DE1913375A1 - New benzhydrylidene compounds and processes for their preparation - Google Patents

Description

_Γ ^; ever

Dr .- '. Nq- "'"'"" ■ · ,.' »-...-. I; before: Ki'eisler
nq-Tii-f-- ·; - - ·. ₍ .- _rU iv "U .- ^ ii · ^ ' ^ö P ^{sch
Dipl | t} ^ 'Kn'ln''"beichmannhaus

^Kü 14. MKrz 1969

SCHERICO LIMITED, LUCERNE, SWITZERLAND

NEW BENZHYDRYLIDE COMPOUNDS AND PROCESSES FOR THEIR PRODUCTION

The invention relates to new benzhydrylidene compounds, processes for their preparation and compositions containing such compounds.

The inventive Benzhydrylidenverbindungen are those in which one consisting of two fused, five or six ring carbon atoms-containing hydrocarbon rings constructed bicyclic group by one of its saturated carbon atoms is bonded to a substituted in p- and p ^T-position by a hydroxy or esterified hydroxy group Benzhydrylidengruppe.

The aliphatic carbon atom that connects the two phenyl groups of the benzhydrylidene group, and that at the same time bonded to the bicyclic group through a double bond will be described later in the description often referred to as "the central carbon atom".

The orfindungsgemässen compounds can by general formula I will be illustrated

909848/1389

(D,

wherein R is a lower alkyl group, each R _{1 is} hydroxy or acyloxy, each A is hydrogen, halogen or alkyl, Q is a bicyclic group as defined above, and η is an integer from 0 to 3>.

When A and R are lower alkyl, then including both straight-chain and branched hydrocarbon groups, such as methyl, ethyl, propyl, Isopropyl, η-butyl, tert-butyl, n-aryl, isoamyl, n-hexyl, etc. Methyl is the preferred lower alkyl substituent. The definition of halogen includes P, Cl, Br and J.

The bicyclic hydrocarbon group Q is preferably saturated, but can have one or more double bonds contain. The ring which is not bonded to the benzhydrylidene group can also be aromatic. Q, can by any of its saturated ring carbon atoms to be bound to the benzhydrylidene group. Typical examples of Q are groups belonging to the the following hydrocarbons are derived: [The nomenclature used is in accordance with the Rules adopted by the International Union of pure and applied Chemistry "(Nomenclature, of Organic Chemistry Sections A and B, second addition, Butterworths ,:

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909848/1 389

London, 1966); the first number indicates which ring carbon atom is attached to the benzhydrylidene group]. 2-cis-bicyclo [4.4.0] decane; 3 ~ trans-bicyclo [4.4.0] decane; 3-cis-bicyclo [4.4.0] decane; 2-cis-bicyclo [4.3.0] nonane; 3-cis-bicyclo [4.3.0] nonane; 2-cis-bicyclo [3.3.O] octane and 1-isopropyl-7 Methylunc homologs davonj l- (l, 2, 3, 4-tetrahydronaphthalene); and 1-indane.

The acyloxy groups represented by R can be, for example, from such physiologically applicable acids as monobasic acids, e.g. acetic acid, propionic acid, butyric acid, Isobutyric acid and benzylic acid or of polybasic, organic and inorganic acids such as e.g. Succinic acid, maleic acid, tartaric acid, citric acid, Carbonic acids. Sulfuric acid and phosphoric acid. In the case that the acyl group is from a polybasic Acid, the remaining free acid groups can be converted into salts, e.g. in columns of alkali metals, alkaline earth metals. Ammonia or amines. Preferably R, denotes a lower alkoxy group, e.g. one that has 1 to 6 carbon atoms, for example formyl, acetyl, propionyl, isobutyryl, Valeryl and Caproyl. The acetoxy group is the most preferred acyloxy group.

The compounds according to the invention can be used in several stereoisomeric forms exist. In particular through the Bicyclic hydrocarbon groups are cis and trans isomers possible, with the relative position of the ring substituents is included, such as in cis and trans decalin. Of course, all isomers are encompassed by the application, although the compounds with a cis-bicyclic configuration generally preferred are. - ·. ■ -... ·· ■ · -.--

BATH ORIGINAL

. 909848/1389

The compounds according to the invention can by processes * those known for the production of previously described compounds of similar structure are known are.

A basic way of making the connections is that there is a double bond between the benzhydrylidene group and the bicyclic group des Molecule is introduced., Starting from a compound, which has a saturated bond between the two groups mentioned. The introduction of the double bond can be carried out using known chemical methods. In a preferred method, a Starting compound of the general formula II

Q-Y

A (II),

wherein A, Q, R and η have the same meaning as given above; R _{2 is} a free or esterified hydroxyl group or a blocked hydroxyl group which, under the prevailing reaction conditions, is converted into a free hydroxyl group by spontaneous solvolysis, or a blocked hydroxyl group which is subsequently set free; and X and Y bonded to two adjacent carbon atoms, under the prevailing · "■■ -.

9 0 9 8 4 8/1 389

Reaction conditions are eliminable groups; subjected to an elimination reaction, "in which the Groups X and Y are split off with the formation of a double bond.

Preferably one of X and Y is hydrogen and the other hydroxy * hydrogen or the remainder of an inorganic one or organic acid, or one is hydroxy and the other is an alkoxycarbonyl group, or both X and Y are halogen. Preferred inorganic acid residues are halogen (e.g. chlorine, bromine or iodine), OSOCl and SH., Typical organic acid residues are those derived from lower carboxylic acids such as acetic acid, and the ethoxycarbonyl group is a typical representative for the alkoxycarbonyl group.

As the definition shows, R can be the same Meaning-have as R- .. But preferably R_ is low Alkoxy such as methoxy or another blocked hydroxy group such as tetrahydropyranyloxy. The low ones Alkoxy groups are subsequently converted into free hydroxyl groups using known methods, such as E.g. ether cleavage, whereby the compounds are treated with potassium hydroxide at elevated temperature or with boron trifluoride or aluminum dichloride at room temperature.

Other blocked hydroxy groups such as the tetrahydropyranyloxy group are often under the reaction conditions of the above-mentioned elimination reactions in free hydroxyl groups transferred without the application of special conditions or subsequent ether cleavage. If no such automatic split occurs, can after-

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909848/1389

slow ether splitting, as above for the lower ones Alkoxy groups described, can be used. The free ' Hydroxy groups either directly in the elimination reaction or through the ether cleavage described above can be obtained afterwards using conventional esterification agents by known esterification processes be converted into esterified hydroxyl groups.

Particularly preferred starting compounds of the formula II are those in which one of X and Y is hydrogen and the other is hydroxy. Thus, the compounds according to the invention can be prepared by dehydrating a benzhydrol of formula III

(TII)

(R)

or a benzhydryl carbinol of the formula IV

(IV)

OH

909848/1389

where in the formulas III and IV A, Q, RR _p and η have the meaning given above, are obtained.

The benzhydrols illustrated by the formula III can be obtained, for example, by reacting a reactive derivative of a bicyclic carboxylic acid, in particular an ester or an anhydride or Acid halides, with two moles of a p-substituted phenylgrignard compound (VI) as follows:

Reaction scheme A; .

(R) _ Q COOR ^ + 2

\ S — Mg.hal—> Magnesium complex (V) (VI) Benzhydrol (III)

wherein A, Q, R, R and η are as defined above, hai Means chlorine, bromine or iodine and R is a lower alkyl group.

The Grignard compounds of the formula VI can in a known manner by reacting a compound of general formula VII

shark (VII)

with magnesium (magnesium shavings) in an ether, e.g. Diethyl ether or tetrahydrofuran. If R is a hydroxy or acyloxy group, the desired would be The reaction is likely to proceed, only an unnecessarily large amount of Grignard reagent would be consumed.

9098 48/1389

The magnesium complex represented by Reaction Scheme A is obtained can be converted into the desired benzhydrol in the usual way, for example by adding of water or dilute acid (e.g. dilute hydrochloric acid) or aqueous ammonium chloride solution.

Although the benzhydrol can be isolated and purified, these work steps are not necessary to the compound for the preparation of the benzhydrylidene compounds to be able to use. It is enough to remove the benzhydrol from the aqueous with an organic solvent Extract reaction solution. Suitable solvents are e.g. higher aliphatic alcohols, ethers, ketones, Hydrocarbons and halogenated hydrocarbons. The preferred solvent is diethyl ether. The extract is evaporated and the residue is used directly as the starting compound for the preparation of the invention Benzhydrylidene compounds are used. If desired, the benzhydrol can be isolated and purified in the usual way, e.g. by recrystallization.

