Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J75/00—Processes for the preparation of steroids in general
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
  • C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
  • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
  • C07J41/0066—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by a carbon atom forming part of an amide group
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
  • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
  • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals

Definitions

• 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- ⁇ -reductase .
• 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.
• 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-17 ⁇ -carboxamide-3-carboxylic acid.
• halogen as used herein and in the claims means chlorine, bromine or iodine.
• halogen as used herein means bromine or iodine.
• the present invention provides a process for the production of a compound of Formula (I)
• 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
• X is halogen; in the presence of a cyanating reagent and an appropriate solvent, preferably dimethylformamide, to form a compound of Formula (III)
• 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.
• R 1 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
• R ⁇ is ⁇ -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 Arthur Barton and U.D. Ollis, Comprehensive Organic Chemistry:
• 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.
• 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.
• R 1 is (i) CONR 2 R 3 , where R 2 and R 3 are each independently selected from hydrogen, C ⁇ _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
• R 1 is; (i) CONR 2 R 3 , where R 2 and R 3 are each independently selected from hydrogen, Ci- ⁇ alkyl, C3_gcycloalkyl and phenyl; or
• R-1- is; ⁇ -CONR 2 R 3 , where R 2 and R 3 are each independently selected from hydrogen, C ⁇ _8alkyl, C3_gcycloalkyl and phenyl.
• 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.
• Chalky means a straight or branched hydrocarbon chain having C ⁇ _ n carbons.
• 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.
• a cyanating reagent 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.
• 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
• 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.
• 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.
• 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 (PP ⁇ 13)2, Zn, PPh.3.
• 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 .
• Preferably said NaCu(CN)2 complex is prepared by adding 1 molar equivalent of sodium cyanide to cuprous cyanide in situ.
• 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.
• the process of the present invention is particularly useful for preparing a compound of structure (IIIA)
• Androst-4-en-3-one-17 ⁇ -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 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.
• N-t-butvl-androst-3.5-diene-3-cvano-17 ⁇ -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-17 ⁇ -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.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Toxicology (AREA)
• Steroid Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1993
  • 1993-02-03 IL IL104602A patent/IL104602A/xx not_active IP Right Cessation
  • 1993-02-05 NZ NZ249382A patent/NZ249382A/en unknown
  • 1993-02-05 AU AU36126/93A patent/AU666177B2/en not_active Ceased
  • 1993-02-05 WO PCT/US1993/001068 patent/WO1993016097A1/en not_active Application Discontinuation
  • 1993-02-05 RU RU94045824/04A patent/RU94045824A/ru unknown
  • 1993-02-05 SI SI19939300065A patent/SI9300065A/sl unknown
  • 1993-02-05 MA MA23079A patent/MA22788A1/fr unknown
  • 1993-02-05 CZ CZ941887A patent/CZ188794A3/cs unknown
  • 1993-02-05 ZA ZA93801A patent/ZA93801B/xx unknown
  • 1993-02-05 CA CA002129342A patent/CA2129342A1/en not_active Abandoned
  • 1993-02-05 AP APAP/P/1996/000790A patent/AP9600790A0/en unknown
  • 1993-02-05 BR BR9305837A patent/BR9305837A/pt not_active Application Discontinuation
  • 1993-02-05 EP EP93904946A patent/EP0643724A4/en not_active Ceased
  • 1993-02-05 HU HU9402303A patent/HUT68303A/hu unknown
  • 1993-02-05 JP JP5514208A patent/JPH07505140A/ja active Pending
  • 1993-02-06 CN CN 93102531 patent/CN1078475A/zh active Pending
  • 1993-02-06 TW TW082100820A patent/TW327175B/zh active
  • 1993-02-08 MX MX9300676A patent/MX9300676A/es unknown
• 1994
  • 1994-08-02 KR KR1019940702656A patent/KR950700319A/ko not_active Application Discontinuation
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