IL42452A - 5,6,7,7a-tetrahydroindanone derivatives - Google Patents

Description

New 5 ,6 ,7,7a-tetrahydro1ndanone derivatives The present Invention 1s concerned with new blcycloalkane^ derivatives and with their manufacture and use.

The present Invention provides compounds of the general formula I 1n which n represents 1 or 2, X represents a U -CH2-Z2-R2, -CH=C-R3, -CH2C00R4 or -CHgCN grouping, Y represents a carbonyl group or a d alkoxymethylene group, Z-j and Z2 each represents a free or ketallsed carbonyl group or a free, esterlfled or etherlfled hydroxy 1 methylene group, U represents a halogen atom, R]« 2 and R3 each represents a lower alkyl group, and R4 represents an alkyl, aryl or aralkyl group.

As lower alkyl groups represent by R^, 2 and R3 there come Into consideration preferably alkyl groups containing 1 to 4 carbon atoms. Suitable alkyl groups are, for example, methyl, ethyl, propyl and butyl groups. Specially preferred alkyl groups represented by R.|, R2 and R3 are methyl and ethyl groups.

As the alkyl, aryl or aralkyl group represented by R^ there come Into consideration preferably groups containing 1 to 10 carbon atoms. A suitable group represented by ^ 1s, for example, the methyl, ethyl, propyl, Isopropyl, butyl, tert. -butyl, pentyl, hexyl, phenyl , benzyl or phenethyl group.

In US Patent 3,644,407 there are described compounds which structurally resemble the compounds of the present Invention however the compounds of the present Invention are produced b a technically simple process as descrl bed on pages 3-5 hereinafter while the similar compounds taught 1n said US Patent are produced only after a complicated and multlstep process. Therefor said patent neither teaches nor suggests the compounds of the present Invention or the process for their preparation which renders said compounds better suited as Intermediate products for the total synthesis of steroids than the compounds of US Patent 3 644,407.

As dlalkoxymethylene groups represented by Y there are suitable*' preferably those groups 1n which the alkoxy groups contain 1 to 4 carbon atoms. A suitable group represented by Y 1s, for example, the dlmethoxy-methylene, dlethoxymethylene, dlpropoxymethylene or dlbutoxymethylene-group.

The symbols and Zg may each represent a free or ketallsed car-bony 1 group or a free, esterlfled or etherl ied hydroxymethylene group.

As suitable ketallsed carbonyl groups represented by Z2 there may be mentioned, for example, the 1 ,2-ethylened1oxy-methylene group, the 1,3-propylenedloxy-methylene group, the 2,3-butylened1oxy-methylene group, the 2' ,2'-d1methyl-V ,3' -propyl enedloxy-methylene group, the 2,4-pentylene-dloxy-methylene group or the 1 ,2-phenyl enedloxy-methylene group. As esterlfled hydroxymethylene groups represented by Z-j and there are used preferably those groups in which the ester groups contain 1 to 10 carbon atoms. As suitable ester groups there may be mentioned, for example, the acetoxy, proplonyloxy, butyryloxy, tr1 methyl acetoxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy or benzoyl oxy group. Suitable etherlfied hydroxymethylene groups represented by Z^ and Zg are preferably alkoxymethylene groups or aralkoxymethylene groups containing 1 to 10 carbon atoms in the alkoxy or aralkoxy group. As suitable alkoxy or aralkoxy groups there may be mentioned, for example, the methoxy, ethoxy, propoxy, butoxy, tert.-butoxy, Isopropoxy or benzyl oxy group.

As halogen atoms represented by U there are preferred chlorine or bromine atoms.

The present Invention also provides a process for the manufacture of the new bicydoalkane derivatives of the general formula Φ, wherein (a) a compound of the general formula II (II), 1n which n., and Z-j have the meanings given above for formula I, 1s reacted 1n the. presence of basic catalyst with a vhyl ketone of the general formula III 0 X-(CH2)2-C-CH=CH2 (III) 1n which X has the meaning given above, and, 1f desired, 1n the resulting compound the free carbonyl group represented by Y 1s converted Into a dlalkoxymethylene group by meansj f a lower alcohol, or (b) a compound of the general formula II, 1n which ji, and R have the meanings given above, 1s reacted In the presence of a basic catalyst with a compound of the general formula IV X-(CH2)2-Y-CH2-CH -W (IV) 1n which Y has the meaning given above and W represents a halogen atom, and, 1f desired, 1n the resulting compound any free carbonyl group represented by Y 1s converted Into a dlalkoxymethylene group by means of a lower alcohol .