The benzhydrols of the formula III can also be obtained by adding a benzophenone (VIII) with a bicyclic, see compound substituted in the ring by halogen is (IX), reacts with two moles of a reactive metal as follows:

" ^δ " ν 9 0 & 848 / Ϊ38

MAR-6-1969 945-FTG-9 SK / Je

Reaction scheme B:

A 4- Q-hai + 2M-} metal complexes

Benzhydrol (ill)

(IX)

where M is a reactive metal such as sodium or lithium (or butyl-lithium) ', and A-, Q, R, - R _? , hai and η have the meanings given above. This condensation reaction is carried out in a solvent suitable for reactive metals, for example liquid ammonia or ether.

The complex obtained can be decomposed in the usual way e.g. by adding ammonium chloride and water. Then it is extracted with ether. The ether extract can be poured into a strong acid and the aqueous layer is then mixed with aqueous Sodium chloride solution extracted. The benzhydrol obtained can be recovered and dehydrated as described above will.

As a variant of the above reaction, the compound IX can be in the form of a Grignard compound are used (which is prepared analogously to compound VI);

90 9848/138 9

(R)

A + 2 Q - Mg. Hai— - ^ Magnesium complex

Benzhydrol (ill)

(X)

wherein A, Q, R ,. R. hai and η have the meaning given above to have. The magnesium complex can, as indicated above, be worked up.

The benzhydryl carbinols of the general formula IV can be prepared by processes analogous to those described above getting produced. For example, using the method in Reaction Scheme B, a bicyclic ketone can be mixed with the corresponding ρ, ρ'-substituted diphenylmethylhalogen compound or the corresponding p, p'-substituted Diphenylmethane in the presence of two moles of a reactive metal are implemented. These benzhydryl carbinols can processed and dehydrated as above given for the benzhydrols III. An example of the preparation of such benzhydryl carbinols is given in Reaction Scheme C:

Reaction scheme C:

Metal complex

Benzhydrylcarbino]

(XII)

(A, R, R, M and η are as defined above).

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90984 8/1389

The garbinols of the formula III and IV can be increased by heating at normal pressure or reduced pressure the corresponding benzhydrylidene compounds are dehydrated. Dehydration can be done by adding different reagents can be accelerated, e.g. by sulfuric acid, phosphoric acid. Phosphorus pentoxide in boiling benzo. Alkali metal bisulphates such as sodium and potassium bisulphate, sodium pyrosulphate, iodine in xylene, etc. Dehydration can also be carried out in aqueous or alcoholic alkali solutions, e.g. of sodium or potassium hydroxide, carried out «or with the help of cerium corresponding lower potassium or sodium alkoxylates.

The inventive Benzhydrylidenverbindungen can be isolated in a customary manner, for example, be further purified by distillation at a pressure of 0.001 to 5 turn Hg, preferably can at a pressure between ₁ O Ol to about 0.2 mm Hg. The product by repeated precipitation or by recrystallization.

The dehydration is illustrated by the following reaction scheme:

Reaction scheme D-

(R)

or the corresponding compound of F ⁷ "r ~ cl IV

I) ¹ IrVIrAt £ E ~. runc:; :::. ittel

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909848/1389

(I ¹ ) "

The compounds of the formula I obtained are _'5 if R_ has the same meaning as R, in formula I, ₅ is identical to the novel compounds of the formula I.

If R ₀ in the formula I 'is a blocked hydroxy

^ man
group is * I must subject the compound of the formula I to the further treatments mentioned above. · in order to obtain the desired products of the formula I.

In addition to the carbinols described above, many other compounds can be subjected to such an elimination reaction. The reaction schemes given below (in which A, RR _p, Q and η are as defined above) illustrate some examples of such starting compounds _} as well as reagents which cause the desired elimination of the respective X and Y groups.

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909848 / 1-3

Reaction scheme E:

(R)

(XVII)

Reaction scheme F:

(XVIII)

Reaction scheme G-:

Heat or strong base e.g. sodium methoxide) \ I '

Elimination of acetic acid.

Oxidation (e.g. with SeO, in pyridine or with mo- ' lekulareti oxygen and a strong base in alcohol

(XIX)

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Reaction scheme H:

(r:

(e.g.

Strong base

(XX) Reaction scheme K:

(R)

S Cl

Strong base

(e.g. sodium methoxide) \.

n.

(XXI)

Reaction scheme L:

(Rl

^H 2 ^S0 4

(or Florisil, or Alumina * or Heat)

(XXII)

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MAR-6-1969

945-FTG-15 SK / each

The starting compounds XVII to XXII and other compounds of the general formula II which have a similar structure can be prepared by known methods. Some of these processes are described in Examples 5-6, 8, 9 and 18 which follow.

De reagents necessary for the elimination of X and Y in Schemes D, E _; P, G, H, K and L can be replaced by other suitable reagents which can cause the same reaction. For example, instead of sodium methoxide in reactions E.H. and K, another strong acid, such as sodium amide, can be used.

Another basic way of making the inventive wetting Prebond is a compound that has the central carbon atom as well bound to this contains two of the three ring systems of the desired compound and a first reactive group, condensed with a compound. the third ring system, the desired connection as well as, to this bonded, contains a second reactive group ,, being with elimination of the two reactive groups desired connection is formed. The reaction schemes M and N give examples of such condensation reactions.

9098A8 / 1389

Reaction scheme M:

(R)

η
(XXIII)

Reaction scheme N:

(xxrv)

A +

Strong Base A (see above)

(R) _n β

(N-bromoacetamide) (N-bromosuccinimide)

In the above reaction schemes, A, Q, R are R, and η as defined earlier. U and V are reactive groups which can be eliminated under the reaction conditions used. U and V can both be monovalent (typical example are two halogen atoms, preferably iodine) or both diva

lente (e.g. one 0 and the second <T ^^) groups.

Another fundamental way of producing the inventive Compounds consists in that a compound which is different from a compound of the formula I ' only differs in that at least one of the different ring systems of the molecule is replaced by an additional Substituents is substituted, is subjected to an elimination reaction, the mentioned additional Substituent is removed.

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Typical representatives for the additional substituents are groups such as COOR, -S- and keto. Reaction schemes 0., P and Q give examples of such elimination reactions.

Reaction scheme O:

, S.

(R) _n - 4

A reduction

(XXVII)

Reaction scheme P:

reduction

(XXVIII)

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909848/138

1β

Reaction scheme Q:

COOR

hydrolysis

COOH

Decarboxylation *,

In the above formulas, A, Q, R, R and have η has the same meaning as above. - · '* ·.

In the reactions, illustrated by the reaction schemes 0 and P _s , any reducing agents can be used which are capable of converting -S- to SH ₂ or keto to CH. to reduce.

Preferably, the reduction in Reaction Scheme 0 is carried out using hydrogen and Raney nickel. The reduction methods, known under the names Clemmensen and Wolff-Kishner, are the preferred methods

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9098A8 / 1389

drive for the reduction of the keto group (reaction scheme P). The keto group can also be eliminated by first reducing the keto group to a hydroxyl group , replacing the hydroxyl group thus obtained with halogen and then removing this by hydrogenation.

The starting compounds XXVII, XXVIII and XXIX as other starting compounds of the same structure can also be prepared by known processes. Some of these procedures are described in Examples 12, 13, 17 and 19.

Another fundamental way of preparing the compounds according to the invention is that a starting compound which differs from a compound of the formula I ¹ only in that one of the rings in the bicyclic group is broken at one point, the two being the breaking point adjacent carbon atoms are each substituted by a reactive group, is subjected to an intramolecular condensation, the two reactive groups being eliminated.

The preferred starting compounds in this group can be illustrated by the general formula XXXI will

909848/1389

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ZO

113375

(XXXI),

where A, R, R _p and η are as defined above., m is 0 or 1, ρ and q are each an integer from 0 to 4, but the sum ρ + q must be J5 or 4, and T and Z are reactive groups which can be eliminated under the reaction conditions. Preferably T and Z are both halogen. Reaction scheme R gives an example of such an intramolecular condensation:

Reaction scheme R:

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As already mentioned, the bicyclic group of compounds of the formula I contain one or more double bonds. If so desired, unsaturated ones To prepare compounds of formula I, the preparation processes listed above, illustrated by Reaction Schemes D through R, can be used, where the corresponding unsaturated starting compounds are used. On the other hand, it can be manufactured in this way unsaturated compounds of the formula I subsequently into the corresponding saturated compounds are converted using conventional hydrogenation processes.

