GB1571181A

GB1571181A - Process for the manufacture of 1,3-oxygenated , -oestratrienes

Info

Publication number: GB1571181A
Application number: GB4638576A
Authority: GB
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 1975-11-12
Filing date: 1976-11-08
Publication date: 1980-07-09
Also published as: DE2551214C2; BE848301A; DK476376A; LU76163A1; JPS5262264A; DE2551214A1; FR2331568A1; CH623061A5; DK137682C; DK137682B

Abstract

1,3-Oxygenated 8 alpha -oestratrienes of the formula <IMAGE> in which R1 is optionally substituted alkyl, R2 is lower alkyl and Ac is alkanoyl, are prepared. These compounds are obtained by condensing a 3,5-dialkoxyphenylethyl p-toluenesulphonate with an appropriate indan compound. The reaction product of the formula <IMAGE> in which R3 is defined in Claim 1, is then cyclised to a 17 beta -acyloxy-1,3-dialkoxy-1,3,5(10),8,14-oestrapentaene, which is subsequently hydrogenated. Ether cleavage and subsequent esterification results in conversion of the compounds of the formula I into corresponding 1,3-dialkanoyloxy compounds. The 1,3-dialkoxy and the 1,3-dialkanoyloxy compounds can be used as agents for the treatment of postmenopausal women.

Description

(54) PROCESS FOR THE MANUFACTURE OF 1,3-OXYGENATED 8a-OESTRATRIENES (71) We, SCHERING AKTIEN GESELLSCHAFT, a Body Corporate organised according to the laws of Germany, of Berlin and Bergkamen, Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention is concerned with a process for the manufacture of 1,3oxygenated 8a-oestratrienes and with some of the products of the process.

1,3 - Oxygenated 8a - oestratrienes of the general formula I, as defined below, have been known to be distinguished by a strong vaginotropic action coupled with a weak uterotropic side effect (British Patent Specification No. 1,479,934), and are consequently suitable above all for the treatment of women in the postmenopause. However, the processes hitherto known for the production of these compounds industrially are very expensive.

The present invention is based on the problem of providing for the production of these compounds an industrially simpler process, which, starting from easily accessible starting compounds, leads to the desired compounds in relatively few stages of synthesis which take place with good to very good yields.

This problem has now been solved by the process of the present invention.

The present invention accordingly provides a process for the manufacture of a 1,3 - oxygenated 8 - oestratriene of the general formula I

in which R1 represents an unsubstituted or substituted alkyl group or a carboxylic acid acyl group, R2 represents an alkyl group containing 1 to 5 carbon atoms, and Ac represents a carboxylic acid acyl group where a compound of the general formula II

in which R1, represents an unsubstituted or substituted alkyl group, and Tos represents a tosyl group, is ~ reacted in the presence of a deprotonizing agent with a compound of the general formula III

in which R2 has the meaning given above, and R3 represents an ether protecting group capable of being easily split off, to form a compound of the general formula IV

in which R1,, R2 and R3 have the meanings given above, the compound of the general formula IV is cyclized in the presence of a strong acid and an acyl anhydride, the acyl anhydride containing an acyl group of the formula Ac, Ac having the meaning given above, to form a compound of the general formula V

in which R1, R2 and Ac have the meanings given above, and the compound of the general formula V is hydrogenated in the presence of hydrogenation catalyst to form a compound of the general formula Ia

in which R,', R2 and Ac have the meanings given above, and then, if desired, the etherified hydroxyl groups present in the A-ring are converted into carboxylic acid acyloxy groups.

As the optically active starting compounds of the general formula III can be synthesized in a simple manner (German Offenlegungschrift No. 2,014,757), the process of the present invention is especially suitable for the preparation of optically active 1,3 - oxygenated 8a - oestratrienes.

The present invention also provides a modification of the aforesaid process of the present invention, wherein, instead of the compound of the general formula II being reacted in the presence of a deprotonizing agent with a compound of the general formula III, the compound of the general formula III is first reacted with the deprotonizing agent and the resulting reaction product is reacted -with the compound of the general formula II to form the compound of the general formula IV.

The present invention further provides some of the optically active 1,3 oxygenated 8a - oestratrienes of the general formula Ia given above obtainable as products in the processes defined above, namely those in which R1, represents a phenylalkyl group and R2 and Ac have the meanings given above.

The present invention further provides a pharmaceutical preparation which comprises such a compound of the present invention, in admixture or conjunction with a pharmaceutically suitable carrier.