In the process of the present Invention there are used as basic catalysts preferably alkali metal alcoholates of secondary or tertiary alcohols, alkali metal hydrides, alkali metal amides or quaternary ammonium bases. As basic catalysts there may be metnloned, for example, sodium hydride, sodamlde, sodium Isopropanol, sodium tertiary butanol, potassium tertiary butanol, lithium amide, tetramethy 1 -ammoni urn hydroxide or tr1 methyl -benzyl ammoni urn hydroxide. When there are used as starting compounds 1n the process of the present Invention vinyl ketones of the formula III, 1t 1s of advantage to use 0.01 mole to 1.0 mole of basic catalyst per mole of vinyl ketone. When the process of the present Invention 1s carried out with the use of compounds of the general formula IV, 1t 1s necessary to use the basic catalyst 1n excess so that 1t not only catalyses the reaction but also binds the hydrogen hallde liberated during the reaction. 9 The additive combination of the vinyl ketones of the general formula III or the optional ly ketal lsed ^-halogeno-ketones of the general formula IV (1n other words the alkylatlon of the compounds of the general formula II ) 1s carried out 1n the presence of Inert solvents. Suitable solvents are, for example, polar ethers , for example 1 ,2-d1methoxy-ethane, 2,2' -d1methoxy-d1 ethyl ether, tetrahydrofuran or dloxan, secondary or tertiary alcohols , for example Isopropanol , butanol-(2) or tertiary butanod, or dipolar aprotlc solvents , for example d1 methyl formamlde, N- methylacetamide, N-methyl -pyrrol 1 done or hexamethyl -phosphoric add tr1am1de. On the other hand, however, 1t The reaction 1s carried out at a reaction temperature of< from about -50°C to +100°C. When vinyl ketones of the general formula III are used for the reaction, 1t 1s preferable to work at a reaction temperature within the range of from 0°C to +50°C. When compounds of the general formula IV are used, 1t 1s preferable to work at a reaction temperature within the range of from -50°C to +50°C.

It 1s surprising to a person ski l led 1n the art that the alkylatlon of the compounds of the general formula II with the vinyl ketones of the general formula III or the compounds of the general formula IV 1s very largely selective, because 1t has been ftnown that 1n the alkylatlon of compounds of the general formula II there are normally, obtained mixtures of different alkylatlon products .

Resulting compounds of the general formula I , Y Represents a. ree carbonyl group can then, if desired, be ketallsed with lower alcohols , and there are thus obtained compounds of the general formula I , in which the symbol Y represents a dialkoxymethylene group. The total isation 1s preferably carried out by reacting the compounds with alcohols 1n the presence of acidic catalysts . Suitable alcohols are lower alcohols containing 1 to 4 carbon atoms , for example methanol , ethanol , propanol or butanol . Suitable addic catalysts are, for example, mineral ac1ds ,\ , for example hydcochloric add , sulphuric add or perchloric add, sul phonic adds , for example methane sul phonic add, Lewis adds , for example boron tri fluoride, or phenols , for example paranltro- ■ phenol or 2,4-d1n1trophenol . The ketal isatlon takes place especial ly wel l when the reaction mixture also contains an agent capable of binding water, for example anhydrous sodium sulphate, magnesium sulphate or calcium sulphate. On the other hand, there are also very suitable as agents capable of binding water, the orthoformlc add esters or acetone-dial kyl-ketals of alcohols that may be used for the ketalisatlon. The ketalisatlon is preferably carried out at a reaction temperature between -20°C and +80°C.

The compounds of the general formula I of the present invention are valuable Intermediate products . They are suitable especial ly for the production by total synthesis of pharmacological ly active steroids .

The fol lowing scheme of formulae show one method of using the compounds o , the general formula I , 1n which Y represents a dialkoxy- methylene group, for the total synthesis of steroids : (VI) (VII) (VIII) In these formulae X, Z-j , and n_ have the meanings given above, and V represents a lower alk l group.