The invention is illustrated further with the aid of the following examples.

9098A8 / 1389

Example 1 ·

Preparation of 2- (p _J , p'-Dihydroxybenzhydryliden) -cisbicyclo [4.4.0] decane and its diacetate

To an arignard connection, made from 3 * 8 g Magnesium (0.16 mol) and 26.2 g p-bromoanisole (0.14 mol) in 100 ml of dry ether, 11.6 g of methyl cis-bicycloC4.4.0] decane-2-carboxylate are added dropwise with vigorous stirring (0.06 mol), dissolved in 100 ml of dry ether. After the addition, the reaction mixture becomes Maintained under reflux for 1 hour with stirring at room temperature and then for 1 1/2 hours. The reaction mixture is then cooled and, after adding ION sulfuric acid, stirred overnight.

The ether layer is separated off and extracted three times with a saturated sodium chloride solution, then dried over anhydrous sodium sulfate and evaporated to dryness. After distillation at 220 ^° C. and a pressure of 0 ^ 3 mm Hg, 13 g of a product are obtained which solidify to a glass-like mass.

5> 8 g of the product obtained, 2- (p, p'-dimethoxybenzhydrylidene) -cis-bicyclo- [4.4.0] -decane, (0.016 mol) is added together with 5 * 8 g of sodium hydroxide and 30 ml of triethylene glycol at 210 ° ⁰ C for 4 hours. After cooling, the mixture is poured into water and extracted with ether. The aqueous layer is separated off, acidified with 5N hydrochloric acid and then mixed with ether. The separated ether layer is washed with a saturated aqueous solution of sodium chloride until a neutral reaction is achieved and then over anhydrous sodium

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9098Λ8 / 1389

913375

sulfate dried. The solution is evaporated to dryness and the residue is dissolved in chloroform. After treatment with activated charcoal and crystallization, 4.8 g of 2- (p, p '-dihydroxybenzliydrylidene) -cisbicyclo [4.4.0] decane, PP 54 ° C. are obtained.

30 ml of acetic anhydride and a drop of sulfuric acid are added to 3.0 g of this product (O _{3 009 mol).} The mixture is heated in a water bath for 30 minutes and then poured into water. After extracting twice with ether, the combined ether layers are extracted twice with a saturated aqueous sodium bicarbonate solution. The ether layer is dried over anhydrous sodium sulfate and evaporated. After crystallization from alcohol, 1.1 g of the diacetate, PP 111 ° C, are obtained

Example 2

Production of l-methyl-2- (ρ, ρ'-dihydroxybenzhydrylides) trans ~ bicyclo- [4.4.Ö] -decane and its diacetate

To a Grignard compound made from 52.5 g p- (2-Tetrahydropyranyloxy) bromobenzene (0.2 mol) and 4.3 g of magnesium (0.2 mol) in 500 ml of tetrahydrofuran 8.4 g of methyl 1-methyl-trans-bicyclic QC4.4.Ö3decan-2-carboxylate are added dropwise with vigorous stirring in the cold (0.-04 mol), dissolved in 100 ml of tetrahydrofuran, added. After the reaction mixture 16 hours Left to stand at room temperature, it will treated with a small amount of water. The resulting gel is filtered off and the filtrate becomes ether added. The mixture is washed well with water and the ether layer then becomes an ION Added sulfuric acid and stirred overnight. Thereafter

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9 09848/1389

it is washed with a saturated aqueous solution of sodium chloride until neutral and then dried over anhydrous sodium sulfate. The solution is evaporated to dryness. To Crystallization gives l-methyl-2- (p., P'-dihydroxybenzhydrylidene) -trans-bicyclo £ 4.4.0] decane.

2 * 3 S (OjOO66 mol) of this product becomes 12 ml Acetic anhydride is added and a drop of sulfuric acid is added to the mixture. After 30 minutes Heating on a water bath is cooled to room temperature and poured into water. The reaction mixture will twice with ether and the combined ethereal layers twice with saturated aqueous sodium bicarbonate solution extracted. After drying over anhydrous sodium sulfate, it is evaporated. The diacetate obtained in this way is dissolved in alcohol, treated with activated charcoal and brought to crystallization.

In a manner similar to that in Examples 1 and 2, other compounds according to the invention can be prepared by using the corresponding bicyclic carboxy esters as starting compounds, such as, for example: methyl cis-bicyclo [4.3-0] nonane-2-carboxylate; 'Ethyl-cis-bicycloQ ⁱ ! -. 4.0] decane-3-carboxylate; Methyl-trans-bicyclo [4.4.Q] decane-3-carboxylate. Methyl-1-methyl-trans-bicyclo [4.4.0] decane-2-carboxylate. Isopropyl-cis-bicyclo C4.3.0! Nonane-9-carboxylate.

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Example 3

Production of 3- (p ^ P'-Dihydroxybenzhydryliden) -cisbicyclot3 ° 3 ° Ö] octane and its diacetate

Of 10.5 g of lithium chips _(l: 5 moles) and 102.8 g Butylbroraid (0.75 mole) in 500 ml of dry ether is prepared first butyllithium at -10 ^0C. A solution of 11.4 g of di-p-methoxyphenylmethane in 400 ml of dry tetrahydrofuran is then added to this reagent with stirring. After one hour at -10 ° C., 62 g of cis-Bicyclor30-03 octan-3-one in 200 ml of dry tetrahydrofuran are added and the mixture is stirred at room temperature overnight. Then water is added and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness.

To 20 g of the carbinol thus obtained in 200 ml of dry Pyridine is added 5 * 2 ml of thionyl chloride with cooling in an ice bath. The mixture is then refluxed for 2 hours. After cooling, 50 ml of one are added Add 50% sodium hydroxide solution and reflux again for 3/4 hours. Then the. Poured reaction mixture into ice water and extracted with ether. The ether layer is washed with water, to remove the pyridine and then evaporated. That product obtained is crystallized from alcohol.

3.7 g of the 3- (ρ ^ Ρ * -Dimethoxybenzhydryliden) -cis-bicyclo £ 3-3-octane obtained in this way are together with 4g sodium hydroxide and 16 ml triethylene glycol at 210 ° C for 4 hours long stirred. After cooling, the mixture is poured into water poured and extracted with ether. The aqueous layer is acidified with 5N hydrochloric acid and mixed with ether Aether layer is saturated with a watery

809 8.4 8/1389

Solution of sodium chloride washed until neutral and dried over anhydrous sodium sulfate. After the solution has evaporated to dryness * by recrystallization 3- (ρ ^ Ρ * -dihydroxybenzhydryliden)

To 2 g of this product (0.006 mol) are added 12 ml of acetic anhydride and added a drop of concentrated sulfuric acid. The mixture will be for 30 minutes Heated for 30 minutes on a water bath, cooled to room temperature and poured into water. After two extractions the combined ethereal layers are treated twice with a saturated aqueous sodium bicarbonate solution with ether extracted. The ether layer is then dried over anhydrous sodium sulfate and evaporated. The diacetate thus obtained is dissolved in alcohol, treated with activated charcoal and crystallized out.

Example 4

Preparation of 2- (p, p ^> -dihydroxybenzhydryliden) -transnicyclo [4.4.0] decane and its diacetate

2151 g of sodium metal (0.11 mol) is in liquid Dissolved ammonia. To this solution are added 12, Ig (0.05 mol) Di-p-methoxybenzophenone in 75 ml of ether added. To Stir for 15 minutes, 8.67 g of 2-chloro-trans-bicyclo C4.4.03 decane (0.05 mol) mixed in with ether. The mixture is stirred for a further 4 hours and left to stand overnight. Then 5 * 4- S ammonium chloride (0.1 mol) is added and the ammonia evaporates. After treatment with water, the mixture is made with ether extracted and the ether layer is in ION. Poured sulfuric acid and stirred overnight.

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9 0 9 8 4 8/1389

The ether layer is separated and extracted three times with a saturated aqueous sodium chloride solution. The separated ether layer is dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization from alcohol gives 2- (p, p'-dimethoxybenzhydrylidene) -trans-bicyclo £ 4. H. OU decane (0.02 mol).

