WO1996011206A1

WO1996011206A1 - Process for preparing 17-beta-substituted-androsta-3,5-dien-3-carboxylic acids

Info

Publication number: WO1996011206A1
Application number: PCT/US1995/012710
Authority: WO
Inventors: Neil Howard Baine; Michael Anthony Mcguire; Marvin Sungwhan Yu
Original assignee: Smithkline Beecham Corporation
Priority date: 1994-10-05
Filing date: 1995-10-04
Publication date: 1996-04-18
Also published as: EP0784627A4; JPH10507176A; AU3826095A; EP0784627A1

Abstract

The disclosed invention is a process for preparing 17-beta-substituted-androsta-3,5-dien-3-carboxylic acids from 3-halo-17-beta-substituted-androsta-3,5-dienes. The process may be performed in either of two ways: (1) the 3-halo compound is reacted with a phosphine, a metal catalyst, and a coupling reagent in a suitable organic solvent, followed by hydrolyzation of the intermediate to a 3-carboxylic acid; or (2) the 3-halo compound is reacted with a phosphine, a metal catalyst, a strong aqueous base, and a phase transfer catalyst to produce the 3-carboxylic acid.

Description

Process for Preparing 17-beta-substituted-androsta-3,5-dien-3-carboxylic acids

Field of the Invention The present invention relates to an improved 5 process for the conversion of substituted steroidal 3- halogen-3, 5-diene derivatives to substituted steroidal 3, 5-diene-3-carboxylic acid derivatives. Such compounds are described in U.S. Patent No. 5,017,568, issued on May 21, 1991 to Holt, et al. and in International 0 Application Number: PCT/US93/11241 - International

Publication Number WO 94/11386 Published on 26 May 1994 as being useful in inhibiting steroid 5-cc-reductase.

Background of the Invention 5 Processes for the preparation of substituted steroidal 3, 5-diene-3-carboxylic acid derivatives from substituted steroidal 3-halogen-3, 5 diene intermediates have previously been described. In particular the use of catalytic or alkyllithium mediated 0 carboxylation\hydrolysis of steroidal 3-bromo-3,5 diene intermediates to yield steroidal 3, 5-diene-3-carboxylic acid derivatives (in 15% yield when N-butyl lithium was used) is reported in U.S. Patent No. 5,017,568. The use of a basic medium, when applicable, to selectively 5 deprotonate acidic hydrogen atoms of the brominated intermediate in the above reaction prior to the addition of a dehalogenating reagent has been shown to increase the yield of the resulting steroidal 3,5-diene-3- carboxylic acid derivative in International Publication 0 Number WO 93/14106, Published 22 July 1993 (63% for the preparation of N-t-butyl-androst-3, 5-diene-17β- carboxamide-3-carboxylic acid from N-t-butyl-androst- 3 , 5-diene-3-bromo-17β-carboxamide) . Disclosed therein as preferred bases utilized in preparing said basic 5 medium are ethylmagnesium bromide and ethylmagnesium chloride. Additionally, the cyanation of steroidal 3- bromo-3 , 5-diene intermediates, with subsequent saponification to yield steroidal 3 , 5-diene-3-carboxylic acid derivatives is described in International Publication Number WO 93/16097, Published 19 August 1993.

In addition to generally low overall yields, the principle shortcoming of these disclosures is that N- butyl lithium and ethylmagnesium bromide and ethylmagnesium chloride are expensive reagents adding significant cost to an industrial process. Further, N- butyl lithium is flammable and the carboxylation reaction is performed at dilute concentrations. The use of cyanating reagents creates an environmental problem as cyanide complexes become hazardous waste in solvent recovery systems. Thus, there is a need in the art for a safe, economical, reliable and environmentally friendly method to convert substituted steroidal 3- halogen-3 , 5-diene derivatives to substituted steroidal 3, 5-diene-3-carboxylic acid derivatives.

Summary of the Invention This invention relates to an improved process for converting steroidal 3-halogen-3 , 5-diene derivatives to steroidal 3, 5-diene-3-carboxylic acid derivatives.

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

This invention specifically relates to an improved process for the preparation of 17β- (phenethylcarbonyl) - androsta-3, 5-diene-3-carboxylic acid.

Detailed Description of the Invention

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:

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.

Unless otherwise specified the term "halogen" as used herein and in the claims means chlorine, bromine or iodine.

Preferably the term "halogen" as used herein means bromine or iodine.

