Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
• • H—ELECTRICITY
  • H10—SEMICONDUCTOR DEVICES; ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
  • H10N—ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
  • H10N30/00—Piezoelectric or electrostrictive devices
  • H10N30/20—Piezoelectric or electrostrictive devices with electrical input and mechanical output, e.g. functioning as actuators or vibrators
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
• • 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
  • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
  • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
• • 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
  • C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
• • 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 preparation of substituted steroidal benzo esters and substituted steroidal benzo acids.
• Such compounds are described in U.S. Patent Nos. 4,954,446; 4,937,237; 4,970,205 and 4,882,319 as being useful for or preparing compounds which are useful for inhibiting steroid 5- ⁇ -reductase.
• said steroidal trifluoromethyl sulfonate intermediate has been reacted in metal-catalyzed coupling reactions in the presence of various coupling reagents (followed by an optional, if applicable hydrolysis reaction) to form the corresponding steroidal benzo esters and the corresponding steroidal benzo acids in U.S. Patent Nos. 4,937,237 and 4,882,319.
• This invention relates to an improved process for converting phenols to benzo esters and benzo acids.
• This invention relates to an improved process for converting steroidal phenols to steroidal benzo esters and steroidal benzo acids.
• This invention specifically relates to an improved process for the preparation of 17Ji-(N-t- butylcarboxamide)-estr-1,3,5(10)-triene-3-carboxylic acid and hydrates thereof.
• the present invention provides a process for the production of a benzo acid or a benzo ester which comprises reacting a phenol with fluorosulfonic anhydride and a base, preferably a tertiaryamine base such as triethylamine, pyridine or tributylamine in an appropriate solvent to form a benzo fluorosulfonate compound and subsequently reacting said benzo fluorosulfonate compound in a metal-catalyzed coupling reaction in the presence of an appropriate coupling reagent followed by an optional, if applicable hydrolysis reaction.
• a phenol with fluorosulfonic anhydride and a base preferably a tertiaryamine base such as triethylamine, pyridine or tributylamine in an appropriate solvent to form a benzo fluorosulfonate compound and subsequently reacting said benzo fluorosulfonate compound in a metal-catalyzed coupling reaction in the presence of an appropriate coupling reagent
• the present invention specifically provides a process for the production of a compound of Formula (I)
• R3 and R 4 are each independently selected form hydrogen, C3_gcycloalkyl, phenyl; or R3 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 moieties which are chemically conterible to moieties of (i) and
• R* is an acid or ester; or a pharmaceutically acceptable salt, hydrate of solvate thereof, which comprises reacting a compound of the Formula (II)
• reaction to convert Formula II compounds to formula III is preformed at a temperature from -78°C to 20°C, particularly preferred temperature range is from -10 to 10°C.
• reaction to convert Formula III compounds to Formula I compounds is preferred at a temperature of 25°C to 100°C a particular preferred temperature range is from 50 to 90°C.
• 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 J. Fried and J. Edwards, Organic Reactions in Steroid Chem stry, Pub: Van Nostrand Reinhold Company (1972) provided that R 1 does not include any such moieties that render inoperative the presently invented process.
• Reactions to convert said moieties to R-- 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.
• Carboxylate substituents can be converted to the acid and treated as above.
• Nitriles can be converted to the carboxamide by reaction with an alkylating agent, such as t- butylacetate or t-butanol under acidic catalysis.
• C ] __ n alkyl means a straight or branched hydrocarbon chain having 1 to n carbons.
• R 1 is (i) H and CONR 3 R 4 , where R 3 and R 4 are each independently selected from hydrogen, 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; or moieties which are chemically convertible to moieties of (i) .
• metal-catalyzed coupling reaction is meant that the prepared fluorosulfonated compound is reacted in a suitable organic solvent, preferably a dimethylsulfoxide-Ci-gOH solution (when an ester is desired) or toluene, dimethylformamide or THF (when an acid is desired) with a base, preferably a tertiaryamine base such as triethylamine, pyridine or tributylamine, a phosphine such as bis (diphenylphosphino)alkane, preferably 1,3 bis(diphenylphosphino)propane or tri-o-tolylphosphine, or a C]__galKOH, and a metal catalyst, preferably a palladium catalyst such as palladium (II) acetate, palladium (II) chloride and bis (triphenylphosphine) palladium II acetate, and a coupling rea
• a suitable organic solvent preferably
• coupling reagent as used herein is meant a compound which is capable of reacting with an aryl radical to form an acid or an ester.
• 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 -COOH) , ethyltributylstannyl acetate (to yield -CH2COOH) , dimethyl phosphite (to yield -P(0) (OH)2) and hypophosphorous acid crystals (to yield -PH(O)OH).
• phenol as used herein is meant a hydroxylated six membered aromatic ring, unsubstituted or substituted with non reactive substituents, said aromatic ring may also be part of a polycyclic molecule such as a naphthyl or steroidal moleucle, said molecule being unsubstituted or substituted with non reactive substituents.