7) 2 g of this compound are stirred together with 6 g of potassium hydroxide and 25 ml of triethylene glycol at 210 ⁰ G 4 hours. After the mixture has cooled, it is poured into water and extracted with ether. The aqueous layer is acidified with 5N hydrochloric acid and mixed with ether. The separated ether layer is washed with a saturated aqueous solution of sodium chloride until a neutral reaction is reached and dried over anhydrous sodium sulfate. After evaporation to dryness and recrystallization, 2- (p _J p'-dihydroxybenzhydrylidene) -trans-bicyclo Q4.4.Oldecane is obtained. 2 g (0.0066 mol) of this compound are mixed with 12 ml of acetic anhydride and a drop of concentrated sulfuric acid and the mixture is heated on a water bath for 30 minutes. After cooling to room temperature, the mixture is poured into water and extracted twice with ether. The combined ether layers are extracted twice with a saturated aqueous sodium bicarbonate solution and then dried over anhydrous sodium sulfate. The ether is evaporated and the desired diacetate is obtained, which is dissolved in alcohol. = Treated with activated charcoal and crystallized out.

Following a procedure as described in Example 4, other compounds according to the invention can be prepared by using other Halo-ring substituted compounds begins. e.g .:

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909 8 48/1389

2-chloro-cis-bicyclo [4.4.0ldecah;
3-chloro ~ 1-methyl-cis-bicycloC4 .. 4.0] decane: 3-bromo-7-methyl-trans-bieyclo | f4.4. Oil decane, · 2-chloro-cis-bieyclo C4 · 3-O] nonanj
3-chloro-8-methyl-trans-bicyclo [4.3.cQnonane; 9-bromo-cis-b-icyclo [4.3-0] nonane and 2-chloro-cis-bicycloI3 »3» O] octane.

When using reagents analogous to those described above Other compounds of the invention may also be made by methods, such as when used other acylating agents, the compounds of general formula I can be prepared in which R ^ a is another esterified hydroxy group, e.g.} 2- (p ^ p'-Dicaproyloxybenzhydryliden) -cis-bicycloC4.4.0] decane; '

2- (p-Acetoxy-p'-isopropoxybenzhydrylidene) -eis-bicyclo Γ4.4.0] decane; and

Disodium 2- (p..p '-dihydroxybenzhydryliden) -eis-bicyclo [4.4.0] decane disulfate.

Example 5 A; Manufacture of 3-

bicyclop'4.4.Ö] decan ■

One solves l8 _; 8 g of phenol (0.2 mol) and 16.6 g of cis-bicyclo [4.4.0] decane -3-carboxyldehyde (0.1 mol) in 350 ml of acetic anhydride, concentrated sulfuric acid is added to this solution with stirring in such a way that the reaction temperature does not exceed 40 ° C. If necessary, a cooling bath must be used. If further addition of sulfuric acid does not cause a further increase in temperature > the addition of sulfuric acid is stopped and the mixture is left to stand for 3 hours. After that it is poured into water,

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the pests are filtered off, dried and recrystallized to give the desired compound.

B. Preparation of 3- [di- (p-hydroxyphenyl) -bromo-methyljcis-bicyclo £ 4.4 · ojdecane; 3- (pjP'-Dihydroxybenzhydryliden) -cis-bicrclo ^r 4.4.0ldecane; and 3- (ρ * Ρ ^Ί -diacetoxy- i benzhydryliden) -cis-bicyclo [4 .4.0] decane

After 3j4g of 3-di- (p-hydroxyphenyl) methyl-cisbicycloC4.4.0] decane (0.01 mol) has dissolved in 30 ml of carbon tetrachloride, 1/8 g of N-bromosuccinimide is added (0.0001 moles). The mixture is heated to reflux until all of the N-bromosuccinimide has reacted, (check with iodine starch paper). After cooling the mixture in an ice bath and filtering off the succinimide, the The solution is evaporated to dryness and the 3-CDI- (p-hydroxyphenyl) -brotn-methyl ^ -cis-bicyclo 0.4.03 is obtained decan.

This compound is dissolved in methanol and II ml of an IN solution of sodium methoxide in methanol is added. The mixture is heated and stirred under reflux for 1 hour, cooled and then treated with water and ether. The ether layer is separated off and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. After recrystallization from chloroform, 3- (p. »P ^l -dihydroxybenzhydrylidene) -cis-bicyclo C4.4.0ldecane, mp 77-78 ° C, is obtained.

To 30 ml of acetic anhydride, 3 g (0.009 mol) of compound obtained above ,. along with a drop concentrated sulfuric acid. The mixture is heated on a water bath for 30 minutes to room temperature cooled and poured into water. After two-

~ ²⁹ ~ 909848/1389

ger extraction with ether, the combined ethereal layers are extracted twice with a saturated aqueous sodium bicarbonate solution and the ethereal layer is then dried over anhydrous sodium sulphate and evaporated. After recrystallization from alcohol, 3- (P / P ^T -Piacetoxybenzhydryliden) -cis-bicyelo £ 4.4.Ö] decane, PP 130-131 ° C. is obtained.

Example 6

Preparation of 3- (pjp'-DiacetoxybenzhydrylidenQ-eisbicyclo f4.4.0] decane

A mixture of 3 »^ g of 3-di- (p-phydroxyphenyl) -methylcis-bicyclo- [4.4.ol-decane (O ₃ mol), 1.3 g of selenium dioxide (0.012 mol) and 25 ml of acetic anhydride is used for 3 hours heated under reflux for a long time - the hot solution is filtered and poured into water. After extracting twice with ether, the remaining ethereal substances are extracted twice with a saturated aqueous sodium bicarbonate solution. The ether layer is dried over anhydrous sodium sulfate and evaporated to dryness. After recrystallization from alcohol, 3- (p * p'-I> iaeetoxybeiizhydryliden) -cis-bicycloP {-. 4.q3 decane, PP 130-131 ° C. is obtained.

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Example 7

Preparation of 3-EPi- (p-methoxyphenyl) -ethoxycarbonyl] -methyl-3-hydroxy-cis-bicyclor4.4.0ldecane, 3- (p ^ p'-dimethoxybenzhydryliden) ^ cis-bicyclo [4.4.ö * jdecan and 5 - (p * P'-Dihydroxybenzhydryliden) -cis-bicyclo £ 4.4.Ojdecane

30 g of ethyl di (p-methoxyphenyl) acetate (0.1 mol) are used dissolved in 500 ml of methanol and under a nitrogen atmosphere 5% sodium methoxide (0.1 mol) are added with stirring. Then 15.2 g of 3-keto-cis-bicyclo [4.4.0] add decane (0.1 mol) in 100 ml of methanol dropwise. After stirring for three hours, it is evaporated to about 50 ml. Water and ether are added and the separated ether layer is washed with water and over anhydrous Dried sodium sulfate. After evaporation, 3- {pi- (p-methoxyphenyl) ethoxycarbonyl] C 1 -C methyl-3-hydroxy-cis-bicyclo [4.4. CO decane.

22.6 g of this compound (0.05 mol) are dissolved in 250 ml of methanol and a solution of 2.7 g of sodium methoxide (0.05 mol) in 100 ml of methanol is added. After heating under reflux and under a nitrogen atmosphere for five hours, the mixture is evaporated to 50 ml, water and ether are added and the ether layer is separated off. Dis. ^ S is washed with water and dried over anhydrous sodium sulfate. After the solution has been evaporated to dryness, ^ - ^, p'-DimetiioxybenzhydrylidenJ-cis-bicyclo [4.4.Ö] decane, PP 102 ° C, is obtained by recrystallization from alcohol.

In an ether cleavage as described in Example 1 becomes the desired 3- (ρ * P'-dihydroxybenzhydrylidene) -eis-bicyclo from the above compound C4.4.CQdecane obtained.

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Example 8 Production of 2- (di- (p-methoxyphenyl) -hydroxy | -methyl-

cis-bioyolol4.4.0ldecanj 2-iDi- (p-methoxyphenyl) - chlor sulfiti-methyl-cis bicyclo | 4,4., Oldecanj .2- (p , P '-Dimethoxybenzhydryliden) -eis bicyclo 14.-4.Ol decane; and 2- (pjp ^T -dihydroxybenzhydryliden) -cis-bicyclo 14.4. Oldecane

To a Grignard solution * made from 3j8 g of magnesium (0.16 mol) and 26.2 g p-bromoanisole (0.14 mol) in 100 ml 11.6 g of methyl cis-bicyclo | 4.4.0 | decane-2-carboxylate are added dropwise to dry ether with vigorous stirring (0.06 mol) dissolved in 100 ml of dry ether, added. After everything has been added the mixture becomes Stirred for one hour at room temperature and then heated to reflux temperature and for more Stirred for 1 1/2 hours. After cooling, the mixture is poured into water, the ether layer is separated off, extracted with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated, with 2- | Di- (p-methoxyphenyl) -hydroxy I methyl-cis-bicyclo ^^. Oldecane receives. 3 * 8 g of this Compound (0.01 mol) are dissolved in 50 ml of petroleum ether and this solution is added dropwise over 2 hours

-32-

9098A8 / 1 389

wise to a solution of 2.4 g of thionyl chloride (0.02 mol) in 25 ml of petroleum ether was added with vigorous stirring at -20 °. Thereafter, most of the hydrogen chloride formed is removed under vacuum and after the Mixture has stood for several hours at room temperature * the petroleum ether and the excess of thionyl chloride at room temperature with the help of a 'water pump removed. 2- [Di- (p-methoxyphenyl) -chlorosulfite} -methyl-cis-bicyclo [4.4.0] decane is obtained.

