DK141993B - METHOD FOR PREPARING 4-SUBSTITUTED ALKYL-5,6,7,7A-TETRAHYDROINDAN-5-ONER OR 5-SUBSTITUTED ALKYL-1,2,3,4,8,8A-HEXAHYDRO-6 (7H) Naphthalenones - Google Patents

Description

(11) PUBLICATION 141993 C 07 B 27/00 r \ Λ Μ MADY (50 int. Cl.3 C 07 C 69/00 DENMAKK c 07 D 325/00 '(21) Application No 5575 / ^ 2 (22) Filed on 9 · HOV · 1972 (23) Running day 9 * nOV · 1 97 2 (44) Application submitted and petition published on 4 · 8, Ug * 1980

DIRECTORATE OF

PATENT AND TRADEMARKET (30> Priority requested from it

8. jun. 1972, 2228474, DE

(71) SCHERING AKTIENGESELLSCHAFT, Berlin and Eergkamen, Muellerstras se 170-T78, 1 Berlin 65, DE.

(72) Inventor: Ulrich Eder, Billerbeckerweg 30, 1 Berlin 27, DE: Ger = hard Ss.uer, Kur fu ers tens trass e 126a, 1 Berlin 30, DE: Gregor Haf fer, Moer = chinger Stråsse 79 * 1 Berlin 37 * DE: Juergen Ruppert, Schlieperstrasse 21, 1 Berlin 27, DE: Rudolf Wiechert, Endestrasse 38, 1 Berlin 39 * I® · (74) Plenipotentiary:

The company Chas. Hude.

(54) Process for the preparation of 4-substituted alkyl-5 * 6,7 * 7a-tetrahydroindan-5-ones or 5-substituted alkyl-1,2,3 * 4,8,8a-hexahydro-6 (7H) - naftalenoner.

The present invention relates to a particular process for the preparation of novel 4-substituted alkyl-5,6,7,7a-tetrahydroindan-5-ones or 5-substituted alkyl-1,2,3,4,8,8a-hexahydroxyl. 6 (7H) -naphthalenones of general formula I

2 T41993 R1 ['' N ^ Cce.iu 2 '3 where n is the number 1 or 2, X is the group -CH0-Z0-R, -CH = CR, 4 _ £ Δ -CH ^ COOR or -CH ^ CN , Y is a carbonyl group or a dialkoxy oxygen ethylene group having 1-4 carbon atoms in the alkoxy groups, Z 2 and% 2 a carbonyl group, the 1,2-ethylenedioxymethylene group, the 1,3-propylenedioxymethylene group, the 2,3-butylenedioxymethylene group, the 2 the dimethyl-1 ', 31-propylenedioxymethylene group, 2,4-pentylene dioxymethylene group, 1,2-phenylenedioxymethylene group or a free, esterified or etherified hydroxymethylene group wherein the ester residue or ether residue has 1-10 carbon atoms, U is a halogen.

atom, R, R and R are alkyl groups having 1-4 carbon atoms, and R

is an alkyl, aryl or aralkyl group having 1-10 carbon atoms.

12 3

As suitable alkyl groups R, R and R can be mentioned e.g. the methyl, ethyl, 12 3 n-propyl or n-butyl] group. Particularly preferred groups R, R and R are the methyl or ethyl group.

4

As suitable alkyl, aryl or aralkyl groups R may be mentioned e.g. the methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl, phenyl, benzyl or phenethyl group.

Suitable dialkoxymethylene groups Y may be mentioned e.g. the dimethoxymethylene group, the diethoxymethylene group, the di-n-proryloxymethylene group or the di-n-butyloxymethylene group.

As esterified hydroxymethylene groups Z 2 or 2-2, e.g. mention is made of the acetoxy, propionyloxy, butyryloxy, trimethylacetoxy, pentanoyl = oxy, hexanoyloxy, heptanoyloxy, octanoyloxy or benzoyloxy groups. Suitable etherified hydroxymethylene groups Z 1 or 22 are e.g. the methoxy, ethoxy, propyloxy, butyloxy, tertiary butyloxy, iso = propyloxy or benzyloxy groups.

