DE1793617A1 - Substituted octalinones and tetrahydroindanones - Google Patents

Description

DR. BERG DIPL. IMG. STAPF

PATENTANWÄLTE β MÜNCHEN 2. HILBLE8TRA88 «

Dr. Berg Dipl.-Ing. Stopf, 8 Munich 1, HilbleilrgB « 20

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19 26k

date

April 15, 197o

Attorney file 19 26k

Dr. Herchel Smith Bryn Mawr, Pennsylvania / USA

"Substituted Octalinones and Tetrahydroindanones"

The invention relates to substituted octalinones or tetrahydroindanones of the general formula

- 2

X / no

209832/1180, .Pw _; .x-io / ii / i2a-o

RR

in which Ar is an optionally substituted phenyl group with an unsubstituted ortho position, each R represents hydrogen or an alkyl group having fewer than 5 carbon atoms, R represents an alkyl group with fewer than 6 carbon atoms, Q is methylene or ethylene and Y is a carbonyl, hydroxymethylene or is a ketalized carbonyl group, and in particular substituted octalinones or tetrahydroindanones of the general formula

CH ₃

in which R is hydrogen or a hydroxy group, Q

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Methylene or ethylene and Y is a carbonyl, hydroxymethylene or an ethylenedioxymethylene group.

Much research has been done in the steroid field over the past 20 years to identify opportunities for To research syntheses of these substances, which are very important for medicine, most of the industrial research work aimed at partial synthesis from naturally occurring steroids, easily as starting materials are available and have continued to be available for the production of analogues and derivatives by modifying the in Nature-found steroid structures turned off. There have been some total syntheses of the steroids with great Acumen and academic merit found, but relatively few numerically and in scope limited syntheses. Typical of these syntheses is the large number of individual steps that are necessary mainly because of the obvious confusion, which the stereochemistry entails. Many of the sub-stages that have been passed through in such syntheses proceeded using known reactions under standard conditions, and in the first place it is essential in the choice of the starting material, which the application of a combination of stages in a given Sequence follows, justifies that a new invention

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SAD ORIGINAL

concept is found. However, it is the number of alternatives The levels and combinations of levels available to the steroid chemist are so great that if he does Once the overall concept of a successful multistage synthesis has been surveyed, it is often possible through application further considerations to modify intermediate products in the synthesis in such a way that other steroids or steroid analogues can be used can be achieved. Such an amendment, although based on a specific intermediate, consequently takes the suggestion of the overall concept, which is shown by the original, inventive sequence, the modification in end products that are the same or different from those of the original syntheses, results.

It is so that the overall inventive conception of a successful multi-stage steroid synthesis brings a step of inventive merit into each new synthesis stage, independently of and in support to any inventive concept, which may have this particular stage, and detached viewed from other levels.

The present invention now relates to novel products of a specific process stage of a new TotsOeyntheee

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of steroids. A new route to the total synthesis of steroid hormones has been found

en / of valuable, new connection. This route has the advantage that the one to form the ring system Steroid's essential carbon atoms are all already present at an early stage in the synthesis the early formation of the steroid structure "helps in the execution of a highly stereospecific synthesis. Thus, a corner methyl group, bound in the 13-position in the steroid molecule, is created at an early stage of the process formed, avoiding the production of an unfavorable ratio of stereoisomers, which generally occurs when one tries to introduce this methyl group at a later stage »With This new way enables analog hormones to be obtained more easily, which otherwise would not or at best not without serious difficulties from naturally occurring steroids are available. So became a gateway to steroids of various types that have an oxygen substituent in the 11-position! also enables the new route is the synthesis of steroids which have a large number of substituents in the 3-position. The new way also makes the production of homologous steroids possible, the corner groups, larger ale have the methyl group in the 13-position.

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In life, the path delivers new total syntheses of oestrone and estradiol, two valuable therapeutic substances. These can easily be carried out using the new syntheses good overall yield and through an effectively smaller number of steps than overall syntheses have required so far, can be achieved. The new way is shown in the following total synthesis of oestrone, in which the digits refer to the structural formulas compiled in the appendix.