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

in which R¹ is

(i) -C(0)NR²R³, where R² and R³ are each independently selected from hydrogen, Ci-galkyl, C3_6cycloalkyl and phenyl; or R² and R³ taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen;

(ii) -C(0)-A-R , where A is absent or present as a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1 to 4 carbon atoms and R^ is a) CF_3/ b) C5 to C7 cycloalkyl or c) Cg to C12 aryl, optionally substituted with one or more substituents selected from the group consisting of: halogen, thio, methylsulfonyl, methylsulfoxyl, methylthio, carboxy, hydroxy, trifluoromethyl, phenoxy and methoxy; or (iii) moieties which are chemically convertible to moieties of (i) or (ii) , such as -C= N, -COOH or -C00C _6alkyl; or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises reacting a compound of Formula (II)

in which R^ is as defined above and

X is halogen; in a metal-catalyzed carbonylation reaction to form a compound of Formula (I) and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate.

Compounds of Formula (II) in which R! is (i)

-C(0)NR²R , where R² and R^ are each independently selected from hydrogen, C _galkyl, C3_gcycloalkyl and phenyl; or R² and R^ taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen can be prepared as described in International Application Number:

PCT/US93/00079 - International Publication Number WO

93/14106 Published on 22 July 1993.

Compounds of Formula (II) in which R¹ is (ii)

-C(0) -A-R4, where A is absent or present as a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1 to 4 carbon atoms and R^ is a) CF₃, b) C5 to C7 cycloalkyl or c) Cg to C12 ^aryl optionally substituted with one or more subs ituents selected from the group consisting of: halogen, thio, methylsulfonyl, methylsulfoxyl, methylthio, carboxy, hydroxy, trifluoromethyl, phenoxy and methoxy; can be prepared as described in International Application Number: PCT/US93/11241 - International Publication Number WO 94/ 11386 Published on 26 May 1994.

Compounds of Formula (II) in which R¹ represents moieties which are chemically convertible to moieties of (i) and (ii) above can be prepared by known methods from readily available starting materials such as described in U.S. Patent No. 5,017,568, issued on May 21, 1991 to Holt, et al.

Preferably R^, as used in the above process, is; (i) -C(0)NR R³, where R² and R³ are each independently selected from hydrogen, C^-galkyl, Cβ.gcycloalkyl and phenyl;

(ii) -C(0)-A-R , where A is absent or present as a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1 to 4 carbon atoms and R^ is a) CF₃ b) C5 to C7 cycloalkyl, or c) Cg aryl, optionally substituted with one or more substituents selected from the group consisting of: halogen, thio, methylsulfonyl, methylsulfoxyl, methylthio, carboxy, hydroxy, trifluoromethyl, phenoxy and methoxy; or (iii) -C≡N,-COOH or -C00Cι_6alkyl. Most, preferably R¹, as used in the above process, is -C(0)NR²R³, where R² and R³ are each independently selected from hydrogen, Ci-galkyl, C_β-scycloalkyl and phenyl or -C(0)-A-R^, where A is absent or present as a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1 to 4 carbon atoms and R^ is phenyl.

Compounds of Formula I comprise R! or moieties which can be chemically converted to those of R^ by known chemical reactions such as described in Derek Barton and U.D. Ollis, Comprehensive Organic Chemistry: The Synthesis and Reactions of Orgainc Compounds. Pub: Pergamon Press (1979) provided that R^ does not include any such moieties that render inoperative the presently invented process . Reactions to convert said moieties to R¹ are performed on products of the synthetic pathways disclosed or claimed herein or, where appropriate or preferable on certain intermediates in these synthetic pathways. For example, carboxylic acid substituents can be converted to the carboxamide by conversion to the acid halide followed by reacting the same with an amine. Esters can be converted to the acid and treated as above. Nitriles can be converted to carboxamides by reaction with an alkylating agent, such as t- butylacetate or t-butanol, under acidic catalysis. Further, nitriles can be converted to -C0₂H by hydrolysis and treated as above.

Preferably the reaction to convert Formula II compounds to Formula I compounds is performed at a temperature of 25°C to 150°C; a particularly preferred temperature range is from 50°C to 110°C.

By the term "metal-catalyzed carbonyla ion reaction" as used herein and in the claims is meant: a) that the steroidal 3-halogen-3, 5-diene intermediate is reacted in a suitable organic solvent or a combination thereof, preferably dimethylsulfoxide, toluene, dimethylformamide or tetrahydrofuran or a combination thereof, with a phosphine, such as a bis (diphenylphosphino)alkane, preferably 1,3 bis (diphenylphosphino)propane, or a triarylphosphine, such as tri-o-tolylphosphine, a metal catalyst, preferably a palladium catalyst such as palladium (.II) acetate or palladium (II) chloride, carbon monoxide and a coupling reagent, thereby forming an intermediate, which is hydrolyzed upon workup to a carboxylic acid, or b) that the steroidal 3-halogen-3, 5-diene intermediate is reacted in a suitable water immiscible organic solvent or a combination thereof, preferably N- amyl alcohol, n-butyl alcohol, 4-methyl-2-pentanone, or a combination thereof, with a phosphine, such as 1,3 bis (diphenylphosphino) propane, tri-o-tolylphosphine or preferably triphenylphosphine, a metal catalyst, preferably a palladium or a nickel catalyst such as palladium (II) acetate, palladium (II) chloride, Ni(CN>2 or nickel carbonyl, carbon monoxide, a strong aqueous base, such as NaOH, KOH, K2CO3 or LiOH, and a phase transfer catalyst, such as, cetyltrimethylammonium bromide or tetrabutylammonium chloride, to afford a carboxylic acid. Conditions under a) above are preferred when the substituent at R¹ of the starting Formula (II) compound is not co patable with transformations in a strong basic medium.

