AP361A

AP361A - Process for the preparation of substituted steroidal benzo esters and acids.

Info

Publication number: AP361A
Application number: APAP/P/1993/000474A
Authority: AP
Inventors: Neil Howard Baine; Michael Maguire
Original assignee: Smithkline Beecham Corp
Priority date: 1992-01-06
Filing date: 1993-01-05
Publication date: 1994-09-09
Also published as: BR9305707A; CN1077200A; NO942531D0; JPH07503008A; OA09959A; ZA938B; BG98888A; MX9300026A; FI943213A0; FI943213A7; RU94037761A; WO1993014107A1; HU9402029D0; HUT67566A; FI943213L; KR940704064A; NO942531L; IL104303A0; MA22762A1; SK80194A3

Abstract

A process for the preparation of benzo esters or

Description

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-a-reductase.

BACKGROUND.. OF. THE INVENTION

Processes for the preparation of substituted steroidal benzo esters and substituted steroidal benzo acids have previously been described. In particular the use of trifluoromethane sulfonic anhydride to convert steroidal A-ring phenols to steroidal trifluoromethyl sulfonate intermediates (in >95% yield) followed by metal-catalyzed carbonylation to the benzoic ester (in 73% yield) with subsequent hydrolysis to the corresponding benzoic acid (in 90% yield) is reported in U.S. Patent No. 4,954,446.

Further, 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

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- 2 benzo esters and the corresponding steroidal benzo acids in U.S. Patent Nos. 4,937,237 and 4,882,319.

In addition to a low overall yield, the principle shortcoming of these disclosures is that trifluoromethane sulfonic anhydride is an expensive reagent adding significant cost to an industrial process. Thus, there is a need in the art for a safe, economical and reliable method to convert steroidal phenols to steroidal benzo esters and steroidal benzo acids .

SUMMARY QF THE INVENTION

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 17β-(N-tbutylcarboxamide)-estr-1,3,5(10)-triene-3-carboxylic acid and hydrates thereof.

In a further aspect of the invention there are provided novel intermediates useful in the presently invented process .

DETAILED DESCRIPTION QF THE INVENTION

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

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- 3 c luorcsulfonate compound in a metal-catalyzed coupling reaction in the presence of an appropriate coupling reagent followed by an optional, if applicable hydrolysis reaction.

the present invention specifically provides a process for the production of a compound of Formula (Z)

3 ¹ :. 3 (i) H and NR^R⁴, where R^ and R⁴ are each independently selected form hydrogen, C^-galkyl, C3-gcycloalkyl, phenyl; or R-^ and R⁴ taken together with the nitrogen to widen they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom .sleeted from oxygen and nitrogen; or moieties which are chemically conterible to moieties of (i) and i_s an acid or ester;

or a pharmaceutically acceptable salt, hydrate of .:0 solvate thereof, which comprises reacting a compound of ·. ho Formula . (II)

in which R¹ and the broken lines are as described above 2o with fluorosulfonic anhydride and a base in a solvent to form a compound of Formula III

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-ί-

λη which R¹ and the broken lines are as described above 5 and subsequently reacting said compound of Formula (III) in a metal-catalyzed coupling reaction in the presence of ar: appropriate coupling reagent, followed by an nptiona', if applicable, hydrolysis reaction to form a ocmpounc of Formula (I), and thereafter optionally terming a pharmaceutically acceptable salt, hydrate or solvate thereof.

Preferably the reaction to convert Formula II compounds to formula III is preformed at a temperature

IS from -'/S°C to 20°C, particularly preferred temperature range is from -10 to 10 °C.

Preferably the reaction to convert Formula III compounds to Formula I compounds is preferred at a temperature of 25°C to lQQ’C a particular preferred temperature range is from 50 to 90°C.

