCu (CN) ₂ reagent, it is a reagent formed by mixing CuCN and NaCN in situ.

Preferred cyanation complexes are especially CuCN and NaCu (CN) ₂ .

A particularly preferred cyanation complex is NaCu (CN) ₂ .

This preferred cyanation complex can be prepared by adding one molar equivalent of sodium cyanide directly to the copper cyanide in the reaction mixture.

As used herein, the term solvent or suitable solvent includes conventional solvents such as methylene chloride, ethylene chloride, chloroform, ethylene glycol, carbon tetrachloride, tetrahydrofuran THF, ethyl ether, toluene, ethyl acetate, dimethylsulfoxide, Ν, N'-dimethyl-N, N'-propyleneurea, N-methyl-2-pyrrolidinone, methanol, isopropyl alcohol, dimethylformamide, water, pyridine, quinoline or ethanol

The process according to the invention is particularly suitable for the preparation of a compound having the structure IIIA

(IIIA) can then be converted to a compound of structure IA

It will be understood that, according to the present disclosure, one skilled in the art can easily carry out and fully utilize the method of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The compounds required to carry out the process of the invention can be obtained from conventional sources. For example, dimethylformamide and cuprous cyanide are available from Aldrich Chemicyl Co., Milwaukee, WI, and androst-4-en-3-one-17-beta-carboxylic acid are available from Berlichem Inc, Wayne, NJ.

Example 1

N-tert-Butlandrost-3,5-diene-17-beta-carboxamide-3-carboxylic acid

i) N-tert-butyllandrost-3,5-diene-3-bromo-17-beta-carboxamide

100 ml of methylene chloride and 6.12 ml, 2.5 molar equivalents of dimethylformamide were charged to the flask under nitrogen. 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 in the range of 0-10 ° C. A white precipitate formed. The mixture was stirred for one hour and 50.1 g (19.6 molar equivalents) of hydrogen bromide gas was bubbled through the solution while maintaining the temperature between 0 and 10 ° C. The suspension becomes a clear colorless solution. The solution is degassed by vacuum distillation, reducing the volume of the solution by approximately one-half, then bringing the solution to its original volume by adding methylene chloride. This concentration is repeated by replenishing the volume.

To the resulting white suspension was added 10.0 g, 1 molar equivalent of androst-4-en-3-one-17-beta-carboxylic acid, and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was then poured into a vessel containing 100 mL of methylene chloride and 23.1 g, 10 molar equivalents of tert-butylamine, maintaining the temperature in the range of 0-10 ° C. The mixture was stirred for 30 minutes, then about 100 ml of water was added and the biphasic mixture was filtered through a pad of celite. The organic phase was separated and the volume reduced by half by distillation in vacuo, then the solution was made up to the original volume with acetone. This concentration followed by volume replenishment was repeated two more times. About 300 mL of the resulting acetone solution was heated to about 50 ° C and about 100 mL of water was added to precipitate the product. The suspension is cooled and the product, N-tert. butylandrost-3,5-diene-3-bromo-7beta-carboxamide was collected by filtration and dried. Yield 89%, mp 181-183 ° C.

ii) N-tert-butyllandrost-3,5-diene-3-cyano-17-beta-carboxamide

A mixture of 50 g, 1 molar equivalent of N-tert-butlandrost-3,5-diene-3-bromo-17-beta-carboxamide, 11.0 g, 1.1 molar equivalent of cuprous cyanide and 200 ml of dimethylformamide was heated at room temperature for 3.5 hours. the reflux temperature. The reaction mixture is cooled to 90-100 ° C and poured into a mixture of 100 ml of concentrated aqueous ammonia and 200 ml of water with stirring. The reaction flask was rinsed with 25 mL dimethylformamide, which was also added to the resulting mixture. The resulting suspension was extracted with 2 x 200 mL methylene chloride and the organic extracts were filtered through a pad of celite. The organic phase is washed with 3 x 200 ml of a 50:50 mixture of concentrated aqueous ammonia and water and then with 2 x 200 ml of water. The organic phase is concentrated in vacuo to a volume of 150 ml and ethanol (250 ml) is added. The solution was again concentrated in vacuo to 150 ml and ethanol (250 ml) was added. The solution was concentrated in vacuo to 300 ml and 30 ml water was added to induce crystallization. The resulting suspension was cooled to 0-5 ° C for 2 hours. The solid product was filtered off and dried under vacuum at 65 ° C to give 37.0 g (85%) of N-tert-butlandrost-3,5-diene-3-cyano-17-beta-carboxamide as yellow crystals at a temperature of 85%. mp 195-197 ° C.

(iii) N-tert-Butlandrost-3,5-diene-17-beta-carboxamide-3-carboxylic acid

A mixture of 20.0 g, 1 molar equivalent of N-tert-butlandrost-3,5-diene-3-cyano-17-beta-carboxamides, 80 ml, 30 molar equivalents of 50% aqueous sodium hydroxide and 200 ml of ethanol is heated to the reflux temperature. The suspension of the reaction mixture was cooled to 50 ° C and added with stirring to a mixture of 300 ml of 6N hydrochloric acid and 200 ml of methylene chloride. The final pH of the aqueous phase is 1.5 to 2.0. The organic phase is separated and the aqueous phase is extracted again with 250 ml of methylene chloride. The organic phases were combined, stirred for 1 hour with 2 g of charcoal to decolorize, and then filtered through a pad of celite. The organic phase is concentrated in vacuo to a volume of 120 ml and 200 ml of ethyl acetate are added. The suspension is again evaporated in vacuo to 120 ml and 200 ml of ethyl acetate are added. The resulting suspension was evaporated in vacuo to a final volume of 120 ml and then heated at reflux for 2 hours. The suspension was then cooled to 0-5 ° C for 2 hours and then filtered. The solid product was dried under vacuum at 65 ° C to give 14.8 g (71% yield) of N-tert-butyllandrost-3,5-diene-17-beta-carboxamide-3-carboxylic acid. By recrystallization of the mother liquor, 3.14 g of product is obtained in 15% yield, the total yield of the reaction being 86%. Melting point: 250-251 ° C.