4.4 g of this compound (0, Ol mol) are dissolved in 50 ^m l of petroleum ether and added to a solution of 2.2 g of sodium methoxide (0.04 mol) and 25 ml of methanol with stirring at ⁰ ° C. After stirring for two hours, water is added and the organic layer is separated. The organic layer is washed with water and evaporated to dryness. After vacuum distillation, 2- (ρ, ρ'-dimethoxybenzhydrylidene) -eis-bicyclo [4.4.0] decane, SP 220 ° σ / 0.3 mm Hg.

This compound can be subjected to an ether cleavage, as described in Example 1, and one receives the 2- (p, p'-dihydroxybenzhydryliden) -cis-bicyclo [4.4. Oj decan.

Example 9

Production of 3-CDi- (p-hydroxyphenyl) -thiol] -methylcis-bicyclo £ 4.4.03decane, and 3- (p _J p'-dihydroxybenzhydrylidene) -cis-bicyelo [4.4.0] decane

With a solution of 4.2 g of 3-CDi- (p-hydroxyphenyl) -bromo] -methyl-cis-bicyclo- [4.4.0] -decane (0.01 mol) in 50 ml of petroleum ether is passed through hydrogen sulfide for 1 hour and then the mixture is left to stand for 3 hours. Evaporation to dryness gives 3- [di- (p-hydroxyphenyl) -thiol] -methyl-eis-bicyclo £ 4.4.0] decane.

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3.7 g of this compound "(O ₅ Ol Mol) are in 50 ml
Dissolved ether, while cooling, ION becomes sulfuric acid
added and the mixture is stirred at room temperature overnight.

The ether layer is separated and treated with a saturated aqueous sodium chloride solution until it is more neutral
Reaction washed and dried over anhydrous sodium sulfate. After evaporation to dryness, the residue is dissolved in chloroform, treated with activated charcoal and crystallized to give 3- (p, p'-dihydroxybenzhydrylidene) -cis-bicycloC4.4.0] decane, PP 77 -

Example 10

Preparation of 3- (pjP'-Diraethoxybenzhydryliden) -cisbicyclo [4.4 .. CQ decane _;

22 ₃ 8 g of di-tp-methoxyphenyl methane (O ₃ I mol) are dissolved in 400 ml of dry alcohol and added to this solution
5, ^ S sodium methoxide (0.1 mol) are given. to
this mixture becomes a solution of while stirring at reflux temperature and under a nitrogen atmosphere
15.2 g of 3-keto-cis-bicyclop · .4.0] decane (0.1 mol) in
100 ml of dry alcohol were added dropwise, and the mixture was stirred under reflux for a further 8 hours.
The solution is evaporated to about 50 ml and mixed with water and ether. The ether layer is separated off, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. To. Recrystallization from alcohol gives the desired compound. PP 102 ⁰ C. - - '.

After an ether splitting, as described in example Γ, one arrives at the corresponding ρ, ρ'-dihydroxy compound. ·

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Example 11

Preparation of 3-a ^ 0L-Dit) rom-p-methoxyben2ylHcis- bicyclo I ~ 4.4. Qj decan; ~ 5-a, α-Di j od-p-methoxybenzy 1 -c is bicyclo £ 4.4.0] decane; 3- (α-iodine-p-methoxybenzylidene) -eis bicycloC4.4.oldecane; and 3- (PjP'-Difflefchoxybenzhydryli- ^ den) -cis-bieyelo C4. 4. Ol decane

3 * 6 g of N-bromosuccinimide (0.02 mol) and 0.024 are added to a solution of 2.6 g of 3-P-methoxybenzyl-cis-bicyclo L4.4.Ö] decane (0.01 mol) in 30 ml of carbon tetrachloride g benzoyl peroxide (0.0001 mol) added. The solution is heated under reflux until the N-bromosuccinic imide has reacted (check with iodine starch paper). The solution is cooled in an ice bath, excess succinimide is filtered off and 3-ct, a-dibromo-p-methoxybenzyl-cis-bicyclo H4.4.0] deean is obtained by evaporation to dryness. 4.2 g of this compound (0.01 mol) are dissolved in 100 ml of acetone, and 23.0 g of sodium iodide are added. After refluxing for two hours, the mixture is filtered off and diluted with 100 ml of water. The thereby precipitated 3-a _i-a-p-Di3od methöxybenzyl-cis-bicyclo £ 4.4.o3decan is filtered off and dried. 1.1 g of sodium carbonate (0.01 mol) are added to a solution of 5.1 g of this compound (0.01 mol) in 100 ml of acetone and the mixture is stirred overnight, 100 ml of water are added and the 3- ( <*, Iodine-p-methoxybenzylidene) -cis-bicyclo £ 4.4. Ol decane is filtered off and dried.

3.8 g of this compound (0.01 mol) are mixed with 2.3 S p-iodoanisole, and then 3 g of copper powder are added in small portions with stirring at 190 ⁰ C. After two and a half hours of heating to 190 ⁰ C, the temperature is increased to 240 ° C and held there for another two and a half hours. After cooling, the mixture is extracted with hot benzene. The benzene will

909848/1389

evaporated to dryness and after Ümkristallisierung from alcohol gives 3- (PJP ^T -Dimethoxybe.nzhydryliden) -cisbicyclot: 4.4.0 * | decane, PP 102 ⁰ C.

After an ether cleavage, the corresponding ρ, ρ'-dihydrox-y compound is obtained, which, if desired, in one following step to a corresponding ρ, ρ'-di-ester compound can be esterified.

Example 12

Preparation of 2- (p, p'-Dihydroxybenzhydryliden) -4-ketobicyclof: 4.4.0ldeca-5 (6) -en

To a Grignard solution made from 52.5 g of p- (2-tetrahydropyranyloxy) bromobenzene (0.2 mol) and 4.83 g of magnesium (0.2 mol) in 500 ml of tetrahydrofuran are added dropwise with vigorous stirring 10.7 g of the ethylene ketal des 4-keto-bicycloi.4.4.0jdeca-5 (6) -en-2-carboxylate in 100 ml of tetrahydrofuran dissolved and added. The mixture is left to stand at room temperature for 16 hours and then treats them with a small amount of water. The resulting gel is filtered off. That Ether is added to the filtrate and the mixture is washed thoroughly with water. The separated ether layer is then stirred in ION sulfuric acid overnight “with a Washed saturated aqueous sodium chloride solution until a neutral reaction and then over anhydrous Dried sodium sulfate. The desired product is obtained after evaporation to dryness and recrystallization Product.

9 0 9 8 k 8/1 3 8 9

Example 13

Production of 2- (p _J p'-Dihydroxybenzhydryliden) -4-ketoeis-bicyclo | 14.4.03deean

A solution of 3. »5 S 2- (p, p'-Dihydroxybenzhydryliden) -4-keto-bicycloC4.4.0ldeca-5 (6) -en (0.01 mol) in 100 ml of dioxane is mixed with 0.2 g of 5% palladium-on-charcoal offset. Then it is set to 1 atm. hydrogenated at room temperature until the theoretical amount of hydrogen has been absorbed is. After filtering off the catalyst, the solution is evaporated to dryness and so the desired connection.

Example 14

Production of 2- (p, p'-Dihydroxybenzhydryliden) -oisbicyclor4.4.03decane and its diacetate

A solution of 20 g of sodium in 2 l of diethylene glycol is mixed with 11j2 g of 2- (ρ,? '- dihydroxy-benzhydrylidene) -4-keto-cisbicycloC4.4.0'-decane (0.032 mol) and heated to 180.degree. Freshly made, anhydrous hydrazine is distilled into the reaction mixture until it boils at 180 ° C. After having the mixture kept at this temperature for about l8 hours, hydrazine is sufficient distilled off to the reflux temperature to increase to 210 ⁰ C and at this temperature the mixture is left for another 24 hours. After cooling, the mixture is acidified with hydrochloric acid, adding ether »The separated ether layer is washed with a saturated aqueous sodium chloride solution to washed to a neutral reaction ^ over anhydrous sodium sulfate, _s evaporated to dryness dissolved in chloroform, treated with Activated carbon and allowed to crystallize to give 2 - (p, p'-Di-hydroxybenzhydrylidenJ-cis-bicyclo [4.4.Oj decane, PP 54 ° C.