This method of synthesis may be carried out, for example, 1n the following manner: The compounds of the formula are heated in benzene with the addition of 0.01 mole of malonic add, and there are obtained compounds of the formula V. When the symbol Z- represents a carbonyl group, the latter may then be reduced with lithium aluminium hydride. Surprisingly, the compounds of the formula V can be hydrogenated stereospedflcally with cataly^tically activated hydrogen, and substances of the formula VI are obtained. This hydrogenation can be carried out, for example, by dissolving the compounds of the formula V in ethyl acetate, and then hydrogenatlng with hydrogen under atmospheric pressure with the use of palladium-animal carbon as catalyst. The compounds of the g formula VI # are dissolved 1n ethanol , maintained for 30 minutes at room temperature with the addition of catalytic quantities of hydrochloric add, and substances of the formula VII are obtained. It 1s not necessary to Isolate the substances of the formula VII, so that an excess of sodium methylate may be added to the resulting reaction mixture, the whole 1s then heated under reflux for about 2 hours , and compounds of the general formula VIII are obtained. The further working up of substf¾ces of the formulae VII and VIII Into pharmacologically active steroids Is known .

The fol lowi ng Examples i l lustrate the i nvention: Example 1 a) 162 grams of 5-oxo-hexanonitri le were dissolved 1n 1 litre of toluene, 243 grams of pyrocatechoi and 3 grams of para- toluene sul phonic add were added, and the whole was heated for 24 hours under a water separator.

The reaction mixture was then allowed to cool , and was then diluted with 1 l itre of benzene, and the organic phase was washed with a IN solution of sodium hydroxide and a dilute solution of sodium chloride, then dried over sodium sulphate, and concentrated in vacuo.

The crude product was distil led in a high vacuum, and 246.5 grams of 5,5-ortho-phenylenedioxy-hexanonitri le were obtained.

Boi l ing point (Q J torr) = 106° - 110°C. b) 183 grans of 5,5-ortho-phenylened1oxy-hexanon1tr1 le were dissolved in 1830 ml of toluene, the solution was cooled to -50°C, 790 ml of a solution of 20% strength of dilsobutyl aluminium hydride 1n toluene were added during the course of one hour, and then the whole Vias stirred for one hour at -50°C.

The reaction mixture was then acidified with 4N- hydrochloric add to a pH- value of 3, the whole was diluted with one litre of ethyl acetate, and the organic phase was washed with a dil ute solution of sodium chloride, dried over sodium sulphate, and concentrated to dryness In vacuo.

The residue was distilled 1n a high vacuum, and there were \ . obtained 174 grams of 5,5-ortho-phenylenedioxy-hexanal .

Boiling point {Q Q5 tQrr) - 90° - 92°C. c) 40 grams of magnesium shavings were reacted with vinyl chloride 1n 800 ml of tetrahydrofuran, the resulting solution was cooled to -30°C a solution of 173 grams of 5,5-ortho-phenylened1oxy-hexanal 1n 1800 ml of tetrahydrofuran was added dropwlse, and the reaction mixture was maintained for 3 hours at -30°C. 260 ml of a saturated solution of ammonium chloride were then added dropwlse to the mixture, the whole was filtered, and the solution so obtained was concentrated 1n vacuo.

The residue was dissolved 1n 2000 ml of acetone, the solution was cooled to -10°C, and 200 ml of Jones reagent (an aqueous solution containing 267 gramsjof chromlum-(VI) oxide and 230 ml of concentrated sulphuric add per litre) were added during the course of 30 minutes.

The mixture was allowed to stand for one hours, then 100 ml of methanol and 7000 ml of methylene chloride were added, and the organic phase was separated off, washed with a dilute solution of sodium chloride, dried over sodium sulphate, and concentrated in vacuo.

The crude product so obtained was distilled in a high vacuum, and there were obtained 172 grams of 7,7-ortho-phenylened1oxy-l-octen-3-one. Boiling point (0 002 t0pr) = 88 - 92°C. d) 23 grams of 7,7-ortho-phenylenedioxy-l-octen-3-one were dissolved 1n 150 ml of chloroform, and the solution was cooled to about 0°C. Dry hydrogen chloride was then passed through the solution for 30 minutes, the chloroform was distilled off in vacuo at a bath temperature of 20°C, and there were obtained 23.9 grams of l-chloro-7,7-ortho-phenyl-ened1oxy-octan-3-one. e) 17 grams of ie-tert.-butoxy-7aB-methyl-5,6,7,7a-tetrahydro1ndan-5-one were dissolved 1n 200 ml of absolute dimethoxyethane, and, after the addition of 2 gramsbf sodium hydride, the whole was boiled for 2 hours under reflux. The solution was then cooled to -20 to 30 C, and a solution of 21.5 gramsbf l-chloro-7,7-ortho-phenylened1oxy-octan-3-one 1n 80 ml of absolute dimethoxyethane was added dropwise during the course of one hour. After the addition, the reaction solution was brought to room temperature during the course of 3 hours. After a further 3 hours, 50 ml of a saturated solution of primary sodium phosphate were added, and working up was carried out.