3 U1993

Chlorine or bromine atoms are preferably suitable as halogen atoms U.

The process according to the invention is characterized in that in the presence of basic catalysts, a compound of the general formula II is alkylated

R1, where n, and is as defined above, with a vinyl ketone of the general formula III or an optionally ketalized β-halo

tonnes of general formula IV

0

II

X “(CH2) 2_C-CH-CH2 (III) X- (CH2) 2-Y-CH2-CH2-W (IV) wherein X and Y have the above meaning and W is a halogen atom and if desired catalyzes a optionally free carbonyl group Y present with alcohols having 1-4 carbon atoms.

For the process according to the invention, alkali metal alcoholates of secondary or tertiary alcohols, alkali metal hydrides, alkali metal amides or quaternary ammonium bases are preferably used as basic catalysts. As basic catalysts, e.g. mention is made of sodium hydride, sodium amide, sodium isopropylate, sodium tertiary butylate, potassium tertiary butylate, lithium amide, tetramethylammonium hydroxide or trimethylbenzylammonium hydroxide. If, as starting compounds for the process of the invention, vinyl ketones of formula III are used, 0.01 mole to 1.0 mole of basic catalyst is suitably used. moles of vinyl ketone. If one performs the process of the invention using compounds of formula IV, it is necessary to use the basic catalyst in excess to bind the halogen hydrogen released by the reaction.

The addition of the vinyl ketones or optionally ketalized β-halogen ketones is conveniently carried out in inert solvents.

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Suitable solvents are e.g. polar ethers such as 1,2-dimethoxyethane, 2,2'-dimethoxydiethyl ether, tetrahydrofuran or dioxane, secondary or tertiary alcohols such as isopropanol, butanol (2) or tertiary butanol or polar aprotic solvents such as dimethylformamide, N-methylacetamide, N-methylpyrrolidone or hexamethylphosphoric acid triamide. On the other hand, it is also possible for this reaction to use solvent mixtures of the aforementioned solvents and relatively unpolar solvents such as benzene or toluene.

The reaction is preferably carried out at a reaction temperature of approx. -50 to + 100 ° C. If the reaction of vinyl ketones of the general formula III is used, the reaction is preferably carried out at a reaction temperature between 0 and + 50 ° C, and using compounds of the formula IV is preferably employed at a reaction temperature between -50 and + 50 ° C.

For those skilled in the art, it is surprising that the alkylation of the compounds of the general formula II with the vinyl ketones of the formula III or the compounds of the formula IV proceeds extensively, for it is known from Tetrahedron letters No. 52, pages 6495-6501, 1966 that upon alkylation of compounds of formula II, mixtures of various alkylation products are usually obtained.

Preferably, the catalysis of group Y occurs by reacting the compounds with the alcohols in the presence of acidic catalysts. Suitable alcohols are e.g. methanol, ethanol, n-propanol or n-butanol. Suitable acidic catalysts are e.g. inorganic acids such as hydrochloric acid, sulfuric acid or perchloric acid, sulfonic acids such as methanesulfonic acid, Lewis acids such as boron trifluoride or phenols such as p-nitrophenol or 2,4-dinitrophenol. Particularly well, the ketalization succeeds when further adding a water-binding agent, e.g. anhydrous sodium sulfate, magnesium sulfate or calcium sulfate. Also, as a water-binding agent, very well are ortho-formic acid esters or acetone dialkyl ketals of alcohols used for the ketalization. The catalysis is preferably carried out at a reaction temperature between -20 and + 80 ° 0.

5 1A19 93

The compounds of the general formula I prepared by the process according to the invention are valuable intermediates. In particular, they are suitable for making pharmacologically effective steroids totally synthetic.

The following formula shows a utility of compounds of formula I wherein Y represents a dialkoxymethylene group within the context of a steroid total synthesis.

R1 R1 voN J -> V I - * (If) (?) R1 r1 fh ^> n / H -y H - * (νΣ) (VII) R1 h | (fVn

i J H

(VIII) In this formula, X, Z 1, and n have the above meaning and V is an alkyl group having 1-4 carbon atoms.

