SK80194A3 - Process for preparing 3-acylestratrienes and acylbenzenes - Google Patents

Abstract

Invented is an improved process for the preparation of benzo esters and benzo acids. Also invented are novel intermediates used in said process.

Description

Technical field

The invention relates to an improved process for the preparation of substituted steroid benzoesters and substituted steroid benzoacids. These compounds are described in U.S. Patent Nos. 4,954,446; 4,937,237; Nos. 4,970,205 and 4,882,319, which are suitable for the preparation of compounds which are useful for inhibiting the steroid 5-α-reductase.

BACKGROUND OF THE INVENTION

Methods for preparing substituted steroid benzoesters and substituted steroid benzoacids have already been described. U.S. Patent No. 4,954,446 mainly describes the use of trifluoromethanesulfonic anhydride to convert steroid A-ring phenols to steroidal trifluoromethyl sulfonate intermediates (in more than 95% yield), followed by metal catalyzed carbonylation to benzoic ester (with 73% yield) followed by 73% yield. hydrolysis to the appropriate benzoic acid (90% yield).

Further, said steroid trifluoromethyl sulfonate intermediate is prepared by metal catalyzed condensation reactions in the presence of various condensation reagents (which may be followed by a hydrolysis reaction as necessary) to form the appropriate steroidal benzoesters and the corresponding steroid benzoacids as disclosed in U.S. Patent Nos. 4,937,237 and 4,882 .

In addition to low overall yields, the basic drawback of these processes is that trifluoromethanesulfonic anhydride is an expensive agent that greatly increases the cost of the industrial process. Thus, there is a need for a safe, economical, and reliable method for converting steroid phenols into steroidal benzoesters and steroidal benzoacids.

The invention relates to an improved process for converting phenols into benzoesters and benzoacids.

The present invention relates to an improved process for converting steroid phenols into steroid benzoesters and steroid benzoacids.

The invention specifically relates to an improvement of the process for the preparation of 17β- (N-t-butylcarboxamide) -estra-1,3,5 (10) -triene-3-carboxylic acid and its hydrates.

Furthermore, the present invention also provides novel intermediates that are used in the process of the invention.

SUMMARY OF THE INVENTION

The invention provides a process for preparing a benzoic acid and a benzoester, which comprises reacting phenol with fluorosulfonic anhydride and a base, preferably a tertiary amine base such as triethylamine, pyridine, or tributylamine, in an appropriate solvent to form a benzofluorosulfonic compound and reacting the benzofluoro compound in the presence of an appropriate condensing agent, optionally followed by a hydrolysis reaction if appropriate.

The invention relates to a process for the preparation of a compound of formula I

where

^R1 is (i) H, and NR ³ R ^4, Length, C £ _ g Shallow L in which R ³ and R ⁴ are independently selected from the VOC _gcykloalkylu _3, phenyl; or R ³ and R ⁴ together with the nitrogen to which they are attached represent a 5 to 6-membered saturated ring comprising up to one heteroatom selected from oxygen and nitrogen; or groups that are chemically related to groups (i) and

ABOUT

R is an acid or an ester;

or a pharmaceutically acceptable salt thereof, a boiling hydrate which comprises reacting a compound of formula II, or

ili) wherein R 1 and the dashed lines are as described above with fluorosulfonic anhydride and a base in 1e to form a compound of formula III of solvents (III)

as described above wherein R ¹ reacts the compound of formula III in a metal catalyzed condensation reaction in the presence of an appropriate condensation agent, optionally followed by a hydrolysis reaction to form a compound of formula I and then optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.

and following

Preferably, the reaction of converting Formula II to Formula (III) takes place at temperatures from -78 ° C to 20 ° C, with a temperature range of -10 ° C to 10 ° C even more preferred.

The reaction of converting the compounds of formula III to the compounds of formula I may preferably take place at temperatures from 25 ° C to 100 ° C, but more preferably in the range of temperatures from 50 ° C to 90 ° C.