As alkyl groups represented by R1 there come into consideration alkyl groups containing I to 8 carbon atoms, which may be substituted in the usual manner or branched. Preferred are alkyl groups containing I to 7 carbon atoms and lower aralkyl groups. Especially preferred are lower straight chained alkyl groups, for example methyl and ethyl groups, and phenylalkyl groups, for example a benzyl group.

The alkyl group represented by R2 may be a methyl, ethyl, propyl, butyl or pentyl group. R2 preferably represents a methyl or ethyl group.

As acyl groups represented by R1 and Ac there come into consideration those of acids capable of forming physiologically tolerable esters, especially alkanoic acids. Preferred are organic carboxylic acids containing 1 to 8 carbon atoms. There may be mentioned, for example, the following carboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, oenanthic acid, succinic acid, benzoic acid, adipic acid and lactic acid. Especially preferred are acids containing 1 to 3 carbon atoms, for example formic acid, acetic acid and propionic acid, of which acetic acid is regarded as the most preferred.

As ether-protecting groups represented by R3 capable of being easily split off there come into consideration, for example, tert.butyl, tetrahydropyranyl, tetrahydrofuranyl, tz-ethoxyethyl, trimethylsilyl and tri - para - xylyl - silyl groups. The tert. butyl and tetrahydropyranyl (THP) groups are preferred.

For the first reaction stage of the process of the present invention (including the aforesaid modification) there are preferably used as deprotonizing agents, for example, alkali hydrides, alkali alcoholates and alkali amides. As specific basic catalysts for the purpose there may be mentioned, for example, sodium hydride, sodamide, potassium hydride, sodium tert.-butylate, lithium amide and triphenyl- methyl potassium. The reaction is carried out in an inert solvent.

Suitable solvents are, for example, polar ethers, for example 1,2 - dimethoxyethane, 2',2'- - dimethoxy - diethyl ether, tetra- hydrofuran or dioxan, secondary or tertiary alcohols, for example isopropanol, butanol - (2) or tertiary butanol, or dipolar aprotic solvents, for example dimethyl formamide, N - methylacetamide, N methylpyrrolidone or hexamethyl phosphoric acid triamide. On the other hand, however, it is also possible to use for this reaction solvent mixtures of the above mentioned solvents and relatively non-polar solvents, for example benzene or toluene.

When, in the first reaction stage of the process of the present invention, the compound of the general formula II is reacted in the presence of the deprotonizing agent with the compound of the general formula III, this reaction is preferably carried out at a temperature within the range of from +100C to 800C.

In the aforesaid modification of the process of the present invention which is preferred it is advantageous to carry out the reaction between the compound of the general formula III and the deprotonizing agent in a solvent under an atmosphere of a protecting gas, for example argon or nitrogen, and at a temperature within the range of from 30"C to the boiling temperature of the solvent. The reaction with the compound of the general formula II is then preferably carried out at a temperature within the range of from +10"C to 800C.

In the first reaction stage there are obtained high yields of 6080% of the compounds of the general formula IV, which is surprising to an expert as structurally analogous mono-oxygenated tosylates can be condensed with the compounds of the general formula III only with moderate yields (United States Patent No. 3,317,566).

The cyclization of the compounds of the general formula IV is preferably carried out in an atmosphere of an inert gas, for example an atmosphere of nitrogen or argon, in the presence of a strong acid, for example a mineral acid, a sulphonic acid, a Lewis acid or a carboxylic acid that dissociates strongly. There may be mentioned as such an acid, for example, formic acid, monofluoracetic acid, trichloracetic acid, oxalic acid, malonic acid, hydrogen chloride, sulphuric acid, phosphoric acid, perchloric acid, methane sulphonic acid, benzene sulphonic acid, paratoluene sulphonic acid or boron trifluoride.

Especially preferred is a mineral acid, for example perchloric acid or phosphoric acid.

Suitable protic solvents for the cyclization- are carboxylic acid, for example formic acid, acetic acid or propionic acid, or dipolar aprotic solvents, for example dimethylformamide, Nmethylpyrrolidone or hexamethylphosphoric acid triamide. The cyclization may be carried out either at akow temperature, from about 0 C, or at a raised temperature, up to about 1500C. Thecyclization is preferably carried out- at a reaction temperature within the range of from 50C to 250C.

The acyl anhydrides present in the reaction mixture are, for example, anhydrides of fatty acids containing 1 to 8 carbon atoms and mixed anhydrides. There may be mentioned preferably formyl anhydride, acetic anhydride and propionic anhydride.