A·: used above and throughout the remainder of the tpec.i 1 ication and. claims the carbons of the steroid nucleus are numbered and the rings arO lettered 3S 25 follows:

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- 5 - “

Compounds of Formula I comprise R¹ or moieties which can he chemically converted to those of R¹ by known chemical· reactions such as described in J. Fried and J.

Ehwλrdz, Organic Reactions in._Steroid Chemistry., Pub:

Van Nostrand Reinhold Company (1972) provided that R¹does not include any such moieties chae lender inoperative the presently invented process. Reactions to convert said moieties to are performed on products of the synthetic pathways disclosed or claimed herein or, whore appropriate or preferable on certain intermediates in these synthetic pathways. For example, carboxy tic acid su'uiiicucnta oan ba converted to the carboxamide by conversion to the acid halide followed by reacting the same with an 3mine. 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 tbutylacetate or t-butanol under acidic catalysis.

Ac used herein, unless otherwise specified,

Ci kyl means a straight or branched hydrocarbon chain having 1 to n carbons.

in utilizing the presently invented process to prepare the preferred steroidal benzo aoloS 2fld preferred steroidal benzoesters, of Formula (I), novel intermediates of the following Formula (IV) are synthesized;

in whi eh:

- 6 (i) H and CONR³R^, where R³ and R^ are each independently selected from hydrogen, Ci_galkyl, C3_gcycloalkyl, phenyl; or R³ and R⁴ taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one ether heteroatom selected from oxygen and nitrogen; or moieties which are chemically convertible to moieties of (i) .

By the term metal-catalyzed coupling reaction as used herein is meant that the prepared fluorosulfonated compound is reacted in a suitable organic solvent, preferably a dimethylsulfoxide-Ci-θΟΗ 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 reagent.

By the term 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 metalcatalyzed coupling reaction, as described herein, yield preferred acid and ester groups, as disclosed herein, are carbon monoxide (to yield -COOH), ethyltributylstannyl acetate (to yield -CH2COGH), dimethyl phosphite (to yield -P (0) (0.8)3) and hypophosphorous acid crystals (to yield -PH(O)OH).

By the term phenol as used herein is meant a hydroxylated six membered aromatic ring, unsubstituted

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- 7 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 .

By the term acid as used herein is meant any group which is capable of acting as a proton donor including but not limited to; -COOH, -P(O)(OH)₂, -PH(O)OH, -SO₃H and -(CH₂)1-3-COOH.

By the term ester 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 .

By the term steroidal benzo as used herein is meant a steroid with an aromatic A ring.

By the term solvent as used herein is meant an organic solvent such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran (THF) , ethyl ether, toluene, ethyl acetate, dimethylsulfoxide, methanol or dimethylforamide.

Preferably the base utilized to prepare compounds of Formula II is triethylamine. Preferably the solvent utilized to prepare compounds of Formula II is methylene chloride. Preferably the catalyst utilized in said metal catalyzed coupling reaction is palladium (II) acetate. Preferred acids used to describe in Formula (I) include; -COOH, -P(O)(OH)₂, -PH(O)OH, -SO3H, and (CH2)i-COOH. Particularly preferred among the above acids is -COOH.

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- 8 λ preferred aspect of the invention is the conversion of steroidal phenols to steroidal benzo c.-ier.' and steroidal benzo acids.

Pharmaceutically acceptable salts of Formula (I) compounds are formed, where appropriate, by methods well Znrwr. to those of skill in the art.

Preferably, therefore the process of the present invention is particularly useful for preparing a compound of Structure IIIA.

and converting the same in one or two steps into the following compound cf structure (IA)

or a pharmaceutically acceptable salt, hydrate of solvate thereof.

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- 9 The following examples illustrate preparation of benzo esters and benzo acids from phenols utilizing fluorosulfonic anhydride. The examples are not intended to limit the scope of the invention as defined above or as claimed below.