Accordingly, as used above and below in this specification and claims, the carbons in the steroid cores are numbered and the rings are lettered as follows:

Compounds of formula I are or contain groups that can be chemically converted to R ¹ by known chemical reactions as described in J. Fried and J. Edwards, Organic Reactions in Steroid Chemistry, Pub: Van Nostrand Reinhold Company (1972), provided that: R ¹ does not contain such groups, which cause neoperatívnosť the method of preparation. Reactions for the conversion of said groups to R 1 take place on the products of the synthetic reaction procedures disclosed or claimed herein, or, where appropriate or preferred, on certain intermediates of these synthetic processes. For example, carboxylic acid substituents can be converted to carboxamide by conversion of the halide acid followed by reaction with the same amine. The carboxylate substituents may be converted to acids and may be followed as described above. Nitriles can be converted to carboxamide by reaction with an alkylating agent such as t-butyl acetate or t-butanol by acid catalysis.

Unless otherwise specified, C ^ _ _n are alkyl means a straight or branched hydrocarbon chain having 1 to n carbons.

Using this process for the preparation of the preferred steroid benzoacids and the preferred steroid benzoesters of formula I, new intermediates of formula IV have been synthesized:

in kwrom:

R.1 is (i) H and CONR ³ R wherein R ³ and may be independently H, C ₁ _galkyl, C ₃ _ cycloalkyl, phenyl; or are together with the nitrogen to which they are attached and represent a 5 to 6 membered saturated ring containing up to one other heteroatom selected from oxygen and nitrogen; or groups that are chemically convertible into groups (i).

As used herein, a metal catalyzed condensation reaction means that the prepared fluorosulfone compound is reacted in a suitable organic solvent, preferably in a solution of C 1-8 -dimethylsulfoxide (if an ester is required) or in toluene, dimethylformamide or THF (if an acid is required) with a base, preferably a tertiary amine such as triethylamine, pyridine or tributylamine, a phosphine such as bis (diphenylphosphino) alkane, preferably 1,3-bis (diphenylphosphino) propane or tri-o-tolylphosphine or C 1-4 galKOH, and a metal catalyst such as preferably palladium ( II) acetate, palladium (II) chloride and bis (triphenylphosphine) palladium (II) acetate and a condensing agent.

As used herein, the term condensing agent refers to a compound that is capable of reacting with an aryl radical to form an acid or ester with it. Preferred condensing agents which, when added to a metal catalyzed condensation reaction as described herein, give preferred acid or ester groups as described herein are carbon monoxide (to yield -COOH), ethyltributylstanylacetate (to obtain -CH 2 COOH), dimethyl phosphite (to obtain -P (O) (OH) 2) and hydrophosphoric acid crystals (to obtain -PH (O) OH).

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The term phenol as used herein refers to a hydroxylated six-membered aromatic ring, unsubstituted or substituted with non-reactive substituents, wherein the aromatic ring may also be part of a polycyclic molecule such as a naphthyl or steroid molecule, wherein the molecule is unsubstituted or substituted with non-reactive substituents.

As used herein, the term acid means any group capable of acting as a proton donor, including but not limited to -COOH, -P (O) (OH) ₂ , -PH (O) OH, -SO 3 H and - (CH ₂ ) ₁ _ ₃ -COOH.

The term ester as used herein refers to a group consisting of an acid as defined above in which the transferable proton or protons are replaced by alkyl substituents.

As used herein, the term steroid benzo refers to an aromatic A ring steroid.

As used herein, the term solvent refers to an organic solvent such as methylene chloride, ethylene chloride, carbon tetrachloride, chloroform, tetrahydrofuran (THF), ethyl ether, toluene, ethyl acetate, dimethylsulfoxide, methanol, or dimethylformamide.

