PROCESS OF PREPARING 3-CARBONYLANDROSTADIENE 17-CARBOXAMIDES

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

Description: Process of Preparing 3-Carbonylandrostadiene 17-Carboxamides The present invention relates to an improved 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 . as being useful in inhibiting steroid 5-α-reductase . Ban rnnnd of the Invention 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 carboxylation 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 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 U.S. Application No. 07/817,179 filed on January 6, 1992 (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 medium are ethylmagnesium bromide and ethylmagnesium chloride. In addition to a low overall yield, 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, Thus, there is a need in the art for a safe, economical and reliable method to convert substituted steroidal 3-halogen 3,5 diene derivatives to substituted steroidal 3,5-diene-3-carboxylic acid derivatives. Summary of h 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. In a further aspect of the invention there are provided novel intermediates useful in the presently invented process. 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 R 1 is (i) CONR 2 R3, where R 2 and R^ are each independently selected from hydrogen, C3_gcycloalkyl and phenyl; or R 2 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; or (ii) moieties which are chemically convertible to moieties of (i) , such as -C=N, -COOH or -COOCi-galkyl; or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises cyanation of a compound of Formula (II) in which R 1 is as defined above and X is halogen; in the presence of a cyanating reagent and an appropriate solvent, preferably dimethylformamide, to form a compound of Formula (III) in which R 1 is as defined above and subsequently saponifying the compound of Formula (III) to form a compound of Formula (I) and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof. Preferably R 1 , as used in the above process, is; (i) CONR 2 R 3 , where R 2 and R 3 are each independently selected from hydrogen, C]__galkyl, C3_gcycloalkyl and phenyl; or (ii) -CΞN,-COOH or -COOCx-galkyl. Most, preferably R^, as used in the above process, is β-CONR R 3 , where R 2 and R 3 are each independently selected from hydrogen, C^-galkyl, C3_gcycloalkyl and phenyl. Compounds of Formula I comprise R^- or moieties which can be chemically converted to those of R 1 by known chemical reactions such as described in Derek Barton and U.D. Ollis, Comprehensive Organic Chemistry: The Synthesis and Reactions of Qrgainc Compounds. Pub: Pergamon Press (1979) provided that R 1 does not include any such moieties that render inoperative the presently invented process. Reactions to convert said moieties to R 1 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. In utilizing the presently invented process to prepare compounds of Formula (I) , novel intermediates of the following Formula (IV) are synthesized; in which: R 1 is (i) CONR 2 R 3 , where R 2 and R 3 are each independently selected from hydrogen, Cι_8alkyl, C3_gcycloalkyl and phenyl; or R 2 and R 3 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; or (ii) moieties which are chemically convertible to moieties of (i) , such as -C= N, -COOH or -COOCi-galkyl; Preferably R 1 , as used in the above compound of formula (iv) , is; (i) CONR 2 R 3 , where R 2 and R 3 are each independently selected from hydrogen, Ci-βalkyl, C3_gcycloalkyl and phenyl; or (ii) -C=N,-COOH or -COOCι_gal yl. Most preferably R-1-, as used in the above compound of formula (IV) , is; β-CONR 2 R 3 , where R 2 and R 3 are each independently selected from hydrogen, Cι_8alkyl, C3_gcycloalkyl and phenyl. The presently invented process discloses several advantages over the cited references. Specifically, reagents and conditions used to convert 3-halogen steroidal-3,5-dienes to steroidal-3,5-diene 3-carboxylic acids are safe, inexpensive, can be reacted in high concentrations and result in high yields of the desired compound thereby rendering said processes appropriate for industrial scale utilization. As used herein and in the claims, unless otherwise specified, Chalky! means a straight or branched hydrocarbon chain having Cι_ n carbons. By the term "cyanating reagent" as used herein and in the claims is meant reagents which are capable of reacting, under certain conditions, with a halogenated moiety to form a cyanated moiety. Preferably said cyanated moiety is prepared by reacting the corresponding halogenated moiety with a cyanating reagent in an appropriate solvent, such as N,N-dimethyl- N,N-propylene urea (DMPU) , N,N-dimethylformamide (DMF) or N-methyl-2-pyrrolidinone (NMP) , preferably DMF, at increased temperatures. By the term "saponifying" as used herein and in the claims is meant a compound or reagent or a series of reagents which are capable of reacting with a nitrile to form a carboxylic acid substituted moiety under appropriate conditions. Preferably said carboxylic acid substituted moiety is prepared by reacting the corresponding cyanated moiety with a hydroxide base, preferably aqueous sodium hydroxide, in an appropriate solvent, such as; ethylene glycol, isopropyl alcohol or ethanol, preferably ethanol, at increased temperatures with