NO751208L - - Google Patents

Description

Method of manufacture

of perhydrobenzindenes.

The present invention relates to a method for the production of perhydrobenzidenes, respectively compounds of the formula

where R means a primary alkyl group of 1-5 C atoms, 2 3 R and R are equal and means alkyl of 1-8 C atoms or a residue of both hydrogen and the other alkyl of 1-8 C atoms, and Z is carbonyl, C 1 -C 8 -alkylenedioxymethylene, di-C 1 -C 6 -alkylene dioxymethylene, phendioxymethylene or a group of the formula

where R 5 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy-C 1-6

alkyl, phenyl-C1-6 alkyl, tetrahydropyranyl or an acyl residue of a C1. —o0-monocarboxylic' acid, R^ hydrogen or an aliphatic hydrocarbon group with 1-8 C-ato-

more and m is 1 or 2.

The term "hydrocarbon residue" used in the description and claims denotes a 1-valent substituent which consists only of carbon and hydrogen atoms. The term "aliphatic" in relation to hydrocarbon residues denotes both saturated and unsaturated groups, e.g.

e.g. alkyl or alkylene groups or corresponding residues with an olefinic or acetylenic double bond. The term "alkyl" denotes both straight-chain and branched saturated hydrocarbon residues. The term "primary alkyl group" denotes an alkyl residue whose free valence starts from a carbon atom with at least 2 hydrogen atoms.

Examples of alkyl, alkenyl, alkylene or alkynyl are methyl, ethyl, butyl, tert.-butyl, hexyl, 2-ethylhexyl, vinyl, butenyl, hexenyl, ethylene, methylene, and ethynyl, formyl, acetyl, benzoyl

are examples of acyl residues of monocarboxylic acids, 2-phenylethyl for a phenylalkyl residue, methoxymethyl, 1-methoxyethyl or 2-methoxyethyl for alkoxyalkyl and methoxy, ethoxy or tert.-butoxy for alkoxy groups.

In the structural formulas used, the various substituents in the ring skeleton are either in the o-position, characterized by a dotted line ( ), in the (3-position, characterized by a straight line ( ) or their position is not precisely determined, characterized by a wavy line ( ^-^^-^-), i.e. they can be in the a- or (3-position. The structural formulas reproduce the compounds in the form of racemates with the exception that the substituent R was arbitrarily assigned to the (3-position.

The method according to the invention is characterized by hydrogenating a compound of formula in the presence of a noble metal catalyst, in a neutral, acidic or weakly basic environment.

The hydrogenation is preferably carried out in a lower alcohol, as a solvent, e.g. in ethanol, preferably using a palladium catalyst on coal as carrier material. It can further be carried out essentially at room temperature and under normal pressure, so that selective hydrogenation of the /^^ °^-ligand, without hydrogenation of the isoxazolyl residue, takes place. Suitable weak bases are mono-, di- or tri-lower alkylamines, preferably triethylamine. It has been shown that when a base is used, the hydrogenation proceeds stereospecifically, and starting from trans-anti-enones of the formula II, compounds of the formula I with a trans-anti-trans configuration are obtained. Starting from a compound of formula II, where R is in the (3-position) and the hydrogen atoms bound to carbon atoms 8 and 14 (steroid numbering) are in the (3- according to a-position), one thus obtains compounds of formula I with a hydrogen atom in the 9a position.

The compounds of formula I according to the invention are valuable intermediates in the production of pharmacologically active steroids, e.g. such of the formula

where R and Z have the above meanings, and R 4 is hydrogen or a C-, --alkyl radical with a CH9-2 3

group less than R or R .

The compound of formula III, where Z is carbonyl, R<-1>ethyl and II m 1 (19-nor-18-homo-androst-4-ene-3,17-dione) can be selectively ethynylated using a suitable metal -organic acetylene compound to norgestrel (13β-ethyl-17-α-ethynyl-17-hydroxygon-4-en-3-one). Norgestrel is a known progestatively active compound. Examples of suitable ethynylating agents are alkali metal acetylides such as lithium, sodium and potassium acetylide. The reaction is carried out in a suitable solvent such as benzene or toluene in the presence of liquid ammonia, in a temperature range between -60° and -30°C, preferably at the reflux temperature of the reaction medium. An example of a further suitable ethynylating agent is a lithium acetylide-diamine complex in dimethylformamide as solvent.

Compounds of formula III, where Z is carbonyl, can be converted to the corresponding pharmaceutically valuable pregnanes, i.e. to compounds of formula III, where Z is a residue of the formula

according to per se known methods. In the conversion of andro-stan-17-ones to corresponding pregnanes, all carbonyl groups with the exception of the one in the 17-position must first be converted to a protected form. 19-nor-androst-4-ene-3,17-dione can e.g. transferred to the 19-nor progesteren.

19-nor compounds of formula III, where R"<*>" is propyl, are ovulation inhibitors. Finally, a compound of formula III, where R^" is methyl and Z is carbonyl, has been converted to 19-nor-testosterone acetate [j.Org.Chem., 26, 3904 (1961), L.J. Chinn et al.].

The production of the starting material of formula II as well as the conversion of the compounds of formula I according to the invention to steroids of formula III is e.g. described in the Belgian patent no. 7 4 2090.

In J

IN

If not expressly stated to the contrary, all claims directed to these compounds relate both in the form of their racemates and in the form of their optical enantiomers.

In the following examples, which explain the invention, all temperatures are given in degrees Celsius.