This synthetic route can be carried out, for example, as follows:

The compounds of formula 1 'are heated in benzene with the addition of catalytic amounts of malonic acid or 0.01 mole of malonic acid per liter. If the substituent Z 1 is a carbonyl group, it can then be reduced with lithium aluminum hydride. Surprisingly, the compounds of formula V can be hydrogenated stereospecifically with catalytically activated hydrogen, and the compounds of formula VI are obtained. This hydrogenation can e.g. is carried out by dissolving the compounds of formula V in ethyl acetate and then hydrogenating with hydrogen using palladium on animal coal as a catalyst at normal pressure. The compounds of formula VI are dissolved in ethanol, stored at room temperature for 30 minutes with the addition of catalytic amounts of hydrochloric acid. The solution is diluted with methylene chloride and washed neutral with sodium bicarbonate solution and water. After drying with sodium sulfate and distilling off the solvent, the compounds of formula VII are obtained. It is not necessary to isolate the substances of formula VII, but the resulting crude product can be dissolved in ethanol, added excess sodium methylate and then heated to ca. 2 hours at reflux. After cooling to room temperature, dilute with diethyl ether, wash the solution neutral with saturated sodium chloride solution, dry with sodium sulfate and evaporate. There are thus obtained the compounds of formula VIII ("des-A steroids").

For example, the final product of Formula I 'prepared in Example 3c is obtained, where Z 2 = trimethylacetoxymethylene, n = 1, R 1 and V = CH 3 X = -CH = C - CH 3 Cl 7 U 19 S 3 -3-diethyl-4,5-seco-2,9-estradien-5-one, a compound of the general formula VIII wherein

Z1 = trimethylacetoxymethylene, n = 1 E1 = CH3 X = -CH = C-CEL

Cl

The further processing of the des-A steroids of general formula VIII into pharmacologically active steroids (estrogens, androgens and retrosteroids) is known and described (L. Velluz, G. Nomirie and J. Matthieu, Angew. Chem. 72, p. 725 (1960), L. Velluz, J. Valls, and G. Nomirie, Angew. Chem. 77, 185 (1965)).

The following examples serve to illustrate the process of the invention.

Example 1 (a) 162 g of 5-oxo-hexanonitrile is dissolved in 1 liter of toluene, 243 g of pyrocatecol and 3 g of p-toluene sulfonic acid are added and heated for 24 hours with a water separator.

The reaction mixture is allowed to cool, diluted with 1 liter of benzene and the organic phase is washed with 1N sodium hydroxide solution and dilute sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The crude product obtained is distilled in high vacuum to give 246.5 g of 5> 5-o-phenylenedioxyhexanonitrile. Kp q itorr = 106-110 ° C.

(b) Dissolve 183 g of 5,5-o-Eenylenedioxyhexanone nitrile in 1830 ml of toluene, cool the solution to -50 ° C and add over 1 hour 790 ml of a 20 µg solution of diisobutylaluminum hydride in toluene and stir hour at -50 ° C.

8 141993

Then, the reaction mixture is sieved with 4N hydrochloric acid to a pH of 3, diluted with 1 liter of ethyl acetate, washed the organic phase with dilute sodium chloride solution, dried over sodium sulfate and evaporated to drybed in vacuo.

The residue is distilled in bending vacuum to give 174 g of 5,5-o-phenylene = dioxybeksanal. Kp q Q5torr = 90-92 ° C.

(c) 40 g of Magnesium Chips are reacted with vinyl chloride in 800 ml of tetrabydrofuran and the resulting solution is cooled to -30 ° C, and a solution of 173 g of 5,5-o-phenylenedioxybeksanal in 1800 ml of tetrahydrofuran is added dropwise and the reaction mixture bake for 3 hours at -30 ° C. Then, 260 ml of saturated ammonium chloride solution is added dropwise to the mixture which is filtered and the resulting solution is evaporated in vacuo.

The residue is dissolved in 2000 ml of acetone, the solution is cooled to -10 ° C and within 30 minutes 200 ml of Jones reagent (an aqueous solution containing 267 g of chromium (Yl) oxide and 230 ml of concentrated sulfuric acid per liter) are added.