subsequent acidification. By the term "increased temperatures" as used herein and in the claims is meant above 25°C, preferably at reflux temperatures. Preferably cyanating reagents for use in the presently invented process utilize cyanide complexes such as described in Richard C. Larock, Comphrehensive Organic Transforma ons: ft Guide tQ Functional GrOUP Prepara ons. Pub: VCH Publishers, Inc. (1989) P. 861. An example of a cyanide complex as used herein is the in situ co-mixture of KCN, iBr2 (PPΪ13)2, Zn, PPh.3. Other 3- examples include: Co(CN) 4 ; K4N12 (CH) , KCN; KCN, cat 3- Pd(PPh3>4; Co(CN) 5 ; CuCN and NaCu(CN)2- As used herein the term "NaCu(CN)2" refers to the reagent formed by co- mixing CuCN and NaCN in situ. Preferred among the above cyanating complexes are CuCN and NaCu(CN) 2 . Particularly preferred among the above cyanating complexes is NaCu(CN)2• Preferably said NaCu(CN)2 complex is prepared by adding 1 molar equivalent of sodium cyanide to cuprous cyanide in situ. By the term "solvent" or "appropriate solvent" as used herein and in the claims is meant a solvent such as methylene chloride, ethylene chloride, chloroform, ethylene glycol, carbon tetrachloride, tetrahydrofuran (THF) , ethyl ether, toluene, ethyl acetate, dimethylsulfoxide, N,N l -dimethyl-N,N'-propylene urea, N- methyl-2-pyrrolidinone, methanol, isopropylalcohol, dimethylformamide, water, pyridine, quinoline or ethanol. Preferably, therefore, the process of the present invention is particularly useful for preparing a compound of structure (IIIA) and converting the same into the following compound of structure (IA) 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 Dimethylformamide, and cuprous cyanide are available from Aldrich Chemical Co, (Milwaukee, WI) androst-4-en-3-one-17β-carboxylic acid is available from Berlichem, Inc. (Wayne, NJ) . Example 1 N-t-frutyl-androst-3,5-dieneτl7fircarboxamide-3- (i) N-t-butyl-androst-3,5-diene-3-bromo-17β- carboxamide A flask under nitrogen atmosphere was charged with 100 L of methylene chloride and 6.12 mL (2.5 molar equivalents) of dimethylformamide. The solution was cooled to 0-5°C, and was treated with 6.9 mL (2.5 molar equivalents) of oxalyl chloride while maintaining the temperature between 0-10°C. A white precipitate formed. After stirring for one hour, 50.1 grams (19.6 molar equivalents) of hydrogen bromide gas were bubbled through the solution while maintaining the temperature between 0-10°C. The suspension became a clear colorless solution. The solution was degassed by reducing the solution volume by about one-half by vacuum distillation and restoring to its original volume with methylene chloride. This concentration/refill procedure was repeated. Androst-4-en-3-one-17β-carboxylic acid, 10.0 grams (1 molar equivalent) , was added to the resulting white suspension and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched into a vessel containing 100 mL of 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 of water were added and the biphase 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 restored to its original volume with acetone. This concentration/fill procedure was repeated twice more. The resulting acetone solution (about 300 mL) was warmed to about 50°C and was treated with about 100 mL of water to precipitate the product. The suspension was cooled, and the product, N- t-butyl-androst-3,5-diene-3-bromo-17β-carboxamide, was isolated by filtration and dried. Yield 89%, mp 181- 183°C. (ii) N-t-butvl-androst- .5-diene-3-cyano-l7β- carboxamide A stirred mixture of N-t-butyl-androst-3,5-diene-3- bromo-17β-carboxamide (50 grams, 1 molar equivalent) , cuprous cyanide (11.0 grams, 1.1 molar equivalents), and dimethylformamide (200 mL) was heated to reflux for 3.5 hours. The reaction was cooled to 90-100°C and quenched with stirring into a solution of 100 mL of cone, aqueous ammonia and 200 mL of water. The reaction flask was rinsed out with 25 mL of dimethylformamide, which was also added to the quench solution. The resulting suspension was extracted twice with 200 mL portions of methylene chloride, and the organic extracts were filtered through a pad of celite. The organic phase was washed with three 200 mL portions of 50/50 v/v cone. aqueous ammonia/water, followed by two 200 L portions of water. The organic phase was concentrated under vacuum to 150 mL and 250 mL of ethanol were added. The solution was again concentrated under vacuum to 150 mL, and 250 L of ethanol were added. The solution was concentrated under vacuum to 300 mL, and 30 mL of water were added to induce crystallization. The resulting suspension was chilled for 2 hours at 0-5°C. The solid product was collected by filtration and was dried at 65°C under vacuum to afford 37.0 grams of N-t-butyl- androst-3,5-diene-3-cyano-17β-carboxamide as yellow crystals in 85% yield, mp 195-197°C. (iii) N-t-butyl-androπt-3, -diene-17β-carfrQxamide- A mixture of N-t-butyl-androst-3,5-diene-3-cyano- 17β-carboxamide (20.0 grams, 1 molar equivalent), 50% aqueous sodium hydroxide (80 mL, 30 molar equivalents) , and ethanol (200 mL) was heated to reflux for 18 hours. The reaction suspension was cooled to 50°C and was added to a stirred mixture of 6N hydrochloric acid (300 mL) and methylene chloride (200 mL) . The final pH of the aqueous phase was 1.5-2.0. The