I ^-SmihETlC-EXAMPLES

Dimethylformamide, oxalyl chloride, tertbutylamine, triethylamine, dimethylsulfoxide, 1,310 bis(diphenylphosphino)propane, palladium acetate, tri-nbutylamine, formic acid, bis (triphenylphosphine)palladium acetate, zinc chloride, tri-o-tolylphosphine, sodium fluoride, phenol, 1,3-dimethylphenol, estrone, trimethylsilylcyanide, zinc iodide, phosphorus oxychloride, 10% palladium on carbon, tert-butylacetate, and 3-hydroxypyridine are available from Aldrich Chemical Co. (Milwaukee, WI).

Carbon monoxide is available from Matheson Gas

Products (E. Rutherford, NJ) .

17p-Cyanoestra-l,3,5(10)-triene-3-yl methanesulphonate was prepared as described by Barton, et. al., J. Chem. Soc. (C), 1968, 2283. Fluorosufonic anhydride was prepared as described by S. Kongpricha, et. al., Inorg. Syn. 1968, XI, 151. Ethyltributylstannyl acetate was prepared as described by A. Zapata, et. al., Syn. Comm. 1984, 14, 27.

Example-1

17p-N-t-Butylcarboxamide-estr-l, 3,5(10)-triene-3carboxylic acid

A. 3-Hydroxyestra-l. 3.5(10) -triene-17-carboxylic acid, 17α/β isomers.

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A mixture of 17p-cyancestra-1,3,5(10)-1riene-3-y1 methanesulphonate_(10.0 grams, 1 molar equivalent), sodium hydroxide (34 grams, 30.5 molar equivalents), and ethylene glycol (200 mL) was heated to 150°C for 5 hours. The hot reaction solution was cooled to 110°C and diluted with water (200 mL). The pH of the solution was adjusted to 2.0 with concentrated hydrochloric acid, and the resulting slurry was chilled to 0°C and stirred for 1 hour. The product was isolated by filtration, washed thoroughly with water (600 mL), and dried under vacuum at 100°C to afford a mixture of 3-hydroxyestra1,3, 5 (10)-triene-17-carboxylic acid, 17α/β isomers (8.5 grams, 77/23:17α/β isomers) in 99% yield, mp 250-270°C.

B^....3-Hv.dr.Q&v.ea.Lr.a-l, 3.5(10) -triene-17fi-N-tbutylcarboxamide

A vigorously stirred solution of DMF (348 mL, 4.1 molar equivalents) and methylene chloride (4800 mL) was slowly charged with oxalyl chloride (384 mL, 4.0 molar equivalents) while maintaining the reaction temperature between 5-15°C. A white flocculant suspension formed while the reaction mixture was stirred for 30 minutes.

The reaction was charged with 3-hydroxyestra-l,3,5(10)triene-17-carboxylic acid, 17α/β isomers (329 g, 1 molar equivalent, 77/23:17α/β isomers) and was stirred for two hours. The reaction solution was slowly quenched into a vigorously stirred mixture of tert-butylamine (1200 mL, 10.4 molar equivalents) and methylene chloride (1600 mL) while maintaining the reaction temperature between 5-15 °C. The reaction mixture was stirred for 45 minutes. The reaction was charged with water (3.0 L) and stirred for one hour. The product was suction filtered and the filter cake was washed with water (14.0 L). The product was dried in a vacuum oven (65°C, house vacuum) to constant weight to afford 3-hydroxyestra-l,3, 5(10)triene-17B-N-t-butylcarboxamide (233 grams) as a white solid in 60% yield, mp 304-3C5°C.