909848/1389

A mixture of 3 * 0 g (0.009 mol) of this product, 30 ml of acetic anhydride and a drop of concentrated sulfuric acid is heated on a water bath for 30 minutes. After cooling to room temperature, the mixture is poured into water ^ extracted twice with ether and then the combined ethereal layers are extracted twice with a saturated aqueous sodium bicarbonate solution. The ether layer is dried over anhydrous sodium sulfate and evaporated. After recrystallization from alcohol, 2- (p, p ^l -diacetoxybenzhy- · drylidene-cis-bicyclol> .4.03decane, FP

Example 15

Preparation of 2- (p, p'-Dihydroxybenzhydryliden) -bieyclo C4.4.0] deca-5 (6) -en

20 g of sodium are dissolved in 2 liters of diethylene glycol,. ^: , with 11.1 g of 2- (p, p'-dihydroxybenzhydrylidene) -4-keto-bicyclo [4.4.d] -deca-5 (6) -en (0.032 mol) and heated to 180 °. Freshly made anhydrous hydrazine is distilled into the reaction mixture _} until it boils at 180 ° C. After refluxing for 18 hours at this temperature, enough hydrazine is distilled off to raise the temperature to 210 ° C. and this temperature is maintained for a further 24 hours. After cooling, it is acidified with hydrochloric acid and mixed with ether. The separated ether layer is washed with a saturated aqueous solution of sodium chloride until the reaction is neutral and then dried over anhydrous sodium sulfate. After evaporation of the solution to dryness and recrystallization, the desired product is obtained.

909848/1389

Example l6

Preparation of 2- (p ₅ p'-Diacetoxybenzhydryliden) -cisbicyclo [4.4. OH decane

3.3 g of 2- (p, p'-dihydroxybenzhydrylidene) bicyclo [4.4.ö3 deca-5 (6) -en (0.01 mol) dissolved in 100 ml of dioxane are mixed with 0.2 g of 5% palladium-on-activated charcoal is at 1 atm. hydrogenated at room temperature until the theoretical amount of hydrogen has been absorbed. Of the The catalyst is filtered off and the solution is evaporated to dryness. The residue obtained in this way is with 30 ml Acetic anhydride and a drop of concentrated sulfuric acid are added and the water bath for 30 minutes heated. After cooling to room temperature, the mixture is poured into water and extracted twice with ether. The combined ether layers are then treated twice with a saturated aqueous sodium bicarbonate solution extracted. The ether layer is then dried over anhydrous sodium sulfate and evaporated. After recrystallization from alcohol, 2- (p, p'-Diacetoxybenzhydryliden) -cis-bicyeloC4.4.CfI.decane is obtained, P.P. 111 ° C.

Example 17

Preparation of 2- (p, p'-dimethoxybenzhydrylidene) -8-ketocis-bicyclo £ 4,4.Ojdecane _unc j 2- (p, p * -dihydroxybenzhydrylidene ~) - c is-bicyclo [4.4. 0} decan

A solution of 4.9 g of cis-2-'ethoxypropionyl-3-ethoxyacetyl-1 -' (p .p "-dimethoxybenzhydrylidenj-cyclohexane ' (0.01 mol) in 6 ml of xylene is powdered with 7, o g ice-cold Potassium (0.02 mol), suspended in 8 ml of xylene, added. After one hour of heating in a water bath, the excess potassium is destroyed with a few drops of alcohol and then the mixture is four hours heated on a water bath. After the solution to dryness

^ "909848/1389

Was evaporated, it is mixed with a potassium carbonate solution until 'the mixture is alkaline and extracted with ether. The separated ether layer is washed with water, dried over anhydrous sodium sulfate and evaporated, whereby the 2- (p ^ p ¹ -dimethoxybenzhydrylidene) -S-keto-cis-bicyclol ^. ^. Oldecane is obtained.

fine solution of 20 g of sodium in 2 liters of diethylene glycol is mixed with 12 g of the compound obtained above (0.032 mol) and heated to 180.degree. Freshly prepared anhydrous hydrazine is distilled into the reaction mixture until it boils at 180 ° C. After heating at this temperature for 18 hours, enough hydrazine is distilled off in order ^{to increase the reflux temperature to 210 °} C., where the mixture is held for a further 24 hours. After cooling, it is acidified with hydrochloric acid and mixed with ether. The ether layer is washed with a saturated aqueous solution of sodium chloride until the reaction is neutral and dried over anhydrous sodium sulfate. The solution is evaporated to dryness, the residue dissolved in chloroform, treated with charcoal and Activ auskristallieiert to give 2- (ρ, ρ'-Dihydroxybenzhydryliden) -eis-bicycloI4.4.01decan, F. T. 54 ° C are obtained. :

Example l8

Preparation of 2- (c-di-p- met hoxyphenyl-7-keto-pentyl) -cyclohexanone; 2- (Di-p-methoxyphenyl-methyl) -3-keto-bieyclo 14.4.01 desa- " ¹ -en; 2- (Di-p-methoxyphenylmethyl) -3-keto-cis-bicyclo 14.4.Oldecane and 2 - (ρ, ρ'-Diacetoxybenzhydryliden) -cis-bicycloj4.4.0 | decane

A mixture of 22.6 g of 1-N-pyrrolidine-1-cyclohexene (0.15 mol) and 28.2 g of 5-di-p-methoxyphenyl-3-keto-pentyl bromide (0.075 mol) in 50 ml of dry dioxane Heated to reflux for three hours. After cooling, the reaction mixture is poured onto ice and

909848 / Ί389

extracted twice with ether. The combined ether extracts are washed with dilute hydrochloric acid, then with water and then over anhydrous sodium sulfate dried. After evaporation to dryness, the 2- (£ -di-p-methoxyphenyl-7-keto-pentyl) -cyclohexynone is obtained.

A solution of 11.8 g of the compound thus obtained (0.03 mol) in 100 ml of methanol is treated with 5.4 g of sodium methoxide (0.1 Mol) in 50 ml of methanol are added with stirring in a nitrogen atmosphere. After heating for two hours the mixture is cooled under reflux and evaporated to half its volume. After that will be Water and ether are added and the separated ether is washed with water and over anhydrous Dried sodium sulfate. After evaporation to dryness, the residue obtained is 2- (di-p-methoxyphenylmethyl) -3-keto-bicyclo £ 4.4. Ol deca-1-en.

A solution of 3.76 g of this compound (0 _s 01 mol) in 100 ml of dioxane is mixed with 0.2 g of 5% palladium-on-charcoal and at 1 atm. and hydrogenated at room temperature until the theoretical amount of hydrogen has been absorbed. After filtering off the catalyst and evaporation, 2- (di-p-methoxyphenyl-methyl) -3-ketocis-bicyclo C4.4 is obtained. Ö] decane.

After reduction of the keto group, as described in Example 15, the 2- (di-p-methoxyphenylmethyl) -cis-bicycloC4.4.ö3decane is obtained. A further treatment according to the method described in Example 5B gives the 2- (p _J p'-diacetoxybenzhydrylidene) -cis-bicycloL4.4.o3decane.

909 848/1389

Example 19. .

Production of 3- (w, 6-dimethoxy-9-thiaxanthenyilden) - c is-bicyclo ftt- Λ . θ3 decane and 3- (PjP'-Diroethoxybenzhydryliden) -cis-bicycloPJ-.4.Q] decane

Butyllithiura is produced at -IQ ⁰ C from 10.5 g of lithium shavings (1.5 mol) and 102.8 g of butyl bromide (0.75 mol) in 500 ml of dry ether. A solution of 129 g of 2,7-dimethoxy-thiaxanthene in 400 ml of dry tetrahydrofuran is added to this reagent with stirring. After one hour at -10 ⁰ C is treated with 76 g of 3-keto-cis-bicyclo [4.Λ.0] decane in 200 ml of dry tetrahydrofuran, the temperature allowed to rise to room temperature and stirred overnight. After adding water, the mixture is extracted with chloroform and the chloroform layer is then dried over anhydrous sodium sulfate and evaporated to dryness.

