BG98955A - Method for the preparation of 3-carbonylandrostadiene 17-carboxyamides - Google Patents

Abstract

The invention relates to an improved process for the preparation of substituted steroid dienes, in particular of 3-carbonylandrostadiene 17-carboxamides, and to novel intermediates used in the process. </ P>

Description

(57) The invention relates to an improved process for the preparation of substituted steroid dienes, in particular 3-carbonyllandrostadiene 17-carboxamides, and to new intermediates used in carrying out the process.

claims, 0

METHOD OF PREPARATION OF Z-CARBONCLANDROSTADPEN

17- CARBOXAGE

The present invention relates to an improved method of converting substituted steroid 3-halogen 3,5-diene derivatives to substituted steroid 3,5-diene-3-carboxylic acid. Such compounds are described in US Patent GR 5,017,568, issued on 21 May 1991 by HoIJ- et al., useful for inhibiting steroid 5-? reductase.

BACKGROUND OF THE INVENTION

Methods for the preparation of substituted steroidal 3,5-diene-3-carboxylic acid derivatives from substituted intermediates of steroidal 3-halogen 3,5-diene are described. In particular, US Patent No. 5,017,568 describes the use of catalytic or by alkyllithium carboxylation of steroid 3-bromo-3,5-diene intermediates to obtain steroid-3,5-diene-3-carboxylic acid derivatives (in 15% yield when using N-butyllithium). applicable for the selective deprotonation of acidic hydrogen atoms of the brominated intermediate c. The above reaction prior to the addition of the dehalogenating reagent has been shown to increase the yield of the obtained steroid 3,5-diene-3-carboxylic acid derivative in US patent application No. 07 / 817,179, filed January 6, 1992. / 63% for the preparation of Tf-t-butylandrost-3,5-diene-17-carboxamide-3-carboxylic acid from M-t. butyl-addrost-3,5-diene-3-bromo-17 (-carboxamide).

The preferred bases used in the preparation of said alkaline medium are ethylmagnesium bromide and ethylmagnesium chloride.

In addition to the low overall yield, the major drawback of the known methods described is that M-butyllithium and ethylmagnesium bromide and ethylmagnesium chloride are expensive reagents, which method results in a significant increase in the cost of industrial

In addition, M-butyllithium is flammable and the carboxylation reaction is carried out using dilute concentrations. Thus, in practice, there is a need for a safe, economical and safe method for converting substituted steroid 3-halogen 3,5-diene derivatives to substituted derivatives of steroid 3,5-diene-3-carboxylic acid.

SUMMARY OF THE INVENTION

This invention relates to an improved method of converting steroid 3-halogen 3,5-diene derivatives to steroid 3,5-diene-3-carboxylic acid derivatives.

In particular, this invention relates to an improved process for the preparation of N-t, -butyl-androst-3, 5-diene-1 H -carboxamide-3-carboxylic acid.

In a further aspect, the invention provides novel intermediates that are useful in the method of the invention.

Detailed description of the invention.

As used above and in the rest of the specification and claims, the carbon atoms of the steroid nuclei are numbered and the rings are denoted by the letters as follows:

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

Unless otherwise indicated, the term halogen "as used herein and by the claims means chlorine, bromine or * OD. Preferably, the term" halogen "as used herein

Shit means bromine or iodine

method of obtaining

in which B / 1U combV, where B / I / are separately selected from

3 phenyl; or B and C taken hydrogen, alkyl, cycloalkyl and together with the nitrogen to which they are attached represent a 5-6 membered saturated ring containing a g of another heteroatom selected from oxygen and nitrogen or (2) moieties capable of chemically converted to portions of (1), such as -C 1-3, -COOH or -COOC 1-6 alkyl; or pharmaceutically acceptable salts, hydrates or solvates thereof which method involves the insertion of a C 1 O group of a compound with

wherein B 2 has the above meanings (II) and X represents halogen, in the presence of a cyanide reagent and a suitable solvent, preferably dimethylformamide, to form a compound of formula (III):

wherein 3B 2 has the above meanings and the subsequent saponification of the compound of formula (III) to form a compound of formula (I), then optionally forming a pharmaceutically acceptable salt, hydrate or solvate.