The cirude product was purified by chromatography over silica gel by means of hexane-acetone gradients. There were obtained 22.4 grams of l£-tert.-butoxy-7aB-methyl-4-(7' ,7'-ortho-phenylened1oxy-3'-keto-octyl )-5,6,7,7a-tetrahydroindan-5-one 1n the form of a colourless oil.

Infra-red bands at 5.86μ; 6.00μ; 6.72μ and 8.1μ. [α]ρ°= +46° (c = 1, benzene). f) 10,3 grams of l3-tert.-butoxy-7ae-methyl-4-(7' ,7'-ortho-pheny 1 enedi oxy-31 -keto-octyl )-5 ,6 ,7 ,7a-tetrahydroi ndan-5-one were dissolved in 100 ml of absolute methanol and 10.3 ml of orthoformic acid trimethyl ester. The whole v/as then cooled to 0°C, 1.5 ml of a methanoUc solution of 0.5% strength of para- toluene sul phonic acid were added, and the whole was stirred for 4 hours at 0°C. The reaction solution was then poured into 500 ml of an ice-cold dilute solution. of sodium bicarbonate, and extracted with methylene chloride, the solution was washed with a semi -saturated solution of sodium chloride, then dried with sodium suilphate, the solvent was distilled off, and the residue was recrystal-11 zed from ether.

There were obtained 9.95 grams of l3-tert.-butoxy-7a0-methyl-4- (3 ' ,3 ' -d1methoxy-71 ,7 ' -ortho-phenyl enedi oxy-octyl )-5,6 ,7 ,7a-tetra-hydroindan-5-one melting at 132 - 134°C . .. [a]?1 * +42.5° ( c = 1, benzene).

Example 2 ^ a) 12t grams of racenvic lp-tert.-butoxy-7a3-ethyl -5,6,7, 7a-tetra-hydro1ndan-5-one were dissolved 1n 150 ml of absolute tetrahydrofuran, and 400 mg of sodium hydride were added. The whole was then boiled under reflux and under argon as protective gas until the evolution of hydrogen ceased, and then the solution was cooled to 0°C. There was then added dropwlse during the course of 30 minutes, while stirring, a solution of 13 grairTs of 7,7-ortho-phenylened1oxy-l-octen-3-one 1n 50 ml of absolute tetrahydrofuran, and the whole was stirred for a further 30 hours at 0°C. The crude product obtained by working up 1n the usual manner was purified by chromatography over silica gel, and there were obtained 10.5 grams of l3-tert.-butoxy-7aB-ethyl-4-(7' ,7'-ortho-phenylene octyl d1oxy-3'-keto-ex4:y-I )-5,6,7,7a-tetrahydro1ndan-5-one in the form of a colourless oil.

Infra-red bands at 5.85μ, 6.05μ, 6.75μ and 8.1μ. b) 3.8 grams of raceinlc lg~tert.-butoxy-7a3-ethyl-4-(7* s7'-ortho-phenylened1oxy-3'-keto-octyl )-5,6,7,7a-tetrahydro1ndan-5-one were reacted with methanol and orthoformlc acid trimethyl ester at, 0°C in the manner described in Example 1(f), then worked up, and there were obtained 3.81 grams of l -tert.-tu*ey butoxy-7a3-ethyl-4-(3' 93'-dimethoxy-7' ,7'-ortho-phenylenedioxy-octyl )-5,6,7,7a-tetrahydro1ndan-5^one as a colourless oil. Infra-red bands at 6.06μ, 6.75μ and 8.1μ.

Example 3 a) 15.8 grams of 7-chloro-l ,6-octad1en-3-one were dissolved 1n 150 ml of absolute chloroform, and the solution was cooled to 0°C. Dry hydrogen chloride was then passed through the mixture for 30 minutes, the solution was evaporated to dryness in vacuo, and there were obtained 16.5 grams of 1 ,7-dichloro-6-octen-3-one in the form of a colourless oil.

Infra-red bands at 5.86μ and 5.97μ. ie-b) 11 grams of racemic/trimethylacetoxy-7a3-methyl-5,6,7,7a-tetra-hydroindan-5-one were dissolved in 100 ml of di methyl formamide and 50 ml of benzene, and, after the addition of 1.3 grams of sodium hydride, the whole was heated under argon at 60 - 70°C.