The preferred base used to prepare the compounds of formula II is triethylamine. The preferred solvent used to prepare the compounds of formula II is methylene chloride. A preferred catalyst used in said catalytic condensation reactions is palladium (II) acetate. Preferred acids used in Formula I are: -COOH, -P (O) (OH) ₉ , -PH (O) OH, -SO 3 H, and (CH ₂ ) 1-3 -COOH. Most preferred acid. is -COOH.

The process of the invention is useful for converting phenols into benzoesters and benzoacids.

A preferred aspect of the invention is the conversion of steroid phenols to steroid benzoesters and steroid benzoacids.

The pharmaceutically acceptable salts of the compounds of formula I are produced, where necessary, by methods well known to those skilled in the art.

The process of the invention compounds of structure IIIA.

is particularly useful for preparation

(IIIA)

FOgSO and its conversion in one or two steps to the following compound of structure IA:

(IA) or a pharmaceutically acceptable salt, hydrate and solvate thereof.

The following examples illustrate the preparation of benzoesters and benzoacids from phenols using fluorosifonic anhydride. These examples are not intended to limit the scope of the invention as set forth in the description and claims.

DETAILED DESCRIPTION OF THE INVENTION

Examples for synthesis

Dimethylphonamide, oxalyl chloride, cereal butylamine, triethylamine, dimethylsulfoxide, 1,3-bis (diphenylphosphino) propane, palladium acetate. formic acid, tri - n - butylamine. bis (triphenylphosphine) palladium acetate, zinc chloride, tri-o-tolylphosphine, sodium fluoride, phenol, 1,3-dimethylphenol, estrone, trimethylsilyl cyanide, zinc iodide, phosphorus oxychloride, 10% palladium on carbon, tertiary-butyl acetate and 3-hydroxypyridine are available from Aldrich Chemical Co. (Milwaukee, Visconsin).

Carbon monoxide is available from Matheson Gas Products (E. Rutheford, NJ).

17β-Cyanoestra-1,3,5 (10) -trien-3-yl methanesulfonate was prepared according to Barton et al. J. Chem. Soc. (C) 1968,

2283. Fluorosulfonic anhydride was prepared according to S. Kongprich et al. Inorg. A son. 1968, XI, 151. Ethyltributylstannyl acetate was prepared according to A. Zapat et al. A son. Comm. 1984, 14, 27.

Example 1

17β-N-t-butylcarboxyamide-estra-1,3,5 (10) -triene-3-carboxylic acid

A. 3-Hydroxyestra-1,3,5 (10) -triene-17-carboxylic acid isomers 17αβ

A mixture of 17β-cyanoestra-1,3,5 (10) -trien-3-yl methanesulfonate (10 grams, 1 mol), sodium hydroxide (34 grams, 30.5 mol, and ethylene glycol (200 mL) was heated to 150 ° C. This hot reaction mixture 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 suspension was cooled to 0 ° C and stirred for one hour. The product was isolated by filtration, washed well with water (600 mL) and dried in vacuo to give a 3-hydroxyestra mixture.

1,3,5 (10) -triene-17-carboxylic acid, 17αβ isomers (8.5 grams, 77/23: 17αβ isomers) in 99% yield. Melting point: 250-270 ° C.

(B) Three-hydroxy-estra-1,3,5 (10) -triene-17β-Ν-t-butylcarboxamide

To a vigorously stirred solution of DMF (348 mL, 4.1 mol) and methylene chloride (4800 mL) was slowly added oxalyl chloride (384 mL, 4.0 mol) at a maintained temperature in the range of 5-15 ° C. A white precipitated slurry was formed and the mixture was stirred for 30 minutes. To this mixture was added 3-hydroxyestra-1,3,5 (10) -triene-17-carboxylic acid, 17αβ isomers (329 grams, 1 mol, 77/23: 17αβ isomers) and stirred for two hours. The reaction solution was slowly poured into a vigorously stirred mixture of tertiary butylamide (1200 mL, 10.4 mol) and methylene chloride, maintaining the reaction temperature between 5 ° C and 15 ° C. The reaction mixture was stirred for 45 minutes. Water (3.0 L) was added to the reaction and the mixture was further stirred for 1 hour. The product was vacuum filtered and the filter cake was washed with water (14.0 L). The product was then dried in a vacuum oven (65 ° C, hose vacuum) to constant weight to give 3-hydroxyestra -1,3,5 (10) -triene-17β-Nt-butylcarboxyamide (233 grams) as a white solid with yield. 60%. Melting point 304-305 ° C