• acid as used herein is meant any group which is capable of acting as a proton donor including but not limited to; -COOH, -P(0) (OH)2, -PH(0)OH, -SO3H and -(CH2) 1-3-COOH.
• esters as used herein is meant a group consisting of an acid, as defined above, in which the donatable proton or protons are replaced by alkyl substituents.
• steroidal benzo as used herein is meant a steroid with an aromatic A ring.
• solvent an organic solvent such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran (THF) , ethyl ether, toluene, ethyl acetate, dimethylsulfoxide, methanol or dimethylforamide.
• organic solvent such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran (THF) , ethyl ether, toluene, ethyl acetate, dimethylsulfoxide, methanol or dimethylforamide.
• the base utilized to prepare compounds of Formula II is triethylamine.
• 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) (0H) 2 , -PH(0)OH, -SO3H, and - (CH2) ⁇ -C00H. Particularly preferred among the above acids is -COOH.
• the present invention is usuful for the conversion of phenols to benzo esters and benzo acids.
• a preferred aspect of the invention is the conversion of steroidal phenols to steroidal benzo esters and steroidal benzo acids.
• the process of the present invention is particularly useful for preparing a compound of Structure IIIA.
• Carbon monoxide is available from Matheson Gas Products (E. Rutherford, NJ) .
• a vessel was charged with dimethylsulfoxide (1350 mL) , methanol (75 mL, 5.4 molar equivalents), 3- fluorosulphonylestra-1, 3,5(10)-triene-17 ⁇ -N-t- butylcarboxamide (150 g, 1 molar equivalent) , triethylamine (76.3 g, 2.2 molar equivalents), and 1,3- bis(diphenylphosphino)propane (1.41 g, 0.01 molar equivalent) . The mixture was stirred until a solution was obtained. Palladium acetate (0.768 g, 0.01 molar equivalent) was added and the flask was filled and evacuated with carbon monoxide three times.
• the vessel was pressurized with 7 psi carbon monoxide and the reaction was stirred rapidly.
• the reaction solution was heated to 75°C.
• the carbon monoxide uptake was finished in about 1.5 hours.
• the reaction was cooled to 15°C and stirred for 2 hours.
• the solid product was isolated by suction filtration, and the mother liquors were used to rinse out the inside of the reactor.
• the solid product was thoroughly washed with water (1.5 L) and dried under vacuum at 95°C to afford pure methyl 17 ⁇ -(N-tert- butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylate C116.4 g) in 85% yield, mp 155-157°C.
• 17 ⁇ -(N-tert-Butylcarboxamide)-estra-1, 3, 5 (10)- triene-3-carboxylic acid is a compound which is currently undergoing clinical investigation for the- treatment of benign prostatic hypertrophy. The isolation of anhydrous and hydrated forms of said compound is necessary in order to establish an optimal and reproducible bioavailability profile for said compound.
• a vessel was charged with 5 volumes of dimethylformamide, 3-fluorosulphonylestra-l,3,5 (10)- triene-17 ⁇ -N-t-butylcarboxamide (1 molar equivalent, prepared as described in Example 1C) , tri-n-butylamine (4.5 molar equivalents), formic acid (2 molar equivalents) and bis (triphenylphosphine)palladium acetate (0.02 molar equivalents) .
• the flask was evacuated and filled with carbon monoxide three times.
• the vessel was pressurized with 7 psi carbon monoxide and the reaction was stirred rapidly.
• the reaction solution was heated to 75°C until the uptake of carbon monoxide was complete.
• the reaction was cooled to room temperature.
• Zinc Chloride (1.91 g, 1.4 molar equivalents) was weighed into a 200 mL flask fitted with a stir bar and serum cap. The mixture was heated to 150°C under vacuum (1.0 mm) for 1 hour. The flask was cooled to 25°C and the vacuum was broken with argon. 3- Fluorosulphonylestra-1,3,5 (10)-triene-17 ⁇ -N-t- butylcarboxamide (4.38 g, 1 molar equivalent, prepared as described in Example 1C) , ethyltributylstannyl acetate (5.28 g, 1.4 molar equivalents), and dimethylformamide ( 20.0 mL) were added to the flask.
• the flask was evacuated and flushed with argon three times. Tri-o-tolyl ⁇ hosphine (0.091 g, 0.03 molar equivalent) and palladium acetate (0.045 g, 0.02 molar equivalent) were added and the reaction vessel was evacuated and flushed with argon three times. The mixture was heated for 1.0 hour at 80°C. Toluene (100 mL) and water (100 mL) were added and the mixture was stirred for 5 minutes. The mixture was filtered through celite and poured into a separatory funnel. The aqueous layer was separated and discarded. The organic phase was washed again with water (100 mL) .