By the term "coupling reagent" as used herein and in the claims is meant a compound or compounds which are capable of inserting into a metalated acyl complex which affords as intermediate which hydrolyses upon workup to yield a -COOH substituent. Preferred coupling reagents, for use herein, are formic acid, acetic acid or their carboxylate salts, preferably calcium formate, potassium acetate or calcium acetate.

By the term "Cg to C12 aryl" as used herein, unless otherwise defined, is meant phenyl, naphthyl, 3,4- methylenedioxyphenyl, pyridyl, or biphenyl. The presently invented process discloses several advantages over the references disclosed herein. Specifically, the claimed reagents and conditions convert 3-halogen steroidal 3,5-dienes directly to steroidal 3, 5-diene 3-acid compounds thereby eliminating the need for a separate hydrolysis step when an ester is formed. Further, the claimed process eliminates the use of cyanating reagents which become a hazardous waste problem in solvent recovery systems.

Additionally, the use of mild conditions as in step a) above eliminate the synthetic concerns associated with the conversion of compounds of the Formula (II) to compounds of the Formula (I) in the presesce of a strong base, which are: i) isomerization of the 17β-ketone, ii) saponification of the 17β-carboxamide and iii) retention of the 3,5 diene double bonds.

The reagents and conditions used in the clamed invention to convert 3-halogen steroidal 3,5-dienes to steroidal 3, 5-diene 3-carboxylic acids are safe, economical and result in high yields of the desired compound thereby rendering said processes appropriate for industrial scale utilization.

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

into the following compound of structure (IA)

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

into the following compound of structure (IB)

Contemplated equivalents of R^ in Formulas (I) and (II) are pharmaceutically acceptable substituents, provided said substituents do not render inoperative the claimed invention, and moieties which are chemically convertible to said substituents. 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.

EXAMPLES Calcium formate was pruchased from Eastman Fine Chemical Co. Rochester, NY. Other reagents utilized herein are available from Aldrich Chemical Co. Milwaukee, WI) N-t-butyl-androst-3,5-diene-3-bromo-17β- carboxamide can be prepared as described in International Application Number: PCT/US93/00079 - International Publication Number WO 93/14106 Published on 22 July 1993. 17β-(Phenethylcarbonyl)-androsta-3- bromo-3, 5-diene can be prepared as described in

International Application Number: PCT/US93/11241 -

International Publication Number WO 94/11386 Published on 26 May 1994.

Example 1

N-t-butyl-androst-3.5-diene-17S-carboxamide-

3-carboxγT.ic aςjd

A vessel charged with dimethylsulfoxide (100 ml) , toluene (50 ml) and N-t-butyl-androst-3, 5-diene-3-bromo- 17β-carboxamide (12.38 g, 28.5 mmol) was heated at 80°C and saturated with bubbling carbon monoxide for 30 min. Palladium II acetate (127 mg, 0.57 mmol), 1,3- bis (diphenylphosphino)propane (235 mg, 0.57 mmol) and calcium formate (2.22 g, 17.1 mmol) were added and the reaction was stirred at 80°C while being kept under 2 lbs. of carbon monoxide for 20 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (800 ml) and washed with 1.0 M HC1 (2 X 300 ml) . The organic layer was dried (MgSθ4) , concentrated and the solid product was collected by filtration to afford the desired product N-t-butyl-androst-3 , 5-diene-17β- carboxamide-3-carboxylic acid (8.36 g, 73% yield) .

Example 2

17β- (phenethvlcarbonvl) -androsta-3.5-diene- 3-carboxylic acid A vessel flushed with carbon monoxide for 1 hour and charged with dimethylformamide (10 ml) , toluene (10 ml), 17β- (phenethylcarbonyl) -androsta-3-bromo-3, 5-diene (1.0 g, 2.20 mmol), calcium formate (286 mg, 2.20 mmol), palladium II acetate (12mg, 0.55mmol) and triphenyphosphine (29mg, 0.11 mmol) was saturated with bubbling carbon monoxide for 30 min. The reaction was stirred at 110°C with carbon monoxide being continuously bubbled through the mixture for 14 hours. The reaction was cooled to room temperature, dilued with ethyl acetate (100 ml) and washed with 1.0 M HC1 (75 ml) . The organic layer was dried (MgSθ4), concentrated and the solid product was collected by filtration to afford the desired product N-t- (phenethylcarbonyl) -androsta-3, 5- diene-17β-carboxylic acid (517 mg, 56% yield) .