The mixture is allowed to stand for 1 hour, 100 ml of methanol and 7000 ml of methylene chloride are added, the organic phase is separated, washed with dilute sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The crude product obtained is distilled in bending vacuum to give 172 g of 7,7-o-phenylenedioxy-1-octene-3-one.

0.002 torr = 88-92 ° 0 · (d) Dissolve 23 g of 7,7-o-ienylenedioxy-1-octen-3-one in 150 ml of chloroform and cool to ca. 0 ° C. Then, for 30 minutes, dry hydrogen chloride is passed through the solution, the chloroform distilled off by one. in vacuo to obtain 23.9 g of 1-chloro-7,7-o-phenylene = dioxooctan-3-dn.

(E) 17 g of 3-tert-butoxy-7a6-methyl-5,6,7,7a-tetrahydroindan-5-one are dissolved in 200 ml of absolute dimethoxyethane and refluxed for 2 hours after addition of 2 g of sodium hydride. Then, the solution is cooled to -20 to -30 ° C, and within 1 hour a solution of 21.5 g of 1-chloro-7,7-o-phenylenedioxy-octan-3-one in 80 ml of absolute dimethoxyethane is added dropwise. After the addition, the reaction solution is allowed to come to room temperature over 3 hours. After an additional 3 hours, 50 ml of saturated primary sodium phosphate solution is added and the solvent is distilled off in a vacuum. The residue is diluted with 100 ml of water and extracted with methyl chloride. The organic extracts are washed with water, dried over sodium sulfate, filtered and the solvent is distilled off in vacuo.

The crude product is purified by chromatography on silica gel using hexane-aoetone gradients. 22.4 g of 1β-teβ-butoxy-7αβ-methyl-4- (7 ', 71-o-phenylenedioxy-3'-ketoctyl) -5,6,7,7a-tetrahydroindan-5-one are obtained as a colorless oil. IR bands at 5.86 µ, β, ΟΟ, α, 6.72 / h and 8.1 / i. / ος7 ^ 0 = + 46 ° (c = 1 in benzene).

(f) 10.3 g of 1β-β-butyloxy-7αβ-methyl 1-4- (7 ', 7'-o-phenylenedioxy-3'-ketoctyl) -5,6,7,7a-tetrahydroindan-5 on is dissolved in 100 ml of absolute methanol and 10.3 ml of orthoformic acid trimethyl ester. It is then cooled to 0 ° C and 1.5 ml of 0.5 g of methanolic p-toluenesulfonic acid solution is added and stirred for 4 hours at 0 ° C. Then, the reaction solution is poured onto 500 ml of ice-cold dilute sodium bicarbonate solution and extracted with methylene chloride, washed with semi-saturated sodium chloride solution, dried with sodium sulfate, distilled off, and recrystallized from ether.

9.95 g of 1β-tert-butyloxy-7αβ-methyl-4- (3,3,3-dimethoxy-7 ', 7β-o-phenylenedioxyoctyl) -5,6,7,7a-tetrahydroindan-5 on, m.p. 132-134 ° C. foj ^ 1 = + 42.5 ° (c = 1 in benzene).

141993 ίο

Example 2 (a) 12 g of Racemic 1 [3-tert-butyloxy-7a3-ethyl-5,6,7,7a-tetrahydro = indan-5-one is dissolved in 150 ml of absolute tetrahydrofuran and 400 mg of sodium hydride is added. Under argon as a shielding gas, it is then refluxed until hydrogen evolution is completed, and then the solution is cooled to 0 ° C. With stirring, a solution of 13 g of 7,7-o-phenylenedioxy-1-octen-3-one in 50 ml of absolute tetrahydrofuran is then dropped over 30 minutes and further stirred at 0 ° C for 30 hours. The crude product obtained in the work described above, for example, is purified by chromatography on silica gel to give 10.5 g of 13-tert-butyl = oxy-7α-ethyl-4- (7 ', 7'-o-phenylenedioxy-3 -ketooctyl) -5,6,7,7a-tetrahydroindan-5-one as a colorless oil. XR bands at 5.85 µ, 6.05 µ 6.75 µ and 8, µ.

