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
  • 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
  • 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
  • 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

Definitions

• the present invention relates to an improved 15 process for the preparation of substituted steroidal dienes.
• Such compounds are described in US Patent No, 5,017,568, issued on May 21, 1991 to Holt et al., as being useful in inhibiting steroid 5- ⁇ -reductase.
• oxalyl bromide is a toxic, expensive liquid which is difficult to store and is not commercially available in the bulk amounts needed for an industrial process.
• This invention relates to a process for the fluorosulphonylation of multiple functional groups on the same molecule.
• This invention specifically relates to a process for the simultaneous fluorosulphonylation and amidation of 3-one- -ene-17-carboxylic acid steroidal compounds.
• This invention specifically relates to an improved process for the preparation of N-t-butyl-androst-3, 5- diene-17 ⁇ -carboxamide-3-carboxylic acid.
• the present invention provides a process for the production of a compound of formula (I)
• R 1 is R ⁇ R 4 , where R ⁇ and R 4 are each independently selected from hydrogen, C ⁇ -galkyl, C3_gcycloalkyl, phenyl; or R ⁇ 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; and
• R2 is an acid or ester; or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises
• reaction to convert Formula II compounds to formula III is performed at a temperature from -78°C to 20°C; A particularly preferred temperature range is from -10°C to 10°C.
• the reaction to convert Formula III compounds to Formula I compounds is performed at a temperature of 25°C to 100°C; a particularly preferred temperature range is from 50 to 90°C.
• compounds of the Formula III are particularly useful as intermediates in the preparation of Formula I compounds.
• C ⁇ _ n alkyl means a straight or branched hydrocarbon chain having 1-n carbons.
• acid as used herein and in the claims is meant any group which is capable of acting as i proton donor including but not limited to; -COOH, -P(0) (OH)2, -PH(0)OH, -SO3H and - (CH 2 ) i-3-COOH.
• esters as used herein and in the claims is meant a group consisting of an acid, as defined above, in which the donatable proton or protons are replaced by alkyl substituents.
• solvent an organic solvent such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran (THF) , ethyl ether, toluene, ethyl acetate, dimethylsufloxide, methanol or dimethylforamide.
• organic solvent such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran (THF) , ethyl ether, toluene, ethyl acetate, dimethylsufloxide, methanol or dimethylforamide.
• the base utilized to prepare compounds of Formula II is triethylamine or pyridine, most preferably pyridine.
• the solvent utilized to prepare compounds of Formula II is methylene chloride.
• the catalyst utilized in said metal catalyzed coupling reaction is palladium (II) acetate.
• Preferred acids used to describe R ⁇ in Formula (I) include; -COOH, -P(0) (OH) 2 , -PH(0)OH, -SO3H, and (CH 2 ) ⁇ -COOH. Particularly preferred among the above acids is -COOH.
• metal-catalyzed coupling reaction as used herein and in the claims is meant that the prepared -b-
• fluorosulfonated compound is reacted in a suitable organic solvent; preferably a dimethylsulfoxide- alkanol (C]_-Cg ) solution (when an ester is desired) or toluene, dimethylformamide, THF or C ⁇ g-CgOH (when an acid is desired) with a base, preferably a tertiary amine base such as triethylamine, pyridine or tributylamine or aqueous KOH or aqueous NaOH; a phosphine such as bis (diphenylphosphino)alkane, preferably 1,3 bis (diphenylphosphino)propane or tri-o-tolylphosphine, and a metal catalyst, preferably a palladium catalyst such as palladium (II) acetate, palladium (II) chloride and bis (triphenylphosphine) palladium II acetate, thereby forming a metalated complex
• coupling reagent as used herein and in the claims is meant a compound which is capable of inserting into said metalated complex with subsequent elimination to yield the corresponding ester or acid.
• Preferred coupling reagents which.when added to the metal-catalyzed coupling reaction, as described herein, yield preferred acid and ester groups, as disclosed herein, are carbon monoxide (to yield -COOC ⁇ - ⁇ ) , formic acid (to yield -COOH) , ethyltributylstannyl acetate (to yield -CH2COOH) , dimethyl phosphite (to yield
• C3_gcycloalkyl, phenyl; or R ⁇ 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.
• the process of the present invention is particularly useful for preparing a compound of Structure IIA
• 1,3-Bis(diphenylphosphino)propane, bis (triphenylphosphine)palladium acetate, and palladium acetate, are commonly available.
• Androst ⁇ 4-en-3-one- 17 ⁇ -carboxylic acid is available from Berlichem, Inc. (Wayne, NJ) .
• Fluorosufonic anhydride was prepared as described by S. Kongpricha, et. al., Inorgr. Syn . 1968, XI, 151.
• a stirred mixture of androst-4-en-3-one-17 ⁇ - carboxylic acid (1 molar equivalent) and pyridine (3 molar equivalents) in 1000 mL of methylene chloride is cooled to 0-5°C, and is treated with fluorosulfonic anhydride (2.5 molar equivalents) while maintaining the temperature between 0-10°C.
• the reaction mixture is quenched into a solution of tert-butylamine (10 molar equivalents) in methylene chloride while maintaining the temperature between 0- 10°C.
• the mixture is stirred for 30 minutes. About 100 ' mL of water is added.
• the organic phase is separated and reduced to about half its volume by vacuum distillation.
• the solution is restored to its original volume with acetone.
• a vessel is charged with dimethylsulfoxide (1350 mL) , methanol (75 mL, 5.4 molar equivalents), N-t-butyl- androst-3,5-diene-3-fluorosulphonyl-17 ⁇ -carboxamide (150 g, 1 molar equivalent), triethylamine (76.3 g, 2.2 molar equivalents), and 1,3-bis (diphenylphosphino)propane (1.4 g, 0.01 molar equivalent). The mixture is stirred until a solution is obtained. Palladium acetate (0.768 g, 0.01 molar equivalent) is added and the flask is filled and evacuated with carbon monoxide three times.
• the vessel is pressurized with 7 psi carbon monoxide and the reaction is stirred rapidly.
• the reaction solution is heated to 75°C.
• the carbon monoxide uptake is finished in about 1.5 hours.
• the reaction is cooled to 15°C and stirred for 2 hours.
• the solid product is isolated by suction filtration, and the mother liquors are used to rinse out the inside of the reactor.
• the solid product is thoroughly washed with water (1.5 L) and dried under vacuum at 95°C to afford pure methyl 17 ⁇ - (N-tert- butylcarboxamide)-androst-3,5-diene-3-carboxylate.
• the hot reaction solution is filtered through celite and the filter pad is washed with 60°C water (80 L) .
• the filtrate is diluted with water (80 mL) .
• the methanol is removed by distillation to a head temperature of 100°C.
• the mixture is cooled to 60°C and is quenched with vigorous stirring into 1.5 N hydrochloric acid (160 mL) .
• a vessel is charged with 5 volumes of dimethylformamide, N-t-butyl-androst-3,5-diene-3- fluorosul ⁇ honyl-17 ⁇ -carboxamide (1 molar equivalent, prepared as described in Example 1 (i) ) , tri-n-butylamine (4.5 molar equivalents), formic acid (2 molar equivalents) and bis(triphenylphosphine)palladium acetate (0.02 molar equivalents).
• the flask is evacuated and filled with carbon monoxide three times.
• the vessel is pressurized with 7 psi carbon monoxide and the reaction is stirred rapidly.
• the reaction solution is heated to 75°C until the uptake of carbon monoxide is complete.
• the reaction is cooled to room temperature.