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- 11 C . 3-riuorcsulfcnylestra-l, 3.5(10)-triene-17β-Ν-ίbutyIcarboxamide

A well-stirred solution of 3-hydroxyestra5 1, 3, 5(10)-triene-17a-N-t-butylcarboxamide (231 grams, 1 molar equivalent), methylene chloride (2300 mL) , and triethylamine (132 grams, 2 molar equivalents) was cooled to 0-10°C. The resulting slurry was treated with fluorosulfonic anhydride (154 grams, 1.3 molar equivalents) while maintaining the reaction temperature below 10°C. The reaction was stirred for 30 min and water (1.0 L) was added with vigorous stirring. The organic phase was separated and distilled at atmospheric pressure to a final volume of about 986 ml. Water (1283 mL) was added, and the distillation was continued until the methylene chloride was completely removed, as indicated by a drop in the head temperature below 35°C. Dimethylsulfoxide (4.26 L) was added to the residue and the mixture was warmed to 100°C. The stirred mixture was cooled to room temperature over a 4 hour period, during which the product crystallized. The reaction mixture was stirred at 15-20°C for 1.0 hour and was isolated by filtration. The solid product was washed with water (1.0 L) and air dry thoroughly. This material was crushed and reslurried in 4 L of water for 30 minutes. The product was isolated by filtration and dried at 80°C under vacuum to afford 3-fluorosulfonylestra-1,3,5 (10)-triene17L-N-t-butylcarboxamide (237.3 grams) in 83% yield, mp 138-141°C.

D. Methyl 17β-(N-tert-butylcarboxamide)-estra1,3,5(10)-triene-3-carboxylate

A vessel was charged with dimethylsulfoxide (1350 mL), methanol (75 mL, 5.4 molar equivalents), 335 fluorosulphonylestra-1,3,5 (10)-triene-17fi-N-tbutylcarboxamide (150 g, 1 molar equivalent), triethylamine (76.3 g, 2.2 molar equivalents), and 1,3BAD ORIGINAL

AP3 6 1 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 17β-(N-tertbutylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylate (116.4 g) in 85% yield, mp 155-157°C.

E . 17p-N-t-Butylcarboxamide-estra-l,3,5(10)-triene3-carboxylic acid (anhydrous and hydrated).

A mixture of methanol (80 mL), water (80 mL), methyl 17β-(N-tert-butylcarboxamide)-estra-1,3,5 (10)triene-3-carboxylate (15.9 g, 1 molar equivalent), and sodium hydroxide (4.80 g, 3 molar equivalents) was heated to reflux for 8-12 hours. The hot reaction solution was filtered through celite and the filter pad was washed with 60°C water (80 mL). The filtrate was diluted with water (80 mL). The methanol was removed by distillation to a head temperature of 100°C. The mixture was cooled to 60°C and was quenched with vigorous stirring into 1.5 N hydrochloric acid (160 mL). The resulting white suspension was stirred for 15 minutes.

The slurry was cooled to 0-5°C and stirred for 1 hour.

The product was isolated by filtration, washed with deionized water, and dried under vacuum at 100°C to afford crude 17p-N-t-butylcarboxamide-estra-l,3,5 (10)triene-3-carboxylic acid (15.1 grams) in 99% yield, mp

235-238’C.

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- 13 Anhydrous 176-N-t-butylcarboxarr.ide-estra-l, 3,5 (10) triene-3-carboxylic acid was prepared by azeotropic removal of water from the crude material by distilling from acetonitrile, concentration, and cooling. The solid was isolated by filtration and dried. Yield 71%. Alternatively a hydrated form of l?p-N-tbutylcarboxamide-estra-1,3, 5(10)-triene-3-carboxylic acid was prepared by recrystallization from aqueous isopropanol. Yield 70-80%.

17β-(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.

Example 2

176-(N-tert-Butylcarboxamide)-estra-1, 3.5 (101-triene-3carbQXy.Hc. acid,_(anhydrous and hydrated)

A vessel was charged with 5 volumes of dimethylformamide, 3-fluorosulphonylestra-1,3,5(10)triene-17B-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. Ethyl acetate and water were added, and the organic layer was separated. The organic phase was

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- 14 washed with water ar.d dried over magnesium sulfate. The organic phase was concentrated under vacuum to yield a crude 17β-(N-tert-butylearboxamide)-estra-1,3,5(10)triene-3-carboxylic acid. Anhydrous and hydrated 17JJ-(Ntert-butylcarboxamide)-estra-1,3,5(10)-triene-3carboxylic acid were prepared as described in Example IE. Yield 70-80%.