The well-known compound 3-m-metho: xyphenylpropan-1-ol (I) is converted to the corresponding Jöromid (II), which with sodium acetylide in liquid ammonia or other suitable solvents to form the acetylene derivative (III) is condensed. This connection, whose acetylenic hydrogen atom is reactive, is subjected to the Mannich reaction, using formaldehyde (or a formaldehyde polymer) and diethylamine to give the acetylenic amine (IV).

The next stage is the hydration of the acetylenes! - binding under suitable conditions, for example with aqueous mercury (II) sulfate and sulfuric acid, to give the 3-ketoamine (V). This 3-ketoamine, which borrows, even when distilled, diethylamine

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splits off, its cleavage product, the vinyl ketone (VI) or a mixture of both, becomes · with 2-methylcyclohexane-1,3-dione (VII) condensed under reflux in benzene containing pyridine. The product of this Michael condensation is the dicyclic triketone (VIII), which has the entire carbon skeleton of a 19-nor-D-homo-steroid. If this triketone is refluxed in xylene in the presence of Triethylammonium benzoate heated as a catalyst finds an internal aldol condensation and dehydration take place, whereby the tricyclic diketone (IX) is formed, which in the newly formed ring, which corresponds to ring C at the 8 (14-) position of the terminal steroid is unsaturated. This tricyclic diketone is a mixture of enantiomers, which has an asymmetric center at G ^. Only the 13-beta connection is explained, though this must be understood to mean that the mixture contains an equal amount of the 13ot compound as the subsequent compounds contains; Separation to obtain a 13-ß enantiomer can be effected at any suitable stage.

The catalytic hydrogenation of the tricyclic diketone mixture saturates ring 0 and gives an oily mixture reduced tricyclic diketones (X), in which two further asymmetric centers ale Og and C ^. appear.

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1783S17

It follows the cyclodehydration dieBesKJemisch.es with methanolic hydrofluoric acid at room temperature, forming ring B and yielding the tetracyclic ketone (Xl). This ketone that comes with $ 51 Yield obtained from the diketone (IX) is (^) - D-homo-9 (11 ) -Dehydroestrone methyl ether, in the correct stereochemical structure at Cg and C- ..

The reduction of the ketone (XI) with potassium and ammonium chloride in liquid ammonia gives (i) -D-homo-estradiol methyl ether (XII), which has a 4th asymmetric center at Cq, whereby the introduced hydrogen is again stereochemically correct for the D-homo- is oestrone series, and contains a 5th center as G ^ ~ . The diol ether (XII) is converted into (-) - D-homo-oestrone methyl ether (XIII) by oxidation with chromic acid in acetone. Ultimately, when the ketonic ether (XIII) is condensed with benzaldehyde in the presence of a base, a benzylidene derivative (XIV) is obtained which is identical to the substance described by Johnson et al., J. Amer. Chem. Soc. , 1952, 21 »2852 can be converted to homomarrianolic acid methyl ether by ozonolysis, by pyrolysis of the lead salt of this acid and demethylation to estrone. Oestrone can easily be reduced to estradiol (XVl).

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Bs was also found to have similar reaction sequences can be carried out in which instead of 2-Methy1-cyclohexane-1,3-dione (YII) The corresponding cyclopentane derivative (XXV) is used to make the dicyclic triketone Michael adduct (XXVI) to form which is the whole carbon skeleton contains a 19-nor steroid; this then leads to the tricyclic diketone (XXXVII) and then directly via the ketones (XXXVIII) and (XXXIX) to (±) -estradiol-3-methyl ether (XXIX) and (i) -ostrone methyl ether (XXX), in which way it is not necessary to narrow the ring D. (t) oestrone methyl ether can can be converted into (i) -estrone (XV) by demethylation.

The substituted octalinones or tetrahydroindanones according to the invention of the present application can according to that in the German patent specification

(P H 43 083.2-42) described method, after which one

(a) a compound of the general formula

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R R

- ίο -

1793817

wherein X is chlorine, bromine or an organic sulphonyloxy group is with a metal Snolat a bond of the general 3?

condensed or

(b) a substituted phenylhexanone of the general formula

R R

cyclodehydrated

and if appropriate, the ketone thus obtained is ketalized in a known manner or reduced to the corresponding alcohol.

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- 11 -

The group R, which "in a steroid synthesis under Use of the intermediates of the invention ultimately forms the corner substituent in the 13-position, preferably has less than 6 carbon atoms and can for example a methyl, ethyl, isopropyl group.