After 3 hours the evolution of hydrogen ceased. The whole 1s cooled to -10°C, and a solution of 8.9 grams of 1 ,7-d1chloro-6-octen-3-one was added dropwlse during the course of 45 minutes. After the addition, the whole was further stirred for 15 hours at 0°C. The procedure was then the same as described 1n Example 1(e), and there were obtained 9.7 grams of lB-tr1methylacetoxy-7a3-methyl -4- (71 -chl oro-3 ' -keto-6 ' -octenyl )-5 ,6 ,7 ,7a-tetfcahydroindan-5-one 1n the form of a colourless oil.

Infra-red bands at 5.85μ , 6.00μ and 5.79μ. 3.2 grams of racemlc ^3-tr1methy^aceto y-7a3-methyl-4-(7'-chloro-3,-keto-6'-octeiTyl)-5,6,7,7a-tetrahydro1ndan-5-pne were reacted at 0°C with 3.5 ml of ortho-formic add trlmethyl ester and 30 ml of absolute met^nnol by catalysis with para-toluene sulphonlc add 1n the manner described 1n Example 1(f), then worked up, and there were obtained 3.12 grams of I3-trlmethyl acetoxy-7ag-methyl -4- (7 ' -chl oro-3 ' ,3 ' -d1methoxy-6 ' -octenyl )-5,6,7 ,7a-tetrahydro1ndan-5-one 1n the form of a colourless oil.

Infra-red bands at 6.77μ and 6.07μ.

Example 4 a) 5.2 grams of racemlc l3-tr1methylacetoxy-7a3-methyl-5,6,7,7a-tetrahydro1ndan-5-one were heated at 60°C with 0.63 gram of sodium hydride In 50 ml of dimethyl formamlde and 50 ml of benzene until the evolution of hydrogen ceased. The whole was then cooled to -10°C, a solution of 4.3 grams of 7-chloro-5-keto-heptano1c add methyl ester 1n 10 ml of absolute benzene was added dropwlse during the course of 20 minutes, and the whole was allowed to stand for 16 hours at 0°C. The crude product obtained after working up 1n the usual manner was chromatographed over slUcaagel, and l3-tr1methyl -acetoxy-7a3-methyl -4- (3 ' -keto-6 ' -methoxycarbonyl -hexyl )-5,6,7,7a-tetrahydro1ndan-5-one was obtained 1n the form of a colourless oil. Infra-red bands at 5.78μ and 6.05μ. b) 6.4 grams of racemlc lfl-tr1methylacetoxy-7a3-methyl-4-(3'-keta-6'-methoxycarbonyl-hexyl)-5,6,7,7a-tetrahydro1ndan-5-one were dissolved 1n 50 ml of tojuene and 10 ml of 2,2-d1methoxypropane, the solution was cooled to 0°C and 3 mg of para-toluene sulphonlc acid were added. After a reaction period of 16 hours at 0°C, the mixture was worked up 1n the normal manner, the crude product was recrystallized from ether, and there were obtained 6.1 grams of l3-tr1methylacetoxy-7a3-methyl-4-(3' ,3'-d1methoxy-6 ' -methoxycarbonyl -hexy 1 ) -5 ,6 ,7 ,7a- tetrahydroi ndan-5-one mel t1 ng at 101-103°C.

Example 5 a) 23 grams of Ig-tert.-butoxy-7a0-methyl-5,6,7,7a-tetrahydro1ndan-5-0ne in 250 ml of absolute tetrahydrofuran were boiled under reflux and under argon for 5 hours with 2.5 grams of sodium hydride.

The whole was then cooled to -30°C, 22 grams of 7-chloro-5-keto-heptanbic acid ethyl ester in 100 ml of absolute tetrahydrofuran were added dropwlse during the course of one hour, and the mixture was allowed to stand for 2 hours at -30°C, and then brought to room temperature during the course of 16 hours. The mixture was worked up as described in Example 1(e), and there were obtained 20.4 grams of 13-' tert. -butoxy-7aS -methyl -4-(31 -keto-6 ' -ethoxycarbonyl -hexyl )-5 ,6 ,7 ,7a-tetrahydro1ndan-5-one 1n the form of a colourless oil. [α]^1» +49° (c · 1, benzene). b) 5 grams of 18-tert. -butoxy-7a3-methyl -4- (3' -keto-6' -ethoxy-carbonyl -hexyl )-5,6,7,7a-tetrahydro1ndan-5-one were reacted as described 1n Example 1(f) at 0°C with methanol and orthoformlc trimethyl ester and a catalytic quantity of para- toluene sulphonlc add, then worked up, and there was obtained 13-tert.-butoxy-7a3-methyl-4-(3' ,3'-d1methoxy-6'-ethoxycarbonyl-hexyl)-5,6,7i7a-tetrahydro1ndan-5-one in the form of a colourless oil. a-red bands at 5.76μ and 6.04U. [a]^0 +44° (c « 1, benzene).