Preferably, as used in the above method is:

3 23/1 / C01MB B, wherein B and B are each independently selected from hydrogen, alkyl, cycloalkyl and phenyl; or (2) -C = Μ, -COOH or -COOC1-6alkyl.

3

The preferred embodiment of B is -COM® B, where

B and E are each independently selected from hydrogen, alkyl, cycloalkyl and phenyl.

The compounds of formula (I) contain B1 or moieties that can be chemically converted to those of B by known chemical reactions, such as those described by Barack ^and I .011 ^is , Comprehensive Organic Chemistry: The Synthesis and Reactions of Organic Compounds, Pub. -Pergamon Press / 1979 / provided that B1 does not include such moieties that remain inactive in the present method of the invention. The reactions for converting said moieties to relative ones? of the products of the synthesis scheme described therein or claimed herein or where appropriate or preferred with respect to certain intermediates in this synthesis scheme.For example, carboxylic acid substituents may be converted to the carboxamide by conversion xx to the acid halide followed by its reaction with an amine. The esters can be converted to the acid and treated as described above.

-5Nitriles can be converted to carboxamides by reaction with an alkylating agent such as t-butyl acetate or t-butanol under acid catalysis.

When using the process of the invention to prepare the compounds of formula (I), new intermediates represented by the following formula (IV) are synthesized:

where x is / 1 / CONE ^ EP ³ , where E ² and E ^{3 are} independently selected from hydrogen,

3 alkyl, cycloalkyl and phenyl; or B and B taken together with the nitrogen atom to which they are attached represent a 5-6 membered saturated ring including another heteroatom selected from oxygen and nitrogen; or (2) parts that can be chemically converted to parts of (1), such as -C-N, -COOH, or -COOC ^ alkyl

Preferably, E2 as used in the above compound is formula (IV) is:

3 2 3/1 / COMB S, wherein E and B are each independently selected from hydrogen, C 1-6 alkyl, cycloalkyl and phenyl; or (2) -C-N, -COOH or -COOC 1-6 alkyl.

The most preferred meaning of B1 as used

3 in the above compound of formula (IV) is: -C0NB E, where

3

R and E are independently selected from hydrogen, C-ji-8 alkyl, C ₃ _ ^ cycloalkyl, and phenyl.

The method according to the present invention reveals several advantages over the prior art.

- optionally, the reagents and conditions used to convert 3-halogen steroid-3,5-dienes to steroid-3,5-dienes 3 ~ carboxylic acid are safe, inexpensive, can react in high concentrations and produce in high yields of the desired compound, thus making said method suitable for industrial application.

As used herein and in the claims, unless otherwise indicated, the term C 1-3 alkyl denotes a hydrocarbon of a chain, straight or branched, having CL carbon atoms.

The term cyanide reagent as used herein and in

Shi Claims means reagents that are capable of reacting under certain conditions with a halogenated moiety to form a cyanide moiety. Preferably, said cyanide moiety is prepared by reacting the respective halogenated moiety with a cyanide reagent in a suitable solvent, such as N, N-dimethyl-N, N-E-propylene urea (DMPC), N, N-dimethylformamide (DMF) or N-methyl-2-pyrrolidinone (KEMP), preferably DMF, at elevated temperatures.

The term saponification as used herein and in the claims: ** 'means a compound or reagent or series of reagents capable of reacting with nitrile to form a substituted portion of carboxylic acid under suitable conditions. Preferably said substituted carboxylic acid moiety is prepared by reacting the corresponding cyanide moiety with a hydroxide base, preferably an aqueous sodium hydroxide solution, in a suitable solvent, such as ethylene glyx isopropyl alcohol or ethanol, preferably ethanol, at elevated temperatures with subsequent acidification.