If one or both groups R in a group GR _{2 is} an organic substituent, such as methyl, ethyl or another alkyl group of less than 5 carbon atoms, steroids with 6- or 7-alkyl groups or other organic Substituents, can be obtained using the compounds according to the invention. Preferably each R group is hydrogen.

The group Ar should have at least one o-position, free of Have substituents, so that optionally the Oyclodehydratisierung to form the ring B carried out can be. It is to be understood that one aryl group cannot be used to make a steroid should contain neighboring substituents that would make a possible OycIodehydratisierung impossible. The aryl group is preferably a phenyl group, the can be free of substituents; she can do one too

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17936t?

or contain more substituents, Tfoihsugswedae contains they have a further substituent in the 3-position (this is the 3-position, both with respect to the next CRp group as well as the optional carbon atoms in the final steroid structure). This 3-substituent is suitably a hydroxy, Acyloxy (e.g. acetoxy), alkoxy (e.g. Methoxy), Mitro, amino, mono alky lamino or dialkylamino (for example diethylamino) group. Ee it has been found that the ease of carrying out the eventual B-ring closure to form tetracyclic compounds is influenced by the nature of the substituent present in the group Ar and that one Cyclization is easier to carry out when the group Ar has a substituent, either in the m-position or elsewhere, which contains the o-position, at which the Cyclization occurs, activated. Substituents which later enable the B-ring closure to be carried out easily, are m-substituents (para to the position of ring closure), which are groups that are in electrophilic aromatic substitution activate an aromatic ring and predominantly o- and p-directing are; for example an alkoxy or hydroxyl group.

If the group Q is an ethylene group, then the 209832/1180 - M> -

Products according to the invention are intermediates for the production of D-homo-steroidsj if Q represents a methylene group, then the products are intermediates for the real steroids with a cyclopentane ring as Hing D. If the end product Y is a ketalized Carbony1 group, then it can be, for example, an ethylenedioxymethylene group = G = (OCHg) ₂ .

The cyclodehydration reaction by means of a basic aldol condensation and dehydration on the correct position for the formation of a ring, which later results in ring C during steroid synthesis easily under conditions suitable for a base-catalyzed aldol condensation reaction.

Weak bases are preferably used or the salt of a strong base and a weak acid, for example Triethylammonium benzoate. If the o-position in the group Ar is not sufficient by a substituent is activated to cause a B-ring closure, the C-ring closure can also be used to form connections, where Y is a carbonyl group, catalyzed by an acid Aldol condensation and Oyclodehydratisierung take place. A suitable acid catalyst is an organic one Sulphonic acid, for example p-toluenesulphonic acid. So

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the desired C-ring closure occurred, where the group Ar was an unsubstituted phenyl group, catalyzed with an acid Cyclodehydration.

Compounds in which Y is a hydroxymethylene group, by selective reduction of the corresponding Compounds in which Y is an oarbonyl group, can be produced, with the carbonyl group mitoc, / MJ unsaturation remains unaffected. This selective reduction can by means of a borohydride, for example with Sodium borohydride. The keto alcohols, which are produced are of particular value because they are used in a later stage of steroid synthesis with a clear stereospecificity for the production of a trans-CD-Ring connection can be hydrogenated.

Compounds in which Y is a ketalized carbonyl group is can by heating the appropriate diketones with an acid catalyst and the right one Amount of ketalizing alcohol (e.g. methanol or ethanol) or glycol (e.g. Ethylene glycol) can be obtained for the mono-ketalization. The ketalization is preferably carried out on the Group Y. The ketoketals so obtained can converted back to diketones by acid hydrolysis

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will. Compounds in which Y is a group, which can be converted to a hydroxymethylene group can, by esterification of the corresponding compound in which Y is a hydroxymethylene group, for example by acetylation or benzoylation, can be obtained. These derivative compounds can be converted to keto alcohols by hydrolysis.

The products of the invention are in total synthesis of the steroids, as outlined above, are of great value as intermediates.

The compounds of the present invention are represented by the following Examples explain the temperatures in ° Celsius and pressures in mm of mercury. Infrared absorption data relate to the location of the maxima in cm "and relate to ultraviolet absorption data refer to the maxima in mu with numbers in brackets indicating the molecular extinction coefficients at these Specify wavelengths.