It is surprising to an expert that in this reaction stage there take place simultaneously the cyclization and the ether splitting of the etherified hydroxyl group in the C,7-position with simultaneous esterification. In this way the path of the synthesis is simplified, as the desired product can be obtained in good yields without expensive separating operations.

The hydrogenation of the compounds of the general formula V is carried out by catalytic hydrogenation. As catalysts there come into consideration, inter alia, heavy metal catalysts, preferably those comprising a heavy metal of Group 8a of the Periodic Table, for example palladium, optionally distributed on a carrier, for example calcium carbonate, active carbon or barium sulphate, or Raney nickel.

The hydrogenation may be carried out either at room temperature or at a lower or higher temperature. For carrying out the reaction a reaction temperature within the range of from OOC to 500C is preferably chosen.

The hydrogenation may be carried out either under atmospheric pressure or at a raised pressure. The hydrogenation is preferably carried out under a pressure of hydrogen within the range of from 1 to 80 atmospheres.

The optional conversion of the etherified hydroxyl groups, for example alkoxy groups, present in the A-ring of the compound of the general formula Ia into acyl groups may be carried out by a method known per se. For example, there may be mentioned splitting with a hydrohalic acid in the presence of a lower carboxylic acid at a temperature below 1500C. The subsequent acylation in the 1,3-position may be carried out in the usual manner with pyridine/acid anhydride or pyridine/acid chloride at room temperature.

The starting compounds of the general formula II may be prepared as follows, taking the 3,5-dimethoxy compound as an example:3,5 - Dimethoxy - phenylacetic acid methyl ester.

To 522.5 grams (3 moles) of acetonedicarboxylic acid dimethyl ester were added in portions, while stirring, 5.3 grams of sodium metal. After 20 hours at room temperature, the mixture was heated for 2 hours at an internal temperature of 140"C, whereby the low boiling constituents were distilled off. To the still warm residue (at about 100"C) were added 2.82 litres of an aqueous solution of 12% strength of sodium hydroxide, and then the mixture was heated for 2 hours at 1000 C, whereby in this case also low boiling constituents (methanol) were distilled off. To the solution, cooled to 80"C, was then added dropwise 245 ml of concentrated sulphuric acid, and the mixture was boiled for 3 hours, cooled and, after saturation with sodium chloride, extracted with ethyl acetate.

The extracts were washed several times with a semi-saturated aqueous solution of sodium chloride, dried with sodium sulphate and filtered. After distilling off the solvent in vacuo, there remained behind 182.9 grams of crude 3,5 - hydroxy - phenylacetic acid in the form of a semi-crystalline product.

To.a boiling suspension of 470 grams of potassium carbonate in 1600 ml of acetone was added dropwise during the course of 40 minutes, while stirring vigorously, a solution of 182.9 grams of crude 3,5 - hydroxy - phenylacetic acid and 315 ml of dimethyl sulphate in 800 ml of acetone, and then the mixture was boiled under reflux for 16 hours. The cooled suspension was filtered, the filter residue was washed several times with acetone, the filtrates were combined and the solvent was distilled off in vacua.

The brown-yellow crude product (188.7 grams) was distilled under a high vacuum.

Yield: 154.2 grams (=49% of the theoretical yield) of 3,5 - dimethoxy phenylacetic acid methyl ester in the form of a colourless oil boiling at 110- 115"C/0.03 Torr.

3,5 - Dimethoxy - phenethyl Alcohol To a solution, cooled to -400C, of 132.3 grams of 3,5 - dimethoxy - phenylacetic acid methyl ester in 1.3 litres of absolute toluene were added dropwise during the course of 40 minutes 1.12 litres of a solution of 20% strength of diisobutyl aluminium hydride in toluene, the temperature rising to -10"C. After a further 20 minutes at -100C, 151 ml of water were cautiously added dropwise in such a manner that the temperature did not exceed + 10 C. 200 Grams of sodium sulphate were added, the mixture was stirred for 2 hours at room temperature, the solid matter was filtered off, and washing with a total of 1 litre of methylene chloride was then carried out.

The solvent was distilled off in vacuo from the combined filtrates, and there were obtained 108.1 grams (=94.4% of the theoretical yield) of crude 3,5 - dimethoxy phenethyl alcohol, which was used for the next stage without further purification.