C. 3-Fluorosulfonylestra-1,3,5 (10) -triene-17β-N-1-butylcarboxyamide

A well stirred solution of 3-hydroxyestra-1,3,5 (10) -trien-17β-Ν-t-butylcarboxamide (231 grams, 1 mol), methylene chloride (2300 mL) and triethylamine (132 grams, 2 mol) was cooled to 0 to 10 ° C. To the resulting suspension was added fluorosulfonic anhydride (154 grams, 1.3 mol) and the temperature was kept below 10 ° C. The solution was stirred for 30 minutes and then water (1 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

K) and continued distillation until the methylene chloride was completely removed, indicating a head temperature drop below 35 ° C. Dimethylsulfoxide (4.26 .1) was added to the residue and the mixture was heated to 100 ° C. The stirred solution was cooled to ambient temperature for more than 4 hours during which the product crystallized. The reaction mixture was stirred at 15-20 ° C for 1 hour and was collected by filtration. The solid product was washed with water (1.0 L) and air dried completely. This material was crushed and resuspended by adding 4 liters of water for 30 minutes. The product was isolated by filtration and dried under vacuum at 80 ° C to give 3-fluorosulfonylestra-1,3,5, (10) -triene-17β-N-t-butylcarboxamide (237.3 grams) at 83% yield. Mp 138-141 ° C.

D. Methyl 17β- (N-tert-butylcarboxamide) -estra-1,3,5 (10) -trene-3-carboxylate

To the flask was added dimethylsulfoxide (1350 mL), methanol (75 mL, 5.4 mol), 3-fluorosulfonylestra-1,3,5, (10) -β-17βN-t-butylcarboxamide (150 g, 1 mol), triethylamine (76.3 g, 2.2 mol) and 1.3 bis (diphenylphosphino) propane (1.41 g, 0.01 mol). The mixture was stirred until a solution was formed. Add palladium acetate (palladium acetate) (0.768 g, 0.01 mol), charge the flask three times and evacuate with carbon monoxide. The flask was pressurized with carbon monoxide at 7 psi and the reaction mixture was stirred rapidly. The reaction solution was heated to 75 ° C. The carbon monoxide dosing was stopped after 1.5 hours. The reaction mixture was cooled to 15 ° C and stirred for 2 hours. The solid was isolated by suction filtration and the mother liquors were used to flush the reactor interior. The solid was thoroughly rinsed with water (1.5 L) and dried under vacuum at 95 ° C to give pure methyl 17β- (N-tert-butylcarboxamide) -estra-1,3,5, (10) -triene-3 -carboxylate (116.4 g) in 85% yield. Mp 155-157 ° C.

E. 17β-N-t-butylcarboxamide-estra-1,3,5 (10) -triene-3-carboxylic acid (anhydride and hydrated)

A mixture of methanol (80 mL), water (80 mL), methyl 17β- (Ν-t-butylcarboxamide) -estra-1,3,5 (10) -triene-3-carboxylate (15.9 g, 1 mol) and sodium hydroxide (4.80 g, 3 moles) was heated and refluxed for 8-12 hours. The hot reaction solution was filtered through celite and the filter was washed with 60 ° C water (80 mL). The filtrate was diluted with water (80 mL). Methanol was removed by distillation at a head temperature of 100 ° C. The mixture was cooled to 60 ° C and poured with vigorous stirring into 1.5 N hydrochloric acid (160 mL). The resulting white suspension was stirred for 15 minutes. It was then 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 give crude 17β-Nt-butylcarboxamide-estra-1,3,5, (10) triene-3-carboxylic acid (15.1 g) with 99% yield. Mp 235-238 ° C.