(b) 3.8 g Racemic: 13-tert-butyloxy-7ap-ethyl-4- (7 ', 7' -ofenylene = dioxy-3'-ketook: tyl) -5,6,7,7a-tetraliy (Acid-5-oi is reacted with methanol and ortho-acid trimethyl ester at 0 ° C, as in Example 1 (f), to give 3.81 g of lp-tert-butyloxy-7ap-ethyl-4- (3 ', 31-dimethoxy-7 ', 7' -o-phenylenedioxy octyl) -5,6,7,7a-tetrahydro = indan-5-one as a colorless oil IR band at 6.06 µl, 6.75/4 and 8.1 / h.

Example 3 (a) 15.8 g of 7-Chloro-1,6-octadien-3-one are dissolved in 150 ml of absolute chloroform and cooled to 0 ° C. The mixture is then allowed to dry in hydrogen chloride for 30 minutes, evaporated to dryness in vacuo to give 16.5 g of 1,7-dichloro-6-octene-3-one as a colorless oil. IR bands at 5.86 µ in and 5.97 µ in.

(b) 11 g of Racemic 13-trimethylacetoxy-7ap-methyl-5,6,7,7a-tetrahydro = indan-5-one are dissolved in 100 ml of dimethylformamide and 50 ml of benzene and, after the addition of 1.3 g of sodium hydride, 60-70 ° 0 under argon.

11 141993

After 3 hours, hydrogen evolution is over. Cool to -10 ° C and drop over a 45 minute solution of 8.9 g of 1,7-di = chloro-6-octene-3-one. After the addition, the mixture is further stirred at 0 ° C for 15 hours. Then proceed as in Example 1 (e) to give 9.7 g of 1β-trimethylacetoxy-7a | 3-methyl-4- (7'-chloro-3'-keto-6'-octenyl) -5,6 , 7.7 α-Tetrahydroindan-5-one as a colorless oil. IR bands at 5.85µ, 6.00µ and 5.79p.

(c) 3.2 g of Racemic 1B-trimethylacetoxy-7a8-methyl-4- (7, -chloro-3'-keto-β'-octenyl) -5,6,7,7a-tetrahydroindan-5-one becomes as of Example 1 (f) reacted with 3.5 ml of orthoic acid trimethyl ester and 30 ml of absolute methanol under catalysis of p-toluenesulfonic acid at 0 ° C, worked up to give 3.12 g of-trimethylacetoxy-7aB-methyl-4- (7). (-chloro-3 ', 3, -di = methoxy-6'-octenyl) -5,6,7,7a-tetrahydroindan-5-one as a colorless oil. IR bands at 5.77µ and 6.07µ.

Example 4 (a) 5.2 g of Racemic 13-trimethylacetoxy-7a | 3-methyl-5,6,7,7a-tetrahydroindan-5-one are heated to 60 ° C together with 0.63 g of sodium hydride in 50 ml dimethylformamide and 50 ml of benzene until hydrogen evolution is complete. It is then cooled to -10 ° C and a solution of 4.3 g of 7-chloro-5-ketoheptanoic acid methyl ester in 10 ml of absolute benzene is added dropwise over 20 minutes and left for 16 hours at 0 ° C. 30 ml of saturated aqueous primary sodium phosphate solution are added and worked up as described in Examples 1e and 2a. The crude product is chromatographed on silica gel to give 13-trimethylacetoxy-7af3-methyl-4- (3'-keto-6'-methoxycarbonylhexyl) -5,6,7,7a-tetrahydroindan-5-one as a colorless oil. IR bands at 5.78µ and 6.05µ.