organic phase was separated and the aqueous phase was reextracted with 250 mL of methylene chloride. The combined organic phases were stirred with 2 grams of decolorizing charcoal for one hour and were filtered through a pad of celite. The organic phase was concentrated under vacuum to 120 mL and 200 mL of ethyl acetate were added. The suspension was again concentrated under vacuum to 120 mL and 200 mL of ethyl acetate were added. The resulting suspension was concentrated under vacuum to a final volume of 120 mL and was heated at reflux for 2 hours. The suspension was chilled at 0-5°C for two hours and filtered. The solid product was dried under vacuum at 65°C to afford 14.8 grams, 71% yield, of N-t-butyl-androst-3,5-diene- 17β-carboxamide-3-carboxylic acid. Recrystalization of the mother liquors afforded an additional 3.14 grams (15% yield) of product. 86% total yield for reaction. mp 250-251°C. Example 2 N-t-butvl-androst-3.5-diene-3-cvano-17β-carboxamide A 5 L 3-neck flask (Morton) equipped with a mechanical stirrer, thermometer, and reflux condenser was charged with 250 grams of N-t-butyl-androst-3,5- diene-3-bromo-17β-carboxamide (prepared as in Example 1 (i) ) , 55 grams of cuprous cyanide, 29 grams of sodium cyanide, and 1 liter of dimethylformamide. The reaction mixture was heated to reflux (152-153°C) for at least 12 hours. The reaction mixture was slowly cooled to 25- 30°C with a cold water bath, and was quenched with one liter of 50% aqueous ammonium hydroxide (50/50 v/v cone, ammonia/water) with rapid stirring. After stirring 15- 20 minutes, one liter of methylene chloride was charged, and the two phase system was allowed to separate. The phases were separated and the aqueous phase was reextracted with 2 x 500 mL of methylene chloride. The combined methylene chloride extracts were passed through a celite filter pad to remove insoluble 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 last traces of copper salts. The organic phase was concentrated by atmospheric distillation, removing approximately 1.5 liters of methylene chloride. A 600 mL portion of ethanol was charged to the reactor and the concentration/displacement of methylene chloride was continued by distilling a second 500 mL portion of solvent. A second 600 mL portion of ethanol was charged to the reactor and the atmospheric distillation was continued until the vapor temperature reached 82-84°C. A 60 mL portion of water was charged to the reactor and the resulting suspension was chilled at 0-5°C for at least two hours. The solid was collected, washed with 75 mL 50% aqueous alcohol and dried at 60-65°C under vacuum to yield 191.3 grams of the title compound. 88% yield; mp=190-192°C. 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 and R 1 is (i) CONR 3 R 4 , where R 3 and R 4 are each independently selected from hydrogen, Cι_8alkyl, C3_ gcycloalkyl, phenyl; or R 3 and R 4 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; or (ii) moieties which are chemically convertible to moieties of (i) ; or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises cyanation of a compound of Formula (II) in which R^ is as defined above and X is halogen, in the presence of a cyanating reagent and an appropriate solvent to form a compound of Formula (III) in which R^ is as defined above and subsequently saponifying the compound of Formula (III) 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 the cyanating reagent comprises a cyanide complex of the formula CuCN and NaCu(CN)2- 3. A process according to claim 2 in which the cyanating reagent consists of a cyanide complex of the formula NaCu(CN) 2 . 4. A process according to claim 3 in which the cyanide complex of the formula NaC (CN) 2 is prepared by adding 1 molar equivalent of sodium cyanide to cuprous cyanide in situ.. 5. A process according to claim 2 in which the cyanide complex is cuprous cyanide. 6. A process according to claim 1 in which X is bromine. 7. A process according to claim 1 in which said solvent is dimethylformamide. 8. The process according to claim 1 in which the saponification comprises reacting N-t-butyl-androst-3,5- diene-3-cyano-17β-carboxamide and a hydroxide base in an appropriate solvent with subsequent acidification. 9. The process according to claim 8 in which the appropriate solvent is ethanol. 10. The process according to claim 9 in which the base is aqueous sodium hydroxide. 11. A process according to claim 1 in which the compound prepared is or a pharmaceutically acceptable salt, hydrate or solvate thereof. 12. A compound of the structure in which R 1 is (i) CONR 2 R 3 , where R 2 and R 3 are each independently selected from hydrogen, C3_gcycloalkyl, phenyl; or R 2 and R 3 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; or (ii) moieties which are chemically convertible to moieties of (i) . 13. A compound of claim 12 wherein R^ is -C≤N, -COOH, -COOCi-galkyl or -CON(H) t-butyl. 14. A compound of claim 13 wherein R 1 is -CON(H)t- butyl. 15. A compound of claim 13 wherein R 1 is -COOH. 16. A compound of claim 13 wherein R 1 is -C=N.

Inventors: BAINE NEIL HOWARD, OWINGS FRANKLIN FELL, BAINE, NEIL, HOWARD, OWINGS, FRANKLIN, FELL
Applicants: SMITHKLINE BEECHAM CORP, SMITHKLINE BEECHAM CORPORATION
Application year: 1993
Main classification: C07J43
IPC codes: C07C235, C07J3, C07J41, C07J43, C07J75