17β-N-ΐ-butylcarboxamide-estra-1,3,5, (10) -triene-3-carboxylic acid anhydride was prepared by azeotropic removal of water from the crude material by distillation from acetonitrile, concentration and cooling. The solid was collected by filtration and dried. 71% yield.

Alternatively, a hydrated form of 17β- [1,1-t-butylcarboxamide-estra-1,3,5, (10) -triene-3-carboxylic acid was prepared by recrystallization from an aqueous solution of isopropanol. Yield 70-80%.

17β- (N-tert-butylcarboxamide) -estra-1,3,5, (10) -triene-3-carboxylic acid is a compound that is currently undergoing clinical trials for the treatment of benign prostatic hypertrophy. Isolation of anhydride and hydrated forms of said compound is needed to determine the optimal and reproducible bioavailability profile of said compound.

2

Example 2

17β - (N-tert-Burylcarboxamide) -estra-1,3,5 (10) - triene-3-carboxylic acid (anhydride and hydrated)

5 volumes of dimethylformamide, 3-fluorosulfonyl-estra-1,3,5 (10) -rien-17β-N-t-buryl-carboxamide (1 mol, prepared as described in Example 1C) were charged to the flask. tri-n-butylamine (4.5 mol), formic acid (2 mol) and bis (triphenylphosphine) palladium acetate. Air was aspirated from the vessel and was charged with carbon monoxide three times. The vessel was pressurized with carbon monoxide at 7 psi and stirred vigorously. The reaction solution was heated to 75 ° C until the uptake of carbon monoxide was complete. The reaction mixture was cooled to room temperature. Water and ethyl acetate were added and the organic layer was separated. This organic phase was washed with water and dried over magnesium sulfate. This organic phase was concentrated under vacuum to give crude 17β- (N-tert-butylcarboxamide) -estra-1,3,5 (10) -triene-3-carboxylic acid. Its anhydride and hydrate were prepared as described in Example 1E. 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 mol) was weighed into a 200 mL flask equipped with a stirrer and a serum cover. The mixture was heated under vacuum (1 mm) at 150 ° C for one hour. The vessel was cooled to 25 ° C and the vacuum was interrupted with argon. To the vessel was added fluorosulfonyl ester 1,3,5 (10) -triene-17β-N-1-butylcarboxamide (4.38 grams, 1 mol prepared as described in Example 1C), ethyltributylate acetate (5.28 grams, 1.4 mol) and dimethylformamide (20 mL). The vessel was evacuated and purged with argon three times. Cr-o-tolylphosphine (0.091 g, 0.03) was added to the reaction vessel

3 mol) and palladium acetate (0.045 grams, 0.02 mol) and the reaction vessel was evacuated three times and flushed with argon. The mixture was heated at 80 ° C for one hour. Toluene (100 ml) and water (100 ml) were added and the mixture was stirred for 5 minutes. The reaction mixture was filtered through celite and poured into a separatory funnel. The aqueous layer was separated and the organic phase was washed again. 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 and concentrated in vacuo. isolated as a thick oil.

Example 4

methylbenzoate

A. Phenylfluorosulfonate

A solution of phenol (1 mol) and triethylamine (2.5 mol) in methylene chloride was cooled to -5 ° C and fluorosulfonic anhydride was added thereto while maintaining the temperature between -5 to 0 ° C. After stirring for 1 hour, water (100 mL) was poured into the reaction mixture. The organic phase was separated and washed with water (100 mL) and dried over magnesium sulfate. The solution was concentrated in vacuo to give phenylfluorosulfonate as a crude colorless oil.