(b) 6.4 g of Racemic 1,3-trimethylacetoxy-7af3-methyl-4- (3'-keto-6'-methoxycarbonylhexyl) -5,6,7,7a-tetrahydroindan-5-one are dissolved in 50 ml of toluene and 10 ml of 2,2-dimethoxypropane, cool to 0 ° C and add 3 mg of p-toluenesulfonic acid. After a reaction time of 16 hours at 0 ° C, as in Example 1 f, the crude product is recrystallized from ether to give 6.1 g of 1β-trimethylacetoxy-7α-methyl-4- (3 ', 3'-dimethoxy-6 (methoxycarbonylhexyl) -5,6,7,7a-tetrahydroindan-5-one, mp 101-103 ° C.

12 141993

Example 5 (a) 23 g of 13-Tert-butyloxy-7a (3-methyl-5,6,7,7a-tetrahydroindan-5-one is boiled for 5 hours under reflux in 250 ml of absolute tetrahydrofuran together with 2.5 g of sodium hydride under argon.

It is then cooled to -30 ° C, drips 22 g of 7-chloro-5-keto-heptanoic acid ethyl ester in 100 ml of absolute tetrahydrofuran over 1 hour, leaves the mixture for 2 hours at -30 ° C and then for 16 hours. comes up at room temperature. The mixture is worked up as in Example 1 (e) to give 20.4 g of (3-tert-butyloxy-7a | 3-methyl-4- (3'-keto-6'-ethoxycarbonylhexyl) -5,6,7,7a -tetrahydroindan-5-one as a colorless oil. [a] + 3- = + 49 ° (c = 1 in benzene).

(b) 5 g of 13-Tert-butyloxy-7af} -methyl-4- (3'-keto-6-ethoxycarbonyl = hexyl) -5,6,7,7a-tetrahydroindan-5-one is reacted according to Example 1 ( f) with methanol and orthoformic acid trimethyl ester and catalytic amounts of p-toluenesulfonic acid at 0 ° C, reprocessing and receiving 13-tert-butyloxy-7-a3-methyl-4- (3 ', 3'-dimethoxy-6'-ethoxycarbonylhexyl) -5 , 6,7,7a-tetrahydroindan-5-one as a colorless oil. IR bands at 5.76p and 6.04p. [α] D = + 44 ° (c = 1 in benzene).

Example 6 (a) 132 g of 5-oxohexanonitrile are dissolved in 700 ml of benzene and 150 g of 2,2-dimethylpropanediol and 2 g of p-toluenesulfonic acid are added and heated for 24 hours with water separator. The mixture is then allowed to cool, 150 ml of saturated sodium bicarbonate solution is added and diluted with 500 ml of toluene. After separation of the aqueous phase, the organic phase is washed neutral with sodium bicarbonate solution and water, dried over sodium sulfate, filtered and the solvent is distilled off in vacuo. The crude product obtained is purified by high vacuum distillation to give 207 g of 5,5- (2 *, 2'-dimethylpropylenedioxy) hexanonitrile.

(B) 75 g of 5,5- (2 ', 2'-dimethyl-propylenedioxy) -hexanonitrile are dissolved in 750 ml of absolute toluene, the solution is cooled to -50 ° C, and 315 ml of a 20% diisobutyl aluminum hydride solution in toluene is added dropwise. The mixture is stirred at -50 ° C for a further 1 hour, added over 10 minutes to 500 ml of saturated sodium dihydrogen phosphate solution, stirred further for 5 hours at room temperature and separated from the aqueous phase, the organic phase is washed with sodium bicarbonate solution and water until neutral. dry with sodium sulfate, filter and distill the solvent in vacuo. The resulting crude product is purified over an alumina column to give 57.3 g of 5.5- (21.2'-dimethylpropylenedioxy) hexane as a colorless oil. IR band at 5.8µ.

(c) 23 g of 5.5- (2 ', 2'-dimethylpropylenedioxy) hexane is reacted with Example 1 (c) Section 1 with vinyl magnesium chloride. The resulting crude product is then dissolved in 500 ml of absolute methylene chloride, 200 mg of hydroquinone and 300 g of brownstone powder are added to the solution and shaken for 8 hours. Filter, evaporate the solution in vacuo, purify the crude product obtained by chromatography over a silica gel column to give 17.3 g of 7,7- (2 ', 2'-dimethylpropylenedioxy) -1-octen-3-one as a colorless oil . IR band at 5.97 µ.