Example 3

Ethyl-17-beta- (N-tert-butylcarboxamide)-estra-1.3,5(10)triene-3-acetic acid

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. 3Fluorosulphonylestra-1,3,5(10)-triene-175-N-tbutylcarboxamide (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-tolylphosphine (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

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- 15 sodium sulfate, filtered and concentrated under vacuum. The product was isolated as a thick oil.

Exar.pl £ ,..4

Methyl Benzoate

A. Phenvlfluorosulphonate.

A solution of phenol (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 phenvlfluorosulphonate as a crude colorless oil.

B. Methyl benzoate

Phenyl fluorosulfonate (1.0 g, 1 molar equivalent) was dissolved in dimethylsulfoxide (10 mL) under a gentle stream of carbon monoxide with stirring at 23°C. Methanol (5.0 mL, 2.2 molar equivalents) and triethylamine (1.15 g, 2 molar equivalents) were added all at once. Palladium acetate (0.064 g, 0.05 molar equivalent) and 1,3-bis(diphenylphosphino)propane (0.116 g, 0.05 molar equivalent) were mixed and added all at once to the rapidly stirred mixture. The reaction temperature was raised to 70°C over a fifteen minute period. 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

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- 16 purified by bulb to bulb distillation to yield methyl benzoate (0.62 gram) as a colorless oil.

Example., 5

Benzoic acid

A vessel was charged with 5 volumes of dimethylformamide, phenylfluorosulphonate (1 molar equivalent, prepared as described in Example 4A), tri-n10 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 acetate).

Example 6

Methyl 3,5-Dimethylbenzoate

A. 1.3-Dimethylphenyl fluorosulfonate

A solution of 1,3-dimethylphenol (1 molar equivalent) and triethyiamine (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 O’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_

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1, 3-dimethylphenyl fluorosulfonate as a crude colorless oil.

B. Methyl 3.5-Dlmethylbenzoate

1,3-Dimethylphenylfluorosulfonate (1.16 g, molar equivalent) was combined with dimethylsulfoxide (10 mL), triethylamine (1.15 g, 2 molar equivalents), and methanol (5.0 mL, 2.2 molar equivalents). The mixture was evacuated and flushed with carbon monoxide three times. The mixture was kept under a slight positive pressure of carbon monoxide. Palladium acetate (0.064 g, 0.05 molar equivalent) and 1,3bis(diphenylphosphino)propane (0.116 g, 0.05 molar equivalent) were added all at once. 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 lTLS^lNzhertoBuLylcarboxamide)-estra-1,3, 5 (10) -triene-3caxboxylic acid,_(anhydrous and hydrated)

A^^.mfluarasulfOflyl-estra-l, 3,5(10) -triene-17-one

A solution of estrone (10.0 grams, 1 molar equivalent) and triethylamine (9.3 grams, 2.5 molar equivalents) in methylene chloride (200 mL) was cooled to -5°C and treated with fluorosulfonic anhydride (4.9 grams, 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

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- 18 organic phase was separated, washed with water (100 mL), and dried over magnesium sulfate. The solution was concentrated under vacuum to afford a crude solid which was recrystallized from methanol using decolorizing carbon, to afford 3-fluorosulfonyiestra-1,3,5(10)triene-17-one (9.6 grams) in 74% yield, mp 99-102°C.