25 g of the carbinol obtained in this way are dissolved in 200 ml of dry pyridine and mixed with 5 * 2 g of thinyl chloride while cooling on an ice bath. The mixture is refluxed for two hours and then cooled. Then 50 ml of a 50 # strength sodium hydroxide solution are added and the mixture is heated under reflux for 3/4 hours. The reaction mixture is poured into ice water and extracted with ether. The ether layer is washed with water to remove the pyridine, dried and. evaporated ₃ whereby the 3- (3 * 6-dimethoxy-9-thiaxynthenyriden) -cis-bicyclopj-4.0ldecane is obtained.

To a solution of 1 g of this compound in 250 ml of mesitylene is added at 100 ⁰ C prepariertes fresh Raney nickel. After the methanol has been distilled off from the catalyst mixture, it is five hours

909848/1389

heated under reflux, then ^{cooled to 10O 0} C and filtered. The filtrate is evaporated in vacuo ml to about 50 and the product thus obtained 3- (p>p'-dimethoxy-benzhydrylidenJ-cis-blcyclo [4.4.Öldecan, PP 102 ⁰ C, crystallizes out.

Example 20

Preparation of 2- (p, p ^t -dimethoxybenzhydryliden) -cisbicy clo [4.4.0] decane

0.7 g of sodium is placed in a flask which is equipped with a reflux condenser and a nitrogen inlet (0.03 mol) given in 50 ml of dry ether, and the Mixture is cooled in ice water. 5 »2 g of cis ~ 2,3-di- (β-bromoethylj-1-ipjp'-dimethoxybenzhydrylidenj-cyclohexane (0.01 mol) are slowly added and after the initially stormy reaction has ended, is heated to reflux temperature. After four hours it will the clear solution decanted, evaporated to dryness and distilled in vacuo. 2- (p, p'-Dimethoxybenzhydryliden) -cls-bicycio [4.4.0] decane is obtained, S.P. 220oc / 0.3 mm Hg.

The inventive ρ _; ρ'-substituted benzhydrylidene compounds are valuable anti-progestative (anti-progestational) compounds. The term anti-progestative used in this context does not refer to the stage of the reproductive process during which the compounds exert their effect. Rather, the term anti-progestative refers to the general result, that is, to the prevention of fetal growth. Although the invention is not limited to any particular theory with regard to the biological mechanism or mode of action of the compounds of the invention, it appears that this is the cause of ovulation

909848/1389

prevent * suppress the production of progesterone and / or prevent implantation or nidation.

The compounds of the invention are in the form of a effective dose administered to the female mammal at a time that is several days before the expected Beginning of the sexual period (i.e. menstruation or oestrus) up to about 1/10 of the gestational period of the mammal in question is over, enough. After this time, the inventive Compounds ineffective or lose their effectiveness due to the chemical changes in the female body and / or in the fetus, which in the meantime appeared.

The effective level of action of the compounds according to the invention can easily be determined by known standard methods. One such laboratory technique is the 12-day mating test as described in "The Journal of Endocrinology" (1965), Vol-33, page 242. After this test, the compound suspended in 1 ml of an aqueous carboxymethyl cellulose solution becomes like mature female rats for 11 days. Breeding and administered by tube probe of approximately the same size. During this period these rats are kept together in a ratio of three female to one male - borrowed rat. As a control, other test animals only receive the suspension medium. On the 12th day, the Anzahl.der pregnancies is Off _r · the Nidatlonsorte count determined. The dosage · is ...., Increased or decreased until the smallest effective dose at which none. Pregnancy occurs, is determined ·. ■;.-....-, ^ This dose, measured in _; mg, per kg. Body weight per, day, referred to as. _; the ΜΡΡχο.Ο * (the minimum protective dose) for $ 100 for the test animals. -,

.909848 / 1389

The following table gives the results of this Tests again, in which two of the compounds according to the invention and two of the known compounds are more similar Structure (described in U.S. Patent No. 3287397) have been studied:

Connections MPD ^ qq

ρ, ρ'-dihydroxybenzhydrylides

cyclohexane. ,. 50

ρ, ρ'-diacetoxybenzhydrylides

cyclohexane 50

2- (p ₃ ρ'-dihydroxybenzhydrylidene) -cis-

b icy clo-Γ4.4.0] de c an ........ 0 * 5

2- (p -p '-DiacetoxybenzhydrylidenJ-cis-

bieyclo- [4.4.0 | decane ... 0.5 *

This clearly shows that in the case of the Connect the heat dose for prevention the gestation is very small.

The dose that prevents gestation in mammals can thus be easily determined by such tests as described above, by standard laboratory methods, as well as by comparison with known antiprogestative compounds. Based on the above, the effective dose is assumed to be 0.1-75 mg / kg body weight. Doses in the lower part of this range, ie between 0.1 and 25 mg / kg, are generally sufficient to prevent gestation * provided they are given before implantation has taken place.

Doses in the upper part of the range, i.e. between 5 'and

75 mg / kg is usually necessary to prevent gestation after implantation has taken place . A suitable procedure is to use a dose of 0.1 to 25 mg / kg of one of the products according to the invention

909848/1388

Compounds administered either (a) on each of the 5 days prior to the expected start of the sexual cycle (ie, menstruation or oestrus) or (b) on each day for 5 to 7 days beginning 10 days after the start of the sexual cycle -j . If pregnancy is suspected, a dose of 5 to 75 mg / kg should be administered once a day until no suspicion is raised

Pregnancy continues or until it can be assumed that 1/10 of the gestational period is over since the day on which conception took place-. In each In each individual case, however, the diagnostician will of course determine the required dose and frequency, taking into account the general health of the female being concerned.

The compounds according to the invention can be used as such administered, or in combination with suitable Carriers. A carrier will vary depending on the route of administration and the physical properties of the compounds chosen. Preferably, the inventive Compounds administered orally, although parenteral administration is also effective.

Typical compositions that the anti-progestative Compounds of Formula I containing are described below. These compositions are examples and are not intended to limit registration in any way.

909848/138

Example A.

250 mg tablets

250 mg p, p'-Diliydroxybenzhydryliden-2-cis-bicyclo | 4.4.0 | decane, 50 mg powdered sugar and 90 mg corn starch are mixed and granulated with a 10 ^ igen gelatin solution. The granules are dried and brought to a uniform size that is suitable for tableting. 45 mg corn starch (as a disintegrant) and approx. 1% magnesium stearate (as a lubricant) are added; 450 mg tablets with a diameter of 11 mm are made from this mixture.

Example B.

....: Injectable suspension, 125 ^m S per ml

The following components are sterilized separately: 125 mg p ^ p ^ -diacetoxybenzhydryliden - ^ - cls-bicyclo [4.4.0] decane, 0.1 mg Tween 80 and corn oil up to a total volume of 1 ml. These components are mixed rseptically. By using "finely divided material" or by grinding in a ball mill (aseptic) a finely divided suspension is obtained which is administered sutiatane or intramuscularly; -can be> .. '. '-----. .-. '. .

909848/1389

Claims (1)