Through the term elevated temperatures as used

The temperature of above 25 ° C is also indicated in the claims, preferably at the reflux temperature of the solvent of the mixture.

Preferred cyanide reagents for use in the method of the invention are cyanide complexes as described in Richard C. Larock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations.Pub:VCH Publishers, Inc. (1989) p86 For example, one is used here cyanide complex, which is an in situ mixture of KSM, NiBr ^ / PBij / g, Ζη, ΡΡΗ ^. Other examples include: Co / CN / 5; K ₄ Ni ₂ / CH / ₆ , KCN; KCN, cat Pd / PPh ^; Co / CN / | ; CuCN ^and NaCu / CN / p. As used herein, NaCu / CN / ₂ ”term refers to a reagent formed by the simultaneous mixing of Cu 0 H ^and NaCN in t.

Preferred among the aforementioned &apos; cyanide complexes are CuCN and NaCu (CN) ₂ ·

Particularly preferred among the above cyanide complexes is NaCu (CN) ₂ .

Preferably, said NaCu (CN) ₂ complex is obtained by the addition of 1 molar equivalent of sodium cyanide to copper cyanide in situ.

The term "solvent" or "suitable solvent" as used herein and in the claims means a solvent such as methylene chloride, ethylene chloride, chloroform, ethylene glycol, tetrachloromethane, tetrahydrofuran (THF), ethyl ether, toluene, ethyl acetyl, dimethyl 14 dimethyl 1-dimethyl-N, N * -propylene urea, Kmethyl-2-pyrrolidinone, methanol, isopropyl alcohol, dimethylformamide, water, pyridine, quinoline or ethanol.

Preferably, the method of the present invention is particularly: useful for preparing a compound having the structure (IIIA):

and converting this compound into the structure / TA /:

/ SHA / junction with

/ 1A / • w ·

Without further specification, it is believed that one of ordinary skill in the art can use the present invention to the fullest extent possible. The following examples should therefore be considered as illustrative only and not limit the scope of the present invention.

EXAMPLES

Dimethylformamide and cuprous cyanide are available from Adrich Che mical Co. (Milwaukee, WI ), ^ Hfl p 0CT _4_ eH _3_ eH _j_7j5 carboxylic acid is available from Berlichem, Inc. (Wayne, NJ ).

EXAMPLE E

KS-t-butyl-androst-3,5-diene-17J2-carboxamide-3-carboxylic acid (1) P-t-butyl-androst-3,5-diene-3-bromo-17y! - carboxamide

Fill a 100 ml flask under a nitrogen atmosphere. methylene chloride and 6.12 ml. /2.5 malaria equivalent / dimethylformamide. The solution was cooled to 0-5 ° C and treated with 6 _in 9 ml. / 2.5 molar equivalents / oxalyl chloride, during which time the temp.

The white precipitate formed. After stirring for one hour, 50.1 grams / 19.6 molar equivalents / hydrogen bromide gas was 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 its volume to about half by vacuum distillation, and then volume is restored to the original by adding methylene chloride. This concentration / volume recovery procedure is repeated. Androst-4-en-3-one-17β-carboxylic acid, 10.0 g / l molar equivalence was added to the resulting white suspension and the mixture warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled sharply in a vessel containing 100 ml. 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 was added. water and the two-phase mixture is filtered through, a pad of Celite. The organic phase is separated and the volume is reduced to about half by vacuum distillation. The volume of the solution is reduced to the original with acetone. This concentration / volume recovery procedure was repeated two more times. The resulting acetone solution (about 300 ml) was warmed to about 50 ° C and treated with about 100 ml. water to precipitate the product. The suspension was cooled and the final product, N-m. ^·; butyl-androst-3,5-diene-3-bromo-17β-carboxamide was isolated by filtration and dried. Yield 89 mp 181-183 ° C. (2) 5D-t-butyl-androst-3,5-diene-3-cyano-17b-carboxamide.