(d) Dissolve 5 g of 10-Tert-butyloxy-7a (3-methyl-5,6,7,7a-tetrahydroindan-5-one in 50 ml of absolute dimethoxyethane and add a solution of 100 mg of sodium in 5 ml of isopropanol 15 minutes after the addition a solution of 5.8 g of 7,7- (21,2'-dimethylpropylenedioxy) -1-octen-3-one in 20 ml of absolute dimethoxyethane is added dropwise over 60 minutes and then stirred for 40 hours. at room temperature.

After adding 10 ml of saturated primary sodium hydrogen phosphate solution, work up as in Example 1 (e) and purify the crude product by chromatography on silica gel using hexane-acetone gradients. 3.75 g of 3-tert-butyloxy-7a | 3-methyl-4- [7 1,7 '- (2 ", 2" -dimethylpropylenedioxy) -3'-ketoctyl] -5,6,7 7a-tetrahydroindan-5-one. IR bands at 5.86µ and 6.03µ. [α] ρ0 = + 47.5 ° (c = 1 in benzene).

(e) 7.8 g of 13-Tert-butyloxy-7a ' -methyl-4- [7 ', 7' - (2 ", 2" -dimethylpropylenedioxy) -3 "-ketoctyl] -5,6,7,7a- Dissolve tetrahydroindan-5-one in 80 ml of absolute ethanol and 10 ml of orthoformic acid triethyl ester, then cool to 0 ° C and add 5 mg of p-nitrophenol. After a reaction time of 7 hours at 0 ° C, pour in 500 r of dilute sodium bicarbonate solution and extract. After washing to neutral with water, dried over sodium sulfate, filtered and the solvent distilled off in vacuo to give 7.95 g of 13-tert-butyloxy-7a3-methyl-4- [3 ', 3'-di -ethoxy-71.7 '- (2 ", 2" -dimethylpropylenedioxy) octyl] -5,6,7,7a-tetrahydroindan-5-one as a colorless oil. IR band at 6.05p. [ = + 42 ° (c = 1 in benzene).

Example 7 (a) 33.5 g of racemic 7α-methyl-5,6,7,7a-tetrahydroindan-1,5-dione are dissolved in 450 ml of absolute dimethoxyethane and to the solution is added 5.1 g of sodium hydride and in an argon atmosphere stir for 5 hours at 50-55 ° C. It is then cooled to -10 ° C, a solution of 57 g of 7,7-o-phenylenedioxy-1-chlorooctan-3-one in 300 ml of absolute dimethoxyethane is added dropwise over 30 minutes and stirred at 0 ° for 6 hours. C.

Then, 100 ml of sodium dihydrogen phosphate solution is added to the reaction mixture and the bulk of dimethoxyethane is distilled off in vacuo. The residue is extracted with methylene chloride, washed neutral with water, dried over sodium sulfate, filtered and the solvent is juxtaposed in vacuo. The crude product obtained is purified by hexane-acetone gradients over a silica gel column to give 34.95 g of racemic 7α-methyl-4- (7 ', 7'-o-phenylenedioxy-3'-ketoctyl) -5,6 , 7,7a-tetrahydroindane-1,5-dione as a pale yellow oil. IR bands at 5.73µ, 5.86µ, 6.07µ, 6.73p and 8.1p.

(b) 32.1 g of racemic 7α-methyl-4- (7,7,7'-o-phenylenedioxy-3,6-ketoctyl) -5,6,7,7a-tetrahydroindan-1,5-dione are dissolved in 300 ml methanol and 32.1 ml of ortho formic acid trimethyl ester, the solution is cooled to 0 ° C and 4 ml of a 5% methanolic p-toluenesulfonic acid solution is added and stored for 4 hours at 0 ° C. Then, the reaction mixture is poured into 1 liter of ice-cold nartium bicarbonate solution, extracted with methylene chloride, washed with methylene chloride phase with 15% sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. 31.2 g of racemic 7α-methyl-4- (3,3,3-dimethoxy-7,7,7-o-phenylenedioxy = octyl) -5,6,7,7a-tetrahydroindan-1,5-dione are obtained. like a yellow oil. IR bands at 5.74p, 6.07p, 6.73p and 8.09p.