Starting materials are mainly in the German patent application S 70439 IVb / 12p by the same applicant described

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179361?

example 1

8.2 g of triketone 2- (6 ^I -m-methoxyph. ^{Enyl-3 l} -oxohexyl) -2-methyl-eyclohexan-1,3-dione (VIII) was in xylene for 24 hours with 3.5 g of benzoic acid and Heated 2.9 ml of triethylamine to reflux using a Dean-Stark water separator. The cooled solution was diluted with ether, washed and dried. Distillation of the product gave 6.5 g of the diketone 5- (2'-m-methoxyphenylethyl) -9-methyl-A'-octaline-1,6-dione (IX ) as a viscous oil with a boiling point of 185 to 195 ° / O, 0.5 mm; Ultraviolet Absorption: 251 (10,000).

Example 2

28 g of the crude triketone 2-methyl-2- (6'-phenyl · - ^ ¹ -oxohexyl) -cyclohexane-1,3-dione were for 24 hours in 162 ml of xylene with 9.9 ml of diethylamine and 11.95 g of benzoic acid refluxed using a Dean-Stark water separator. The cooled solution was diluted with ether, washed and dried. Distillation of the product gave 15 g of the diketone 9-methyl-5- (2-phenylethyl) -A ⁵ ' ¹ ° -octalin-1,6-dione as a viscous oil with a boiling point of 184 ° / 0.05 mm | TJltraviolet absorption: 253 (9500).

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Example 3

5 f 5 g of 8-ethyl-5 »6,7,8-tetrahydroindane-1,5-dione (Boyce and Whitehurst, J.Ghem. Soc. , 1959, 2022) in 30 ml of benzene was potassium tert .-Butoxide (based on potassium 1.45 g) in 150 ml of benzene was added under dry nitrogen. The benzene-tert-butanol azeotrope was removed using a Fenske fractionation column with a variable vent. The remaining benzene solution of the potassium enolate was cooled to room temperature and 8 g of 2-m-methoxyphenylethyl bromide (Collins and Smith, J.Ohem. Soc , 1956, 4308) in 50 ml of benzene was added dropwise in 15 minutes, after which the mixture was stirred for 1 hour, then refluxed for an additional hour. The product was treated with ether and evaporation of the ether extract gave a resin residue which was distilled, a fraction yielding 2.1 g of the product having a boiling point of 160-190 ° / 0.05 mm. This product was the diketone 4- (2'-m-methoxyphenylethyl) -8-methyl-5,6,7,8-tetrahydroindane-1,5-dione, a viscous oil which contained some impurities; Ultraviolet absorption: (8300) j Infrared absorption: 1740, 1660, 1605, 1590, 780 and 698. The structure of this diketone was confirmed by a further cyclization to give (-) 8,14-bi8dehydroestrone methyl ether.

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Example 4

To the crude triketone 2- (6'-m-Metho: xyphenyl-3 ^f -oxohexyl) -2-jaethylcyclopentan-i j3-dione (XXVI) 16.5 g) in 120 ml of xylene, 7.1 g of benzoic acid and 5 , 9 ml of triethylamine added. The mixture was refluxed using the Dean-Stark separator for 6 days and then cooled, ether added and the solution washed, dried and evaporated. The resulting resin was taken up in a mixture of mineral spirits and benzene and chromatographed on neutral alumina. The bleeding with a benzene-ether mixture gave 12.2 g of the ethylenic diketone 4 - (2 ^! -M-methoxyphenylethyl) -8-methyl-5,6,7,8-tetrahydroindane-1,5-dione; Ultraviolet Absorption 248 (8500).

Example 5

0.74 g of the crude triketone used as the starting material in Example 4, the treatment was carried out as described above, but using 20 ml of xylene and 0.50 g of aluminum tert-butanoate. The product was treated with ether and chromatographed as before. Blution of the column with Ether, which contained a small amount of benzene, gave 0.11 g of 15% ethylenic diketone infrared absorption: 1740, 1660.