Stirred mixture of N-t-butyl-andorst-3,5-diene-3-bromo-17 (-c arboxamide (50 grams, 1 molar equivalent), copper cyanide. (11.0 grams, 1.1 molar equivalent) and dimethylformamide / 200 ml. _y is heated at the boiling point of the solvent of the mixture;

The reaction mixture was cooled to 90-100 ° C and cooled sharply with stirring in a solution of 100 ml. Of a concentrated solution of ammonia and 200 ml. Of water. Fill the reaction flask with 25 ml. dimethylformamide, which is also added to the cooled solution. The resulting suspension is extracted twice with 200 m parts of methylene chloride and the organic extracts are filtered through a pad of celite. The organic phase is washed with three 200 ml. Portions of a 50/50 volume / volume of concentrated aqueous ammonia / water, followed by two 200 ml. parts of water. The organic phase is concentrated in vacuo to 150 ml. and 250 ml was added. ethanol.

The solution was again concentrated in vacuo to 150 ml. and 250 ml was added. ethanol. The solution was concentrated in vacuo to 300 ml, and 30 ml was added. water to cause crystallization. The resulting slurry was cooled sharply for 2 hours at 0-5 ° C. The solid was collected by filtration and dried at 65 ° C in vacuo to give 37.0 g of т-t .-Butyl-androst-3,5-diene-3-cyano17 / -carboxamide as yellow crystals in 85% yield and melting point 195-197 ° C.

(3) 51- [butyl-androst-3,5-diene-17,4-carboxamide-3-carbon

7, acid.

Mixture of N-t-butyl-androst-3,5-diene-3-cyano-17β-carboxamide (20.0 grams, 1 molar equivalent), 50% aqueous sodium hydroxide solution (80 ml, 30 molar equivalents) and ethanol (200 ml) was heated at reflux for 18 hours. The reaction slurry was cooled to 50 ° C and added to a stirred mixture of 6Ν hydrochloric acid (300 ml). methylene chloride (200 ml.). The final pH of the aqueous phase is 1.5-2.0. The organic phase was separated and the aqueous phase was extracted a second time with 250 ml. methylene chloride. The combined organic phases are stirred with 2 grams of decolourising carbon for one

-11h and filtered through a pad of celite. The organic phase is concentrated in vacuo to 120 ml. and 200 ml were added. ethyl acetate The suspension was again concentrated in vacuo to 120 ml. and attract 200 ml. ethyl acetate.The resulting suspension was concentrated in vacuo to a final volume of 120 ml. and heated at reflux for 2 hours. The suspension was cooled sharply at 0-5 ° C for two hours and filtered. The solid was dried under vacuum at 65 ° C to give 14.8 grams, yielding 71% N-butyl-androst3,5-diene -17 β-carboxamide-3-carboxylic acid. Recrystallization of the mother liquor gave an additional 3.14 grams (15:% yield) of the product. The total yield for the reaction is 86%. Melting point 250 - 251 ° C.

EXAMPLE 2

N-t.-butyl-androst-3,5-diene-3-cyano-17H-carboxamide.