B. Methylbenzoate

Phenyl fluorosulfonate (1.0 grams, 1 mol) was dissolved in dimethylsulfoxide (10 mL) under a gentle stream of carbon monoxide with stirring at 23 ° C. Methanol (5.0 mL, 2.2 mol) and triethylamine (1.15 g, 2 mol) were added in one portion. Palladium acetate (0.064 grams, 0.05 mol) and 1,3-bis (diphenylphosphino) propane (0.116 grams, 0.05 mol) were mixed and added at once to the vigorously stirred mixture. The reaction temperature was raised to 15 ° C over 15 minutes. as 70 ° C. The color of the reaction solution changed from light yellow to black / red. After one hour, the reaction was cooled to 23 ° C. The reaction mixture was poured into water (50 mL) and extracted with methylene chloride (50 mL). This methylene chloride layer was extracted three times with water (50 mL) and dried over magnesium sulfate and filtered. The solvent was removed under vacuum. The crude product was purified by distillation from flask to flask to give methyl benzoate (0.62 grams) as a colorless oil.

Example 5

Benzoic acid

The vessel was charged with 5 volumes of dimethylformamide, 1fluorosulfonate (1 mol, prepared according to Example 4A), tri-n-butylamine (4.5 mol), formic acid (2 mol) and bis (triphenylphosphine) palladium acetate (0.02) mol). The vessel was evacuated three times and filled with carbon monoxide. The vessel was pressurized to 7 psi with carbon monoxide and stirred rapidly. The reaction solution was heated to 75 ° C until the uptake of carbon monoxide was complete. The reaction mixture was cooled to room temperature. Ethyl acetate and water were added and the organic layer separated. The organic phase was washed with water and dried over magnesium sulfate. The organic phase was concentrated under vacuum to give crude benzoic acid which was purified by silica chromatography (hexane / ethyl acetate).

Example 6

Methyl 3,5-dimethylbenzoane

A. 1,3-Dimethylphenyl fluorosulfonate

A solution of 1,3-dimethylphenol (1 mol) and triethylamine (2.5 mol) in methylene chloride was cooled to -5 ° C and fluorosulfonic anhydride (1.3 mol) was added thereto while maintaining the temperature between -5 ° C. to 0 ° C. After stirring for 1 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 give 1,3-dimethylphenyl fluorosulfonate as a crude colorless oil.

B. Methyl 3,5-dimethylbenzoate

1,3-Dimethylphenyl fluorosulfonate (1.16 grams, mol) was mixed with dimethyl sulfoxide (10 mL), triethylamine (1.15 grams, 2 mol) and methanol (5 mL, 2.2 mol). The mixture was evacuated three times and flushed with carbon monoxide. The mixture was kept under a slight positive pressure of carbon monoxide. Palladium acetate (0.064 grams, 0.05 moles) and 1,3-bis (diphenylphosphino) propane (0.116 grams, 0.05 moles) were added in one portion. The mixture was evacuated and purged with carbon monoxide. The mixture was heated to 65 ° C under low carbon monoxide pressure in two hours. The mixture was poured into water (50 mL) and 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 obtained was dehydrated over magnesium sulfate and filtered. The solvent was removed under vacuum to give methyl 3,5-dimethylbenzoate, 0.750 grams, as a colorless oil.

Example 7

17β- (N-tert-butylcarboxamide) -estra-1,3,5 (10) -triene-3-carboxylic acid (anhydride and hydrated)

And. 3-Fluorosulfonyl-estra-1,3,5 (10) -trien-17-one

A solution of estrone (10.0 grams, 1 mol) and triethylamine (6.3 grams, 2.5 moles) in methylene chloride (200 mL) was cooled to -5 ° C and fluorosulfonic anhydride (4.9 grams) was added thereto. (1.3 molar equivalents) at a temperature maintained between -5 ° C and 0 ° C. After stirring for 1 hour, the reaction was quenched with water (100 mL). The organic phase was separated, washed with water (100 mL) and dehydrated over magnesium sulfate. The solution was concentrated in vacuo to give a crude solid which was recrystallized from methanol by decolorizing carbon to give 3-fluoro-sulfonyl-estra-1,3,5 (10) -trien-17-one (9.6 g) ) 74% yield. Melting point 99-102 ° C.