15 141993

Example of use of the compounds prepared.

11.3 g of 10-tert.-butyloxy-7α-methyl-4- (3 ', 3'-dimethoxy-7', 7'-o-phenylenedioxy-octyl) -5,6,7,7a-tetrahydroindan-5 -one dissolves 1200 ml of absolute benzene and 100 mg of malonic acid is added. Then reflux, removing 100 ml of distillate over an hour. To the cooled solution is then added 100 ml of saturated sodium = bicarbonate solution and worked up. 10.3 g of 3-methoxy-70-tert.-butyloxy-6af} -methyl-3- (4 ', 4'-o-phenylenedioxy-pentyl) -1,2,3,5,6,6a are obtained. 7 <x, 8-octahydrocyclopenta- [f] [1] -benzopyran as a colorless oil. IR bands at 6.0 y, 6.75 y and 8.1 y. [α] D = + 1.8 ° (c = 1.01 in benzene).

22.9 g of crude 3-methoxy-70-tert.-butyloxy-6α-methyl-3- (4 ', 4'-o-phenylene = dioxypentyl) -1,2,3,5,6,6a, 7a, 8-octahydrocyclopenta- [f] [1] -benzo = pyran is hydrogenated in 500 ml of acetic acid ethyl ester with 2.5 g of 10% palladium / carbon, thereby absorbing 1.19 l of hydrogen over 3 hours. The catalyst is filtered off, evaporated in vacuo, the residue is dissolved in 200 ml of ethanol and stirred after adding 3 ml of 1 N hydrochloric acid for 2 hours at room temperature. Then 1 g of sodium methylate is added, heated for 3 hours under reflux and the solvent is distilled off in vacuo. The residue is taken up in 500 ml ether, washed once with semi-saturated sodium dihydrogen phosphate solution and then neutral with water. The crude product obtained after drying with sodium sulfate and distillation of the ether gives, after chromatography on 3 kg of silica gel with hexane / acetone (acetone content increasing from 0 to 33%) 18.2 g (84.9%) 170-t-butoxy -3,3-o-phenylenedioxy-4,5-seco-oestr-9-ene-5-one as a colorless oil. [α] D = -9.1 ° (c = 0.5).

C28H38 ° 4 (438.61). Calculated: C, 76.68; H, 8.73%.

Found: C, 76.21; H, 8.82%.

Claims (1)

16 141993 Patent Claims. Process for the preparation of 4-substituted alkyl-5,6,7,7a-tetrahydroindan-5-ones or 5-substituted alkyl-1,2,3,4,8,8a-hexahydro-6 (7H) -naphthalenones with the general formula I R 1 (D 2 where n is the number 1 or 2, X is the group -CH 2 -Z 2 -r, U 1 3 4 -CH = CR, -CH 2 -COOR or -CH 2 CN, Y is a carbonyl group or a dialkoxymethylene group having 1-4 carbon atoms in the alkoxy groups, Z 1 and Z 2 a carbonyl group, 1,2-ethylenedioxymethylene group, 1,3-propylene = dioxymethylene group, 2,3-butylenedioxymethylene group, 2 ', 2'-dimethyl-1', 3'-propylene dioxymethyl group The 2,4-pentylenedioxymethylene group, the 1,2-phenylenedioxymethylene group or a free esterified or etherified hydroxymethylene group, wherein the ester residue or ether residue has 12 to 3 to 10 carbon atoms, U is a halogen atom, R, R and R are alkyl groups having 1-4 carbon atoms, and R 4 is an alkyl, aryl or aralkyl group having 1-10 carbon atoms, characterized in that in the presence of basic catalysts, a compound is alkylated with the general formula II R 1 '(fVn (II) cAv - wherein n, R 1 and are as defined above, with a vinyl ketone of the general formula III or an optionally ketalized 3-halogen = ketone of the general formula IV (CH2) 2-C-CH = CH2 (III) X- (CH2) 2-Y-CH2-CH2-W (IV)