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

Priority Applications (4)

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Publications (1)

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Citations (2)

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• 1993
  • 1993-02-03 IL IL104601A patent/IL104601A0/xx unknown
  • 1993-02-05 EP EP93904948A patent/EP0626972A4/en not_active Withdrawn
  • 1993-02-05 MA MA23078A patent/MA22787A1/fr unknown
  • 1993-02-05 SI SI19939300067A patent/SI9300067A/sl unknown
  • 1993-02-05 AU AU36128/93A patent/AU3612893A/en not_active Abandoned
  • 1993-02-05 WO PCT/US1993/001071 patent/WO1993016098A1/en not_active Application Discontinuation
  • 1993-02-05 CA CA002129347A patent/CA2129347A1/en not_active Abandoned
  • 1993-02-05 ZA ZA93802A patent/ZA93802B/xx unknown
  • 1993-02-05 JP JP5514211A patent/JPH07505618A/ja active Pending
  • 1993-02-06 CN CN 93102530 patent/CN1078474A/zh active Pending
  • 1993-02-06 TW TW082100819A patent/TW241266B/zh active
  • 1993-02-08 MX MX9300677A patent/MX9300677A/es unknown
• 1994
  • 1994-08-02 KR KR1019940702657A patent/KR950700320A/ko not_active Application Discontinuation

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