Example 2

N-tert-Butlandrost-3,5-diene-3-cyano-17-beta-carboxamide

In a 5-liter, three-necked (Morton) flask equipped with a mechanical stirrer, a thermometer and a reflux condenser was charged 250 g of N-tert-butyllandrost-3,5-diene-3-bromo13

17beta-carboxamide, prepared according to the method of Example 1 i), 55 g of copper (I) cyanide, 29 g of sodium cyanide and 1 liter of dimethylformamide. The reaction mixture is heated to reflux at about 152-153 ° C for at least 12 hours. The reaction mixture was slowly cooled to 25-30 ° C in a cold water bath, then quenched by the rapid addition of 1 liter of aqueous ammonium hydroxide (50:50 concentrated ammonia / water) with vigorous stirring. The mixture was stirred for a further 15-20 minutes and then 1 liter of methylene chloride was added and the two-phase system was allowed to separate into two phases. The phases are separated and the aqueous phase is extracted again with 2 x 500 ml of methylene chloride. The methylene chloride extracts were combined and passed through a pad of celite to remove insoluble copper salts. The celite pad was washed with methylene chloride (150 ml). The methylene chloride phases were combined and washed with 3 x 500 mL ammonium hydroxide to remove the last traces of copper salts. The organic phase is then concentrated by distillation at atmospheric pressure, leaving approximately 1.5 liters of methylene chloride solution. 600 ml of ethanol are added to the reaction vessel and the solution is again concentrated to remove methylene chloride by distilling off an additional 500 ml of solvent. An additional 600 ml of ethanol was then added to the reaction mixture and distillation at atmospheric pressure was continued until the vapor temperature reached 82-84 ° C. 60 ml of water are then added and the resulting suspension is cooled to 0-5 ° C for at least two hours. The solid was collected, washed with 75 mL of 50% aqueous alcohol, and dried at 60-65 ° C under vacuum to give 191.3 g (88%), m.p. 190-192 ° C.

The invention has been elucidated on preferred embodiments, but it will be apparent that many modifications, within the scope of the invention, may be made.

Claims (14)

PATENT CLAIMS A process for the preparation of 3-carbonylandrostadiene-17-carboxamides of the general formula I wherein R ¹ represents 2 3 2 3 (i) a CONR R group in which R and R are independently selected from hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms and phenyl, or taken together with the nitrogen atom to which they are attached, a five- or six-membered saturated ring, optionally containing an additional heteroatom, oxygen or nitrogen, or (ii) groups which can be chemically converted to the groups of (i) ₄ 2. The process according to claim 1, wherein the cyanation is carried out with a cyanating agent which is a cyanide complex of CuCN and NaCl (CN). 2 3 2 3 i) CONR R, wherein R and R are independently selected from hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, and phenyl, or form together with the nitrogen atom to which they are attached a five- or (ii) groups which can be chemically converted to the groups of (i), for example -CSN, -COOH or -COOC 4-6 -alkyl, or pharmaceutically acceptable salts, hydrates or solvates thereof, the process comprising cyanating a compound of formula II X (II) where R ¹ has the above meaning and X represents a halogen atom, in the presence of a cyanating solvent, preferably a dime reagent in thylformamide, with a suitable compound of formula A compound of formula III wherein R ¹ is as defined above, followed by saponification of a compound of formula III to form a compound of formula I, which can then be converted into a pharmaceutically acceptable salt, hydrate or solvate thereof. The process of claim 2, wherein the cyanating reagent is a NaCu (CN) ₂ cyanide complex. team The process according to claim 3, wherein the cyanation is carried out with a NaCu (CN) g cyanide complex prepared by adding 1 molar equivalent of sodium cyanide to copper (I) cyanide in situ. 5. The process of claim 2 wherein the cyanation is carried out with cuprous cyanide. A process according to claim 1, characterized in that a compound of formula (II) in which X represents a bromine atom and is as defined in claim 1 is subjected to cyanation. 7. The process of claim 1 wherein the reaction is carried out in dimethylformamide as a solvent. 8. The process of claim 1 wherein the saponification is carried out by reacting N-tert-butlandrost-3,5-diene-3-cyano-17-beta-carboxamide and hydroxide in a suitable solvent followed by acidification. The process according to claim 8, wherein the solvent is ethanol. The process according to claim 9, wherein the base is sodium hydroxide. A process according to claim 1 wherein the product is a compound of formula IA or a pharmaceutically acceptable salt, hydrate or solvate thereof. 12. A novel intermediate of formula (IV) EMI3.0 wherein is The novel intermediate of claim 12, wherein R ¹ is -C = N, -COOH, -COOC 6 -alkyl or -CON (H) -tert-butyl. 14. New intermediate according to claim 13, in which R ^x zna- the names -CON (H) t-butyl. 15. Intermediate according to claim 13, in which R ¹ zna- names -COOH. 16. New intermediate according to claim 13, in which R ¹ zna- names -C = N.