Para - toluene Sulphonic Acid (3,5 dimethoxy - phenethyl) Ester To a solution, cooled to OOC, of 109.9 grams of crude 3,5 - dimethoxyphenethyl alcohol in 330 ml of pyridine was added dropwise during the course of 40 minutes a solution of 150grams of para-toluene sulphochloride in 330 ml of pyridine. After 2 hours while cooling with ice and 2 hours at room temperature, the suspension was stirred into 5 litres of ice-cold 1 .5N - hydrochloric acid, and extracted with methylene chloride. The extracts were washed twice with a semi-saturated aqueous sodium bicarbonate solution and then washed until neutral with a dilute aqueous solution of sodium chloride. After drying with sodium sulphate, the solvent was distilled off in vacuo and the residue (about 200 grams) was crystallized from ether.

Yield: 135.4 grams (62.1% of the theoretical yield) of para-toluene sulphonic acid (3,5 dimethoxyphenethyl) ester melting at 73 75"C.

The following Example illustrates the invention: Example 1st Stage (lS,7aS) - 1 - tert.-Butoxy - 7a - methyl 4- (3,5 - dimethoxyphenethyl) 5,6,7,7a - tetrahydroindan - 5 - one.

To a degassed solution, present under argon, of 75 grams of (lS,7aS) - 1 - tert. butoxy - 7a - methyl - 5,6,7,-7a - tetrahydroindan - 5 - one - (+) in 750 ml of absolute tetrahydrofuran were added 9.74 grams of sodium hydride (deoiled with hexane), and the whole was boiled under reflux for 20 hours. At 40-450C there was then added dropwise during the course of 20 minutes a solution of 125 grams of para toluene sulphonic acid (3,5 - dimethoxy phenethyl) ester in 375 ml of absolute tetrahydrofuran. After a reaction period of 20 hours at 4045 C there were added 300 ml of a saturated aqueous solution of sodium dihydrogen phosphate, the solvent was distilled off in vacuo, and the residue was extracted with a total of 2 litres of methylene chloride. After washing until neutral, drying with sodium sulphate and distilling off the solvent in vacuo, 146.6 grams of a brown oily crude product remained behind.

2nd Stage: 17p - Acetoxy - 1,3 - dimethoxy Ql,3,5(10Z.8.14 - oestrapentaene To a solution of 146.6 grams of crude (lS,7aS) - 1 - tert.-butoxy - 7a - methyl 4 - (3,5 - dimethoxyphenethyl) - 5,6,7,7a tetrahydroindan - 5 - one in 375 ml of glacial acetic acid and 87 ml of acetic anhydride were added under argon protecting gas while cooling 3.6 ml of aqueous perchloric acid of 72% strength.

After a further hour while cooling (10- 15"C) stirring was carried out for 30 hours at room temperature, and the dark brown reaction solution was stirred into 3 litres of ice-water. In this way the product precipitated in a partially crystalline state.

Extraction with toluene was then carried out several times, the toluene extracts were washed with a semi-saturated aqueous solution of sodium bicarbonate and then with water to neutrality, and dried with sodium sulphate, and the solvent was distilled off in vacuo. The crystalline crude product was chromatographed over silica gel with hexane-acetone (0-150%). The thin-layer unitary fractions were collected and dried in a high vacuum.

Yield: 67.19 grams (=56% of the theoretical yield).

Melting point: 142.5-143.50C (diisopropyl ether).

3rd Stage: 17P - Acetoxy - 1,3 - dimethoxy - 8a 1,3.5X10} ~ oestratriene 18.85 Grams of 17p- - acetoxy - 1,3 - dimethoxyl - Al 35tlO} 3 l4 - oestrapentaene was hydrogenated in 400 ml of toluene with 5 grams of anhydrous Raney nickel. The reaction period at room temperature and 50 atmospheres pressure of hydrogen was 16 hours.

Yield: 14.8 grams (78.5 /" of the theoretical yield) melting at 109-1 l00C (methanol).

4th Stage: 1,3,17P - Triacetoxy - 8a - A13510 - oestratriene A solution of 9 grams of 17p - acetoxy 1,3 - dimethoxy - 8a - A1,3510 oestratriene in 99 ml of hydrogen bromide, glacial acetic acid (37%) and 27 ml of water was heated for 6 hours on a steam bath, then cooled, stirred into ice-water-sodium chloride and extracted with methylene chloride. The methylene chloride extracts were washed several times with a semisaturated aqueous solution of sodium chloride, and dried with sodium sulphate, and the solvent was distilled off in vacuo. To the residue were added 185 ml of pyridine and 80 ml of acetic anhydride, and, after 16 hours at room temperature after being stirred into an ice-water-sodium chloride mixture, worked up in the usual manner.