B . 17g-Cy ano-17B-.tr imethyl si Ivloxyes tra-1,3.5(10)triene-3-yl fluorosulfonate

A mixture of 3-fluorosuifonyl-estra-1,3,5(10)triene-17-one (2.0 grams, 1 molar equivalent), trimethylsilylcyanide (1.4 grams, 2.5 molar equivalents), zinc iodide (0.1 gram, 0.05 molar equivalent) , and methylene chloride (20 ir.L) was warmed to 45°C and stirred for 45 minutes. The reaction was quenched with water (25 mL). The organic phase was separated, washed with water (25 mL), and dried over magnesium sulfate. The organic phase was concentrated under vacuum to afford a crude solid which was recrystallized from methanol to afford 17a-cyano-17ptrimethylsilyloxyestra-1,3,5(10) - triene-3-yl fluorosulfonate (1.9 grams) in 76% yield, mp 104-108°C.

C . 17-Cyano-l, 3,.5-(10) ,16-tetraene-3-yl fluorosulfonate

A mixture of 17a-cyano-17p-trimethylsilyloxyestra1, 3, 5(10)-triene-3-yl fluorosulfonate (2.0 grams, 1 molar equivalent), phosphorus oxychloride (2.2 grams,

2.5 molar equivalents), and pyridine (8 mL) was heated to reflux for 17 hours. The reaction was cooled to room temperature and was quenched into a mixture of concentrated hydrochloric acid (25 mL) and crushed ice (20 mL). The aqueous phase was separated and extracted ethyl acetate (50 mL). The organic phases were combined, washed with water (2 x 25 mL), and dried over magnesium sulfate. The organic phase was concentrated under vacuum to afford a crude oil which was triturated and

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- 19 recrystallized from ethanol to afford 17-cyano1, 3,5(10) , 16-tetraene-3-yl fluorosulfonate (1.0 grams) in 50% yield, rr.p 110-112°C.

IL._17p-C.yano-l, 3.5 (10) -triene-3-yl fluorosulfonate

A mixture of 17-cyano-l,3,5(10),16-tetraene-3-yl fluorosulfonate (0.5 gram, 1 molar equivalent), 10% palladium on carbon (35 mg), glacial acetic acid (2 mL) , and ethyl acetate (25 mL) was stirred at room temperature over one atmosphere of hydrogen for 6 hours. The catalyst was removed by filtration, and the filtrate was concentrated under vacuum to afford an oil which was triturated with ethanol and recrystallized from the same solvent to afford 17p-cyano-l, 3, 5(10)-triene-3-yl fluorosulfonate (0.45 gram) in 90% yield, mp 126-129°C.

E. 3-Fluorosulfonvlestra-l, 3.5(10) -triene-17fi-N-tbutylcarboxamide

A well-stirred solution of I7p-cyano-l,3,5 (10)20 triene-3-yl fluorosulfonate(5 grams, 1 molar equivalent), and tert-butylacetate (40 mL) was warmed to 60°C. Concentrated sulfuric acid (1.0 mL, 1.3 molar equivalents) was added, and the solution was stirred at 40-55°C for 6.5 hours. The solution was cooled to room temperature, and was quenched into water (30 mL). More water (40 mL) was added, and the mixture was extracted with methylene chloride (200 mL). The mixture was adjusted to pH 7 with 3N aqueous sodium hydroxide. The organic phase was separated and concentrated under vacuum to give a crude solid. This solid was recrystallized from DMSO (90 mL)/water (45 mL) and dried to afford 3-f luorosulfor.ylestra-1,3, 5 (10) -triene-17H-Nt-butylcarboxamide (5.23 grams) in 85% yield, mp 148150°C.

3-Fluorosulfonylestra-1,3,5(10)-triene-17fi-N-tbutylcarboxamide was treated as described in Examples ID

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- 20 and IE to prepare 17β-(N-tert-butylcarboxamide)-estra1,3,5 (10)-triene-3-carboxylic acid, anhydrous and hydrated .

Example 8 Methyl nicotinate;

A. Pyridine-3-fluorosulfonate

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.

B, Methyl nicotinate

Pyridine-3-fluorosulfonate (1 molar equivalent) was dissolved in dimethylsulfoxide ( 10 mL) under a gentle stream of carbon monoxide with stirring at 23°C.