EXAMPLE 1

A mixture of 1.00 g of racemic trans-anti-6-[(3,5-dimethyl-isoxazol-4-yl)-methyl]-3a-methyl-3,7-dioxo-1,2,3a,4, 5,7,8,9,9a,9b-decahydro-3H-benz[ejinde, 60 mg of palladium on charcoal (lo%) and 100 ml of a 3:1 mixture of ethanol and triethylamine were hydrogenated at room temperature and under atmospheric pressure. IN

over the course of 1 hour, one equivalent of hydrogen was taken up. The hydrogenation product was not normally isolated. Exceptionally, however, after removal of the catalyst by filtration and of the solvent from benzene-hexane, pure racemic trans-anti-trans-anti-6-[(3,5-dimethyl-isoxazol-4-yl)-methyl]-3a was recrystallized -methyl-3,7-dioxo-perhydro-benz[e]indene was obtained in the form of white prisms with melting point 137.5 - 139.5°.

EXAMPLE 2

A solution of 1.308 g of (+)-trans-anti-6-[(3,5-dimethylisoxazol-4-yl)-methyl]-3a-methyl-3,7-dioxo-1,2,3a,4, 5,7,8,9,9a,9b-decahydro-3H-benz[e]indene in 100 ml of a 3:1 mixture of ethanol and triethylamine was hydrogenated at room temperature and under atmospheric pressure in the presence of 80 mg of palladium on charcoal ( 10%). The hydrogen absorption stopped after 1 1/2 hours. Filtration and removal of the solvent gave trans-anti-trans-6-[(3,5-dimethyl-isoxazol-4-yl)-methyl]-3a-methyl-3,7-dioxo-perhydro-! benz[e]inden as foamless foam. This crude product was taken up in 10 ml of ethylene glycol and 75 ml of petroleum ether (petrol) and heated for 20 hours with 750 mg of p-toluenesulfonic acid under reflux cooling and a nitrogen atmosphere by azeotropic removal of water. The cooled solution was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated to give trans-anti-trans-3,3,7,7-bis-(ethylenedioxy)-6-[(3,5 -dimethylisoxazol-4-yl)-methyl]-3a-methyl-per-hydro-benz[e]indene in the form of a pale yellow resin. A solution of this crude product in 100 ml of ethanol was hydrogenated under normal pressure and at room temperature in the presence of 2.5 g of potassium hydroxide

syd and 100 mg of palladium on charcoal (10%). In the course of 5 hours, one equivalent of hydrogen was taken up. The catalyst was removed by filtration and the filtrate concentrated to approx. 5 ml. To this solution of the vinylogous amide was added 150 ml of a 20% aqueous potassium hydroxide solution. The mixture was degassed,

placed under nitrogen, heated 16 hours under a nitrogen atmosphere

brought to reflux, cooled and extracted with benzene. The benzene solution was washed with sodium chloride solution and dried over anhydrous sodium sulfate. Removal of the solvent gave trans-anti-trans-bis-(ethylenedioxy)-3α-methyl-6-(3-oxobutyl)-perhydrobenz[e]indene as a colorless resin. This material was taken up in 50 ml of methanol, degassed and set aside

where nitrogen. After addition of 5 ml of 4 N hydrochloric acid, the mixture was heated for 3 hours under reflux, cooled, diluted with water and extracted with benzene. The benzene solution was washed with water, saturated aqueous sodium bicarbonate solution and sodium bicarbonate solution and dried over anhydrous sodium sulfate.

After removal of the solvent, crude (+)-19-nor-androst-4-ene-3,17-dione was obtained, which was purified over silica gel with benzene-ether (9:1) and by crystallization from acetone-hexane; m.p. 173-174°.

EXAMPLE 3

A solution of 11.35 g of racemic trans-anti-3a-ethyl-6-[(3,5-dimethyl-isoxazol-4-yl)-methyl]-3,7-dioxo-l.,2,3a,4 , 5 , 7 ,8 , 9, 9a, 9b-decahydro-3H-benz[e]indene in 300 ml absolute ethane and 100 ml triethylamine was hydrogenated in the presence of 500 mg palladium on charcoal (5%) at room temperature and under normal pressure . After 2 hours, hydrogen uptake was complete. The catalyst was removed by filtration and washed with fresh ethanol. After removal of the solvent under reduced pressure (finally at 50°

and 0.01 mm to remove the last traces of triethylamine) became racemic trans-anti-trans-3α-ethyl-6-[(3,5-dimethyl-isoxazol-4-yl)-methyl]-3,7- dioxo-perhydro-benz[e]indene obtained in the form of white needles, m.p. 143.5 - 146° (from methylene chloride-ether).

Claims (4)

1. Process for the preparation of perhydrobenzindenes of the formula where R"*" means a primary alkyl group with 1-5 C atoms, R and R are the same and mean alkyl of 1-8 C atoms or a residue of both hydrogen and the other alkyl of 1-8 C atoms, and Z is carbonyl, C 1 -g -alkylenedioxymethylene, di-C 1 -g -alkoxymethylene, phendioxymethylene or a group of formula one j where R is hydrogen, C1 _g-alkyl, C1 _g- alkoxy-C1 _g- j alkyl, phenyl-C1-6-alkyl, tetrahydropyranyl or an acyl residue of a C-^ g-monocarboxylic acid, R hydrogen or an aliphatic hydrocarbon group with 1-8 C- atoms and m is 1 or 2, characterized by hydrogenating a compound of the formula in the presence of a noble metal catalyst, in a neutral, acidic or weakly basic environment. 2. Procedure after crawling, characterized in that the hydrogenation is carried out in an inert organic solvent at room temperature and under normal pressure. 3. Method according to claims 1 and 2, characterized in that palladium is used as catalyst. 4. Method according to claims 1-3, characterized in that the reaction medium contains a mono-, di- or tri-lower alkylamine.