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Example 6

3.8 g of 2-methyl-2- (6 ^l -phenyl-3 ^l -oxohexyl) -cyclopentane-1,3-dione, 1.9 g of benzoic acid and 1.6 ml of triethylamine were dissolved in 30 ml of xylene and for 72 Refluxed for hours using a Dean-Stark water separator. The cooled solution was diluted with ether, washed with water, then with acid, and dried. After evaporation of the ether, a resin remained as residue, which was taken up in 10 ml of light gasoline and the solution was chromatographed with neutral clay. After elution with light gasoline, further bleeding with a mixture of light gasoline and benzene, a fraction was obtained which contained the desired ethylenic diketone 4- (2'-phenylethyl) -8-methyl-5,6,7,8-tetrahydroindane-1, 5-dione contained as a viscous oil (1.2 g, $ 32); Ultraviolet absorption: 249 ($ 9650 Infrared absorption: 1740, 1160.

Example 7

5.8 g of the triketone 2-methyl-2- (6 ^l -phenyl-3 ^l -oxohexyl) -cyclopentane-1,3-dione was dissolved in 20 ml of benzene with 16 g of p-toluenesulfonic acid using a Dean-Stark separator refluxed, flattened for 2 hours

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another 0.15 g of this acid was added and the mixture as long as refluxed until the theoretical amount of water for a single dehydration was collected, The cooled reaction mixture was diluted with ether and the solution washed and dried. JAfter removing Evaporation of the solvent gave a resin which was then distilled and the ethylene Diketone, boiling point 145 to 150 ° / 0.5 mm, as a pale yellow Resin (5g, $ 87). Ultraviolet Absorption: 249 (9900); Infrared absorption: 1744, 1663.

Example 8

0.55 g of sodium borohydride in 80 ml of ethanol was added to the diketone 5- (2 ^l -m-methoxyphenylethyl) -9-methyl- ^ _l ^ * -octaline-1,6-dione (IX, 3 g) in 80 ml of ethanol 8 ° added. After 12 minutes, excess acetic acid was added and the solution was evaporated to dryness under reduced pressure. 75% water was added and the product was taken up in ether. The ether solution was washed, dried and evaporated.

Recrystallization of the product from ether gave 2 g of keto alcohol, 5- (2'-m-methoxyphenylethyl) -9-methy1-6-oxo-A ^{5 '10} -octalin-1-ol (XVII, 66 #, melting point 96 up to 97 °;

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(Analysis found: $ 76.2 C, $ 8.2 H; gross formula ^C 20 ^H 26 ° 5 ^requires $ 76.4 G and $ 8.35 H).

■ Example 9

To 12.35 g of ethylenic diketone 4- (2'-m-methoxyphenylethyl) -8-methyl-5,6,7,8-tetrahydroindane-1,5-dione in 500 ml of ethanol while at 0 ° was 1 g of sodium borohydride in 50 ml of ethanol are added for 20 minutes. The mixture warmed to room temperature and was then stirred for 12 minutes. A slight excess of acetic acid was added and the solvent evaporated under reduced pressure. The residue was treated with 60 ml of water and extracted with ether; the extracts were washed, dried and evaporated to give a glassy residue which crystallized on cooling and scratching. 9.4 g of ethylenic keto alcohol 4- (2'-m-methoxyphenylethyl) -8-methy1-5-0X0-5 »6,7,8-tetrahydroindan-1-ol was crystallized from a mixture of light gasoline and di-isopropyl ether with a melting point of 88 to 90 °; Infrared absorption: 3400, 1660? (Analysis found $ 75.7 G, $ 8.0 Hj gross formula G ₁ QHp ₄ O, requiring $ 76.0 G and $ 8.05 H).

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Example 10

6.3 g of 9-methyl-5- (2 ^f -phenylethyl) -A ^{5> 10} -octalin-1,6-dione was dissolved in 315 ml of benzene with 1.5 cc of ethylene glycol and 0.63 g of p-toluenesulphonic acid Refluxed for 4 hours using a Dean-Stark apparatus to remove the water. The resulting solution was cooled, washed, dried and evaporated to give a yellow resin; this was dissolved in mineral spirits and the solution was chromatographed in neutral alumina. The elution with light gasoline was followed by the elution with mixtures of gasoline and benzene and a fraction was obtained which, after evaporation, contained 5.05 g of a ketoketal of the formula 1,1-ethylene-dioxy-9-methyl-5- (2'-phenylethyl) -Δ ⁵ * ° -octalin-6-one gave as a resin; (Analysis found $ 77.2> 0.7.99 ^ H; the gross formula O ₂₁ Hp ₆ O ₅ 77.3 # C and $ 8.0 H); Infrared absorption: 1665, 1170, 750, 700.