The crude product was chromatographed over silica gel with gasoline-acetone (10- 30%).

Yield: 7.67 grams melting at 156-1570C (isopropyl ether).

WHAT WE CLAIM IS: 1. A process for the manufacture of a 1,3 - oxygenated 8 - oestratriene of the general formula I

in which R, represents an unsubstituted or substituted alkyl group or a carboxylic acid acyl group, R2 represents an alkyl group containing 1 to 5 carbon atoms, and Ac represents a carboxylic acid acyl group, wherein a compound of the general formula II

in which R,' represents an unsubstituted or substituted alkyl group, and Tos represents a tosyl group, is reacted in the presence of a deprotonizing agent with a compound of the general formula III

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. toluene sulphonic acid (3,5 - dimethoxy phenethyl) ester in 375 ml of absolute tetrahydrofuran. After a reaction period of 20 hours at 4045 C there were added 300 ml of a saturated aqueous solution of sodium dihydrogen phosphate, the solvent was distilled off in vacuo, and the residue was extracted with a total of 2 litres of methylene chloride. After washing until neutral, drying with sodium sulphate and distilling off the solvent in vacuo, 146.6 grams of a brown oily crude product remained behind. 2nd Stage: 17p - Acetoxy - 1,3 - dimethoxy Ql,3,5(10Z.8.14 - oestrapentaene To a solution of 146.6 grams of crude (lS,7aS) - 1 - tert.-butoxy - 7a - methyl 4 - (3,5 - dimethoxyphenethyl) - 5,6,7,7a tetrahydroindan - 5 - one in 375 ml of glacial acetic acid and 87 ml of acetic anhydride were added under argon protecting gas while cooling 3.6 ml of aqueous perchloric acid of 72% strength. After a further hour while cooling (10- 15"C) stirring was carried out for 30 hours at room temperature, and the dark brown reaction solution was stirred into 3 litres of ice-water. In this way the product precipitated in a partially crystalline state. Extraction with toluene was then carried out several times, the toluene extracts were washed with a semi-saturated aqueous solution of sodium bicarbonate and then with water to neutrality, and dried with sodium sulphate, and the solvent was distilled off in vacuo. The crystalline crude product was chromatographed over silica gel with hexane-acetone (0-150%). The thin-layer unitary fractions were collected and dried in a high vacuum. Yield: 67.19 grams (=56% of the theoretical yield). Melting point: 142.5-143.50C (diisopropyl ether). 3rd Stage: 17P - Acetoxy - 1,3 - dimethoxy - 8a 1,3.5X10} ~ oestratriene 18.85 Grams of 17p- - acetoxy - 1,3 - dimethoxyl - Al 35tlO} 3 l4 - oestrapentaene was hydrogenated in 400 ml of toluene with 5 grams of anhydrous Raney nickel. The reaction period at room temperature and 50 atmospheres pressure of hydrogen was 16 hours. Yield: 14.8 grams (78.5 /" of the theoretical yield) melting at 109-1 l00C (methanol). 4th Stage: 1,3,17P - Triacetoxy - 8a - A13510 - oestratriene A solution of 9 grams of 17p - acetoxy 1,3 - dimethoxy - 8a - A1,3510 oestratriene in 99 ml of hydrogen bromide, glacial acetic acid (37%) and 27 ml of water was heated for 6 hours on a steam bath, then cooled, stirred into ice-water-sodium chloride and extracted with methylene chloride. The methylene chloride extracts were washed several times with a semisaturated aqueous solution of sodium chloride, and dried with sodium sulphate, and the solvent was distilled off in vacuo. To the residue were added 185 ml of pyridine and 80 ml of acetic anhydride, and, after 16 hours at room temperature after being stirred into an ice-water-sodium chloride mixture, worked up in the usual manner. The crude product was chromatographed over silica gel with gasoline-acetone (10- 30%). Yield: 7.67 grams melting at 156-1570C (isopropyl ether). WHAT WE CLAIM IS:

1. A process for the manufacture of a 1,3 - oxygenated 8 - oestratriene of the general formula I

in which R,', R2 and R3 have the meanings given above, the compound of the general formula IV is cyclized in the presence of a strong acid and an acyl anhydride, the acyl anhydride containing an acyl group of the formula Ac, Ac having the meaning given above, to form a compound of the general formula V

in which R,', R2 and Ac have the meanings given above, and the compound of the general formula V is hydrogenated in the presence of hydrogenation catalyst to form a compound of the general formula Ia

2. A process as claimed in claim 1, wherein the unsubstituted alkyl group represented by R, is a straight chained alkyl group containing 1 to 7 carbon atoms.