Example 6 \ a) 132 grams of 5-oxo-hexanon1tr1le were dissolved 1n 700 ml of benzene, 150 grams of 2»2-dimethyl-propaned1ol and 2 grams of para-toluene sulphonlc add were added, and the whole was heated for 24 hours under a water separator. The mixture was then allowed to cool, 150 ml of a saturated solution of sodium bicarbonate were added, and working up was carried out in the usual manner. The crude product so obtained was purified by distillation 1n a high vacuum, and there were obtained 207 grams of 5,5- (2' ,2 '-dimethyl -propyl ened1oxy)-hexanon1 -trile.

Boiling point {0Λ tofrp) - 93 - 94°C. b) 75 grams of 5,5-(2' ,2 '-dimethyl -propyl ened1oxy)-hexanontr1le were dissolved in 750 ml of absolute toluene, the solution was cooled to -50°C, and 315 ml of a solution of 20% strength of dlisoftutyl-alum1n1um hydride 1n toluene were added dropwise. The mixture was stirred for a further hour at -50°C, 500 ml of a saturated solution of sodium dihydrqgen phosphate were added during the course of 10 minutes, and the mixture was further stirred for 5 hours at room temperature and worked up in the usual maneer. The crude product so obtained was purified over a column of aluminium oxide, and there were obtained 57.3 grams of 5,5-(2' ,2'-d1methyl-propylenedioxy)-hexanal 1n the form of a colourless oil.

Infra-red bands at 5.8μ. c) 23 grams of 5,5-(2' ,2'=d1methyl-propylenedioxy)-hexanal were reacted with vinyl -magnesium c loride In the manner described 1n the first paragraph of Example 1(c). The crude product so obtained was then dissolved in 500 ml of absolute methylene chloride, 200 mg of hydroqulnone and 300 grams of active pyroluslte were added to the solution, and the mixture was agitated for 8 hours. The mixture was filtered, the solution was concentrated 1n vacuo, the crude product so obtained was purified by chromatography over a column of silica gel, and there were obtained 17.3 grams of 7,7-(2' ,2'-d1methyl-propylened1oxy)-l-octen-3-one 1n the form of a colourless oil.

Infra-red bands at 5.97μ. d) 5 grams of l0-tert.-butoxy-7a|3-methyl -5,6,7, 7a-tetrahydroindan-5-one were dissolved 1n 50 ml of absolute dlmethoxyethane, and a solution of 100 mg of sodium 1n 50 ml of isopropanol was added. 15 minutes after the addition, there was added dropwlse during the course of 60 minutes a solution of 0.8 grams of 7,7-(2,i2,-d1methylpropylened1oxy)-l-octen-3-one 1n 20 ml of absolute dlmethoxyethane, and the whole was then stirred for 40 hours at room temperature. After the addition of 10 ml of a saturated solution of primary sodium hydrogen phosphate, working up was carried out as described In Example 1(f), and the crude product was purified by chromatography over silica gel by means of hexane-acetone gradients. There were obtained 3.75 grams of l0-tert.-lbutoxy-7a3-methyl-4~[7' ,7'-(2",2"-dimethyl -propyl nedi ox ) -3 ' -keto-octy 1 ]-5 ,6 ,7 ,7a- tetrahydroi ndan-5-one . Infra-red bands at 5.86y and 6.03μ. [α]ρ°= +47.5° (c = 1, benzene). e) 7.8 grams of l0-tert.-butoxy-7af. -methyl -4-[7' ,7'-(2" ,2"-d1methyl-propylened1oxy)-3'-keto-octyl j-5,6,7 ,7a-tetrahydroindan-5-one were dissolved in 80 ml of absolute ethanol and 10 ml of orthof omvic add triethyl ester, The mixture was then cooled to 0°C and 5 mg of para-nltrophenol were added. After a reaction period of 7 hours at 0°C, the mixture was poured into 500 ml of a* dilute solution of sodium bicarbonate and worked up in the usual manner. There were obtained 7.95 grams of l3-tert.-butoxy-7a3-meth/l-4-[3' ,3'-diethoxy-7' ,7'-(2" ,2"-dimethyl- . . propyl enedi oxy )-oc,tyl]-5, 6, 7, 7a- tetrahydroi ndan-5-one in the form of a colourless oil.