Example 3

N-t-butvl-androst-3.5-diene-17β-carboxamide-

3-carboxylic acid

A vessel was charged with 6N NaOH (20 mL) , N-amyl alcohol (10.0 mL) , cetyltrimethylammonium bromide (20 mg, 0.054 mmol) and triphenylphosphine (40.0 mg, 0.153 mmol) . The reaction mixture was degassed under aspirator vacuum (12 mm) and charged with carbon monoxide (1.0 atm) . This was repeated three times. Palladium acetate (20.0 mg, 0.089 mmol) was added and the mixture was heated to 50°C for 0.5 hours under 1.0 atm CO. In a separate vessel, the steroid N-t-butyl- androst-3 , 5-diene-3-bromo-17β-carboxamide (2.0 g, 4.6 mmol) was dissolved in warm amyl alcohol (35°, 10.0 mL) and degassed and flushed with carbon monoxide. The steroid mixture was added to the catalyst mixture over a 5 minute period at 50°C. The reaction mixture was then heated at 80°C for 18 hours. The mixture was filtered hot and the amyl alcohol was removed by vacuum distillation. The reaction mixture was bought to pH 1.0 with HC1 (12.0 N) . The acid mixture was extracted with methylene chloride (2 x 40 mL) , and the organic layer was dried over MgS04 and filtered. The solvent was removed by vacuum distillation. The crude product was recrystallized from boiling acetonitrile (50 mL) to yield the desired product N-t-butyl-androst-3, 5-diene- 17β-carboxamide-3-carboxylic acid (1.41 g, 77%) as a white crystalline solid.

Example 4

N-t-butvl-androst-3.5-diene-17β-carboxamide- 3-carboxylic acid A vessel was charged with n-butanol (20 mL) , 20% NaOH (20 mL) , and Ni(CN)2-4H 0 (131 mg 0.72 mmol) . The reaction mixture was degassed under vacuum (12 mm) (3x) and flushed with carbon monoxide (1.0 atm) . The mixture was heated with vigorous stirring to 80°C for 0.5 hours under 1.0 atm of carbon monoxide.

Cetyltrimethylammonium bromide (100 mg, 0.266 mmol) was added and the mixture was stirred for 5 minutes. N-t- butyl-androst-3 , 5-diene-3-bromo-17β-carboxamide (2.0 g 4.6 mmol) was added all at once, and the mixture was heated at 87°C under 1.0 atm. carbon monoxide for 18 hours. The mixture was filtered and the organic solvent was removed by vacuum distillation. The basic solution was brought to pH 2 with 1.0 N HCl and was extracted with methylene chloride (2 x 20 mL) . The methylene chloride layer was dried over MgS04 and filtered. The solvent was removed under vacuum. The crude product was recrystallized from boiling acetonitrile (50 mL) to yield the desired product N-t-butyl-androst-3 , 5-diene- 17β-carboxamide-3-carboxylic acid (1.10 g, 60%) as a white crystalline solid.

While the preferred embodiments of the invention are illustrated by the above, it is understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.

Claims

What is claimed is:

1. A process for the preparation of a compound of Formula (I)

in which

R¹ is

(i) -C(0)NR²R³, where R² and R³ are each independently selected from hydrogen, Cι_galkyl, C3_gcycloalkyl and phenyl; or R² and R³ taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen;

(ii) -C(0)-A-R4, where A is absent or present as a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1 to 4 carbon atoms and R^ is a) CF_3/ b) C5 to C7 cycloalkyl or c) Cg to C12 ^aryl' optionally substituted withone or more substituents selected from the group consisting of: halogen, thio, methylsulfonyl, methylsulfoxyl, methylthio, carboxy, hydroxy, trifluoromethyl, phenoxy and methoxy; or (iii) moieties which are chemically convertible to moieties of (i) or (ii) , or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises reacting a compound of Formula (II)

in which R¹ is as defined above and X is halogen; in a metal-catalyzed carbonylation reaction to form a compound of Formula (I) and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate.

2. A process according to claim 1 in which X is bromine.

3. A process according to claim 1 in which the compound prepared is

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

4. A process according to claim 1 in which the compound prepared is

or a pharmaceutically acceptable salt, hydrate or solvate thereof .