• the organic phase was washed with saturated sodium fluoride (2 x 50 mL) and filtered through celite after each wash.
• the organic phase was washed with water (2 x 50 mL) , dried over sodium sulfate, filtered and concentrated under vacuum.
• the product was isolated as a thick oil.
• the color of the reaction solution went from light yellow to red/black. After 1.0 hour the reaction was cooled to 23°C. The reaction mixture was poured into water (50 mL) and the mixture was extracted with methylene chloride (50 mL) . The methylene chloride layer was extracted with water (50 mL) three times and was dried over magnesium sulfate and filtered. The solvent was removed under vacuum. The crude product was purified by bulb to bulb distillation to yield methyl benzoate (0.62 gram) as a colorless oil.
• a vessel was charged with 5 volumes of dimethylformamide, phenylfluorosulphonate (1 molar equivalent, prepared as described in Example 4A) , tri-n- butylamine (4.5 molar equivalents), formic acid (2 molar equivalents) and bis (triphenylphosphine)-palladium acetate (0.02 molar equivalents) .
• the flask was evacuated and filled with carbon monoxide three times.
• the vessel was pressurized with 7 psi carbon monoxide and the reaction was stirred rapidly.
• the reaction solution was heated to 75°C until the uptake of carbon monoxide was complete.
• the reaction was cooled to room temperature. Ethyl acetate and water were added, and the organic layer was separated.
• the organic phase was washed with water and dried over magnesium sulfate.
• the organic phase was concentrated under vacuum to yield a crude benzoic acid which was purified by silica chromatography (hexane/ethyl
• the mixture was evacuated and flushed with carbon monoxide.
• the mixture was heated to 65°C for two hours under a slight positive carbon monoxide pressure.
• the mixture was poured into water (50 mL) and was extracted with methylene chloride (3 x 50 mL) .
• the methylene chloride layers were combined and extracted with water (2 x 100 mL) .
• the methylene chloride layer was dried over magnesium sulfate and filtered. The solvent was removed under vacuum to afford methyl-3, 5-dimethylbenzoate, 0.750 g, as a colorless oil.
• Example 7 17 ⁇ - (N-tert-Bntylcarboxamide) -estra-1.3. (10)-triene-3- carboxyiic acid. (anhydrous and hydrated)
• a solution of 3-hydroxypyridine (1 molar equivalent) and triethylamine (2.5 molar equivalents) in methylene chloride was cooled to -5°C and treated with fluorosulfonic anhydride (1.3 molar equivalents) while maintaining the temperature between -5 and 0°C. After stirring for one hour the reaction was quenched with water (100 mL) . The organic phase was separated, washed with water (100 mL) , and dried over magnesium sulfate. The solution was concentrated under vacuum to afford pyridine-3-fluorosulfonate as a crude colorless oil.
• the methylene chloride layer was extracted with water (50 mL) three times and was dried over magnesium sulfate and filtered. The solvent was removed under vacuum. The crude product was purified by silica gel chromatography to yield methyl nicotinate as a crystals.

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Cited By (6)

Citations (3)

• 1993
  • 1993-01-04 ZA ZA938A patent/ZA938B/xx unknown
  • 1993-01-04 IL IL104303A patent/IL104303A0/xx unknown
  • 1993-01-05 AP APAP/P/1993/000474A patent/AP361A/en active
  • 1993-01-05 MA MA23051A patent/MA22762A1/fr unknown
  • 1993-01-06 CA CA002127274A patent/CA2127274A1/en not_active Abandoned
  • 1993-01-06 HU HU9402029A patent/HUT67566A/hu unknown
  • 1993-01-06 RU RU94037761/04A patent/RU94037761A/ru unknown
  • 1993-01-06 KR KR1019940702342A patent/KR940704064A/ko not_active Application Discontinuation
  • 1993-01-06 WO PCT/US1993/000078 patent/WO1993014107A1/en not_active Application Discontinuation
  • 1993-01-06 CN CN93101174A patent/CN1077200A/zh active Pending
  • 1993-01-06 SI SI19939300005A patent/SI9300005A/sl unknown
  • 1993-01-06 JP JP5512541A patent/JPH07503008A/ja active Pending
  • 1993-01-06 EP EP93902956A patent/EP0621866A4/en not_active Withdrawn
  • 1993-01-06 BR BR9305707A patent/BR9305707A/pt not_active Application Discontinuation
  • 1993-01-06 MX MX9300026A patent/MX9300026A/es unknown
  • 1993-01-06 SK SK801-94A patent/SK80194A3/sk unknown
  • 1993-01-06 AU AU34347/93A patent/AU3434793A/en not_active Abandoned
• 1994
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  • 1994-07-05 FI FI943213A patent/FI943213A0/fi not_active Application Discontinuation
  • 1994-07-05 BG BG98888A patent/BG98888A/xx unknown
  • 1994-07-05 NO NO942531A patent/NO942531L/no unknown

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