A five-liter three-necked flask (Mog5-op) equipped with a stirrer mechanic, thermometer and reflux was charged with 250 grams of KE-t-butyl-androst-3,5-diene-3-bromo-17-carboxamide. / obtained as described in Example 1/1 //, 55 grams of copper cyanide, 29 grams *** of sodium cyanide and 1 liter of dimethylformamide. The reaction mixture was heated at reflux temperature of the mixture ποί reflux / 152-153 °. With / for at least 12 hours. The reaction mixture was slowly cooled to 25-30 ° C with a cold water bath and cooled sharply with one liter of 50% aqueous ammonium hydroxide / 50/50 volume / volume of concentrated ammonia / water / with rapid stirring. After stirring for 15- One liter of methylene chloride was added for 20 minutes and the two-phase system was allowed to separate! The phases were separated and the aqueous phase was extracted a second time with 2 x 5C ml. The combined methylene chloride extracts were passed through a celite filter pad to remove the undiluted copper salts. The celite pad was washed with 150 ml of methylene chloride. The combined methylene chloride phases were washed with 3 x 500 ml. ammonium hydroxide to remove the last trace of copper salts. The organic phase was concentrated under atmospheric distillation, yielding about 1.5 liters of methylene chloride. 600 ml was charged to the reactor. portion of ethanol and the procedure of concentrating / displacing methylene chloride was continued by distillation of a second portion of 500 ml. solvent. Second serving of 600 ml. ethanol was fed to the reactor and atmospheric distillation continued until the vapor temperature reached 82-84 ° C. 60 ml were fed to the reactor. water and the resulting suspension; was cooled sharply at 0-5 ° C for at least two hours. The solid was collected, washed with 75 ml. 50% aqueous alcohol solution and dried at 60-65 ° C in vacuo to yield 191.3 grams of the title compound. $ 88 yield; melting point 190 - 192 ° C.

While the preferred embodiments of the invention are illustrated above, it should be understood that the invention is not limited to the exact instructions described herein and that the right for all modifications falling within the scope of the following claims is reserved.

Claims (12)

Patent Claims A process for the preparation of a compound of formula (I): ^ τ ·· ^; N 2 in which B is (1) COMB 2 B 2, where B 2 and B 2 are independently selected from hydrogen, Alkyl, cycloalkyl, phenyl; or B and B, taken together with the nitrogen to which they are attached, represent a 5-6 membered saturated ring, including another heteroatom selected from oxygen and nitrogen; or (2) parts that are capable of being chemically converted to parts of (1); or a pharmaceutically acceptable salt, hydrate or solvate thereof, characterized in that it comprises cyanidation of a compound of formula (II): a cyanide reagent and a suitable solvent to form a compound of formula (III): in which $ has the above meanings and subsequent saponification of the compound of formula (III) to form a compound of formula (I) and then optionally a pharmaceutically acceptable salt, hydrate or solvate is obtained. A method according to claim 1, characterized in that the cyanide reagent contains a cyanide complex of the formula or A method according to claim 2, characterized in that the cyanide reagent comprises a cyanide complex of the formula A method according to claim 3, characterized in that the cyanide complex of the formula NaCu (CN) £ is prepared by adding 1 molar equivalent of sodium cyanide to copper cyanide in situ. 5. Method according to claim 2, characterizing se p this, that cyanide complex is copper cyanide. b. Method according to claim 1, characterizing se e toza, that X means . bromine. 7. Method according to claim 1, characterizing with e p toza, that said solvent is dimethylformamide. 8. Method according to claim 1, characterizing se p toza, that saponification involves the reaction of Ν-τ, -butyl-androst-3,5diene-3-cyano-17ub-carboxamide and a hydroxyl base in a suitable solvent followed by acidification. A process according to claim 8, characterized in that the suitable solvent is ethanol. The method of claim 9, wherein the base is aqueous sodium hydroxide. A method according to claim 1, wherein the compound obtained is (IA) or a pharmaceutically acceptable salt hydrate or solvate thereof. 12. Compound with structure: in which $ stands for I I p h / 1 / COIIE ° ffi, where $ and are separately selected from hydrogen, 2 3 C1-6 alkyl, C1-8 cycloalkyl, phenyl; or ® and B taken together with the nitrogen to which they are attached are 5-6 membered saturated? a ring containing also another heteroatom selected from oxygen and nitrogen; or / 2 / parts which are capable of being chemically converted to parts of / 1 /. -16ι ₌ The compound of claim 12, wherein $ is -C-II-COOH, -COOC 1-6 alkyl or -COII (N) t-butyl. A compound according to claim 13, wherein E ¹ is -COIl / H / t-butyl. The compound of claim 13, wherein B is -COOH. The compound of claim 13, wherein -C-II. this,