Infra-red band at 6.05μ. [α]^- +42° ( c = 1, benzene).

Example 7 a) 33.5 grams of racemic 7a-methyl-5,6,7,7a-tetrahydro1ndan-l ,5-dlone were dissolved in 450 ml of absolute dimethoxyethane, 5.1 grams of sodium hydride were added to the solution, and the whole was stirred 1n an atmosphere of argon for 5 hours at 50°C - 55°C. The mixture was then cooled to -10°C, a solution of 57 grams of 7,7-ortho-phenyl enedl oxy?l-chloro-octan-3-one 1n 300 ml of absolute dimethoxyethane was added dropwlse during the course of 30 minutes, and the whole was stirred for 6 hours at.0°C. 100 ml of a solution of sodium d1 hydrogen phosphate were added to the reaction mixture, and the latter was worked up. The crude product so obtained was purified over a column of silica gel by means of a hexane-acetone gradient, and there were obtained 34.95 grams of raceml c 7a-methyl -4- (7 ' ,7 ' -ortho-phenyl enedl oxy-3 ' -keto-octy 1 )-5 ,6 ,7 ,7a-tetrahydro1ndan-l ,5-d1one 1n the form of a pale yellow oil.

Infra-red bands at 5.73μ, 5.86μ, 6.07u, 6.73μ and 8.1μ. b) 32.1 grams of racemic 7a-methyl-4-(7' ,7 '-ortho-phenyl enedl oxy-3'-keto-octyl)-5,6,7,7a-tetrahydro1ndan-l ,5-d1one were dissolved 1n 300 ml of methanol and 32.1 ml of orthoformlc add tri methyl ester, the solution was cooled to 0°C, 4 ml of a methanolic solution of 5% strength of para-toluene sul phonic add were added, and tl)e whole was kept for 4 hours at 0°C. The reaction mixture was then poured Into 1 litre of an Ice-cold solution of sodium bicarbonate, the mixture was extracted with methylene chloride, and the methylene chloride phase was washed with a solution of 15% strength of sodium chloride, dried over sodium sulphate, and concentrated in vacuo. There were obtained 31.2 grams of racemic 7a-methyl -4- (3' ,3' -d1methoxy-7' ,7' -ortho-phenyl -ened1oxy-octyl)-5,6,7,7a-tetrahydro1ndan-l ,5-d1one 1n the form of a yellow oil .

Infra-red bands at 5.74μ, 6.07μ, 6.73μ and 8.09μ.

Claims (21)

What we claim 1s:

1. A compound of the general formula I 1n which n. represents 1 ΘΡ-2, X represents a U -CH2-Z2-R2, -CH=C-R3, -CH2-C00R4 or--CH¾CN grouping, Y represents a carbonyl group or a dlalkoxymethylene group and Z2 each represents a free or ketallsed carbonyl group or a free, esterlfied or etherlfled hydroxymethylene group, as herein defined U represents a halogen atom, R.J, R2 and R^ each represents a lower alkyl group, and R4 represents an alkyl, a J-w-araJk J- group.

2. l3-Tert.-butoxy-7a3-methyl-4-(7' ,7'-ortho-phenylened1oxy-3'-keto-octyl )-5,6,7,7a-tetrahydro1ndan-5-one.

3. 13-Trimethyl acetoxy-7a3-methyl -4- (7 ' -chl oro-3 ' -keto-6 ' -octenyl )-5,6,7 ,7a-tetrahydro1 ndan-5-one .

4. 1$-Tert. -butoxy-7a3-methyl -4- (3 ' -keto-6 * -ethoxycarbonyl hexyl )-5 ,6 ,7 ,7a- tetrahydrol ndan-5-one .

5. lB-Tert.-butoxy-7a3-methyl-4-[7' ,7'-(2",2"-d1methyl-propylened1oxy)-31 -keto-octyl ]-5 ,6 ,7 ,7a-tetrahydro1 ndan-5-one .

6. l3-Tert.-butoxy-7a3-ethyl-4-(7' ,7 '-ortho-phenylened1oxy-3' -keto-octyl )-5 ,6 ,7 ,7a-tetrahydro1 ndan-5-one. 's.