Methanol (5.0 mL) and triethylamine (2 molar equivalents) were added all at once. Palladium acetate (0.05 molar equivalents) and 1,3bis(diphenylphosphino)propane (0.05 molar equivalents) were mixed and added all at once to the rapidly stirred mixture. The reaction temperature was raised to 70°C over a fifteen minute period. 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

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- 21 purified by silica gel chromatography to yield methyl nicotinate as a crystals.

Claims

What is claimed is:

l. A process for the preparation of benzo esters or benzo acids which comprises reacting a phenol

5 with lluorosulfonic anhydride and a base in a solvent to torn the corresponding benzo fluorosulfonate compound and subsequently subjecting said benzo f1uorosulίonate compound in a metal-catalyzed coupling reaction in the presence of an appropriate coupling reagent, followed by

0 an optional, if applicable hydrolysis reaction.
2. A process for the preparation of steroidal benzo esters or steroidal benzo acids which comprises reacting-a steroidal phenol with fluorosulfonic

15 anhydride and a base in a solvent to form the corresponding benzo fluorosulfonate steroid and subsequently reacting said benzo fluorosulfonate steroid in a metal-catalyzed coupling reaction in the presence of an appropriate coupling reagent, followed by on

2q optional·, ic applicable, hydrolysis reaction.
3. A process for the preparation of a compound of Formula (I) if) Which ar.d it- is

BAD ORIGINAL &

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- 23 :x: H and CONR³rS where R³ and R⁴ are each independently selected from hydrogen, Cj-galkyl, ¢3. ^cycloaikyi, phenyl; or R³ and' R⁴ taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other hetcroatom selected from oxygen and nitrogen; or moieties which are chemically convertible to moieties 0 f (i i

R² is an acid or.ester;

or a pharmaceutically acceptable salt, hydrate of solvate thereof, which comprises reacting a compound of I-or.T.ula (II) rn wp.icn R¹ is as described above with fluorosulfonic anhydride and a base in a solvent to form a compound of Formula III in which R¹ is as described in Formula (II) and subsequently reacting said compound of Formula (III) in a metal-catalyzed coupling reaction in the presence of an appropriate coupling reagent, followed by an optional, if applicable, hydrolysis reaction to form a compound of Formula I, and thereafter optionally if applicable, forming a pharmaceutically acceptable salt, hydrate or solvate.

BAD ORIGINAL

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- 21 . Λ process according to claim 3 in which said base is triethyiamine.
5. A process according to claim 3 in which said

5 metai catalyst is a palladium catalyst.
6. A process according to claim 3 in which the prepared compound of Formula I is isolated by crystallization from an aqueous organic solvent thereby

10 forming a hydrated product.
7. The process of claim 6 in which the compound prepared is in the monohydratc form.

lb θ. The process of claim 7 in which the compound prepared is 17Λ-(N-t-butylearboxamide, - estra-1,3, 5(10)tri'.*r.e-3-carboxylic acid monohydratc.
9. A process according to claim 3, in which R/ is:

²⁰ -SO3K, -P (0) (OJI, ₂, -PH (0, Ofl or - (Cll₂) I-3COOH .
10. A process according to claim 3 in which i ·, -f.OOll.
11. Λ process according to claim 10 in which the compound prepared is ³⁵ or a pharmaceutically acceptable salt, hydrate or

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- 2i
12. Λ compound ot the structure

5 in which R- Is {i) !· snd CONR³R⁴, where R³ and R‘¹ are each independently selected from hydrogen, Ci-flalkyl, C3-$cycloalkyl, phenyl/ or R³ and R⁴ taken together with

10 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 cf <iϊ .
13. Λ compound of claim 12 wherein R¹ is -CN^-COOH, CONG!) t-butyl.
14. The process of claim 6 in which the compound of Formula I is 17fl-(N-t-butylcarboxamide)-estra-1,3, 5(10)tvicne-3-carboxylic acid.