Claims 1. Benzhydry1idenverbindungen, in which one of two condensed, five or six ring carbon atoms each containing ~ hydrocarbon rings built-up bicyclic group through one of their saturated carbon atoms to one in the p- and ρ'-positions through a hydroxy-- or esterified hydroxy group substituted benzhydrjlidengruppe is bonded. 2. Benzhydrylidene compounds of the general Formula I. where each * '^ is hydrogen, halogen or alkyl., R is a lower alkyl group, each R, stands for a hydroxyl or esterified hydroxyl group, Q is a composed of two condensed hydrocarbon rings, each containing five or six ring carbon atoms means a bicyclic group and η is an integer from 0 to 3. 9098A8 / 1389 3-Benzhydrylidene compounds of the general formula wherein R "and R have the same meaning as in claim 2, _S η is an integer from 0 to 2 and each m and r = 0 or 1. 4. Compounds according to claim J >> wherein m and r are each 1. 5. Compounds according to claim 3 * wherein m = 1 and r = 0. 6. Compounds according to any one of claims 1 to 6, wherein each R 1 is a hydroxy group. 7. Compounds according to any one of claims 1 to 6, ■ wherein each R 1 is a lower alkanoyloxy group. 8. Compounds according to claim X, wherein the bicyclic Group has an ice configuration. 9. 2- (p, p '-Diacetoxybenzhydryliden) -cis -bicyclo [4.4.0 jdecan.- 909 8 4 8/1389 10. 2- (ρ, ρ'-Dihydroxybenzhydryliden) -cis-bicyclo [4.4.0] decane. 11. Process for the preparation of new Benzhydrylidenverbindungen in which one of two condensed, each '-'i £ *> ~ i ^ v-Xiä ^ sali ^ «^^. hydrocarbon rings containing five or six ring carbon atoms is bonded through one of its saturated carbon atoms to a benzhydrylidene group which is substituted in the p- and ρ'-positions by a hydroxy or esterified hydroxy group. 12. The method according to claim 11, characterized in that a double bond between the benzhydrylidene group and the bicyclic group of the molecule is introduced, starting from a compound having a has saturated bond between the two groups mentioned. 13. The method according to claim 12, characterized in that that a compound of the general formula II (II), 909848/1389 wherein A is hydrogen _s is halogen or alkyl; R is a lower alkyl group ; R is a free or esterified hydroxyl group or a blocked hydroxyl group which, under the prevailing reaction conditions, is converted into a free hydroxyl group by spontaneous solvolysis ; or a blocked hydroxyl group which is subsequently set free; X and Y are bonded to two adjacent carbon atoms _s eliminable under the prevailing reaction conditions groups; and η is an integer from 0 to 5; ; is subjected to an elimination reaction , in which d; Groups X and Y are split off with the formation of a double bond; that optionally in a compound of the general formula I 'obtained in this way (R) η ' wherein A, Q, 'Jl, R ₂ ^and η are as defined above, blocked hydroxyl groups are set free; that esterified hydroxyl groups contained in the compound of formula I obtained are saponified if desired and / or free hydroxyl groups therein are esterified if desired; and that, if desired, before or after such saponification and / or esterification, any double bonds present in the bicyclic group are hydrogenated. 09848/1389 14. The method according to claim 13, characterized in that _s is used as the starting compound of formula II a compound * have in the A, Q ₃ R, R and η have the same meaning as in claim 13 and in that of X and Y is hydrogen and the other "is hydroxy, hydrogen, or the residue of an inorganic or organic acid. 15. The method according to claim 13, characterized in that that a compound is used as the starting compound of the formula II in which A, Q, R, R and η are the same Have the same meaning as in claim I3 and in that of X and Y is one hydroxy and the other is alkoxycarbonyl. 16. The method according to claim 13> characterized in that the starting compound of the formula II is a compound is used in which A, Q, R., R and η have the same meaning As in claim I3 and X and Y both have halogen s ind. 17. The method according to claim 14, characterized in that a compound is used as the starting compound of the formula II in which A, Q, R ₅ R and η have the same meaning as in claim 13, X is chlorine, bromine, iodine, OSOCl or SH and Y are hydrogen. 18. The method according to claim 14, characterized in that that a compound is used as the starting compound of the formula II in which A, Q, R ,. R and η have the same meaning as in claim I3 and in that of X and Y is one hydrogen and the other is lower alkanoylpxy. 909848/1389 19. The method according to claim 14, characterized in that that, as the starting compound of the formula II, a compound is used in which A, Q, R, Rp and η are the same Have the same meaning as in claim 13 and in which one of X and Y is hydrogen and the other is hydroxy. 20. The method according to claim 15, characterized in that that a compound is used as the starting compound of the formula II in which A, Q ^ R, R and η have the same meaning have as in claim 13 * X is ethoxycarbonyl and Y is hydroxy. 21. The method according to claim H _5, characterized in that a compound containing the central carbon atom (ie the aliphatic carbon atom, to which the three different ring systems of the molecule are bound) and, bound to this, two of the three ring systems of the desired compound and contains a first reactive group, condensed with a compound which contains the third ring system of the desired compound and, bound to this, a second reactive group, the desired compound being formed with elimination of the two reactive groups; that optionally in a compound of the general formula I ¹ thus obtained, in which A, Q, R, R ₂ and η have the same meaning as in claim 13, blocked hydroxyl groups are set free; that esterified hydroxyl groups contained in the compound of formula I obtained are saponified if desired and / or free hydroxyl groups therein are esterified if desired; and that, if desired, before or after such saponification and / or esterification, any double bonds present in the bicyclic group are hydrogenated. 909848/1389 SH 22. The method according to claim 21, characterized in that ₃ as a starting compound a compound of general formula used with a compound of general formula (R) '. I. is condensed * where in the formulas A ₅ R _s R and η have the same meaning as in claim 13 and U. and V are reactive groups which can be eliminated under the reaction conditions employed. 23- method according to claim 22, characterized in, that of U and V one is oxygen and the other -H is. 24. The method according to claim 21, characterized in that the starting compound is a compound of the general Formula. 0 9 8 4 8/1389 -υ used with a compound of general formula is condensed, where in the formulas A, Q _f R, R and η have the same meaning as in claim 13 and U and V are elixninatable reactive groups under the reaction conditions used. 25. The method according to claim 2k, characterized in that __ and V are both halogen, preferably iodine. Pj-. Process according to Claim 11, characterized in that a compound which differs from a compound of the formula I 'only in that at least one of the different ring systems of the molecule is substituted by an additional liciiun iSuhstituciiten is subjected to an elimination reaction _; wherein said additional substituent is removed; that optionally in a compound obtained in this way of the general 909848/1389 BATH Formula Γ ¹ .. in which A ^ Q, R ₅ R _p and η have the same meaning as in claim \ ~ 5 _S blocked hydroxyl groups are set free; that esterified hydroxyl groups contained in the compound of formula I thus obtained are saponified if desired and / or free hydroxyl groups therein are esterified if desired ^ and that, if desired, any double bonds present in the bicyclic group are hydrogenated before or after such saponification and / or esterification. 27. The method according to claim 2β. characterized _s that the additional substituent is bound to the bicyclic keto group is _s and that the connection ,, containing such a keto group _s a reduction of said ketone is subjected to CH. 28. The method according to claim 2.6, characterized in that the additional substituent is an -S- group which connects the o- and the o ¹ -position of the phenyl rings in the benzhydrylidene group with one another, and that such an -S group is linked by reduction to H _p S is eliminated. 2Q method ~ λ according to claim 11, characterized in that a starting compound which differs from a compound of the formula I 'only in that one of the rings in the bicyclic group is broken at one point; wherein the two carbon atoms adjacent to the breaking point are each substituted by a reactive group, being subjected to an intramolecular condensation _; being the two reactive groups 909848/1389 be eliminated; that optionally in a compound of the general formula I 'obtained in this way, in which A, Q, R; R and η have the same meaning as in claim 1J>, blocked hydroxyl groups are set free; that esterified hydroxyl groups contained in the compound of formula I obtained are saponified if desired and / or free hydroxyl groups therein are esterified if desired; and that, if desired, before or after such saponification and / or esterification, any double bonds present in the bicyclic group are hydrogenated. _S 30. The method according to claim 29 characterized in that as Äusgangsverbindung a compound of general formula is used; where A, R, R _p and η have the same meaning as in claim Γ3, m = 0 or 1, ρ and q are each an integer from 0 to 4, but the sum ρ + q = 3 or 4 must be j and T and Z are reactive groups that can be eliminated under the reaction conditions used. 909848/1389 31. The method according to claim 30, characterized., that T and Z "are both halogen, preferably bromine. 32. Process for the production of Benzhydrylidenver- bonds ₅ in which one of two condensed each atoms five or six ring carbon 'containing hydrocarbon rings built up bicyclic group through one of its saturated carbon atoms to one in p- and p'-position benzhydrylidene group substituted by a hydroxyl or esterified hydroxyl group is bonded, as described herein, with particular reference to the examples. 33 «Benzhydrylidene compounds in which a bicyclic group composed of two condensed hydrocarbon rings each containing five or six ring carbon atoms is bonded through one of their saturated carbon atoms to a benzhydrylidene group substituted in the p- and ρ'-positions by a hydroxyl or esterified hydroxyl group, under special reference to the examples. ψ ~ $ k. A gestation-preventing agent which contains at least one of the active compounds of claims 1 to 10 in admixture with a suitable carrier. 35 · Means according to claim 3 ^ in the form of a solid, shaped Dosage unit. 36.. Composition according to claim 35 * wherein the dosage unit is a tablet. 909848/1389 5g - 37 · Means according to claim 35. » wherein the dosage unit is a capsule. .38. Agent according to claim 3 ^ in the form of a liquid Solution or suspension. 39 · Means according to claim 38, wherein the liquid is sterile for injections. 40. Method of producing a gestational device Means, characterized in that an active compound according to any one of claims 1 to is brought into a form suitable for administration. 41. The method according to claim 40 ^ characterized in that that the active compound is mixed with a suitable carrier. 909848/1389