7. 13-Trf methyl acetoxy-7a3-methy 1 -4- (3 ' -keto-6 * -methoxycarbony 1 -hexy 1 )-6 ,6 ,7 ,7a- tetrahydrol ndan-5-one .

8. lg-Tert.-butoxy-7a3-methyl-4-(3' ,3'-d1methoxy-7' ,7'-ortho-phenyl enedi oxy-octyl) -5, 6, 7, 7a-tetrahydro1ndan-5-one.

9. l3-Tr1methylacetoxy-7a3-methyl-4-(7'-chloro-3' ,3'-d1methoxy-6'-octenyl )-5,6,7,7a-tetrahydroindan-5-one.

10. 13-Tert . -butoxy-7a3-methy 1 -4- (3 · ,3 ' -d1 methoxy-61 -ethoxycarbqny 1 -hexyl )-5 ,6 ,7 ,7a-tetrahydro1 ndan-5-one.

11. l3-Tert.-butoxy-7a3-m«hyl-4-[3,.3'-d1ethoxy-7,,7f-(2%2"-d1methyl-propyl enedloxy )-octyl ]-5 ,6 ,7 ,7a-tetrahydro1 ndan-r5-one .

12. le-Tert.-butoxy^ae-ethyl^iS'.S'-dlmethoxy^' '-ortho-pheny 1 enedi oxy-octyl )-5 ,6 ,7 ,7a- tetrahydrol ndan-5-one .

13. 13-Tr1methyl acetoxy-7a3-methy 1 -4- (3 ' ,3 ' -d1methoxy-6 ' -methoxy-carbonyl -hexyl ) -5..6 ,? , 7a- tetrahydrol ndan-5-one .

14. 7a-Methyl-4-(7' ,7'-ortho-phenylened1oxy-3'-keto-octyl )-5,6,7,7a-tetrahydro1ndan-l ,5-d1one.

15. 7a- ethyl-4-(3' ,3*-d1methoxy-7,.,7,-ortho-phenylened1oxyoctyl)-6 ,6 ,7 ,7a-tetrahydro1 ndan-1 ,5-d1one .

16. A' process for the manufacture of a compound of the general formula I 1n which n represents 1 ©e=2, X represents a U OK-..CLLCM grouping, Y represents a carbonyl group or a dialkoxymethylene group, Z.| and ∑2 each represents a free or ketallsed carbonyl group or a free, esterlfled or etherfffed hydroxymethylene group, as herein defined U represents a halogen atom, R Rg and 3 each represents a lower alkyl group, and R^ represents an alkyl, a ^-er-araJky^- group, wherein (a) a compound of the general formula II 1n which n., R^ and have the meanings given above, 1s reacted 1n the presence of a basic catalyst with a vinyl ketone of the general formula III X-(CH2)2-C-CH=CH2 (III) 1n which X has the meanings given above, and, 1f desired, 1n the resulting compound the free carbonyl group represented by Y 1s converted into a dialkoxymethylene group by means of a lower alcohol, or (b) a compound of the general formula II, 1n which n_, R^ and have the meanings given above, 1s reacted 1n the presence of a basic catalyst with a compound of the general formula IV X-(CH2)2-Y-CH2-CH2-W (IV) 1n which Y has the meaning given above and W represents a halogen atom, and, 1f desired, 1n the resulting compound any free carbonyl group represented by Y 1s converted Into a dialkoxymethylene group by means of a lower alcohol.

17. A process as claimed 1n claim 16, wherein the reaction with the vinyl ketone 1s carried out 1n the presence of 0.01 mole to 1.0 mole of the basic catalyst per mole of the vinyl ketone.

18. A process as claimed 1n claim 16 or 17 , wherein the reaction with the vinyl ketone is carried out at a temperature within the range of from 0°C to +50°C.

19. fl process as claimed 1n claim 16, wherein the reaction with the compound of the general formula IV 1s carried out 1n the presence of an amount of the basic catalyst sufficient to catalyse the reaction and to bind the hydrogen hal lde l iberated during the reaction.

20. A process as claimed 1n claim 16 or 19 , wherein the reaction with the compound of the general formula IV 1s carried out at a temperature within the range of from -50°C to +50°C.

21. A process as claimed in claim 16 , conducted substantial ly as described in any one of Examples 1 to 7 herein. For the Applicants Wolff, Bregman and Gol ler