(B) 17-cyano-17-trimethylsilyloxyestra-l, 3,5 (10) -trien-3-ylfluórsulfonát

A mixture of 3-fluorosulfonyl-estra-1,3,5 (10) -trien-17-one (2.0 grams, 1 mol), trimethylsilyl cyanide (1.4 grams, 2.5 mol), zinc iodide (0.1 gram (0.05 mol) and methylene chloride (20 ml) were heated 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 give a crude solid which was recrystallized from methanol to give 17α-cyano-17β-trimethylsilyloxyestra-1,3,5 (10) -trien-3-yl-fluorosulfonate (1.9 g) at 76% yield. Melting point 104-108 ° C.

C. 17-Cyano-1,3,5 (10), 16-tetraen-3-yl-fluorosulfonate

A mixture of 17α-cyano-173-trimethylsilyloxyestra-1,3,5 (10) -trien-3-yl-fluorosulfonate (2.0 grams, 1 mol), phosphorus oxychloride (2.2 grams, 2.5 mol) and pyridine (8 mL) was heated under reflux for 17 hours. The reaction mixture was cooled to room temperature and poured into a mixture of concentrated hydrochloric acid (25 mL) and crushed ice (20 mL). The aqueous phase was separated and extracted with ethyl acetate (50 mL). The organic phases were combined, washed with water (2 x 25 mL) and dried over magnesium sulfate. The obtained organic phase was concentrated in vacuo to give a crude oil which was triturated and recrystallized from ethanol to give 17-cyano-1,3,5 (10,16-tetraen-3-yl-fluorosulfonate (1.0 g) in 50% yield). Melting point 110-112 ° C.

D. 17β-Cyano-1,3,5 (10) -trien-3-yl-fluorosulfonate

A mixture of 17-cyano-1,3,5 (10), 16-tetraen-3-yl fluorosulfonate (0.5 g, 1 mol), 10% palladium on carbon (35 mg), glacial acetic acid (2 mL) and ethyl acetate (25 mL) was stirred at room temperature under 1 atmosphere of hydrogen for 6 hours. The catalyst was removed by filtration and the filtrate was concentrated under vacuum to give an oil which was triturated with ethanol and recrystallized from the same solvent to give 17β-cyano-1,3,5 (10) -trien-3-yl fluorosulfonate (0.45). gram) at 90% yield. Melting point 126-129 ^e C.

E. 3-Fluorosulfonylestra-1,3,5 (10) -triene-17β-N-t-butylcarboxyamide

A well stirred solution of 17β-cyano-1,3,5 (10) -trien-3-ylfluorosulfonate (5 grams, 1 mol) and tertiary butyl acetate (40 mL) was heated to 60 ° C. Concentrated sulfuric acid (1.0 mL, 1 mol) was added and the solution was stirred at 40-55 ° C for 6.5 hours. The solution was cooled to room temperature and poured into water (30 mL). An additional 40 mL of water was added and the mixture was extracted with methylene chloride (200 mL). The pH of the mixture was adjusted to 7 with 3N aqueous sodium hydroxide solution. The organic phase was separated and concentrated under vacuum to give a crude solid. This was recrystallized from DMSO (90 mL) / water (45 mL) and dried to give 3-fluorosulfonylestra-1,3,5 (10) -triene-17β-N-t-butylcarboxamide (5.23 grams) in 85% yield. Mp 148-150 ° C.

The 3-fluorosulfonylestra-1,3,5 (10) -triene-17β-Nt-butylcarboxamide was followed as in Example 1D and 1E to prepare 17β- (N-tert-butylcarboxamide) -estra- 1,3,5 (10) triene-3-carboxylic acid anhydride and hydrated.