3. A process as claimed in claim 2, wherein the unsubstituted alkyl group represented by R, is a methyl or ethyl group.

4. A process as claimed in claim 1, wherein the substituted alkyl group represented by Rl is a phenylalkyl group.

5. A process as claimed in claim 4, wherein the phenylalkyl group is a benzyl group.

6. A process as claimed in- any one of claims 1 to 5, wherein each of the acyl groups represented by Rl and Ac is an alkanoyl group.

7. A process as - claimed in claim 6, wherein the alkanoyl group is an acetyl group.

8. A process as claimed in claim 6, wherein the alkanoyl group is a formyl or propionyl group.

9. A process as claimed in any one of claims 1 to 8, wherein the alkyl group represented by R2 is a methyl or ethyl group.

10. A process as claimed in any one of claims 1 to 9, wherein the ether protecting group represented by R3 is a tert.-butyl or a tetrahydropyranyl group.

11. A process as claimed in any one of claims 1 to 10, wherein the reaction with the compound of the general formula III is carried out at a temperature within the range of from +10"C to 80"C.

12. A modification of the process claimed in any one of claims 1 to 10, wherein, instead of the compound of the general formula II being reacted in the presence of a deprotonizing agent with a compound of the general formula III, the compound of the general formula III is first reacted with the deprotonizing agent and the resulting reaction product is reacted with the compound of the general formula II to form the compound of the general formula IV.

13. A process as claimed in claim 12, wherein the reaction between the compound of the general formula III and the deprotonizing agent is carried out in a solvent under an atmosphere of a protecting gas and at a temperature within the range of from 30"C to the boiling temperature of the solvent.

14. A process as claimed in claim 12 or 13, wherein the reaction with the compound of the general formula II is carried out at a temperature within the range of from +10"C to 800 C.

15. A process as claimed in any one of claims 1 to 14, wherein the deprotonizing agent is an alkali hydride, alkali alcoholate or alkali amide.

16. A process as claimed in any one of claims I to 14, wherein the deprotonizing agent is sodium hydride, sodamide, potassium hydride, sodium tert.-butylate, lithium amide or triphenylmethyl potassium.

17. A process as claimed in any one of claims 1 to 16, wherein the strong acid is a mineral acid, a sulphonic acid, a Lewis acid or a carboxylic acid that dissociates strongly.

18. A process as claimed in claim 17, wherein the mineral acid is perchloric acid or phosphoric acid.

19. A process as claimed in any one of claims 1 to 18, wherein the cyclization is carried out at a temperature within the range of from 5"C to 250C.

20. A process as claimed in any one of claims 1 to 19, wherein the hydrogenation catalyst comprises a heavy metal of Group 8a of the Periodic Table.

21. A process as claimed in any one of claims 1 to 20, wherein the hydrogenation is carried out at a temperature within the range of from OOC to 500 C.

22. A process as claimed in any one of claims 1 to 21, wherein the hydrogenation is carried out under a pressure of hydrogen within the range of from 1 to 80 atmospheres.

23. A process as claimed in claim 1 or 12, conducted substantially as described herein.

24. A process as claimed in claim 12, conducted substantially as described in the Example herein.

25. A 1,3 - oxygenated 8 - oestratriene of the general formula I given in claim 1, in which Rl, R2 and Ac have the meanings given in claim 1, whenever made by the process claimed in any one of claims 1 to 24.

26. An optically active 1,3 - oxygenated 8a-oestratriene of the general formula Ia

in which R1, represents a phenylalkyl group, R2 represents an alkyl group containing 1 to 5 carbon atoms, and Ac represents a carboxylic acid acyl group

27. A compound as claimed in claim 26, wherein the phenylalkyl group is a benzyl group.

28. A compound as claimed in claim 26 or 27, wherein the alkyl group represented by R2 is a methyl or ethyl group.

29. A compound as claimed in any one of claims 26 to 28, wherein the acyl group represented by Ac is an alkanoyl group.

30. A compound as claimed in claim 29, wherein the alkanoyl group is an acetyl group.

31. A compound as claimed in claim 29, wherein the alkanoyl group is a formyl or propionyl group.

32. A pharmaceutical preparation which comprises a compound as claimed in any one of claims 26 to 31, in admixture or conjunction with a pharmaceutically suitable carrier.