Example 11

0.8 g of the diketone 8-methy1-4- (2-phenylethyl) -5,6,7,8-tetrahydroindane-1,5-dione was as in the previous example in 20 ml of benzene with 0.2 ml of ethylene glycol and 0.085 g of p-toluenesulfonic acid kept under reflux. The product was treated as before, in light petroleum

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dissolved and on an activated puller earth chromatograph! Awake elution with light gasoline eluted a mixture of petroleum and benzene, the ketoketal of the formula 1,1-A "thylenedioxy-8-methyl-4- (2'-phenylethyl) -5,6,7,8-tetrahydroindan-5-one (0.54- g), infrared absorption: 1660, 750, 700.

Example 12

The diketone 4- (2'-m-methoxyphenylethyl) -8-methyl-5,6,7,8-tetrahydroindane-1,5-dione (1.15 g) was, as in Example 10, in benzene (28 ml) with ethylene glycol (0.25 ml) and Heated p-toluenesulfonic acid (0.11 g) to reflux and processed as before to give a pale yellow resin (1 g). This was dissolved in light petrol and the Solution on neutral clay, Ehromatographed. The elution was carried out first with mixtures of gasoline and benzene and then with benzene; this latter Solvent eluted the desired ketal 1,1-ethylenedioxy-4 ~ (2'-m-methoxyphenyl-ethyl) -8-methyl-5,6,7,8-tetrahydroindan-5-one (0.5 g) »Infrared Absorption: 1660, 1600, 780, 700.

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Example 15

1 g of 2-methyl-2- (6 ^l -m-nitrophenyl-3'-oxohexyl) -cyclopentane-1,3-dione (obtained as described in Example 8 of German patent application S 70 439 ITb / 12 o) was given a 0 , Refluxed 1 g of p-toluenesulfonic acid in 35 ml of dry benzene for 4 hours using a Dean-Stark trap. The mixture was then cooled, diluted with a little ether, washed and dried. On evaporation of the solvent, 0.82 g of a resin which easily crystallized out was obtained as residue. Recrystallization from ethanol gave a diketone with an ethylene bond of 8-methyl-4- (2'-m-nitrophenylmethyl) -5,6,7,8-tetrahydroindane-1,5-dione with a melting point of 101 to 103 °; Ultrared Absorption: 1740, 1660, 1530 and 1360 millimicrons; Ultraviolet Absorption: (in ethanol) 252 millimicrons (18,000).

Example 14

1/2 g of the crude nitro-ethylenic diketone product of Example 13 was dissolved in 45 ml of ethanol - at 18 ° temperature - whereupon 0.05 g of sodium borohydride was added. The mixture was shaken for 5 minutes. The homogeneous solution obtained was left for 6 minutes

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stand for a long time, whereupon the same is acidified with acetic acid and evaporated almost to dryness under reduced pressure became. 35 ml of ether were then added together with water in order to dissolve the inorganic salts present. The organic layer was separated, washed and dried. After evaporation of the solvent and recrystallizing the residue from a mixture Ethyl acetate and light gasoline gave the ethylenic keto alcohol 8-methyl-4- (2'-m-nitrophenylethyl) -5-oxo-5,6,7,8-tetrahydroindanol-1 (0.35 g) having a melting point of 117 to 119 °; Ultrared absorption: 3425, 1650, 1525, 1350 millimicrons; Ultraviolet Absorption (in ethanol): 252 millimicrons (17 060).

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Claims (2)

Claims Substituted octalinone or tetrahydroindanone of the general formula RR in which Ar is an optionally substituted phenyl group with an unsubstituted ortho position, each radical R is hydrogen or an alkyl group with less than 5 carbon atoms, R is an alkyl group with less than 6 carbon atoms, Q is methylene or ethylene and Y. is a carbonyl, hydroxymethylene or a ketalized Oarbony1 group. 2. Substituted octalinone or terahydroindanone general formula 209832/1180 - 27 - ρ
in which R is hydrogen or a hydroxyl group, Q is methylene or ethylene and Y is an oxymethylene, hydroxymethylene or ethylenedioxymethylene group. 209832/1180 ORIGINAL