Example 8

methylnicotinate

A. Pyridine-3-fluorosulfonate

A solution of 3-hydroxypyridine (1 mol) and triethylamine (2.5 mol) in methylene chloride was cooled to -5 ° C and fluorosulfonic anhydride (1.3 mol) was added thereto while maintaining the temperature at -5 ° C. up to 0 “C. After stirring for 1 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 give pyridine-3-fluorosulfonate as a crude colorless oil.

B. Methylnicotinate

Pyridine-3-fluorosulfonate (1 mol) 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 moles) were added in one portion. Palladium acetate (0.05 mol) and 1,3-bis (diphenylphosphino) propane were mixed and added simultaneously to this vigorously stirred mixture. The reaction temperature rose to 70 ° C in 15 minutes. After one hour, the reaction mixture was cooled to 23 C. C. The reaction mixture was poured into water (50 mL). The methylene chloride layer was extracted with water (50 mL) three times and dried over magnesium sulfate and filtered. The solvent was removed under vacuum. The crude product was purified by silica gel chromatography to give methyl nicotinate as crystals.

Claims (14)

PATENT CLAIMS A process for the preparation of a compound of formula I, R (I) wherein R ¹ is (i) H and CONR ³ R ⁴ , wherein R ³ and R ⁴ may each be hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl, phenyl; or R ³ and R ⁴ together with the nitrogen to which they are attached represent a 5-6 membered saturated ring containing up to one additional heteroatom selected from oxygen and nitrogen; or groups that are chemically convertible into groups (i). R is an acid or an ester; or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein the compound of formula II R (II) HO kde R ¹ as described above, is reacted with fluorosulfonic anhydride and a base in a solvent to form a compound of formula III (III) wherein R ¹ is described above in Formula II and the subsequently reacting compound of Formula III, in a metal catalyzed condensation reaction in the presence of an appropriate condensing agent, followed by a possible hydrolysis reaction to form a compound of Formula I and then optionally forming an acceptable pharmaceutical salt, hydrate or solvate. Method according to Claim 1, characterized in that triethylamine is used as the base. 3. The process according to claim 1, wherein palladium is used as the metal catalyst. A process according to claim 1, characterized in that the prepared compound of formula (I) is isolated by crystallization from an aqueous organic solvent to form a hydrated product. A process according to claim 4 wherein the compound is prepared in the form of a monohydrate. 6. The method of claim 5 wherein the compound is 17β- (N-1-butylcarboxamide) estra-1,3,5 (10) -triene-3-carboxylic acid monohydrate. A process according to claim 1, wherein R ² is: -SO 4 H, -P (O) (OH) ₂ , -PH (O) OH, or - (CH ₂ ) _{1. 3} cooh. A process according to claim 1 wherein R 1 is -COOH. Process according to Claim 8, characterized in that the solvate is present. 10. A process for the preparation of steroid benzoesters or steroid benzoacids, characterized in that they are formed by reacting a steroid phenol with fluorosulfonic anhydride and a base in a solvent to form the corresponding benzofluorosulfonate steroid and subsequently reacting in a metal catalyzed condensation reaction in the presence optionally by a hydrolysis reaction. 11. A process for the preparation of benzoesters or benzoacids, characterized in that they are formed by reacting phenol with fluorosulfonic anhydride and a base in a solvent to form the corresponding benzofluorosulfonic compound and subsequently reacting in a metal catalyzed condensation reaction in the presence of an appropriate condensing agent, optionally hydrolysis reaction. 12. Compound with structure FO2SO in which ^R1 is (i) IIa CONR R ^4, wherein R ⁴ and can be independently H, C ₁ _galkyl, C ^^ cycloalkyl, phenyl; or and R ⁴ together with the nitrogen to which they are attached represent a 5-6 membered saturated ring containing up to one additional heteroatom selected from oxygen and nitrogen; or groups that are chemically convertible to ............. ... 13. A compound according to claim 12, wherein R-10 is -CN-COOH, CON (H) t-butyl. Process according to Claim 4, characterized in that the compound of formula I is 17β- (tert-butylcarboxyamide) -estra-1,3,5 (10) -triene-3-carboxylic acid.